Refractory Psychosis and Clozapine

Essential Concepts

Not all patients with schizophrenia have a meaningful response to antipsychotics: 1 patient in 4 benefits little from first-line antipsychotics; 1 in 10 has no response at all to any antipsychotic, including clozapine.
Make sure you are not dealing with “pseudo-refractoriness”: wrong diagnosis or missed diagnoses, unrecognized adherence problem, or drug use.
Before switching, optimize the dose of the antipsychotic that the patient is already taking.
Consider a (time-limited) clozapine trial after two failed, adequate antipsychotic trials; one of the antipsychotics should have been olanzapine.

“The tragedy of life is what dies inside a man while he lives.”

—Albert Schweitzer, 1875-1965, Nobel Prize for Peace 1952

Most patients with schizophrenia have a meaningful reduction in positive symptoms from first-line antipsychotics. Unfortunately, the tragedy of life, to paraphrase Schweitzer, leaves 20% to 30% of patients treatment refractory, with little to no symptomatic response to first-line antipsychotics. Some estimate that 10% of patients with schizophrenia have no response whatsoever to any antipsychotic, including clozapine.

I will call “refractory” those patients who do not have a clinically meaningful reduction in impairing positive symptoms despite two adequate (in dose and duration) antipsychotic trials. In this definition, clozapine is not counted toward refractoriness. Note that while the definition I use refers to positive symptoms, functional impairment is implied. Patients who are refractory to clozapine fall into a category by themselves. It is, of course, the illness that is refractory, not the patient; put differently, it is our treatment that is ineffective for a patient.

CLINICAL APPROACH FOR REFRACTORY PSYCHOSIS

When faced with a poor medication response, ask yourself three questions:

Is the patient truly refractory, or are you dealing with “pseudo-refractoriness”?
Is your currently prescribed regimen adequate and optimized?
Has the patient had several, well-conducted sequential antipsychotic trials?

Rule out “Pseudo-refractoriness”

Before you label a patient refractory, make sure that you have ruled out the following three problems that can contribute to an apparent poor medication response:

Wrong and/or missed diagnoses
Drug misuse
Partial adherence or nonadherence

Comorbid drug use is probably one of the more common reasons for a poor response. If there is any chance that partial adherence might be the problem, consider a time-limited trial of a long-acting antipsychotic to clarify the issues. There is the additional possibility that some patients respond better to this type of “smooth” drug delivery compared to the intermittent spiking from oral dosing.

A mistaken assumption of refractoriness has grievous consequences. It leads to polypharmacy, higher than necessary medication doses, poor treatment choices, and more side effects. Patients with intermittent compliance do not get used to side effects, and they might even run the risk of dangerous problems from starting a medication at full dose after missing a week of medications. Mistaken assumption of nonresponse to a
particular medication can lead the clinician to giving up on a potentially valuable medication for the rest of that patient’s life.

Optimize Current Regimen

Assuming you are confident that your diagnosis is correct and that neither drug misuse nor partial adherence is to blame for continuing symptoms, review your currently prescribed treatment: Is it adequate in duration and optimized in dose?

The duration of an adequate trial depends on the clinical situation and cannot be boiled down to one number. You should expect some clearly detectable clinical response after 4 to 6 weeks of treatment (not counting a titration period). If there is no response at all after 4 to 6 weeks, I would probably switch treatment earlier rather than later, particularly if symptoms are severe. If there is a clear response, it is important to allow symptoms to resolve and not switch prematurely: Time on medication is as important as the dose of medication since psychosis needs to be given time to resolve. Similarly, functional benefits of adequate symptom control will accrue only with time. Giving more medication cannot accelerate this process. It is a mistake to “push the dose” after 1 week of hospitalization, with little change in core psychotic symptoms. In other words, optimizing a medication can mean decreasing the dose or adding something to counteract side effects. Many patients will in fact often show some signs of improvement as early as week 1 (e.g., in sleep, in agitation). It is simply unrealistic to expect the resolution of delusions during a brief hospitalization.

Some patients might require a higher antipsychotic dose because of smoking, drug interactions (e.g., somebody on carbamazepine), or idiosyncrasies in drug metabolism.