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Quick! Name 2 psychiatric medications that are associated with a lower risk of suicide. You’ve got 1. Well, you read the title of this Quick Take, right? And the other is, yes, lithium. But how firm are these associations? Can you really include suicide risk reduction among your reasons for considering clozapine? Is this a class effect shared by other antipsychotics? Does it make a difference in this purported risk reduction whether clozapine is being used for a diagnosis of schizophrenia or a bipolar I?
Hi! Jim Phelps here for the Psychopharmacology Institute. Perhaps you’ve already concluded that clozapine is more strongly associated with a reduced risk of suicide than other treatments, in which case you’re right. This article will only reinforce your impression. But there’s at least 1 finding in here that you probably would not have predicted, one that might even affect your medication choices.
In this study, Alberto Forte and his colleagues found 18 studies with direct comparisons of at least 2 antipsychotics, with one-third of these studies being randomized trials. All were selected because they included outcome data on suicide. In all these data, suicide refers to attempts or completions. These compiled studies give us insight regarding multiple antipsychotics, including quetiapine, aripiprazole, risperidone, and ziprasidone.
When pooled together with clozapine, all antipsychotics were associated with a lower rate of suicide than the comparison treatments used in the various studies, but it turns out that clozapine is the backbone of that result. In 7 out of 7 comparisons with placebo or with other antipsychotics, patients receiving clozapine had lower suicide rates. In contrast, for all the other antipsychotics, reduction in suicide rates was seen in only 17 of 28 comparisons. If you remove clozapine from the overall comparison set, the remaining antipsychotics are not associated with a statistically significant reduction in risk.
That’s a very nice demonstration of research technique, but here’s an interesting result. One second-generation antipsychotic was associated with an increased risk of suicide. Which one? Would you have guessed quetiapine? This finding of an increased risk with quetiapine has lots of potential explanations. The authors note that for clozapine, all 7 studies focused on the treatment of schizophrenia, whereas with quetiapine, half of the studies focused on the treatment of bipolar disorder, with its particularly high suicide risk. The quetiapine finding is not entirely incidental. It’s not just the statistical result of multiple comparisons because the authors did set out to calculate odds ratios for all the antipsychotics studied. But the authors do suggest that their result not be interpreted as indicating an increased risk with quetiapine but more of a hypothesis-generating finding. Nevertheless, this certainly highlights the opposite effect of clozapine.
So, what exactly was found for quetiapine and clozapine? The study results are given as odds ratios, or the probability of suicide, attempts, or completions relative to a comparison suicide rate pretreatment, placebo, or on another antipsychotic. For clozapine, the odds ratio across the 7 studies was 0.23 or a 77% reduction in risk. For quetiapine, the odds ratio was 1.23 or an apparent 23% increase in risk. But remember the caveats—in the studies, quetiapine and clozapine were not treating the same conditions.
To conclude, reduction in suicide risk is not a class effect of antipsychotics; clozapine has the specific effect in this regard. As you weigh the complexity and risk of clozapine vs other options, suicide risk reduction might be a factor that could tip the balance.
For more on this, see the comparable study showing that lithium also lowers suicide risk by Andrea Cipriani and colleagues in the references.
Abstract
Background: Clozapine is the only treatment with regulatory-recognition of lowering suicidal risk, at least in schizophrenia patients. It remains uncertain whether such effects extend to other drugs for psychosis.
Methods: We searched for reports on rates of suicidal behavior during treatment with clozapine and other modern drugs for psychosis (aripiprazole, olanzapine, risperidone, quetiapine, and ziprasidone) versus comparison or control treatments and analyzed the contrasts by random-effect metaanalysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs).
Results: We identified 35 paired comparisons of modern drugs for psychosis versus comparison or control treatments in 18 reports. There was moderate overall superiority of all agents tested over alternatives (OR = 0.522, p = 0.004). With clozapine, this effect was large (OR = 0.229, p< 0.0001) and consistent (7/7 trials), but significant antisuicidal effects were not found with other drugs for psychosis in 28 other trials (OR = 0.941, p = 0.497). Apparent efficacy of specific agents ranked: risperidone ⩾ olanzapine ⩾ aripiprazole ⩾ ziprasidone ⩾ mixed drugs for psychosis ⩾ quetiapine, but none of these differences was significant.
Conclusions: An ability of clozapine to reduce risk of suicides and attempts in schizophrenia patients appears to be a unique effect not shared with other modern medicines indicated for schizophrenia or bipolar disorder.
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Reference
Forte, A., Pompili, M., Imbastaro, B., De Luca, G. P., Mastrangelo, M., Montalbani, B., & Baldessarini, R. J. (2021). Effects on suicidal risk: Comparison of clozapine to other newer medicines indicated to treat schizophrenia or bipolar disorder. Journal of Psychopharmacology, 35(9), 1074–1080.
Related References
Cipriani, A., Hawton, K., Stockton, S., & Geddes, J. R. (2013). Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ, 346.
