Henry A. Nasrallah, MD, CURESZ Foundation Scientific Director and Richard Sanders, MD, Psychiatrist at Midwest Clinical Research, Dayton, Ohio

Clozapine is a unique medication, with higher efficacy than all the other antipsychotic medicines for patients with treatment resistant schizophrenia. However, it can be more difficult to manage, it can have serious physical side effects, and certain rare side effects can be life-threatening. Still, what’s most important is that according to published longitudinal studies, patients with treatment-resistant schizophrenia receiving clozapine have a lower mortality from medical conditions or suicide than those treated with other antipsychotic medications. This isn’t because clozapine has a better safety profile than the other antipsychotics. People taking clozapine live longer because it works better against psychosis.

Clozapine’s serious side effects are uncommon. For example, the weekly blood test will tell you if you are in danger of developing neutropenia (a white blood cell drop) which happens in only 1% of patients, and the medication can be discontinued without any danger. Because of this, the risk of death from clozapine-induced neutropenia happens about 1 in 10,000 people worldwide, and even less in the United States due to better monitoring.

The risk of seizures is uncertain, but it is higher than the 1% risk of seizures with other antipsychotic medicines. Seizure risk is related to higher clozapine dose, but this is typically an easily managed adverse effect.  Death due to clozapine-related seizures is very rare. Inflammation of the heart muscle (myocarditis) occurs in 1%-3% of people starting clozapine during the initial 6 weeks of treatment, but less often when the dose is increased slowly. Many doctors check serum troponin and CRP (a blood test that reflects inflammation), every week for the first 6 weeks of treatment, the same time the patient undergoes lab tests for neutropenia.

Pneumonia occurs in 2-3% of people in the first two months of starting clozapine, and may be related to an unusual side effect, sialorrhea (i.e. drooling). Drooling usually happens during sleep (people find a wet pillow in the morning) but it can happen while awake. This is treated by reducing the dose and/or using one of several medications (oral atropine drops, or Botox injections in the salivary glands) that slow down saliva production. Pneumonia does not require that clozapine be stopped, but the dose may need to be lowered temporarily until drooling problems are better managed.

Constipation can become a serious problem to the extent that the FDA issued an advisory in January 2020 warning about the use of clozapine with other anticholinergic medicines that slow gastrointestinal motility. Those combinations can cause a severe problem (ileus).  When starting clozapine, doctors usually prescribe a stool softener (docusate), and then add other medications (e.g. polyethylene glycol-3350, bisacodyl, linaclotide etc.) to prevent extreme constipation and ileus.

Weight gain and sedation are common side effects, but they are rarely dangerous. Metformin, a widely used diabetes pill is often used to help prevent weight gain due to clozapine, and is started when clozapine is started.  The new glucagon-like peptide-1 agonists (e.g. semaglutide) have FDA approval for obesity in nondiabetics, and have been studied in clozapine treated patients to help manage weight gain. Sedation can be short-lived or persistent, and it can be mild or a real hindrance. It can be addressed in a variety of ways including the administration of a waking medication like modafinil. Doctors should regularly check weights as well as lab tests, and should ask patients about side effects at every visit.

Clozapine is worth the risks, especially when managed carefully, as treatment resistant patients have no viable effective medication alternatives. It is the only antipsychotic medication that can restore mental wellness in patients who otherwise would remain disabled for the rest of their lives with intractable hallucinations and delusions. It is more likely to prolong than to shorten lives. It is also more likely than other antipsychotic medications to enable patients with severe schizophrenia to function vocationally and socially, and improve their quality of life.