• The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics.DSM-IIIschizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 ±14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the doubleblind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.

Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine

• Positron emission tomography and selective radioligands were used to determine D,and D2dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2occupancy than those without side effects. This finding indicates that neurolepticinduced extrapyramidal syndromes are related to the degree of central D2occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D,occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1occupancy was 38% to 52%. The D,occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.

Positron Emission Tomographic Analysis of Central D1 and D2 Dopamine Receptor Occupancy in Patients Treated With Classical Neuroleptics and Clozapine: Relation to Extrapyramidal Side Effects

Cognitive function is markedly impaired in most patients with schizophrenia. Antecedents of this impairment are evident in childhood. The cognitive disability is nearly fully developed at the first episode of psychosis in most patients. The contribution of cognitive impairment to outcome in schizophrenia, especially work function, has been established. Preliminary results indicate that cognitive function, along with disorganization symptoms, discriminate schizophrenia patients who are able to work full-time from those who are not. Typical neuroleptic drugs lack the ability to improve the various domains of cognitive function impaired in schizophrenia. Atypical antipsychotic drugs pharmacologically related to clozapine-quetiapine, olanzapine, risperidone, sertindole, and ziprasidone--share the ability to produce fewer extrapyramidal symptoms than typical neuroleptic drugs and more potent antagonism of serotonin2a relative to dopamine2 receptors. However, they have a number of different clinical effects. We have identified all the studies of clozapine, olanzapine, and risperidone that provide data on their effects on cognition in schizophrenia. Data for each drug are reviewed separately in order to identify differences among them in their effects on cognition. Twelve studies that report cognitive effects of clozapine are reviewed. These studies provide (1) strong evidence that clozapine improves attention and verbal fluency and (2) moderate evidence that clozapine improves some types of executive function. However, results of the effects of clozapine on working memory and secondary verbal and spatial memory were inconclusive. Risperidone has relatively consistent positive effects on working memory, executive functioning, and attention, whereas improvement in verbal learning and memory was inconsistent. Preliminary evidence presented here suggests that olanzapine improves verbal learning and memory, verbal fluency, and executive function, but not attention, working memory, or visual learning and memory. Thus, atypical antipsychotic drugs as a group appear to be superior to typical neuroleptics with regard to cognitive function. However, available data suggest that these drugs produce significant differences in specific cognitive functions. These differences may be valuable adjunctive guides for their use in clinical practice if cognitive improvements reach clinical significance. The effects of the atypical antipsychotic drugs on cholinergic and 5-HT2a-mediated neurotransmission as the possible basis for their ability to improve cognition are discussed. It is suggested that the development of drugs for schizophrenia should focus on improving the key cognitive deficits in schizophrenia: executive function, verbal fluency, working memory, verbal and visual learning and memory, and attention.

/pdf/the-effects-of-clozapine-risperidone-and-olanzapine-on-48v19hz1al.pdf

The Effects of Clozapine, Risperidone, and Olanzapine on Cognitive Function in Schizophrenia

Olanzapine versus placebo and haloperidol: Acute phase results of the North American double-blind olanzapine trial

Clozapine administration to schizophrenic patients was found to produce dopamine2 (D-2) and serotonin2 (5-HT2) receptor blockade, as evidenced by the ability to block the increases in growth hormone and cortisol secretion produced by apomorphine and MK-212, respectively, direct acting dopamine (DA) and 5-HT2 agonists. Clozapine did not increase plasma prolactin (PRL) levels nor did it block the apomorphine-induced decrease in plasma PRL concentration, as would be expected from a D-2 receptor antagonist. These PRL results are consistent with the observation that clozapine may increase DA release. Clozapine also decreased plasma tryptophan, plasma homovanillac acid (HVA) and basal plasma cortisol levels. Rodent studies suggest clozapine also increases 5-HT release. We hypothesize that antagonism of D-2 and 5-HT2 receptors and enhancement of DA and 5-HT release are critical elements in the action of clozapine to minimize both positive and negative symptoms without producing significant extrapyramidal symptoms or plasma PRL increases. It is proposed that schizophrenia may also involve a dysregulation of 5-HT2- and D-2-mediated neurotransmission, and that a more normal balance in serotonergic and dopaminergic neurotransmission is at least partially restored by clozapine.

Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia.

The authors determined serum prolactin levels in 13 patients receiving clozapine, an antipsychotic drug that does not produce extrapyramidal side effects. Morning serum prolactin levels, 11 hours after the last dose, were not elevated during chronic treatment with clozapine in any subject despite its therapeutic effects. Serum prolactin levels were moderately increased between 90 minutes and 4 hours after administration of very high doses of oral clozapine in 4 patients but were smaller than those produced by chlorpromazine in other subjects. The authors suggest that clozapine in other subjects. The authors suggest that clozapine may achieve its antipsychotic effect differently than do classical neuroleptics and that sustained prolactin increases are not essential for antipsychotic action.

Effect of Clozapine on Human Serum Prolactin Levels

Five normal subjects exercised for two hours on two of three consecutive days using isometric and isotonic exercise procedures. Urinary levels of norepinephrine (NE), normetanephrine (NM), metanephrine (M), and urine and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured for the two-hour periods before, during, and after exercise. A ten-fold increase in urinary NE levels was Present after both exercise procedures. No increase in urinary levels of MHPG or M was observed during or two hours after exercise. Slight increases of plasma MHPG levels and urinary NM levels were observed during one of the two exercise periods compared to the two hours preceding exercise. Since urinary MHPG, NM, and M levels did not parallel the large increase in NE levels produced by exercise, it is probable that the NE produced by exercise is largely excreted or removed from circulation without metabolic breakdown. Thus, changes in urine MHPG levels in Patients with affective psychoses are not likely to be due to variations in the amounts of isotonic or isometric motor activity.

Relation of Exercise to MHPG Excretion in Normal Subjects

Effect of incubation in human plasma on electrophoretic mobility of brain-type creatine phosphokinase

The rate of recovery of the H-reflex, an electrical evoked monosynaptic spinal cord reflex, was abnormally high (fast) in over 20% of unmedicated psychotic patients of all major diagnostic classes. A few patients had significantly lower H-reflex recovery curves. Chronic neuroleptic treatment produced relatively lower recovery curves, whereas fluoxetine, a specific serotonin uptake blocker, produced relatively higher curves.

Descriptive studies of H-reflex recovery curves in psychiatric patients

• The effect of isometric exercise on serum creatinine phosphokinase (CPK) activity in 14 psychotic patients in remission and ten normal controls was studied. The increases in serum CPK activity at 18 and 42 hours after exercise were not significantly different in patients and controls. The postexercise serum CPK activities in the patients were significantly less than the peak serum CPK levels when they were psychotic. There were no significant correlations between postexercise serum CPK activity and preexercise or peak serum CPK activity in the patient group. It is unlikely that increased isometric muscle tension is a major causative factor in the increased serum CPK levels frequently found in psychotic patients.

https://jamanetwork.com/journals/psych/articlepdf/491610/archpsyc_33_10_007.pdf

David J. Goode

Papers

Effect of Clozapine on Human Serum Prolactin Levels

Relation of Exercise to MHPG Excretion in Normal Subjects

Effect of incubation in human plasma on electrophoretic mobility of brain-type creatine phosphokinase

Descriptive studies of H-reflex recovery curves in psychiatric patients

Effects of isometric exercise on serum creatine phosphokinase activity.