'Game Changer' for First-Episode Schizophrenia

Megan Brooks

June 25, 2015

After a first episode of schizophrenia, starting a long-acting injectable (LAI) antipsychotic is a better bet than starting an oral antipsychotic, according to results of a randomized controlled trial.

In the 12-month study, the LAI formulation of risperidone (Risperdal, Janssen Pharmaceuticals, Inc) proved superior to oral risperidone on measures of relapse and symptom control, which were partially related to better adherence.

"Our findings indicate that long-acting antipsychotic medications should become a first-line treatment soon after the initial episode of schizophrenia. This may be the period in which use of long-acting antipsychotic medication has the greatest impact on the course of the disorder," first author Kenneth L. Subotnik, PhD, of the Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, told Medscape Medical News.

LAI antipsychotics are typically not used following first psychotic episodes, but on the basis of these findings, that needs to change, the investigators note.

The study was published online June 24 in JAMA Psychiatry.

"Striking" Difference

The study included 86 patients with a recent first episode of schizophrenia who were randomly assigned to receive LAI risperidone (n = 43) or oral risperidone (n = 43) for 12 months. The modal dosage of oral risperidone was 2 mg/day, but some patients needed substantially higher doses, raising the mean dosage to 3.6 mg/day (range, 1.0 - 7.5 mg/day). The modal dosage of LAI risperidone was 25 mg every 2 weeks (range, 12.5 - 37.5 mg).

Half of the participants in each group were simultaneously randomly assigned to receive cognitive remediation to improve cognitive functioning or healthy-behaviors training to improve lifestyle habits and well-being.

Only 3 (7%) of the 43 patients assigned to LAI risperidone refused treatment, attesting to the acceptability of injectable antipsychotics, the researchers note.

There was a "striking" sixfold difference in 12-month relapse rates between the groups, favoring LAI risperidone. The psychotic exacerbation and/or relapse rate was 5% in the LAI risperidone group vs 33% in the oral risperidone group ― a relative risk reduction of 84.7%. Treatment with LAI risperidone also provided better control of hallucinations and delusions.

Adherence to medication, which was better with LAI risperidone than oral risperidone, was associated with prevention of exacerbation and/or relapse and control of breakthrough psychotic symptoms.

This study shows that LAI antipsychotic medication is "readily accepted by schizophrenia patients soon after the onset of the disorder and is excellent for preventing psychotic symptom return and psychiatric hospitalization," said Dr Subotnik.

"Patients with schizophrenia very commonly question the need for medication, even moreso early in the course of schizophrenia than later," he noted. "Yet taking antipsychotic medication consistently is the single greatest modifiable factor in reducing psychotic exacerbations and relapses. The use of [LAI] antipsychotic medication can help patients maintain adherence. Why wait until for a patient to become demoralized by repeated psychotic episodes, multiple hospitalizations, and disability to offer a long-acting medication?"

The two psychosocial interventions did not differ significantly from each other regarding control or prevention of the return of psychotic symptoms or rate of hospitalization, and there were no significant interactions between the two medications and the two psychosocial treatments. Early treatment discontinuation owing to intolerable side effects was more common with oral than LAI risperidone (21% vs 10%; P = .14).

Time for an Attitude Adjustment

The researchers note that the superiority of LAI risperidone extends beyond preventing the return of psychotic symptoms. In prior studies, they found that use of LAI risperidone in first- episode patients also led to better maintenance of intracortical myelination as well as improved cognitive functioning.

If this "trifecta" of improved psychotic symptom control, cognition, and intracortical myelination is replicated in longer-term studies, it would suggest that use of LAI antipsychotics early in schizophrenia can modify the trajectory of the disorder and lead to better long-term outcomes, the researchers say. This possibility would be a "game changer" for the field, they conclude.

Dr Subotnik acknowledges that getting clinicians to turn to LAI antipsychotics earlier will not happen overnight.

"For this change in clinical practice to occur, clinicians will need to overcome their current tendency to resort to long-acting injectable antipsychotic medications only after repeated medication nonadherence and multiple hospitalizations, what has been referred to as the 'revolving door syndrome.' Clinicians will not only need to change their attitudes about injectable medication but will also need to modify their practice settings to be able to give injections or arrange for the injections to be given at a local clinic or pharmacy," Dr Subotnik said.

The authors of a linked editorial note that LAI antipsychotic medications are "significantly underused" and that that is "unfortunate" in light of their documented efficacy.

"Our field needs to recalibrate its attitudes and practice related to LAI drugs," write William Carpenter Jr, MD, and Robert Buchanan, MD, from the Maryland Psychiatric Research Center, University of Maryland School of Medicine, in Baltimore.

This study indicates that LAI medications "should be a first-line treatment for a first episode of psychosis, an important advance for treating individuals who frequently struggle with adherence and for whom inadequate symptom control impedes the recovery process," they write.

But Dr Carpenter and Dr Buchanan say LAI antipsychotics are not for every patient. Good candidates might include those who prefer injections to daily pill-taking routines; have trouble taking medication daily; have a history of nonadherence; reduce their oral medications when using alcohol or drugs; and seek a high level of stability when entering the workforce.

The study was supported by grants from the National Institute of Mental Health, with additional support and medication provided by Janssen Scientific Affairs. Dr Subotnik and several coauthors report financial relationships with Janssen and other pharmaceutical companies.

JAMA Psychiatry. Published online June 24, 2015. Abstract, Editorial

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