Focus on Clozapine

Miriam Naheed and Ben Green

ben@priory.com

Dr Miriam Naheed, Specialist Registrar, Hollins Park Hospital, Warrington, Cheshire and Dr Ben Green, Senior Lecturer in  Psychiatry, Royal Liverpool University Hospital, L69 3GA.



Introduction

Clozapine is a dibenzodiazepine derivative and a truly atypical anti-psychotic. Its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. Although it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia, its general use is limited because of the risk of agranulocytosis.
Clozapine is manufactured by Novartis pharmaceuticals and marketed by the trade name of 'Clozaril'.
Clozapine is an atypical anti-psychotic agent whose mode of action is thought to pertain to its interaction with dopaminergic and serotonergic neurotransmitter systems. Its clinical efficacy may depend on plasma clozapine concentrations; but its response rate varies widely. The response rate is anywhere between 30-100% of patients on short term therapy; while during long term treatment 60% of patients unresponsive to  or intolerant of previous antipsychotics respond to clozapine. Significant improvements in both positive  and negative psychotic symptoms, quality of life, social functioning and suicidality have been  demonstrated.
It represents the first major advance in the treatment of schizophrenia since the advent of antipsychotics  in the1950's (Lieberman, 1996). 
Although Clozapine has been found to be the most effective antipsychotic drug for treatment-resistant schizophrenia, its use has been greatly limited because of the risk of agranulocytosis, which has in fact been shown to have a frequency which is less than 1%. (Honingfield G, 1996). In balancing benefits against risks it is worth noting that the suicide mortality rate in patients with schizophrenia not treated with clozapine is much higher than the mortality from agranulocytosis in the patients treated on 
clozapine. (Walker et al, 1997, Meltzer et al, 1995). With periodic blood monitoring, the agranulocytosis  risk is 0.38% (Honigfield G, 1996).

Background history

Clozapine was introduced in Europe in 1975.As a result of reports from Finland, where 16 patients out of 2260 exposed (0.7%) developed agranulocytosis and 8 (50%) of them subsequently died from secondary infections, the drug was voluntarily withdrawn from use.
Following pressure from psychiatrists to reintroduce clozapine, trials in patients with treatment resistant schizophrenia, under close haematological monitoring were devised, which showed significant improvement in 30% of patients after six months (Kane et al, 1988). Subsequent studies showed improvement in 61% of patients if treatment was continued for up to one year (Meltzer et al, 1989; Meltzer, 1992). These data, together with a proposal for a national co-ordinated mandatory 
haematological monitoring service for all patients, enabled clozapine to be given a product licence in the UK in January 1990, and in Ireland in August 1993.
All patients treated with clozapine in the UK must register with the Clozaril Patient Monitoring Services(CPMS) ensuring that no patient can receive the drug without a recent satisfactory haematological result. It also helps guarantee that clozapine is stopped immediately if a patient develops a fall in the white cell count. Since the introduction of the CPMS only one patient has died in UK as a direct result of clozapine-induced agranulocytosis. (Mangan and Toal, 1994). Despite its proven benefits, clozapine is probably underprescribed because of its limited indication of treatment-resistant and treatment-intolerant schizophrenia and the negative perception relating to the risk of agranulocytosis. 

Indications

Under the terms of its UK license clozapine should only be used for patients with schizophrenia who are unresponsive to two or more anti-psychotics or who are intolerant of their neurological side effects. Only psychiatrists registered with the manufacturer's Clozaril Patient Monitoring Services (CPMS) can prescribe it.
Clozapine's beneficial use in several unlicensed disorders is being investigated, including psychosis secondary to dopaminergic therapy or coexisting psychiatric disorders in Parkinson's disease, other psychotic disorders, affective disorders, dyskinesias and related disorders, dementia, mental retardation, and polydipsia / hyponatraemia.
There are a number of reports, showing its dramatically beneficial effect in the patients with severe personality disorder where all other treatment options failed. These case reports and small studies show marked reduction in self harming behaviour, aggression and intensive affective response in this patient group (Frankenburge et al, 1993;Steinert et al, 1995;Chengappa et al , 1995; Benedetti et al, 1998).
There is evidence to suggest that, used in schizophrenia, clozapine may improve social functioning, occupational functioning and quality of life and that it may also reduce affective symptoms, hospitalisation, secondary negative symptoms and tardive dyskinesia.

Pharmacology

Clozapine is a prototype 'broad- spectrum' antagonist. Its binding profile is quite different from other anti-psychotics both within and outside the dopaminergic system. It has relatively low affinity for D2 receptors in the striatum, while its in vitro affinity for the D4 receptors is approximately 10 times greater than that for D2 receptors and it has also been shown to bind to the D1, D3 and D5 receptors. Since D4 density is highest in the frontal cortex and amygdala but relatively low in the basal ganglia, that may be the explanation for the efficacy of clozapine in alleviating the symptoms of schizophrenia without causing extra pyramidal side effects.
Clozapine has been recognized to show significant activity at a broad range of receptors outside the DA system. Of particular interest is clozapine's high affinity for 5-HT receptors including 5-HT2, 5-HT3, 5-HT6 and 5-HT7 subtypes. Clozapine has high affinity for a1, a2 and muscarinic receptors, while it also has significant effect on GABA-ergic and glutamatergic mechanisms.

Pharmacokinetics and metabolism

After oral administration the drug is rapidly absorbed. There is extensive first pass metabolism and only 27-50%of the dose reaches the systemic circulation unchanged.
Clozapine's plasma concentration has been observed to vary from patient to patient. Various individual factors may vary response such as smoking, hepatic metabolism, gastric absorption, age, and possibly gender.
Clozapine is rapidly distributed; it crosses the blood-brain barrier and is distributed in breast milk. It is 95% bound to plasma proteins. Steady state plasma concentration is reached after 7-10 days. The onset of anti-psychotic effect can take several weeks, but maximum effect may require several months. In treatment resistant schizophrenia, patients have been reported to continue to improve for at least two years after the start of clozapine treatment. 
Clozapine metabolizes into various metabolites, out of which only norclozapine (desmethyl metabolite) is pharmacologically active. The other metabolites do not appear to have clinically significant activity.
Its plasma concentration declines in the biphasic manner, typical of oral anti-psychotics and its mean elimination half-life ranges from 6-33 hours. About 50% of a dose is excreted in urine and 30% in the 
faeces.

Dose

Clozapine is started from a dose of 12.5mg/day. On day two the dose can be increased to 12.5mg twice daily. If the patient is tolerating the clozapine, the dose can then be increased by 25mg to 50mg a day, until a dose of 300mg a day is reached. This can usually be achieved in two to three weeks.
Further dosage increases should be made slowly in increments of 50mg to 100mg each week.
A dose of 450mg/day or a plasma level of 350mcg/L should be aimed for. The total clozapine dose should be divided and, if sedation is a problem, a larger proportion of dose can be given at night.
(The Bethlem & Maudsley NHS Trust Prescribing Guidelines, 1999).

Therapeutic Efficacy

The efficacy of clozapine has been examined in a large number of studies since it was first introduced.
There is a substantive number of randomised double blind trials, in which clinical efficacy of clozapine in acutely psychotic and treatment resistant schizophrenics has been rigorously examined.

Effect on Positive and Negative Symptoms of Schizophrenia

Both positive and negative symptoms of schizophrenia appeared to be improved with clozapine 
treatment). Negative symptoms improve in direct relation to positive symptoms in 40 schizophrenic patients after clozapine therapy for eight weeks. (Tandon and Goldman et al, 1993).
Lieberman et al; 1969, reported that negative symptoms responded to treatment approximately 7 weeks after decrease in positive symptoms in 84 patients with treatment-resistant schizophrenia. The results of these studies imply that the greater improvement in negative symptoms seen in patients receiving clozapine compared with those receiving classical anti-psychotic agents may be associated with the greater improvement in positive symptoms and fewer extra pyramidal symptoms (which can mimic negative symptoms) in these patients, rather than an independent action on negative symptoms (Breier; Buchanan et al; 1994). However, in a cohort of 36 patients with schizophrenia unresponsive to previous therapy, statistically significant reduction in Brief Psychiatric Rating Scale (BPRS) on withdrawal/retardation score were seen after six months' therapy with clozapine and psychosocial treatment in patients with high negative/low positive as well as in those with high negative/high positive symptoms (Meltzer et al;1995)

Acute Psychosis

Most of the studies found clozapine to be more effective than conventional neuroleptics in treating both positive as well as negative symptoms in acutely ill schizophrenics (Ekblom and Haggstrom 1974, Singer and Law 1974, Chiu et al 1976, Gelenberg and Dollar 1979, Claghorn et al 1987).

Treatment resistant schizophrenia

Clozapine is still the only drug of proven efficacy in treatment resistant schizophrenia (Conley et al-1997, Weiden PJ et al- 1997).The significant response of neuroleptic- resistant schizophrenia patients to clozapine validates its efficacy in this group (Baldessarini et al-1991).
Kane et al 1988 in their famous multicentre double-blind trial compared chlorpromazine with clozapine in equivalent doses and found that 4% chlorpromazine vs. 30% clozapine group responded by marked reduction in BPRS score (both positive and negative symptoms) in 6 weeks. 
Lieberman et al reported that the response rate of clozapine was 50% among previously treatment-refractory patients and 76% among treatment-intolerant patients.
Objective measures have indicated a marked improvement in psychopathology, including negative symptoms such as blunted affect, emotional withdrawal and apathy. (UK clozapine study group-1993, 
Breier et al-1994). Besides improvement of positive and negative symptoms, clozapine may improve organization of thought, certain aspects of cognitive function and enable patients to resume functioning in a low normal range. (Meltzer HY-1992)
In line with an improvement in overall psychopathology, treatment with clozapine is associated with improved compliance with medication regimen and less need for hospitalisation (Meltzer HY-1992, 
Arnon et al-1995, Grace et al- 1996).

Effect of clozapine on aggressive behaviour

The improvement in aggressive behaviour among schizophrenic patients receiving clozapine has been an interesting finding in the clinical trials. (Maier et al- 1992, Wilson-1992, Volavka et al-1993, Chiles et al- 1994, Ebrahim et al-1994, Buckley- 1995Spivak B et al- 1997).
Question arises whether clozapine's efficacy derives from a specific antiaggressive effect or, the reduction in violent behaviour merely reflects an overall improvement in psychosis.
Buckley et al have addressed this issue by comparing the symptomatic response to clozapine in 30 institutionalized schizophrenic patients, 11 of whom displayed persistent violent behaviour before initial use of clozapine. Although the violent patients showed a dramatic reduction in aggression during 6 months of clozapine treatment, their overall response to measures on BPRS was comparable to that of nonviolent patients.
This suggests that violent behaviour was not tightly coupled to severity of illness per se and raises the possibility of a distinct antiaggressive effect.
Volavka et al-1993 in New York have also demonstrated a selective effect of clozapine on hostility that is above and beyond the improvement of psychosis.
It is presently uncertain how clozapine could be incorporated in the pharmacological treatment of aggression. Its side effects limit its broad use for patients of varying conditions and severity who also exhibit violent behaviour.
If the violence was a severe problem however, the benefit could outweigh the potential risk. 

Drug and Alcohol abuse

Clozapine significantly decreases co-morbid use of alcohol and drugs in people with schizophrenia, possibly by reduction in craving (Harvard review of Psychiatry,1999)(Albanese et al-1994)(Frankenburg FR-1994). In one case study, a decrease in cocaine use after clozapine therapy was reported in a treatment resistant 37 year old man with schizoaffective disorder (Yovell - 1994). There are other reports of dramatic cessation of substance abuse, attenuated craving, and improved psychosocial functioning during clozapine therapy (Buckley -1998). Patients report reduction in craving, which has been considered to be due to the differential effect of clozapine on dopamine neurotransmission in nucleus accumbens, a region known to be involved in the neurobiology of craving.

Prevention of Suicide

Evidence is accumulating that clozapine is efficacious in reducing suicidality in schizophrenia.
Meltzer, (1999) in the Clozapine and InterSepT study reported a 80-85% reduction in the incidence of suicide in neuroleptic resistant patients on clozapine. 
Walker et al (1997) reported the results of a retrospective analysis of mortality of 67,072 schizophrenic patients receiving clozapine in the interval between April 1 ,1991 and December 31, 1993. The data were acquired from the clozaril national registry. Patients were classified as current, recent, or past clozapine users. The striking finding was that of a dramatic reduction in the incidence of suicide among current users of clozapine. While the incidence of suicide in this cohort was 19% of overall mortality, the patients who completed suicide were primarily those who had stopped using clozapine.

Mood Disorders

Clozapine has been shown to be effective in severe mood disorders. In a 1-year randomized trial of clozapine versus treatment-as- usual among 39 bipolar patients, clozapine's superiority was evident within the first 6 months of treatment and was maintained throughout the duration of this study. (Suppes, Rush, et al - 1996). Zarate et al-1995 reported that, for schizoaffective disorder, 70% of patients achieved demonstrable improvement in symptoms with clozapine therapy.
Clozapine has also been reported to be of benefit in psychotic depression. (McElroy SL-1991).

Drug induced psychosis in Parkinson's Disease

A randomised, double blind, placebo controlled trial of low doses of clozapine (25 to 50mg per day) in 60 patients over a period of 14 months showed significant improvement in drug induced psychosis in Parkinson's disease, without worsening Parkinsonism (The Parkinson Study Group, 1999).

Borderline personality disorder

Individual case reports and small studies have shown clozapine to be effective in the treatment of resistant cases of borderline personality disorder in reducing self harm, aggressive behaviour and other associated symptoms. (Frankenburge et al, 1993; Steinert et al, 1995; Chengappa et al, 1995 ; Benedetti et al, 1998).

Economic considerations

A full appraisal of the pharmacological benefits and costs associated with clozapine in the treatment of schizophrenia has been provided by Fitton and Benfield (Fitton and Benfield, 1993).
When inpatient and outpatient care, Residential care, Community- based services, drug therapy, and lost productivity and earnings are taken into consideration, it may be readily understood that schizophrenia places a major economical burden in society. The direct annual treatment cost of schizophrenia in the UK is estimated to be £1669 per person, comprising hospital inpatient care (£572), other residential care (£662), outpatient visits (£56), day care (£228), community work, social work, general practitioner fees (£63), depot injection clinic (£32) and drug therapy.(£56); 3.4% of total cost. Indirect costs associated with schizophrenia include morbidity, morality, productive losses borne by relatives, and administration costs incurred by the community relating to criminal justice and social welfare. The overall cost of untreated aggression and violence within the health care system and on society is difficult to estimate. Affective treatment of psychotic symptoms and associated aggression can bring the total cost down considerably.

Cautions and contra indications

1-Patients with myeloproliferative disorders, a history of of toxic or idiosyncratic agranulocytosis or 
severe granulocytopenia (with the exception of granulocytopenia/ agranulocytosis from previous chemotherapy)

2-Clozapine is contraindicated in patients with active liver disease, progressive liver disease and hepatic failure. 

3-Other contraindications include severe CNS depression or comatose state, severe renal and cardiac disease, uncontrolled epilepsy, circulatory collapse, alcoholic/toxic psychosis and previous hypersensitivity to clozapine.

Side effects

The most serious of clozapine's side effects is agranulocytosis. Other important side effects include 
postural hypotension and tachycardia, sedation, seizures, weight gain, and rebound psychosis.

Clozapine can also cause:

Interactions

1-Drugs that cause CNS depression, if used concomitantly with clozapine, can increase 
both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and possibly respiratory depression. Ethanol and drugs like, histamine blockers, benzodiazepines, opiate agonists, sedative-hypnotics and tricyclic antidepressants should be used with caution.

2-Concomitant use of drugs known to cause bone marrow depression might increase the possibility of 
developing myelosuppressive effects.
3-Clozapine has marked anticholinergic activity, and concurrent use with other anticholinergic drugs can 
increase side effects such as dry mouth, constipation, loss of accommodation, and urinary retention.
4-Carbamazepine, phenytoin and other cytochrome P-450 enzyme inducers can reduce clozapine plasma 
concentration, Clozapine in turn can increase the serum concentration of of the following drugs; digoxin, 
heparin, phenytoin, and warfarin.
5-Drugs such as erythromycin, Cimetidine fluoxetine or fluvoxamine, can inhibit cytochrome P-450 
metabolism and can increase clozapine plasma concentration.
6-Clozapine used concomitantly with other antihypertensive agents can increase the risk and severity of hypotension.
7- Clozapine used in combination with Lithium can increase the risk of developing seizures, confusion, dyskinesia, and possibly, neuroleptic malignant syndrome.

Conclusions

In terms of efficacy against conventional treatment-resistant schizophrenia, clozapine remains an unparalleled choice although its general use is limited because of the risk of agranulocytosis.

References


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Focus on Clozapine

Miriam Naheed and Ben Green

ben@priory.com

Dr Miriam Naheed, Specialist Registrar, Hollins Park Hospital, Warrington, Cheshire and Dr Ben Green, Senior Lecturer in 
Psychiatry, Royal Liverpool University Hospital, L69 3GA

First Published in Psychiatry On-Line as Version 1.0 10/5/2000


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