20 - Approaches to the Treatment of Schizophrenia
Editors: Shader, Richard I.
Title: Manual of Psychiatric Therapeutics, 3rd Edition
Copyright 2003 Lippincott Williams & Wilkins
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20
Approaches to the Treatment of Schizophrenia
Richard I. Shader
For more than 100 years, extensive efforts have been made to define or classify schizophrenia as an illness or group of illnesses. At the present time, a reasonable consensus about clinical phenomenology and descriptive diagnostic criteria has been reached, but the etiology and pathobiology remain obscure. Fortunately, most clinicians have little difficulty reaching diagnostic agreement about patients deemed to be suffering from schizophrenia; inevitably, though, some patients do appear for whom a diagnostic consensus is difficult to reach. These less easily categorized patients are sometimes given other diagnoses, including borderline or schizotypal personality disorder (see Chapter 13), delusional disorder (see Chapter 4), bipolar disorder (see Chapter 19), latent schizophrenia, pseudoneurotic or pseudopsychopathic schizophrenia, and even psychotic depression. The misguided tradition of categorizing schizophrenia as a functional illness prevailed for much of the 20th century and contributed to an underinvestment in research and to some continuing confusion about nosology and treatment. Functional suggests to many an exclusively interpersonal, social, or intrapsychic origin for this group of disorders. The sections that follow should make apparent the fact that schizophrenia represents a heterogeneous group of disorders with multiple etiologies linked to one or more forms of genetically based vulnerabilities and to some as yet unspecified environmental mishaps or trauma (e.g., inadequate nutrition during pregnancy from a local famine, exposure to influenza virus during gestation or perinatally).
I. Symptoms and Diagnostic Considerations
In 1896, Emil Kraepelin organized the observations of previous workers (e.g., Morel, Hecker, and Kahlbaum) and developed the concept of dementia praecox, which he saw as a peculiar pathologic condition of the internal connections of the personality that resulted in a disturbed emotional and volitional life. In 1911, Eugen Bleuler extended these efforts and offered the concept of a group of schizophrenias characterized by disturbances of thinking, feelings, and relationships to the external world. He isolated the following four fundamental diagnostic criteria, sometimes called The 4 A s: loosening of associations, inappropriate affects, autistic thoughts, and ambivalence. These four features overlap to some extent with the following 6 A s that characterize the so-called negative symptoms of schizophrenia: alogia, affective blunting (flattening), anhedonia, asociality, avolition, and apathy. Many clinicians consider these features, in the aggregate, to be the core impairments in schizophrenia and believe that they do not receive adequate emphasis in the current diagnostic schema, the International Statistical Classification of Diseases and Related Health Problems, tenth revision, (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Some clinicians and researchers prefer to emphasize alterations in selective attention, information processing, or cue response (e.g., if the word dog had been misheard or misprocessed as frog, green as an association would not be loose).
In the 1930s, Kurt Schneider elaborated a phenomenologic definition of the schizophrenias. He asserted the primacy of 11 empirically determined first-rank symptoms that he considered pathognomonic of schizophrenia. Some research has challenged their specificity to schizophrenia (e.g., some of these symptoms are not uncommon in bipolar disorder) and thereby their value in assessing prognosis. However, Schneider's approach is useful for organizing some of the disparate experiences patients report. As Table 20.1 illustrates, Schneider's symptoms are grouped into five broad categories. These symptoms are central to the so-called positive symptoms of schizophrenia.
In 1958, K. Conrad focused attention on the time course and differing stages of symptom appearance. Table 20.2 lists his notions about progressive stages.
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Few patients actually articulate a progressive decompensation; nevertheless, this conceptualization may help the clinician appreciate the importance of course to the diagnosis of schizophrenia, as well as the existential distress that some patients experience in the early stages of illness.
TABLE 20.1. SCHNEIDER'S FIRST-RANK SYMPTOMS OF SCHIZOPHRENIA | ||
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Course, other historical data, and specific symptom requirements may help separate schizophrenia from toxic or other causes of schizophrenia-like presentations or from the affective psychoses. DSM-IV criteria for schizophrenia require the consideration of course variables in conjunction with particular positive or negative symptoms. A listing of some positive and negative symptoms seen in schizophrenia is provided in Table 20.3.
That the symptoms observed at any given point in time will depend on many factors, including when in the course of the illness a patient is seen, past or present treatments, and the type and prognosis of the patient's illness, should be apparent to the reader. Diagnosis also must take into account whether or not the patient is psychotic at the time of observation; the presence of other etiologic factors (e.g., toxic conditions due to cocaine or amphetamines); a past history of alterations in mood, behavior, perceptions, thought, and present mental status; and social and cultural expectations (e.g., a belief in voodoo could significantly influence the assessment).
TABLE 20.2. CONRAD'S PROGRESSIVE STAGES OF SCHIZOPHRENIA | ||
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TABLE 20.3. SOME POSITIVE AND NEGATIVE SYMPTOMS OF SCHIZOPHRENIA | ||||||||||||||||||||
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A. Schizophrenia
The following is a description of schizophrenia that draws on the author's clinical experiences and on the DSM-IV and ICD-10 (Table 20.4). Schizophrenia is the diagnostic concept used to classify a group of psychotic patients who, at some points in time, suffer from a defect state characterized by apathy, avolition, asociality, affective blunting, and alogia. They also have alterations in thoughts, percepts, mood, and behavior subjective experiences of disordered thought are manifested in disturbances of concept formation that sometimes lead to misinterpretations of reality; delusions, particularly of influence and ideas of reference; and hallucinations, particularly of voices repeating the patient's thoughts or commenting on his or
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her thoughts and actions. Mood changes include ambivalence, constriction, or inappropriateness of feeling and loss of empathy with others; behavior may be withdrawn, regressive, or bizarre. These alterations usually occur in a setting of clear consciousness; disorientation and amnesia typically are absent.
TABLE 20.4. DIAGNOSTIC CRITERIA FOR SCHIZOPHRENIAa | ||
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Central to this characterization is the concept of a disorder of thought. This may be manifested in the inappropriate rate, flow, or content of thinking or communication. It may be evident in the supervening style of the thinking process and the associated verbal productions. Typical manifestations of disordered thought processes in schizophrenia arranged according to the mnemonic B/NOT/MVP/DDT are as follows:
Blocking, often associated with the subjective feeling of not being in control of one's own thoughts;
Neologisms, new personal language;
Overinclusive thinking in which usual conceptual boundaries are lost or blurred;
Thinking that is overly personalized and not abstract;
Muteness;
Verbigeration (the senseless repetition of words and phrases, seen particularly in chronic patients);
Private logic;
Difficulties in generalizing correctly and in seeing similarities and differences;
Difficulties in separating relevant from irrelevant and in screening out the irrelevant;
Things may be seen as identical because they share a common or similar property.
B. Schizoaffective Disorder
Clinicians often see psychotic patients who reveal delusions, hallucinations, and disordered thoughts but who also appear elated or depressed. When depressive symptoms are prominent, such patients are classified as depressive type in the DSM-IV. Patients with the depressive type must be differentiated from patients with psychotic depressions whose delusions usually involve guilt or bizarre somatic concerns (e.g., my stomach is rotting away ) or both. Patients presenting with initial episodes of psychotic depressions are typically over the age of 40; patients with schizoaffective disorder are often younger.
Patients with bipolar type must be distinguished from patients in the psychotic phase of bipolar disorder (see Chapter 19). In patients with schizoaffective disorder, the disturbance in thinking is more typical of schizophrenia (e.g., blocking, illogical thinking, overinclusive thinking) rather than of mania (e.g., pressure to keep talking, racing thoughts). For patients with bipolar disorder in an excited psychotic episode to have an element of humor in their verbal productions is also typical. By contrast, patients with schizoaffective disorder are more likely to seem bizarre, and patients with schizophrenia, disorganized type, (sometimes older and more chronically ill) are more likely to appear silly and inappropriate. Patients with schizoaffective disorder usually have an episodic course with a good prognosis for a particular episode.
That patients with schizoaffective disorder were often classified as atypical or as having early forms of schizophrenia or bipolar disorder is understandable. K. Leonhard, who would have classified many of these patients as having cycloid psychoses, noted that their episodic course could eventually become chronic, with only partial remission from episodes once the illness pattern was well established. He considered these patients to have an independent endogenous psychosis that was neither schizophrenia nor bipolar disorder. Another alternative would be to see these disorders as reflecting a genetic mixing of bipolar disorder and schizophrenia. Careful observation of
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such patients suggests they are an extremely heterogeneous group; their family history patterns reveal more relatives with major depressive disorder and bipolar disorder and somewhat more relatives with schizophrenia and schizoaffective disorder than do those of control subjects. They also are likely to have first-degree relatives with alcoholism.
C. Schizophreniform Disorder
When G. Langfeldt introduced this term in 1939, it referred to acute reactive psychotic decompensations in previously well-functioning (i.e., normal) persons. Currently (i.e., in DSM-IV), this diagnosis is used for patients who appear to be having a more attenuated form of schizophrenia in terms of both duration and degree of disturbance in behavior and functioning. Rather than lasting for at least 6 months, the prodromal, active, and residual psychopathology in schizophreniform disorder lasts more than 3 months but less than 6 months with no severe impairment of functioning. Three modifiers are recommended.
Provisional. This term is used when schizophreniform disorder appears to be the appropriate diagnosis, but the patient is still ill (i.e., not enough time has elapsed since onset to assess whether recovery will take place before 6 months have passed). For patients who do not improve after 6 months, changing the diagnosis to schizophrenia is appropriate.
With good prognostic features. At least two of the following should be present:
The time between any evidence of disturbed behavior and functioning and marked psychotic symptomatology is no more than 1 month (i.e., a relatively more rapid onset and a short prodromal phase).
At the height of the psychotic decompensation, symptoms of confusion or perplexity should be apparent.
Premorbid job or school and social role functioning should not be significantly compromised.
Affect should not be flat or blunted.
Without good prognostic features.
D. Brief Psychotic Disorder
In the DSM-IV, this term is used for patients whose psychotic picture lasts for longer than 24 hours but for less than 1 month. The symptom pattern seen in these patients should be precipitated by an intensely distressing experience and should be followed by complete recovery of functioning to premorbid levels. As was noted earlier, the term provisional can be used as a modifier. The psychotic features should not be secondary to a medical condition or substance or medication use nor should they be part of a mood disorder or schizophrenia. One of four features (delusions, hallucinations, disorganized speech, and grossly disorganized or catatonic behavior) must be present, and this must not solely reflect a culture-bound behavior.
E. Symptoms of Depression in Schizophrenia
In addition to patients who have schizoaffective disorder, depressive type, other schizophrenic patients may show depression or depression-like symptoms at various times in the course of their disease. These symptoms may reflect the negative symptoms of schizophrenia. However, they may represent other conditions or manifestations of depression, broadly defined. The following subsections review selected considerations or conceptualizations that the author has found clinically useful, even though they are not incorporated into the DSM-IV or ICD-10.
Depressive position. Some patients appear to be in a depressive position or phase in their recovery from an acute episode of decompensation, as if they are demoralized about what has befallen them. Some appear to be grieving, whereas others appear to have shifted from paranoid thinking or delusions and distortions to depressive content (e.g., They hate me has become I hate myself ).
Depression per se. Clinical experience clearly shows that schizophrenic patients are not immune to depression. For example, a schizophrenic
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patient can experience and reveal a dysphoric mood or can move into an episode of major depressive disorder in connection with the loss of a significant person and yet not show further worsening of any preexisting schizophrenic symptoms. Antidepressant therapy added to the regimen of antipsychotic drugs may be of benefit to some of these patients. In other patients, depression may appear before the onset of psychotic symptoms in a first episode or during an exacerbation of symptoms in a patient who had been in remission. Although a few may benefit from antidepressants alone, more commonly these patients are likely to become more overtly psychotic when antidepressants are prescribed in the absence of antipsychotic agents.Neurasthenia. These patients appear stuck. They have often been chronically ill, or they have symptoms consistent with schizophrenia, residual type. They may seem depressed, without the will to reengage with active life outside an institutional or sheltered setting. Many seem demoralized (e.g., Why bother! Nothing gets better ). In some patients, this may be an iatrogenic condition, a result of prolonged hospitalization or inadequate rehabilitation and socialization. In others, it may result when a well-meaning therapist tries to get the patient to do what the therapist wants for the patient rather than what the patient wants for himself or herself. The literature also contains a speculation that neurasthenia is a phase some patients must pass through as part of their reintegration process.
Overmedicated patients. Some schizophrenic patients who appear retarded and depressed may simply be overmedicated, especially those receiving conventional antipsychotic agents (CAPs). Dosage reduction should produce an amelioration of their psychomotor retarded-depressed presentation.
Akinetic parkinsonism. Some patients may have neuroleptic-induced akinetic parkinsonism, especially those using CAPs, which presents to the observer as depression and psychomotor retardation. A trial of an antiparkinsonian agent may identify this subgroup.
II. Etiology and Genetic Factors
Although an in depth discussion of the etiology and pathobiology of schizophrenia is beyond the scope of this chapter, certain observations compel comment and these are mentioned in the appropriate sections. Schizophrenia tends to aggregate in families; data from investigations of twins and of children born to schizophrenic mothers but placed for adoption at birth argue for a major genetic factor in the etiology of the illness for some patients. About 50% of monozygotic twin pairs are concordant for schizophrenia; this argues against a simple genetic explanation. Nevertheless, there is reason to suspect that certain individuals inherit a susceptibility to the expression of schizophrenic disorganization. In some people, this susceptibility may lead to an early expression of symptoms, as in the schizophrenias of childhood and adolescence. More typically, the symptoms appear during adolescence or early adult life, perhaps when the stresses of separation from family or the requirements for living autonomously expose a schizophrenic vulnerability. An individual who is so burdened may be unable to cope with the stresses and demands of everyday life or to bear the losses, disappointments, or defeats that usually are encountered.
At the present time, genetic studies implicate several genes that may be linked to vulnerability to schizophrenia. This diverse group includes chromosomes 1q, 6p, 6q, 8p, 10p, 15q, and 22q. The strongest and most replicated evidence involves the 7-nicotinic receptor subunit gene (CHRNA7) at the 15q13-14 locus.
III. Differentiating Schizophrenia from Other Conditions that May Produce Similar Symptoms
The diagnosis of schizophrenia must still be made in part by exclusion. Table 20.5 lists some conditions and illnesses that can present with psychotic symptoms. Because so many of the symptoms of schizophrenia may be manifestations of a variety of local or systemic processes that alter central nervous system function, a complete consideration of these possibilities is beyond the scope of this chapter.
TABLE 20.5. SOME CONDITIONS AND ILLNESSES THAT CAN MANIFEST SCHIZOPHRENIFORM SYMPTOMS | |||||||
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Of primary importance in this differential diagnosis is a careful personal and family history and physical examination, together with the judicious use of the clinical laboratory. Any history of exposure to drugs or toxins, a family history of a genetic disease, or the presence of neurologic deficits or the stigmata of systemic disease may be particularly significant.
IV. Epidemiology and Pathobiology
The lifetime risk for schizophrenia is estimated at 0.8% to 1.9%. The current estimate is that schizophrenia is present in about 2 million persons in the United States. The prevalence among men and women is probably approximately equal. Recently, some investigators have suggested a slightly higher prevalence among men; other investigators have concluded that more women develop schizophrenia. The age at onset of the first psychotic decompensation is in the mid-20s for women and is about 5 years earlier for men. Most men with schizophrenia have revealed obvious evidence of the disease before the age of 30. For men who develop schizophrenia to have shown a pattern of unsocialized aggression during their early adolescent years is not uncommon.
The risk of schizophrenia is 40% to 50% for the offspring of two schizophrenic parents and about 5% for those with one schizophrenic parent. A significantly
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greater likelihood is seen of finding schizophrenia among the first-degree relatives of schizophrenic patients than among the third-degree relatives (i.e., first cousins). The latter have rates that approximate the rate in the general population. As one might expect, the prevalence rates in second-degree relatives (aunts, uncles) fall between the two. These estimates are complemented by findings from adoption studies of children, both with schizophrenia and without, that were conducted in Denmark in the 1970s and 1980s. Rates for schizophrenia were higher among the first-degree biologic relatives of the adoptees with schizophrenia than among the relatives of the control subjects, and no increase in the rate of schizophrenia was observed among the adoptees who had nonschizophrenic parents but who were adopted by families in which one parent was schizophrenic.
Given the diverse symptomatology seen in patients with schizophrenia, that imaging studies (e.g., magnetic resonance imaging, positron emission tomography, single photon emission computed tomography) do not reveal consistent neuroanatomic changes is not surprising. Some of the following findings, however, occur with reasonable frequency: enlarged ventricles, widened sulci, hypofrontality as reflected in lowered glucose utilization, volume reductions in the gray matter of the left temporal lobe, and atrophy of the cerebellar vermis. The thalamus and striatum may also show changes. The frontal lobe changes are consistent with the defect state or negative symptoms seen in schizophrenic patients, and one group of investigators recently suggested that reductions in the volume of the left posterior superior temporal gyrus correlate with the degree of disordered thinking. Similarly, reduced insular gray matter volume and cortical surface size correlate negatively with the severity of psychotic symptomatology. In a meaningful proportion of patients with schizophrenia, reduced blood flow has been found in four brain regions cerebellar vermis, parahippocampal gyrus, nucleus accumbens, and insular cortex the latter three of which are limbic structures. A reasonable conclusion from these varied findings is that alterations in the interactions among frontal and mesolimbic pathways and structures may be the basis for many of the symptoms of schizophrenia.
An intriguing finding from postmortem brain tissue of persons known to have had schizophrenia is down-regulation of the gene for Reelin (RELN), a high affinity ligand for integrin receptors that is synthesized by -aminobutyric acid (GABA)ergic frontal cortex neurons. RELN is known to bind to the dendrites and dendritic spines of pyramidal neurons. Down-regulation is consistent with the shortened dendrites and the lower dendritic spine expression densities in pyramidal neurons that are found in the postmortem tissue from some deceased schizophrenic patients. Because similar changes have been found in cortical tissue from deceased patients who had bipolar disorder but not in those with major depressive disorder without psychotic features, this finding is not specific to schizophrenia.
Other findings suggest a reduction of GABAergic activity that may result in increased limbic and prefrontal area dopaminergic activity. A possible cause of these observations could be the disinhibition of glutamatergic activity or the hypofunction of N-methyl-D-aspartate receptors on GABAergic interneurons. This concept is consistent with the occurrence of schizophrenic-like symptoms after subanesthetic doses of the noncompetitive dissociative anesthetic N-methyl-D-aspartate receptor antagonists, such as phencyclidine, ketamine, and MK-801. The role of excitatory amino acids and their interactions with GABAergic interneurons and dopaminergic neurons remains an incompletely explored yet potentially important area of study that also includes the termination of glutamatergic activity by astrocytes.
Changes in dopaminergic activity, if they are not causal, appear to be at least contributory to the manifest symptomatology of schizophrenia. Mesolimbic and mesocortical dopaminergic tracts arise in the ventral tegmental area of the A10 region and project to the limbic areas (i.e., amygdala, pyriform cortex, lateral septal nuclei, nucleus accumbens) and to the prefrontal and frontal cortex and septohippocampal regions, respectively. Dopamine 2 (D2) and D3 postsynaptic
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receptors along these pathways appear to be important mediators of behavior. All currently marketed antipsychotic agents are antagonists at these receptors. D3 (limbic area) receptor antagonism shows a strong correlation with the average therapeutic dose or potency of CAPs. The atypical antipsychotic agent (AAP) clozapine (see section VI.B.6.h) has a high affinity for D4 receptors.
A more specific understanding of the actions of antipsychotic agents on various dopamine receptors is difficult to achieve at the present time because of the complicated interplay of regional receptor differences and actions at both presynaptic and postsynaptic sites. In the striatum, for example, D2 receptors inhibit acetylcholine release. On dopaminergic nerve terminals, these receptors also function as autoreceptors; their activation reduces the firing rates, synthesis, and release of dopamine. Experimental dopamine autoreceptor agonists stimulate supersensitive but not normosensitive postsynaptic receptors. In the substantia nigra, CAPs acting on both presynaptic and postsynaptic D2 receptors inhibit neuronal firing. Clozapine, olanzapine, quetiapine, ziprasidone, and risperidone show a reduced likelihood of decreasing the firing of these same neurons. As a group, these agents are all called AAPs. Mesocortical D2, D3, and D4 receptor antagonism appears to be particularly important to the alleviation of psychotic symptomatology. Clozapine use may, however, actually increase prefrontal dopaminergic activity. This could explain how clozapine is beneficial for negative symptoms that have been hypothesized to be related, at least in part, to decreased dopaminergic activity in this area. Data from experimental autoreceptor agonists suggest that they too may improve negative symptoms. However, data from clozapine, olanzapine, quetiapine, ziprasidone, and risperidone in vitro studies also argue for an important linkage to concomitant 5-hydroxytryptamine (5-HT)2 receptor antagonism for at least some patients. Indeed, a positive ratio favoring 5-HT2 over D2 receptor binding is central to the definition of an AAP (Table 20.6; see also Table 20.10).
V. Course, Outcome, and Prognosis
One of the crucial elements in Kraepelin's distinctions between manic-depressive psychosis and dementia praecox arose from data generated by follow-up examination. Dementia praecox was seen as an illness from which recovery was not common. In the 1910 edition of his textbook, Kraepelin, although he did acknowledge recovery in some 13% of patients, cited many contemporary investigations that emphasized deterioration and lack of recovery.
Eugen Bleuler's concept of a group of schizophrenias suggested the possibility of a broad spectrum of courses, outcomes, and prognosis. However, E. Bleuler emphasized that, despite periods of arrest or reversal, the patients would probably never be totally free of schizophrenia. As was noted earlier, Langfeldt emphasized a dichotomization of diagnoses based on outcome. Narrowly defined (nuclear) schizophrenic patients were predicted to have poor outcomes at follow-up. Another subset of patients was seen to recover and was considered schizophreniform by virtue of both their recovery and the presence of certain features in their behaviors and histories (e.g., acute rather than insidious onset, good rather than poor premorbid functioning, depressive symptoms). Langfeldt, noting
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M. Sakel's observation that 88% of schizophrenic patients recovered, suggested that this was based on diagnostic error and that the patient population must have included many reaction types with a tendency to spontaneous recovery. Many other clinicians have restated this position. J.H. Stephens, for example, wrote that apparent schizophrenia with a good prognosis is not a mild form of schizophrenia, but is a different illness.
TABLE 20.6. A WORKING AND EVOLVING DEFINITION OF ATYPICALITY FOR ANTIPSYCHOTIC AGENTS | ||
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Course and outcome must be considered not only in terms of manifest psychopathology but also with regard to adjustment or performance criteria as reflected by working capacity, interpersonal relationships, autonomy, and self-regard. Outcome may best be viewed as a process rather than as a dimension measured at a fixed point in time. Manfred Bleuler, for example, using observations from a study of over 500 schizophrenic patients seen by 1941, outlined seven possible longitudinal patterns to describe the course and outcome of schizophrenia as follows:
Acute onset leading to chronic severe psychosis;
Insidious onset leading slowly to chronic severe psychosis;
Acute onset leading to chronic mild psychosis;
Insidious onset leading slowly to chronic mild psychosis;
Several acute episodes leading to chronic severe psychosis;
Several acute episodes leading to chronic mild psychosis;
One or several acute episodes leading to recovery.
The first four patterns show a rather continuous evolution; the latter three are phasic. Having followed the life experiences of this cohort of schizophrenic patients for 23 years, M. Bleuler concluded that these patterns subsumed the experiences of 90% of patients. Other patterns, however, are certainly possible (e.g., insidious onset leading to recovery, chronic psychosis followed by acute episodes).
M. Bleuler began to accumulate a new cohort of over 200 patients in 1942. Twenty-six years later, more than a decade after the introduction of effective antipsychotic agents, Bleuler wrote about his 23-year follow-up of these 200 patients and indicated that the pattern acute psychosis leading to chronic severe psychosis had almost disappeared. He further suggested that cases evolving to a mild chronic psychosis had increased, whereas those involving severe chronic psychoses had diminished. He cautioned, however, that although the most malignant acute schizophrenias are under control now, the most chronic schizophrenias are not. The percentage of chronic onset leading slowly to chronic severe psychosis has remained nearly the same within the last 25 years A further finding is also disappointing: it was not possible to increase the percentage of recoveries much over one-third of all cases. The reader should remember that M. Bleuler's data and perspective antedate the use of clozapine and other AAPs.
O.H. Arnold, who wrote in the mid-1950s before the advent of effective antipsychotic agents, described a large cohort of 500 schizophrenic patients that he followed for 3 to 30 years. His results revealed the following: (a) a phasic course of illness leading to complete remission in 15.6%, (b) a phasic course that became shift-like (new acute symptomatology that was followed by partial recovery) in 4%, (c) a phasic course leading to deterioration in 0.4%, (d) a phasic course leading to deterioration punctuated by exacerbations of symptomatology in 3.4%, (e) a shift-like course with some residual pathology in 9.6%, (f) a shift-like course leading to deterioration in 3.6%, (g) a shift-like course leading to deterioration punctuated by exacerbation in 14%, (h) a gradual deterioration in 7.2%, (i) a gradual deterioration punctuated by exacerbation in 38%, and (j) mixed psychotic courses in 6.6%. The important theme in his findings was that only about 16% recovered, whereas 67% of patients had chronic or eventually deteriorating courses, an ominous prognosis for patients with schizophrenia who do not receive effective antipsychotic therapies.
Many authors have examined and reviewed historical and clinical features that may not be dependent on treatment, yet they do correlate with improvement in schizophrenia. Table 20.7 summarizes some of the predictor variables that appear in these reviews. From this literature, one appears to be able to predict more
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readily those who are less likely to do well than those who are likely to have a hopeful outcome.
TABLE 20.7. SOME PREDICTORS OF OUTCOME IN SCHIZOPHRENIA | ||||||||||||||||||||||||
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Even with effective agents, can an individual really get over schizophrenia? Is remission merely a phase of arrest or reversal, as E. Bleuler suggested? Does he or she remain predisposed to decompensations under certain conditions? One cannot be cured of diabetes, for example, even though, with proper treatment, the expression of, and morbidity from, the illness can often be greatly modified. An ulcer may heal, but a predisposition to hyperacidity or infection by Helicobacter pylori may remain. Schizophrenia is not merely a pattern of overt symptomatology; it also appears to be an underlying vulnerability. Even when substantial or complete improvement has been achieved (either with or without treatment), does the patient still warrant the diagnosis of schizophrenia in remission? Unfortunately, no resolution has yet been reached for this perplexing question.
VI. Selected Aspects of the Treatment of Schizophrenia
A. Hospitalization as a Therapy
In this era of cost containment and managed care, ambiguity is present about the place of hospitalization in treatment planning for patients with schizophrenia. Historically, extended periods of hospitalization were observed to have negative effects. J.K. Wing in Great Britain and E. Goffman in the United States thoroughly described the harmful and dehumanizing effects of institutionalization. At the present time, the pendulum appears to have swung too far in the opposite direction, and patients may spend too little time in the hospital to benefit from the positive effects of hospitalization. Many patients now have an increased number of all too brief hospitalizations; others are rarely or never hospitalized, and instead they join the ever-growing ranks of the homeless.
The onset of symptoms of schizophrenia is not by itself an indication for psychiatric hospitalization. When sufficient support exists in the community and patients' symptomatology does not constitute a threat to themselves or others, outpatient treatment should almost always be attempted. Keeping patients in community-based care may help to preserve their existing matrix of social supports. Studies of why patients are hospitalized suggest that many hospitalizations can be avoided when adequate family and community resources are available.
When patients are a threat to themselves or others, hospitalization is usually recommended, even in today's cost-conscious managed care environment. Suicidal and homicidal ideation and attempts are especially serious in schizophrenic patients (see Chapter 17). Psychotic patients often lack the impulse control or judgment to modify such feelings, especially when they
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are having command hallucinations. They also may become distressed by delusional beliefs, especially persecutory ideation. However, one characteristic of many schizophrenic patients is that they often do not appear to feel distressed by experiences that others would find upsetting.
Moreover, when patients are confused or so anxious that they cannot adequately care for themselves, hospitalization is indicated. Although the sensorium is usually clear in schizophrenia, confusion and frank disorientation occasionally may occur. In assessing a patient's capacity for self-care outside the hospital, assessing factors such as the patient's abilities to plan daily activities or to have a full night's sleep is important.
Occasionally, temporary hospitalization of the schizophrenic patient becomes necessary when those caring for the patient in the community are unable to do so or when interpersonal pressures on the patient become intolerable. Such occasions may include the illness of a parent or sibling or the birth of a child in the patient's family. The ability and willingness of a backup hospital to help to support a patient, and indirectly the family, may influence the acceptance of the chronically disturbed patient within the community. Table 20.8 summarizes some of the major indications for hospitalization.
When the clinical decision to hospitalize the patient has been reached, the reasons for such an action should be clear; they should be explained to the patient in an unambiguous way. Whenever possible, the patient's collaboration and participation should be obtained. Although some patients may be too disturbed to participate in such a decision, most will be able to respond in some positive way to the clinician's firm resolve that temporary hospitalization will be helpful. Once patients are hospitalized, some experience the relief from
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being in a place where they can feel relatively safe and can obtain help in controlling their impulses. The moratorium of, and distance from, upsetting experiences may also be beneficial. Because the modal duration of acute hospitalization under some managed care plans is 7 to 14 days, engaging acutely ill patients in any form of milieu therapy is rarely possible.
TABLE 20.8. SOME PURPOSES OF HOSPITALIZATION | ||
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Patients with schizophrenia often decompensate in unhealthy settings that are too stressful or too stimulating or in which abusable substances are available. Hospitalization may interrupt, not perpetuate, or even reverse this experience. Ideally, it should help patients regain interpersonal stability, and it should enable them to receive positive concern and regard from others. Adequate space and clearly written ward policies about passes, visitors, smoking, and personal possessions must exist. Stimuli in the ward setting that could encourage violence or sexual activity (e.g., television) should be minimized. Violence occurring within the ward setting is more likely to come from intolerance of restrictions or as a result of provocation by others than to be due to command hallucinations. Interpretive or oblique communications can increase patients' anxieties, anger, and disorganization. Communication with regressed patients must be clear, unambiguous, and brief.
Difficult management problems, such as acts of violence, inappropriate sexual behavior, and the refusal of food or medications, commonly occur. Because such activities can injure patients and those around them, the clinician should act in a firm but nonpunitive way to prevent such behavior. When the patient's behavior cannot be modified or contained by interpersonal interventions, such as clear verbal confrontation and exhortation, or by temporary placement in a quiet area, the use of physical restraints or seclusion may be indicated (see Chapters 25 and 26). Ideally, this need will be obviated by the patient's favorable response to antipsychotic agents.
The patient's refusal of food or fluids should not be allowed to endanger his or her health. This concern should be explained to the patient and his or her family. Although the legal issues regarding involuntary care and patients' rights to refuse treatment are being addressed, the emergency use of intravenous fluids and assisted feeding should be instituted when necessary. Acutely regressed, suicidal, or homicidal patients should not remain untreated when treatment is clearly indicated. When patients refuse oral medications, intramuscular administration or even electroconvulsive therapy (see Chapter 24) should be considered. After a short period of time, patients usually accept oral medications. Firmness in dealing with acutely regressed patients must not preclude efforts to reach an empathic understanding of their feelings or of what they may fear or of what they are trying to express.
In the past, hospitalizing the acutely schizophrenic patient allowed the clinician a more complete opportunity for clinical evaluation and a more controlled setting for effectively titrating the patient's dosage of antipsychotic medication. Currently, dosage titration is continued into the outpatient phase of care; unfortunately, some patients continue on the higher than needed doses that were previously necessary during hospitalization.
Discharge from the hospital-based phase of treatment to outpatient follow-up or community-based aftercare should be carefully planned. Premature discharge or discharge without adequate efforts to ensure that the patient is entering an environment that can tolerate his or her current level of functioning and psychopathology may make successful discharge and continued rehabilitation difficult if not impossible. These considerations are particularly relevant for acute exacerbations in chronically ill patients and for those who may have become alienated from family and friends. Table 20.9 summarizes many of the factors to be considered when evaluating the discharge readiness of patients.
B. Pharmacotherapy
The efficacy of CAPs (sometimes called neuroleptics or major tranquilizers) in treating acute and chronic schizophrenic patients has been established by a vast number of adequately designed controlled studies conducted over the
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past 45 years. These studies repeatedly demonstrate the usefulness of antipsychotic agents for reducing disordered thinking, anxiety, delusions, hallucinations, and other symptoms associated with schizophrenia. Marked improvement of negative symptoms, such as apathy or social withdrawal, is not always demonstrated in studies with CAPs. After the introduction of the AAP clozapine, the fact that improvement in both negative and positive symptoms was more possible than was previously expected became apparent.
TABLE 20.9. SOME FACTORS TO BE CONSIDERED DURING DISCHARGE PLANNING | ||
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Selection and specificity. Although claims are made for differential therapeutic effectiveness among antipsychotic agents, controlled replications do not consistently substantiate such differences. One exception to this is clozapine (see section VI.B.6.h), which may have differential efficacy in some treatment-resistant patients. The choice of a particular antipsychotic medication rests primarily on a consideration of its main and secondary pharmacologic properties, its side effects, and its toxicity, as well as the patient's and the clinician's past experience with the drug. Cost may also be a factor in some settings. Clinical experience might suggest that a given patient should respond better to one drug than to another; however, in the absence of prior exposure or pharmacogenetic data, drug selection is empirical. In choosing an antipsychotic medication, the clinician must anticipate the patient's probable overall reaction. For instance, an agitated or sleepless young adult patient could benefit from the soporific effects of thioridazine, whereas an elderly or dehydrated patient might be harmed by the hypotensive and anticholinergic effects of this agent.
A patient's past experience with a particular medication may partially determine the clinician's current choice. In addition to inquiring about a past history of adverse drug reactions, including allergies, the clinician should try to ascertain which drugs the patient believes were of
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benefit and which were poorly tolerated because of particular unwanted effects. This investigation will not only supply the clinician with needed clinical information, but it will also promote the patient's cooperation with, and participation in, the treatment process.Finally, clinicians should consider their own observations about a particular drug. Because many antipsychotic medications, including five AAPs, remain on the market today, extensive experience with all of these is unlikely. The author recommends that the clinician select about eight representative drugs from the currently available pool of CAPs and AAPs and become familiar with their clinical effects, both wanted and unwanted. Table 20.10 lists some features of eight representative antipsychotic agents.
Dosage adjustments. When titrating the dosage of a particular antipsychotic medication, the stage of the patient's decompensation and his or her target symptoms, body size, weight, and known response to the drug or similar agents must be considered. Antipsychotic medications exert their therapeutic effects over a broad dosage range; particular patients who do not respond favorably to a drug at one dosage level may respond at a higher or lower dosage.
When beginning the use of antipsychotic medication for the first time, administration of a small test dose of the drug is sometimes desirable (i.e., 25 to 50 mg orally or 25 mg intramuscularly [i.m.] of chlorpromazine, or the equivalent dose of another antipsychotic drug). This is particularly relevant for low potency CAPs. Doing so will give the clinician an opportunity to observe the patient for the development of orthostatic hypotension or other idiosyncratic effects. If such reactions do not occur within 2 hours of the administration of such a test dose, the clinician may then begin titrating the drug dosage into an effective antipsychotic range.
TABLE 20.10. SOME PROPERTIES OF SELECTED ANTIPSYCHOTIC AGENTS
Agents 5-HT2/D2a (KDs) Dosage Rangeb in mg (maximum) Ds Oral Dose Equivalencec in mg Conventional Chlorpromazine 14 30 800 100 Thioridazine 1.2 50 400 (800) 60 100 Haloperidol 0.11 6 15 (100) 1 5 Atypical Clozapine 81 12.5 450 (900) 60 100 Quetiapine 25 25 750 (800) 25 75 Olanzapine 13 5 10 (15) 2 5 Risperidone 25 2 8 (16) 1 3 Ziprasidone 21 20 100 (160) 3 7.5 aThese estimates are reproduced with permission from Richelson E, Nelson A. Eur J Pharmacol 1984;103:197 204; Wander TJ, et al. Eur J Pharmacol 1987;143:279 282; Richelson E, Souder T. Life Sci 2000;68:29 39, with permission.
bSee page xiv. These data are based on the author's clinical experience and awareness of the literature; lower dosages are generally required for the elderly and slow titration, when clinically appropriate, is desirable; maximum doses reflect either manufacturers' recommendations or the author's synthesis of safety literature.
cOral dosage equivalence is at best an approximation because of variables, such as formulation dissolution characteristics (e.g., particle size, excipients, presystemic extraction, amounts of liquid consumed); also equating conventional to atypical agents is not always straightforward because of tolerability differences.Abbreviations: D2, dopamine; 5-HT, 5-hydroxytryptamine; KDs, dissociation constant. P.300
Table 20.10 lists the approximate relative potencies of eight antipsychotic agents when given orally. These are at best rough approximations. For example, they may apply during the acute treatment phase but not to maintenance therapy. The values that are given are more accurate in the lower dosage ranges. Relative potencies of various drugs at high dosage ranges and for parenteral routes have not been studied adequately. Therefore, establishing the proper therapeutic dosage for a specific patient is largely an empirical process. These and the other dosage recommendations that follow are meant simply as guidelines to the clinician as he or she adjusts the dosage of a particular antipsychotic medication to meet the needs of the specific patient.
The usual antipsychotic dosage range for acutely ill schizophrenic patients, for example, is 2 to 8 mg per day of risperidone or 5 to 15 mg per day of haloperidol or an equivalent amount of another drug. Lower doses in such patients are not consistently effective, and higher doses, even if they are adequately tolerated, usually do not produce enhanced therapeutic effects. Although containing a patient's agitated, destructive, or regressed behavior is important, snowing the patient with excessive doses of antipsychotic medication may only treat the staff's anxieties, not the patient's turmoil or distress. The clinician should remember that antipsychotic drugs often have a cumulative or time-dependent therapeutic effect. Such an effect usually begins within the first 48 hours of treatment, but it may take up to several weeks after beginning a drug. In the author's experience, this is particularly common with olanzapine; initial concomitant use of risperidone or haloperidol during the first 5 to 21 days of treatment may hasten or improve the patient's response. As a general rule, the author advises titration of dosage until an adequate therapeutic response is achieved or troublesome side effects are encountered.
Rapid tranquilization and parenteral administration. Some authors advocate rapid tranquilization for acutely agitated schizophrenic patients, particularly when extreme agitation is present. This may involve frequent i.m. dosing (every 1 to 4 hours) until improvement is observed. Rapid tranquilization primarily achieves a quieting effect or sedation. The initial benefits are usually observed within 30 minutes to 2 hours. No rapid antipsychotic effect per se is present, unless calming the patient reduces his or her psychotic terror and agitation. Improvement often occurs within a day; frequent dosing for longer than 2 days is rarely beneficial.
Although i.m. haloperidol is not sedating, it is still used worldwide for rapid tranquilization by many clinicians. Supplementation with a benzodiazepine, such as lorazepam, is common. Droperidol, another butyrophenone, is also used in some emergency departments for rapid tranquilization. Because of its association with cases of ventricular tachyarrhythmias, droperidol is no longer available in some countries; in the United States, its use is restricted to those for whom other treatments have failed and who have no know risk factors for QT interval prolongation. Risperidone also enjoys some popularity when rapid tranquilization is needed but only when an oral medication (tablet or oral solution) is suitable.
Both i.m. olanzapine and i.m. ziprasidone have recently received United States Food and Drug Administration (FDA) approval for the treatment of agitation. In submitted studies, i.m. olanzapine in doses of 2.5 to 10 mg was shown to be statistically superior to the placebo and to be comparable with haloperidol or lorazepam on a scale that assessed positive and negative symptoms. In trials with ziprasidone, patients with schizophrenia and schizoaffective disorder, as well as patients with bipolar disorder, were given injections of either 10 mg every 2 hours (up to a maximum of 40 mg in 24 hours) or 20 mg every 4 hours
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(up to a maximum of 80 mg in 24 hours) for their agitation, and rapid improvement was noted. Both i.m. preparations appear to be well tolerated. Bradycardia secondary to olanzapine occurred in about 8%. This may reflect the drug's antagonist actions at the 1-adrenergic receptors. According to the manufacturer, bradycardia and some degree of postural hypotension occur more often in the nonagitated control patients and in those who have not been previously treated with an oral dose. With ziprasidone, a concern about cardiac side effects (i.e., QT interval prolongation) does exist. Manufacturer's data suggest that the mean change in QTc after administration of i.m. ziprasidone does not exceed the prolongation found with the oral formulation, which averaged approximately 10 ms longer than that seen with risperidone, olanzapine, quetiapine, or haloperidol; that increment was less than the average change with a 300 mg dosage of thioridazine.These parenteral approaches to treating psychotic agitation emphasize the frequency of, or time interval, between dosage increments. Although these procedures may be of value to some patients, especially in emergency situations, many clinicians do not believe this approach has an acceptable benefit-to-risk ratio.
Dosage schedules. After picking an antipsychotic medication and titrating its dose, the clinician should carefully rationalize the patient's dosage schedule. After the first few days of treatment, intensive administration of medication four to five times a day is usually unnecessary. Antipsychotic agents usually are generally well tolerated in large single oral doses. Reducing the number of daily administrations, while making appropriate increases in the tablet or capsule strengths, to a single bedtime dose or to two doses a day saves nursing time and costs, and it lessens the inconvenience to the patient and the cost per milligram of the medication. Furthermore, patient discomfort from many side effects is minimized by single bedtime doses, because the patient is asleep during the time of maximal anticholinergic or orthostatic hypotensive effects; this will not be beneficial unless the patient is sedated.
Maintenance and discontinuation of treatment. For first-episode patients, experience and published studies suggest that maintenance pharmacotherapy supplemented by psychosocial treatments, particularly family interventions when they are appropriate, is the best way to reduce relapse rates. Once the acute psychotic symptoms are controlled and the patient's condition has stabilized (usually 2 to 12 weeks), the daily dosage of medication may be slightly reduced over a period of weeks, but it should be kept at a full antipsychotic dose (usually about 100 to 400 mg per day [range, 100 to 600 mg per day] in chlorpromazine equivalents). Maintenance therapy is effective in more than 50% of patients. Benzodiazepines are sometimes used to reduce any exacerbations of symptomatology during maintenance treatment.
Drug-free intervals of 1 to 3 consecutive days a week (e.g., during weekends) are advocated by some clinicians to reduce the total amount of drug ingested by the patient, and these may be accomplished in many patients without ill effects. At this time, drug-free periods do not appear to be needed with AAP use. In contexts where CAP use is involved, whether this holiday approach alters the likelihood of serious side effects, such as tardive dyskinesias (TDs), from CAPs remains unclear.
Other than relapse or the emergence of serious unwanted effects, no clear guidelines exist for dictating the discontinuation or the switching of antipsychotic medications. Indeed, with AAPs, indefinite maintenance seems to be warranted. Discontinuation of maintenance medications in chronic ambulatory schizophrenic patients usually leads to relapse. Some clinicians still advocate a trial with no medication for patients who have attained a complete remission for about 6 months or for
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those who have been in chronic care settings and are being maintained on very low doses of medication. The clinician must remember that these agents leave the body slowly; therefore, drug-related relapse may not occur until weeks or months after discontinuation. One possible approach to trial discontinuation in chronically schizophrenic patients is to decrease the maintenance dosage by about 30%. If no deterioration is seen in 6 to 8 weeks, further decreases of 30% can be attempted at similar intervals. When a patient's aftercare program provides for reasonably frequent visits, the clinician should be able to see whether a patient's clinical status is beginning to deteriorate. In most instances, the medication can be reinstituted or the dosage can be increased before frank relapse occurs.Many patients in aftercare status do not follow their prescribed treatment regimens. They may purchase or pick up their pills but then not swallow them. This may even happen when the pills are handed directly to the patient. Some data with CAPs suggest that a small number of very chronic patients require at least 2 years of antipsychotic drug treatment before changes are seen and that these changes are sometimes limited to more integrated behavior in a sheltered and structured living situation. What significant changes for which chronically ill patients can be accomplished in these expected outcomes with the use of clozapine or other AAPs has not yet been fully established.
Controlled studies generally show the benefits of the continuous use of antipsychotic agents to both chronic and acute schizophrenic patients. Depot medications may be necessary and appropriate for facilitating this in some patients.
General comments and specific considerations
Oral dosage forms are usually effective. Time-release or sustained-action forms should not be necessary because of the long half-lives of these compounds. Liquid forms may be necessary for some patients, but they significantly increase the cost per milligram of most drugs.
The use of more than one antipsychotic agent at a time is seldom indicated. Little evidence exists to suggest that combining drugs is more useful than raising the dose of one drug or switching to another drug. One exception may be the initial use of haloperidol or risperidone during the early weeks of exposure to olanzapine. (Note: Rather than combining agents, some clinicians prefer to use a loading dose approach with olanzapine, instead of following the usual strategy of gradual incremental dosing.)
Long-acting (depot forms) antipsychotic agents may be indicated for patients who are unreliable medication takers. Estimates are that significant problems with adherence not taking one's medication in the amount or frequency prescribed or missing days rather than merely skipping occasional doses occur in 20% to 50% of chronically ill schizophrenic patients. Some studies suggest that most schizophrenic patients who stop their medications will relapse within 12 months. Several conventional agents are available in a variety of long-acting formulations as follows: fluphenazine enanthate (usually effective for 10 to 14 days), fluphenazine decanoate (usually effective for 14 to 21 days), and haloperidol decanoate (usually effective for 26 to 30 days). Dosage conversion is generally based on the assumption that 5 mg per day of oral fluphenazine equals 25 mg of either fluphenazine enanthate or fluphenazine decanoate given every 10 to 14 or 14 to 21 days, respectively; 5 mg per day of oral haloperidol is replaced by haloperidol decanoate given monthly (50 to 75 mg). Individual adjustment of dosage to meet a specific patient's needs is essential, and the lowest possible dose should be given. Customary maintenance doses of these depot
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agents are 5 to 50 mg every 3 weeks for fluphenazine decanoate, 5 to 75 mg every 2 weeks for fluphenazine enanthate, and 50 to 150 mg every 4 weeks for haloperidol decanoate. A slightly increased incidence of neuroleptic malignant syndrome (see Chapter 3) and TD may be associated with the use of these depot forms. Some estimates suggest that the use of depot preparations can reduce relapse rates among chronically ill patients by up to about 45%.Risperidone is also available as a long-acting injectable microsphere formulation for i.m. use that is given every 2 weeks (25 to 75 mg). The microspheres are made from a biodegradable polymer. The side effects associated with its use are considerably milder than those seen in patients taking conventional depot antipsychotic agents; they consist mainly of headache, agitation, drowsiness, and increased anxiety.
Drug interactions are discussed in Chapter 29. Particularly noteworthy are the pharmacodynamic interactions involving other drugs with anticholinergic effects (e.g., thioridazine plus amitriptyline); carbamazepine's ability to induce the metabolism of antipsychotic agents, such as haloperidol; and the increased clearance of quetiapine by thioridazine (putatively through induction of cytochrome P-450 [CYP] 3A4).
The use of electroconvulsive therapy for schizophrenic patients is discussed in Chapter 24.
The use of antidepressants in schizophrenic patients is briefly discussed in section I.E.2.
Lithium and mood-stabilizing anticonvulsants, when added to antipsychotic agents, may be beneficial in some schizoaffective patients of the excited type who do not respond adequately to the antipsychotic agents alone. (Note: The use of lithium for patients without a bipolar disorder diagnosis is not currently approved by the FDA.) In many instances, these patients actually may have an atypical bipolar disorder; subsequent episodes sometimes clarify the diagnosis. The dosage of lithium should be monitored and kept as low as possible. Some reports in the literature suggest a lowered threshold to neurotoxicity from lithium when it is combined with antipsychotic agents such as haloperidol. A few patients who have developed neurotoxicity while taking the combination of lithium and an antipsychotic agent were in seclusion rooms on extremely hot days or they had concomitant febrile illnesses. The importance of these factors for the appearance of neurotoxicity is not known (see Chapter 19).
Clozapine is a dibenzodiazepine derivative, and it is the first marketed agent in the United States to be considered an AAP. It is an effective treatment for both positive and negative symptoms in schizophrenic patients; its FDA approval is limited to refractory schizophrenia. About 50% to 60% of the 5% to 25% of patients with schizophrenia who do not respond to a CAP and perhaps half of the 5% to 20% who are intolerant to these agents because of the untreatable extrapyramidal side effects show noticeable improvement on clozapine. Moreover, clozapine provides an additional 20% benefit in the treatment of chronically ill schizophrenic patients. Although its current FDA approval is for use in refractory or treatment-resistant schizophrenic patients, it also appears to be beneficial in other schizophrenic patients and for psychoses secondary to L-dopa or bromocriptine (i.e., in patients treated for Parkinson disease). Its mechanism of action is not fully clarified, but it is an antagonist at D4, D3, D2, and D1 receptors and at 5-HT2A and 5-HT2C receptors. Its affinity for limbic D2 receptors is three times greater than that for
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striatal D2 receptors. In contrast to other CAP-type D2 antagonists, it produces only transient elevations in plasma prolactin concentrations (secondary to its capacity to increase briefly dopamine turnover in tuberoinfundibular neurons). Other antipsychotic agents known to produce an increase in dopamine turnover are thioridazine and quetiapine; however, thioridazine produces a somewhat more sustained increase in prolactin levels.Clozapine's half-life is about 8 hours, and its time to peak plasma concentration is about 2.5 hours. Up to 6 months may be required for clozapine to reach its full effectiveness. Plasma levels can be used to guide dosage; preliminary observations suggest that optimal levels may be in the range of 375 to 450 ng per mL. The manufacturer recommends divided dosing, and the dosage interval typically is twice a day.
Clozapine causes sedation, orthostatic hypotension, and hypersalivation (sialorrhea). Its most dangerous toxic effect, which occurs in about 1% to 2% of exposed patients, is agranulocytosis; the risk may be higher in Eastern European (Ashkenazi) Jews, elderly women, and people born in Finland. Clozapine has a low risk for causing TD, although a few cases have been reported in patients previously taking other CAPs. Other AAPs also are less likely than CAPs to put patients at risk for TD. Seizures are more common at doses greater than 600 mg per day. Weight gain and increased insulin resistance can occur.
Risperidone was the second AAP to be approved. Its approval is for the treatment of psychosis. A member of the benzisoxazole class, it binds with high affinity as an antagonist at both the 5-HT2 and D2 receptors (its D2 affinity is 100 times greater than its D1 affinity). Some authorities have been reluctant to classify risperidone as an AAP because, at higher doses, extrapyramidal side effects are not uncommon.
Risperidone is rapidly absorbed orally, and it reaches peak plasma concentrations after about 1 hour. Its elimination half-life together with its active metabolite 9-hydroxyrisperidone is about 1 day. Risperidone is a CYP 2D6 substrate. Its modal effective dosage range is 4 to 8 mg per day, but a few studies have shown efficacy within the range of 2 to 16 mg per day. The manufacturer recommends once or twice daily dosing. Mild drowsiness, as well as tiredness and weakness, is not uncommon. As has been noted, some postural hypotension and extrapyramidal effects, particularly akathisia, have been observed, particularly in the higher dosage range. These effects are consistent with its profile of activity at various central nervous system receptors; in addition to its 5-HT2 and D2 effects, it shows H1 antagonism and transient 1-adrenergic antagonism. Risperidone raises prolactin levels in a pattern that is more similar to CAPs than to other AAPs.
Quetiapine, a dibenzothiazepine, is an orally administered AAP that is approved for the treatment of psychosis. As a CYP 3A4 substrate, it is affected by both CYP 3A4 inhibitors and inducers (see Chapter 29). Its half-life is 6 hours, and peak concentrations are reached in 1.5 hours. The manufacturer recommends that dosing occur on a twice or three times a day schedule. Quetiapine has predictable sedating properties and minimal anticholinergic activity, and some clinicians consider it to be particularly useful for elderly patients. One caution regarding this latter use is quetiapine's potential to cause orthostatic hypotension. Although periodic eye examinations are formally recommended, this precaution derives mainly from animal, rather than human, toxicity data.
Olanzapine is a thienobenzodiazepine AAP that is approved for the treatment of psychosis. A partial substrate for CYP 1A2, its clearance
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is subject to both inhibition and induction (e.g., from aromatic hydrocarbons in cigarette smoke) by agents affecting this pathway (see Chapter 29). Weight gain and increased insulin resistance are drawbacks to this effective and widely accepted AAP. Some data suggest that both olanzapine and clozapine are inverse agonists at 5-HT2C receptors; this may be linked to the tendency of both of these agents to be associated with weight gain. Sedation and anticholinergic effects are moderate. After the oral administration of a single dose, olanzapine reaches peak concentrations after 6 hours. Its half-life ranges from 21 to 54 hours. The manufacturer recommends once daily dosing. A unique orally disintegrating tablet formulation is also available; this can be useful for selected patients, particularly those with swallowing difficulties.Ziprasidone is the most recently marketed AAP. The capsule formulation is approved for schizophrenia. Although it is an antagonist at both dopamine and serotonin postsynaptic receptors, ziprasidone also affects additional binding sites, including histamine (H1) receptor antagonism and the blockade of presynaptic transporters for serotonin and norepinephrine. Unlike other antipsychotic agents, it is an agonist at 1-adrenergic receptors. Ziprasidone has a half-life of 7 hours, and peak concentrations are reached 6 to 8 hours after a single oral dose. Twice daily dosing is recommended by the manufacturer. It is a CYP 3A4 substrate, but its major pathway is via aldehyde oxidase, which renders it less likely to be involved in pharmacokinetic drug interactions (i.e., no clinically used inhibitors or inducers of aldehyde oxidase are known). Only modest changes (30% to 40%) in ziprasidone's area under the plasma concentration curve are found when CYP 3A4 inducers or inhibitors are coingested. Product information warns of QTc interval prolongation; in perspective, though, use of this agent may convey a risk comparable with that of many other antipsychotic agents and may have less risk than that from thioridazine, mesoridazine, or droperidol.
Aripiprazole is an AAP developed in Japan and marketed in Mexico that is now available in the United States. It has a unique binding profile because it accomplishes its postsynaptic D2 effects not as a competitive receptor antagonist but as a partial agonist instead. It is also a partial agonist at the 5-HT1A receptors and an antagonist at the 5-HT2A receptors. The advantages and disadvantages of this drug are not yet fully understood. However, improved tolerability has been seen in switching studies. The improvements noted to date depend on the comparator drug (e.g., variable weight loss when given after olanzapine, lowered prolactin levels after risperidone, less extrapyramidal side effects [e.g., akathisia] compared with haloperidol). The typical daily dose is 30 mg per day.
Additional comments on side effects. Side effects and toxic reactions of antipsychotic drugs are varied; they potentially are extremely serious. They include neurologic and hepatic effects, hormonal alterations, weight gain, increased insulin resistance, blood dyscrasias, and pigmentary retinopathy (note: to avoid pigmentary retinopathy, an upper limit of 800 mg is placed on thioridazine dosage by the manufacturer). A full discussion of all possible reactions is beyond the scope of this chapter; nevertheless, prescribing clinicians must be thoroughly familiar with these reactions before using antipsychotic agents. Some side effects occur with sufficient frequency to merit brief review here (Table 20.11). Even though some schizophrenic patients may not fully comprehend discussions of potential side effects from these agents, discussing side effects with the patient and with any family members whenever this is possible is important.
Nonspecific sedation. Agitation, hyperactivity, and disordered sleep are common manifestations of schizophrenia. Because antipsychotic
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agents ameliorate the contribution of any thought disorder responsible for such manifestations, any drug of this type can have a calming effect and can improve sleep in a psychotic patient. In nonpsychotic persons, antipsychotic agents produce variable nonspecific sedation that depends on the particular drug and the patient's sensitivity to it. Both CAPs and AAPs with histamine (H1) receptor antagonist properties and, to a slightly lesser extent, piperidine phenothiazines and ziprasidone have sedative effects. Other CAPs and AAPs are less sedating. When sedation is the only unwanted effect of an otherwise effective agent, bedtime use or dosage reduction should be attempted before switching to another agent.TABLE 20.11. PATTERNS OF SIDE EFFECTS OF ANTIPSYCHOTIC AGENTS DURING ACUTE TREATMENTa
Antipsychotic Agent Effect (Receptors Antagonized) Anticholinergic (Muscarinic) Extrapyramidal (Dopamine) Hypotensive (Norepinephrine/Adrenergic) Sedative (Histamine) Chlorpromazine ++ ++ ++b ++++ Fluphenazine + ++++ + + Perphenazine + ++++ + ++ Trifluoperazine + ++++ + + Mesoridazine ++ + ++ ++++ Thioridazine +++ + ++ ++++ Chlorprothixene ++ ++ ++ +++ Thiothixene + +++ + + Haloperidol + ++++ + + Molindone + + + ++ Loxapine ++ ++ ++ ++ Pimozide + ++ ++ + Clozapine +++c ++ ++ +++ Risperidone +++ ++d + +e Olanzapine ++ + + +++ Quetiapine + + ++ ++ Ziprasidone + + + ++ +, slight; ++, mild; +++, moderate; ++++, strong. aThese estimates of the frequencies of selected side effects are based on the author's assessment of the use of these agents during the acute phase of treatment. Patterns may change during longer-term use (e.g., sedative effects usually are reduced). bIntramuscular administration enhances orthostatic (postural) hypotension.
cHypersalivation, particularly at night, is not uncommon.
dMore likely at higher doses (e.g., >6 mg/d).
eRisperidone can be more sedating in youth.The spectrum of effects produced by antipsychotic agents may also be influenced by variables such as the underlying disease for which the agent is being given. A person taking haloperidol to relieve nausea and vomiting may experience little or no sedation, whereas the same dose may have a calming or even soporific effect when given to an agitated and sleepless schizophrenic patient.
Adrenergic antagonism. 1-Adrenergic receptor antagonist properties of antipsychotic agents approximately parallel their nonspecific sedative effects. Aliphatic phenothiazines, thioxanthenes, and dibenzodiazepines are potent 1-antagonists; piperazine derivatives, butyrophenones, dihydroindolones, and benzisoxazoles are weak antagonists. Dibenzoxazepines appear to be intermediate. Orthostatic
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(postural) hypotension is the most important consequence of this property; this effect must be considered, especially when chlorpromazine, chlorprothixene, thioridazine, or clozapine is prescribed. An increased risk may also be seen with quetiapine. In some instances, drug-induced hypotension has been serious or fatal, but exactly how frequently such events occur has not been established. As was noted earlier, taking the patient's blood pressure in supine and standing positions both before and after a test dose is recommended, particularly in the elderly. Patients who experience mild postural changes should be advised to get up slowly. Nighttime use of pressure (TEDs) stockings may also be beneficial.A serious episode of orthostatic hypotension should not be treated with epinephrine, which is an agonist at both -adrenergic and -adrenergic receptors. -Agonists are contraindicated. Norepinephrine and phenylephrine are the agents of choice. Serious hypotension and shock must be treated as a medical emergency (see Chapter 3).
A second consequence of 1-adrenergic antagonism is inhibition of ejaculation. For reasons that are not completely clear, this troublesome side effect is most commonly reported with the piperidine phenothiazine CAPs, thioridazine, and mesoridazine.
Extrapyramidal symptoms. CAPs can induce a variety of involuntary motor movements. They are also seen more frequently with high doses of risperidone than with lower doses or with other AAPs. Antagonism at dopamine-2 (D2) receptors in the basal ganglia is the postulated cause of these drug-related extrapyramidal movement disorders. Extrapyramidal effects appear to be correlated with the location and degree of D2-receptor occupancy by antipsychotic agents (typically greater than 75% to 80%).
Acute dystonic reactions. These are the most troublesome of the extrapyramidal symptoms. These acute spasms of nuchal, truncal, buccal, or oculomotor muscle groups can be frightening or disabling; they typically occur within 10 to 14 days after the initiation of treatment. Because AAPs are currently the most commonly prescribed agents, many clinicians will never see a patient with an acute dystonia. When they do occur, dystonic reactions most frequently are induced by piperazine derivatives (e.g., trifluoperazine) or haloperidol or with initial high doses of risperidone. Acute dystonias can occur in young, otherwise healthy persons, particularly in younger men, after even a single dose of one of these drugs. Prochlorperazine is most often implicated in dystonic reactions in children (usually following accidental ingestions). Acute dystonic reactions may require parenteral treatment. Benztropine (0.5 to 2 mg) or diphenhydramine (25 to 50 mg) given intravenously or i.m. can provide a dramatic reversal of such reactions. For most patients with acute dystonic reactions who need to remain on the same antipsychotic medication, adding oral benztropine for the next 10 to 14 days protects them through their period of vulnerability. Treatment for longer than 6 weeks is almost never necessary.
Akathisia and drug-induced parkinsonism. More chronic, insidiously developing extrapyramidal symptoms can occur with any CAP. Occurrence is much less frequent with AAPs. These troublesome symptoms include the syndrome of motor restlessness or akathisia and the triad of akinesia, rigidity, and resting tremor resembling parkinsonism (often associated with increased salivation). Middle-aged and elderly chronic schizophrenic patients taking CAPs for weeks or months seem to be the most susceptible to drug-induced akathisia or parkinsonism.
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Akathisia, which occurs in about 20% of persons receiving CAPs, is experienced subjectively as anxiety, emotional disease, or inner tension and objectively as frequent pacing, foot shifting or rocking, or leg swinging while sitting. It can feel like a mobile internal anxiety that rushes from the abdomen into the chest. Reasonably predictable relief can be provided by -adrenergic receptor antagonists (often called -blockers). Lipophilic -adrenergic receptor antagonists, such as propranolol (20 to 80 mg per day), may be more effective than the more hydrophilic ones (e.g., nadolol, atenolol). Anticholinergic antiparkinson agents or benzodiazepines, such as lorazepam (0.5 to 2 mg per day), may also provide mild benefit for some patients.
Drug-induced parkinsonism occurs in about 40% of patients treated chronically with CAPs; this can be ameliorated by antiparkinsonian drugs such as benztropine or trihexyphenidyl in oral doses of 2 to 8 mg per day. Oral antiparkinsonian drugs (Table 20.12) are effective in most patients when they are given once or twice a day. They do not compromise the efficacy of antipsychotic agents. Some authorities suggest that antiparkinsonian drugs should not be given prophylactically; instead, they should be administered only when the extrapyramidal reactions appear. Once therapy is started, it should not be continued indefinitely.
TD (Table 20.13) appears in an undetermined percentage of patients who have received long-term treatment with CAPs; it is seen only rarely with AAPs. Signs of TD, however, may also appear in patients who have never received these drugs. The signs of TD may appear with dosage reduction or discontinuation or when another CAP is introduced at lower dosage equivalents. If an agent with D2 antagonism is introduced at doses that block a sufficient number of receptors, the TD signs may disappear. This can be an effective treatment strategy (i.e., when a CAP is replaced by an AAP and the AAP is then tapered, some patients may no longer have TD). In the author's experience, this latter approach is quite different from the masking of TD that can occur when higher doses of a CAP are prescribed.
In some patients, these signs appear to be related to the patient's development of tolerance to a particular dosage level. Current hypotheses to explain TD generally assume that the condition results from rebound supersensitivity to dopamine in basal ganglion areas that have been subjected to prolonged antagonism at dopamine receptors. An interaction among the
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dopaminergic, serotonergic, and cholinergic systems is likely involved. Antiparkinsonian drugs are most often of no benefit; their use may exacerbate the symptoms of TD.TABLE 20.12. SOME ANTIPARKINSONIAN DRUGS IN CURRENT USE
Generic Name Trade Name Tropine derivatives Benztropine Cogentin Piperidine compounds Biperiden Akineton Procyclidine Kemadrin Trihexyphenidyl Artane, Pipanol, Tremin Ethanolamine antihistamines Diphenhydramine Benadryl Orphenadrine Disipal TABLE 20.13. PROMINENT FEATURES OF TARDIVE DYSKINESIAS
Lingual-facial hyperkinesias
Chewing movements
Smacking and licking of the lips
Sucking movements
Tongue movements within the oral cavity
Tongue protrusion
Tongue tremor with mouth open
Myokemic movements (worm-like movement on the surface of the tongue)
Blinking
Grotesque grimaces and spastic facial distortions
Neck and trunk movements
Spasmodic torticollis
Retrocollis
Torsion movements of the trunk
Axial hyperkinesia (hip-rocking)
Choreoathetoid movements of the extremitiesWhen a patient's clinical condition requires the continued use of antipsychotic agents, both the clinician and the patient must weigh the benefit derived from this against any adverse implications of their continued use. Patients who develop TD are at higher risk for clinical relapse.
Cardiac toxicity. Possible cardiotoxic effects, including prolongation of the QT interval, by antipsychotic agents also evoke concern. Reports of sudden unexplained deaths among previously healthy patients taking these drugs suggest that some antipsychotic agents may have the potential to precipitate fatal ventricular tachyarrhythmias, such as torsade de pointes. In general, caution should be exercised in any patient whose baseline electrocardiogram reveals a QTc interval of greater than 450 ms. Antipsychotic agents should be discontinued when a QTc interval of more than 450 ms occurs. Thioridazine, mesoridazine, and droperidol carry black box warnings about dose-dependent QTc interval prolongation based on accumulated clinical experience or clinical study data (see page xiv). The reader should note that drug interactions that reduce the clearance of any of these agents could enhance this risk. As was noted earlier, a concern exists about QTc interval prolongation from ziprasidone. Manufacturer's data suggest that the mean changes in the QTc interval after both oral and i.m. ziprasidone are comparable with, and that they do not exceed an average prolongation of approximately 10 ms longer than that seen with, risperidone, olanzapine, quetiapine, or haloperidol. These mean changes are also less than the average increment observed after a 300 mg dose of thioridazine.
Thioridazine and mesoridazine can also produce electrocardiographic changes resembling hypokalemia; these are almost always modifiable with small amounts of potassium. Because these latter changes are usually benign, adding potassium supplements is not generally advised. However, true hypokalemia could contribute to life-threatening arrhythmias in patients with prolonged QT intervals secondary to the use of antipsychotic agents.
Cholinergic (muscarinic) receptor antagonism. Many antipsychotic agents have clinically important anticholinergic effects. Manifestations usually are limited to mild dryness of the mouth or tachycardia. In some people, these drugs can exacerbate untreated glaucoma or can precipitate urinary retention or intestinal obstruction. Antipsychotic agents can potentiate toxicity due to other medications with anticholinergic properties, and they should never be used to treat delirium or hyperpyrexia due to muscarinic receptor antagonists. Anticholinergic effects are particularly prominent with thioridazine and clozapine.
Hepatic disturbances. Hepatic disturbances have been reported with most antipsychotic agents. The incidence of drug-induced jaundice appears to have diminished since the 1950s. Chlorpromazine has been more frequently implicated than other agents. Most cases develop during the third and fourth weeks of treatment. The clinical picture and time of onset suggest a hypersensitivity reaction; obstructive jaundice, fever, and eosinophilia are typical. Although some clinical experience suggests that cross-tolerance is rare and that some patients can even be placed back on the same drug without a recurrence, conservative treatment should include switching to another class of antipsychotic drugs (e.g., from a CAP to an AAP), preferably after a drug-free interval.
Leukopenia and agranulocytosis. These rarely occur. Most cases occurring secondary to drugs other than clozapine typically appear during the interval between the end of the first month and the beginning of the fourth month. Elderly debilitated women appear to be at the greatest risk. However, careful clinical investigation should be made for any patient who develops pharyngitis or unexplained fevers. Immediate discontinuation of the offending drug and the use of antibiotics may be indicated. Clozapine causes agranulocytosis in about 1% to 2% of exposed patients, and regular monitoring of white blood cells is essential. When the white blood cell counts drop below 3 1012 per L, discontinuation of clozapine is essential. Other AAPs may be an alternative for those patients who cannot tolerate clozapine.
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C. Psychotherapies
Barring the unforeseen development of new techniques, Freud discouraged psychotherapeutic work with schizophrenics because he believed that their withdrawal of libido from the object world prevented the formation of a transference, a step he saw as essential to psychotherapy. Subsequent therapists modified this view. P. Federn, one of Freud's pupils, reformulated the therapeutic task as helping patients reestablish faulty ego boundaries. Other specific approaches were developed by M. Klein, M. Schehaye, J. Rosen, H.S. Sullivan, F. Fromm-Reichmann, G. Bychowsky, H. Searles, and many others. Understandably, well-designed studies of various psychotherapies for schizophrenic patients have been rare. A limited number have been conducted in both chronic and acute patients to assess the relative benefits of pharmacotherapies and individual or group psychotherapies. Comparisons among them are difficult because they lack consistency across a variety of important dimensions, including study design, stage of illness, type and frequency of psychotherapy, therapists' training, drugs and dosages used, and outcome measures.
Despite this, stating some important conclusions is warranted there are probably no acute or chronic schizophrenic patients who can be treated successfully by individual psychotherapy alone. From a public health point of view, the most useful single therapeutic intervention is antipsychotic medication, which is both the least costly and the most effective way to reduce schizophrenic symptomatology. However, a more preferable approach is a cogently designed multimodality treatment program that provides current
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pharmacotherapies and psychoeducation, reality-based ego-supportive psychotherapy, appropriate living situations, rehabilitation strategies (i.e., social and job skills training), family therapy, and ample community-based support systems.
For those who have the time and support to carry out such a program, an overview of one approach the author has found useful is presented here. In the first phase (usually hospital based), the focus is on providing the essentials of a trusting relationship, in which the therapist offers lend-lease ego strength, and on helping the patient to understand more about schizophrenia and to cope with regularly encountered reality-based issues. Establishing such a stable, trusting relationship is not an easy task for schizophrenic patients; their feelings of fear, indifference, distrust, worthlessness, and hostility may predominate. In beginning such a relationship, the therapist must find a way to establish affective contact with the patient before any understanding of the patient's concerns and feelings is likely to emerge. Because schizophrenic patients often do not communicate how they feel directly, the clinician must place importance on paying close attention to their nonverbal communications, including facial expression, posture, and activity. Furthermore, remembering that words can take on peculiar and concrete meanings for them is of great importance; the therapist must speak in simple, direct, and unambiguous terms. Clinicians must demonstrate constancy in their commitment to patients, together with an ability to share some aspect of their own human responses to the patient in an open constructive way.
During these acute stages, one should avoid making interpretations concerning the emotional conflicts that may have been temporally associated with the patient's decompensation into psychosis. Instead, the emphasis should be placed on gathering information about the patient's recent circumstances and any relevant past history. When this information cannot be obtained from the patient and permission is given by the patient, the patient's relatives or friends should be contacted. One goal of collecting such information is an understanding of any factors that may have contributed to the patient's later vulnerability to schizophrenia or of any events associated with the onset of decompensation. The clinician also needs to learn about the areas of healthy personal and occupational functioning available to the patient. These initial contacts should be brief; 15-minute to 20-minute sessions are often appropriate. Excessive closeness is invariably harmful.
In taking this history, the clinician not only demonstrates a concrete interest in the patient and the facts of his or her life, but he or she also observes the patient's characteristic avoidances of unpleasant feelings and experiences. Such observations of the patient's patterns of denial, distortion, and projection may later allow the therapist to help the patient understand the areas of his or her life that have been the most troublesome.
Bringing the issue of medication into the therapeutic work and exploring patients' feelings about taking medicine or any administrative issues are crucial so that they can be considered in planning treatment. The clinician should also help the patient to understand what is happening on the ward or in other therapeutic or living situations; clarifications about practical matters (e.g., ward policies) may also be beneficial.
As the acuteness of the psychotic process abates and the process of reintegration begins, many patients develop neurasthenic, hypochondriacal, obsessive-compulsive, or depressive symptoms. Suicide may become a serious risk at this time. During this time, the patient may also repeatedly challenge the therapist's interest in continuing the therapeutic relationship. Appointments are often missed by the patient, and both the patient and the therapist may begin to believe that the focus of the therapy has become obscure. From time to time, however, patients are able to use the therapeutic relationship at this stage to integrate some of the experiences and sources of lowered self-esteem that may have stressed them before their decompensation.
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Coming to an empathic understanding with the patient of any specific stresses that may have contributed to the onset of the psychosis may also help the patient to anticipate future difficulties. The timing of this phase of the therapeutic work is crucial, and it is usually dependent on the clinician's experience and intuition and the patient's motivation and ability to go into such matters. Whenever possible, the clinician should demonstrate and encourage negotiation and compromise.
In advocating this approach, the author assumes that a schizophrenic patient's predisposition to disorganized thinking under stress has led to difficulties in adapting to and resolving problematic situations. This obviously affects the patient's self-image and experiential learning. The clinician tries to help the patient see what may evoke distortions of reality (e.g., not being able to stand feelings of loss, loneliness, helplessness, or rage), what consequences these distortions may have, or even how to limit their consequences. For example, not all patients are terrified by their auditory hallucinations. Some patients can learn to distract themselves from their voices by listening to music, exercising, or meditating. Some can even learn to ignore their voices. Others may learn to listen selectively and then to tell their negative voices that they have no time for them or that they will not listen to them. Still others set time limits for their voices (e.g., I allow them to speak to me only from 9 p.m. to 10 p.m. ). The clinician can try to help the patient increase his or her tolerance of uncertainty and ambiguity in interpersonal relationships. Evaluation of family interactions may provide useful information for therapeutic work, particularly when this reveals a pattern of highly expressed emotion in the family. Some patients are significantly helped by ongoing conjoint work with other family members that aims to lower the intensity of their interactions.
D. Rehabilitation and Psychosocial Therapies During Aftercare
Rehabilitation refers to the process of helping patients develop or relearn those personal, interpersonal, or job skills that could make them more self-reliant and productive members of the community. This process may be a major source of increased self-esteem because it should provide the patient with feelings of increased self-control, competence, and mastery. A patient's premorbid level of adolescent or adult functioning is one of the better indices of eventual ability to resume a more independent life. Those patients who are married or who had a successful vocational adjustment before their illness are more likely to achieve a successful adjustment. A given patient's probability of returning to community life often depends on the availability of adequate social supports.
Psychosocial therapies encourage rehabilitation and improved interpersonal relationships. Techniques such as major role therapy emphasize coping with personal and environmental factors that may contribute to relapse, and they try to determine what rates and types of activities lead to improvement rather than regression for each patient. For example, working on improving eye contact or on reducing any awkward or inappropriate gestures or facial expressions may be helpful. That a number of clinical studies have demonstrated that settings (e.g., families, groups, programs) that are too high in both positive and negative expressed emotions can be stressful for many chronically ill patients should not be surprising. Expectations should be appropriate to the current state of the patient and not to notions of what the patient should be accomplishing based on prior history (e.g., education, family background, prior work). Aftercare efforts that integrate medications, rehabilitation opportunities, and appropriate psychosocial therapies with family education and support, 24-hour crisis intervention teams, and varying community-based living arrangements have the highest likelihood of maintaining patients outside of hospitals and of improving their quality of life.
VII. The National Alliance for the Mentally Ill
National Alliance for the Mentally III (NAMI) is a critically important lay organization that provides support and education to families and patients and advocacy
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for improved and comprehensive services and research. NAMI's national telephone number is (800) 950-NAMI; more than 1,000 local chapters exist.
VIII. Treatment Algorithms
Algorithms for treatment of schizophrenia can be found in Appendix VII.
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