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Clozapine

A Review of its Pharmacological Properties, and Therapeutic Use in Schizophrenia

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Summary

Synopsis

Clozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug’s wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics.

Pharmacodynamic Properties

In comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine D2-receptors, and produces a more potent blockade of central dopamine D1-, cholinergic, serotonergic S2-, histamine H1, and α1 - and α2-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparable in vivo blockade of striatal dopamine D1- and D2-receptors; at clinically effective doses central dopamine D2-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine D1-receptor function and produces down-regulation of serotonergic S2-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine’s marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans.

Pharmacokinetic Properties

Peak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 μg/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteins in vitro. In humans, clozapine undergoes extensive metabolism via TV-oxidation, N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose).

Therapeutic Use

Noncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia.

Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms.

Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians’ and ward nurses’ ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement.

Adverse Effects

Sedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period.

Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown.

Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy.

Dosage and Administration

Clozapine may be administered orally or intramuscularly. The manufacturer recommends initiation of clozapine therapy with 25 to 75 mg/day administered in 2 or 3 divided doses, followed by titration in 25 to 50 mg/day increments to achieve a target dose of 300 to 450 mg/day after 2 weeks. Subsequent dosage increases of ≤ 100 mg/day should be performed no more than twice weekly, to a maximum dose of 900 mg/day. After initial titration, the dose should be progressively reduced to the minimum level necessary to maintain clinical remission. In view of the continuing risk of agranulocytosis, weekly haematological surveillance is essential during the initial 18 weeks of clozapine administration; thereafter monthly monitoring is considered satisfactory. Clozapine is contraindicated in conjunction with drugs with the potential to depress bone marrow function/induce agranulocytosis, as well as in patients with severe CNS depression, myeloproliferative disorders or a history of drug-induced agranulocytosis.

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Various sections of the manuscript reviewed by: M. Ackenheil, Psychiatric Hospital, University of Munich, Munich, Federal Republic of Germany; D.E. Casey, Psychiatric Service, Veterans Administration Medical Center, Portland, Oregon, USA; W.W. Fleischhacker, Department of Psychiatry, Innsbruck University Clinics, Innsbruck, Austria; J. Gerlach, St Hans Hospital, Roskilde, Denmark; G.A. Gudelsky, Department of Psychiatry, University Hospitals of Cleveland, Cleveland, Ohio, USA; H. Kaiya, Department of Neurology and Psychiatry, Gifu University School of Medicine, Gifu, Japan; M.H. Lader, Institute of Psychiatry, University of London, London, England; J.A. Lieberman, Hillside Hospital, Long Island Jewish Medical Center, Glen Oaks, New York, USA; L. Lindström, Psychiatric Research Center, University of Uppsala, Uppsala, Sweden; D.K. Luscombe, Welsh School of Pharmacy, University of Wales Institute of Science and Technology, Cardiff, Wales; H. Y. Meltzer, Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; R.R. Owen, National Institute of Mental Health, Bethesda, Maryland, USA; J.G. Small, Department of Psychiatry, Larue D. Carter Memorial Hospital, Indiana University School of Medicine, Indianapolis, Indiana, USA; P. Turner, Department of Clinical Pharmacology, St Bartholomew’s Hospital Medical College, University of London, London, England; J.A. Vale, West Midlands Poisons Unit, Dudley Road Hospital, Birmingham, England.

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Fitton, A., Heel, R.C. Clozapine. Drugs 40, 722–747 (1990). https://doi.org/10.2165/00003495-199040050-00007

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