Clozapine


Clozapine was was first used in the 1960s but was withdrawn after an association with low white cell counts. It was reintroduced in the late 1980s after a pivotal study showed that it was more effective than typical antipsychotic drugs, with compulsary blood tests to monitor the white blood cells.

Currently patients must be registered with a clozapine monitoring service and need to have blood counts weekly for 18 weeks, and then fortnightly until 52 weeks of treatment, and then monthly thereafter.

About 30% of patients who have been refractory to treatment will improve significantly after 6 weeks, and up to 60% will respond up to one year after initiation of treatment. Patients can therefore expect to see continued improvement up to one year.

Even patients who do not show improvement, describe a subjective improvement on clozapine.

Clozaril is a common trade name and is an antipsychotic for the treatment of resistant schizophrenia. Resistance is defined by poor response to at least 2 medications from 2 different classes, at adequate dose and for an adequate period of time. Obviously the patient needs to be taking (compliant) with the medications and continued illicit drug abuse which could account for the ongoing psychosis must be excluded.

Clozaril has an extremely low incidence of extra-pyramidal side effects, and it is also used in schizophrenia when there is there is the development of a tardive dyskinesia, which occurs as a possible longterm side effect of other medications, usually first generation medications. It is also not associated with an increase in prolactin (see endocrine side effects at side effects of antispychotics, and will therefore not have menstrual changes.

Clozaril has also shown to be beneficial in reducing suicide risk.

Clozapine dosing
The maximum dose is 900mg given as a single or divided daily dose. It is started at a low dose (about 25mg) and then increased slowly every 3 days or longer. Average therapeutic doses are about 300mg daily but can be greater if symptoms are severe. The reason for the slow titration is 2-fold. The first reason is to reduce the risk of neutropenia. The second reason is to reduce risks of hypotension and cardiac toxicity.

Levels can be measured in the blood. This will indicate if the patient is compliant, and if a therapeutic dose has been reached yet.

See this link on clozapine and smoking for important information on dosing.

The one draw back of clozapine is that it is only available in tablet form. There is no depot injection preparation.

Outcomes
You can expect about a third of patients on clozapine to show significant improvement. Improvement can be noticed within a few weeks or months, and this improvement can sometimes occur up to one year following initiation of clozapine.

Common side effects of clozaril

Hyypersalivation or drooling of the saliva occurs commonly. There are medications which can be prescribed for this. At night practical measures should be taken such as sleeping on towels. Weight gain, sedation, constipation, tachycardia (fast pulse), postural hypotension, and lowered seizure threshold are other possible side effects. The lowered seizure threshold happens at higher doses of clozapine and predisposes patients to fits or seizures. This means that if the patient is epileptic, he might have breakthrough seizures, which means that his anti-epileptic medication might need to be adjusted. Someone who had never had seizures before, might also experience a seizure. This does not mean that he has developed epilepsy. Usually this can be controlled with the addition of an anti-convulsant medication. Another possible side effect is enuresis, which is bed-wetting whilst sleeping. This is quite distressing and potentially a reason for stopping medication. But these are medications which can be used for this problem. Sedation might be helped by dividing the dose, so that smaller doses are given daytime and the larger dose is given nighttime.

Postural hypotension is the lowered blood pressure which can occur. This can lead to dizziness and collapse, especially when getting up suddenly from a sitting or lying position. Patients must be aware of this, especially when getting up. Increasing the medication slowly helps the body to adapt to the dose and decreases the likelihood of severe hypotension.

Clozaril however has an undeserved bad reputation amongst the medications, because it is associated with neutropenia and agranulocytosis. One of its side effects is that it can potentially cause a drop in the production of white blood cells which fight infections. The severity of this decrease can range from a slight transient drop to complete bone marrow failure. This effect is usually reversed when the medication is stopped; the possibility remains of rechallenging the patient at a slower titration. Despite this potential complication, the actual incidence of clozapine induced bone marrow failure is low.

Other rare side effects are cardiomyopathy (weakening of heart muscle), carditis (allergic heart reaction), and pulmonary embolism. Raised body temperature can also be a possible side effect at initiation. This usually settles after days to few weeks. Raised body temperature can also occur with carditis and low white cell count, so these conditions must be excluded.

The rate of any fatal side effects is however low, and the benefits outweigh the risks. Patients usually do well, if blood counts are closely monitored, and clinicians of mindful of the serious side effects.

Clozaril adverse effects
Clozaril neutropenia
Clozaril and smoking
Clozaril interactions



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