22 - Kidney

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

Copyright ©2007 McGraw-Hill

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25

Psychiatric Disorders

Stuart J. Eisendrath MD

Jonathan E. Lichtmacher MD

Psychiatric Assessment

Psychiatric diagnosis rests upon the established principles of a thorough history and examination. All of the forces contributing to the individual's life situation must be identified, and this can be done only if the examination includes the history, mental status, medical conditions (including drugs), and pertinent social, cultural, and environmental factors impinging on the individual.

The examination of a psychiatric patient must include a complete medical history and physical examination (with emphasis on the neurologic examination) as well as all necessary laboratory and other special studies. Physical illness may frequently present as psychiatric disease, and vice versa. In many instances, the physical examination is completed by the primary care provider who is working with a psychiatrist.

Interview

Every psychiatric history should cover the following points: (1) complaint, from the patient's viewpoint; (2) the present illness, or the evolution of the symptoms; (3) neurovegetative signs such as libido, appetite, and sleep; (4) previous disorders and the nature and extent of their treatment; (5) the family history—important for genetic aspects and family influences; (6) the personal history—childhood development, adolescent adjustment, level of education, and adult coping patterns; (7) current life functioning, with attention to vocational, social, educational, and avocational areas; and (8) present or past use of alcohol and other drugs.

It is often essential to obtain additional information from the family. Observing interactions of the patient with significant others in the context of a family interview may give important diagnostic information and may even underscore the nature of the problem and suggest a therapeutic approach.

The formal mental status examination should be particularly detailed when there is any evidence or high risk of cognitive dysfunction. The mental status examination includes the following: (1) Appearance: Note unusual modes of dress, use of makeup, etc. (2) Activity and behavior: Gait, gestures, coordination of bodily movements, etc. (3) Affect: Outward manifestation of emotions such as depression, anger, elation, fear, resentment, or lack of emotional response. (4) Mood: The patient's report of feelings and observable emotional manifestations. (5) Speech: Coherence, spontaneity, articulation, hesitancy in answering, and duration of response. (6) Content of thought: Associations, preoccupations, obsessions, depersonalization, delusions, hallucinations, paranoid ideation, anger, fear, or unusual experiences; suicidal and homicidal ideation. (7) Thought process: Loose associations, flight of ideas, thought blocking, tangentiality, circumstantiality, perseveration, racing thought. (8) Cognition: (a) orientation to person, place, time, and circumstances; (b) remote and recent memory and recall; (c) calculations, digit retention (six forward is normal), serial sevens or threes; (d) general fund of knowledge (presidents, states, distances, events); (e) abstracting ability, often tested with common proverbs or with analogies and differences (eg, “How are a lie and a mistake the same, and how are they different?”); (f) ability to identify by naming, reading, and writing specified test names and objects; (g) ideomotor function, which combines understanding and the ability to perform a task (eg, “Show me how to throw a ball”); (h) ability to reproduce geometric constructions (eg, parallelogram, intersecting squares); and (i) right-left differentiation. (9) Judgment regarding commonsense problems such as what to do when one runs out of medicine. (10) Insight into the nature and extent of the current difficulty and its ramifications in the patient's daily life.

Formal cognitive screens can quantify impairments and point to the need for further evaluation. The Mini-Mental State Examination produces a numerical score with up to 30 points given for correct answers to questions (likely organic < 27 points) (Figure 25-1). Specific cognitive assessment must be performed, since many patients are able to cover a deficit in routine conversation.

Figure 25-1. Mini-Mental State Exam. (Adapted from

Folstein MF et al: Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189.

)

Special Diagnostic Aids

Many tests and evaluation procedures are available that can be used to support and clarify initial diagnostic impressions.

A. Psychological Testing

Testing by a psychologist may measure intelligence and cognitive functioning; provide information about personality, feelings, psychodynamics, and psychopathology; and help differentiate psychic problems from

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organic ones. The place of such tests is similar to that of other tests in medicine—helpful in diagnostic problems but may be an unnecessary expense if the diagnosis is clear.

1. Objective tests

These tests provide quantitative evaluation compared to standard norms.

a. Intelligence tests

The test most frequently used is the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Intelligence tests often reveal more than IQ. The results, given expert interpretation, can quantify intellectual deterioration that has occurred.

b. Minnesota Multiphasic Personality Inventory (MMPI-2)

The MMPI-2 is an empirically based test of personality assessment. The patient's scores are interpreted in comparison with data about others with the same response pattern to assess psychopathologic changes.

c. Screening instruments

These tests include the Beck Depression Inventory, which quantifies degrees of dysphoria, and the Patient Health Questionnaire, which is a broad measure of the patient's concerns and assists with differential diagnosis.

d. Neuropsychological assessment

Such an assessment is made when an organic deficit is present but information on anatomic location and extent of dysfunction is required.

2. Projective tests

These tests are unstructured, so that the patient is forced to respond in ways that reflect fantasies and individual modes of adaptation. They are particularly useful in identifying psychotic disorders and unconscious motivations.

a. Rorschach Psychodiagnostics

This test utilizes ten inkblots to provide important information on psychodynamic themes and aberrations.

b. Thematic Apperception Test (TAT)

This test uses 20 pictures of people in different situations to assess areas of interpersonal conflicts.

B. Neurologic Evaluation

Consultation is often necessary and may include specialized tests. Brain imaging is useful for detecting structural abnormalities in the patient who presents with a nondefinitive history and examination (eg, dissociative episodes, unusual psychotic episodes not explained by drug abuse, or an acute change in mental status). MRI is particularly useful in delineating lesions and identifying demyelinating and degenerative diseases (eg, Huntington's disease). Electroencephalography is particularly useful for the diagnosis of seizure disorders and in differentiating delirium from depression or dementia. Typically, delirium is associated with generalized electroencephalographic slowing, while depression and dementia do not have this change. Single photon emission computed tomography (SPECT), functional MRI (fMRI), and positron emission tomography (PET) provide tomographic images of brain activity. These imaging modalities are opening new understanding of brain functioning.

Formulation of the Diagnosis

A psychiatric diagnosis must be based on positive evidence accumulated by the above techniques. It must not be based simply on the exclusion of organic findings.

A thorough psychiatric evaluation has therapeutic as well as diagnostic value and should be expressed in ways best understood by the patient, family, and other clinicians.

Crum RM et al: Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA 1993;269:2386.

Lowe B et al: Comparative validity of three screening questionnaires for DSM IV depressive disorders and physicians' diagnoses. J Affect Disord 2004;78:131.

Treatment Approaches

The approaches to treatment of psychiatric patients are, in a broad sense, similar to those in other branches of medicine. For example, the internist treating a patient with heart disease uses not only medical measures such as drugs and pacemakers but also psychological techniques to change attitudes and behaviors, social and environmental manipulation to mitigate deleterious influences, and behavioral techniques to change behavior patterns.

Regardless of the methods used, treatment must be directed toward an objective, ie, it must be goal-oriented. This usually involves (1) obtaining active cooperation on the part of the patient, (2) establishing reasonable goals and modifying the goal if failure occurs, (3) emphasizing positive behavior (goals) instead of symptom behavior (problems), (4) delineating the method, and (5) setting a time frame (which can be modified later).

The clinician must resist pressures for instantaneous results. In almost all cases, psychiatric treatment involves the active participation of the significant people in the patient's life. Time must be spent with the patient, but the frequency and duration of appointments are highly variable and should be adjusted to meet both the patient's psychological needs and financial restrictions. Adherence (collaboration) is the end product of many factors, the most important being clear communication, attention to cost, and simple dosage regimens when drugs are prescribed. The clinician can unwittingly promote chronic illness by prescribing medication inappropriately. The patient may come to believe that problems respond only to medication, and the more drugs prescribed, the stronger the misconception becomes.

Psychiatric Consultation

All clinicians are in an excellent position to meet their patients' emotional needs in an organized and competent way, referring to psychiatrists for consultation or for ongoing treatment of patients whose problems are considered beyond the expertise of the referring clinician. The most pressing problems involve evaluation of suicidal or

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assaultive potential and diagnostic differentiation in mood disorders and psychoses. Psychiatric problems associated with unusual psychopharmacologic therapy and with medications used in other branches of medicine may require pharmacologic consultation. When a psychiatric referral is made, it should be conducted like any other referral: in an open manner, with full explanation of the problem to the patient.

Hospitalization

Hospital care may be indicated when patients are too sick to care for themselves or when they present serious threats to themselves or others, when observation and diagnostic procedures are necessary, or when specific kinds of treatment such as complex medication trials or a hospital environment (“milieu therapy”) are required. Symptoms calling for hospitalization include self-neglect, violent or bizarre behavior, suicidal risk, paranoid ideation or delusions, marked intellectual impairment, and poor judgment. The trend over recent years has been to admit patients to hospitals and treat them aggressively with the expectation of prompt discharge to the next appropriate level of care—day hospital, halfway house, outpatient therapy, etc. The decision to propose involuntary hospitalization should be taken only after weighing the potential benefits to the patient and the community against the individual's loss of autonomy.

The disadvantages of psychiatric hospitalization include decreased self-confidence as a result of needing hospitalization, the stigma of being a “psychiatric patient,” possible increased dependency and regression, and the expense. Generally, there is no advantage to prolonged hospital stays for most psychiatric disorders. Partial hospitalization or “day” programs are providing many of the benefits of hospitalization without some of the disadvantages; in these programs, the patient attends daytime treatment but sleeps at home.

Bateman A et al: Health service utilization costs for borderline personality disorder patients treated with psychoanalytically oriented partial hospitalization versus general psychiatric care. Am J Psychiatry 2003;160:169.

Hedrick SC et al: Effectiveness of collaborative care depression treatment in Veterans' Affairs primary care. J Gen Intern Med 2003;18:9.

Common Psychiatric Disorders

Stress & Adjustment Disorders (Situational Disorders)

Essentials of Diagnosis

  • Anxiety or depression clearly secondary to an identifiable stress.

  • Subsequent symptoms of anxiety or depression commonly elicited by similar stress of lesser magnitude.

  • Alcohol and other drugs are commonly used in self-treatment.

General Considerations

Stress exists when the adaptive capacity of the individual is overwhelmed by events. The event may be an insignificant one objectively considered, and even favorable changes (eg, promotion and transfer) requiring adaptive behavior can produce stress. For each individual, stress is subjectively defined, and the response to stress is a function of each person's personality and physiologic endowment.

Classification & Clinical Findings

Opinion differs about what events are most apt to produce stress reactions. The causes of stress are different at different ages—eg, in young adulthood, the sources of stress are found in the marriage or parent-child relationship, the employment relationship, and the struggle to achieve financial stability; in the middle years, the focus shifts to changing spousal relationships, problems with aging parents, and problems associated with having young adult offspring who themselves are encountering stressful situations; in old age, the principal concerns are apt to be retirement, loss of physical capacity, major personal losses, and thoughts of death.

An individual may react to stress by becoming anxious or depressed, by developing a physical symptom, by running away, having a drink, starting an affair, or in limitless other ways. Common subjective responses are fear (of repetition of the stress-inducing event), rage (at frustration), guilt (over aggressive impulses), and shame (over helplessness). Acute and reactivated stress may be manifested by restlessness, irritability, fatigue, increased startle reaction, and a feeling of tension. Inability to concentrate, sleep disturbances (insomnia, bad dreams), and somatic preoccupations often lead to self-medication, most commonly with alcohol or other central nervous system depressants. Maladaptive behavior in response to stress is called adjustment disorder, with the major symptom specified (eg, “adjustment disorder with depressed mood”).

%Posttraumatic stress disorder (PTSD)—included among the anxiety disorders in DSM-IV—is a syndrome characterized by “reexperiencing” a traumatic event (eg, rape, severe burns, military combat) and decreased responsiveness and avoidance of current events associated with the trauma. Patients with PTSD experience physiologic hyperarousal, including startle reactions, intrusive thoughts, illusions, overgeneralized associations, sleep problems, nightmares, dreams about the precipitating event, impulsivity, difficulties in concentration, and hyperalertness. The symptoms may be precipitated or exacerbated by events that are a reminder of the original stress. Symptoms frequently

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arise after a long latency period (eg, child abuse can result in later-onset posttraumatic stress syndrome). The sooner therapy is initiated after the trauma, the better the prognosis. Therapy at that time should be brief and simple (once in a safe environment), expecting quick recovery and promoting a sense of mastery over the traumatic event.

Treatment initiated later, when symptoms have crystallized, includes programs for cessation of alcohol and other drug abuse, group and individual psychotherapy, and improved social support systems. The therapeutic approach is to facilitate the normal recovery that was blocked at the time of the trauma.

Differential Diagnosis

Adjustment disorders must be distinguished from anxiety disorders, affective disorders, and personality disorders exacerbated by stress and from somatic disorders with psychic overlay.

Treatment

A. Behavioral

Stress reduction techniques include immediate symptom reduction (eg, rebreathing in a bag for hyperventilation) or early recognition and removal from a stress source before full-blown symptoms appear. It is often helpful for the patient to keep a daily log of stress precipitators, responses, and alleviators. Relaxation and exercise techniques are also helpful in reducing the reaction to stressful events.

B. Social

The stress reactions of life crisis problems are—more than any other category—a function of psychosocial upheaval, and patients frequently present with somatic symptoms. While it is not easy for the patient to make necessary changes (or they would have been made long ago), it is important for the therapist to establish the framework of the problem, since the patient's denial system may obscure the issues. Clarifying the problem allows the patient to begin viewing it within the proper context and facilitates the sometimes difficult decisions the patient eventually must make (eg, change of job or relocation of adult-dependent offspring).

C. Psychological

Prolonged in-depth psychotherapy is seldom necessary in cases of isolated stress response or adjustment disorder. Supportive psychotherapy (see above) with an emphasis on the here and now and strengthening of existing defenses is a helpful approach so that time and the patient's own resiliency can restore the previous level of function. In posttraumatic stress syndromes, psychological debriefing in a single session, once a mainstay in prevention of PTSD, is now considered to be ineffective and possibly harmful. Posttraumatic stress syndromes respond to interventions that help patients integrate the event in an adaptive way with some sense of mastery in having survived the trauma. Early cognitive behavioral therapy has been shown to speed recovery. Marital problems are a major area of concern, and it is important that the clinician have available a dependable referral source when marriage counseling is indicated.

D. Medical

Judicious use of sedatives (eg, lorazepam, 1–2 mg orally daily) for a limited time and as part of an overall treatment plan can provide relief from acute anxiety symptoms. Problems arise when the situation becomes chronic through inappropriate treatment or when the treatment approach supports the development of chronicity.

In PTSD, early treatment of anxious arousal with β-blockers (eg, propranolol, 80–160 mg daily) may lessen the peripheral symptoms of anxiety (eg, tremors, palpitations) and help prevent development of the disorder; however, research in this area is preliminary. Antidepressant drugs—particularly selective serotonin reuptake inhibitors (SSRIs)—in full dosage are helpful in ameliorating depression, panic attacks, sleep disruption, and startle responses in chronic PTSD. Sertraline and paroxetine are approved by the US Food and Drug Administration (FDA) for this purpose. Antiseizure medications such as carbamazepine (400–800 mg daily) will often mitigate impulsivity and difficulty with anger management. Benzodiazepines such as clonazepam (1–4 mg daily) will reduce anxiety and panic attacks when used in adequate dosage, but dependency problems are a concern, particularly when the patient has had such problems in the past.

Prognosis

Return to satisfactory function after a short period is part of the clinical picture of this syndrome. Resolution may be delayed if others' responses to the patient's difficulties are thoughtlessly harmful or if the secondary gains outweigh the advantages of recovery. The longer the symptoms persist, the worse the prognosis.

Ehlers A et al: Early psychological interventions for survivors of trauma: a review. Biol Psychiatry 2003;53:817.

Schoenfeld FB et al: Current concepts in pharmacotherapy for posttraumatic stress disorder. Psychiatr Serv 2004;55:519.

Vaiva G et al: Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry 2003;54:947.

Anxiety Disorders & Dissociative Disorders

Essentials of Diagnosis

  • Overt anxiety or an overt manifestation of a defense mechanism (such as a phobia), or both.

  • Not limited to an adjustment disorder.

  • Somatic symptoms referable to the autonomic nervous system or to a specific organ system (eg, dyspnea, palpitations, paresthesias).

  • Not a result of physical disorders, psychiatric conditions (eg, schizophrenia), or drug abuse (eg, cocaine).

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General Considerations

Stress, fear, and anxiety all tend to be interactive. The principal components of anxiety are psychological (tension, fears, difficulty in concentration, apprehension) and somatic (tachycardia, hyperventilation, palpitations, tremor, sweating). Other organ systems (eg, gastrointestinal) may be involved in multiple-system complaints. Fatigue and sleep disturbances are common. Sympathomimetic symptoms of anxiety are both a response to a central nervous system state and a reinforcement of further anxiety. Anxiety can become self-generating, since the symptoms reinforce the reaction, causing it to spiral. This is often the case when the anxiety is an epiphenomenon of other medical or psychiatric disorders.

Anxiety may be free-floating, resulting in acute anxiety attacks, occasionally becoming chronic. When one or several defense mechanisms (see above) are functioning, the consequences are well-known problems such as phobias, conversion reactions, dissociative states, obsessions, and compulsions. Lack of structure is frequently a contributing factor, as noted in those people who have “Sunday neuroses.” They do well during the week with a planned work schedule but cannot tolerate the unstructured weekend. Planned-time activities tend to bind anxiety, and many people have increased difficulties when this is lost, as in retirement.

Some believe that various manifestations of anxiety are not a result of unconscious conflicts but are “habits”—persistent patterns of nonadaptive behavior acquired by learning. The “habits,” being nonadaptive, are unsatisfactory ways of dealing with life's problems—hence the resultant anxiety. Help is sought only when the anxiety becomes too painful. Exogenous factors such as stimulants (eg, caffeine, cocaine) must be considered as a contributing factor.

Clinical Findings

A. Generalized Anxiety Disorder

This is the most common of the clinically significant anxiety disorders. Initial manifestations appear at age 20–35 years, and there is a slight predominance in women. The anxiety symptoms of apprehension, worry, irritability, difficulty in concentrating, insomnia, and somatic complaints are present more days than not for at least 6 months. Manifestations can include cardiac (eg, tachycardia, increased blood pressure), gastrointestinal (eg, increased acidity, nausea, epigastric pain), and neurologic (eg, headache, near-syncope) systems. The focus of the anxiety may be a number of everyday activities.

B. Panic Disorder

This is characterized by short-lived, recurrent, unpredictable episodes of intense anxiety accompanied by marked physiologic manifestations. Agoraphobia, fear of being in places where escape is difficult, such as open spaces or public places, may be present. Distressing symptoms and signs such as dyspnea, tachycardia, palpitations, headaches, dizziness, paresthesias, choking, smothering feelings, nausea, and bloating are associated with feelings of impending doom (alarm response). Recurrent sleep panic attacks (not nightmares) occur in about 30% of panic disorders. Anticipatory anxiety develops in all these patients and further constricts their daily lives. Panic disorder tends to be familial, with onset usually under age 25; it affects 3–5% of the population, and the female-to-male ratio is 2:1. The premenstrual period is one of heightened vulnerability. Patients frequently undergo emergency medical evaluations (eg, for “heart attacks” or “hypoglycemia”) before the correct diagnosis is made. Gastrointestinal symptoms are especially common, occurring in about one-third of cases. Myocardial infarction, pheochromocytoma, hyperthyroidism, and various recreational drug reactions can mimic panic disorder. Mitral valve prolapse may be present but is not usually a significant factor. Patients who have recurrent panic disorder often become demoralized, hypochondriacal, agoraphobic, and depressed. These individuals are at increased risk for major depression and the suicide attempts associated with that disorder. Alcohol abuse (about 20%) results from self-treatment and is not infrequently combined with dependence on sedatives. Some patients have atypical panic attacks associated with seizure-like symptoms that often include psychosensory phenomena (a history of stimulant abuse often emerges). About 25% of panic disorder patients also have obsessive-compulsive disorder (OCD).

C. Obsessive-Compulsive Disorder

In the obsessive-compulsive reaction, the irrational idea or the impulse persistently intrudes into awareness. Obsessions (constantly recurring thoughts such as fears of exposure to germs) and compulsions (repetitive actions such as washing the hands many times) are recognized by the individual as absurd and are resisted, but anxiety is alleviated only by ritualistic performance of the action or by deliberate contemplation of the intruding idea or emotion. Many patients do not mention the symptoms and must be asked about them. These patients are usually predictable, orderly, conscientious, and intelligent—traits that are seen in many compulsive behaviors such as food binging and purging and compulsive running. There is an overlapping of OCD and other behaviors (“OCD spectrum”), including tics, trichotillomania (hair pulling), onychophagia (nail biting), hypochondriasis,

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Tourette's syndrome, and eating disorders (see Chapter 29). The 2–3% incidence of OCD in the general population is much higher than was previously recognized. In addition, there is a high comorbidity of OCD and major depression; two-thirds of OCD patients will develop major depression during their lifetime. Male to female ratios are similar, with the highest rates occurring in the young, divorced, separated, and unemployed (all high-stress categories). Neurologic abnormalities of fine motor coordination and involuntary movements are common. Under extreme stress, these patients sometimes exhibit paranoid and delusional behaviors, often associated with depression, and can mimic schizophrenia.

D. Phobic Disorder

Phobic ideation can be considered a mechanism of “displacement” in which patients transfer feelings of anxiety from their true object to one that can be avoided. However, since phobias are ineffective defense mechanisms, there tends to be an increase in their scope, intensity, and number. Social phobias are global or specific; in the former, all social situations are poorly tolerated, while the latter group includes performance anxiety or well-delineated phobias. Agoraphobia (fear of open places and public areas) is frequently associated with severe panic attacks, and it often develops in early adult life, making a normal lifestyle difficult.

E. Dissociative Disorder

Fugue (the sudden, unexpected travel away from one's home with inability to recall one's past), amnesia, somnambulism, dissociative identity disorder (multiple personality disorder), and depersonalization are all dissociative states. The reaction is precipitated by emotional crisis. The symptom produces anxiety reduction and a temporary solution of the crisis. Mechanisms include repression and isolation as well as particularly limited concentration as seen in hypnotic states. Dissociative symptoms are similar in many ways to symptoms seen in patients with temporal lobe dysfunction.

Treatment

In all cases, underlying medical disorders must be ruled out (eg, cardiovascular, endocrine, respiratory, and neurologic disorders and substance-related syndromes, both intoxication and withdrawal states). These and other disorders can coexist with panic disorder.

A. Medical

1. Generalized anxiety

Benzodiazepines are the anxiolytics of choice in the acute management of generalized anxiety (Table 25-1). They are almost immediately effective. Antidepressants can be efficacious for the long-term treatment of generalized anxiety disorder, panic disorder, social phobia, and OCD.

All of the benzodiazepines may be given orally, and several are available in parenteral formulations. Benzodiazepines such as lorazepam are absorbed rapidly when given intramuscularly. In psychiatric disorders, the benzodiazepines are usually given orally; in controlled medical environments (eg, the ICU), where the rapid onset of respiratory depression can be assessed, they are often given intravenously. Onset of action is a function of the rate of absorption (related to lipophilic property) and varies, with diazepam and clorazepate being the most rapidly absorbed. This characteristic, along with high lipid solubility, may explain the popularity of diazepam. In the average case of anxiety, diazepam, 5–10 mg orally every 6–8 hours as needed, is a reasonable starting regimen.

The duration of action of the benzodiazepines varies as a function of the active metabolites they produce. Benzodiazepines such as lorazepam do not produce active metabolites and have intermediate half-lives of 10–20 hours, characteristics useful in treating elderly patients. Ultra-short-acting agents such as triazolam have half-lives of 1–3 hours and may lead to rebound withdrawal anxiety. Longer-acting benzodiazepines such as flurazepam and diazepam produce active metabolites, have half-lives of 20–120 hours, and should be avoided in the elderly. Since people vary widely in their response and since the drugs are long-lasting, the dosage must be individualized. Once this is established, an adequate dose early in the course of symptom development will obviate the need for “pill popping,” which contributes to dependency problems. Panic disorder does not usually respond to benzodiazepines other than clonazepam and alprazolam. Those high-potency benzodiazepines and the antidepressants are most commonly used for panic disorder. Notably, alprazolam has a relatively short half-life and over time can lead to interdose rebound anxiety, although the extended release form is available and obviates some of this difficulty.

Whether the indications for benzodiazepines are anxiety or insomnia, the drugs should be used judiciously. The longer-acting benzodiazepines are used for the treatment of alcohol withdrawal and anxiety symptoms; the intermediate drugs are useful as sedatives for insomnia (eg, lorazepam), while short-acting agents (eg, midazolam) are used for medical procedures such as endoscopy.

The side effects of all the benzodiazepine antianxiety agents are patient and dose dependent. As the dosage exceeds the levels necessary for sedation, the side effects include disinhibition, ataxia, dysarthria, nystagmus, and errors of commission. (The patient should be told not to operate machinery until he or she is well stabilized without side effects.)

Paradoxical agitation, anxiety, psychosis, confusion, mood lability, and anterograde amnesia have been reported, particularly with the shorter-acting benzodiazepines. These agents produce cumulative clinical effects with repeated dosage (especially if the patient has not had time to metabolize the previous dose), additive effects when given with other classes of sedatives or alcohol (many apparently “accidental” deaths are the result of concomitant use of sedatives and alcohol), and residual

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effects after termination of treatment (particularly in the case of drugs that undergo slow biotransformation).

Table 25-1. Commonly used antianxiety and hypnotic agents.

Drug Usual Daily Oral Dose Usual Daily Maximum Dose Cost for 30 Days Treatment Based on Maximum Dosage1
Benzodiazepines (used for anxiety)
   Alprazolam (Xanax)2 0.5 mg 4 mg $117.60
   Chlordiazepoxide (Librium)3 10–20 mg 100 mg $40.80
   Clonazepam (Klonopin)3 1–2 mg 10 mg $177.00
   Clorazepate (Tranxene)3 15–30 mg 60 mg $260.40
   Diazepam (Valium)3 5–15 mg 30 mg $27.90
   Lorazepam (Ativan)2 2–4 mg 4 mg $76.80
   Oxazepam (Serax)2 10–30 mg 60 mg $98.40
Benzodiazepines (used for sleep)
   Estazolam (Prosom)2 1 mg 2 mg $29.70
   Flurazepam (Dalmane)3 15 mg 30 mg $10.50
   Midazolam (Versed IV)4 5 mg IV   $3.58/dose
   Quazepam (Doral)3 7.5 mg 15 mg $117.90
   Temazepam (Restoril)2 15 mg 30 mg $26.40
   Triazolam (Halcion)5 0.125 mg 0.25 mg $20.24
Miscellaneous (used for anxiety)
   Buspirone (Buspar)2 10–30 mg 60 mg $218.10
   Phenobarbital3 15–30 mg 90 mg $2.10
Miscellaneous (used for sleep)
   Chloral hydrate (Noctec)2 500 1000 mg $8.39
   Eszopiclone (Lunesta)5 2–3 mg 3 mg $111.00
   Hydroxyzine (Vistaril)2 50 mg 100 mg $66.60
   Zolpidem (Ambien)5 5–10 mg 10 mg $111.90
   Zaleplon (Sonata)6 5–10 mg 10 mg $91.50
1Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 25, No. 5, May 2006. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
2Intermediate physical half-life (10–20 hours).
3Long physical half-life (> 20 hours).
4Intravenously for procedures.
5Short physical half-life (1–6 hours).
6Short physical half-life (about 1 hour).

Overdosage results in respiratory depression, hypotension, shock syndrome, coma, and death. Flumazenil, a benzodiazepine antagonist, is effective in overdosage. Overdosage (see Chapter 39) and withdrawal states are medical emergencies. Serious side effects of chronic excessive dosage are development of tolerance, resulting in increasing dose requirements, and physiologic dependence, resulting in withdrawal symptoms similar in appearance to alcohol and barbiturate withdrawal (withdrawal effects must be distinguished from reemergent anxiety). Abrupt withdrawal of sedative drugs may cause serious and even fatal convulsive seizures. Psychosis, delirium, and autonomic dysfunction have also been described. Both duration of action and duration of exposure are major factors.

Common withdrawal symptoms after low to moderate daily use of benzodiazepines are classified as somatic (disturbed sleep, tremor, nausea, muscle aches), psychological (anxiety, poor concentration, irritability, mild depression), or perceptual (poor coordination, mild paranoia, mild confusion). The presentation of symptoms will vary depending on the half-life of the drug. There are no significant side effects on organ systems other than the brain, and the drugs are safe in most medical conditions. Benzodiazepine interactions with other drugs are listed in Table 25-2.

Antidepressants are the first-line medications for sustained treatment of generalized anxiety disorder, having the advantage of not causing serious physiologic dependency problems. At initiation of treatment, antidepressants can themselves be anxiogenic—thus, an initial dose, in conjunction with short-term treatment with a benzodiazepine,

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is often indicated. Venlafaxine (a sustained-release serotonin and norepinephrine reuptake inhibitor) is FDA-approved for the treatment of generalized anxiety disorder in usual antidepressant doses (75–225 mg). Initial daily dosing should start low (37.5–75 mg) and be titrated upward as needed. SSRIs, such as paroxetine, are also used. Similarly, buspirone, sometimes used as an augmenting agent in the treatment of depression and compulsive behaviors, is also effective for generalized anxiety. Buspirone is usually given in a dosage of 15–60 mg/d in three divided doses. Higher doses tend to be counterproductive and produce gastrointestinal symptoms and dizziness. There is a 2- to 4-week delay before antidepressants and buspirone take effect, and patients require education regarding this lag. Sleep is sometimes negatively affected. β-Blockers such as propranolol may help reduce peripheral somatic symptoms. Alcohol is the most frequently self-administered drug and should be interdicted. The highly addicting drugs with a narrow margin of safety such as glutethimide, ethchlorvynol, methprylon, meprobamate, and the barbiturates (with the exception of phenobarbital) should be avoided. Phenobarbital, in addition to its anticonvulsant properties, is a reasonably safe and very inexpensive sedative but has the disadvantage of causing hepatic microsomal enzyme stimulation (not the case with benzodiazepines), which markedly reduces its usefulness if any other relevant medications are being used by the patient.

Table 25-2. Benzodiazepine interactions with other drugs.

Drug Effects
Antacids Decreased absorption of benzodiazepines
Cimetidine Increased half-life of diazepam and triazolam
Contraceptives Increased levels of diazepam and triazolam
Digoxin Alprazolam and diazepam raise digoxin level
Disulfiram Increased duration of action of sedatives
Isoniazid Increased plasma diazepam
Levodopa Inhibition of antiparkinsonism effect
Propoxyphene Impaired clearance of diazepam
Rifampin Decreased plasma diazepam
Warfarin Decreased prothrombin time

2. Panic attacks

Panic attacks may be treated in several ways. A sublingual dose of lorazepam (0.5–2 mg) or alprazolam (0.5–1 mg) is often effective for urgent treatment. For sustained treatment, SSRIs are the initial drugs of choice (adequate blood levels will require dosages similar to those used in the treatment of depression). For example, sertraline starting at 25 mg/d and increased after 1 week to 50 mg/d may be effective. Because of initial agitation in response to antidepressants, doses should start low and be very gradually increased. High-potency benzodiazepines may be used for symptomatic treatment as the antidepressant dose is titrated upward. Clonazepam (1–6 mg/d orally) and alprazolam (0.5–6 mg/d orally) are effective alternatives to antidepressants. Both drugs may produce marked withdrawal if stopped abruptly and should always be tapered. Because of chronicity of the disorders and the problem of dependency with benzodiazepine drugs, it is generally desirable to use antidepressant drugs as the principal pharmacologic approach. Antidepressants have been used in conjunction with β-blockers in resistant cases. Propranolol (40–160 mg/d orally) can mute the peripheral symptoms of anxiety without significantly affecting motor and cognitive performance. They block symptoms mediated by sympathetic stimulation (eg, palpitations, tremulousness) but not nonadrenergic symptoms (eg, diarrhea, muscle tension). Contrary to current belief, they usually do not cause depression as a side effect and can be used cautiously in patients with depression. Valproate has been found to be as effective in panic disorder as the antidepressants and is another useful alternative.

3. Phobic disorder

Phobic disorder may be part of the panic disorder and is treated within that framework. Global social phobias may be treated with SSRIs, such as paroxetine, sertraline, and fluvoxamine, or monoamine oxidase (MAO) inhibitors in the same dosage as used for depression. Gabapentin, an anticonvulsant with anxiolytic properties, may be an alternative to antidepressants in the treatment of social phobia in a dosage of 300–3600 mg/d, depending on response versus sedation. Specific phobias such as performance anxiety may respond to moderate doses of β-blockers, such as propranolol, 20–40 mg 1 hour prior to exposure. A sustained effect is often not obtained with drugs alone; a combination of drugs, behavioral techniques, and cognitive psychotherapy is most effective. If there is any indication of seizure-like phenomena, carbamazepine or valproic acid should be considered.

4. Obsessive-compulsive disorder

OCD responds to serotonergic drugs in about 60% of cases and usually requires a longer response time than for depression (up to 12 weeks). Clomipramine has proved effective in doses equivalent to those used for depression. Fluoxetine (an SSRI drug) has been widely used in this disorder but in doses higher than those used in depression (up to 60–80 mg/d). The other SSRI drugs such as sertraline, paroxetine, and fluvoxamine are being used with comparable efficacy, each with its own side-effect profile. Buspirone in doses of 15–60 mg/d appears to be effective primarily as an anti-obsessional augmenting agent for the SSRI drugs. Psychosurgery has a limited place in selected cases of severe unremitting OCD. The stereotactic techniques now being used, including modified cingulotomy, are great improvements over the crude methods of the past.

B. Behavioral

Behavioral approaches are widely used in various anxiety disorders, often in conjunction with medication. Any of the behavioral techniques (see above) can be

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used beneficially in altering the contingencies (precipitating factors or rewards) supporting any anxiety-provoking behavior. Relaxation techniques can sometimes be helpful in reducing anxiety. Desensitization, by exposing the patient to graded doses of a phobic object or situation, is an effective technique and one that the patient can practice outside the therapy session. Emotive imagery, wherein the patient imagines the anxiety-provoking situation while at the same time learning to relax, helps decrease the anxiety when the patient faces the real-life situation. Physiologic symptoms in panic attacks respond well to relaxation training. Exposure techniques with response prevention are useful for OCD.

C. Psychological

Cognitive behavioral approaches have been effective in treatment of panic disorders, phobias, and OCD when erroneous beliefs need correction. These approaches share a common technique of exposing the individual to the feared object or situation. The combination of medical and cognitive behavioral therapy is more effective than either alone. Group therapy is the treatment of choice when the anxiety is clearly a function of the patient's difficulties in dealing with others, and if these other people are part of the family, it is appropriate to include them and initiate family or couples therapy.

D. Social

Peer support groups for panic disorder and agoraphobia have been particularly helpful. Social modification may require measures such as family counseling to aid acceptance of the patient's symptoms and avoid counterproductive behavior in behavioral training. Any help in maintaining the social structure is anxiety-alleviating, and work, school, and social activities should be maintained. School and vocational counseling may be provided by professionals, who often need help from the clinician in defining the patient's limitations.

Prognosis

Anxiety disorders are usually of longstanding and may be quite difficult to treat. All can be relieved to varying degrees with medications and behavioral techniques. The prognosis is much better if the commonly observed anxiety-panic-phobia-depression cycle can be broken with a combination of the therapeutic interventions discussed above.

Kaplan A et al: A review of pharmacologic treatments for obsessive-compulsive disorder. Psychiatr Serv 2003;54:1111.

Leopola U et al: Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder. J Clin Psychiatry 2003;64:654.

Rickels K et al: Paroxetine treatment of generalized anxiety disorder: a double blind, placebo controlled study. Am J Psychiatry 2003;160:749.

Somatoform Disorders (Abnormal Illness Behaviors)

Essentials of Diagnosis

  • Physical symptoms may involve one or more organ systems and are not intentional.

  • Subjective complaints exceed objective findings.

  • Correlations of symptom development and psychosocial stresses.

  • Combination of biogenetic and developmental patterns.

General Considerations

A major source of diagnostic confusion in medicine has been to assume cause-and-effect relationships when parallel conditions exist. This problem is particularly vexing in situations where the individual exhibits psychosocial distress that could well be secondary to a chronic illness but has been assumed to be primary and causative. An example is the person with a chronic bowel disease who becomes querulous and demanding. Is this behavior a result of problems of coping with a chronic disease, or is it a personality pattern that causes the gastrointestinal problem?

Vulnerability in one or more organ systems and exposure to family members with somatization problems play a major role in the development of particular symptoms, and the “functional” versus “organic” dichotomy is a hindrance to good treatment. Clinicians should suspect psychiatric disorders in a number of conditions. For example, 45% of patients complaining of palpitations had lifetime psychiatric diagnoses including generalized anxiety, depression, panic, and somatization disorders. Similarly, 33–44% of patients who undergo coronary angiography for chest pain but have negative results have been found to have panic disorder.

In any patient presenting with a condition judged to be somatoform, depression must be considered in the diagnosis.

Clinical Findings

A. Conversion Disorder

“Conversion” (formerly “hysterical conversion”) of psychic conflict into physical symptoms in parts of the body innervated by the sensorimotor system (eg, paralysis, aphonia) is a disorder that is more common in individuals from lower socioeconomic classes and certain cultures. The defense mechanisms used in this condition are repression (a barring from consciousness) and isolation (a splitting of the affect from the idea). The somatic manifestation that takes the place of anxiety is typically paralysis, and in some instances the organ dysfunction may

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have symbolic meaning (eg, arm paralysis in marked anger). Pseudoepileptic (“hysterical”) seizures are often difficult to differentiate from intoxication states or panic attacks. Retention of consciousness, random flailing with asynchronous movements of the right and left sides, and resistance to having the nose and mouth pinched closed during the attack all point toward a pseudoepileptic event. Electroencephalography, particularly in a video-EEG assessment unit, during the attack is the most helpful diagnostic aid in excluding genuine seizure states. Serum prolactin levels rise abruptly in the postictal state only in true epilepsy. La belle indifférence (an unconcerned affect) is not a significant identifying characteristic, as commonly believed. Important criteria in diagnosis include a history of conversion or somatization disorder, modeling the symptom after someone else who had a similar presentation, a serious precipitating emotional event, associated psychopathology (eg, depression, schizophrenia, personality disorders), a temporal correlation between the precipitating event and the symptom, and a temporary “solving of the problem” by the conversion. It is important to identify physical disorders with unusual presentations (eg, multiple sclerosis).

B. Somatization Disorder (Briquet's Syndrome, Hysteria)

This is characterized by multiple physical complaints referable to several organ systems. Anxiety, panic disorder, and depression are often present, and major depression is an important consideration in the differential diagnosis. There is a significant relationship (20%) to a lifetime history of panic-agoraphobia-depression. It usually occurs before age 30 and is ten times more common in women. Polysurgery is often a feature of the history. Preoccupation with medical and surgical therapy becomes a lifestyle that excludes most other activities. The symptoms are a reflection of maladaptive coping techniques and reactivity of the particular organ system. There is often evidence of longstanding somatic symptoms (particularly dysmenorrhea, a lump in the throat, vomiting, shortness of breath, burning in the sex organs, painful extremities, and amnesia), often with a history of similar organ system involvement in other family members. Multiple symptoms that constantly change and inability of more than three doctors to make a diagnosis are strong clues to the problem.

C. Pain Disorder Associated with Psychological Factors (Formerly Somatoform Pain Disorder)

This involves a long history of complaints of severe pain not consonant with anatomic and clinical signs. This diagnosis must not be one of exclusion and should be made only after extended evaluation has established a clear correlation of psychogenic factors with exacerbations and remissions of complaints.

D. Hypochondriasis

This is a fear of disease and preoccupation with the body, with perceptual amplification and heightened responsiveness. A process of social learning is usually involved, frequently with a role model who was a member of the family and may be a part of the underlying psychodynamic causation. It is common in panic disorders.

E. Factitious Disorders

These disorders, in which symptom production is intentional, are not somatoform conditions in that symptoms are produced consciously, in contrast to the unconscious process of the above conditions. They are characterized by self-induced symptoms or false physical and laboratory findings for the purpose of deceiving clinicians or other hospital personnel. The deceptions may involve self-mutilation, fever, hemorrhage, hypoglycemia, seizures, and an almost endless variety of manifestations—often presented in an exaggerated and dramatic fashion (Munchausen syndrome). “Munchausen by proxy” is the term used when a parent creates an illness in a child so the adult (usually the mother) can maintain a relationship with clinicians. The duplicity may be either simple or extremely complex and difficult to recognize. The patients are frequently connected in some way with the health professions; they are often migratory; and there is no apparent external motivation other than achieving the patient role.

Complications

A poor doctor-patient relationship, with iatrogenic disorders and “doctor shopping,” tends to exacerbate the problem. Sedative and analgesic dependency is the most common iatrogenic complication.

Treatment

A. Medical

Medical support with careful attention to building a therapeutic practitioner-patient relationship is the mainstay of treatment. It must be accepted that the patient's distress is real. Every problem not found to have an organic basis is not necessarily a mental disease. Diligent attempts should be made to relate symptoms to adverse developments in the patient's life. It may be useful to have the patient keep a meticulous diary, paying particular attention to various pertinent factors evident in the history. Regular, frequent, short appointments that are not symptom-contingent may be helpful. Drugs (frequently abused) should not be prescribed to replace appointments. One person should be the primary clinician, and consultants should be used mainly for evaluation. An empathic, realistic, optimistic approach must be maintained in the face of the expected ups and downs. Ongoing reevaluation is necessary, since somatization can coexist with a concurrent physical illness.

B. Psychological

Psychological approaches can be used by the primary clinician when it is clear that the patient is ready to make some changes in lifestyle in order to achieve

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symptomatic relief. This is often best approached on a here-and-now basis and oriented toward pragmatic changes rather than an exploration of early experiences that the patient frequently fails to relate to current distress. Group therapy with other individuals who have similar problems is sometimes of value to improve coping, allow ventilation, and focus on interpersonal adjustment. Hypnosis or lorazepam interviews used early are helpful in resolving conversion disorders. If the primary clinician has been working with the patient on psychological problems related to the physical illness, the groundwork is often laid for successful psychiatric referral.

For patients who have been identified as having a factitious disorder, early psychiatric consultation is indicated. There are two main treatment strategies for these patients. One consists of a conjoint confrontation of the patient by both the primary clinician and the psychiatrist. The patient's disorder is portrayed as a cry for help, and psychiatric treatment is recommended. The second approach avoids direct confrontation and attempts to provide a face-saving way to relinquish the symptom without overt disclosure of the disorder's origin. Techniques such as biofeedback and self-hypnosis may foster recovery using this strategy. Another face-saving approach is to use a double bind with the patient. For example, the patient is told there are two possible diagnoses: (1) an organic disease that should respond to the next medical intervention (usually modest and noninvasive), or (2) factitious disorder for which the patient will need psychiatric treatment. Given these options, many patients will choose to recover and not have to admit the origin of their problem.

C. Behavioral

Behavioral therapy is probably best exemplified by biofeedback techniques. In biofeedback, the particular abnormality (eg, increased peristalsis) must be recognized and monitored by the patient and therapist (eg, by an electronic stethoscope to amplify the sounds). This is immediate feedback, and after learning to recognize it, the patient can then learn to identify any change thus produced (eg, a decrease in bowel sounds) and so become a conscious originator of the feedback instead of a passive recipient. Relief of the symptom operantly conditions the patient to utilize the maneuver that relieves symptoms (eg, relaxation causing a decrease in bowel sounds). With emphasis on this type of learning, the patient is able to identify symptoms early and initiate the countermaneuvers, thus decreasing the symptomatic problem. Migrainoid and tension headaches have been particularly responsive to biofeedback methods.

D. Social

Social endeavors include family, work, and other interpersonal activity. Family members should come for some appointments with the patient so they can learn how best to live with the patient. This is particularly important in treatment of somatization and pain disorders. Peer support groups provide a climate for encouraging the patient to accept and live with the problem. Ongoing communication with the employer may be necessary to encourage long-term continued interest in the employee. Employers can become just as discouraged as clinicians in dealing with employees who have chronic problems.

Prognosis

The prognosis is much better if the primary clinician is able to intervene early before the situation has deteriorated. After the problem has crystallized into chronicity, it is very difficult to effect change.

Krahn LE et al: Patients who strive to be ill: factitious disorder with physical symptoms. Am J Psychiatry 2003;160:1163.

Yeung A et al: Somatoform disorders. West J Med 2002;176:253.

Chronic Pain Disorders

Essentials of Diagnosis

  • Chronic complaints of pain.

  • Symptoms frequently exceed signs.

  • Minimal relief with standard treatment.

  • History of having seen many clinicians.

  • Frequent use of several nonspecific medications.

General Considerations

A problem in the management of pain is the lack of distinction between acute and chronic pain syndromes. Most clinicians are adept at dealing with acute pain problems but have difficulty handling the patient with a chronic pain disorder. This type of patient frequently takes too many medications, stays in bed a great deal, has seen many clinicians, has lost skills, and experiences little joy in either work or play. All relationships suffer (including those with clinicians), and life becomes a constant search for succor. The search results in complex clinician-patient relationships that usually include many drug trials, particularly sedatives, with adverse consequences (eg, irritability, depressed mood) related to long-term use. Treatment failures provoke angry responses and depression from both the patient and the clinician, and the pain syndrome is exacerbated. When frustration becomes too great, a new clinician is found, and the cycle is repeated. The longer the existence of the pain disorder, the more important become the psychological factors of anxiety and depression. As with all other conditions, it is counterproductive to speculate about whether the pain is “real.” It is real to the patient, and

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acceptance of the problem must precede a mutual endeavor to alleviate the disturbance.

Figure 25-2. Algorithm for assessing psychiatric component of chronic pain. (Modified and reproduced, with permission, from

Eisendrath SJ: Psychiatric aspects of chronic pain. Neurology 1995;45[Suppl 9]:S26.

)

Clinical Findings

Components of the chronic pain syndrome consist of anatomic changes, chronic anxiety and depression, anger, and changed lifestyle. Usually, the anatomic problem is irreversible, since it has already been subjected to many interventions with increasingly unsatisfactory results. An algorithm for assessing chronic pain and differentiating it from other psychiatric conditions is illustrated in Figure 25-2.

Chronic anxiety and depression produce heightened irritability and overreaction to stimuli. A marked decrease in pain threshold is apparent. This pattern develops into a hypochondriacal preoccupation with the body and a constant need for reassurance. The pressure on the clinician becomes wearing and often leads to covert rejection devices, such as not being available or making referrals to other clinicians. This is perceived by the patient, who then intensifies the effort to find help, and the typical cycle is repeated. Anxiety and depression are seldom discussed, almost as if there is a tacit agreement not to deal with these issues.

Changes in lifestyle involve some of the pain behaviors. These usually take the form of a family script in which the patient accepts the role of being sick, and this role then becomes the focus of most family interactions and may become important in maintaining the family, so that neither the patient nor the family wants the patient's role to change. Demands for attention and efforts to control the behavior of others revolve around the central issue of control of other people (including clinicians). Cultural factors frequently play a role in the behavior of the patient and how the significant people around the patient cope with the problem. Some cultures encourage demonstrative behavior, while others value the stoic role.

Another secondary gain that frequently maintains the patient in the sick role is financial compensation or other

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benefits (“green poultice”). Frequently, such systems are structured so that they reinforce the maintenance of sickness and discourage any attempts to give up the role. Clinicians unwittingly reinforce this role because of the very nature of the practice of medicine, which is to respond to complaints of illness. Helpful suggestions from the clinician are often met with responses like, “Yes, but.…” Medications then become the principal approach, and drug dependency problems may develop.

Treatment

A. Behavioral

The cornerstone of a unified approach to chronic pain syndromes is a comprehensive behavioral program. This is necessary to identify and eliminate pain reinforcers, to decrease drug use, and to use effectively those positive reinforcers that shift the focus from the pain. It is critical that the patient be made a partner in the effort to alleviate pain. The clinician must shift from the idea of biomedical cure to ongoing care of the patient. The patient should agree to discuss the pain only with the clinician and not with family members; this tends to stabilize the patient's personal life, since the family is usually tired of the subject. At the beginning of treatment, the patient should be assigned self-help tasks graded up to maximal activity as a means of positive reinforcement. The tasks should not exceed capability. The patient can also be asked to keep a self-rating chart to log accomplishments, so that progress can be measured and remembered. Instruct the patient to record degrees of pain on a self-rating scale in relation to various situations and mental attitudes so that similar circumstances can be avoided or modified.

Avoid positive reinforcers for pain such as marked sympathy and attention to pain. Emphasize a positive response to productive activities, which remove the focus of attention from the pain. Activity is also desensitizing, since the patient learns to tolerate increasing activity levels.

Biofeedback techniques (see Somatoform Disorders, above) and hypnosis have been successful in ameliorating some pain syndromes. Hypnosis tends to be most effective in patients with a high level of denial, who are more responsive to suggestion. Hypnosis can be used to lessen anxiety, alter perception of the length of time that pain is experienced, and encourage relaxation.

B. Medical

A single clinician in charge of the comprehensive treatment approach is the highest priority. Consultations as indicated and technical procedures done by others are appropriate, but the care of the patient should remain in the hands of the primary clinician. Referrals should not be allowed to raise the patient's hopes unrealistically or to become a way for the clinician to reject the case. The attitude of the doctor should be one of honesty, interest, and hopefulness—not for a cure but for control of pain and improved function. If the patient manifests opioid addiction, detoxification may be an early treatment goal.

Nonsteroidal anti-inflammatory drugs are often the first-line of treatment for pain. If opioid analgesics or sedatives are prescribed, they should not be given on an “as-needed” schedule (see Chapter 5). A fixed schedule lessens the conditioning effects of these drugs. Tricyclic antidepressants (TCAs) (eg, nortriptyline) and venlafaxine in doses up to those used in depression may be helpful, particularly in neuropathic pain syndromes. In other conditions, their effects on pain may be less clear, but ameliorating depression is usually important nonetheless. Gabapentin, an anticonvulsant with possible applications in the treatment of anxiety disorders, has been shown to be useful in postherpetic and diabetic neuropathy and somatoform disorders.

In addition to medications, a variety of alternative strategies may be offered, including physical therapy and acupuncture.

C. Social

Involvement of family members and other significant persons in the patient's life should be an early priority. The best efforts of both patient and therapists can be unwittingly sabotaged by other persons who may feel that they are “helping” the patient. They frequently tend to reinforce the negative aspects of the chronic pain disorder. The patient becomes more dependent and less active, and the pain syndrome becomes an immutable way of life. The more destructive pain behaviors described by many experts in chronic pain disorders are the results of well-meaning but misguided efforts of family members. Ongoing therapy with the family can be helpful in the early identification and elimination of these behavior patterns.

D. Psychological

In addition to group therapy with family members and others, groups of patients can be helpful if properly led. The major goal, whether of individual or group therapy, is to gain patient involvement. A group can be a powerful instrument for achieving this goal, with the development of group loyalties and cooperation. People will frequently make efforts with group encouragement that they would never make alone. Individual therapy should be directed toward strengthening existing defenses and improving self-esteem. For example, teaching patients to challenge expectations induced by chronic pain may lead to improved functioning. As an illustration, many chronic pain patients, making assumptions more derived from acute injuries, incorrectly believe they will damage themselves by attempting to function. The rapport between patient and clinician, as in all psychotherapeutic efforts, is the major factor in therapeutic success.

Ciaramella A et al: When pain is not fully explained by organic lesion: a psychiatric perspective on chronic pain patients. Eur J Pain 2004;8:3.

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Evers AW et al: Tailored cognitive-behavioral therapy in early rheumatoid arthritis for patients at risk: a randomized controlled trial. Pain 2002;100:141.

Lin EH et al: Effect of improving depression care on pain and functional outcomes among older adults with arthritis: a randomized controlled trial. JAMA 2003;290:2428.

Psychosexual Disorders

The stages of sexual activity include excitement (arousal), orgasm, and resolution. The precipitating excitement or arousal is psychologically determined. Arousal response leading to plateau is a physiologic and psychological phenomenon of vasocongestion, a parasympathetic reaction causing erection in men and labial-clitoral congestion in women. The orgasmic response includes emission in men and clonic contractions of the analogous striated perineal muscles of both men and women. Resolution is a gradual return to normal physiologic status.

While the arousal stimuli—vasocongestive and orgasmic responses—constitute a single response in a well-adjusted person, they can be considered as separate stages that can produce different syndromes responding to different treatment procedures.

Clinical Findings

There are three major groups of sexual disorders.

A. Paraphilias (Sexual Arousal Disorders)

In these conditions, formerly called “deviations” or “variations,” the excitement stage of sexual activity is associated with sexual objects or orientations different from those usually associated with adult sexual stimulation. The stimulus may be a woman's shoe, a child, animals, instruments of torture, or incidents of aggression. The pattern of sexual stimulation is usually one that has early psychological roots. Poor experiences with sexual activity frequently reinforce this pattern over time.

Exhibitionism is the impulsive behavior of exposing the genitalia to unsuspecting strangers in order to achieve sexual excitation. It is a childhood sexual behavior carried into adult life.

Transvestism consists of recurrent cross-dressing behavior in a heterosexual man for the purpose of sexual excitation. Such fetishistic behavior can be part of masturbation foreplay. Transvestism in homosexuality and transsexualism is not for the purpose of sexual excitement but is a function of preference or gender identity disorder.

Voyeurism involves the achievement of sexual arousal by watching the activities of an unsuspecting person, usually in various stages of undress or sexual activity. In both exhibitionism and voyeurism, excitation leads to masturbation as a replacement for sexual activity.

Pedophilia is the use of a child of either sex to achieve sexual arousal and, in many cases, gratification. Contact is frequently oral, with either participant being dominant, but pedophilia includes intercourse of any type. Adults of both sexes engage in this behavior, but because of social and cultural factors it is more commonly identified with men. The pedophile has difficulty in adult sexual relationships, and men who perform this act are frequently impotent.

Incest involves a sexual relationship with a person in the immediate family, most frequently a child. In many ways it is similar to pedophilia (intrafamilial pedophilia). Incestuous feelings are fairly common, but cultural mores are usually sufficiently strong to act as a barrier to the expression of sexual feelings.

Sexual sadism is the attainment of sexual arousal by inflicting pain upon the sexual object. Much sexual activity has aggressive components (eg, biting, scratching). However, forced sexual acquiescence (eg, rape) is considered to be primarily an act of aggression.

Sexual masochism is the achievement of erotic pleasure by being humiliated, enslaved, physically bound, and restrained. It is life-threatening, since neck binding or partial asphyxiation usually forms part of the ritual. The practice is much more common in men than in women.

Necrophilia is sexual intercourse with a dead body or the use of parts of a dead body for sexual excitation, often with masturbation.

B. Gender Identity Disorder

Core gender identity reflects a biologic self-image—the conviction that “I am a boy” or “I am a girl” that is usually well developed by age 3 or 4. Gender dysphoria refers to the development of a sexual identity that is the opposite of the biologic one.

Transsexualism is an attempt to deny and reverse biologic sex by maintaining sexual identity with the opposite gender. Transsexuals do not alternate between gender roles; rather, they assume a fixed role of attitudes, feelings, fantasies, and choices consonant with those of the opposite sex, all of which clearly date back to early development. For example, male to female transsexuals in early childhood behave, talk, and fantasize as if they were girls. They do not grow out of feminine patterns; they do not work in professions traditionally considered to be masculine; and they have no interest in their own penises either as evidence of maleness or as organs for erotic behavior. The desire for sex change starts early and may culminate in assumption of a feminine lifestyle, hormonal treatment, and use of surgical procedures, eg, castration and vaginoplasty.

C. Psychosexual Dysfunction

This category includes a large group of vasocongestive and orgasmic disorders. Often, they involve problems of sexual adaptation, education, and technique that are often initially discussed with, diagnosed by, and treated by the primary care provider.

There are two conditions common in men: erectile dysfunction and ejaculation disturbances.

Erectile dysfunction (impotence) is inability to achieve or maintain an erection firm enough for satisfactory intercourse; patients sometimes use the term to

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mean premature ejaculation. Careful questioning is necessary, since causes of this vasocongestive disorder can be psychological, physiologic, or both. The majority are pathophysiologic and, to varying degrees, treatable. After onset of the problem, a history of occasional erections—especially nocturnal penile tumescence, which may be evaluated by a simple monitoring device, or a sleep study in the sleep laboratory—is usually evidence that the dysfunction is psychological in origin, with the caveat that decreased nocturnal penile tumescence occurs in some depressed patients. Psychological erectile dysfunction is caused by interpersonal or intrapsychic factors (eg, marital disharmony, depression). Organic factors are discussed in Chapter 23.

Ejaculation disturbances include premature ejaculation, inability to ejaculate, and retrograde ejaculation. (One may ejaculate even though impotent.) Ejaculation is usually connected with orgasm, and ejaculatory control is an acquired behavior that is minimal in adolescence and increases with experience. Pathogenic factors are those that interfere with learning control, most frequently sexual ignorance. Intrapsychic factors (anxiety, guilt, depression) and interpersonal maladaptation (marital problems, unresponsiveness of mate, power struggles) are also common. Organic causes include interference with sympathetic nerve distribution (often due to surgery or trauma) and the effects of pharmacologic agents (eg, SSRIs or sympatholytics).

In women, the two most common forms of sexual dysfunction are vaginismus and frigidity.

Vaginismus is a conditioned response in which a spasm of the perineal muscles occurs if there is any stimulation of the area. The desire is to avoid penetration. Sexual responsiveness and vasocongestion may be present, and orgasm can result from clitoral stimulation.

Frigidity is a complex condition in which there is a general lack of sexual responsiveness. The woman has difficulty in experiencing erotic sensation and does not have the vasocongestive response. Sexual activity varies from active avoidance of sex to an occasional orgasm. Orgasmic dysfunction—in which a woman has a vasocongestive response but varying degrees of difficulty in reaching orgasm—is sometimes differentiated from frigidity. Causes for the dysfunctions include poor sexual techniques, early traumatic sexual experiences, interpersonal disharmony (marital struggles, use of sex as a means of control), and intrapsychic problems (anxiety, fear, guilt). Organic causes include any conditions that might cause pain in intercourse, pelvic pathology, mechanical obstruction, and neurologic deficits.

Disorders of sexual desire consist of diminished or absent libido in either sex and may be a function of organic or psychological difficulties (eg, anxiety, phobic avoidance). Any chronic illness can sap desire. Hormonal disorders, including hypogonadism or use of antiandrogen compounds such as cyproterone acetate, and chronic renal failure contribute to deterioration in sexual activity. Although menopause may lead to diminution of sexual desire in some women, the relationship between menopause and libido is complicated and may be influenced by sociocultural factors. Alcohol, sedatives, opioids, marijuana, and some medications may affect sexual drive and performance.

Treatment

A. Paraphilias and Gender Identity Disorders

1. Psychological

Sexual arousal disorders involving variant sexual activity (paraphilia), particularly those of a more superficial nature (eg, voyeurism) and those of recent onset, are responsive to psychotherapy in a moderate percentage of cases. The prognosis is much better if the motivation comes from the individual rather than the legal system; unfortunately, however, judicial intervention is frequently the only stimulus to treatment, because the condition persists and is reinforced until conflict with the law occurs. Therapies frequently focus on barriers to normal arousal response; the expectation is that the variant behavior will decrease as normal behavior increases.

2. Behavioral

Aversive and operant conditioning techniques have been tried frequently in gender role disorders but have only occasionally been successful. In some cases, the sexual arousal disorders improve with modeling, role-playing, and conditioning procedures. Emotive imagery is occasionally helpful in lessening anxiety in fetish problems.

3. Social

Although they do not produce a change in sexual arousal patterns or gender role, self-help groups have facilitated adjustment to an often hostile society. Attention to the family is particularly important in helping persons in such groups to accept their situation and alleviate their guilt about the role they think they had in creating the problem.

4. Medical

Medroxyprogesterone acetate, a suppressor of libidinal drive, is used to mute disruptive sexual behavior in men of all ages. Onset of action is usually within 3 weeks, and the effects are generally reversible. Fluoxetine or other SSRIs at depression doses (see Table 25-8) may reduce some of the compulsive sexual behaviors including the paraphilias. A recent focus of study in the treatment of severe paraphilia has been agonists of luteinizing hormone-releasing hormone. Although some transsexuals are treated with genital reconstructive surgery, many others are screened out by trial periods of living as the other sex prior to operation.

B. Psychosexual Dysfunction

1. Medical

Identification of a contributory reversible cause is most important. Even if the condition is not reversible, identification of the specific cause helps the patient to accept the condition. Marital disharmony, with its exacerbating effects, may thus be avoided. Of all the sexual dysfunctions, erectile dysfunction is the condition most likely to have an organic basis. Sildenafil citrate, a phosphodiesterase type 5 inhibitor, is an effective oral agent for the treatment of penile erectile dysfunction in the recommended dose of 25–100 mg 1 hour

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prior to intercourse. Sildenafil is effective for SSRI-induced erectile dysfunction in men and in some cases for SSRI-associated sexual dysfunction in women. Use of the medication in conjunction with any nitrates, particularly in individuals with coronary artery disease, can have significant hypotensive effects leading to death in some cases. The medication, which does not appear to impact sexual desire, should be used only once a day. The newer phosphodiesterase type 5 inhibitors tadalafil and vardenafil have similar efficacy. Because of their common effect in delaying ejaculation, the SSRIs have been effective in premature ejaculation.

2. Behavioral

Syndromes resulting from conditioned responses have been treated by conditioning techniques, with excellent results. Vaginismus responds well to desensitization with graduated Hegar dilators along with relaxation techniques. Masters and Johnson have used behavioral approaches in all of the sexual dysfunctions, with concomitant supportive psychotherapy and with improvement of the communication patterns of the couple.

3. Psychological

The use of psychotherapy by itself is best suited for those cases in which interpersonal difficulties or intrapsychic problems predominate. Anxiety and guilt about parental injunctions against sex may contribute to sexual dysfunction. Even in these cases, however, a combined behavioral-psychological approach usually produces results most quickly.

4. Social

The proximity of other people (eg, a mother-in-law) in a household is frequently an inhibiting factor in sexual relationships. In such cases, some social engineering may alleviate the problem.

Kostis JB et al: Sexual dysfunction and cardiac risk (The Second Princeton Consensus Conference). Am J Cardiol 2005;96: 313.

Shiri R et al: Effect of chronic diseases on incidence of erectile dysfunction. Urology 2003;62:1097.

Worthington JJ et al: Treatment of antidepressant-induced sexual dysfunction. Drugs Today 2003;39:887.

Personality Disorders

Essentials of Diagnosis

  • Long history dating back to childhood.

  • Recurrent maladaptive behavior.

  • Low self-esteem and lack of confidence.

  • Minimal introspective ability with a tendency to blame others for all problems.

  • Major difficulties with interpersonal relationships or society.

  • Depression with anxiety when maladaptive behavior fails.

General Considerations

An individual's personality structure, or character, is an integral part of self-image. It reflects genetics, interpersonal influences, and recurring patterns of behavior adopted in order to cope with the environment. The classification of subtypes of personality disorders depends on the predominant symptoms and their severity. The most severe disorders—those that bring the patient into greatest conflict with society—tend to be classified as antisocial (psychopathic) or borderline.

Personality disorders can be considered a matrix for some of the more severe psychiatric problems (eg, schizotypal, relating to schizophrenia, and avoidance types, relating to some anxiety disorders).

Classification & Clinical Findings

See Table 25-3.

Differential Diagnosis

Patients with personality disorders tend to show anxiety and depression when pathologic coping mechanisms fail, and their symptoms can be similar to those occurring with anxiety disorders. Occasionally, the more severe cases may decompensate into psychosis under stress and mimic other psychotic disorders.

Treatment

A. Social

Social and therapeutic environments such as day hospitals, halfway houses, and self-help communities utilize peer pressures to modify the self-destructive behavior. The patient with a personality disorder often has failed to profit from experience, and difficulties with authority impair the learning experience. The use of peer relationships and the repetition possible in a structured setting of a helpful community enhance the behavioral treatment opportunities and increase learning. When problems are detected early, both the school and the home can serve as foci of intensified social pressure to change the behavior, particularly with the use of behavioral techniques.

B. Behavioral

The behavioral techniques used are principally operant conditioning and aversive conditioning. The former simply emphasizes the recognition of acceptable behavior and its reinforcement with praise or other tangible rewards. Aversive responses usually mean punishment, although this can range from a mild rebuke to some specific punitive responses such as deprivation of privileges. Extinction plays a role in that an attempt is made not to respond to inappropriate behavior, and the lack of response eventually causes the person to abandon that type of behavior. Pouting and tantrums, for example, diminish

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quickly when such behavior elicits no reaction. Dialectical behavioral therapy is a program of individual and group therapy specifically designed for patients with chronic suicidality and borderline personality disorder. It blends mindfulness and a cognitive-behavioral model to address self-awareness, interpersonal functioning, affective lability, and reactions to stress.

Table 25-3. Personality disorders: Classification and clinical findings.

Personality Disorder Clinical Findings
Paranoid Defensive, oversensitive, secretive, suspicious, hyperalert, with limited emotional response.
Schizoid Shy, introverted, withdrawn, avoids close relationships.
Obsessive-compulsive Perfectionist, egocentric, indecisive, with rigid thought patterns and need for control.
Histrionic (hysterical) Dependent, immature, seductive, egocentric, vain, emotionally labile.
Schizotypal Superstitious, socially isolated, suspicious, with limited interpersonal ability, eccentric behaviors, and odd speech.
Narcissistic Exhibitionist, grandiose, preoccupied with power, lacks interest in others, with excessive demands for attention.
Avoidant Fears rejection, hyperreacts to rejection and failure, with poor social endeavors and low self-esteem.
Dependent Passive, overaccepting, unable to make decisions, lacks confidence, with poor self-esteem.
Antisocial Selfish, callous, promiscuous, impulsive, unable to learn from experience, has legal problems.
Borderline Impulsive; has unstable and intense interpersonal relationships; is suffused with anger, fear, and guilt; lacks self-control and self-fulfillment; has identity problems and affective instability; is suicidal (a serious problem–up to 80% of hospitalized borderline patients make an attempt at some time during treatment, and the incidence of completed suicide is as high as 5%); aggressive behavior, feelings of emptiness, and occasional psychotic decompensation. This group has a high drug abuse rate, which plays a role in symptoms. There is extensive overlap with other diagnostic categories, particularly mood disorders and posttraumatic stress disorder.

C. Psychological

Psychological intervention is best conducted in group settings. Group therapy is helpful when specific interpersonal behavior needs to be improved. This mode of treatment also has a place with so-called acting-out patients, ie, those who frequently act in an impulsive and inappropriate way. The peer pressure in the group tends to impose restraints on rash behavior. The group also quickly identifies the patient's types of behavior and helps improve the validity of the patient's self-assessment, so that the antecedents of the unacceptable behavior can be effectively handled, thus decreasing its frequency. Individual therapy should initially be supportive, ie, helping the patient to restabilize and mobilize defenses. If the individual has the ability to observe his or her own behavior, a longer-term and more introspective therapy may be warranted. The therapist must be able to handle countertransference feelings (which are frequently negative), maintain appropriate boundaries in the relationship (no physical contacts, however well-meaning), and refrain from premature confrontations and interpretations.

D. Medical

Hospitalization is indicated in the case of serious suicidal or homicidal danger. In most cases, treatment can be accomplished in the day treatment center or self-help community. Antipsychotics may be required for short periods in conditions that have temporarily decompensated into transient psychoses (eg, haloperidol, 2–5 mg orally every 3–4 hours until the patient has quieted down and is regaining contact with reality). Olanzapine (2.5–10 mg/d) or risperidone (0.5–2 mg/d) may be given with lorazepam (1–2 mg orally every 4 hours as needed). In some cases, these drugs are required only for several days and can be discontinued after the patient has regained a previously established level of adjustment; they can also provide ongoing support. Carbamazepine, 400–800 mg orally daily in divided doses, decreases the severity of behavioral dyscontrol. Antidepressants have improved anxiety, depression, and sensitivity to rejection in some borderline patients. SSRIs may have a role in reducing aggressive behavior in impulsive aggressive patients.

Prognosis

Antisocial and borderline categories generally have a guarded prognosis. Those patients with poor outcomes are more likely to have a history of parental abuse and a family history of mood disorder, whereas persons with mild schizoid or passive-aggressive tendencies have a better prognosis with appropriate treatment.

Rocca P et al: Treatment of borderline personality disorder with risperidone. J Clin Psychiatry 2002;63:241.

Swenson CR et al: Implementing dialectical behavior therapy. Psychiat Ser 2002;53:171.

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Schizophrenic & Other Psychotic Disorders

Essentials of Diagnosis

  • Social withdrawal, usually slowly progressive, often with deterioration in personal care.

  • Loss of ego boundaries, with inability to perceive oneself as a separate entity.

  • Loose thought associations, often with slowed thinking or overinclusive and rapid shifting from topic to topic.

  • Autistic absorption in inner thoughts and frequent sexual or religious preoccupations.

  • Auditory hallucinations, often of a derogatory nature.

  • Delusions, frequently of a grandiose or persecutory nature.

  • Symptoms of at least 6 months' duration.

Frequent additional signs:

  • Flat affect and rapidly alternating mood shifts irrespective of circumstances.

  • Hypersensitivity to environmental stimuli, with a feeling of enhanced sensory awareness.

  • Variability or changeable behavior incongruent with the external environment.

  • Concrete thinking with inability to abstract; inappropriate symbolism.

  • Impaired concentration worsened by hallucinations and delusions.

  • Depersonalization, wherein one behaves like a detached observer of one's own actions.

General Considerations

The schizophrenic disorders are a group of syndromes manifested by massive disruption of thinking, mood, and overall behavior as well as poor filtering of stimuli. The characterization and nomenclature of the disorders are quite arbitrary and are influenced by sociocultural factors and schools of psychiatric thought.

It is currently believed that the schizophrenic disorders are of multifactorial cause, with genetic, environmental, and neurotransmitter pathophysiologic components. At present, there is no laboratory method for confirming the diagnosis of schizophrenia. There may or may not be a history of a major disruption in the individual's life (failure, loss, physical illness) before gross psychotic deterioration is evident.

Schizophrenic symptoms have been classified into positive and negative categories. Positive symptoms include hallucinations, delusions, and formal thought disorders; these symptoms appear to be related to increased dopaminergic (D2) activity in the mesolimbic region. Negative symptoms include diminished sociability, restricted affect, and poverty of speech; these symptoms appear to be related to decreased D2 activity in the mesocortical system.

“Other psychotic disorders” are conditions that are similar to schizophrenic disorders in their acute symptoms but have a less pervasive influence over the long term. The patient usually attains higher levels of functioning. The acute psychotic episodes tend to be less disruptive of the person's lifestyle, with a fairly quick return to previous levels of functioning.

Classification

A. Schizophrenic Disorders

Schizophrenic disorders are subdivided on the basis of certain prominent phenomena that are frequently present. Disorganized (hebephrenic) schizophrenia is characterized by marked incoherence and an incongruous or silly affect. Catatonic schizophrenia is distinguished by a marked psychomotor disturbance of either excitement (purposeless and stereotyped) or rigidity with mutism. Infrequently, there may be rapid alternation between excitement and stupor (see under catatonic syndrome, below). Paranoid schizophrenia includes marked persecutory or grandiose delusions often consonant with hallucinations of similar content and with less marked disorganization of speech and behavior. Undifferentiated schizophrenia denotes a category in which symptoms are not specific enough to warrant inclusion of the illness in the other subtypes. Residual schizophrenia is a classification that includes persons who have clearly had an episode warranting a diagnosis of schizophrenia but who at present have no overt psychotic symptoms, although they show milder signs such as social withdrawal, flat affect, and eccentric behaviors.

B. Delusional Disorders

Delusional disorders are psychoses in which the predominant symptoms are persistent, nonbizarre delusions with minimal impairment of daily functioning. (The schizophrenic disorders show significant impairment.) Intellectual and occupational activities are little affected, whereas social and marital functioning tend to be markedly involved. Hallucinations are not usually present. Common delusional themes include paranoid delusions of persecution, delusions of being related to or loved by a well-known person, and delusions that one's partner is unfaithful.

C. Schizoaffective Disorders

Schizoaffective disorders are those cases that fail to fit comfortably either in the schizophrenic or in the affective categories. They are usually cases with affective symptoms that precede or develop concurrently with psychotic manifestations. There has been increasing

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interest in studying prodromal schizophrenia with a goal to early treatment.

D. Schizophreniform Disorders

Schizophreniform disorders are similar in their symptoms to schizophrenic disorders except that the duration of prodromal, acute, and residual symptoms is more than 1 week but less than 6 months.

E. Brief Psychotic Disorders

These disorders last less than 1 week. They are the result of psychological stress. The shorter duration is significant and correlates with a more acute onset and resolution as well as a much better prognosis.

F. Late Life Psychosis

Brain abnormalities occur in 40% of patients who develop psychotic symptoms after age 60. The psychotic symptoms are typical, and there are other findings such as low IQ scores and diminished cognitive function.

G. Atypical Psychoses

This group includes a wide range of conditions with psychotic symptoms. The cause is often not clear, but later events (eg, new symptoms) may clarify the diagnosis. The most common example is chronic psychosis developing either during periods of heavy abuse of drugs or at some time after the drug use has ceased. Other conditions include temporal lobe dysfunction, HIV infection, and a number of the conditions noted in the differential diagnosis (see below). They often have a good premorbid history, a precipitous onset, and an episodic course with symptom-free intervals.

Clinical Findings

A. Symptoms and Signs

The symptoms and signs of schizophrenia vary markedly among individuals as well as in the same person at different times. The patient's appearance may be bizarre, although the usual finding is a mild to moderate unkempt blandness. Motor activity is generally reduced, although extremes ranging from catatonic stupor to frenzied excitement occur. Social behavior is characterized by marked withdrawal coupled with disturbed interpersonal relationships and a reduced ability to experience pleasure. Dependency and a poor self-image are common. Verbal utterances are variable, the language being concrete yet symbolic, with unassociated rambling statements (at times interspersed with mutism) during an acute episode. Neologisms (made-up words or phrases), echolalia (repetition of words spoken by others), and verbigeration (repetition of senseless words or phrases) are occasionally present. Affect is usually flattened, with occasional inappropriateness. Depression is present in almost all cases but may be less apparent during the acute psychotic episode and more obvious during recovery. Depression is sometimes confused with akinetic side effects of antipsychotic drugs. It is also related to boredom, which increases symptoms and decreases the response to treatment. Work is generally unavailable and time unfilled, providing opportunities for counterproductive activities such as drug abuse, withdrawal, and increased psychotic symptoms.

Thought content may vary from a paucity of ideas to a rich complex of delusional fantasy with archaic thinking. One frequently notes after a period of conversation that little if any information has actually been conveyed. Incoming stimuli produce varied responses. In some cases a simple question may trigger explosive outbursts, whereas at other times there may be no overt response whatsoever (catatonia). When paranoid ideation is present, the patient is often irritable and less cooperative. Delusions (false beliefs) are characteristic of paranoid thinking, and they usually take the form of a preoccupation with the supposedly threatening behavior exhibited by other individuals. This ideation may cause the patient to adopt active countermeasures such as locking doors and windows, taking up weapons, covering the ceiling with aluminum foil to counteract radar waves, and other bizarre efforts. Somatic delusions revolve around issues of bodily decay or infestation. Perceptual distortions usually include auditory hallucinations—visual hallucinations are more commonly associated with organic mental states—and may include illusions (distortions of reality) such as figures changing in size or lights varying in intensity. Cenesthetic hallucinations (eg, a burning sensation in the brain, feeling blood flowing in blood vessels) occasionally occur. Lack of humor, feelings of dread, depersonalization (a feeling of being apart from the self), and fears of annihilation may be present. Any of the above symptoms generate higher anxiety levels, with heightened arousal and occasional panic and suicidal ideation, as the individual fails to cope.

The development of the acute episode in schizophrenia frequently is the end product of a gradual decompensation. Frustration and anxiety appear early, followed by depression and alienation, along with decreased effectiveness in day-to-day coping. This often leads to feelings of panic and increasing disorganization, with loss of the ability to test and evaluate the reality of perceptions. The stage of so-called psychotic resolution includes delusions, autistic preoccupations, and psychotic insight, with acceptance of the decompensated state. The process is frequently complicated by the use of caffeine, alcohol, and other recreational drugs. Life expectancy of schizophrenics is as much as 20% shorter than that of cohorts in the general population (usually because of a higher mortality rate in younger people).

Polydipsia may produce water intoxication with hyponatremia—characterized by symptoms of confusion, lethargy, psychosis, seizures, and occasionally death—in any psychiatric disorder, but most commonly in schizophrenia. These problems exacerbate the schizophrenic symptoms. Possible pathogenetic factors in polydipsia include a hypothalamic defect,

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inappropriate antidiuretic hormone (ADH) secretion, neuroleptic medications (anticholinergic effects, stimulation of hypothalamic thirst center, effect on ADH), smoking (nicotine and syndrome of inappropriate antidiuretic hormone [SIADH]), psychotic thought processes (delusions), and other medications (eg, diuretics, antidepressants, lithium, alcohol). Other causes of polydipsia must be ruled out (eg, diabetes mellitus, diabetes insipidus, renal disease).

B. Imaging

Ventricular enlargement and cortical atrophy, as seen on CT scan, have been correlated with chronic course, severe cognitive impairment, and nonresponsiveness to neuroleptic medications. Decreased frontal lobe activity seen on PET scan has been associated with negative symptoms.

Differential Diagnosis

One should not hesitate to reconsider the diagnosis of schizophrenia in any person who has received that diagnosis in the past, particularly when the clinical course has been atypical. A number of these patients have been found to actually have atypical episodic affective disorders that have responded well to lithium. Manic episodes often mimic schizophrenia. Furthermore, schizophrenia has been diagnosed in many individuals because of inadequacies in psychiatric nomenclature. Thus, schizophrenia was often inappropriately diagnosed in persons with brief reactive psychoses, OCD, paranoid disorders, and schizophreniform disorders.

Psychotic depressions, psychotic organic mental states, and any illness with psychotic ideation tend to be confused with schizophrenia, partly because of the regrettable tendency to use the terms interchangeably. Adolescent phases of growth and counterculture behaviors constitute another area of diagnostic confusion. It is particularly important to avoid a misdiagnosis in these groups, because of the long-term implications arising from having such a serious diagnosis made in a formative stage of life.

Medical disorders such as thyroid dysfunction, adrenal and pituitary disorders, reactions to toxic materials (eg, mercury, PCBs), and almost all of the organic mental states in the early stages must be ruled out. Postpartum psychosis is discussed under Mood Disorders. Complex partial seizures, especially when psychosensory phenomena are present, are an important differential consideration. Toxic drug states arising from prescription, over-the-counter, herbal and street drugs may mimic all of the psychotic disorders. The chronic use of amphetamines, cocaine, and other stimulants frequently produces a psychosis that is almost identical to the acute paranoid schizophrenic episode. The presence of formication and stereotypy suggests the possibility of stimulant abuse. Phencyclidine (see below), a very common street drug, may cause a reaction that is difficult to distinguish from other psychotic disorders. Cerebellar signs, excessive salivation, dilated pupils, and increased deep tendon reflexes should alert the clinician to the possibility of a toxic psychosis. Industrial chemical toxicity (both organic and metallic), degenerative disorders, and metabolic deficiencies must be considered in the differential diagnosis.

Catatonic syndrome, frequently assumed to exist solely as a component of schizophrenic disorders, is actually the end product of a number of illnesses, including various organic conditions. Neoplasms, viral and bacterial encephalopathies, central nervous system hemorrhage, metabolic derangements such as diabetic ketoacidosis, sedative withdrawal, and hepatic and renal malfunction have all been implicated. It is particularly important to realize that drug toxicity (eg, overdoses of antipsychotic medications such as fluphenazine or haloperidol) can cause catatonic syndrome, which may be misdiagnosed as a catatonic schizophrenic disorder and inappropriately treated with more antipsychotic medication.

Treatment

A. Medical

Hospitalization is often necessary, particularly when the patient's behavior shows gross disorganization. The presence of competent family members lessens the need for hospitalization, and each case should be judged individually. The major considerations are to prevent self-inflicted harm or harm to others and to provide the patient's basic needs. A full medical evaluation and CT scan or MRI should be considered in first episodes of schizophreniform disorder and other psychotic episodes of unknown cause.

Antipsychotic medications (see below) are the treatment of choice. They block the response to stimulation. The relapse rate can be reduced by 50% with proper maintenance neuroleptic therapy. Long-acting, injectable depot neuroleptics are used in noncompliant patients or nonresponders to oral medication.

Antipsychotic drugs include the “typical” neuroleptics phenothiazines, thioxanthenes (both similar in structure), butyrophenones, dihydroindolones, dibenzoxazepines, and benzisoxazoles, and the newer “atypical” neuroleptics clozapine, risperidone, olanzapine, quetiapine, and ziprasidone (Table 25-4). Generally, increasing milligram potency of the typical neuroleptics is associated with decreasing anticholinergic and adrenergic side effects and increasing extrapyramidal symptoms (Table 25-5). For example, chlorpromazine has lower potency and more severe anticholinergic and adrenergic side effects. The increased anticholinergic effect of chlorpromazine, however, lowers the risk of extrapyramidal symptoms.

Table 25-4. Commonly used antipsychotics.

Drug Usual Daily Oral Dose Usual Daily Maximum Dose1 Cost per Unit Cost for 30 Days Treatment Based on Maximum Dosage2
Phenothiazines
   Chlorpromazine (Thorazine; others) 100-400 mg 1 g $1.05/200 mg $157.50
   Thioridazine (Mellaril) 100–400 mg 600 mg $1.10/200 mg $99.00
   Mesoridazine (Serentil) 50–200 mg 400 mg   Not available in USA
   Perphenazine (Trilafon)3 16–32 mg 64 mg $1.54/16 mg $184.80
   Trifluoperazine (Stelazine) 5–15 mg 60 mg $1.58/10 mg $284.40
   Fluphenazine (Permitil, Prolixin)3 2–10 mg 60 mg $1.15/10 mg $207.00
Thioxanthenes
   Thiothixene (Navane)3 5–10 mg 80 mg $0.65/10 mg $156.00
Dihydroindolone
   Molindone (Moban) 30–100 mg 225 mg $4.05/50 mg $546.75
Dibenzoxazepine
   Loxapine (Loxitane) 20–60 mg 200 mg $2.57/50 mg $308.40
Dibenzodiazepine
   Clozapine (Clozaril) 300–450 mg 900 mg $3.33/100 mg $899.10
Butyrophenone
   Haloperidol (Haldol) 2–5 mg 60 mg $3.12/20 mg $280.80
Benzisoxazole
   Risperidone4 (Risperdal) 2–6 mg 10 mg $6.70/2 mg $835.78
Thienbenzodiazepine
   Olanzapine (Zyprexa) 5–10 mg 10 mg $11.76/10 mg $352.80
Dibenzothiazepine
   Quetiapine (Seroquel) 200–400 mg 800 mg $6.62/200 mg $612.00
Benzisothiazolyl piperazine
   Ziprasidone (Geodon) 40–160 mg 160 mg $5.72/80 mg $343.02
Dipiperazine
   Aripiprazole (Abilify) 10–15 mg 30 mg $16.33/30 mg $489.97
1Can be higher in some cases.
2Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 25, No. 5, May 2006. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
3Indicates piperazine structure.
4For risperidone, daily doses above 6 mg increase the risk of extrapyramidal syndrome. Risperidone 6 mg is approximately equivalent to haloperidol 20 mg.

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was a complex investigation that compared “atypical” and “typical” neuroleptic drugs. Although it was not definitive, it suggested similar antipsychotic efficacy for both classes and a tendency for the atypicals, particularly olanzapine, to be better tolerated leading to enhanced compliance.

The phenothiazines comprise the bulk of the currently used “typical” neuroleptic drugs. The only butyrophenone

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commonly used in psychiatry is haloperidol, which is totally different in structure but very similar in action and side effects to the piperazine phenothiazines such as fluphenazine, perphenazine, and trifluoperazine. These drugs and haloperidol (dopamine [D2] receptor blockers) have high potency and a paucity of autonomic side effects and act to markedly lower arousal levels. Molindone and loxapine, while less potent, are similar in action, side effects, and safety to the piperazine phenothiazines.

The first “atypical” (novel) antipsychotic drug developed, clozapine, a dibenzodiazepine derivative, has dopamine (D4) receptor-blocking activity as well as central serotonergic, histaminergic, and α-noradrenergic receptor-blocking activity. It is effective in the treatment of about 30% of psychoses resistant to other neuroleptic drugs. Research suggests that clozapine may have specific efficacy in decreasing suicidality in patients with schizophrenia. It is associated with a 1% risk of agranulocytosis, which requires weekly white blood cell count monitoring for the first 6 months followed by monitoring every other week. Weekly monitoring for 1 month after discontinuation of the medication is recommended. Because of an association between clozapine and myocarditis, the drug is contraindicated in patients with severe heart disease.

Table 25-5. Relative potency and side effects of antipsychotics.

Drug Chlorpromazine:Drug Potency Ratio Anticholinergic Effects1 Extrapyramidal Effect1
Phenothiazines
   Chlorpromazine 1:1 4 1
   Thioridazine 1:1 4 1
   Mesoridazine 1:2 3 2
   Perphenazine 1:10 2 3
   Trifluoperazine 1:20 1 4
   Fluphenazine 1:50 1 4
Thioxanthene
   Thiothixene 1:20 1 4
Dihydroindolone
   Molindone 1:10 2 3
Dibenzoxazepine
   Loxapine 1:10 2 3
Butyrophenone
   Haloperidol 1:50 1 4
Dibenzodiazepine
   Clozapine 1:1 4
Benzisoxazole
   Risperidone 1:50 1 1
Thienbenzodiazepine
   Olanzapine 1:20 1 1
Dibenzothiazepine
   Quetiapine 1:1 1
Benzisothiazolyl piperazine
   Ziprasidone 1:1 1 1
Dipiperazine
   Aripiprazole 1:20 1 0
14 = strong effect; 1 = weak effect.

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Risperidone is an antipsychotic that blocks some serotonin receptors (5-HT2) and dopamine receptors (D2). Risperidone causes fewer extrapyramidal side effects than the typical antipsychotics at doses less than 6 mg. It appears to be as effective as haloperidol and possibly as effective as clozapine in treatment-resistant patients without requiring weekly white cell counts. Risperidone-induced hyperprolactinemia, even on low doses, has been reported, and that effect is thought to be more common with risperidone than with other atypical antipsychotics. Risperidone is available in a long-acting injectable preparation.

Olanzapine is a potent blocker of muscarinic, anticholinergic, 5-HT2, and dopamine D1, D2, and D4 receptors. High doses of olanzapine (12.5–17.5 mg daily) appear to be more effective than lower doses. The drug appears to be more effective than haloperidol in the treatment of negative symptoms. It is available in an orally disintegrating form for patients who are unable to tolerate standard oral dosing and in an injectable form for the management of acute agitation associated with schizophrenia and bipolar disorder. Serum alanine aminotransferase is more elevated in patients taking olanzapine than in those taking haloperidol. Olanzapine is associated with a much lower incidence of dystonic reaction than haloperidol and is perhaps less likely to induce tardive dyskinesia. Its most common side effects include somnolence, agitation, nervousness, headache, insomnia, dizziness, and significant weight gain. Multiple case reports have linked olanzapine and clozapine to new-onset type 2 diabetes. Further investigation is ongoing to clarify the risk, risk factors, and pathophysiology. The manufacturer has alerted physicians to an association between olanzapine and a significantly higher risk of stroke and death in elderly patients.

Quetiapine is a neuroleptic with greater 5-HT2 relative to D2 receptor blockade as well as a relatively high

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affinity for α1- and α2-adrenergic receptors. It appears to be as efficacious as haloperidol in treating positive and negative symptoms of schizophrenia, with less extrapyramidal side effects even at high doses. More common side effects include somnolence, dizziness, and postural hypotension. Because of an association with lens changes seen in patients on long-term treatment, an eye examination to detect cataract formation is recommended at initiation of treatment and then at 6-month intervals during treatment.

Ziprasidone has both anti-dopamine receptor and anti-serotonin receptor effects, with good efficacy for both positive and negative symptoms of schizophrenia. Ziprasidone is not associated with significant weight gain, hyperlipidemia, or new-onset diabetes and offers a good alternative for some patients. It has been implicated in QTc interval delay of > 500 ms in some patients, although in several cases of overdose there were no incidents of torsades de pointes or sudden death. Patients taking ziprasidone should be screened for cardiac risk factors. A pretreatment ECG is indicated for patients at risk for cardiac sequelae (including patients taking other medications that might prolong the QTc interval).

Aripiprazole is the first neuroleptic that is a dopamine stabilizer. A partial agonist at the dopamine D2 and serotonin 5-HT1 receptors and an antagonist at 5-HT2 receptors, it is effective against positive and negative symptoms of schizophrenia. It functions as an antagonist or agonist, depending on the dopaminergic activity at the dopamine receptors. This may help decrease side effects. More activating than sedating, aripiprazole is thought to impose a low risk of extrapyramidal symptoms, weight gain, hyperprolactinemia, and delayed QT interval.

None of the antipsychotics produce true physical dependency. All decrease adrenergic responses. Despite higher costs, atypical neuroleptics are often considered preferable to traditional antipsychotics because they are thought to be associated with reduced extrapyramidal symptoms and a lesser risk of tardive dyskinesia.

Clinical Indications

The antipsychotics are used to treat all forms of the schizophrenias as well as psychotic ideation in organic brain psychoses, delirium and dementia, drug-induced psychoses, psychotic depression, and mania. They are also effective in Tourette's disorder. They quickly lower the arousal (activity) level and, perhaps indirectly, gradually improve socialization and thinking. The improvement rate is about 80%. Patients whose behavioral symptoms worsen with use of antipsychotic drugs may have an undiagnosed organic condition such as anticholinergic toxicity.

Symptoms that are ameliorated by these drugs include hyperactivity, hostility, aggression, delusions, hallucinations, irritability, and poor sleep. Individuals with acute psychosis and good premorbid function respond quite well. The most common cause of failure in the treatment of acute psychosis is inadequate dosage, and the most common cause of relapse is noncompliance.

Although typical antipsychotics are efficacious in the treatment of so-called positive symptoms of schizophrenia such as hallucinations and delusions, atypical antipsychotics are thought to have efficacy in reducing both positive symptoms and negative symptoms such as withdrawal, psychomotor retardation, and poor interpersonal relationships. Antidepressant drugs may be used in conjunction with neuroleptics if significant depression is present. Resistant cases may require concomitant use of lithium, carbamazepine, or valproic acid. The addition of a benzodiazepine drug to the neuroleptic regimen may prove helpful in treating the agitated or catatonic psychotic patient who has not responded to neuroleptics alone—lorazepam, 1–2 mg orally, can produce a rapid resolution of catatonic symptoms and may allow maintenance with a lower neuroleptic dose. Electroconvulsive therapy (ECT) has also been effective in treating catatonia.

Dosage Forms & Patterns

The dosage range is quite broad. For example, risperidone, 0.5–1 mg orally at bedtime, may be sufficient for the elderly person with mild dementia, whereas up to 6 mg/d may be used in a young patient with acute schizophrenia. For quick response, an atypical antipsychotic may be started in combination with a benzodiazepine (eg, risperidone oral solution, 2 mg, or olanzapine, 10 mg orally, and lorazepam, 2 mg orally, every 2–4 hours as needed). In an acutely distressed, psychotic patient one might use haloperidol, 10 mg intramuscularly, which is absorbed rapidly and achieves an initial tenfold plasma level advantage over equal oral doses. Psychomotor agitation, racing thoughts, and general arousal are quickly reduced. The dose can be repeated every 3–4 hours; when the patient is less symptomatic, oral doses can replace parenteral administration in most cases. In the elderly, both atypical (eg, risperidone 0.25 mg-0.5 mg daily or olanzapine 1.25 mg daily) and conventional (eg haloperidol 0,5 mg daily or perphenazine 2 mg daily) antipsychotics, often used effectively in small doses for behavioral control, have been linked to premature death in some cases.

Various factors play a role in the absorption of oral medications. Of particular importance are previous gastrointestinal surgery and concomitant administration of other drugs. There are racial differences in metabolizing the neuroleptic drugs—eg, many Asians require only about half the usual dosage. Bioavailability is influenced by other factors such as smoking or hepatic microsomal enzyme stimulation with alcohol or barbiturates and enzyme-altering drugs such as carbamazepine or methylphenidate. Neuroleptic plasma drug level determinations are not currently of major clinical assistance.

Divided daily doses are not necessary after a maintenance dose has been established, and most patients can then be maintained on a single daily dose, usually taken at bedtime. This is particularly appropriate in a case where the sedative effect of the drug is desired for nighttime sleep, and undesirable sedative effects can be avoided during the day. Risperidone is an exception,

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being given twice daily. First-episode patients especially should be tapered off medications after about 6 months of stability and carefully monitored; their rate of relapse is lower than that of multiple-episode patients.

Psychiatric patients—particularly paranoid individuals—often neglect to take their medication. In these cases and in nonresponders to oral medication, the enanthate and decanoate (the latter is slightly longer-lasting and has fewer extrapyramidal side effects) forms of fluphenazine or the decanoate form of haloperidol may be given by deep subcutaneous injection or intramuscularly to achieve an effect that will usually last 7–28 days. A patient who cannot be depended on to take oral medication (or who overdoses on minimal provocation) will generally agree to come to the clinician's office for a “shot.” The usual dose of the fluphenazine long-acting preparations is 25 mg every 2 weeks. Dosage and frequency of administration vary from about 100 mg weekly to 12.5 mg monthly. Use the smallest effective amount as infrequently as possible. A monthly injection of 25 mg of fluphenazine decanoate is equivalent to about 15–20 mg of oral fluphenazine daily. Risperidone is the first atypical neuroleptic now available in a long-acting injectable form (25–50 mg intramuscularly every 2 weeks). Concomitant use of a benzodiazepine (eg, lorazepam, 2 mg orally twice daily) may permit reduction of the required dosage of oral or parenteral antipsychotic drug.

Intravenous haloperidol, the neuroleptic most commonly used by this route, is often used in critical care units in the management of agitated, delirious patients. Intravenous haloperidol should be given no faster than 1 mg/min to reduce cardiovascular side effects, such as torsades de pointes, and is associated with a lower risk of extrapyramidal side effects.

Side Effects

For both typical and atypical neuroleptic agents, a range of side effects has been reported. The most common anticholinergic side effects include dry mouth (which can lead to ingestion of caloric liquids and weight gain or hyponatremia), blurred near vision, urinary retention (particularly in elderly men with enlarged prostates), delayed gastric emptying, esophageal reflux, ileus, delirium, and precipitation of acute glaucoma in patients with narrow anterior chamber angles. Other autonomic effects include orthostatic hypotension and sexual dysfunction—problems in achieving erection, ejaculation (including retrograde ejaculation), and orgasm in men (approximately 50% of cases) and women (approximately 30%). Delay in achieving orgasm is often a factor in medication noncompliance. Electrocardiographic changes occur frequently, but clinically significant arrhythmias are much less common. Elderly patients and those with preexisting cardiac disease are at greater risk. The most frequently seen electrocardiographic changes include diminution of the T wave amplitude, appearance of prominent U waves, depression of the ST segment, and prolongation of the QT interval. Thioridazine has been given an FDA warning for dose-related QTc delay and risk of fatal cardiac arrhythmias. As noted above, ziprasidone can produce QTc prolongation. An ECG prior to treatment in some patients may be indicated. In some critical care patients, torsades de pointes has been associated with the use of high-dose intravenous haloperidol (usually > 30 mg/24 h).

Associations have been suggested between the atypical neuroleptics and new-onset diabetes, hyperlipidemia, QTc prolongation, and weight gain (Table 25-6). The FDA has particularly noted the risk of hyperglycemia and new-onset diabetes in this class of medication that is not related to weight gain. Monitoring of weight, fasting blood sugar and lipids prior to initiation of treatment and at regular intervals thereafter is an important part of medication monitoring. Neuroleptic medications in general may have metabolic and endocrine effects, including weight gain, hyperglycemia, infrequent temperature irregularities (particularly in hot weather), and water intoxication, that may be due to inappropriate

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ADH secretion. Lactation and menstrual irregularities are common (antipsychotic drugs should be avoided, if possible, in breast cancer patients because of potential trophic effects of elevated prolactin levels on the breast). Both antipsychotic and antidepressant drugs inhibit sperm motility. Bone marrow depression and cholestatic jaundice occur rarely; these are hypersensitivity reactions, and they usually appear in the first 2 months of treatment. They subside on discontinuance of the drug. There is cross-sensitivity among all of the phenothiazines, and a drug from a different group should be used when allergic reactions occur.

Table 25-6. Adverse factors associated with atypical antipsychotics.

  Weight Gain Hyperlipidemia New-Onset Diabetes QTc Prolongation1
Clozapine +++ + + +/-
Olanzapine +++ + + +/-
Risperidone ++ Unclear data Unclear data +
Quetiapine ++ Unclear data Unclear data ++
Ziprasidone +/- +++
1QTc prolongation is a side effect of many medications and suggests a possible risk for arrhythmia. Among atypical neuroleptics, only ziprasidone carries a special warning regarding the risk of QTc prolongation.
Adapted from Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care 2004;27:596.

Clozapine is associated with a 1.6% risk of agranulocytosis (higher in persons of Ashkenazi Jewish ancestry), and its use must be strictly monitored with weekly blood counts during the first 6 months of treatment, with monitoring every other week thereafter. Discontinuation of the medication requires weekly monitoring of the white blood cell count for 1 month. Recently, clozapine has been associated with fatal myocarditis and is contraindicated in patients with severe heart disease. In addition, clozapine lowers the seizure threshold and has many side effects, including sedation, hypotension, increased liver enzyme levels, hypersalivation, respiratory arrest, weight gain, and changes in both the ECG and the EEG.

Photosensitivity, retinopathy, and hyperpigmentation are associated with use of fairly high dosages of chlorpromazine and thioridazine. The appearance of particulate melanin deposits in the lens of the eye is related to the total dose given, and patients on long-term medication should have periodic eye examinations. Teratogenicity has not been causally related to these drugs, but prudence is indicated particularly in the first trimester of pregnancy. The seizure threshold is lowered, but it is safe to use these medications in epileptics who take anticonvulsants.

The neuroleptic malignant syndrome (NMS) is a catatonia-like state manifested by extrapyramidal signs, blood pressure changes, altered consciousness, and hyperpyrexia; it is an uncommon but serious complication of neuroleptic treatment. Muscle rigidity, involuntary movements, confusion, dysarthria, and dysphagia are accompanied by pallor, cardiovascular instability, fever, pulmonary congestion, and diaphoresis and may result in stupor, coma, and death. The cause may be related to a number of factors, including poor dosage control of neuroleptic medication, affective illness, decreased serum iron, dehydration, and increased sensitivity of dopamine receptor sites. Lithium in combination with a neuroleptic drug may increase vulnerability, which is already increased in patients with an affective disorder. In most cases, the symptoms develop within the first 2 weeks of antipsychotic drug treatment. The syndrome may occur with small doses of the drugs. Intramuscular administration is a risk factor. Elevated creatine kinase and leukocytosis with a shift to the left are present early in about half of cases. Treatment includes controlling fever and providing fluid support. Dopamine agonists such as bromocriptine, 2.5–10 mg orally three times a day, and amantadine, 100–200 mg orally twice a day, have also been useful. Dantrolene, 50 mg intravenously as needed, is used to alleviate rigidity (do not exceed 10 mg/kg/d due to hepatotoxicity risk). There is ongoing controversy about the efficacy of these three agents as well as the use of calcium channel blockers and benzodiazepines. ECT has been used effectively in resistant cases. Clozapine has been used with relative safety and fair success as an antipsychotic drug for patients who have had NMS. The syndrome must be differentiated from acute lethal catatonia, malignant hyperthermia, neurotoxic syndromes (including AIDS), and a variety of other conditions such as viral encephalitis, Wilson's disease, central anticholinergic syndrome, and hypertonic states (eg, tetany, strychnine poisoning).

Akathisia is the most common (about 20%) so-called extrapyramidal symptom. It usually occurs early in treatment (but may persist after neuroleptics are discontinued) and is frequently mistaken for anxiety or exacerbation of psychosis. It is characterized by a subjective desire to be in constant motion followed by an inability to sit or stand still and consequent pacing. It may include suicidality or feelings of fright, rage, terror, or sexual torment. Insomnia is often present. In all cases, reevaluate the dosage requirement or the type of neuroleptic drug. One should inquire also about cigarette smoking, which in women has been associated with an increased incidence of akathisia. Antiparkinsonism drugs such as trihexyphenidyl, 2–5 mg orally three times daily, or benztropine mesylate, 1–2 mg twice daily, may be helpful. In resistant cases, symptoms may be alleviated by propranolol, 30–80 mg/d orally, diazepam, 5 mg three times daily, or amantadine, 100 mg orally three times daily.

Acute dystonias usually occur early, although a late (tardive) occurrence is reported in patients (mostly men after several years of therapy) who previously had early severe dystonic reactions and a mood disorder (see below). Younger patients are at higher risk for acute dystonias. The most common signs are bizarre muscle spasms of the head, neck, and tongue. Frequently present are torticollis, oculogyric crises, swallowing or chewing difficulties, and masseter spasms. Laryngospasm is particularly dangerous. Back, arm, or leg muscle spasms are occasionally reported. Diphenhydramine, 50 mg intramuscularly, is effective for the acute crisis; one should then give benztropine mesylate, 2 mg orally twice daily, for several weeks, and then discontinue gradually, since few of the extrapyramidal symptoms require long-term use of the antiparkinsonism drugs (all of which are about equally efficacious—though trihexyphenidyl tends to be mildly stimulating and benztropine mildly sedating).

Drug-induced parkinsonism is indistinguishable from idiopathic parkinsonism, but it is reversible, occurs later in treatment than the preceding extrapyramidal symptoms, and in some cases appears after neuroleptic withdrawal. The condition includes the typical signs of apathy and reduction of facial and arm movements (akinesia, which can mimic depression), festinating

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gait, rigidity, loss of postural reflexes, and pill-rolling tremor. AIDS patients seem particularly vulnerable to extrapyramidal side effects. High-potency neuroleptics often require antiparkinsonism drugs (see Table 24-6). The neuroleptic dosage should be reduced, and immediate relief can be achieved with antiparkinsonism drugs in the same dosages as above. After 4–6 weeks, these antiparkinsonism drugs can often be discontinued with no recurrent symptoms. In any of the extrapyramidal symptoms, amantadine, 100–400 mg daily, may be used instead of the antiparkinsonism drugs. Neuroleptic-induced catatonia is similar to catatonic stupor with rigidity, drooling, urinary incontinence, and cogwheeling. It usually responds slowly to withdrawal of the offending medication and use of antiparkinsonism agents.

Tardive dyskinesia is a syndrome of abnormal involuntary stereotyped movements of the face, mouth, tongue, trunk, and limbs that may occur after months or (usually) years of treatment with neuroleptic agents. The syndrome affects 20–35% of patients who have undergone long-term neuroleptic therapy. Predisposing factors include older age, many years of treatment, cigarette smoking, and diabetes mellitus. Pineal calcification is higher in this condition by a margin of 3:1. There are no known differences among any of the antipsychotic drugs in the development of this syndrome. Although the atypical antipsychotics appear to offer lower risk, the CATIE study did not address the long-term effects of these drugs.

Early manifestations include fine worm-like movements of the tongue at rest, difficulty in sticking out the tongue, facial tics, increased blink frequency, or jaw movements of recent onset. Later manifestations may include bucco-linguo-masticatory movements, lip smacking, chewing motions, mouth opening and closing, disturbed gag reflex, puffing of the cheeks, disrupted speech, respiratory distress, or choreoathetoid movements of the extremities (the last being more prevalent in younger patients). The symptoms do not necessarily worsen and in rare cases may lessen even though neuroleptic drugs are continued. The dyskinesias do not occur during sleep and can be voluntarily suppressed for short periods. Stress and movements in other parts of the body will often aggravate the condition.

Early signs of dyskinesia must be differentiated from those reversible signs produced by ill-fitting dentures or nonneuroleptic drugs such as levodopa, TCAs, antiparkinsonism agents, anticonvulsants, and antihistamines. Other neurologic conditions such as Huntington's chorea can be differentiated by history and examination.

The emphasis should be on prevention. Use the least amount of neuroleptic drug necessary to mute the psychotic symptoms; atypical drugs appear to offer less risk as first line agents. Detect early manifestations of dyskinesias. When these occur, stop anticholinergic drugs and gradually discontinue neuroleptic drugs. Weight loss and cachexia sometimes appear on withdrawal of neuroleptics. In an indeterminate number of cases, the dyskinesias will remit. Keep the patient off the drugs until reemergent psychotic symptoms dictate their resumption, at which point they are restarted in low doses and gradually increased until there is clinical improvement. If neuroleptic drugs are restarted, clozapine and olanzapine appear to offer less risk of recurrence. The use of adjunctive agents such as benzodiazepines or lithium may help directly or indirectly by allowing control of psychotic symptoms with a low dosage of neuroleptics. If the dyskinesic syndrome recurs and it is necessary to continue neuroleptic drugs to control psychotic symptoms, informed consent should be obtained. Benzodiazepines, buspirone (in doses of 15–60 mg/d), phosphatidylcholine, clonidine, calcium channel blockers, vitamin E, and propranolol all have had limited usefulness in treating the dyskinetic side effects.

B. Social

Environmental considerations are most important in the individual with a chronic illness, who usually has a history of repeated hospitalizations, a continued low level of functioning, and symptoms that never completely remit. Family rejection and work failure are common. In these cases, board and care homes staffed by personnel experienced in caring for psychiatric patients are most important. There is frequently an inverse relationship between stability of the living situation and the amounts of required antipsychotic drugs, since the most salutary environment is one that reduces stimuli. Nonresidential self-help groups such as Recovery, Inc., should be utilized whenever possible. They provide a setting for sharing, learning, and mutual support and are frequently the only social involvement with which this type of patient is comfortable. Vocational rehabilitation and work agencies (eg, Goodwill Industries, Inc.) provide assessment, training, and job opportunities at a level commensurate with the person's clinical condition.

C. Psychological

The need for psychotherapy varies markedly depending on the patient's current status and history. In a person with a single psychotic episode and a previously good level of adjustment, supportive psychotherapy may help the patient reintegrate the experience, gain some insight into antecedent problems, and become a more self-observant individual who can recognize early signs of stress. Insight-oriented psychotherapy is often counterproductive in this type of disorder. Research suggests that cognitive behavioral therapy—in conjunction with medication management—may have some efficacy in the treatment of symptoms of schizophrenia. Cognitive behavioral therapy for schizophrenia involves helping the individual challenge their psychotic thinking and alter their response to hallucinations. Family therapy should be given concomitantly to help alleviate the patient's stress and to assist relatives in coping with the patient.

D. Behavioral

Behavioral techniques (see above) are most frequently used in therapeutic settings such as day treatment centers,

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but there is no reason why they cannot be incorporated into family situations or any therapeutic setting. Many behavioral techniques are used unwittingly (eg, positive reinforcement—whether it be a word of praise or an approving nod—after some positive behavior), and with some careful thought this approach can be a powerful instrument for helping a person learn behaviors that will facilitate social acceptance. Music from portable cassette players with earphones is one of many ways to divert the patient's attention from auditory hallucinations.

Prognosis

In any psychosis, in the large majority of patients the prognosis is excellent for alleviation of positive symptoms such as hallucinations or delusions treated with medication. Negative symptoms such as diminished affect and sociability are much more difficult to treat but appear responsive to atypical antipsychotics. Unavailability of structured work situations and lack of family therapy are two other reasons why the prognosis is so guarded in such a large percentage of schizophrenic patients. Psychosis connected with a history of serious drug abuse has a guarded prognosis because of the central nervous system damage, usually from the drugs themselves and associated medical illnesses.

Chandran GJ et al: Neuroleptic malignant syndrome: case report and discussion. CMAJ 2003;169:439.

Eisendrath SJ, Chamberlain J: Psychiatric problems. In: Current Diagnosis and Treatment in Critical Care, 2nd ed. Bongard FS, Sue DY (editors). McGraw-Hill, 2002.

Freedman R: Schizophrenia. N Engl J Med 2003;349:1738.

Koro CE et al: Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population-based nested case-control study. BMJ 2002;325:243.

Lieberman JA et al: Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1286.

Wang PS et al: Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 2005; 353:2335.

Mood Disorders (Depression & Mania)

Essentials of Diagnosis

Present in most depressions:

  • Lowered mood, varying from mild sadness to intense feelings of guilt, worthlessness, and hopelessness.

  • Difficulty in thinking, including inability to concentrate, ruminations, and lack of decisiveness.

  • Loss of interest, with diminished involvement in work and recreation.

  • Somatic complaints such as headache; disrupted, lessened, or excessive sleep; loss of energy; change in appetite; decreased sexual drive.

  • Anxiety.

Present in some severe depressions:

  • Psychomotor retardation or agitation.

  • Delusions of a hypochondriacal or persecutory nature.

  • Withdrawal from activities.

  • Physical symptoms of major severity, eg, anorexia, insomnia, reduced sexual drive, weight loss, and various somatic complaints.

  • Suicidal ideation.

Present in mania:

  • Mood ranging from euphoria to irritability.

  • Sleep disruption.

  • Hyperactivity.

  • Racing thoughts.

  • Grandiosity.

  • Variable psychotic symptoms.

General Considerations

Depression is extremely common, with up to 30% of primary care patients having depressive symptoms. Depression may be the final expression of (1) genetic factors (neurotransmitter dysfunction), (2) developmental problems (personality problems, childhood events), or (3) psychosocial stresses (divorce, unemployment). It frequently presents in the form of somatic complaints with negative medical workups. Although sadness and grief are normal responses to loss, depression is not. Patients experiencing normal grief tend to produce sympathy and sadness in the clinician caregiver; depression often produces frustration and irritation in the clinician. Grief is usually accompanied by intact self-esteem, whereas depression is marked by a sense of guilt and worthlessness.

Mania is often combined with depression and may occur alone, together with mania in a mixed episode, or in cyclic fashion with depression.

Clinical Findings

In general, there are four major types of depressions, with similar symptoms in each group.

A. Adjustment Disorder with Depressed Mood

Depression may occur in reaction to some identifiable stressor or adverse life situation, usually loss of a person by death (grief reaction), divorce, etc; financial reversal (crisis); or loss of an established role, such as being needed. Anger is frequently associated with the loss, and this in turn often produces a feeling of guilt. The disorder occurs within 3 months of the stressor

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and causes significant impairment in social or occupational functioning. The symptoms range from mild sadness, anxiety, irritability, worry, lack of concentration, discouragement, and somatic complaints to the more severe symptoms of the next group.

B. Depressive Disorders

The subclassifications include major depressive disorder and dysthymia.

1. Major depressive disorder

A major depressive disorder (eg, “endogenous” unipolar disorder, melancholia) consists of at least one episode of serious mood depression that occurs at any time of life. Many consider a physiologic or metabolic aberration to be causative. Complaints vary widely but most frequently include a loss of interest and pleasure (anhedonia), withdrawal from activities, and feelings of guilt. Also included are inability to concentrate, some cognitive dysfunction, anxiety, chronic fatigue, feelings of worthlessness, somatic complaints (unidentifiable somatic complaints frequently indicate depression), loss of sexual drive, and thoughts of death. Diurnal variation with improvement as the day progresses is common. Vegetative signs that frequently occur are insomnia, anorexia with weight loss, and constipation. Occasionally, severe agitation and psychotic ideation (paranoid thinking, somatic delusions) are present. These symptoms are more common in depressed persons who are older than 50 years. Paranoid symptoms may range from general suspiciousness to ideas of reference with delusions. The somatic delusions frequently revolve around feelings of impending annihilation or hypochondriacal beliefs (eg, that the body is rotting away with cancer). Hallucinations are uncommon.

Subcategories include major depression with atypical features characterized by hypersomnia, overeating, lethargy, and rejection sensitivity. Major depression with a seasonal onset (seasonal affective disorder) is a dysfunction of circadian rhythms that occurs more commonly in the winter months and is believed to be due to decreased exposure to full-spectrum light. Common symptoms include carbohydrate craving, lethargy, hyperphagia, and hypersomnia. Major depression with postpartum onset usually occurs 2 weeks to 6 months postpartum.

Most women (up to 80%) experience some mild letdown of mood in the postpartum period. For some of these (10–15%), the symptoms are more severe and similar to those usually seen in serious depression, with an increased emphasis on concerns related to the baby (obsessive thoughts about harming it or inability to care for it). When psychotic symptoms occur, there is frequently associated sleep deprivation, volatility of behavior, and manic-like symptoms. Postpartum psychosis is much less common (< 2%), often occurs within the first 2 weeks, and requires early and aggressive management. Biologic vulnerability with hormonal changes and psychosocial stressors all play a role. The chances of a second episode are about 25% and may be reduced with prophylactic treatment.

2. Dysthymia

Dysthymia is a chronic depressive disturbance. Sadness, loss of interest, and withdrawal from activities over a period of 2 or more years with a relatively persistent course is necessary for this diagnosis. Generally, the symptoms are milder but longer-lasting than those in a major depressive episode.

3. Premenstrual dysphoric disorder

Depressive symptoms during the late luteal phase of the menstrual cycles may occur throughout the year.

C. Bipolar Disorders

Bipolar disorders consist of episodic mood shifts into mania, major depression, hypomania, and mixed mood states. The ability of bipolar disorder to mimic aspects of many other Axis I disorders and a high comorbidity with substance abuse can make the initial diagnosis of bipolar disorder difficult.

1. Mania

A manic episode is a mood change characterized by elation with hyperactivity, over involvement in life activities, increased irritability, flight of ideas, easy distractibility, and little need for sleep. The overenthusiastic quality of the mood and the expansive behavior initially attract others, but the irritability, mood lability with swings into depression, aggressive behavior, and grandiosity usually lead to marked interpersonal difficulties. Activities may occur that are later regretted, eg, excessive spending, resignation from a job, a hasty marriage, sexual acting out, and exhibitionistic behavior, with alienation of friends and family. Atypical manic episodes can include gross delusions, paranoid ideation of severe proportions, and auditory hallucinations usually related to some grandiose perception. The episodes begin abruptly (sometimes precipitated by life stresses) and may last from several days to months. Spring and summer tend to be the peak periods. Generally, the manic episodes are of shorter duration than the depressive episodes. In almost all cases, the manic episode is part of a broader bipolar (manic-depressive) disorder. Patients with four or more discrete episodes of a mood disturbance in 1 year are called “rapid cyclers.” (Substance abuse, particularly cocaine, can mimic rapid cycling.) These patients have a higher incidence of hypothyroidism. Manic patients differ from patients with schizophrenia in that the former use more effective interpersonal maneuvers, are more sensitive to the social maneuvers of others, and are more able to utilize weakness and vulnerability in others to their own advantage. Creativity has been positively correlated with mood disorders, but the best work done is between episodes of mania and depression.

2. Cyclothymic disorders

These are chronic mood disturbances with episodes of depression and hypomania. The symptoms must have at least a 2-year duration and are milder than those that occur in depressive or manic episodes. Occasionally, the symptoms will escalate into a full-blown manic or depressive episode, in which case reclassification as bipolar I or bipolar II disorder would be warranted.

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D. Mood Disorders Secondary to Illness and Drugs

Any illness, severe or mild, can cause significant depression. Conditions such as rheumatoid arthritis, multiple sclerosis, and chronic heart disease are particularly likely to be associated with depression, as are other chronic illnesses. Hormonal variations clearly play a role in some depressions. Varying degrees of depression occur at various times in schizophrenic disorders, central nervous system disease, and organic mental states. Alcohol dependency frequently coexists with serious depression.

The classic model of drug-induced depression occurs with the use of reserpine, both in a clinical and a neurochemical sense. Corticosteroids and oral contraceptives are commonly associated with affective changes. Antihypertensive medications such as methyldopa, guanethidine, and clonidine have been associated with the development of depressive syndromes, as have digitalis and antiparkinsonism drugs (eg, levodopa). It is unusual for β-blockers to produce depression when given for short periods, such as in the treatment of performance anxiety. Sustained use of β-blockers for medical conditions such as hypertension may produce depression in some patients, although the literature is unclear on this subject. It is also unclear whether non-lipid-soluble β-blockers are less likely to be associated with depression than lipid-soluble ones. Infrequently, disulfiram and anticholinesterase drugs may be associated with symptoms of depression. All stimulant use results in a depressive syndrome when the drug is withdrawn. Alcohol, sedatives, opiates, and most of the psychedelic drugs are depressants and, paradoxically, are often used in self-treatment of depression.

Differential Diagnosis

Since depression may be a part of any illness—either reactively or as a secondary symptom—careful attention must be given to personal life adjustment problems and the role of medications (eg, reserpine, corticosteroids, levodopa). Schizophrenia, partial complex seizures, organic brain syndromes, panic disorders, and anxiety disorders must be differentiated. Subtle thyroid dysfunction must be ruled out.

Complications

The longer the depression continues, the more crystallized it becomes—particularly when there is an element of secondary reinforcement. The most important complication is suicide, which often includes some elements of aggression. Suicide rates in the general population vary from 9 per 100,000 in Spain to 20 per 100,000 in the United States to 58 per 100,000 in Hungary. In individuals with depression, the lifetime risk rises to 10–15%. Men tend toward successful suicide, particularly in older age groups, whereas women make more attempts with lower mortality rates. An increased suicide rate is being observed in the younger population, ages 15–35. Patients with cancer, respiratory illnesses, AIDS, and those being maintained on hemodialysis have higher suicide rates. Alcohol is a significant factor in many suicide attempts.

There are four major groups of people who make suicide attempts. By far the greatest number fall into the category of situational problems (the despair of ordinary people). There is often great ambivalence—they don't really want to die, but they don't want to go on as before either. A suicide attempt in such cases may be an impulsive or aggressive act not associated with significant depression. In other cases a suicide attempt is clearly a stratagem for controlling or hurting others.

The high-risk groups are those with severe depressions or psychotic illnesses. Severe depression may be due to exogenous conditions (eg, AIDS, whose victims have a suicide rate over 30 times that of the general population) or endogenous conditions (eg, panic disorders). This group also includes those who may not be diagnosed as having depression but who are overwhelmed by a serious stressful situation (eg, the man charged with child molestation who hangs himself in his cell). Anxiety, panic, and fear are major findings in suicidal behavior. A patient may seem to make a dramatic improvement, but the lifting of depression may be due to the patient's decision to commit suicide. Those with psychotic illness tend not to verbalize their concerns, are unpredictable, and are often successful but make up only a small percentage of the total.

Suicide is ten times more prevalent in patients with schizophrenia than in the general population, and jumping from bridges is a more common means of attempted suicide by schizophrenics than by others. In one study of 100 jumpers, 47% had schizophrenia.

The immediate goal of psychiatric evaluation is to assess the current suicidal risk and the need for hospitalization versus outpatient management. The intent is less likely to be truly suicidal, for example, if small amounts of poison or drugs were ingested or scratching of wrists was superficial, if the act was performed in the vicinity of others or with early notification of others, or if the attempt was arranged so that early detection would be anticipated. Alcohol, hopelessness, delusional thoughts, and complete or nearly complete loss of interest in life or ability to experience pleasure are all positively correlated with suicide attempts. Other risk factors are previous attempts, a family history of suicide, medical or psychiatric illness (eg, anxiety, depression, psychosis), male sex, older age, contemplation of violent methods, a humiliating social stressor, and drug use (including long-term sedative or alcohol use), which contributes to impulsiveness or mood swings. Successful treatment of the patient at risk for suicide cannot be achieved if the patient continues to abuse drugs.

The patient's current mood status is best evaluated by direct evaluation of plans and concerns about the future, personal reactions to the attempt, and thoughts about the reactions of others. The patient's immediate resources should be assessed—people who can be significantly involved (most important), family support, job situation, financial resources, etc.

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If hospitalization is not indicated (eg, gestures, impulsive attempts; see above), the clinician must formulate and institute a treatment plan or make an adequate referral. Medication should be dispensed in small amounts to at-risk patients. Although TCAs and SSRIs are associated with an equal incidence of suicide attempts, the risk of successful suicide is higher with TCA overdose. Guns and drugs should be removed from the patient's household. Driving should be interdicted until the patient improves. The problem is often worsened by the long-term complications of the suicide attempt, eg, brain damage due to hypoxia, peripheral neuropathies caused by staying for long periods in one position causing nerve compressions, and medical or surgical problems such as esophageal strictures and tendon dysfunctions.

The reasons for self-mutilation, most commonly wrist cutting (but also autocastration, autoamputation, and autoenucleation, which are associated with psychoses), may be very different from the reasons for a suicide attempt. The initial treatment plan, however, should presume suicidal ideation, and conservative treatment should be initiated.

Sleep disturbances in the depressions are discussed below.

Treatment of Depression

A. Medical

Depression associated with reactive disorders usually does not call for drug therapy and can be managed by psychotherapy and the passage of time. In severe cases—particularly when vegetative signs are significant and symptoms have persisted for more than a few weeks—antidepressant drug therapy is often effective. Drug therapy is also suggested by a family history of major depression in first-degree relatives or a past history of prior episodes.

The antidepressant drugs may be conveniently classified into three groups: (1) the newer antidepressants, including the SSRIs and bupropion, venlafaxine, nefazodone, and mirtazapine, (2) the TCAs and clinically similar drugs, and (3) the MAO inhibitors (see Table 25-8). These groups are described in greater detail below. ECT is effective in all types of depression and will also rapidly resolve a manic episode. It is also very effective for postpartum depression. Megavitamin treatment, acupuncture, and electrosleep are of unproved usefulness for any psychiatric condition.

Hospitalization is necessary if suicide is a major consideration or if complex treatment modalities are required.

Drug selection is influenced by the history of previous responses if that information is available. If a relative has responded to a particular drug, this suggests that the patient may respond similarly. If no background information is available, a drug such as sertraline, 50 mg daily, or desipramine, starting with 50 mg and gradually increasing to 150 mg daily, can be selected and a full trial instituted. The medication trial should be monitored with patient assessments every 1–2 weeks until week 6. If successful, the medication should be continued for 6–12 months at the full therapeutic dose before tapering is considered. Antidepressants should usually be continued indefinitely at full dosage in individuals with more than two episodes after age 40 or one episode after age 50. If the response is inadequate despite a diagnosis supported by review and adequate drug levels, a second drug (eg, citalopram) should be substituted and given a trial. If the second drug fails, augmentation with lithium (eg, 600–900 mg/d) or thyroid medication (eg, liothyronine, 25 mcg/d) should be considered. Dysthymia is also treated in this way. The Agency for Health Care Policy and Research has produced clinical practice guidelines that outline one algorithm of treatment decisions (Figure 25-3).

Psychotic depression can be treated with a combination of an antipsychotic such as olanzapine and an antidepressant such as an SSRI at their usual doses. Mifepristone may have specific and early activity against psychotic depression.

Major depression with atypical features or seasonal onset can be treated with an MAO inhibitor or an SSRI with good results.

Stimulants such as dextroamphetamine (5–30 mg/d) and methylphenidate (10–45 mg/d) have enjoyed a resurgence of interest for the short-term treatment of depression in medically ill and geriatric patients. Their 50–60% efficacy rate is slightly below that of other agents. The stimulants are notable for rapid onset of action (hours) and a paucity of side effects (tachycardia, agitation) in most patients. They are usually given in two divided doses early in the day (eg, 7 AM and noon) so as to avoid interfering with sleep. These agents may also be useful as adjunctive agents in refractory depression.

Caution: Depressed patients may have suicidal thoughts, and the amount of drug dispensed should be appropriately controlled. The older TCAs have a narrow therapeutic index, and one advantage of the newer drugs is their wider margin of safety. Nonetheless, even with newer agents, because of the possibility of suicidality early in antidepressant treatment, close follow-up is indicated. This is particularly true in the treatment of children and adolescents where suicide risk has received special scrutiny. In all cases of pharmacologic management of depressed states, caution is indicated until the risk of suicide is considered minimal.

Figure 25-3. Overview of treatment for depression. (Reproduced, with permission, from

Agency for Health Care Policy and Research: Depression in Primary Care. Vol. 2: Treatment of Major Depression. United States Department of Health and Human Services, 1993.

)

1. SSRIs and atypical antidepressants

The chief advantages of these agents are that they do not generally cause significant cardiovascular or anticholinergic side effects, as do the TCAs. The SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and its enantiomer escitalopram. The atypical antidepressants are bupropion, which appears to exert its effect through the dopamine neurotransmitter system; venlafaxine and duloxetine, both of which inhibit the reuptake of both serotonin and norepinephrine; nefazodone, which blocks the reuptake of serotonin but also inhibits the 5-HT2 postsynaptic receptors; and

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mirtazapine, which selectively blocks presynaptic α2-adrenergic receptors and enhances both noradrenergic and serotonergic transmission. All of these antidepressants are effective in the treatment of depression, both typical and atypical. The SSRI drugs have been effective in the treatment of panic attacks, bulimia, generalized anxiety disorder, OCD, and PTSD. They do not seem to be as clearly effective in some pain syndromes as the TCAs, although venlafaxine may have some efficacy in the treatment of neuropathic pain, and duloxetine is FDA-approved for the treatment of diabetic peripheral neuropathy.

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Most of the drugs in this group tend to be activating and are given in the morning so as not to interfere with sleep. Some patients, however, may have sedation, requiring that the drug be given at bedtime. This reaction occurs most commonly with paroxetine, fluvoxamine, and mirtazapine. The SSRIs can be given in once-daily dosage. Nefazodone and venlafaxine are usually given twice daily. Bupropion and venlafaxine are available in extended-release formulations and can be given once daily. There is usually some delay in response; fluoxetine, for example, requires 2–6 weeks to act in depression, 4–8 weeks to be effective in panic disorder, and 6–12 weeks in treatment of OCD. The starting dose (10–20 mg) is the usual daily dose for depression, while OCD may require up to 80 mg daily. Some patients, particularly the elderly, may tolerate and benefit from as little as 10 mg/d or every other day. The other SSRIs have shorter half-lives and a lesser effect on hepatic enzymes, which reduces their impact on the metabolism of other drugs (thus not increasing significantly the serum concentrations of other drugs as much as fluoxetine). The shorter half-lives also allow for more rapid clearing if adverse side effects appear. Venlafaxine appears to be more effective with doses greater than 200 mg/d, although some individuals respond to doses as low as 75 mg/d.

The side effects common to all of these drugs are headache, nausea, tinnitus, insomnia, and nervousness. Akathisia has been common with the SSRIs; other extrapyramidal symptoms (eg, dystonias) have occurred infrequently but particularly in withdrawal states. Sexual side effects of erectile dysfunction, retrograde ejaculation, and dysorgasmia are very common with the SSRIs. Antidotes to SSRI-induced sexual dysfunction are occasionally helpful. Sildenafil, 25–50 mg 1 hour prior to sexual activity, can improve erectile dysfunction in some patients. Cyproheptadine, 4 mg orally prior to sexual activity, may be helpful in countering drug-induced anorgasmia. Adjunctive bupropion (75–150 mg daily) may also help with restoring erectile function. The SSRIs are strong serotonin uptake blockers and may in high dosage or in combination with MAO inhibitors, including the antiparkinsonian drug selegiline, cause a “serotonin syndrome.” This syndrome is manifested by rigidity, hyperthermia, autonomic instability, myoclonus, confusion, delirium, and coma. This syndrome can be a particularly troublesome problem in the elderly. Several cases of angina have been reported in association with SSRIs. However, current research indicates that SSRIs are safer agents to use than TCAs in patients with cardiac disease. A study has found that sertraline is a safe and effective antidepressant treatment in patients with acute myocardial infarction or unstable angina.

Withdrawal syndromes have been reported for the SSRIs and venlafaxine. These include dysphoric mood, agitation, and a flu-like state. These medications should be discontinued gradually over a period of weeks or months to reduce the risk of withdrawal phenomena.

Fluoxetine, fluvoxamine, sertraline, venlafaxine, and citalopram in customary antidepressant doses do not appear to increase the risk of major fetal malformation when used during pregnancy. Recent evidence, however, has suggested that paroxetine may be associated with a twofold increased risk of cardiac abnormalities. Postpartum developmental effects are thought to be minimal, but this question calls for ongoing investigation. Peripartum effects may be a of concern and are documented anecdotally in the literature. The risk of depression to the mother and fetus needs to be part of the discussion with the patient about treatment options. The decision to use SSRIs and other psychotropic agents during pregnancy and postpartum must be based on a thorough risk-benefit analysis for each individual. A recent review of the literature on antidepressants levels in breast-feeding mothers and their infants suggests that nortriptyline, paroxetine, and sertraline are least likely to lead to detectable levels in infants.

Venlafaxine is reported to be well-tolerated without significant anticholinergic or cardiovascular side effects. Nausea, nervousness, and profuse sweating appear to be the major side effects. Venlafaxine appears to have few drug-drug interactions. It does require monitoring of blood pressure because dose-related hypertension may develop in some individuals. Nefazodone appears to lack the anticholinergic effects of the TCAs and the agitation sometimes induced by SSRIs. Nefazodone should not be given with terfenadine, astemizole, or cisapride. (Terfenadine and astemizole are not commercially available in the United States.) Because nefazodone inhibits the liver's cytochrome P450 3A4 isoenzymes, concurrent use of these medications can lead to serious QT prolongation, ventricular tachycardia, or death. Through the same mechanism of enzyme inhibition, nefazodone can elevate cyclosporine levels sixfold to tenfold. Nefazodone has been given an FDA warning because it has been implicated in liver failure in rare cases. Pretreatment and ongoing monitoring of liver enzymes are indicated.

Mirtazapine is thought to enhance central noradrenergic and serotonergic activity with minimal sexual side effects compared with the SSRIs. Its action as a potent antagonist of histaminergic receptors may make it a useful agent for patients with depression and insomnia. Its most common adverse side effects include somnolence, increased appetite, weight gain, lipid abnormalities, and dizziness. There have been reports of agranulocytosis in 2 of 2796 patients. Although it is metabolized by P450 isoenzymes, it is not an inhibitor of this system. It is given in a single dose at bedtime starting at 15 mg and increasing in 15-mg increments every week or every other week up to 45 mg.

Duloxetine may also result in small increases in blood pressure. Common side effects include dry mouth, dizziness, and fatigue. Inhibitors of 1A2 and 2D6 may increase duloxetine levels with a risk of toxicity.

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2. Tricyclic antidepressants and clinically similar drugs

These drugs were the mainstay of drug therapy for depression for many years. They have also been effective in panic disorders, pain syndromes, and anxiety states. Specific ones have been effective in OCD (clomipramine), enuresis (imipramine), psychotic depression (amoxapine), and reduction of craving in cocaine withdrawal (desipramine).

TCAs are characterized more by their similarities than by their differences. There is a lag in clinical response for up to several weeks, partly as a result of side effects that prevent rapid increase in dosage and partly because of their neurotransmitter effects. They tend to affect both serotonin and norepinephrine reuptake; some drugs act mainly on the former and others principally on the latter neurotransmitter system. Individuals receiving the same dosages vary markedly in therapeutic drug levels achieved (elderly patients require smaller doses), and determination of plasma drug levels is helpful when clinical response has been disappointing. Nortriptyline is usually effective when plasma levels are between 50 and 150 ng/mL; imipramine at plasma levels of 200–250 ng/mL; and desipramine at plasma levels of 100–250 ng/mL. High blood levels are not more effective than moderate levels and may be counterproductive (eg, delirium, seizures). Patients with gastrointestinal side effects benefit from plasma level monitoring to assess absorption of the drug. Most TCAs can be given in a single dose at bedtime, starting at fairly low doses (eg, nortriptyline 25 mg orally) and increasing by 25 mg every several days as tolerated until the therapeutic response is achieved (eg, nortriptyline, 100–150 mg) or to maximum dose if necessary (eg, nortriptyline, 150 mg). The most common cause of treatment failure is an inadequate trial. A full trial consists of giving maximum daily dosage for at least 6 weeks. To reach maximum dosage, the trial encompasses a total of about 8 weeks. Because of marked anticholinergic and sedating side effects, clomipramine is started at a low dose (25 mg/d orally) and increased slowly in divided doses up to 100 mg/d, held at that level for several days, and then gradually increased as necessary up to 250 mg/d. Any of the TCA-like drugs should be started at very low doses (eg, 10–25 mg/d) and increased slowly in the treatment of panic disorder.

The TCAs have anticholinergic side effects to varying degrees (amitriptyline 100 mg is equivalent to atropine 5 mg). One must be particularly wary of the effect in elderly men with prostatic hyperplasia. The anticholinergic effects also predispose to other medical problems such as heat stroke or dental problems from xerostomia. Orthostatic hypotension is fairly common, may not remit with time, and may predispose to falls and hip fractures in the elderly. Cardiac effects of the TCAs are functions of the anticholinergic effect, direct myocardial depression (quinidine-like effect), and interference with adrenergic neurons. These factors may produce altered rate, rhythm, and contractility, particularly in patients with preexisting cardiac disease, such as bundle-branch or bifascicular block. Electrocardiographic changes range from benign ST segment and T wave changes and sinus tachycardia to a variety of complex and serious arrhythmias, the latter requiring a change in medication. Because TCAs have class I antiarrhythmic effects, they should be used with caution in patients with ischemic heart disease, arrhythmias, or conduction disturbances. SSRIs or the atypical antidepressants may be better initial choices for this population. TCAs lower the seizure threshold so this is of particular concern in patients with a propensity for seizures (eg, previous head injury, alcohol withdrawal). Loss of libido and erectile, ejaculatory, and orgasmic dysfunction are fairly common and can compromise compliance. Trazodone rarely causes priapism, which requires treatment within 12 hours (epinephrine 1:1000 injected into the corpus cavernosum). Delirium, agitation, and mania are infrequent complications. Sudden discontinuation of some of these drugs can produce “cholinergic rebound,” manifested by headaches and nausea with abdominal cramps. Overdoses of TCAs are often serious because of the narrow therapeutic index and quinidine-like effects (see Chapter 39).

3. Monoamine oxidase inhibitors

The MAO inhibitors are generally used as third-line drugs for depression (after a failure of SSRIs, TCAs, or the atypical antidepressants) because of the dietary and other restrictions required (see below and Table 25-7). They should be considered third-line drugs for refractory panic disorder and depression. This may change in the future, as MAO inhibitor skin patches are expected to become available. They bypass the gastrointestinal tract so that dietary restrictions will not be necessary.

MAO inhibitors are administered in gradual stepwise dosage and may be given in the morning or evening, depending upon their effect on sleep. They tend to take effect in a fairly low dosage range (Table 25-8). Blood levels are not congruent with therapeutic response.

The MAO inhibitors commonly cause symptoms of orthostatic hypotension (which may persist) and sympathomimetic effects of tachycardia, sweating, and tremor. Nausea, insomnia (often associated with intense afternoon drowsiness), and sexual dysfunction

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are common. Trazodone, 25–75 mg orally at bedtime, may ameliorate the MAO-induced insomnia. Central nervous system effects include agitation and toxic psychoses. Dietary limitations (Table 25-7) and abstinence from drug products containing phenylpropanolamine, phenylephrine, meperidine, dextromethorphan, and pseudoephedrine are mandatory for MAO-A type inhibitors (those marketed for treatment of depression), since the reduction of available monoamine oxidase leaves the patient vulnerable to exogenous amines (eg, tyramine in foodstuffs).

Table 25-7. Principal dietary restrictions in MAOI use.

  1. Cheese, except cream cheese and cottage cheese and fresh yogurt
  2. Fermented or aged meats such as bologna, salami
  3. Broad bean pods such as Chinese bean pods
  4. Liver of all types
  5. Meat and yeast extracts
  6. Red wine, sherry, vermouth, cognac, beer, ale
  7. Soy sauce, shrimp paste, sauerkraut
MAOI = monoamine oxidase inhibitor.

Table 25-8. Commonly used antidepressants.

Drug Usual Daily Oral Dose (mg) Usual Daily Maximum Dose (mg) Sedative Effects1 Anticholinergic Effects1 Cost per Unit Cost for 30 Days Treatment Based on Maximum Dosage2
SSRIs
Fluoxetine (Prozac, Sarafem) 5–40 80 < 1 < 1 $2.67/20 mg $320.40
Fluvoxamine (Luvox) 100–300 300 1 < 1 $2.64/100 mg $237.60
Nefazodone (Serzone) 300–600 600 2 < 1 $1.60/200 mg $144.00
Paroxetine (Paxil) 20–30 50 1 1 $2.73/20 mg $163.80
Sertraline (Zoloft) 50–150 200 < 1 < 1 $2.90/100 mg $174.00
Citalopram (Celexa) 20 40 < 1 1 $2.53/40 mg $75.90
Escitalopram (Lexapro) 10 20 < 1 1 $2.81/20 mg $84.30
TRICYCLIC AND CLINICALLY SIMILAR COMPOUNDS
Amitriptyline (Elavil) 150–250 300 4 4 $1.16/150 mg $69.60
Amoxapine (Asendin) 150–200 400 2 2 $1.67/100 mg $200.40
Clomipramine (Anafranil) 100 250 3 3 $1.47/75 mg $157.20
Desipramine (Norpramin) 100–250 300 1 1 $1.50/100 mg $135.00
Doxepin (Sinequan) 150–200 300 4 3 $1.00/100 mg $90.00
Imipramine (Tofranil) 150–200 300 3 3 $1.22/50 mg $219.60
Maprotiline (Ludiomil) 100–200 300 4 2 $0.93/75 mg $111.60
Nortriptyline (Aventyl, Pamelor) 100–150 150 2 2 $1.62/50 mg $148.20
Protriptyline (Vivactil) 15–40 60 1 3 $1.58/10 mg $248.40
MONOAMINE OXIDASE INHIBITORS
Phenelzine (Nardil) 45–60 90 $0.60/15 mg $108.00
Tranylcypromine (Parnate) 20–30 50 $0.80/10 mg $120.00
OTHER COMPOUNDS
Venlafaxine XR (Effexor) 150–225 225 1 < 1 $3.52/75 mg $316.80
Duloxetine (Cymbalta) 40 60 2 3 $3.84/60 mg $115.30
Mirtazapine (Remeron) 15–45 45 4 2 $2.80/30 mg $165.46
Bupropion XL (Wellbutrin XL) 3003 4503   < 1 $4.65/300 mg $245.21
Bupropion SR (Wellbutrin SR) 300 4004 < 1 $3.76/200 mg $226.12
Trazodone (Desyrel) 100–300 400 4 < 1 $0.73/100 mg $87.60
Trimipramine (Surmontil) 75–200 200 4 4 $2.96/100 mg $177.60
14 = strong effect; 1 = weak effect.
2Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: Red Book Update, Vol. 25, No. 5, May 2006. AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.
3Wellbutrin XL is a once-daily form of bupropion. Bupropion is still available as immediate release, and, if used, no single dose should exceed 150 mg.
4200 mg twice daily.
SSRIs = serotonin selective reuptake inhibitors.

Treatment for a resultant hypertensive crisis has been the same as for pheochromocytoma (see Chapter 26), but there have been reports of success with nifedipine, 10 mg chewed and placed under the tongue, normalizing blood pressure in 1–5 minutes. The restrictions on the proscribed foodstuffs and sympathomimetic drugs are in effect during treatment and for 2–3 weeks after cessation of therapy. Termination of therapy with MAO inhibitors may be associated with anxiety, agitation, cognitive slowing, and headache. Very gradual withdrawal and short-term benzodiazepine therapy will ameliorate symptoms.

4. Switching and combination therapy

If the therapeutic response has been poor after an adequate trial with the chosen drug, the diagnosis should be reassessed. Assuming that the trial has been adequate and the diagnosis is correct, a trial with a drug from another group is appropriate. In switching from one group to another, an adequate “washout time” must be allowed. This is critical in certain situations—eg, in switching from an MAO inhibitor to a TCA, allow 2–3 weeks between stopping one drug and starting another; in switching from an SSRI to an MAO inhibitor, allow 4–5 weeks. In switching within groups—eg, from one TCA to another (amitriptyline to desipramine, etc)—no washout time is needed, and one can rapidly decrease the dosage of one drug while increasing the other. Combining two antidepressants requires caution and is usually reserved for refractory patients after psychiatric consultation.

However, in any of the three groups, one can augment the antidepressant drug if the therapeutic response has been less than satisfactory. Psychiatric consultation may be helpful in selecting the augmenting agent. Lithium is an excellent augmentation agent for the 25–40% of depressed patients who do not respond to an adequate trial of an antidepressant. Half of these patients will respond to the addition of lithium (600–900 mg/d) with an enhanced antidepressant effect.

5. Maintenance and tapering

When clinical relief of symptoms is obtained, medication is continued for 12 months in the effective maintenance dosage, which is the dosage required in the acute stage. The full dosage should be continued indefinitely when the individual has a first episode before age 20 or after age 50, is over age 40 with two episodes, or has had three episodes at any age. Major depression should often be considered as a chronic disease. If the medication is being tapered, it should be done gradually over several months, monitoring closely for relapse.

6. Drug interactions

Interactions with other drugs are listed in Table 25-9.

7. Electroconvulsive therapy

ECT causes a generalized central nervous system seizure (peripheral convulsion is not necessary) by means of electric current. The key objective is to exceed the seizure threshold, which can be accomplished by a variety of means. Electrical stimulation is more reliable and simpler than the use of chemical convulsants. The mechanism of action is not known, but it is thought to involve major neurotransmitter responses at the cell membrane. Current insufficient to cause a seizure produces no therapeutic benefit.

ECT is the most effective (about 70–85%) treatment of severe depression—particularly the delusions and agitation commonly seen with depression in the elderly. It is indicated when medical conditions preclude the use of antidepressants or in cases of nonresponsiveness to these medications. Comparative controlled studies of ECT in severe depression show that it is more effective than chemotherapy. It is also effective in the manic disorders and psychoses during pregnancy (when drugs may be contraindicated). It has not been shown to be helpful in chronic schizophrenic disorders, and it is generally not used in acute schizophrenic episodes unless drugs are not effective and it is urgent that the psychosis be controlled (eg, a catatonic stupor complicating an acute medical condition).

The most common side effects are memory disturbance and headache. Memory loss or confusion is usually related to the number and frequency of ECT treatments and proper oxygenation during treatment. Unilateral ECT is associated with less memory loss than bilateral ECT. Some memory loss is occasionally permanent, but most memory faculties return to full capacity within several weeks. There have been reports that lithium administration concurrent with ECT resulted in greater memory loss. Before anesthesia was used, spinal compression fractures and severe anticipatory anxiety were common.

Increased intracranial pressure is a serious contraindication. Other problems such as cardiac disorders, aortic aneurysms, bronchopulmonary disease, and venous thrombosis are relative contraindications and must be evaluated in light of the severity of the medical problem versus the need for ECT. Serious complications arising from ECT occur in less than 1 in 1000 cases. Most of these problems are cardiovascular or respiratory in nature (eg, aspiration of gastric contents). Poor patient understanding and lack of acceptance of the technique by the public are the biggest obstacles to the use of ECT.

Table 25-9. Antidepressant drug interactions with other drugs.

Drug Effects
Tricyclic and other non-MAOI antidepressants
  Antacids Decreased absorption of antidepressants
  Anticoagulants Increased hypoprothrombinemic effect
  Cimetidine Increased antidepressant blood levels and psychosis
  Clonidine Decreased antihypertensive effect
  Digitalis Increased incidence of heart block
  Disulfiram Increased antidepressant blood levels
  Guanethidine Decreased antihypertensive effect
  Haloperidol Increased clomipramine levels
  Insulin Decreased blood sugar
  Lithium Increased lithium levels with fluoxetine
  Methyldopa Decreased antihypertensive effect
  Other anticholinergic drugs Marked anticholinergic responses
  Phenytoin Increased blood levels
  Procainamide Decreased ventricular conduction
  Procarbazine Hypertensive crisis
  Propranolol Increased hypotension
  Quinidine Decreased ventricular conduction
  Rauwolfia derivatives Increased stimulation
  Sedatives Increased sedation
  Sympathomimetic drugs Increased pressor effect
  Terfenadine,1 astemizole,1 cisapride Torsades de pointes
MAOIs
  Antihistamines Increased sedation
  Belladonna-like drugs Increased blood pressure
  Dextromethorphan Same as meperidine
  Guanethidine Decreased blood pressure
  Insulin Decreased blood sugar
  Levodopa Increased blood pressure
  Meperidine Increased agitation, seizures, coma, death
  Methyldopa Decreased blood pressure
  Pseudoephedrine Hypertensive crisis (increased blood pressure)
  Reserpine Increased blood pressure and temperature
  Succinylcholine Increased neuromuscular blockade
  Sulfonylureas Decreased blood sugar
  Sympathomimetic drugs Increased blood pressure
1Terfenadine and astemizole are not commercially available in the United States.
MAOIs = monoamine oxidase inhibitors.

8. Phototherapy

Phototherapy is used in major depression with seasonal onset. It consists of exposure (at a 3-foot distance) to a light source of 2500 lux for 2 hours daily. Light visors are an adaptation that provides greater mobility and an adjustable light intensity. The price of these full-spectrum light sources ranges

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between $300 and $400. The dosage varies, with some patients requiring morning and night exposure. One effect is alteration of biorhythm through melatonin mechanisms.

9. Experimental treatments

In preliminary studies, transcranial magnetic stimulation appears to be effective in nonpsychotic depression. Vagal nerve stimulation has shown promise in extremely refractory cases and has recently been approved by the FDA.

B. Psychological

It is seldom possible to engage an individual in penetrating psychotherapeutic endeavors during the acute stage of a severe depression. While medications may be taking effect, a supportive approach to strengthen existing defenses and appropriate consideration of the patient's continuing need to function at work, to engage in recreational activities, etc, are necessary as the severity of the depression lessens. If the patient is not seriously depressed, it is often quite appropriate to initiate intensive psychotherapeutic efforts, since flux periods are a good time to effect change. A catharsis of repressed anger and guilt may be beneficial. Therapy during or just after the acute stage may focus on coping techniques, with some practice of alternative choices. When lack of self-confidence and identity problems are factors in the depression, individual psychotherapy can be oriented to ways of improving self-esteem, increasing assertiveness, and lessening dependency. Interpersonal psychotherapy for depression has shown efficacy in the treatment of acute depression, helping patients master interpersonal stresses and develop new coping strategies. Cognitive behavioral therapy for depression addresses patients' patterns of negative thoughts, called cognitive distortions, that lead to feelings of depression and anxiety. Treatment usually includes homework assignments such as keeping a journal of cognitive distortions and of positive responses to them. As previously noted, numerous studies have shown that the combination of drug therapy plus interpersonal psychotherapy or cognitive behavioral therapy is more effective than either modality alone. It is usually helpful to involve the spouse or other significant family members early in treatment. Mindfulness based cognitive therapy is a new form of therapy showing promise in reducing depression recurrence. This therapy incorporates meditation and teaches patients to distance themselves from depressive thinking.

C. Social

Flexible use of appropriate social services can be of major importance in the treatment of depression. Since alcohol is often associated with depression, early involvement in alcohol treatment programs such as Alcoholics Anonymous can be important to future success (see Alcohol Dependency and Abuse, below). The structuring of daily activities during severe depression is often quite difficult for the patient, and loneliness is often a major factor. The help of family,

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employer, or friends is often necessary to mobilize the patient who experiences no joy in daily activities and tends to remain uninvolved and to deteriorate. Insistence on sharing activities will help involve the patient in simple but important daily functions. In some severe cases, the use of day treatment centers or support groups of a specific type (eg, mastectomy groups) is indicated. It is not unusual for a patient to have multiple legal, financial, and vocational problems requiring legal and vocational assistance.

D. Behavioral

When depression is a function of self-defeating coping techniques such as passivity, the role-playing approach can be useful. Behavioral techniques, including desensitization, may be used in problems such as phobias where depression is a by-product. When depression is a regularly used interpersonal style, behavioral counseling to family members or others can help in extinguishing the behavior in the patient.

Treatment of Mania

Acute manic or hypomanic symptoms will respond to lithium or valproic acid after several days of treatment, but it is increasingly common to use atypical neuroleptics as adjunctive treatment or monotherapy. High-potency benzodiazepines (eg, clonazepam) may also be useful adjuncts in managing acute cases. Some schizoaffective disorders and some cases of so-called schizophrenia are probably atypical bipolar affective disorder, for which lithium treatment may be effective.

A. Neuroleptics

Acute manic symptoms of agitation and psychosis may be treated initially with the atypical antipsychotic olanzapine, (eg, 5–20 mg orally), risperidone (2–3 mg orally), or aripiprazole (15–30 mg) in conjunction with a benzodiazepine if indicated. Alternatively, when behavioral control is immediately necessary, olanzapine in an injectable form (2.5–10 mg intramuscularly) or haloperidol, 5–10 mg orally or intramuscularly repeated as needed until symptoms subside, may be used. The dosage of the neuroleptic may be gradually reduced after lithium or another mood stabilizer is started (see below). Olanzapine is approved as a maintenance treatment for bipolar disorder.

B. Clonazepam

Clonazepam can be an alternative or adjunct to a neuroleptic in controlling acute behavioral symptoms. Clonazepam has the advantage of causing no extrapyramidal side effects. Although 1–2 mg orally every 4–6 hours may be effective, up to 16 mg/d may be necessary.

C. Lithium

As a prophylactic drug for bipolar affective disorder, lithium significantly decreases the frequency and severity of both manic and depressive attacks in about 70% of patients. A positive response is more predictable if the patient has a low frequency of episodes (no more than two per year with intervals free of psychopathology). A positive response occurs more frequently in individuals who have blood relatives with a diagnosis of manic or hypomanic attacks. Patients who swing rapidly back and forth between manic and depressive attacks (at least four cycles per year) usually respond poorly to lithium prophylaxis initially, but some improve with continued long-term treatment. Carbamazepine (see below) has been used with success in this group.

In addition to its use in manic states, lithium is sometimes useful in the prophylaxis of recurrent unipolar depressions (perhaps undiagnosed bipolar disorder). Lithium may ameliorate nonspecific aggressive behaviors and dyscontrol syndromes. The dosages are the same as used in bipolar disorder. Most patients with bipolar disease can be managed long-term with lithium alone, although some will require continued or intermittent use of a neuroleptic, antidepressant, or carbamazepine. An excellent resource for information pertaining to lithium is the Information Centers, Madison Institute of Medicine, 7617 Mineral Point Road, Suite 300, Madison, WI 53717–1914.

Before treatment, the clinical workup should include a medical history and physical examination; complete blood count; T4, thyroid-stimulating hormone, blood urea nitrogen (BUN), serum creatinine, and serum electrolyte determinations; urinalysis; and electrocardiography in patients over age 45 or with a history of cardiac disease.

1. Dosage

Lithium carbonate is generally prescribed in the 300 mg unit. In a small minority of patients, a slow release form or units of different dosage may be required. Lithium citrate is available as a syrup. The dosage is that required to maintain blood levels in the therapeutic range. For acute attacks, this ranges from 1 to 1.5 mEq/L. Although there is controversy about the optimal long-term maintenance dose, many clinicians reduce the acute level to 0.6–1 mEq/L in order to reduce side effects. The dose required to meet this need will vary in different individuals. For acute mania, doses of 1200–1800 mg/d are generally recommended. Augmentation of antidepressants is usually achieved with half of these doses. Once-a-day dosage is acceptable, but most patients have less nausea when they take the drug in divided doses with meals.

Lithium is readily absorbed, with peak serum levels occurring within 1–3 hours and complete absorption in 8 hours. Half of the total body lithium is excreted in 18–24 hours (95% in the urine). Blood for lithium levels should be drawn 12 hours after the last dose. Serum levels should be measured 5–7 days after initiation of treatment and changes in dose. For maintenance treatment, lithium levels should be monitored initially every 1–2 months but may be measured every 6–12 months in stable, long-term patients. Levels should be monitored more closely when there is any condition

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that causes volume depletion (eg, diarrhea, dehydration, use of diuretics).

2. Side effects

Mild gastrointestinal symptoms (take lithium with food), fine tremors (treat with propranolol, 20–60 mg/d orally, only if persistent), slight muscle weakness, and some degree of somnolence are early side effects that are usually transient. Moderate polyuria (reduced renal responsiveness to ADH) and polydipsia (associated with increased plasma renin concentration) are often present. Potassium administration can blunt this effect, as may once-daily dosing of lithium. Weight gain (often a result of calories in fluids taken for polydipsia) and leukocytosis not due to infection are fairly common.

Other side effects include goiter (3%; often euthyroid), hypothyroidism (10%; concomitant administration of lithium and iodide or lithium and carbamazepine enhances the hypothyroid and goitrogenic effect of either drug), changes in the glucose tolerance test toward a diabetes-like curve, nephrogenic diabetes insipidus (usually resolving about 8 weeks after cessation of lithium therapy), nephrotic syndrome, edema, folate deficiency, and pseudotumor cerebri (ophthalmoscopy is indicated if there are complaints of headache or blurred vision). A metallic taste, hair loss, and Raynaud's phenomenon have been reported in a few cases. Thyroid and kidney function should be checked at 3- to 4-month intervals. Most of these side effects subside when lithium is discontinued; when residual side effects exist, they are usually not serious. Most clinicians treat lithium-induced hypothyroidism (more common in women) with thyroid hormone while continuing lithium therapy. Hypercalcemia and elevated parathyroid hormone levels occur in some patients. Electrocardiographic abnormalities (principally T wave flattening or inversion) may occur during lithium administration but are not of major clinical significance. Sinoatrial block may occur, particularly in the elderly. Other drugs that prolong intraventricular conduction, such as TCAs, must be used cautiously in conjunction with lithium. Lithium impairs ventilatory function in patients with airway obstruction. Lithium alone does not have a significant effect on sexual function, but when combined with benzodiazepines (clonazepam in most symptomatic patients) it causes sexual dysfunction in about 50% of men. Lithium may precipitate or exacerbate psoriasis in some patients.

Patients receiving long-term lithium therapy may have cogwheel rigidity and, occasionally, other extrapyramidal signs. Lithium potentiates the parkinsonian effects of haloperidol. Long-term lithium therapy has also been associated with a relative lowering of the level of memory and perceptual processing (affecting compliance in some cases). Some impairment of attention and emotional reactivity has also been noted. Lithium-induced delirium with therapeutic lithium levels is an infrequent complication usually occurring in the elderly and may persist for several days after serum levels have become negligible. Encephalopathy has occurred in patients receiving combined lithium and neuroleptic therapy and in those who have cerebrovascular disease, thus requiring careful evaluation of patients who develop neurotoxic signs at subtoxic blood levels.

Some reports have suggested that the long-term use of lithium may have adverse effects on renal function (with interstitial fibrosis or tubular atrophy). A rise in serum creatinine levels is an indication for in-depth evaluation of renal function and consideration of alternative treatments if the individual can tolerate a change. Incontinence has been reported in women, apparently related to changes in bladder cholinergic-adrenergic balance.

Prospective studies suggest that the overall risk imposed by lithium in pregnancy may be overemphasized. However, lithium exposure in early pregnancy does increase the frequency of congenital anomalies, especially Ebstein's and other major cardiovascular anomalies. For women who take psychotropic medications who become pregnant, the decision to make a change in medication is complex and requires informed consent regarding the relative risks to the patient and fetus. Indeed, the risk of untreated bipolar disorder carries its own risks for pregnancy. Formula feeding should be considered in mothers taking lithium, since concentration in breast milk is one-third to half that in serum.

Frank toxicity usually occurs at blood lithium levels above 2 mEq/L. Because sodium and lithium are reabsorbed at the same loci in the proximal renal tubules, any sodium loss (diarrhea, use of diuretics, or excessive perspiration) results in increased lithium levels. Symptoms and signs include vomiting and diarrhea, the latter exacerbating the problem since more sodium is lost and more lithium is absorbed. Other symptoms and signs, some of which may not be reversible, include tremors, marked muscle weakness, confusion, dysarthria, vertigo, choreoathetosis, ataxia, hyperreflexia, rigidity, lack of coordination, myoclonus, seizures, opisthotonos, and coma. Toxicity is more severe in the elderly, who should be maintained on slightly lower serum levels. Lithium overdosage may be accidental or intentional or may occur as a result of poor monitoring.

Patients with massive ingestions of lithium or blood lithium levels above 2.5 mEq/L should be treated with induced emesis and gastric lavage. If renal function is normal, osmotic and saline diuresis increases renal lithium clearance. Urinary alkalinization is also helpful, since sodium bicarbonate decreases lithium reabsorption in the proximal tubule, as does acetazolamide as well. Aminophylline potentiates the diuretic effect by increasing the clearance of lithium. Drugs affecting the distal loop have no effect on lithium reabsorption. Blood lithium levels above 2.5 mEq/L (confirmed by cerebrospinal fluid lithium levels) should be considered an indication for hemodialysis.

Compliance with lithium therapy is adversely affected by the loss of some hypomanic experiences valued by the patient. These include social extroversion and a sense of heightened enjoyment in many activities such as sex and business dealings, often with increased productivity in the latter.

3. Drug interactions

Patients receiving lithium should use diuretics with caution and only under close medical supervision. The thiazide diuretics cause increased

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lithium reabsorption from the proximal renal tubules, resulting in increased serum lithium levels (Table 25-10), and adjustment of lithium intake must be made to compensate for this. Reduce lithium dosage by 25–40% when the patient is receiving 50 mg of hydrochlorothiazide daily. Potassium-sparing diuretics (spironolactone, amiloride, triamterene) may also increase serum lithium levels and require careful monitoring of lithium levels. Loop diuretics (furosemide, ethacrynic acid, bumetanide) do not appear to alter serum lithium levels. Concurrent use of lithium and angiotensin-converting enzyme inhibitors requires a 50–75% reduction in lithium intake to achieve therapeutic lithium levels.

Table 25-10. Lithium interactions with other drugs.

Drug Effects
ACE inhibitors ↑ Lithium levels
Fluoxetine ↑ Lithium levels
Ibuprofen ↑ Lithium levels
Indomethacin ↑ Lithium levels
Methyldopa Rigidity, mutism, fascicular twitching
Osmotic diuretics (urea, mannitol) ↑ Lithium excretion
Phenylbutazone ↑ Lithium levels
Potassium-sparing diuretics (spironolactone, amiloride, triamterene) ↑ Lithium levels
Sodium bicarbonate ↑ Lithium excretion
Succinylcholine ↑ Duration of action of succinylcholine
Theophylline, aminophylline ↑ Lithium excretion
Thiazide diuretics ↑ Lithium levels
Valproic acid ↑ Lithium levels
COX-2 inhibitors ↑ Lithium levels
ACE = angiotensin-converting enzyme; COX-2 = cyclooxygenase-2.

D. Valproic Acid

Valproic acid (divalproex) is an antiseizure drug whose activity is at least partially related to GABA neurotransmission. It is a first-line treatment for mania because it has a broader index of safety than lithium. This issue is particularly important in AIDS or other medically ill patients prone to dehydration or malabsorption with wide swings in serum lithium levels. Valproic acid has also been used effectively in panic disorder and migraine headache. Treatment is often started at a dose of 750 mg/d orally in divided doses, and dosage is then titrated to achieve therapeutic serum levels. Oral loading in acutely manic bipolar patients in an inpatient setting (initiated at a dosage of 20 mg/kg/d) can safely achieve serum therapeutic levels in 2–3 days. Concomitant use of aspirin, carbamazepine, warfarin, or phenytoin may affect serum levels. Gastrointestinal symptoms are the main side effects. Liver function tests, complete blood counts, glucose levels, and weight should be monitored, and teratogenic effects are a concern.

E. Carbamazepine

Carbamazepine, an antiseizure drug that stabilizes the activity of cell membranes, has been used with increasing frequency in the treatment of bipolar patients who cannot be satisfactorily treated with lithium (nonresponsive, excessive side effects, or rapid cycling). It is often effective at 800–1600 mg/d orally. It has also been used in the treatment of resistant depressions, alcohol withdrawal, and hallucinations (in conjunction with neuroleptics) and in patients with behavioral dyscontrol or panic attacks. It suppresses some phases of kindling (see Stimulants) and has been used to treat residual symptoms in previous stimulant abusers (eg, PTSD with impulse control problems). Dose-related side effects include sedation and ataxia. Dosages start at 400–600 mg orally daily and are increased slowly to therapeutic levels. Skin rashes and a mild reduction in white count are common. SIADH occurs rarely. Nonsteroidal anti-inflammatory drugs (except aspirin), the antibiotics erythromycin and isoniazid, the calcium channel blockers verapamil and diltiazem (but not nifedipine), fluoxetine, propoxyphene, and cimetidine all increase carbamazepine levels. Carbamazepine can be effective in conjunction with lithium, although there have been reports of reversible neurotoxicity with the combination. Carbamazepine stimulates hepatic microsomal enzymes and so tends to decrease levels of haloperidol and oral contraceptives. It also lowers T4, free T4, and T3 levels. Cases of fetal malformation (particularly spina bifida) have been reported along with growth deficiency and developmental delay. Liver tests and complete blood counts should be monitored in patients taking carbamazepine. Oxcarbazepine, a derivative of carbamazepine, does not appear to induce its own metabolism and is associated with fewer drug interactions, although it may impose a higher risk of hyponatremia. FDA-approved for partial seizures, oxcarbazepine may have efficacy in acute mania. It appears to be a safer alternative to carbamazepine due to its lower risk of hepatotoxicity.

F. Newer Anticonvulsants

Lamotrigine is thought to inhibit neuronal sodium channels and the release of the excitatory amino acids, glutamate and aspartate. It is FDA approved for long-term maintenance of bipolar disorder. Two double-blind studies support its efficacy in the treatment of acute bipolar depression as adjunctive therapy or as monotherapy. Its metabolism is inhibited by coadministration

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of valproic acid—doubling its half-life—and accelerated by hepatic enzyme-inducing agents such as carbamazepine. More frequent mild side effects include headache, dizziness, nausea, and diplopia. Rash occurring in 10% of patients is an indication for immediate cessation of dosing, since lamotrigine has been associated with Stevens-Johnson syndrome (1:1000) and, rarely, toxic epidermal necrolysis. Dosing starts at 25–50 mg/d and is titrated upward slowly to decrease the likelihood of rash. Slower titration and a lower total dose are indicated for patients taking valproic acid. Topiramate, which has been labeled for use as an anticonvulsant, has been found to be effective in the adjunctive treatment of bipolar disorder in a series of open-label studies. It has the unique feature of promoting weight loss as a side effect. Other common side effects include somnolence, difficulty with memory, dizziness, and anxiety.

G. Calcium Channel Blockers

Calcium channel blockers (eg, verapamil) have been used in bipolar states that have failed to respond to lithium, carbamazepine, or valproic acid. This has come about with the realization that a number of drugs used in psychiatry (eg, lithium, antidepressants, neuroleptics, and carbamazepine) have calcium channel-blocking activity. There is also preliminary evidence that these drugs may be useful in the treatment of tardive dyskinesia and panic attacks. Verapamil may be safer than lithium or carbamazepine during pregnancy, although it decreases uterine contractility and must be discontinued before delivery.

Prognosis

Reactive depressions are usually time-limited, and the prognosis with treatment is good if a pathologic pattern of adjustment does not intervene. Major affective disorders frequently respond well to a full trial of drug treatment.

Mania and bipolar disorder have a good prognosis with adequate treatment.

Glassman AH et al: Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 2002; 288:701.

Nulman I et al: Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159:1889.

Nurnberg HG et al: Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA 2003;289:56.

Segal ZV et al: Challenges in preventing relapse in major depression. A report of a National Institute of Mental Health Workshop on state of the science of relapse prevention in major depression. J Affect Disord 2003;77:97.

Swartz HA et al: A pilot study of brief interpersonal psychotherapy for depression among women. Psychiatr Serv 2004;55: 448.

Williams M et al: Paroxetine (Paxil) and congenital malformations. CMAJ 2005;173:1320.

Sleep Disorders

Sleep consists of two distinct states as shown by electroencephalographic studies: (1) REM (rapid eye movement) sleep, also called dream sleep, D state sleep, paradoxic sleep, and (2) NREM (non-REM) sleep, also called S stage sleep, which is divided into stages 1, 2, 3, and 4 and is recognizable by different electroencephalographic patterns. Stages 3 and 4 are “delta” sleep. Dreaming occurs mostly in REM and to a lesser extent in NREM sleep.

Sleep is a cyclic phenomenon, with four or five REM periods during the night accounting for about one-fourth of the total night's sleep (1.5–2 hours). The first REM period occurs about 80–120 minutes after onset of sleep and lasts about 10 minutes. Later REM periods are longer (15–40 minutes) and occur mostly in the last several hours of sleep. Most stage 4 (deepest) sleep occurs in the first several hours.

Age-related changes in normal sleep include an unchanging percentage of REM sleep and a marked decrease in stage 3 and stage 4 sleep, with an increase in wakeful periods during the night. These normal changes, early bedtimes, and daytime naps play a role in the increased complaints of insomnia in older people. Variations in sleep patterns may be due to circumstances (eg, “jet lag”) or to idiosyncratic patterns (“night owls”) in persons who perhaps because of different “biologic rhythms” habitually go to bed late and sleep late in the morning. Creativity and rapidity of response to unfamiliar situations are impaired by loss of sleep. There are also rare individuals who have chronic difficulty in adapting to a 24-hour sleep-wake cycle (desynchronization sleep disorder), which can be resynchronized by altering exposure to light.

The three major sleep disorders are discussed below.

1. Dyssomnias (Insomnia)

Classification & Clinical Findings

Patients may complain of difficulty getting to sleep or staying asleep, intermittent wakefulness during the night, early morning awakening, or combinations of any of these. Transient episodes are usually of little significance. Stress, caffeine, physical discomfort, daytime napping, and early bedtimes are common factors.

Psychiatric disorders are often associated with persistent insomnia. Depression is usually associated with fragmented sleep, decreased total sleep time, earlier onset of REM sleep, a shift of REM activity to the first half of the night, and a loss of slow wave sleep—all of which are nonspecific findings. In manic disorders, sleeplessness is a cardinal feature and an important early sign of impending mania in bipolar cases. Total sleep time is decreased, with shortened REM latency and increased REM activity. Sleep-related panic attacks occur in the transition from stage 2 to stage 3

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sleep in some patients with a longer REM latency in the sleep pattern preceding the attacks.

Abuse of alcohol may cause or be secondary to the sleep disturbance. There is a tendency to use alcohol as a means of getting to sleep without realizing that it disrupts the normal sleep cycle. Acute alcohol intake produces a decreased sleep latency with reduced REM sleep during the first half of the night. REM sleep is increased in the second half of the night, with an increase in total amount of slow wave sleep (stages 3 and 4). Vivid dreams and frequent awakenings are common. Chronic alcohol abuse increases stage 1 and decreases REM sleep (most drugs delay or block REM sleep), with symptoms persisting for many months after the individual has stopped drinking. Acute alcohol or other sedative withdrawal causes delayed onset of sleep and REM rebound with intermittent awakening during the night.

Heavy smoking (more than a pack a day) causes difficulty falling asleep—apparently independently of the often associated increase in coffee drinking. Excess intake near bedtime of caffeine, cocaine, and other stimulants (eg, over-the-counter cold remedies) causes decreased total sleep time—mostly NREM sleep—with some increased sleep latency.

Sedative-hypnotics—specifically, the benzodiazepines, which are the most commonly prescribed drugs to promote sleep—tend to increase total sleep time, decrease sleep latency, and decrease nocturnal awakening, with variable effects on NREM sleep. Withdrawal causes just the opposite effects and results in continued use of the drug for the purpose of preventing withdrawal symptoms. Antidepressants decrease REM sleep (with marked rebound on withdrawal in the form of nightmares) and have varying effects on NREM sleep. The effect on REM sleep correlates with reports that REM sleep deprivation produces improvement in some depressions.

Persistent insomnias are also related to a wide variety of medical conditions, particularly delirium, pain, respiratory distress syndromes, uremia, asthma, and thyroid disorders. Adequate analgesia and proper treatment of medical disorders will reduce symptoms and decrease the need for sedatives.

Treatment

In general, there are two broad classes of treatment for insomnia, and the two may be combined: psychological (cognitive-behavioral) and pharmacologic. In situations of acute distress, such as a grief reaction, pharmacologic measures may be most appropriate. With primary insomnia, however, initial efforts should be psychologically based. This is particularly true in the elderly to avoid the potential adverse reactions of medications. The elderly population is at risk for complaints of insomnia because sleep becomes lighter and more easily disrupted with aging. Medical disorders that become more common with age may also predispose to insomnia.

A. Psychological

Psychological strategies should include educating the patient regarding good sleep hygiene: (1) Go to bed only when sleepy. (2) Use the bed and bedroom only for sleeping and sex. (3) If still awake after 20 minutes, leave the bedroom and only return when sleepy. (4) Get up at the same time every morning regardless of the amount of sleep during the night. (5) Discontinue caffeine and nicotine, at least in the evening if not completely. (6) Establish a daily exercise regimen. (7) Avoid alcohol as it may disrupt continuity of sleep. (8) Limit fluids in the evening. (9) Learn and practice relaxation techniques. A recent study suggests that cognitive behavioral therapy for insomnia was as effective as zolpidem with benefits sustained 1 year after treatment.

The clinician should also discuss any myths or misconceptions about sleep that the patient may hold.

B. Medical

When the above measures are insufficient, medications may be useful. Pharmacologic measures currently rely primarily on safe hypnotic medications that are difficult to overdose with. Lorazepam (0.5 mg orally nightly), temazepam (7.5–15 mg orally nightly) and the nonbenzodiazepine hypnotics, zolpidem (5–10 mg orally nightly), and zaleplon (5–10 mg orally nightly), are often effective for the elderly population and can be given in larger doses—twice what is prescribed for the elderly—in younger patients. A new nonbenzodiazepine hypnotic, eszopiclone (2–3 mg), is similar in action to zolpidem and zaleplon but dissimilar in that it is not restricted to short-term use. A lower dose of 1 mg is indicated in the elderly or those with hepatic impairment. It is important to note that short-acting agents like triazolam or zolpidem may lead to amnestic episodes if used on a daily ongoing basis. Longer-acting agents such as flurazepam (half-life of > 48 hours) may accumulate in the elderly and lead to cognitive slowing, ataxia, falls, and somnolence. In general, it is appropriate to use medications for short courses of 1–2 weeks. The medications described above have largely replaced barbiturates as hypnotic agents because of their greater safety in overdose and their lesser hepatic enzyme induction effects. Antihistamines such as diphenhydramine (25 mg nightly) or hydroxyzine (25 mg nightly) may also be useful for sleep, as they produce no pharmacologic dependency; their anticholinergic effects may, however, produce confusion or urinary symptoms in the elderly. Trazodone, an atypical antidepressant, is a non-habit-forming, effective sleep medication in lower than antidepressant doses (25–150 mg at bedtime). Priapism is a rare side effect requiring emergent treatment.

Triazolam has achieved popularity as a hypnotic drug because of its very short duration of action. Because it has been associated with dependency, transient psychotic reactions, anterograde amnesia, and rebound anxiety, it has been removed from the market in several European countries. If used, it must be prescribed only for short periods of time.

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2. Hypersomnias (Disorders of Excessive Sleepiness)

The hypersomnias are a more severe problem than insomnia.

Classification & Clinical Findings

A. Sleep Apnea

This disorder is characterized by cessation of breathing for at least 30 episodes (each lasting about 10 seconds) during the night. There are two types: obstructive and central. (See Chapter 9.)

B. Narcolepsy

Narcolepsy consists of a tetrad of symptoms: (1) Sudden, brief (about 15 minutes) sleep attacks that may occur during any type of activity; (2) cataplexy—sudden loss of muscle tone involving specific small muscle groups or generalized muscle weakness that may cause the person to slump to the floor, unable to move, often associated with emotional reactions and sometimes confused with seizure disorder; (3) sleep paralysis—a generalized flaccidity of muscles with full consciousness in the transition zone between sleep and waking; and (4) hypnagogic hallucinations, visual or auditory, which may precede sleep or occur during the sleep attack. The attacks are characterized by an abrupt transition into REM sleep—a necessary criterion for diagnosis. The disorder begins in early adult life, affects both sexes equally, and usually levels off in severity at about 30 years of age.

REM sleep behavior disorder, characterized by motor dyscontrol and often violent dreams during REM sleep, may be related to narcolepsy.

C. Kleine-Levin Syndrome

This syndrome, which occurs mostly in young men, is characterized by hypersomnic attacks three or four times a year lasting up to 2 days, with hyperphagia, hypersexuality, irritability, and confusion on awakening. It has often been associated with antecedent neurologic insults. It usually remits after age 40.

D. Nocturnal Myoclonus

Periodic lower leg movements occur during sleep with subsequent daytime sleepiness, anxiety, depression, and cognitive impairment.

Treatment

Narcolepsy can be managed by daily administration of a stimulant such as dextroamphetamine sulfate, 10 mg in the morning, with increased dosage as necessary. Modafinil is a schedule IV medication FDA-approved for treating the excessive daytime fatigue of narcolepsy. Usual dosing is 200 mg each morning. Its mechanism of action is unknown, yet it is thought to be less of an abuse risk than stimulants that are primarily dopaminergic. Common side effects include headache and anxiety; however, modafinil appears to be generally well tolerated. Modafinil may reduce the efficacy of cyclosporine, oral contraceptives, and other medications by inducing their hepatic metabolism. Imipramine, 75–100 mg daily, has been effective in treatment of cataplexy but not narcolepsy.

Nocturnal myoclonus and REM sleep behavior disorder can be treated with clonazepam with variable results. There is no treatment for Kleine-Levin syndrome.

Treatment of sleep apnea is discussed in Chapter 9.

3. Parasomnias (Abnormal Behaviors during Sleep)

These disorders are fairly common in children and less so in adults.

Classification & Clinical Findings

A. Sleep Terror

Sleep terror (pavor nocturnus) is an abrupt, terrifying arousal from sleep, usually in preadolescent boys although it may occur in adults as well. It is distinct from sleep panic attacks. Symptoms are fear, sweating, tachycardia, and confusion for several minutes, with amnesia for the event.

B. Nightmares

Nightmares occur during REM sleep; sleep terrors in stage 3 or stage 4 sleep.

C. Sleepwalking

Sleepwalking (somnambulism) includes ambulation or other intricate behaviors while still asleep, with amnesia for the event. It affects mostly children aged 6–12 years, and episodes occur during stage 3 or stage 4 sleep in the first third of the night and in REM sleep in the later sleep hours. Sleepwalking in elderly people may be a feature of dementia. Idiosyncratic reactions to drugs (eg, marijuana, alcohol) and medical conditions (eg, partial complex seizures) may be causative factors in adults.

D. Enuresis

Enuresis is involuntary micturition during sleep in a person who usually has voluntary control. Like other parasomnias, it is more common in children, usually in the 3–4 hours after bedtime, but is not limited to a specific stage of sleep. Confusion during the episode and amnesia for the event are common.

Treatment

Treatment for sleep terrors is with benzodiazepines (eg, diazepam, 5–20 mg at bedtime), since it will suppress stage 3 and stage 4 sleep. Somnambulism responds to the same treatment for the same reason, but simple safety measures should not be neglected. Enuresis

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may respond to imipramine, 50–100 mg at bedtime, although desmopressin nasal spray (an ADH preparation) has increasingly become the treatment of choice for nocturnal enuresis. Behavioral approaches (eg, bells that ring when the pad gets wet) have also been successful.

Brielmaier BD: Eszopiclone (Lunesta): a new nonbenzodiazepine hypnotic. Proc (Bayl Univ Med Cent) 2006;19:54.

Jacobs GD et al: Cognitive behavioral therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med 2004;164:1888.

Jindal RD et al: Maintenance treatment of insomnia: what can we learn from the depression literature? Am J Psychiatry 2004; 161:19.

Disorders of Aggression

Acts performed with the deliberate intent of causing physical harm to persons or property have a wide variety of causative features. Aggression and violence are symptoms rather than diseases, and most frequently they are not associated with an underlying medical condition. Clinicians are unable to predict dangerous behavior with greater than chance accuracy. Depression, schizophrenia, personality disorders, mania, paranoia, temporal lobe dysfunction, and organic mental states may be associated with acts of aggression. Impulse control disorders are characterized by physical abuse (usually of the aggressor's domestic partner or children), by pathologic intoxication, by impulsive sexual activities, and by reckless driving. Anabolic steroid usage by athletes has been associated with increased tendencies toward violent behavior.

In the United States, a significant proportion of all violent deaths are alcohol-related. The ingestion of even small amounts of alcohol can result in pathologic intoxication that resembles an acute organic mental condition. Amphetamines, crack cocaine, and other stimulants are frequently associated with aggressive behavior. Phencyclidine is a drug commonly associated with violent behavior that is occasionally of a bizarre nature, partly due to lowering of the pain threshold. Domestic violence and rape are much more widespread than previously recognized. Awareness of the problem is to some degree due to increasing recognition of the rights of women and the understanding by women that they do not have to accept abuse. Acceptance of this kind of aggressive behavior inevitably leads to more, with the ultimate aggression being murder—20–50% of murders in the United States occur within the family. Police are called in more domestic disputes than all other criminal incidents combined. Children living in such family situations frequently become victims of abuse.

Features of individuals who have been subjected to long-term physical or sexual abuse are as follows: trouble expressing anger, staying angry longer, general passivity in relationships, feeling “marked for life” with an accompanying feeling of deserving to be victimized, lack of trust, and dissociation of affect from experiences. They are prone to express their psychological distress with somatization symptoms, often pain complaints. They may also have symptoms related to posttraumatic stress, as discussed above. The clinician should be suspicious about the origin of any injuries not fully explained, particularly if such incidents recur.

Treatment

A. Psychological

Management of any violent individual includes appropriate psychological maneuvers. Move slowly, talk slowly with clarity and reassurance, and evaluate the situation. Strive to create a setting that is minimally disturbing, and eliminate people or things threatening to the violent individual. Do not threaten or abuse, and do not touch or crowd the person. Allow no weapons in the area (an increasing problem in hospital emergency departments). Proximity to a door is comforting to both the patient and the examiner. Use a negotiator the violent person can relate to comfortably. Food and drink are helpful in defusing the situation (as are cigarettes for those who smoke). Honesty is important. Make no false promises, bolster the patient's self-esteem, and continue to engage the subject verbally until the situation is under control. This type of individual does better with strong external controls to replace the lack of inner controls over the long term. Close probationary supervision and judicially mandated restrictions can be most helpful. There should be a major effort to help the individual avoid drug use (eg, Alcoholics Anonymous). Victims of abuse are essentially treated as any victim of trauma and, not infrequently, have evidence of PTSD.

B. Pharmacologic

Pharmacologic means are often necessary whether or not psychological approaches have been successful. This is particularly true in the agitated or psychotic patient. The drug of choice in psychotic aggressive states is haloperidol, 5–10 mg intramuscularly every hour until symptoms are alleviated. Benzodiazepine sedatives (eg, diazepam, 5 mg orally or intravenously every several hours) can be used for mild to moderate agitation, but an antipsychotic drug is preferred for management of the seriously violent and psychotic patient. Chronic aggressive states, particularly in retardation and brain damage (rule out causative organic conditions and medications such as anticholinergic drugs in amounts sufficient to cause confusion), have been ameliorated with propranolol, 40–240 mg/d orally, or pindolol, 5 mg twice daily orally (pindolol causes less bradycardia and hypotension). Carbamazepine and valproic acid are effective in the treatment of aggression and explosive disorders, particularly when associated with known or suspected brain lesions. Lithium and SSRIs are also effective for some intermittent explosive outbursts. Buspirone (10–45 mg/d orally) is helpful for aggression, particularly in mentally retarded patients.

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C. Physical

Physical management is necessary if psychological and pharmacologic means are not sufficient. It requires the active and visible presence of an adequate number of personnel (five or six) to reinforce the idea that the situation is under control despite the patient's lack of inner controls. Such an approach often precludes the need for actual physical restraint. When adequate personnel are not available, however, two people shielded by a mattress (single-bed size) can usually corner and subdue the patient without injury to anyone. Seclusion rooms and restraints should be used only when necessary (ambulatory restraints are an alternative), and the patient must then be observed at frequent intervals. Design of corridors and seclusion rooms is important. Narrow corridors, small spaces, and crowded areas exacerbate the potential for violence in an anxious patient.

D. Other

The treatment of victims (eg, battered women) is challenging and often complicated by their reluctance to leave the situation. Reasons for staying vary, but common themes include the fear of more violence because of leaving, the hope that the situation may ameliorate (in spite of steady worsening), and the financial aspects of the situation, which are seldom to the woman's advantage. Concerns for the children often finally compel the woman to seek help. An early step is to get the woman into a therapeutic situation that provides the support of others in similar straits. Al-Anon is frequently a valuable asset and quite appropriate when alcohol is a factor. The group can support the victim while she gathers strength to consider alternatives without being paralyzed by fear. Many cities now offer temporary emergency centers and counseling. Use the available resources, attend to any medical or psychiatric problems, and maintain a compassionate interest. Some states now require physicians to report injuries caused by abuse to police authorities.

Jonassen JA et al: Identification of physician and patient attributes that influence the likelihood of screening for intimate partner violence. Acad Med 2003;78(10 Suppl):S20.

McFarlane J et al: Abuse during pregnancy and femicide: urgent implications for women's health. Obstet Gynecol 2002;100: 27.

Walthan CN et al: Interventions for violence against women: scientific review. JAMA 2003;327:708.

Substance Use Disorders (Drug Dependency, Drug Abuse)

The term “drug dependency” is used in a broad sense here to include both addictions and habituations. It involves the triad of compulsive drug use referred to as drug addiction, which includes: (1) a psychological dependence or craving and the behavior involved in procurement of the drug; (2) physiologic dependence, with withdrawal symptoms on discontinuance of the drug; and (3) tolerance, ie, the need to increase the dose to obtain the desired effects. Drug dependency is a function of the amount of drug used and the duration of usage. The amount needed to produce dependency varies with the nature of the drug and the idiosyncratic nature of the user. The frequency of use is usually daily, and the duration is inevitably greater than 2–3 weeks. Polydrug abuse is very common. Transgenerational continuity of drug abuse is also common.

There is accumulating evidence that an impairment syndrome exists in many former (and current) drug users. It is believed that drug use produces damaged neurotransmitter receptor sites and that the consequent imbalance produces symptoms that may mimic other psychiatric illnesses. “Kindling”—repeated stimulation of the brain—renders the individual more susceptible to focal brain activity with minimal stimulation. Stimulants and depressants can produce kindling, leading to relatively spontaneous effects no longer dependent on the original stimulus. These effects may be manifested as mood swings, panic, psychosis, and occasionally overt seizure activity. The imbalance also results in personal nonproductivity: frequent job changes, marital problems, and generally erratic behavior. Patients with PTSD frequently have treated themselves with a variety of drugs. Chronic abusers of a wide variety of drugs exhibit cerebral atrophy on CT scans, a finding that may relate to the above symptoms. Early recognition is important, mainly to establish realistic treatment programs that are chiefly symptom-directed.

The clinician faces three problems with substance abuse: (1) the prescribing of substances such as sedatives, stimulants, or opioids that might produce dependency; (2) the treatment of individuals who have already abused drugs, most commonly alcohol; and (3) the detection of illicit drug use in patients presenting with psychiatric symptoms. The usefulness of urinalysis for detection of drugs varies markedly with different drugs and under different circumstances (pharmacokinetics is a major factor). Water-soluble drugs (eg, alcohol, stimulants, opioids) are eliminated in a day or so. Lipophilic substances (eg, barbiturates, tetrahydrocannabinol) appear in the urine over longer periods of time: several days in most cases, 1–2 months in chronic marijuana users. Sedative drug determinations are quite variable, amount of drug and duration of use being important determinants. False-positives can be a problem related to ingestion of some legitimate drugs (eg, phenytoin for barbiturates, phenylpropanolamine for amphetamines, chlorpromazine for opioids) and some foods (eg, poppy seeds for opioids, coca leaf tea for cocaine). Manipulations can alter the legitimacy of the testing. Dilution, either in vivo or in vitro, can be detected by checking urine specific gravity. Addition of ammonia, vinegar, or salt may invalidate the test, but

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odor and pH determinations are simple. Hair analysis can determine drug use over longer periods, particularly sequential drug-taking patterns. The sensitivity and reliability of such tests are considered good, and the method may be complementary to urinalysis.

Kosten TR et al: Management of drug and alcohol withdrawal. N Engl J Med 2003;348:1786.

Rigotti NA: Treatment of tobacco use and dependence. N Engl J Med 2002;346:506.

Thom B: From alcoholism treatment to the alcohol harm reduction strategy for England: an overview of alcohol policy since 1950. Am J Addict 2005;14:416.

Alcohol Dependency & Abuse (Alcoholism)

Essentials of Diagnosis

Major criteria:

  • Physiologic dependence as manifested by evidence of withdrawal when intake is interrupted.

  • Tolerance to the effects of alcohol.

  • Evidence of alcohol-associated illnesses, such as alcoholic liver disease, cerebellar degeneration.

  • Continued drinking despite strong medical and social contraindications and life disruptions.

  • Impairment in social and occupational functioning.

  • Depression.

  • Blackouts.

Other signs:

  • Alcohol stigmas: alcohol odor on breath, alcoholic facies, flushed face, scleral injection, tremor, ecchymoses, peripheral neuropathy.

  • Surreptitious drinking.

  • Unexplained work absences.

  • Frequent accidents, falls, or injuries of vague origin; in smokers, cigarette burns on hands or chest.

  • Laboratory tests: elevated values of liver function tests, mean corpuscular volume, serum uric acid, and triglycerides.

General Considerations

Alcoholism is a syndrome consisting of two phases: problem drinking and alcohol addiction. Problem drinking is the repetitive use of alcohol, often to alleviate anxiety or solve other emotional problems. Alcohol addiction is a true addiction similar to that which occurs following the repeated use of other sedative-hypnotics. Alcohol and other drug abuse patients have a much higher prevalence of lifetime psychiatric disorders. While male-to-female ratios in alcoholic treatment agencies remain at 4:1, there is evidence that the rates are converging. Women delay seeking help, and when they do they tend to seek it in medical or mental health settings. Adoption and twin studies indicate some genetic influence. Ethnic distinctions are important—eg, 40% of Japanese have aldehyde dehydrogenase deficiency and are more susceptible to the effects of alcohol. Depression is often present and should be evaluated carefully. The majority of suicides and intrafamily homicides involve alcohol. Alcohol is a major factor in rapes and other assaults.

There are several screening instruments that may help identify alcoholism. One of the most useful is the CAGE questionnaire (see Table 1-10).

Clinical Findings

A. Acute Intoxication

The signs of alcoholic intoxication are the same as those of overdosage with any other central nervous system depressant: drowsiness, errors of commission, psychomotor dysfunction, disinhibition, dysarthria, ataxia, and nystagmus. For a 70-kg person, an ounce of whiskey, a 4- to 6-oz glass of wine, or a 12-oz bottle of beer (roughly 15, 11, and 13 grams of alcohol, respectively) may raise the level of alcohol in the blood by 25 mg/dL. For a 50-kg person, the blood alcohol level would rise even higher (35 mg/dL) with the same consumption. Blood alcohol levels below 50 mg/dL rarely cause significant motor dysfunction. Intoxication as manifested by ataxia, dysarthria, and nausea and vomiting indicates a blood level above 150 mg/dL, and lethal blood levels range from 350 to 900 mg/dL. In severe cases, overdosage is marked by respiratory depression, stupor, seizures, shock syndrome, coma, and death. Serious overdoses are frequently due to a combination of alcohol with other sedatives.

B. Withdrawal

There is a wide spectrum of manifestations of alcoholic withdrawal, ranging from anxiety, decreased cognition, and tremulousness through increasing irritability and hyperreactivity to full-blown delirium tremens. Symptoms of mild withdrawal, including tremor, elevated vital signs, and anxiety, begin within about 8 hours after the last drink and usually have passed by day 3. Generalized seizures occur within the first 24–38 hours and are more prevalent in persons who have a history of withdrawal syndromes. Delirium tremens is an acute organic psychosis that is usually manifest within 24–72 hours after the last drink (but may occur up to 7–10 days later). It is characterized by mental confusion, tremor, sensory hyperacuity, visual hallucinations (often of snakes, bugs, etc), autonomic hyperactivity, diaphoresis, dehydration, electrolyte disturbances (hypokalemia, hypomagnesemia), seizures, and cardiovascular abnormalities. The acute withdrawal syndrome is often completely

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unexpected and occurs when the patient has been hospitalized for some unrelated problem and presents as a diagnostic problem. Suspect alcohol withdrawal in every unexplained delirium. The mortality rate from delirium tremens has steadily decreased with early diagnosis and improved treatment.

In addition to the immediate withdrawal symptoms, there is evidence of persistent longer-term ones, including sleep disturbances, anxiety, depression, excitability, fatigue, and emotional volatility. These symptoms may persist for 3–12 months, and in some cases they become chronic.

C. Alcoholic (Organic) Hallucinosis

This syndrome occurs either during heavy drinking or on withdrawal and is characterized by a paranoid psychosis without the tremulousness, confusion, and clouded sensorium seen in withdrawal syndromes. The patient appears normal except for the auditory hallucinations, which are frequently persecutory and may cause the patient to behave aggressively and in a paranoid fashion.

D. Chronic Alcoholic Brain Syndromes

These encephalopathies are characterized by increasing erratic behavior, memory and recall problems, and emotional instability—the usual signs of organic brain injury due to any cause. Wernicke-Korsakoff syndrome due to thiamine deficiency may develop with a series of episodes. Wernicke's encephalopathy consists of the triad of confusion, ataxia, and ophthalmoplegia (typically sixth nerve). Early recognition and treatment with thiamine can minimize damage. One of the possible sequelae is Korsakoff's psychosis, characterized by both anterograde and retrograde amnesia, with confabulation early in the course. Early recognition and treatment of the alcoholic with intravenous thiamine and B complex vitamins can minimize damage.

Differential Diagnosis

The differential diagnosis of problem drinking is essentially between primary alcoholism (when no other major psychiatric diagnosis exists) and secondary alcoholism, when alcohol is used as self-medication for major underlying psychiatric problems such as schizophrenia or affective disorder. The differentiation is important, since the latter group requires treatment for the specific psychiatric problem.

The differential diagnosis of alcohol withdrawal includes other sedative withdrawals and other causes of delirium. Acute alcoholic hallucinosis must be differentiated from other acute paranoid states such as amphetamine psychosis or paranoid schizophrenia. An accurate history is the most important differentiating factor. The history and laboratory test results (elevated liver function tests, increased mean corpuscular volume, increased serum uric acid and triglycerides, decreased serum potassium and magnesium) are the most important features in differentiating chronic organic brain syndromes due to alcohol from those due to other causes. The form of the brain syndrome is of little help—eg, chronic brain syndromes from lupus erythematosus may be associated with confabulation similar to that resulting from longstanding alcoholism.

Complications

The medical, economic, and psychosocial problems of alcoholism are staggering. The central and peripheral nervous system complications include chronic brain syndromes, cerebellar degeneration, cardiomyopathy, and peripheral neuropathies. Direct effects on the liver include cirrhosis, esophageal varices, and eventual hepatic failure. Indirect effects include protein abnormalities, coagulation defects, hormone deficiencies, and an increased incidence of liver neoplasms.

Fetal alcohol syndrome includes one or more of the following developmental defects in the offspring of alcoholic women: (1) low birth weight and small size with failure to catch up in size or weight (2) mental retardation, with an average IQ in the 60s, and (3) a variety of birth defects, with a large percentage of facial and cardiac abnormalities. The fetuses are very quiet in utero, and there is an increased frequency of breech presentations. There is a higher incidence of delayed postnatal growth and behavior development. The risk is appreciably higher the more alcohol ingested by the mother each day. Cigarette and marijuana smoking as well as cocaine use can produce similar effects on the fetus.

Treatment of Problem Drinking

A. Psychological

The most important consideration for the clinician is to suspect the problem early and take a nonjudgmental attitude, although this does not mean a passive one. The problem of denial must be faced, preferably with significant family members at the first meeting. This means dealing from the beginning with any enabling behavior of the spouse or other significant people. Enabling behavior allows the alcoholic to avoid facing the consequences of his or her behavior.

There must be an emphasis on the things that can be done. This approach emphasizes the fact that the clinician cares and strikes a positive and hopeful note early in treatment. Valuable time should not be wasted trying to find out why the patient drinks; come to grips early with the immediate problem of how to stop the drinking. Although total abstinence should be the ultimate goal, a harm reduction model indicates that gradual progress toward abstinence can be a useful treatment stratagem.

B. Social

Get the patient into Alcoholics Anonymous and the spouse into Al-Anon. Success is usually proportionate to

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the utilization of Alcoholics Anonymous, religious counseling, and other resources. The patient should be seen frequently for short periods and charged an appropriate fee.

Do not underestimate the importance of religion, particularly since the alcoholic is often a dependent person who needs a great deal of support. Early enlistment of the help of a concerned religious adviser can often provide the turning point for a personal conversion to sobriety.

One of the most important considerations is the patient's job—fear of losing a job is one of the most powerful motivations for giving up drink. The business community has become painfully aware of the problem, with the result that about 70% of the Fortune 500 companies offer programs to their employees to help with the problem of alcoholism. In the latter case, some specific recommendations to employers can be offered: (1) Avoid placement in jobs where the alcoholic must be alone, eg, as a traveling buyer or sales executive. (2) Use supervision but not surveillance. (3) Keep competition with others to a minimum. (4) Avoid positions that require quick decision making on important matters (high-stress situations). In general, commitment to abstinence and avoidance of situations that might be conducive to drinking are most predictive of a good outcome.

C. Medical

Hospitalization is not usually necessary. It is sometimes used to dramatize a situation and force the patient to face the problem of alcoholism, but generally it should be used on medical indications.

Because of the many medical complications of alcoholism, a complete physical examination with appropriate laboratory tests is mandatory, with special attention to the liver and nervous system. The most definitive biologic marker for chronic alcoholism is carbohydrate deficient transferrin, which can detect heavy use (60 mg/d over 7–10 days) with high specificity. Two other tests that may provide clues to an alcohol problem are γ-glutamyl transpeptidase measurement (levels above 30 units/L are suggestive of heavy drinking) and mean corpuscular volume (> 95 fL in men and > 100 fL in women). If both are elevated, a serious drinking problem is likely. Use of other recreational drugs with alcohol skews and negates the significance of these tests. High-density lipoprotein cholesterol elevations combined with elevated γ-glutamyl transpeptidase concentrations also can help identify heavy drinkers.

Use of sedatives as a replacement for alcohol is not desirable. The usual result is concomitant use of sedatives and alcohol and worsening of the problem. Lithium is not helpful in the treatment of alcoholism.

Disulfiram (250–500 mg/d orally) has been used for many years as an aversive drug to discourage alcohol use. Disulfiram inhibits alcohol dehydrogenase, causing toxic reactions when alcohol is consumed. The results have generally been of limited effectiveness and depend on the motivation of the individual to be compliant.

Naltrexone, an opiate antagonist, in a dosage of 50 mg daily, has been helpful in lowering relapse rates over the 3–6 months after cessation of drinking, apparently by lessening the pleasurable effects of alcohol. One study suggests that naltrexone is most effective when given during periods of drinking in combination with therapy that supports abstinence but accepts the fact that relapses occur. Naltrexone is FDA-approved for maintenance therapy. Studies indicate that it reduces alcohol craving when used as part of a comprehensive treatment program. Acamprosate (333–666 mg orally three times daily) has recently become available for maintenance of abstinence and can be continued even during periods of relapse.

Topiramate, an anticonvulsant, may have efficacy in reducing alcohol consumption and craving in patients with alcohol dependence by blunting mesolimbic dopamine.

D. Behavioral

Conditioning approaches have been used in some settings in the treatment of alcoholism, most commonly as a type of aversion therapy. For example, the patient is given a drink of whiskey and then a shot of apomorphine, and proceeds to vomit. In this way a strong association is built up between the vomiting and the drinking. Although this kind of treatment has been successful in some cases, many people do not sustain the learned aversive response.

Treatment of Hallucinosis & Withdrawal

A. Medical

1. Alcoholic hallucinosis

Alcoholic hallucinosis, which can occur either during or on cessation of a prolonged drinking period, is not a typical withdrawal syndrome and is handled differently. Since the symptoms are primarily those of a psychosis in the presence of a clear sensorium, they are handled like any other psychosis: hospitalization (when indicated) and adequate amounts of antipsychotic drugs. Haloperidol, 5 mg orally twice a day for the first day or so, usually ameliorates symptoms quickly, and the drug can be decreased and discontinued over several days as the patient improves. It then becomes necessary to deal with the chronic alcohol abuse, which has been discussed.

2. Withdrawal symptoms

The onset of withdrawal symptoms is usually 8–12 hours and the peak intensity of symptoms is 48–72 hours after alcohol consumption is stopped. Providing adequate central nervous system depressants (eg, benzodiazepines) is important to counteract the excitability resulting from sudden cessation of alcohol intake. The choice of a specific sedative is less important than using adequate doses to bring the patient to a level of moderate sedation, and this will vary from person to person. Mild dependency requires “drying out.” In some instances for outpatients, a short course of tapering benzodiazepines—eg, 20 mg of diazepam initially, decreasing by 5 mg daily—may be a useful adjunct. In moderate to severe

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withdrawal, hospitalize the patient and use diazepam orally in a dosage of 5–10 mg hourly depending on the clinical need as judged by withdrawal symptoms, including nausea, tremor, autonomic hyperactivity, agitation; tactile, visual, and auditory hallucinations; and disorientation. This type of symptom-driven medication regimen for withdrawal appears to reduce total benzodiazepine usage over fixed-dose schedules. Antipsychotic drugs should not be used. Monitoring of vital signs and fluid and electrolyte levels is essential for the severely ill patient.

In very severe withdrawal, intravenous administration is necessary. After stabilization, the amount of diazepam required to maintain a sedated state may be given orally every 8–12 hours. If restlessness, tremulousness, and other signs of withdrawal persist, the dosage is increased until moderate sedation occurs. The dosage is then gradually reduced by 20% every 24 hours until withdrawal is complete. This usually requires a week or so of treatment. Clonidine, 5 mcg/kg orally every 2 hours, or the patch formulation of appropriate dosage strength, suppresses cardiovascular signs of withdrawal and has some anxiolytic effect. Carbamazepine, 400–800 mg daily orally, compares favorably with benzodiazepines for alcohol withdrawal.

Atenolol, as an adjunct to benzodiazepines, can reduce symptoms of alcohol withdrawal. The daily oral atenolol dose is 100 mg when the heart rate is above 80 beats per minute and 50 mg for a heart rate between 50 and 80 beats per minute. Atenolol should not be used when bradycardia is present.

Meticulous examination for other medical problems is necessary. Alcoholic hypoglycemia can occur with low blood alcohol levels (see Chapter 27). Alcoholics commonly have liver disease and associated clotting problems and are also prone to injury—and the combination all too frequently leads to undiagnosed subdural hematoma.

Phenytoin does not appear to be useful in managing alcohol withdrawal seizures per se. Sedating doses of benzodiazepines are effective in treating alcohol withdrawal seizures. Thus, other anticonvulsants are not usually needed unless there is a preexisting seizure disorder.

A general diet should be given, and vitamins in high doses: thiamine, 50 mg intravenously initially, then intramuscularly on a daily basis; pyridoxine, 100 mg/d; folic acid, 1 mg/d; and ascorbic acid, 100 mg twice a day. Intravenous glucose solutions should not be given prior to thiamine for fear of precipitation of Wernicke's syndrome. Thiamine is necessary as a ketolase enzyme cofactor. Concurrent administration is satisfactory, and hydration should be meticulously assessed on an ongoing basis.

Chronic brain syndromes secondary to a long history of alcohol intake are not clearly responsive to thiamine and vitamin replenishment. Attention to the social and environmental care of this type of patient is paramount.

B. Psychological and Behavioral

The comments in the section on problem drinking apply here also; these methods of treatment become the primary consideration after successful treatment of withdrawal or alcoholic hallucinosis. Psychological and social measures should be initiated in the hospital shortly before discharge. This increases the possibility of continued post-hospitalization treatment.

Dongier M: What are the treatment options for comorbid alcohol abuse and depressive disorders? J Psychiatry Neurosci 2005; 30:224.

Johnson BA et al: Oral topiramate for the treatment of alcohol dependence: a randomized controlled trial. Lancet 2003; 361:1677.

Mayo-Smith MF et al: Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med 2004;164:1405. Erratum in: Arch Intern Med 2004; 164:2068. dosage error in text.

Moore AA et al: Beyond alcoholism: identifying older, at risk drinkers in primary care. J Stud Alcohol 2002;63:316.

Morgenstern J et al: Examining mechanisms of action in 12-step treatment. J Stud Alcohol 2002;63:665.

Williams SH: Medications for treating alcohol dependence. Am Fam Physician 2005;72:1775.

Other Drug & Substance Dependencies

Opioids

The terms “opioids” and “narcotics” are used interchangeably and include a group of drugs with actions that mimic those of morphine. The group includes natural derivatives of opium (opiates), synthetic surrogates (opioids), and a number of polypeptides, some of which have been discovered to be natural neurotransmitters. The principal narcotic of abuse is heroin (metabolized to morphine), which is not used as a legitimate medication. The other common opioids are prescription drugs that differ in milligram potency, duration of action, and agonist and antagonist capabilities (see Chapter 1). All of the opioid analgesics can be reversed by the opioid antagonist naloxone.

The clinical symptoms and signs of mild narcotic intoxication include changes in mood, with feelings of euphoria; drowsiness; nausea with occasional emesis; needle tracks; and miosis. The incidence of snorting and inhaling heroin (“smoking”) is increasing, particularly among cocaine users. This coincides with a decrease in the availability of methaqualone (no longer marketed) and other sedatives used to temper the cocaine “high” (see discussion of cocaine under Stimulants, below). Overdosage causes respiratory depression, peripheral vasodilation, pinpoint pupils, pulmonary edema, coma, and death.

Dependency is a major concern when continued use of narcotics occurs, although withdrawal causes only moderate morbidity (similar in severity to a bout of “flu”). Addicted patients sometimes consider themselves more addicted than they really are and may not require a withdrawal program. Grades of withdrawal are categorized from 0 to 4: grade 0 includes craving and anxiety;

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grade 1, yawning, lacrimation, rhinorrhea, and perspiration; grade 2, previous symptoms plus mydriasis, piloerection, anorexia, tremors, and hot and cold flashes with generalized aching; grades 3 and 4, increased intensity of previous symptoms and signs, with increased temperature, blood pressure, pulse, and respiratory rate and depth. In withdrawal from the most severe addiction, vomiting, diarrhea, weight loss, hemoconcentration, and spontaneous ejaculation or orgasm commonly occur. Complications of heroin administration include infections (eg, pneumonia, septic emboli, hepatitis, and HIV infection from using nonsterile needles), traumatic insults (eg, arterial spasm due to drug injection, gangrene), and pulmonary edema.

Treatment for overdosage (or suspected overdosage) is naloxone, 2 mg intravenously. If an overdose has been taken, the results are dramatic and occur within 2 minutes. Since the duration of action of naloxone is much shorter than that of the narcotics, the patient must be under close observation. Hospitalization, supportive care, repeated naloxone administration, and observation for withdrawal from other drugs should be maintained for as long as necessary.

Treatment for withdrawal begins if grade 2 signs develop. If a withdrawal program is necessary, use methadone, 10 mg orally (use parenteral administration if the patient is vomiting), and observe. If signs (piloerection, mydriasis, cardiovascular changes) persist for more than 4–6 hours, give another 10 mg; continue to administer methadone at 4- to 6-hour intervals until signs are not present (rarely more than 40 mg of methadone in 24 hours). Divide the total amount of drug required over the first 24-hour period by 2 and give that amount every 12 hours. Each day, reduce the total 24-hour dose by 5–10 mg. Thus, a moderately addicted patient initially requiring 30–40 mg of methadone could be withdrawn over a 4- to 8-day period. Clonidine, 0.1 mg several times daily over a 10- to 14-day period, is both an alternative and an adjunct to methadone detoxification; it is not necessary to taper the dose. Clonidine is helpful in alleviating cardiovascular symptoms but does not significantly relieve anxiety, insomnia, or generalized aching. There is a protracted abstinence syndrome of metabolic, respiratory, and blood pressure changes over a period of 3–6 months.

Narcotic antagonists (eg, naltrexone) can also be used successfully for treatment of the patient who has been free of opioids for 7–10 days. Naltrexone blocks the narcotic “high” of heroin when 50 mg is given orally every 24 hours initially for several days and then 100 mg is given every 48–72 hours. Liver disorders are a major contraindication. Compliance tends to be poor, partly because of the dysphoria that can persist long after opioid discontinuance. Buprenorphine, a partial agonist, is approved for office-based management of opiate addiction. Its use requires special training.

Alternative strategies for the treatment of opioid withdrawal have included rapid and ultrarapid detoxification techniques. In rapid detoxification, withdrawal is precipitated by opioid antagonists followed by naltrexone maintenance. Ultrarapid detoxification precipitates withdrawal with opioid antagonists under general anesthesia in a hospital. However, recent data do not support the use of either method. Methadone maintenance programs are of some value in chronic recidivism. Under carefully controlled supervision, the narcotic addict is maintained on fairly high doses of methadone (40–120 mg/d) that satisfy craving and block the effects of heroin to a great degree.

Sedatives (Anxiolytics)

See Anxiety Disorders, this chapter.

Psychedelics

About 6000 species of plants have psychoactive properties. All of the common psychedelics (LSD, mescaline, psilocybin, dimethyltryptamine, and other derivatives of phenylalanine and tryptophan) can produce similar behavioral and physiologic effects. An initial feeling of tension is followed by emotional release such as crying or laughing (1–2 hours). Later, perceptual distortions occur, with visual illusions and hallucinations, and occasionally there is fear of ego disintegration (2–3 hours). Major changes in time sense and mood lability then occur (3–4 hours). A feeling of detachment and a sense of destiny and control occur (4–6 hours). Of course, reactions vary among individuals, and some of the drugs produce markedly different time frames. Occasionally, the acute episode is terrifying (a “bad trip”), which may include panic, depression, confusion, or psychotic symptoms. Preexisting emotional problems, the attitude of the user, and the setting where the drug is used affect the experience.

Treatment of the acute episode primarily involves protection of the individual from erratic behavior that may lead to injury or death. A structured environment is usually sufficient until the drug is metabolized. In severe cases, antipsychotic drugs with minimal side effects (eg, haloperidol, 5 mg intramuscularly) may be given every several hours until the individual has regained control. In cases where “flashbacks” occur (mental imagery from a “bad trip” that is later triggered by mild stimuli such as marijuana, alcohol, or psychic trauma), a short course of an antipsychotic drug—eg, olanzapine, 5–10 mg/d, or risperidone, 2 mg/d, initially, and up to 20 mg/d and 6 mg/d, respectively—is usually sufficient. Lorazepam, 1–2 mg orally or intramuscularly every 2 hours as needed for acute agitation, may be a useful adjunct. An occasional patient may have “flashbacks” for much longer periods and require small doses of neuroleptic drugs over the longer term.

Phencyclidine

Phencyclidine (PCP, angel dust, peace pill, hog), developed as an anesthetic agent, first appeared as a street drug deceptively sold as tetrahydrocannabinol (THC). Because it is simple to produce and mimics to

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some degree the traditional psychedelic drugs, PCP has become a common deceptive substitute for LSD, THC, and mescaline. It is available in crystals, capsules, and tablets to be inhaled, injected, swallowed, or smoked (it is commonly sprinkled on marijuana).

Absorption after smoking is rapid, with onset of symptoms in several minutes and peak symptoms in 15–30 minutes. Mild intoxication produces euphoria accompanied by a feeling of numbness. Moderate intoxication (5–10 mg) results in disorientation, detachment from surroundings, distortion of body image, combativeness, unusual feats of strength (partly due to its anesthetic activity), and loss of ability to integrate sensory input, especially touch and proprioception. Physical symptoms include dizziness, ataxia, dysarthria, nystagmus, retracted upper eyelid with blank stare, hyperreflexia, and tachycardia. There are increases in blood pressure, respiration, muscle tone, and urine production. Usage in the first trimester of pregnancy is associated with an increase in spontaneous abortion and congenital defects. Severe intoxication (20 mg or more) produces an increase in degree of moderate symptoms, with the addition of seizures, deepening coma, hypertensive crisis, and severe psychotic ideation. The drug is particularly long-lasting (several days to several weeks) owing to high lipid solubility, gastroenteric recycling, and the production of active metabolites. Overdosage may be fatal, with the major causes of death being hypertensive crisis, respiratory arrest, and convulsions. Acute rhabdomyolysis has been reported and can result in myoglobinuric renal failure.

Differential diagnosis involves the whole spectrum of street drugs, since in some ways phencyclidine mimics sedatives, psychedelics, and marijuana in its effects. Blood and urine testing can detect the acute problem.

Treatment is discussed in Chapter 39.

Marijuana

Cannabis sativa, a hemp plant, is the source of marijuana. The parts of the plant vary in potency. The resinous exudate of the flowering tops of the female plant (hashish, charas) is the most potent, followed by the dried leaves and flowering shoots of the female plant (bhang) and the resinous mass from small leaves of inflorescence (ganja). The least potent parts are the lower branches and the leaves of the female plant and all parts of the male plant. Mercury may be a contaminant in marijuana grown in volcanic soil. The drug is usually inhaled by smoking. Effects occur in 10–20 minutes and last 2–3 hours. “Joints” of good quality contain about 500 mg of marijuana (which contains approximately 5–15 mg of tetrahydrocannabinol with a half-life of 7 days). Marijuana soaked in formaldehyde and dried (“AMP”) has produced unusual effects, including autonomic discharge and severe though transient cognitive impairment.

With moderate dosage, marijuana produces two phases: mild euphoria followed by sleepiness. In the acute state, the user has an altered time perception, less inhibited emotions, psychomotor problems, impaired immediate memory, and conjunctival injection. High doses produce transient psychotomimetic effects. No specific treatment is necessary except in the case of the occasional “bad trip,” in which case the person is treated in the same way as for psychedelic usage. Marijuana frequently aggravates existing mental illness and adversely affects motor performance.

Studies of long-term effects have conclusively shown abnormalities in the pulmonary tree. Laryngitis and rhinitis are related to prolonged use, along with chronic obstructive pulmonary disease. Electrocardiographic abnormalities are common, but no long-term cardiac disease has been linked to marijuana use. Chronic usage has resulted in depression of plasma testosterone levels and reduced sperm counts. Abnormal menstruation and failure to ovulate have occurred in some women. Cognitive impairments are common. Health care utilization for a variety of health problems is increased in chronic marijuana smokers. Sudden withdrawal produces insomnia, nausea, myalgia, and irritability. Psychological effects of chronic marijuana usage are still unclear. Urine testing is reliable if samples are carefully collected and tested. Detection periods span 4–6 days in acute users and 20–50 days in chronic users.

Stimulants: Amphetamines & Cocaine

Stimulant abuse is quite common, either alone or in combination with abuse of other drugs. The amphetamines, including Methedrine (“speed”)—one variant is a smokable form called “ice,” which gives an intense and fairly long-lasting high—methylphenidate, and phenmetrazine, are under prescription control, but street availability remains high. Moderate usage of any of the stimulants produces hyperactivity, a sense of enhanced physical and mental capacity, and sympathomimetic effects. The clinical picture of acute stimulant intoxication includes sweating, tachycardia, elevated blood pressure, mydriasis, hyperactivity, and an acute brain syndrome with confusion and disorientation. Tolerance develops quickly, and, as the dosage is increased, hypervigilance, paranoid ideation (with delusions of parasitosis), stereotypy, bruxism, tactile hallucinations of insect infestation, and full-blown psychoses occur, often with persecutory ideation and aggressive responses. Stimulant withdrawal is characterized by depression with symptoms of hyperphagia and hypersomnia.

People who have used stimulants chronically (eg, anorexigenics) occasionally become sensitized (“kindling”) to future use of stimulants. In these individuals, even small amounts of mild stimulants such as caffeine can cause symptoms of paranoia and auditory hallucinations.

Cocaine is a stimulant. It is a product of the coca plant. The derivatives include seeds, leaves, coca paste, cocaine hydrochloride,

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and the free base of cocaine. Coca paste is a crude extract that contains 40–80% cocaine sulfate and other impurities. Cocaine hydrochloride is the salt and the most commonly used form. Free base, a purer (and stronger) derivative called “crack,” is prepared by simple extraction from cocaine hydrochloride.

There are various modes of use. Coca leaf chewing involves toasting the leaves and chewing with alkaline material (eg, the ash of other burned leaves) to enhance buccal absorption. One achieves a mild high, with onset in 5–10 minutes and lasting for about an hour. Intranasal use is simply snorting cocaine through a straw. Absorption is slowed somewhat by vasoconstriction (which may eventually cause tissue necrosis and septal perforation); the onset of action is in 2–3 minutes, with a moderate high (euphoria, excitement, increased energy) lasting about 30 minutes. The purity of the cocaine is a major determinant of the high. Intravenous use of cocaine hydrochloride or “freebase” is effective in 30 seconds and produces a short-lasting, fairly intense high of about 15 minutes' duration. The combined use of cocaine and ethanol results in the metabolic production of cocaethylene by the liver. This substance produces more intense and long-lasting cocaine-like effects. Smoking freebase (volatilized cocaine because of the lower boiling point) acts in seconds and results in an intense high lasting several minutes. The intensity of the reaction is related to the marked lipid solubility of the freebase form and produces by far the most severe medical and psychiatric symptoms.

Cardiovascular collapse, arrhythmias, myocardial infarction, and transient ischemic attacks have been reported. Seizures, strokes, migraine symptoms, hyperthermia, and lung damage may occur, and there are several obstetric complications, including spontaneous abortion, abruptio placentae, teratogenic effects, delayed fetal growth, and prematurity. Cocaine can cause anxiety, mood swings, and delirium, and chronic use can cause the same problems as other stimulants (see above).

Clinicians should be alert to cocaine use in patients presenting with unexplained nasal bleeding, headaches, fatigue, insomnia, anxiety, depression, and chronic hoarseness. Sudden withdrawal of the drug is not life-threatening but usually produces craving, sleep disturbances, hyperphagia, lassitude, and severe depression (sometimes with suicidal ideation) lasting days to weeks.

Treatment is imprecise and difficult. Since the high is related to blockage of dopamine reuptake, the dopamine agonist bromocriptine, 1.5 mg orally three times a day, alleviates some of the symptoms of craving associated with acute cocaine withdrawal. Other dopamine agonists such as apomorphine, levodopa, and amantadine are under study for this purpose. Carbamazepine may be a useful adjunct in treating symptoms of alcohol withdrawal, and desipramine in moderate doses has been useful in helping maintain abstinence in the early stages of treatment. Treatment of psychosis is the same as that of any psychosis: antipsychotic drugs in dosages sufficient to alleviate the symptoms. Any medical symptoms (eg, hyperthermia, seizures, hypertension) are treated specifically. These approaches should be used in conjunction with a structured program, most often based on the Alcoholics Anonymous model. Hospitalization may be required if self-harm or violence toward others is a perceived threat (usually indicated by paranoid delusions).

Caffeine

Caffeine, along with nicotine and alcohol, is one of the most commonly used drugs worldwide. About 10 billion pounds of coffee (the richest source of caffeine) are consumed yearly throughout the world. Tea, cocoa, and cola drinks also contribute to an intake of caffeine that is often astoundingly high in a large number of people. Low to moderate doses (30–200 mg/d) tend to improve some aspects of performance (eg, vigilance). The approximate content of caffeine in a (180-mL) cup of beverage is as follows: brewed coffee, 80–140 mg; instant coffee, 60–100 mg; decaffeinated coffee, 1–6 mg; black leaf tea, 30–80 mg; tea bags, 25–75 mg; instant tea, 30–60 mg; cocoa, 10–50 mg; and 12-oz cola drinks, 30–65 mg. A 2-oz chocolate candy bar has about 20 mg. Some herbal teas (eg, “morning thunder”) contain caffeine. Caffeine-containing analgesics usually contain approximately 30 mg per unit. Symptoms of caffeinism (usually associated with ingestion of over 500 mg/d) include anxiety, agitation, restlessness, insomnia, a feeling of being “wired,” and somatic symptoms referable to the heart and gastrointestinal tract. It is common for a case of caffeinism to present as an anxiety disorder. It is also common for caffeine and other stimulants to precipitate severe symptoms in compensated schizophrenic and manic-depressive patients. Chronically depressed patients often use caffeine drinks as self-medication. This diagnostic clue may help distinguish some major affective disorders. Withdrawal from caffeine (> 250 mg/d) can produce headaches, irritability, lethargy, and occasional nausea.

Miscellaneous Drugs, Solvents

The principal over-the-counter drugs of concern have been phenylpropanolamine and an assortment of antihistaminic agents, frequently in combination with a mild analgesic promoted as cold remedies. Medications containing phenylpropanolamine have been removed from sale in the United States due to an FDA ban. The major problem in use of phenylpropanolamine relates to its side effects as a stimulant, including precipitation of anxiety states, increased pressure effects, auditory and visual hallucinations, paranoid ideation, and occasionally delirium. Aggressiveness and some loss of impulse control were reported as well as sleep disturbances even with small doses.

Antihistamines usually produce some central nervous system depression—thus their use as over-the-counter sedatives. Practically all of the so-called sleep aids are antihistamines. Drowsiness may be a problem. The mixture of antihistamines with alcohol usually exacerbates the central nervous system effects. Scopolamine

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and bromides have generally been removed from over-the-counter products.

The abuse of laxatives sometimes can lead to electrolyte disturbances that may contribute to the manifestations of a delirium. The greatest use of laxatives tends to be in the elderly and in those with eating disorders, both of whom are the most vulnerable to physiologic changes.

Anabolic steroids are being abused by people who wish to increase muscle mass for cosmetic reasons or for greater strength. In addition to the medical problems, the practice is associated with significant mood swings, aggressiveness, and paranoid delusions. Alcohol and stimulant use is higher in these individuals. Withdrawal symptoms of steroid dependency include fatigue, depressed mood, restlessness, and insomnia.

Amyl nitrite has been used as an “orgasm expander.” The changes in time perception, “rush,” and mild euphoria caused by the drug prompted its nonmedical use, and popular lore concerning the effects of inhalation just prior to orgasm has led to increased use. Subjective effects last from 5 seconds to 15 minutes. Tolerance develops readily, but there are no known withdrawal symptoms. Abstinence for several days reestablishes the previous level of responsiveness. Long-term effects may include damage to the immune system and respiratory difficulties.

Sniffing of solvents and inhaling of gases (including aerosols) produce a form of inebriation similar to that of the volatile anesthetics. Agents include gasoline, toluene, petroleum ether, lighter fluids, cleaning fluids, paint thinners, and solvents that are present in many household products (eg, nail polish, typewriter correction fluid). Typical intoxication states include euphoria, slurred speech, hallucinations, and confusion, and with high doses, acute manifestations are unconsciousness and cardiorespiratory depression or failure; chronic exposure produces a variety of symptoms related to the liver, kidney, bone marrow, or heart. Lead encephalopathy can be associated with sniffing leaded gasoline. In addition, studies of workers chronically exposed to jet fuel showed significant increases in neurasthenic symptoms, including fatigue, anxiety, mood changes, memory difficulties, and somatic complaints. These same problems have been noted in long-term solvent abuse.

The so-called designer drugs are synthetic substitutes for commonly used recreational drugs and are produced in small, clandestine laboratories. The most common designer drugs have been methyl analogues of fentanyl and have been used as heroin substitutes. MDMA (methylenedioxymethamphetamine), an amphetamine derivative sometimes called “ecstasy,” is also a designer drug with high abuse potential and neurotoxicity. Often not detected by standard toxicology screens, these substances can present a vexing problem for clinicians faced with symptoms from a totally unknown cause.

Collins ED et al: Anesthesia-assisted vs buprenorphine- or clonidine-assisted heroin detoxification and naltrexone induction: a randomized trial. JAMA 2005;294:903.

Fudala PJ et al: Office-based treatment of opiate addiction with sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 2003;349:949.

Khalsa JH et al: Clinical consequences of marijuana. J Clin Pharmacol 2002;42 (11 Suppl):7S.

Delirium, Dementia, & other Cognitive Disorders (Formerly: Organic Brain Syndrome)

Essentials of Diagnosis

  • Transient or permanent brain dysfunction.

  • Cognitive impairment to varying degrees: may include impaired recall and recent memory, inability to focus attention, random psychomotor activity such as stereotypy, and problems in perceptual processing, often with psychotic ideation.

  • Emotional disorders frequently present: depression, anxiety, irritability.

  • Behavioral disturbances may include problems of impulse control, sexual acting-out, attention deficits, aggression, and exhibitionism.

General Considerations

The organic problem may be a primary brain disease or a secondary manifestation of some general disorder. All of the cognitive disorders show some degree of impaired thinking depending on the site of involvement, the rate of onset and progression, and the duration of the underlying brain lesion. Emotional disturbances (eg, depression) are often present as significant comorbidities. The behavioral disturbances tend to be more common with chronicity, more directly related to the underlying personality or central nervous system vulnerability to drug side effects, and not necessarily correlated with cognitive dysfunction.

The causes of cognitive disorders are listed in Table 25-11.

Clinical Findings

The manifestations are many and varied and include problems with orientation, short or fluctuating attention span, loss of recent memory and recall, impaired judgment, emotional lability, lack of initiative, impaired impulse control, inability to reason through problems, depression (worse in mild to moderate types), confabulation (not limited to alcohol organic brain syndrome), constriction of intellectual functions, visual and auditory hallucinations, and delusions. Physical findings will

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naturally vary according to the cause. The EEG usually shows generalized slowing in delirium.

Table 25-11. Etiology of delirium and other cognitive disorders.

Disorder Possible Causes
Intoxication Alcohol, sedatives, bromides, analgesics (eg, pentazocine), psychedelic drugs, stimulants, and household solvents.
Drug withdrawal Withdrawal from alcohol, sedative-hypnotics, corticosteroids.
Long-term effects of alcohol Wernicke-Korsakoff syndrome.
Infections Septicemia; meningitis and encephalitis due to bacterial, viral, fungal, parasitic, or tuberculous organisms or to central nervous system syphilis; acute and chronic infections due to the entire range of microbiologic pathogens.
Endocrine disorders Thyrotoxicosis, hypothyroidism, adrenocortical dysfunction (including Addison's disease and Cushing's syndrome), pheochromocytoma, insulinoma, hypoglycemia, hyperparathyroidism, hypoparathyroidism, panhypopituitarism, diabetic ketoacidosis.
Respiratory disorders Hypoxia, hypercapnia.
Metabolic disturbances Fluid and electrolyte disturbances (especially hyponatremia, hypomagnesemia, and hypercalcemia), acid-base disorders, hepatic disease (hepatic encephalopathy), renal failure, porphyria.
Nutritional deficiencies Deficiency of vitamin B1 (beriberi), vitamin B12 (pernicious anemia), folic acid, nicotinic acid (pellagra); protein-calorie malnutrition.
Trauma Subdural hematoma, subarachnoid hemorrhage, intracerebral bleeding, concussion syndrome.
Cardiovascular disorders Myocardial infarctions, cardiac arrhythmias, cerebrovascular spasms, hypertensive encephalopathy, hemorrhages, embolisms, and occlusions indirectly cause decreased cognitive function.
Neoplasms Primary or metastatic lesions of the central nervous system, cancer-induced hypercalcemia.
Seizure disorders Ictal, interictal, and postictal dysfunction.
Collagen-vascular and immunologic disorders Autoimmune disorders, including systemic lupus erythematosus, Sjögren's syndrome, and AIDS.
Degenerative diseases Alzheimer's disease, Pick's disease, multiple sclerosis, parkinsonism, Huntington's chorea, normal pressure hydrocephalus.
Medications Anticholinergic drugs, antidepressants, H2-blocking agents, digoxin, salicylates (chronic use), and a wide variety of other over-the-counter and prescribed drugs.

A. Delirium

Delirium (acute confusional state) is a transient global disorder of attention, with clouding of consciousness, usually a result of systemic problems (eg, drugs, hypoxemia). Onset is usually rapid. The mental status fluctuates (impairment is usually least in the morning), with varying inability to concentrate, maintain attention, and sustain purposeful behavior. (“Sundowning”—mild to moderate delirium at night—is more common in patients with preexisting dementia and may be precipitated by hospitalization, drugs, and sensory deprivation.) There is a marked deficit of short-term memory and recall. Anxiety and irritability are common. Amnesia is retrograde (impaired recall of past memories) and anterograde (inability to recall events after the onset of the delirium). Orientation problems follow the inability to retain information. Perceptual disturbances (often visual hallucinations) and psychomotor restlessness with insomnia are common. Autonomic changes include tachycardia, dilated pupils, and sweating. The average duration is about 1 week, with full recovery in most cases. Delirium can coexist with dementia.

B. Dementia

(See also Chapter 4.) Dementia is characterized by chronicity and deterioration of selective mental functions. Onset is insidious over months to years in most cases. Dementia is usually progressive, more common in the elderly, and rarely reversible even if underlying disease can be corrected. Dementia can be classified as cortical or subcortical.

There are three types of cortical dementia: (1) primary degenerative dementia (eg, Alzheimer's), accounting for about 50–60% of cases; (2) atherosclerotic (multi-infarct) dementia, 15–20% of cases (this figure is probably low because of the tendency to overuse the diagnosis of Alzheimer's dementia); and (3) mixtures of the first two types or dementia due to miscellaneous causes, 15–20% of cases (see also Chapter 4). Examples of primary degenerative dementia are Alzheimer's dementia

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(most common) and Pick, Creutzfeldt-Jakob, and Huntington dementias (less common).

In all types, loss of impulse control (sexual and language) is common. The tenuous level of functioning makes the individual most susceptible to minor physical and psychological stresses. The course depends on the underlying cause, and the general trend is steady deterioration.

HIV infection can produce a primary neurogenic disorder (partially due to neuronal loss) and secondary effects due to opportunistic infections, neoplasias, or the effects of drug therapy. At present there has been a reduction in dementia symptoms in both early and late stages, perhaps due to earlier use of zidovudine. The general trend is variable, and patients require ongoing monitoring of neuropsychiatric status.

Pseudodementia is a term applied to depressed patients who appear to be demented. These patients are often identifiable by their tendency to complain about memory problems vociferously rather than try to cover them up. They usually say they can't complete cognitive tasks but with encouragement can often do so. In some reports, they can be considered to have depression-induced reversible dementia that remits when the depression resolves.

C. Amnestic Syndrome

This is a memory disturbance without delirium or dementia. It is usually associated with thiamine deficiency and chronic alcohol use (eg, Korsakoff's syndrome). There is an impairment in the ability to learn new information or recall previously learned information.

D. Substance-Induced Hallucinosis

This condition is characterized by persistent or recurrent hallucinations (usually auditory) without the other symptoms usually found in delirium or dementia. Alcohol or hallucinogens are often the cause. There does not have to be any other mental disorder, and there may be complete spontaneous resolution.

E. Personality Changes Due to a General Medical Condition (Formerly Organic Personality Syndrome)

This syndrome is characterized by emotional lability and loss of impulse control along with a general change in personality. Cognitive functions are preserved. Social inappropriateness is common. Loss of interest and lack of concern with the consequences of one's actions are often present. The course depends on the underlying cause (eg, frontal lobe contusion may resolve completely).

Differential Diagnosis

The differential diagnosis consists mainly of schizophrenia and the other psychoses, which are sometimes confused with cognitive disorders are often accompanied by psychotic symptoms.

Complications

Chronicity may result from delayed correction of the defect, eg, subdural hematoma, low-pressure hydrocephalus. Accidents secondary to impulsive behavior and poor judgment are a major consideration. Secondary depression and impulsive behavior not infrequently lead to suicide attempts. Drugs—particularly sedatives—may worsen thinking abilities and contribute to the overall problems.

Treatment

(See also Chapter 4.)

A. Medical

Delirium should be considered a syndrome of acute brain dysfunction analogous to acute renal failure. The first aim of treatment is to identify and correct the etiologic medical problem. Evaluation should consist of a comprehensive physical examination including a search for neurologic abnormalities, infection, or hypoxia. Routine laboratory tests may include serum electrolytes, serum glucose, BUN, serum creatinine, liver function tests, thyroid function tests, arterial blood gases, complete blood count, serum calcium, phosphorus, magnesium, vitamin B12, folate, blood cultures, urinalysis, and cerebrospinal fluid analysis. Discontinue drugs that may be contributing to the problem (eg, analgesics, corticosteroids, cimetidine, lidocaine, anticholinergic drugs, central nervous system depressants, mefloquine). Do not overlook any possibility of reversible organic disease. Electroencephalography, CT, MRI, PET, and SPECT evaluations may be helpful in diagnosis. Ideally, the patient should be monitored without further medications while the evaluation is carried out. There are, however, two indications for medication in delirious states: behavioral control (eg, pulling out lines) and subjective distress (eg, pronounced fear due to hallucinations). If these indications are present, medications may be used. If there is any hint of alcohol or substance withdrawal (the most common cause of delirium in the general hospital), a benzodiazepine such as lorazepam (1–2 mg every hour) can be given parenterally. If there is little likelihood of withdrawal syndrome, haloperidol is often used in doses of 1–10 mg every hour. Given intravenously, it appears to impose slight risk of extrapyramidal side effects. In addition to the medication, a pleasant, comfortable, nonthreatening, and physically safe environment with adequate nursing or attendant services should be provided. Once the underlying condition has been identified and treated, adjunctive medications can be tapered.

Treatment of dementia syndrome usually involves symptomatic management with one exception. Since there is a cholinergic deficiency in Alzheimer's disease, research has focused on drugs to increase cholinergic activity by inhibiting cholinesterase. Tacrine was the first reversible cholinesterase inhibitor approved by the FDA.

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Three better-tolerated FDA-approved cholinesterase inhibitors are donepezil (5–10 mg at night), rivastigmine (3–6 mg twice daily), and galantamine (8–12 mg twice daily). Donepezil and galantamine doses need adjustment for liver disease, and the galantamine dose should be adjusted for renal failure. They are thought to be efficacious in the short-term preservation of cognitive function and activities of daily living in mild to moderate dementia and, unlike tacrine, are not thought to be hepatotoxic. Gastrointestinal side effects are common but may be least frequent with donepezil. Further research continues to clarify the long-term efficacy of these medications on cognition and behavior. None of the cholinesterase inhibitors to date are thought to slow disease progression. An N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, is the first medication approved by the FDA for the treatment of moderate to severe Alzheimer's disease. Memantine may improve performance and cognition in some patients and has been used as an augmenting agent with the cholinesterase inhibitors.

Aggressiveness and rage states in central nervous system disease can be reduced with lipophilic β-blockers (eg, propranolol, metoprolol) in moderate doses. Since the serotonergic system has been implicated in arousal conditions, drugs that affect serotonin have been found to be of some benefit in aggression and agitation. Included in this group are lithium, trazodone, buspirone, and clonazepam. Dopamine blockers (eg, the neuroleptic drugs such as haloperidol) have been used for many years to attenuate aggression. Atypical neuroleptics may have a role in selected geriatric patients; however, there are reports of increased mortality in some studies related to the use of atypical neuroleptics in this population. There are also recent reports of reduced agitation in Alzheimer's disease from carbamazepine, 100–400 mg/d orally (with slow increase as needed). Emotional lability in some cases responds to small doses of imipramine (25 mg orally one to three times per day) or fluoxetine (5–20 mg/d orally); depression, which often occurs early in the course of Alzheimer's dementia, responds to the usual doses of antidepressant drugs, preferably those with the least anticholinergic side effects (eg, SSRIs and MAO inhibitors).

Cerebral vasodilators were originally used on the assumption that cerebral arteriosclerosis and ischemia were the principal causes of the dementias. Although there is a slight reduction of blood flow in primary degenerative dementia (probably as a result of the basic disorder), there is no evidence that this is a major factor in this group of disorders or that vasodilators are of value. Ergotoxine alkaloids (ergoloid mesylates: Hydergine, others) have been studied with mixed results; improvement in ambulatory self-care and depressed mood has been noted, but there has been no improvement of cognitive functioning on any standardized tests. Hyperbaric oxygen treatment has not produced significant improvement. Stimulant drugs (eg, methylphenidate) do not change cognitive function but can improve affect and mood, which helps the caretakers cope with the problem.

Failing sensory functions should be supported as necessary, with hearing aids, cataract surgery, etc.

B. Social

Substitute home care, board and care, or convalescent home care may be most useful when the family is unable to care for the patient. The setting should include familiar people and objects, lights at night, and a simple schedule. Counseling may help the family to cope with problems and may help keep the patient at home as long as possible. Information about local groups can be obtained from the Alzheimer's Disease and Related Disorders Association, 70 East Lake Street, Suite 600, Chicago, IL 60601. Volunteer services, including homemakers, visiting nurses, and adult protective services, may be helpful in maintaining the patient at home.

C. Behavioral

Behavioral techniques include operant responses that can be used to induce positive behaviors, eg, paying attention to the patient who is trying to communicate appropriately, and extinction by ignoring inappropriate responses. Alzheimer's patients can learn skills and retain them but do not recall the circumstances in which they were learned.

D. Psychological

Formal psychological therapies are not usually helpful and may make things worse by taxing the patient's limited cognitive resources.

Prognosis

The prognosis is good for recovery of mental functioning in delirium when the underlying condition is reversible. For most dementia syndromes, the prognosis is for gradual deterioration, although new drug treatments may prove helpful.

Clegg A et al: Clinical and cost-effectiveness of donepezil, rivastigmine, and galantamine for Alzheimer's disease. Int J Technol Assess Health Care 2002;18:497.

Reisberg B et al: Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348:1333.

Trinh N et al: Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease, a meta-analysis. JAMA 2003; 289:210.

Geriatric Psychiatric Disorders (See also Chapter 4)

There are three basic factors in the process of aging: biologic, sociologic, and psychological.

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The complex biologic changes depend on inherited characteristics (the best chance of long life is to have long-lived parents), nutrition, declining sensory functions such as hearing or vision, disease, trauma, and lifestyle. A definite correlation between hearing loss and paranoid ideation exists in the elderly. (See Dementia, above.) As a person ages, relatively minor disorders or combinations of disorders may cause deficits in cognition and affective response. Hypochondriasis is frequently a mechanism of compensating for decreased function (eg, preoccupation with bowel function).

The sociologic factors derive from stresses connected with occupation, family, and community. Any or all of these areas may be disrupted in a general phenomenon of “disengagement” and lack of intimacy that older people experience as friends die, the children move away, and the surroundings become less familiar. Retirement commonly precipitates a major disruption in a well-established life structure. This is particularly stressful in the person whose compulsive devotion to a job has inhibited the development of other interests, so that sudden loss of this outlet leaves a void that is not easily filled. New duties, such as caring for a spouse with dementia, may also lead to depression.

The psychological withdrawal of the elderly person is frequently related to a loss of self-esteem, which is based on the economic insecurity of older age with its congruent loss of independence, the recognition of decreasing physical and mental ability, loneliness, and the fear of approaching death. The process of aging is often poorly accepted, and the real or imagined loss of physical attractiveness may have a traumatic impact that the plastic surgeon can only soften for a time. In a culture that stresses physical and sexual attractiveness, it is difficult for some people to accept the change.

Clinical Findings & Complications

The most common psychiatric syndrome in the elderly is dementia of varying degrees. Psychotic ideation (usually paranoid) may coexist with dementia. Frequently, in milder cases, the individual is aware of the deficiency in cognition and becomes depressed about actual or threatened loss of function. Depression may then amplify the apparent cognitive decline.

Overt depression, often presenting as a somatic complaint, is often related to life changes (80% of people over age 65 have some kind of medical problem). Alcoholism is present in approximately 15% of older patients presenting with psychiatric symptoms. The incidence of suicide is higher in elderly people—loneliness, age, and medical problems being directly related. Deprivation of full-spectrum light may be a factor in some patients (eg, nursing home residents). Anxiety, often associated with organic illness, heightens preexisting confusion in the patient with cognitive dysfunction.

Abuse of the elderly—both physical neglect (passive) and physical injury (active)—demands early recognition. Bruises, welts, fractures, and debilitation should alert the clinician. The battered elderly are probably just as numerous as battered children, but less reported, and require the same diligence in clinician recognition.

Polypharmacy (with both prescription and over-the-counter drugs) is a major cause of accidents (often with resultant hip fracture) and illness in the elderly. Cognitive impairment increases as the number of drugs used increases; sedatives and anticholinergic drugs are the major culprits (eg, overuse in sleep problems). The increased and varied complaints are often an attempt to compensate and divert attention from decreased mental function.

Treatment

A. Social

Socialization, a structured schedule of activities, familiar surroundings, continued achievement, and avoidance of loneliness (probably the most important factor) are some of the major considerations in prevention and amelioration of the psychiatric problems of old age. The patient can be supported in the primary environment by various agencies that can help avoid a premature change of habits. For patients with disabilities that make it difficult to cope with the problems of living alone, homemaker services can assist in continuing the day-to-day activities of the household; visiting nurses can administer medications and monitor the physical condition of the patient; and geriatric social groups can help maintain socialization and human contacts. In the hospital or nursing home, attention to the kinds of people placed in the same room is most important (mix active and inactive patients).

B. Medical

Treatment of any reversible components of a dementia syndrome is obviously the major medical consideration. One commonly overlooked factor is self-medication, frequently with nonprescription drugs or herbal remedies that further impair the patient's already precarious functioning. Common culprits are antihistamines and anticholinergic drugs, sometimes mixed with alcohol abuse.

Any signs of psychosis, such as paranoid ideation, agitation, and delusions, respond very well to small doses of antipsychotics. Risperidone, 0.25–1 mg orally daily, or olanzapine, 1.25–5 mg orally once a day, will usually decrease psychotic ideation markedly; monitoring for significant orthostatic hypotension (resulting in dizziness, falls, fractures) is mandatory with these agents.

Antidepressants (in one-third to half the doses given to young adults) are used when indicated for depression. Occasionally, a stimulant in small doses (eg, methylphenidate, 5–30 mg orally usually given in two doses at 7 AM and noon) can be used to treat apathy. The stimulant may help increase the patient's energy

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for social involvement and help the patient to maintain life activities.

The appropriate use of wine and beer for mild sedative effects is quite rewarding in the hospital and other care facilities as well as at home.

C. Behavioral

The impaired cognitive abilities of the geriatric patient necessitate simple behavioral techniques. Positive responses to appropriate behavior encourage the patient to repeat desirable kinds of behavior, and frequent repetition offsets to some degree the defects in recent memory and recall. It also results in participation—a most important element, since there is a tendency in the older population to withdraw, thus increasing isolation and functional decline.

One must be careful not to reinforce and encourage obstreperous behavior by responding to it; in this way, extinction or at least gradual reduction of inappropriate behavior will occur. At the same time, the obstreperous behavior often represents a nondirective response to frustration and inability to function, and a structured program of activity is necessary.

D. Psychological

Patients may require help in adjusting to changing roles and commitments and in finding new goals and viewpoints. The older person steadily loses an important commodity—the future—and may attempt to compensate by preoccupation with the past. Involvement with the present and psychotherapy on a here-and-now basis can help make the adjustment easier.

Lane HY et al: Shifting from haloperidol to risperidone for behavioral disturbances in dementia: safety, response predictors, and mood effects. J Clin Psychopharmacol 2002;22:4.

Unutzer J et al: Collaborative care management of late-life depression in the primary care setting: a randomized controlled trial. JAMA 2002;288:2836.

Psychiatric Problems Associated with Hospitalization & Medical & Surgical Disorders

Diagnostic Categories

A. Acute Problems

  • Delirium with psychotic features secondary to the medical or surgical problem, or compounded by effect of treatment.

  • Acute anxiety, often related to ignorance and fear of the immediate problem as well as uncertainty about the future.

  • Anxiety as an intrinsic aspect of the medical problem (eg, hyperthyroidism).

  • Denial of illness, which may present during acute or intermediate phases of illness.

B. Intermediate Problems

  • Depression as a function of the illness or acceptance of the illness, often associated with realistic or fantasied hopelessness about the future.

  • Behavioral problems, often related to denial of illness and, in extreme cases, causing the patient to leave the hospital against medical advice.

C. Recuperative Problems

  • Decreasing cooperation as the patient sees improvement and compliance are not compelled.

  • Readjustment problems with family, job, and society.

General Considerations

A. Acute Problems

1. “Intensive care unit psychosis”

The stressful ICU environment may be a cause of delirium. Critical care unit factors include sleep deprivation, increased arousal, mechanical ventilation, and social isolation. Other causes include those common to delirium and require vigorous investigation (see Delirium, above).

2. Pre- and postsurgical anxiety states

Such problems are common and commonly ignored. Presurgical anxiety is very common and is principally a fear of death (many surgical patients make out their wills). Patients may be fearful of anesthesia (improved by the preoperative anesthesia interview), the mysterious operating room, and the disease processes that might be uncovered by the surgeon. Such fears frequently cause people to delay examinations that might result in earlier surgery and a greater chance of cure.

The opposite of this is surgery proneness, the quest for surgery to escape from overwhelming life stresses. Polysurgery patients may be classified as “factitious” ones. Dynamic motivations include narcissism, societal pressures (eg, breast implants), unconscious guilt, a masochistic need to suffer, an attempt to deal with another family member's illness, and somatoform disorders and body dysmorphic disorder (an obsession that a body part is disfigured). More apparent reasons may include an attempt to get relief from pain and a lifestyle that has become almost exclusively medically oriented, with all of the risks entailed in such an endeavor.

Postsurgical anxiety states are usually related to pain, procedures, and loss of body image. Acute pain problems are quite different from chronic pain disorders (see Chronic Pain Disorders, this chapter); the former are readily handled with adequate analgesic medication (see Chapter 5). Alterations in body image,

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as with amputations, ostomies, and mastectomies, often raise concerns about relationships with others.

3. Iatrogenic problems

These usually pertain to medications, complications of diagnostic and treatment procedures, and impersonal and unsympathetic staff behavior. Polypharmacy is often a factor. Patients with unsolved diagnostic problems are at higher risk. They are desirous of relief, and the quest engenders more diagnostic procedures with a higher incidence of complications. The upset patient and family may be very demanding. Excessive demands usually result from anxiety. Such behavior is best handled with calm and measured responses.

B. Intermediate Problems

1. Prolonged hospitalization

Prolonged hospitalization presents unique problems in certain hospital services, eg, burn units, orthopedic services, and tuberculosis wards. The acute problems of the severely burned patient are discussed in Chapter 38. The problems often are behavioral difficulties related to length of hospitalization and necessary procedures. For example, in burn units, pain is a major problem in addition to anxiety about procedures. Disputes with staff are common and often concern pain medication or ward privileges. Some patients regress to infantile behavior and dependency. Staff members must agree about their approach to the patient in order to ensure the smooth functioning of the unit.

Denial of illness may present in the patient with acute myocardial infarction. Intervention by an authority figure (eg, immediate work supervisor) may help the patient accept treatment and eventually abandon the defense of denial.

2. Depression

Depression frequently occurs during this period. Therapeutic drugs (eg, corticosteroids) may be a factor. Depression can contribute to irritability and overt anger. Severe depression can lead to anorexia, which further complicates healing and metabolic balance. It is during this period that the issue of disfigurement arises—relief at survival gives way to concern about future function and appearance.

C. Recuperative Problems

1. Anxiety

Anxiety about return to the posthospital environment can cause regression to a dependent position. Complications increase, and staff forbearance again is tested. Anxiety occurring at this stage usually is handled more easily than previous behavior problems.

2. Posthospital adjustment

Adjustment difficulties after discharge are related to the severity of the deficits and the use of outpatient facilities (eg, physical therapy, rehabilitation programs, psychiatric outpatient treatment). Some patients may experience posttraumatic stress symptoms (eg, from traumatic injuries or even from necessary medical treatments). Lack of appropriate follow-up can contribute to depression in the patient, who may feel that he or she is making poor progress and may have thoughts of “giving up.” Reintegration into work, educational, and social endeavors may be slow. Life is simply much more difficult when one is disfigured, disabled, or disfranchised.

Clinical Findings

The symptoms that occur in these patients are similar to those discussed in previous sections of this chapter, eg, delirium, stress and adjustment disorders, anxiety, and depression. Behavior problems may include lack of cooperation, increased complaints, demands for medication, sexual approaches to nurses, threats to leave the hospital, and actual signing out against medical recommendations. The underlying personality structure of the individual is a major factor in coping styles (eg, the compulsive individual increases indecision, the hysterical individual increases dramatic behavior).

Differential Diagnosis

Delirium and dementia (including cases associated with HIV infection and drug abuse) must always be ruled out, since they often present with symptoms resembling anxiety, depression, or psychosis. Personality disorders existing prior to hospitalization often underlie the various behavior problems, but particularly the management problems.

Complications

Prolongation of hospitalization causes increased expense, deterioration of patient-staff relationships, and increased probabilities of iatrogenic and legal problems. The possibility of increasing posthospital treatment problems is enhanced.

Treatment

A. Medical

The most important consideration by far is to have one clinician in charge, a clinician whom the patient trusts and who is able to oversee multiple treatment approaches (see Somatoform Disorders, above). In acute problems, attention must be paid to metabolic imbalance, alcohol withdrawal, and previous drug use—prescribed, recreational, or over-the-counter. Adequate sleep and analgesia are important in the prevention of delirium. When absolute behavioral control is urgently needed, agents such as propofol, dexmedetomidine, opioids, and midazolam have been used.

Most clinicians are attuned to the early detection of the surgery-prone patient. Plastic and orthopedic surgeons are at particular risk. Appropriate consultations may help detect some problems and mitigate future ones.

Postsurgical anxiety states can be alleviated by personal attention from the surgeon. Anxiety is not so effectively lessened by ancillary medical personnel, whom the patient perceives as lesser authorities, until after the physician has reassured the patient. Inappropriate

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use of “as needed” analgesia places an unfair burden on the nurse. “Patient-controlled analgesia” can improve pain control, decrease anxiety, and minimize side effects.

Depression should be recognized early. If severe, it may be treated by antidepressant medications (see Antidepressant Drugs, above). High levels of anxiety can be lowered with judicious use of anxiolytic agents. Unnecessary medications tend to reinforce the patient's impression that there must be a serious illness or medication would not be required.

B. Psychological

Prepare the patient and family for what is to come. This includes the types of units where the patient will be quartered, the procedures that will be performed, and any disfigurements that will result from surgery. Repetition improves understanding. The nursing staff can be helpful, since patients frequently confide a lack of understanding to a nurse but are reluctant to do so to the physician.

Denial of illness is frequently a block to acceptance of treatment. This too should be handled with family members present (to help the patient face the reality of the situation) in a series of short interviews (for reinforcement). Dependency problems resulting from long hospitalization are best handled by focusing on the changes to come as the patient makes the transition to the outside world. Key figures are teachers, vocational counselors, and physical therapists. Challenges should be realistic and practical and handled in small steps.

Depression is usually related to the loss of familiar hospital supports, and the outpatient therapists and counselors help to lessen the impact of the loss. Some of the impact can be alleviated by anticipating, with the patient and family, the signal features of the common depression to help prevent the patient from assuming a permanent sick role (invalidism).

Suicide is always a concern when a patient is faced with despair. An honest, compassionate, and supportive approach will help sustain the patient during this trying period.

C. Behavioral

Prior desensitization can significantly allay anxiety about medical procedures. A “dry run” can be done to reinforce the oral description. Cooperation during acute problem periods can be enhanced by the use of appropriate reinforcers such as a favorite nurse or helpful family member. People who are positive reinforcers are even more helpful during the intermediate phases when the patient becomes resistant to the seemingly endless procedures (eg, debridement of burned areas).

Specific situations (eg, psychological dependency on the respirator) can be corrected by weaning with appropriate reinforcers (eg, watching a favorite movie on a videorecorder when disconnected from the ventilator). Behavioral approaches should be used in a positive and optimistic way for maximal reinforcement.

Relaxation techniques and attentional distraction can be used to block side effects of a necessary treatment (eg, nausea in cancer chemotherapy).

D. Social

A change in environment requires adaptation. Because of the illness, admission and hospitalization may be more easily handled than discharge. Reintegration into society can be difficult. In some cases, the family is a negative influence. A predischarge evaluation must be made to determine whether the family will be able to cope with the physical or mental changes in the patient. Working with the family while the patient is in the acute stage may presage a successful transition later on.

Development of a new social life can be facilitated by various self-help organizations (eg, the stoma club). Sharing problems with others in similar circumstances eases the return to a social life, which may be quite different from that prior to the illness.

Prognosis

The prognosis is good in all patients who have reversible medical and surgical conditions. It is guarded when there is serious functional loss that impairs vocational, educational, or societal possibilities—especially in the case of progressive and ultimately life-threatening illness.

Blumenthal JA et al: Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003;362:604.

Ciechanowski P et al: Influence of patient attachment style on self-care and outcomes in diabetes. Psychosom Med 2004; 66:720.

Hogarth DK et al: Management of sedation in mechanically ventilated patients. Curr Opin Crit Care 2004;10:40.