Clozapine has been found to be superior to traditional neuroleptics in the treatment of refractory schizophrenia and is increasingly being used to treat schizophrenia, affective disorders, some neurological disorders, and aggression. For many patients, clozapine offers new hope for the successful pharmacological management of a disabling mental disorder. However, up to 17 percent of patients must discontinue treatment with clozapine because of adverse effects, which also limit the rate at which the dose can be increased and the maximum dose that can be tolerated. This article reviews strategies for minimizing and managing the adverse effects of clozapine, including agranulocytosis, seizures, sedation, delirium, obsessive-compulsive symptoms, hypotension, tachycardia, weight gain, sialorrhea, elevated liver enzymes, constipation, nausea, enuresis, fever, and neuromuscular effects. Incidence and morbidity are presented first. Then, the known or hypothesized pathophysiology of the adverse effects are described. Finally, nonpharmacological and pharmacological interventions are reviewed. Under-standing the incidence, pathophysiology, and treatments of adverse effects is essential for a positive therapeutic outcome when prescribing clozapine.

Clozapine is increasingly being used for clinical indications in addition to treatment-resistant schizophrenia; this article reviews the relevant literature. The first section reassesses the risks associated with clozapine treatment, particularly agranulocytosis. The next section discusses its use for schizophrenia in patients who are treatment resistant, not treatment resistant, and intolerant of traditional drug treatments. Subsequent sections address its use in mood disorders, neurologic conditions, comorbid substance abuse, aggressive behavior, and childhood schizophrenia. Each includes the initial rationale for the use of clozapine in the disorder, a critical evaluation of the relevant literature, and theories as to why clozapine's unique pharmacodynamic profile may be efficacious for the specific condition. This body of literature suggests clozapine may be an effective treatment for a wide range of disorders.

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Sir: Hallucinogen persisting perception disorder is the reexperiencing of the perceptual symptoms experienced while intoxicated with the hallucinogen. Examples of these perceptual distortions include geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of color, positive afterimages, macropsia, and micropsia. Various pharmacologic treatments of "flashbacks," including neuroleptics and benzodiazepines, and electroconvulsive therapy have met with limited success. 1 Case report. Mr. A, a 22-year-old male college student, presented to a college counseling center with symptoms of mild depression. Six months prior to his evaluation, he had stopped using lysergic acid diethylamide (LSD), after an 8-month history of LSD abuse during which he had used between 1000 to 1800 µg at least twice a week. Despite his abstinence, he noticed the persistence of LSD-like phenomena. These phenomena included visual illusions, trailing images, depersonalization, images in his peripheral field, and visions of colorful geometric forms when he closed his eyes. They occurred almost daily, were not distressing to the patient, and had preceded the onset of his depressive symptoms. He had no history of seizures or migraines.Antidepressant treatment was begun with sertraline 25 mg and was titrated upward slowly owing to concern about these flashbacks. Mild exacerbations of these LSD-like phenomena were noted for 2 to 4 days after each dosage increase, primarily as flashes of color, positive afterimages, and fleeting hallucinations in his peripheral vision. Within 1 month after the target dose of 100 mg was reached, these perceptual disturbances decreased until they had almost completely remitted. The depressive symptoms also improved. These gains were maintained for 4 months, at which point Mr. A graduated and terminated treatment.

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Sir: Pine et al. 1 described a series of patients hospitalized for mania who were also found to have multiple sclerosis, thus reminding us of the importance of considering multiple sclerosis in patients presenting with psychiatric symptoms plus neurologic abnormalities. We present a case illustrative of this point, yet raise the issue that magnetic resonance imaging (MRI) findings, commonly used to differentiate bipolar disorder from multiple sclerosis, are similar for both disorders. This complicates diagnosis and points to a similar etiology for symptoms that overlap both bipolar illness and multiple sclerosis.Case report. Ms. A, a 48-year-old woman with a 10-year history of "mood swings," presented for her first psychiatric admission with symptoms of irritability, pressured speech, racing thoughts, circumstantiality, and persecutory delusions. Neuropsychological testing found difficulty with attention and concentration, poor short-term memory, and impaired perceptual-motor skills. Neurologic examination was normal other than for poor grip strength. Pharmacotherapy consisted of lithium carbonate 600 mg b.i.d. (serum lithium level = 0.84 mmol/L), haloperidol 5 mg q.h.s., and benztropine 1 mg q.h.s. Ms. A was discharged after 10 days following significant improvement of manic symptoms.One month later, Ms. A was readmitted with a 10-day history of increasing lethargy, restlessness, difficulty concentrating, urinary incontinence, and periodic disorientation, although she was without manic symptoms. The patient's serum lithium level at readmission was 0.98 mmol/L. Her neurologic examination was significant for hyperreflexia, mildly decreased motor strength, clumsiness of the right upper extremity, and a Babinski reflex on the left. An MRI of the brain showed T 2 signal hyperintensities in the periventricular and subcortical white matter, corpus callosum, right cerebral peduncle, and right brain stem. While these lesions were suggestive of multiple sclerosis, none were enhanced with the addition of contrast and therefore were not thought to be acute. There were no prior studies available for comparison.Lithium and haloperidol were discontinued, and Ms. A's delirium cleared over 4 days. Further investigation of her past medical history revealed an isolated episode of transient unilateral numbness, dysarthria, and blurry vision 12 years previously. Prophylactic treatment of mania was begun with divalproex sodium 250 mg t.i.d. and perphenazine 8 mg q.h.s. Follow-up at 5 weeks revealed no mania, psychosis, or delirium.

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