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Using Clozapine Effectively, Safely

The Carlat Psychiatry Blog, Volume , Number ,

According to most treatment guidelines, you should consider clozapine after inadequate response to at least two antipsychotics. For patients who are extremely aggressive or suicidal, the APA treatment guidelines state that a trial of clozapine may be reasonable as a first or second line antipsychotic. Here are some additional tips for prescribing clozapine from this article in The Carlat Psychiatry Report:

Take REMS certification. Before you can prescribe clozapine, you must complete a REMS certification course online. The entire process usually takes less than an hour. Enrollment, the training course, and the quiz can be found at
Achieve buy-in from your patient and the family. You’ll need to give adequate disclosure about potential side effects, but this doesn’t need to be a long speech. Introduce the use of clozapine with a discussion about how other medications haven’t been completely effective. Tell patients, “Clozapine is more effective for people when other antipsychotics haven’t worked. It has a bunch of side effects, but we can monitor for them. Should we try it for a little while? If it works, I think you might decide that the side effects are worth putting up with.”

Ensure proper dosing. Start with a low dose of 12.5 mg to 25 mg a day to minimize side effects. Increase the dose by 25 mg to 50 mg every few days. Dividing the dose to twice or three times daily can help minimize the sedation and orthostasis. The initial target dose in healthy adults is 300 mg to 450 mg daily, and for older adults is 150 mg–300 mg daily. Once the titration is complete, all or most of the clozapine can be given at night to help with adherence. Since the seizure risk increases with higher clozapine concentrations, avoid going above 450 mg/mL (Xiang YQ et al, Schizophr Res 2006;83(2-3):201-210) or consider adding divalproex sodium.

Properly monitor. You need to monitor only the ANC every week for 6 months, then every other week for 6 months, and then monthly thereafter. Continuation of clozapine is based on the absolute ANC value, not changes in ANC over time.

Manage the side effects. The most common side effects are weight gain, hypersalivation, sedation, orthostatic hypotension, and constipation.

In addition to these common side effects, there are a few rare but serious side effects—agranulocytosis is one of them. Myocarditis/cardiomyopathy is very rare, and there is no agreed upon monitoring for it, but some experts recommend that you get troponin and CRP (c-reactive protein) levels weekly for the first 8 weeks. This represents an abundance of caution and is not commonly done. Since clozapine can cause significant constipation, routine questioning about bowel habits is important. Sialorrhea is also particularly annoying side effect.

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