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Clozapine Therapy

Clozapine is an antipsychotic agent that has proved to be effective in treatment-resistant schizophrenia. Its use is reserved for patients unresponsive to other medication or intolerant of alternatives due to their adverse effects.
It may also be prescribed for psychosis associated with Parkinson's disease where conventional treatment has failed.
In treatment-resistant schizophrenia, clozapine should only be prescribed by physicians well versed in the use of clozapine therapy in psychiatric illness or by psychiatrists. In psychosis associated with Parkinson's disease, clozapine may also be prescribed by a neurologist.
When treated with clozapine many schizophrenic patients can be managed in the community. Primary care physicians should therefore be familiar with the principles of monitoring clozapine therapy (frequent laboratory testing, recognition of adverse effects).
Clozapine therapy is associated with lower overall mortality than no treatment or treatment with other antipsychotic drugs. Suicidal mortality rate is lower than with other antipsychotic drugs. In spite of the metabolic adverse effects of the drug, cardiovascular mortality is not higher than with other treatment options.

Serious adverse effects of clozapine include neutropenia or agranulocytosis (in 0.8% of patients) and also myocarditis and cardiomyopathy.
High doses of clozapine, in particular, may cause epileptic seizures in 2-5% of patients.
Constipation is a common adverse effect. If left untreated it may lead to paralytic ileus.
Despite clozapine possessing strong anticholinergic activity, hypersalivation [sic] is very common.
Clozapine use is associated with an increased risk of pneumonia (aspiration of saliva).
Weight gain of more than 20% from the initial weight is not rare.
May decrease glucose tolerance and increase serum lipid concentrations (triglycerides, cholesterol).
Fatigue, orthostatic hypotension and tachycardia are common adverse effects.
Clozapine lacks many of the typical adverse effects of other antipsychotic agents, such as extrapyramidal symptoms, tardive dyskinesia or elevation of serum prolactin concentration.
If it is necessary to abruptly withdraw the therapy (e.g. due to neutropenia), the psychotic symptoms may return within a few days. In such cases, many patients will experience adverse effects (e.g. agitation, nausea, diarrhoea, headache) mainly due to the cholinergic rebound effect.

Clozapine must not be used concomitantly with medication that is likely to cause myelosuppression. Long-acting antipsychotic depot injections must not be used concomitantly.
Factors that may cause clinically significant changes in clozapine concentrations, mainly by affecting the CYP₁A₂ mediated metabolism, include
- several drugs
  - Drugs having a potent inhibitory effect on the CYP₁A₂ enzyme (e.g. fluvoxamine) must be avoided in patients using clozapine.
- smoking (decreases concentration)
  - Smoking cessation may significantly increase the concentration but not more than to the double.
- ample coffee consumption (increases concentration); caffeine in large quantities inhibits the CYP1A2 enzyme
- infections (may increase concentration manyfold; the probable mechanism is cytokine-mediated CYP1A2 inhibition).

The recommended maximum dose of clozapine in accordance with the Summary of Product Characteristics is 900 mg/day in psychoses associated with schizophrenia and 50(-100) mg/day in psychoses associated with Parkinson's disease. The dose can be divided into 2-3 doses in such a way that a larger proportion is given at bedtime.
A primary care physician should not change the dose without first consulting the treating psychiatrist.

Cooperation with the laboratory must be arranged so that the leucocyte count of the patient is immediately reported to the treating physician and that the count is recorded in the patient's notes. Monitoring charts are available from the manufacturer of the drug.
- Before starting clozapine therapy (usually in hospital), a leucocyte count with a differential count must be carried out.
- After the therapy has been initiated, a leucocyte count and an absolute neutrophil count must be carried out weekly for the first 18 weeks of treatment.
- After 18 treatment weeks, a leucocyte count must be carried out at least monthly for as long as the patient is taking clozapine.
The patient should be reminded to immediately visit a physician should any signs of an infection occur, e.g. fever or sore throat (leucocyte and neutrophil counts are controlled). Especially in the initial phase of treatment there may be a transient rise in temperature > 38ºC not related to an infection.
If agranulocytosis and neuroleptic malignant syndrome Neuroleptic Malignant Syndrome (Nms) have been excluded, clozapine therapy can be continued in a febrile patient with infection. If the fever is high (38.5-39°C or more), it is advisable to halve the clozapine dose for the duration of the fever due to the increase in the clozapine concentrations associated with it (see above chapter Interactions).

The treatment is continued as usual if the leucocyte count is above 3.5 × 10⁹ /l and the neutrophil count is above 2.0 × 10⁹ /l.
If the leucocyte count is 3.0-3.5 × 10⁹ /l, or if the neutrophil count is 1.5-2.0 × 10⁹ /l, both counts must be repeated at least twice weekly until the values have returned to normal.
If the leucocyte count is below 3.0 × 10⁹ /l or the neutrophil count below 1.5 × 10⁹ /l, clozapine therapy must be discontinued immediately and the patient's WBC count checked daily until the values begin to rise (if monitoring cannot easily be arranged over the weekend the measurements can be postponed until the next weekday with instructions to the patient to seek emergency care if signs of infection appear).
- In the USA, the threshold for discontinuing clozapine treatment has been lowered to neutrophil count 1.0 × 10⁹ /l.
If clozapine therapy has been discontinued and the leucocyte count continues to fall to below 2.0 × 10⁹ /l or if the neutrophil count is below 1.0 × 10⁹ /l, the management must be supervised by an experienced haematologist.
Agranulocytosis may be treated with a granulocyte stimulating factor.
If clozapine therapy has been discontinued because of significant neutropenia, clozapine therapy must not be restarted.

de Leon J, Ruan CJ, Schoretsanitis G ym. A rational use of clozapine based on adverse drug reactions, pharmacokinetics, and clinical pharmacopsychology. Psychother Psychosom 2020:1-15. [PubMed]
Marder SR, Cannon TD. Schizophrenia. N Engl J Med 2019;381(18):1753-1761. [PubMed]
Clark SR, Warren NS, Kim G ym. Elevated clozapine levels associated with infection: A systematic review. Schizophr Res 2018;192:50-56. [PubMed]
Land R, Siskind D, McArdle P ym. The impact of clozapine on hospital use: a systematic review and meta-analysis. Acta Psychiatr Scand 2017;135(4):296-309. [PubMed]
Tiihonen J, Lönnqvist J, Wahlbeck K et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009;374(9690):620-7. [PubMed]