36.24 - Nefazodone

Authors: Sadock, Benjamin James; Sadock, Virginia Alcott

Title: Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition

Copyright ©2007 Lippincott Williams & Wilkins

> Table of Contents > 12 - Substance-Related Disorders > 12.11 - Phencyclidine (or Phencyclidine-like)-Related Disorders

12.11

Phencyclidine (or Phencyclidine-like)-Related Disorders

Phencyclidine (PCP; 1-1 [phenylcyclohexyl] piperidine), also known as angel dust, was first developed as a novel anesthetic in the late 1950s. This drug and the closely related compound ketamine were termed dissociative anesthetics, because they produced a condition in which subjects were awake but apparently insensitive to, or dissociated from, the environment. The symptoms induced by PCP and ketamine closely resemble those observed in schizophrenia. As early as 1959, therefore, it was proposed that PCP psychosis might serve as a heuristically valuable model for schizophrenia. PCP entered the illicit street market in 1965. In the late 1970s, it was one of the leading drugs of abuse in the United States. Although its popularity has subsequently declined, the popularity of ketamine has been steadily increasing.

Phencyclidine and ketamine exert their unique behavioral effects by blocking N-methyl-D-aspartate (NMDA)–type receptors for the excitatory neurotransmitter glutamate. PCP and ketamine intoxication can present with a variety of symptoms, from anxiety to psychosis. Treatment remains largely symptomatic and supportive. Few studies have assessed medication effects on PCP or ketamine intoxication effects directly. PCP and ketamine induce psychotic symptoms that closely resemble those of schizophrenia. As such, these drugs have been frequently used in challenge studies to investigate brain mechanisms in schizophrenia. Although PCP is no longer used in controlled human studies, ketamine challenge studies are ongoing and continue to provide critical insights into schizophrenia.

Phencyclidine was first used illicitly in San Francisco in the late 1960s. Since then, about 30 chemical analogues have been produced and are intermittently available on the streets of major US cities. The effects of PCP are similar to those of such hallucinogens as lysergic acid diethylamide (LSD). Because of differing pharmacology and some difference in clinical effects, however, the text revision of the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) classifies the arylcyclohexylamines as a separate category. PCP has also been of interest to schizophrenia researchers, who have used PCP-induced chemical and behavioral changes in animals as a possible model of schizophrenia.

Epidemiology

Phencyclidine and some related substances are relatively easy to synthesize in illegal laboratories and relatively inexpensive

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to buy on the streets. The variable quality of the laboratories, however, results in a range of potency and purity. PCP use varies most markedly with geography. Most users of PCP also use other substances, particularly alcohol, but also opiates, opioids, marijuana, amphetamines, and cocaine. PCP is frequently added to marijuana, with severe untoward effects on users. According to DSM-IV-TR, the actual rate of PCP dependence and abuse is not known, but PCP is associated with 3 percent of substance abuse deaths and 32 percent of substance-related emergency room visits nationally.

Some areas of some cities have a tenfold higher usage rate of PCP than other areas. The highest PCP use in the United States is in Washington, DC, where PCP accounts for 18 percent of all substance-related deaths and more than 1,000 emergency room visits per year. In Los Angeles, Chicago, and Baltimore, the comparable figure is 6 percent. Overall, most users are between 18 and 25 years of age and they account for 50 percent of cases. Patients are more likely to be male rather than female, especially those who visit emergency rooms. Twice as many white as blacks are users, although blacks account for more visits to hospitals for PCP-related disorders than do whites. PCP use appears to be rising, with some reports showing a 50 percent increase, particularly in urban areas.

Neuropharmacology

Phencyclidine and its related compounds are variously sold as a crystalline powder, paste, liquid, or drug-soaked paper (blotter). PCP is most commonly used as an additive to a cannabis- or parsley-containing cigarette. Experienced users report that the effects of 2 to 3 mg of smoked PCP occur in about 5 minutes and plateau in 30 minutes. The bioavailability of PCP is about 75 percent when taken by intravenous administration and about 30 percent when smoked. The half-life of PCP in humans is about 20 hours, and the half-life of ketamine in humans is about 2 hours.

The primary pharmacodynamic effect of PCP and ketamine is as an antagonist at the NMDA subtype of glutamate receptors. PCP binds to a site within the NMDA-associated calcium channel and prevents the influx of calcium ions. PCP also activates the dopaminergic neurons of the ventral tegmental area, which project to the cerebral cortex and the limbic system. Activation of these neurons is usually involved in mediating the reinforcing qualities of PCP.

Tolerance for the effects of PCP occurs in humans, although physical dependence generally does not occur. In animals that are administered more PCP per pound for longer times than virtually any humans, PCP does induce physical dependence, however, with marked withdrawal symptoms of lethargy, depression, and craving. Physical symptoms of withdrawal in humans are rare, probably as a function of dose and duration of use. Although physical dependence on PCP is rare in humans, psychological dependence on both PCP and ketamine are common, and some users become psychologically dependent on the PCP-induced psychological state.

That PCP is made in illicit laboratories contributes to the increased likelihood of impurities in the final product. One such contaminant is 1-piperidenocyclohexane carbonitrite, which releases hydrogen cyanide in small quantities when ingested. Another contaminant is piperidine, which can be recognized by its strong, fishy odor.

Table 12.11-1 DSM-IV-TR Phencyclidine-Related Disorders

Phencyclidine use disorders
Phencyclidine dependence
Phencyclidine abuse
Phencyclidine-induced disorders
Phencyclidine intoxication
Specify if:
   With perceptual disturbances
Phencyclidine intoxication delirium
Phencyclidine-induced psychotic disorder, with delusions
Specify if:
   With onset during intoxication
Phencyclidine-induced psychotic disorder, with hallucination
Specify if:
   With onset during intoxication
Phencyclidine-induced mood disorder
Specify if:
   With onset during intoxication
Phencyclidine-induced anxiety disorder
Specify if:
   With onset during intoxication
Phencyclidine-related disorder not otherwise specified
(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; copyright 2000, with permission.)

Diagnosis

The DSM-IV-TR lists a number of PCP (or PCP-like)-related disorders (Table 12.11-1), but outlines the specific diagnostic criteria for only PCP intoxication (Table 12.11-2) within the PCP (or PCP-like)-related disorders section. The diagnostic criteria for other PCP (or PCP-like)-related disorders are listed in the

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sections that deal with specific symptoms—for example, PCP-induced anxiety disorder is in the anxiety disorders section.

Table 12.11-2 DSM-IV-TR Diagnostic Criteria for Phencyclidine Intoxication

  1. Recent use of phencyclidine (or a related substance).
  2. Clinically significant maladaptive behavioral changes (e.g., belligerence, assaultiveness, impulsiveness, unpredictability, psychomotor agitation, impaired judgment, or impaired social or occupational functioning) that developed during, or shortly after, phencyclidine use.
  3. Within an hour (less when smoked, “snorted,” or used intravenously), two (or more) of the following signs:
    1. vertical or horizontal nystagmus
    2. hypertension or tachycardia
    3. numbness or diminished responsiveness to pain
    4. ataxia
    5. dysarthria
    6. muscle rigidity
    7. seizures or coma
    8. hyperacusis
  4. The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.
Specify if:
   With perceptual disturbances
(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; copyright 2000, with permission.)

PCP Dependence and PCP Abuse

The DSM-IV-TR uses the general criteria for PCP dependence and PCP abuse (see Tables 12.1-3, 12.1-4, and 12.1-5). Some long-term users of PCP are said to be “crystallized,” a syndrome characterized by dulled thinking, decreased reflexes, loss of memory, loss of impulse control, depression, lethargy, and impaired concentration.

According to DSM-IV-TR, in the United States, more than 3 percent of those age 12 and older acknowledged ever using PCP, with 0.2 percent reporting use in the prior year. The highest lifetime prevalence was in those aged 26 to 34 years (4 percent), whereas the highest proportion using PCP in the prior year (0.7 percent) was in those aged 12 to 17 years.

PCP Intoxication

Short-term PCP intoxication can have potentially severe complications and must often be considered a psychiatric emergency. DSM-IV-TR gives specific criteria for PCP intoxication (Table 12.11-2). Clinicians can specify the presence of perceptual disturbances.

Some patients may be brought to psychiatric attention within hours of ingesting PCP, but often 2 to 3 days elapse before psychiatric help is sought. The long interval between drug ingestion and the appearance of the patient in a clinic usually reflects the attempts of friends to deal with the psychosis by “talking down.” Persons who lose consciousness are brought for help earlier than those who remain conscious. Most patients recover completely within a day or two, but some remain psychotic for as long as 2 weeks. Patients who are first seen in a coma often exhibit disorientation, hallucinations, confusion, and difficulty communicating on regaining consciousness. These symptoms may also be seen in noncomatose patients, but their symptoms appear to be less severe than those of comatose patients. Behavioral disturbances sometimes are severe; they can include public masturbation, stripping off clothes, violence, urinary incontinence, crying, and inappropriate laughing. Patients frequently have amnesia for the entire period of the psychosis.

The patient was a 20-year-old man who was brought to the hospital, trussed in ropes, by his four brothers. This was his seventh hospitalization in the last 2 years, each for similar behavior. One of his brothers reported that he “came home crazy,” threw a chair through a window, tore a gas heater off the wall, and ran into the street. The family called the police, who apprehended him shortly thereafter as he stood, naked, directing traffic at a busy intersection. He assaulted the arresting officers, escaped from them, and ran home screaming threats at his family. There, his brothers were able to subdue him.

On admission, the patient was observed to be agitated, with his mood fluctuating between anger and fear. He had slurred speech and staggered when he walked. He remained extremely violent and disorganized for the first several days of his hospitalization, then began having longer and longer lucid intervals, still interspersed with sudden, unpredictable periods in which he displayed great suspiciousness, a fierce expression, slurred speech, and clenched fists.

After calming down, the patient denied ever having been violent or acting in an unusual way (“I'm a peaceable man”) and said he could not remember how he got to the hospital. He admitted using alcohol and marijuana socially, but denied phencyclidine (PCP) use except for once, experimentally, 3 years previously. Nevertheless, blood and urine tests were positive for phencyclidine, and his brother believed “he gets dusted every day.”

According to his family, the patient was perfectly normal until about 3 years before. He made above-average grades in school, had a part-time job and a girlfriend, and was of a sunny and outgoing disposition. Then, at age 17 he had his first episode of emotional disturbance. This was of very sudden onset, with symptoms similar to the present episode. He quickly recovered entirely from that first episode, went back to school, and graduated from high school. From subsequent episodes, however, his improvement was less and less encouraging.

After 3 weeks of the recent hospitalization, the patient was sullen and watchful, and quick to remark sarcastically on the smallest infringement of the respect due him. He was mostly quiet and isolated from others, but was easily provoked to fury. His family reported that “this is as good as he gets” and that he had returned to his baseline functioning. When he was at home, he kept himself physically clean, but mostly lied around the house, did no housework, and had not held a job for nearly 2 years. The family does not know how he obtained spending money or how he spent his time outside the house. (Courtesy of DSM-IV-TR Casebook.)

PCP Intoxication Delirium

Phencyclidine intoxication delirium is included as a diagnostic category in DSM-IV-TR (see Table 10.2-6). An estimated 25 percent of all PCP-related emergency room patients may meet the criteria for the disorder, which can be characterized by agitated, violent, and bizarre behavior.

PCP-Induced Psychotic Disorder

Phencyclidine-induced psychotic disorder is included as a diagnostic category in DSM-IV-TR (see Table 14.4-7). Clinicians can further specify whether the predominant symptoms are delusions or hallucinations. An estimated 6 percent of PCP-related emergency room patients may meet the criteria for the disorder. About 40 percent of these patients have physical signs of hypertension and nystagmus, and 10 percent have been injured accidentally during the psychosis. The psychosis can last from 1 to 30 days, with an average of 4 to 5 days.

PCP-Induced Mood Disorder

Phencyclidine -induced mood disorder is included as a diagnostic category in DSM-IV-TR (see Table 15.3-10). An estimated 3 percent of PCP-related emergency room patients meet the criteria for the disorder, with most fitting the criteria for a manic-like episode. About 40 to 50 percent have been accidentally injured during the course of their manic symptoms.

PCP-Induced Anxiety Disorder

Phencyclidine-induced anxiety disorder is included as a diagnostic category in DSM-IV-TR (see Table 16.7-3). Anxiety is

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probably the most common symptom causing a PCP-intoxicated person to seek help in an emergency room.

Table 12.11-3 DSM-IV-TR Diagnostic Criteria for Phencyclidine-Related Disorder Not Otherwise Specified

The phencyclidine-related disorder not otherwise specified category is for disorders associated with the use of phencyclidine that are not classifiable as phencyclidine dependence, phencyclidine abuse, phencyclidine intoxication, phencyclidine intoxication delirium, phencyclidine-induced psychotic disorder, phencyclidine-induced mood disorder, or phencyclidine-induced anxiety disorder.
(From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; copyright 2000, with permission.)

PCP-Related Disorder Not Otherwise Specified

The diagnosis of PCP-related disorder not otherwise specified is the appropriate diagnosis for a patient who does not fit into any of the previously described diagnoses (Table 12.11-3).

Clinical Features

The amount of PCP varies greatly from PCP-laced cigarette to cigarette; 1 g may be used to make as few as four or as many as several dozen cigarettes. Less than 5 mg of PCP is considered a low dose, and doses above 10 mg are considered high. Dose variability makes it difficult to predict the effect, although smoking PCP is the easiest and most reliable way for users to titrate the dose.

Persons who have just taken PCP are frequently uncommunicative, appear to be oblivious, and report active fantasy production. They experience speedy feelings, euphoria, bodily warmth, tingling, peaceful floating sensations, and, occasionally, feelings of depersonalization, isolation, and estrangement. Sometimes, they have auditory and visual hallucinations. They often have striking alterations of body image, distortions of space and time perception, and delusions. They may experience intensified dependence feelings, confusion, and disorganization of thought. Users may be sympathetic, sociable, and talkative at one moment but hostile and negative at another. Anxiety is sometimes reported; it is often the most prominent presenting symptom during an adverse reaction. Nystagmus, hypertension, and hyperthermia are common effects of PCP. Head-rolling movements, stroking, grimacing, muscle rigidity on stimulation, repeated episodes of vomiting, and repetitive chanting speech are sometimes observed.

The short-term effects last 3 to 6 hours and sometimes give way to a mild depression in which the user becomes irritable, somewhat paranoid, and occasionally belligerent, irrationally assaultive, suicidal, or homicidal. The effects can last for several days. Users sometimes find that it takes 1 to 2 days to recover completely; laboratory tests show that PCP can remain in the patient's blood and urine for more than a week.

Differential Diagnosis

Depending on a patient's status at the time of admission, the differential diagnosis may include sedative or narcotic overdose, psychotic disorder as a consequence of the use of psychedelic drugs, and brief psychotic disorder. Laboratory analysis may help to establish the diagnosis, particularly in the many cases in which the substance history is unreliable or unattainable.

Treatment

Treatment of PCP intoxication aims to reduce systemic PCP levels and to address significant medical, behavioral, and psychiatric issues. For intoxication and PCP-induced psychotic disorder, although resolution of current symptoms and signs is paramount, the long-term goal of treatment is to prevent relapse to PCP use. PCP levels can fluctuate over many hours or even days, especially after oral administration. A prolonged period of clinical observation is therefore mandatory before concluding that no serious or life-threatening complications will ensue.

Trapping of ionized PCP in the stomach has led to the suggestion of continuous nasogastric suction as a treatment for PCP intoxication. This strategy, however, can be needlessly intrusive and can induce electrolyte imbalances. Administration of activated charcoal is safer, and it binds PCP and diminishes toxic effects of PCP in animals.

Trapping of ionized PCP in urine has led to the suggestion of urinary acidification as an aid to drug elimination. This strategy, however, may be ineffective and is potentially dangerous. Only a small portion of PCP is excreted in urine, metabolic acidosis itself carries significant risks, and acidic urine can increase the risk of renal failure secondary to rhabdomyolysis. Because of the extremely large volume of distribution of PCP, neither hemodialysis nor hemoperfusion can significantly promote drug clearance.

No drug is known to function as a direct PCP antagonist. Any compound binding to the PCP receptor, which is located within the ion channel of the NMDA receptor, would block NMDA receptor–mediated ion fluxes as does PCP itself. NMDA receptor mechanisms predict that pharmacological strategies promoting NMDA receptor activation (e.g., administration of a glycine site agonist drug) would promote rapid dissociation of PCP from its binding sites. No clinical trials of NMDA agonists for PCP or ketamine intoxication in humans have been carried out to date. Treatment must therefore be supportive and directed at specific symptoms and signs of toxicity. Classic measures should be used for medical crises, including seizures, hypothermia, and hypertensive crisis.

Because PCP disrupts sensory input, environmental stimuli can cause unpredictable, exaggerated, distorted, or violent reactions. A cornerstone of treatment, therefore, is minimization of sensory inputs to PCP-intoxicated patients. Patients should be evaluated and treated in as quiet and isolated an environment as possible. Precautionary physical restraint is recommended by some authorities, with the risk of rhabdomyolysis from struggle against the restraints balanced by the avoidance of violent or disruptive behavior. Pharmacological sedation can be accomplished with oral or intramuscular (IM) antipsychotics or benzodiazepines; no convincing evidence indicates that either class of compounds is clinically superior. Because of the

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anticholinergic actions of PCP at high doses, neuroleptics with potent intrinsic anticholinergic properties should be avoided.

Course and Prognosis

Complete recovery from PCP intoxication is the rule in the absence of major medical complications. Many patients, however, relapse to PCP use immediately after discharge from treatment, even for severe PCP-related complications. Intoxication usually occurs in the context of abuse, dependence, or both. No specific behavioral treatments for PCP abuse and dependence have been described, however. Case reports indicate successful responses to residential and intensive outpatient treatment regimens with long-term follow-up, including urine monitoring with or without contingency contracting.

Ketamine

Ketamine is a dissociative anesthetic agent, originally derived from PCP, that is available for use in human and veterinary medicine. It has become a drug of abuse, with sources exclusively from stolen supplies. It is available as a powder or in solution for intranasal, oral, inhalational, or (rarely) intravenous use. Ketamine functions by working at the NMDA receptor and, as with PCP, can cause hallucinations and a dissociated state in which the patient has an altered sense of the body and reality and little concern for the environment.

Ketamine causes cardiovascular stimulation and no respiratory depression. On physical examination, the patient may be hypertensive and tachycardic, have increased salivation and bidirectional or rotary nystagmus, or both. The onset of action is within seconds when used intravenously, and analgesia lasting 40 minutes and dissociative effects lasting for hours have been described. Cardiovascular status should be monitored and supportive care administered. A dystonic reaction has been described, as have flashbacks, but a more common complication is related to a lack of concern for the environment or personal safety.

Ketamine has a briefer duration of effect than PCP. Peak ketamine levels occur approximately 20 minutes after IM injection. After intranasal administration, the duration of effect is approximately 1 hour. Ketamine is N-demethylated by liver microsomal cytochrome P450, especially CYP3A, into norketamine. Ketamine, norketamine, and dehydronorketamine can be detected in urine, with half-lives of 3, 4, and 7 hours, respectively. Urinary ketamine and norketamine levels vary widely from individual to individual and can range from 10 to 7,000 ng/mL after intoxication. As of yet, the relationship between serum ketamine levels and clinical symptoms has not been formally studied. Ketamine is often used in combination with other drugs of abuse, especially cocaine. Ketamine does not appear to interfere with, and may enhance, cocaine metabolism.

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