Clozapine schizophrenia

In addition to being effective in the treatment of schizophrenia, clozapine also is effective in the treatment of the manic phase of bipolar disorder. Although not a first-line treatment for mania, clozapine is useful for patients who are not responding well to more traditional treatments. Finally, clozapine is the one antipsychotic proven to help treatment-resistant schizophrenia. Fully one-third of patients who do not respond to other antipsychotics will respond to clozapine. 

Clozapine can certainly be a difficult and expensive medication to take. However, for the treatment-resistant patient with schizophrenia, clozapine is often well worth the trouble. 

Revicki DA. Pharmacoeconomic evaluation of treatments for refractory schizophrenia clozapine-related studies. J Clin Psychiatry 1999 60(suppl 1) 7-11 discussion 28-30. 

Diabetes was also more common in 63 patients taking clozapine than in 67 receiving typical depot neuroleptic drugs (299). The percentages of type 2 diabetes mellitus were 12% and 6% respectively. Nevertheless, the mechanism is not known. In six patients with schizophrenia, clozapine increased mean concentrations of blood glucose, insulin, and C peptide (300). The authors concluded that the glucose intolerance was due to increased insulin resistance. 

Clozapine and SSRIs are often used together, because depressive syndromes are common in patients with schizophrenia. Clozapine carries a relatively high risk of agranulocytosis, but this adverse effect is very rarely seen with SSRIs, although a case of possible fluoxetine-induced neutropenia has been described (SEDA-22, 15). Two cases in which the addition of paroxetine to clozapine was associated with neutropenia have been reported (11). The patients had been taking stable doses of clozapine for 6-12 months and had previously tolerated other SSRIs without adverse hematological consequences. In both cases the white cell count recovered when clozapine was withdrawn, although paroxetine was continued. 

Clozapine (Clozaril), a 5-HT2A/2c-receptor antagonist, represents a class of atypical antipsychotic drugs with reduced incidence of extrapyramidal side effects compared to the classical neuroleptics, and possibly a greater efficacy for reducing negative symptoms of schizophrenia. Clozapine also has a high affinity for subtypes of dopamine receptors. 

A woman was taking thiamazole for Graves disease, at times with various different antipsychotics including haloperidol, flupentixol, zuclopen-thixol and perphenazine for schizophrenia. Because of the severe extrapyramidal reactions and failure to control the schizophrenia, clozapine, increased over 5 days to 250 mg daily, was started instead. Within 5 days her white cell count had fallen to 2200/mm, which rose to 4000/mm, one month after both drugs were stopped. Later, after the thiamazole was stopped she was given the same dose of clozapine without these adverse effects. ... 

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

Your patient is prescribed clozapine for schizophrenia that has not responded to other drugs. You must discuss this new therapy with the family. Discuss what points to include in this family teaching session. 

Zimmet SV, Strous RD, Burgess ES, et al Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder a retrospective survey. J Clin Psychopharmacol 20 94—98, 2000... 

Fitton A, Benfield P (1993). Clozapine an appraisal of its pharmacoeconomic benefits in the treatment of schizophrenia. 

Ginsberg G, Shani S, Lev B (1998). Cost-benefit analysis of risperidone and clozapine in the treatment of schizophrenia in Israel. Pharmacoeconomics 13,231—41. 

Jonsson D, WSlinder J (1995). Cost-effectiveness of clozapine treatment in therapy-refractory schizophrenia. Aaa Psychiatr Scand l 199-201. 

Pollack S, Woerner MG, Howard A, et al (1998). Clozapine reduces rehospitalization among schizophrenia patients. Psychopharmacol Bull 34, 89-92. 

Rosenheck R, Cramer J, Xu W, et al (1997). A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med b b7> 809-15. 

WagstafFAJ, Bryson HM (1995). Clozapine—a review of its pharmacological properties and therapeutic use in patients with schizophrenia... 

Wahlbeck K, Cheine M, Essali A, Adams C (1999). Evidence of clozapine s effectiveness in schizophrenia a systematic review and metaanalysis of randomised trials. Am J Psychiatry 156, 990-9. 

Reference has been made already to the shortcomings of the term neuroleptic . We now have a situation in which the drugs that are most useful in schizophrenia are regarded as atypical. While the term was introduced to cover those neuroleptics that do not cause EPSs, it has become synonymous with clozapine which has additional advantages over other neuroleptics (e.g. reduces negative symptoms, see text). Thus it is not always clear what is meant or covered by atypical. Hopefully this distinction between the neuroleptics will become unnecessary as better compounds are developed and the older ones become obsolete. 

K (nM) values for clozapine at D2 and Di receptors are 56 and 141 compared with 0.5 and 27 for haloperidol giving D1/D2 ratios of 2.5 and 54 for the two drugs. A relatively strong block of Di compared with D2 receptors may not be the answer for schizophrenia but it could reduce the tendency to produce dyskinesias, if this depends on Di receptor activation (see Fig. 17.2). 

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