Clozapine

Clozapine is a prescription drug used for the treatment of schizophrenia. Clozapine is also used to reduce the risk of suicide in schizophrenia and schizoaffective disorder. Clozapine belongs to a family of drugs called atypical antipsychotics. Other members of this family are risperidone (Risperdal) and olanzapine (Zyprexa). Clozapine is particularly effective in schizophrenia which has failed to adequately respond to other medicines.

Other Names

• Clozaril (Novartis)
• FazaClo (Azur Pharma)

Uses

Clozapine is specifically indicated for treating patients with schizophrenia who do not respond adequately to standard drug regimens. Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

How Clozapine is Taken

Clozapine comes in tablet and rapidly disintegrating tablet oral forms.

Treatment with clozapine begins with half of a 25-mg tablet (12.5 mg) once or twice daily. The dosage is increased by 25-50 mg daily to eventually achieve a target dose of 300-450 mg per day by the end of 2 weeks.

Subsequent dose changes are made no more than once or twice weekly. Increments usually should not exceed 100 mg. Dosing usually does not exceed 900 mg daily.

How It Works

Like other antipsychotics, clozapine blocks the binding of the neurotransmitter dopamine to its receptor. The specific dopamine receptors blocked are: D1, D2, D3 and D5. Clozapine also binds with the D4 receptor.

How the Body Affects Clozapine

Peak circulating levels occur at 2.5 hours after dosing.

Clozapine is almost completely metabolized prior to excretion. Approximately 50% of the original dose is excreted in the urine and 30% in the feces in the form of various metabolites.

Benefits

The benefits of cloazpine are threefold:

• Effectiveness: Clozapine adds an alternative for treatment of the symptoms of schizophrenia (hallucinations, delusions, bizarre behavior and hostility) where other medicines have not been effective. It also significantly improves the negative symptoms (withdrawal, blunted emotions, lack of motivation, and inability to experience pleasure or enjoyment).
• Lack of usual side effects: Clozapine has virtually no incidence of the muscle spasms, cramps, and posturing movements common to other drugs, and minimal incidence of the less serious neurological side effects such as restlessness, muscle rigidity, and tremor.
• Lack of tardive dyskinesia: Tardive dyskinesia (TD) is characterized by involuntary movements such as grimacing, sucking and smacking of lips, and spasmodic movements of the extremities. It usually begins after several months of treatment and may be irreversible. There have been no confirmed cases of TD directly caused by clozapine alone.

Side Effects

The most common side effects of clozapine are:

• Drowsiness or sedation
• Dizziness (vertigo)
• Headache
• Tremor
• Increased salivation (especially at night)
• Sweating
• Dry mouth
• Visual disturbances
• Tachycardia (rapid heart rate)
• Hypotension (low blood pressure)
• Syncope (fainting)
• Constipation
• Nausea
• Fever

Risks

Complications

Clozapine has two associated warnings:

Agranulocytosis

Agranulocytosis is characterized by a marked decrease in the number of granulocytes. Granulocytes are a type of white blood cell filled with enzymes that digest microorganisms and fight infection. Symptoms of agranulocytosis include:

• Weakness
• Fever
• Sore throat
• Malaise
• Mucous membrane ulceration
• Flu-like symptoms or other possible signs of infection

Regular blood tests must be performed on a routine basis when a person is taking clozapine; initially weekly for several months before switching to monthly. This is because the person's blood must be monitored regularly for signs of agranulocytosis, which can be life-threatening. There is also a patient registry in which physicians enroll patients and report laboratory results. These measures were designed to monitor the number of patients with agranulocytosis, as cessation of clozapine will reverse the drop in white cells.

Increased mortality in the elderly

The FDA issued a public health advisory in 2005 stating that treating elderly patients with behavioral disorders with atypical antipsychotic medicines is associated with increased mortality. The cause of death was most often heart-related events (heart failure or sudden death) or infections (pneumonia). Clozapine was not specifically studied but the warning extends to all atypical antipsychotics. ^[1]

Interactions

Clozaril may interact with the following drugs:

• nictoine
• Cimetidine (Tagamet)
• Citalopram (Celexa)
• Lithium (Eskalith, Lithobid)
• Rifampin (Rifadin, Rimactane)
• Blood pressure medications
• Heart rhythm medications such as propafenone (Rythmol) or flecaininde (Tambocor)
• Seizure medicine such as phenytoin (Dilantin) or carbamazepine (Tegretol)
• Antibiotics such as ciprofloxacin (Cipro) or erythromycin (E-Mycin)
• Atropine (Donnatal), belladonna, clidinium (Quarzan), dicyclomine (Bentyl), scopolamine (Transderm-Scop)
• Diazepam (Valium), alprazolam (Xanax), clonazepam(Klonopin), lorazepam (Ativan), midazolam (Versed), or temazepam (Restoril)

Effectiveness

The UK Cochrane Collaboration published a systematic review of clozapine compared to typical antipsychotics in the treatment of schizophrenia.^[2] The study group found no significant differences in effectiveness for long term outcomes such as mortality, patient satisfaction, working ability or suitability for hospital discharge at the end of the study. However, in the short term, patients on clozapine had fewer relapses and more frequent clinically-important improvements.

History

Clozapine was first developed in the 1960s and introduced in Europe ten years later. In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was taken off the market.

After studies demonstrated that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics, the FDA and health authorities in most other countries approved its use only for treatment-resistant schizophrenia. In December of 2002, clozapine was also approved for reducing the risk of suicide in schizophrenics or schizoaffective patients judged to be at chronic risk for suicidal behavior. ^[3]

Research

Recent discoveries

One study showed that clozapine may decrease the risk of substance abuse with schizophrenia. Other antipsychotic drugs may make substance abuse in schizophrenics as likely or more likely. ^[4]

Another study evaluated a possible need for doses of clozapine as high as 1400 mg/day, especially in young male smokers. ^[5]

Clinical Trials

A list of clinical trials is available from ClinicalTrials.gov: Clozapine clinical trials.

References

1. ↑ U.S. Food and Drug Administration. FDA Public Health Advisory: Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances.
2. ↑ Campbell M, Young PI, Bateman DN. The use of atypical antipsychotics in the management of schizophrenia. Br J Clin Pharmacol. 1999 Jan;47(1):13-22. Abstract | Full Text
3. ↑ U.S. Food and Drug Administration. FDA talk paper. FDA Approves Clozaril to Reduce the Risk of Suicidal Behavior in Patients with Schizophrenia or Schizoaffective Disorder
4. ↑ Green AI, Zimmet SV, Strous RD, Schilddraut JJ. Clozapine for comorbid substance use disorder and schizophrenia: do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine? Harv Rev Psychiatry. 1999 Mar-Apr;6(6):287-96. Abstract
5. ↑ Maccall C, Billcliff N, Igbrude W. Clozapine: more than 900 mg/day may be needed. J. Psychopharmacol. 2008 May 30. (Epub ahead of print)Abstract

External Links

FDA: Patient Information Sheet

National Institute of Mental Health: Schizophrenia

Medline Plus: Clozapine