Clozapine, LAI Antipsychotics Found Best at Preventing Relapse

Long-acting injectable (LAI) antipsychotic medications, along with clozapine, appear to be associated with the lowest risk for relapse and rehospitalization among patients with schizophrenia, according to a landmark report published June 7 in JAMA Psychiatry.

A prospective study of all patients in Sweden with schizophrenia who were prescribed 18 antipsychotic formulations, no antipsychotic at all, or some combination of antipsychotics found that apart from oral clozapine, LAI formulations were superior to equivalent oral formulations in preventing relapse.

The superiority of clozapine for patients with schizophrenia is well established, despite its relative underuse by clinicians. But the data for effectiveness of LAI antipsychotics have been less clear, as randomized, controlled trials (RCTs) of LAI antipsychotics have had mixed results.

Proponents of using LAI antipsychotics, such as John Kane, M.D., senior vice president for behavioral health services of the North Shore-Long Island Jewish Health System and chair of psychiatry at the Zucker Hillside Hospital, say the mixed results of the LAI trials may be due to an artifact of the methodology of RCTs. Patients who enter such trials are likely to have fewer problems with adherence, and RCTs typically involve much more monitoring than is typical in “real-world” settings. As a result, the superiority of LAIs in ensuring adherence among patients who have a history of non-adherence may get “washed out” in the experimental setting of an RCT.

The current study, looking at real-world effectiveness of the antipsychotics in a very large group of patients, appears to vindicate LAI proponents. “This is a very important report, with many methodological strengths, that supports our belief that clozapine and long-acting injectable medications offer important individual and public health advantages in reducing the risk of rehospitalization and pharmacotherapy treatment failure,” Kane told Psychiatric News. “Despite such evidence, these treatments remain grossly underutilized, particularly in the U.S. We need to redouble our efforts to provide the necessary training to facilitate their appropriate use, including skills such as psycho-education, motivational interviewing, and shared decision making.”

Swedish researchers used national databases to analyze the risk of rehospitalization and treatment failure from July 1, 2006, to December 31, 2013, among all patients in Sweden with a schizophrenia diagnosis who were 16 to 64 years of age in 2006 (n=29,823). The main outcome was risk of rehospitalization and treatment failure (defined as psychiatric rehospitalization, suicide attempt, discontinuation or switch to other medication, or death).

Patients were prescribed either no antipsychotic or one of five first-generation LAI medications (fluphenazine, flupentixol, haloperidol, perphenazine, zuclopenthixol); one of the equivalent first-generation oral medications (with oral levomepromazine instead of fluphenazine); one of three second-generation LAI medications (olanzapine, paliperidone, risperidone); or one of the equivalent oral formulations, as well as either aripiprazole or clozapine. Some patients also received some combination of antipsychotics. (Flupentixol and zuclopenthixol are not approved for use in the United States.)

During the follow-up period, 13,042 of the 29,823 patients (43.7 percent) were rehospitalized, and 20,225 of 28,189 patients (71.7 percent) experienced treatment failure. The risk of psychiatric rehospitalization was the lowest during monotherapy with (in order of increasing hazard ratio) once-monthly LAI paliperidone, LAI zuclopenthixol, clozapine, LAI perphenazine, and LAI olanzapine.

Oral flupentixol, quetiapine, and perphenazine were associated with the highest risk of rehospitalization.

LAI antipsychotic medications were associated with substantially lower risk of rehospitalization compared with equivalent oral formulations, and all LAI antipsychotic medications were associated with the lowest rates of treatment failure compared with the most widely used medication, oral olanzapine.

William Carpenter, M.D., a professor of psychiatry and pharmacology at the University of Maryland School of Medicine, hailed the report as “very important, especially for clinicians in the United States where LAI medications are underutilized and too often reserved for ‘special problem’ patients.” Carpenter was not involved with the study.

He added that the results regarding LAI medications are especially strong precisely because high relapsing patients and those who have been difficult to manage—for reasons related to medication adherence, for instance—are more likely to be prescribed LAI formulations. “Hence, the observed advantages are even more important,” Carpenter said.

Kane added that psychiatrists “need to be conscious of the ‘hassle factor’ that might diminish the use of these treatments and be sure that prescribers as well as their clinical and administrative teams have the necessary consultative, logistical, financial, and other supports necessary to optimize utilization.” ■