Clozapine may consistently protect from suicidal behaviors while other antipsychotics may lack a specific protective effect: a comprehensive VigiBase study interpreted in the context of the prior literature.

BACKGROUND: In the United States, clozapine was first approved for treatment-resistant schizophrenia and then for suicidality in schizophrenia psychoses. Systematic reviews support clozapine's anti-suicidal effect, but the forensic literature stresses its lethality during overdoses. RESEARCH DESIGN AND METHODS: Clozapine reports to the international pharmacovigilance database (VigiBase) were analyzed for suicidal ideation, suicide attempts, intentional overdose, and completed suicides from introduction to 1 January 2024. VigiBase uses the information component (IC) as a disproportionality analysis. RESULTS: The clozapine ICs (range: other antipsychotics) were: 1) suicidal ideation IC = 0.570 with IC025 = 0.454 to IC975 = 0.680 (IC = 3.568 for aripiprazole and 1.729 for risperidone), 2) suicide attempt IC = 1.428 with IC025 = 1.323 to IC975 = 1.529 (IC = 4.150 for quetiapine and 2.968 for risperidone), 3) intentional overdose: IC = 0.995 with IC025 = 0.864 to IC975 = 1.120 (IC = 4.080 for quetiapine and 1.957 for aripiprazole), and 4) completed suicide IC = 1.133 with IC025 = 1.026 to IC975 = 1.235 (IC = 4.648 for quetiapine and 2.160 for risperidone). In summary, all clozapine ICs were significantly lower. We found 2391 clozapine-treated patients on the suicidality spectrum (627 cases with suicidal ideation, 752 with suicide attempt, 488 with intentional overdose, and 731 with completed suicide) but many were taking other antipsychotics. The most frequent reporting countries were the United States, the United Kingdom, and Croatia. CONCLUSION: This pharmacovigilance study, with all its inherent limitations, provides independent proof, not overlapping with prior literature, that clozapine may have specific strong anti-suicidal effects that do not appear to be present in other antipsychotics. Further VigiBase studies are needed to compare the lethality of an intentional overdose of clozapine (14.3%) with other antipsychotics.

Nitrous Oxide: an emerging novel treatment for treatment-resistant depression.

Stemming from the results of the historic STAR-D trial, it is evident that a significant subset of individuals (20-25%) with major depressive disorder (MDD) do not respond to conventional antidepressant medications. As a result, an emphasis has been placed on the development of novel therapeutics for MDD over the last two decades. Recently, substantial research efforts have been focused on the use of ketamine as an antidepressant whose mechanism of action is via the N-methyl-d-aspartate (NMDA) receptor. Another potential therapeutic compound of interest is nitrous oxide, which has been utilized for more than a century in multiple fields of medicine for its analgesic and anesthetic properties. Recent clinical studies suggest that nitrous oxide may be effective for treatment-resistant depression. In this review, we will discuss the administration of nitrous oxide as a psychiatric intervention, current use in psychiatry, putative mechanisms of action, and future directions highlighting knowledge gaps and other potential utilities in the field of psychiatry.