Can Atypical Antipsychotics Reduce Suicide Risk in Patients With Schizophrenia? An Evidence-Based Analysis

Psychiatric Times. Vol. 25 No. 5

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An Evidence-Based Analysis

By Eduardo J. Aguilar, MD, PhD, Samuel G. Siris, MD, and Carmen Leal, MD, PhD | April 15, 2008

Dr Aguilar is a psychiatrist at the Clinic University Hospital in Valencia, Spain. Dr Siris is affiliated with the Zucker-Hillside Hospital of the North Shore, Long Island Jewish Health System, in Glen Oaks, NY, and is professor of psychiatry at Albert Einstein College of Medicine. Dr Leal is chair of the psychiatric unit and a member of the faculty of medicine at Valencia University, and head of Psychiatric Services at Clinic University Hospital, Valencia, Spain. The authors report no conflicts of interest concerning the subject matter of this article.

There is a similar level of evidence for risperidone(Drug information on risperidone), but there have been more studies of this medication. Double-blind, randomized studies that compared this drug with olanzapine(Drug information on olanzapine) have found superiority of olanzapine,⁴⁴ nonsignificant differences,⁴⁵ and superiority of risperidone.⁴⁶ Peuskens and colleagues⁴⁷ analyzed pooled data (N = 1294) from 6 double-blind trials and found risperidone to be superior in comparison to haloperidol(Drug information on haloperidol) or placebo in reducing the Positive and Negative Syndrome Scale anxious/depressive factor. Myers and Thase⁴⁸ reviewed 7 randomized, controlled trials of risperidone (vs haloperidol, olanzapine, and clozapine(Drug information on clozapine)) in patients with schizophrenia or schizoaffective disorders and concluded that risperidone was efficacious in the treatment of depressive symptoms in these pathologies; the greatest support came from the haloperidol studies. More recently, a study that reanalyzed data from the North American risperidone trial showed similar results.⁴⁹

Examining the only long-acting atypical antipsychotics (risperidone microspheres) is relevant at this point, since poor adherence to treatment has also been linked with suicidal risk.²⁸ Several open-label, uncontrolled studies have demonstrated that long-acting risperidone improves anxiety and depression symptoms in stable patients with schizophrenia and/or schizoaffective disorder.^50,51

Amisulpride also has a fairly good level of evidence for treating depressive symptoms in schizophrenia. Peuskens and colleagues⁵² compiled data from 3 short-term, double-blind, randomized studies. They found a greater improvement in the anx- ious/depressive factor for amisulpride(Drug information on amisulpride) compared with haloperidol and risperidone in patients with acute exacerbations of schizophrenia. Eighty-five adults fulfilling DSM-IV criteria for schizophrenia and presenting with a depressive episode were randomized to amisulpride or olanzapine for 8 weeks. There were no significant differences in depressive symptom improvements between the 2 drugs.⁵³ A multicenter, double-blind, randomized study that evaluated patients with chronic schizophrenia (DSM-IV) showed that amisulpride was not inferior to risperidone in improving symptoms of depression.⁵⁴ Finally, findings from an open-label, 12-week study of patients who were initially treated with risperidone and were randomized to a risperidone-continuation group or an amisulpride-switch group showed that improvements in depressive symptoms were significantly greater in the amisulpride-switch group than in the risperidone-continuation group.⁵⁵

Quetiapine is superior to placebo in reducing anxiety, depression, and hostility⁵⁶ but, to the best of our knowledge, it has not yet been compared with another atypical antipsychotic for its antidepressant effect in schizophrenia. This efficacy for treatment of affective symptoms is maintained in long-term treatment.⁵⁷ Additional evidence comes from a multicenter, double-blind, randomized trial of quetiapine(Drug information on quetiapine) compared with high doses of haloperidol (20 mg/d). The study demonstrated superiority of quetiapine in reducing depressive symptoms in patients with refractory schizophrenia.⁵⁸ Haloperidol dosage is a strong limitation of this study, since higher doses of antipsychotics could be associated with worsening of depressive symptoms.

Somewhat surprisingly, scarce attention has been paid to the effect of clozapine on depressive symptoms. Indirect data come from the study by Meltzer and colleagues.¹² These investigators reported that patients who received clozapine required less concomitant treatment with antidepressants than the patients who were treated with olanzapine.

For the rest of the compounds, the highest level of evidence corresponds to flupentixol(Drug information on flupentixol) and ziprasidone(Drug information on ziprasidone), although very little information is available. In a randomized, double-blind, multicenter study of patients with predominant negative symptoms, flupenthixol demonstrated noninferiority compared with risperidone.⁵⁹ Similarly, in a 6-week, multicenter, double-blind, parallel-design, flexible-dose trial, ziprasidone and olanzapine showed comparable efficacy in reducing depressive symptoms of acutely ill inpatients with schizophrenia or schizoaffective disorder.⁶⁰

Aripiprazole is also a potentially good choice for treating depressive symptoms in patients with schizophrenia, but there are no comparisons with other atypical antipsychotics. Relevant indirect data come from a recent study of aripiprazole(Drug information on aripiprazole) augmentation in a group of outpatients who had chronic schizophrenia and were treated with clozapine. The researchers found that the augmentation led to a substantial improvement in depressive symptoms.⁶¹ Furthermore, analysis of data from 2 randomized, double-blind, multicenter studies of 1294 patients with chronic schizophrenia in acute relapse who had previously responded to antipsychotic medications suggests that aripiprazole is superior to haloperidol in improving depressive symptoms.⁶²

Conclusion
Although clozapine is the only strictly evidence-based treatment for reducing the risk of suicide in schizophrenia, several other atypical anti- psychotics may be reasonable options when treating specific symptoms associated with suicide risk, such as depressive symptoms. Olanzapine, risperidone, and amisulpride also may be helpful. These and the other atypical antipsychotics need to be compared in head-to-head randomized and, preferably, independent studies. Further reviews and meta-analyses will confirm the steps for preventing suicide through evidence-based use of these drugs.

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• Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: a meta-analysis. Schizophr Res. 2005;73:139-145.
• Mamo DC. Managing suicidality in schizophrenia. Can J Psychiatry. 2007;52(6 suppl 1):59S-70S.

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Can Atypical Antipsychotics Reduce Suicide Risk in Patients With Schizophrenia?

An Evidence-Based Analysis

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