Can Atypical Antipsychotics Reduce Suicide Risk in Patients With Schizophrenia?

Suicide is a devastating, tragically frequent outcome for persons with varying psychiatric conditions, including schizophrenia. An estimated 5% to 10% of persons with schizophrenia commit suicide and 20% to 50% attempt suicide during their lifetime.^1,2 Patients with schizophrenia have more than an 8-fold increased risk of completing suicide (based on the standardized mortality ratio) than the general population.³ Antipsychotic treatment is the cornerstone of the therapeutic approach to schizophrenia and has been thought to influence suicidal tendencies.⁴ Yet, both typical and atypical antipsychotics (the latter of which have been considered to have a better profile for reducing the risk of suicide than the former) have not been shown to have a net positive effect on suicidality.^5,6

Atypical antipsychotics are now considered to be a first-line treatment for schizophrenia. It is therefore crucial that we have an evidence-based approach to minimizing suicidal thinking and behavior. We have recently reviewed the relationship between antipsychotic drugs and suicide in patients with schizophrenia, observing that many inconsistencies exist among the studies. This, in turn, prevents any definitive conclusions; the sole exception is clozapine(Drug information on clozapine), which should be considered when suicide risk is detected.⁷

This article reviews the evidence for the various atypical antipsychotics in potentially reducing the risk of suicide in patients with schizophrenia. A high degree of efficacy should not be expected, since 2 large reviews on premarketing data have failed to demonstrate the efficacy of atypical antipsychotics (excluding clozapine) in reducing the risk of suicidality in patients with schizophrenia.^8,9 Further limitations come from methodological issues, which may be seen in some studies that originate within the pharmaceutical industry.¹⁰

Evidence for the antisuicidal effect of atypicals In spite of the vast amount of literature on atypical antipsychotics, there is a dearth of studies evaluating their specific antisuicidal effect. The existing evidence is summarized in Table 1.

Clozapine has the strongest level of evidence for antisuicidal effect. A recent meta-analysis found a lower overall risk of both suicidal behaviors and completed suicide with clozapine as compared with other treatments.¹¹ However, 3 major caveats merit attention. First, only 6 studies were included and only 1 of these was randomized. Moreover, its conclusions only referred to suicide attempts.¹² Second, we still do not have a comprehensive understanding of this drug's mode of action in preventing suicide. Finally, the more recent the study, the smaller the relative benefit for clozapine was shown. In spite of this, clozapine was the first medical treatment approved by the FDA for reducing the risk of suicidal behaviors in patients with schizophrenia or schizoaffective illness.¹³

Clinical guidelines also support the use of clozapine for reducing suicide risk in patients with schizophrenia. The most recent version of the Texas Medication Algorithim Project antipsychotic algorithm for schizophrenia recommends that persistent symptoms of suicidality should prompt earlier (ie, before the usual 2-trial failures) treatment with clozapine.¹⁴

Risperidone and olanzapine(Drug information on olanzapine) have generated some evidence that permits their consideration as an alternative to clozapine in clinical settings. Herings and Erkens¹⁵ demonstrated a 4-fold increase in suicide attempts for patients who interrupt or stop treatment with these drugs. Similarly, another study found a significant association between good versus poor adherence with these atypical antipsychotics and quetiapine, as well as a decreased risk of suicidal behaviors.¹⁶ In addition, risperidone(Drug information on risperidone) and olanzapine have been reported to be safer in overdose than clozapine.¹⁷

Although no meta-analysis or randomized study supports the use of risperidone for preventing suicide, an interesting study analyzing deaths due to poisoning involving antipsychotics in England and Wales (1993 through 2002) reported relevant data on deaths per million prescriptions for quetiapine (31.3 per million), amisulpride(Drug information on amisulpride) (17.0 per million), olanzapine (13.2 per million), flupentixol(Drug information on flupentixol) (3.3 per million), and risperidone (1.1 per million).¹⁸

The strongest evidence for risperidone comes from retrospective studies that compare it with typical antipsychotics¹⁹ and olanzapine (nonsignificant differences).²⁰ There is not enough information about the long-acting preparation of risperidone, but conclusions may differ. For example, in a subgroup analysis of the open-label Switch to Risperidone Microspheres trial, the authors reported a suicide attempt that was possibly related to this drug.²¹ On the other hand, 2 prospective, randomized, double-blind studies supported the superiority of olanzapine compared with haloperidol(Drug information on haloperidol)²² and risperidone²³ in preventing suicide attempts.

There are not enough data on the rest of the atypical antipsychotics to suggest their effectiveness and, thus, potential use for treating suicidal tendencies in patients with schizophre nia. One review reported a potential antisuicidal effect of quetiapine(Drug information on quetiapine),²⁴ but the data are lacking for this drug if studies on affective disorders are excluded. Findings from a recent, multicenter, observational study involving 8608 patients showed that suicide mortality rates with sertindole in real-life practice are not higher than those found in clinical trials.²⁵ Finally, while a case report recently suggested a suicide-potentiating effect with aripiprazole(Drug information on aripiprazole),²⁶ another study reported a good safety profile in cases of overdose.²⁷

Affective symptoms
Hopelessness and other affective symptoms such as depression or low self-esteem are probably the most common contributors to suicide in patients who have chronic schizophrenia.^1,28 This is the case even when psychotic motivations predominate (Table 2).²⁹ There is good evidence about the potential antidepressant properties of atypical antipsychotics, but we should not forget that depression from antipsychotic adverse effects can also occur.⁷ In fact, dysphoric responses to both typical and atypical antipsychotics may, and often do, occur with high individual variability. Dynamic interactions between the state of the dopamine(Drug information on dopamine) receptor and the pharmacological properties of conventional antipsychotics may be responsible for the variability in dysphoric responses.³⁰