Clozapine

Clozapine is the first atypical antipsychotic medication to have been discovered. It is usually used in tablet or liquid form for people diagnosed with schizophrenia who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson's disease. In the US it is also licensed for use in patients with recurrent suicidal behaviour associated with schizophrenia or schizoaffective disorder. It is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines. Compared to other antipsychotic drug treatments, initiating and maintaining clozapine is complex, expensive and time-consuming. The role of clozapine in treatment-resistant schizophrenia was established by the Clozaril Collaborative Study Group Study #30 in which clozapine showed marked benefits compared to chlorpromazine in a group of patients with protracted psychosis and who had already shown an inadequate response to other antipsychotics. There are a range of different adverse effects and compulsory blood monitoring is required in most developed countries. Whilst there are significant side effects, clozapine remains the most effective treatment when one or more other antipsychotics have had an inadequate response, and clozapine use is associated with multiple improved outcomes including all cause mortality, suicide and reduced hospitalisation. In a network comparative meta-analysis of 15 antipsychotic drugs, clozapine was significantly more effective than all other drugs. Surveys of patient satisfaction show preference over other antipsychotics.

Compared to other antipsychotics there is an increased risk of agranulocytosis in the first 18 weeks of treatment; after one year this risk reduces to that found with most other antipsychotics and so its use is reserved for people who have not responded to two other antipsychotics and then only with stringent blood monitoring, although the exact frequency and blood count thresholds used vary by country. Although it has been assumed that clozapine can also cause neutropenia this is not supported by the best available evidence. The stringent risk monitoring and management systems that have been in place for several decades have resulted in deaths from these complications being extremely rare, in the order of 1 in 7700. It remains the only treatment likely to be effective in treatment-resistant schizophrenia.

Common adverse effects include: agitation; amenorrhoea; arrhythmias; constipation; dizziness; drowsiness; dry mouth; erectile dysfunction; fatigue; galactorrhoea; gynaecomastia; hyperglycaemia; hyperprolactinaemia; hypersalivation; hypotension (dose-related); insomnia; leucopenia; movement disorders; muscle rigidity; neutropenia; parkinsonism; postural hypotension (dose-related); QT interval prolongation; rash; seizure; tremor; urinary retention; vomiting; and increased weight. Uncommon side effects include: agranulocytosis; confusion; embolism and thrombosis; neuroleptic malignant syndrome. Clozapine is not normally associated with tardive dyskinesia (TD)—although some case reports describe clozapine-induced TD—and is recommended as the drug of choice when this is present. Other serious risks include seizures, inflammation of the heart, high blood sugar levels, constipation resulting from clozapine-induced gastric hypomotility syndrome which can be severe and lead to bowel obstruction and death, and in older people with psychosis as a result of dementia, an increased risk of death. Clozapine's mechanism of action is not entirely clear.

It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.