Study Challenges Schizophrenia Guidelines

Switching to clozapine after a first schizophrenia relapse was associated with a lower risk of second relapse compared with other strategies, a population-based cohort study in Finland found.

The risk of a second relapse was lower with a switch to clozapine compared with continuing any non-clozapine oral antipsychotic monotherapy (57.1% vs 73.2%, adjusted HR 0.66, 95% CI 0.49-0.89), reported Heidi Taipale, PhD, of the University of Eastern Finland in Kuopio, and co-authors.

Switching to another non-clozapine oral antipsychotic monotherapy (adjusted HR 0.99, 95% CI 0.76-1.28) was just as ineffective as not using an antipsychotic (adjusted HR 1.07, 95% CI 0.80-1.42), the researchers wrote in Lancet Psychiatry.

The findings challenge current guidelines recommending clozapine as a third-line treatment, which can lead to long delays in starting the drug, Taipale and colleagues observed.

“When a person with first-episode schizophrenia has a first psychosis relapse despite the use of non-clozapine oral antipsychotics, continuation with the same antipsychotic or a switch to another non-clozapine oral antipsychotic is not beneficial in relapse prevention,” they wrote. “Instead, clozapine initiation should be considered as part of shared decision-making with the person with schizophrenia and carers.”

Clozapine is recommended for the third of people with schizophrenia who have not responded to two or more conventional antipsychotics, noted Sameer Jauhar, MBChB, PhD, of King’s College in London, England, and co-authors in an accompanying editorial.

The current study “questions that orthodoxy and asks whether clozapine should be offered after first-line antipsychotic treatment failure,” setting the scene for a randomized controlled trial of clozapine after an initial antipsychotic has failed, they wrote.

Although clozapine has been available since the 1950s, and despite being the only licensed treatment for treatment-resistant schizophrenia, it continues to be underused for a variety of reasons, Jubal and colleagues suggested, including a need for close blood monitoring and a side-effect profile of constipation, hypersalivation, and weight gain. In the U.S., possible barriers include a risk evaluation and mitigation strategy (REMS) program designed around clozapine’s risk for severe neutropenia.

If clinical trials show benefit, “the issue for the field will be implementation, addressing legitimate concerns about side effects through better monitoring and adjunctive treatment, and how benefits and risks of clozapine are conveyed to clinicians, patients, and their families,” the editorialists observed. “The question will therefore not be should we offer clozapine, but how do we offer clozapine?”

Guidelines from the American Psychiatric Association (APA) recommend clozapine for treatment-resistant schizophrenia or when the risk for suicide attempts or suicide remains substantial despite other schizophrenia treatments. The APA guidelines also suggest clozapine when the risk for aggressive behavior remains substantial despite other treatments.

Taipale and colleagues evaluated 3,000 people ages 45 or younger who had first-episode schizophrenia and were hospitalized with a first relapse from 1996 through 2014. All were included in the Finnish hospital discharge register. None had been taking antipsychotics in the year preceding initial diagnosis or hospitalization, and all had a relapse within 5 years of discharge from their initial hospitalization.

The mean age was 30 years and 35.6% were women. Before the first relapse, most participants were either not using antipsychotics (45.5%) or were using non-clozapine oral antipsychotic monotherapy (32.4%). Of the 3,000 patients in the overall cohort, 71.7% had a second relapse within 2 years.

Treatments were assessed during the 30 days before hospitalization for the first relapse and 30 days after discharge, and were classified as long-acting injectable antipsychotics, clozapine, non-clozapine oral antipsychotic monotherapy, non-clozapine oral antipsychotic polypharmacy, or non-antipsychotics.

Long-acting injectables have shown benefits in patients with first-episode schizophrenia and this study extends these findings, Taipale and co-authors noted. In this cohort, initiating a long-acting injectable in antipsychotic non-users was associated with a decreased risk of a second relapse relative to non-use (adjusted HR 0.67, 95% CI 0.53-0.84).

Taipale and colleagues acknowledged that treatment changes later than 30 days after discharge and before a second relapse were not included in the study. It was likely that non-clozapine oral antipsychotic treatments were discontinued by patients, resulting in high relapse rates, they noted.

Finland’s health care system provides reimbursed medications and access to healthcare services with very low cost, and findings may not be generalizable to other settings. The study also did not include all schizophrenia-spectrum disorders.

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