Bipolar Disorder Medication Spotlight: Clozaril (Clozapine)

By Candida Fink MD

With this post, we continue our biweekly series on medications used to treat bipolar disorder and related symptoms. Over the past several weeks, we covered five commonly used atypical antipsychotics, including Zyprexa (olanzapine) and Seroquel (quetiapine). Because the Zyprexa post contains a great deal of information that applies to the atypical antipsychotics as a group, we encourage you to read it first.

Clozaril is a unique medication, even within the class of “atypical antipsychotics” and has been around for many years – it was first formulated in 1960 and studied in the 60’s and 70’s for the treatment of schizophrenia. In 1975, research was halted in the US and the UK due to a severe and frequent side effect causing reduction of white blood cell counts, leading to deadly infections.

Clozaril continued to be seen as quite effective for schizophrenia, especially treatment-resistant schizophrenia; therefore, it was ultimately re-introduced in the US and UK with a formal blood test monitoring system required for those who take it. It received approval in 1990, making it the first of the atypical antispsychotics to be prescribed.

Clozaril has FDA indications for schizophrenia, treatment-resistant schizophrenia, suicidal behavior in schizophrenia, and suicidal behavior in schizoaffective disorder. It does not have FDA indications for any phases of bipolar disorder. There are a number of clinical studies, however, that have found Clozaril to be effective in bipolar mania. It is not clear what benefits Clozaril has for bipolar depression or maintenance treatment of bipolar, but it has some clear benefits in the closely related schizoaffective disorder.

Clozaril was an exciting medication when it first came out because it can be effective in treating some people with schizophrenia who were unresponsive to many other antipsychotics. It was described as a miracle for some patients. Patients and prescribers were also pleased that Clozaril seemed to reduce negative symptoms in schizophrenia more effectively than other antipsychotics. Negative symptoms are things like withdrawal, inertia, and low motivation and energy, Clozaril has also been found to effectively reduce aggression in some patients with schizophrenia.

Clozaril can improve symptoms of schizophrenia and psychotic symptoms that may occur in bipolar, including the following:

• Hallucinations (audio and visual)
• Delusions
• Disorganized thinking
• Paranoia

It may also improve conditions such as social isolation, limited motivation, and reduced speech activity for some people.

Clozaril can also improve symptoms related specifically to mania, including the following:

• Irritability
• Elevated mood
• Impulsivity
• Racing thoughts
• Inflated self esteem
• Decreased need for sleep

Typical Dose

Clozaril must be introduced very gradually because of the potential for severe “orthostatic hypotension” – meaning drop in blood pressure when someone stands up. It is also quite sedating. The typical goal dose is 500 mg per day, in divided doses, but starting dose is much lower – more like 25 mg per day. The range of therapeutic doses is 400-700 mg per day. At doses about 500 mg per day, the risk of seizures increases significantly.

In my practice, I have not used Clozaril much, since I do not work in a hospital or clinic setting. When I did prescribe it for schizophrenia or severe mood disturbances, it was often effective but poorly tolerated due to a number of side effects, including terrible weight gain, drooling, and sedation.

Potential Side Effects

Clozaril can cause agranulocytosis – in which the bone marrow stops making white blood cells, which the body needs to fight off infection. To combat this side effect, patients taking Clozaril must have their blood drawn once a week to check white blood cell counts for the first year of treatment. Beyond the first year, the monitoring can go to every two weeks. Clozaril tends to have a limited scope of use because of this restriction. It tends to be used more in clinic and hospital settings than private practice. It is probably an underutilized medication because of concerns about this side effect and the intrusive blood draws required when someone is on Clozaril.

Other potentially serious side effects include the following:

• Weight gain: Severe and rapid weight gain can occur.
• Diabetes: Development of diabetes type II or pre-diabetes – problems with sugar and insulin metabolism (this is a potential side effect among all atypical antipsychotics). Regular lab tests are necessary to monitor this.
• Elevation of blood lipids: Elevation of blood lipids, such as cholesterol and triglycerides. Regular lab work will be part of treatment to monitor this.
• Sedation: Clozaril can be very sedating, so it must be carefully titrated, and patients must be monitored closely. This does get better usually with time.
• Orthostatic hypotension: Dropping blood pressure when going from lying to sitting or sitting to standing – this can be severe.
• Constipation: Also a common and often persistent side effect with Clozaril.
• Increased salivation: This can also be severe and persistent.
• Seizures: If you have a history of seizures, be sure to discuss it with your doctor. The risk of seizures may be reduced by gradually increasing the dose. Higher doses are associated with higher risks of seizures.
• Myocarditis: Myocarditis is an inflammation of the heart muscle, which, if it does occur, usually appears during the first month of treatment. If myocarditis is suspected, the medication should be promptly discontinued.
• Increased mortality in elderly patients with dementia-related psychosis: Clozaril, like most atypical antipsychotics is counter-indicated for use in elderly patients with dementia-related psychosis due to an increased risk of sudden death.
• Tremor or rigid muscles: Tremor or rigid muscles (parkinsonian or extrapyramidal symptoms). These are dose related and reversible. These side effects are much less likely in Clozaril than in older antipsychotic medications.
• Tardive dyskinesia: Involuntary, abnormal movements that can be irreversible. It is believed that Clozaril presents a much lower risk of tardive dyskinesia than older antipsychotics

For additional information about Clozaril, visit Novartis Pharmaceuticals’ Clozaril page.

If you’ve taken any form of Clozaril for bipolar disorder or are a doctor who has prescribed it, please share your experiences, insights, and observations.

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