The Underuse of Clozapine in Schizophrenia

Schizophrenia remains one of the most challenging illnesses to treat. Antipsychotic medications have revolutionized the management of this illness and helped millions of people to live more normal lives. However, a substantial proportion of individuals derive insufficient benefit from most routinely used medications.

Estimates suggest that 10-15% of those experiencing their very first episode of illness will be considered “treatment resistant” based on experiencing little improvement in symptoms following two or even three trials of standard medications.1 Among patients with more chronic illness, the proportion of treatment resistant patients is much higher, with estimates ranging as high as 30%.2

There are no universally accepted definitions of treatment resistance, although for the present purposes, I will rely on the indications promulgated for clozapine use by the American Psychiatric Association (APA). The APA suggests “strong consideration” if psychotic symptoms are persistent after two adequate trials of antipsychotic drugs.2

For the purpose of determining a patient’s eligibility for a trial of clozapine, we define treatment resistance as an inadequate response to at least two antipsychotic drugs at the maximally tolerated dose within the recommended therapeutic range, in trials lasting six weeks or more. Termination of a medication due to adverse events before reaching the appropriate dose and duration should not be regarded as a failed trial due to non-response to the medication.

There are other important issues that should be considered before assuming that a patient is treatment resistant: potential misdiagnosis; co-occurring psychiatric or substance-use disorders, or medical conditions; non-adherence to prescribed medications; and drug-drug interactions. In addition, evidence-based psychosocial interventions should be provided to patients with appropriate indications and the patient’s nonpharmacologic treatment should be evaluated and optimized prior to diagnosing treatment resistance.