Journal Article Annotations
2025, 2nd Quarter

Suicide

Annotations by Sharvari Shivanekar, MD
July, 2025

Anti-Suicidal Effects of Lithium, Ketamine, and Clozapine-A 10-Year Systematic Review.

PUBLICATION #1 — Suicide

Anti-Suicidal Effects of Lithium, Ketamine, and Clozapine-A 10-Year Systematic Review.

Przemyslaw M Waszak, Jan Opalko, Natalia Olszańska, Paweł Zagożdżon.

Abstract: Pharmaceuticals (Basel). 2025 May 18;18(5):742. doi: 10.3390/ph18050742.

Background/Objectives:
Suicide is a complex issue resulting in approximately 700,000 deaths annually. Individuals with mood disorders or schizophrenia are at an increased risk. Pharmacological interventions, such as lithium, clozapine, and ketamine, show promise in reducing suicidality.

Methods:
A systematic search was conducted across Google Scholar, Scopus, and PubMed to identify studies evaluating the effects of lithium, clozapine, and ketamine on suicidality. Peer-reviewed articles published between 2014 and 2024 that focused on adult populations were included. After screening 1297 records, 49 studies met the eligibility criteria: 14 on lithium, 23 on ketamine, and 12 on clozapine.

Results:
Multiple studies highlight lithium’s significant anti-suicidal effects in patients with bipolar disorder, showing superior suicide risk reduction compared to valproate and other mood stabilizers. Ketamine has been shown to rapidly reduce suicidal ideation, with effects observable within hours and lasting up to a week. While most studies support its short-term efficacy, findings regarding its long-term benefits and the impact of repeated dosing remain inconsistent. Clozapine has consistently demonstrated a reduction in suicide risk for individuals with schizophrenia. Large-scale cohort studies report a significant decrease in suicide attempts and mortality when compared to other antipsychotics.

Conclusions:
Lithium, ketamine, and clozapine were proven to be effective in reducing suicidality. However, limited data, adherence challenges, and methodological differences across studies highlight the need for more robust, large-scale experimental research. Effective suicide prevention is an extremely complex topic and also requires consideration of healthcare and social system factors.

Annotation

The finding:
This systematic review examined the anti-suicidal effects of lithium, ketamine (including esketamine), and clozapine over the past decade. Reviewing 49 studies (14 on lithium, 23 on ketamine, and 12 on clozapine), the authors evaluated findings from randomized controlled trials, cohort studies, and case series published between 2014 and 2024 with the goal was to assess how these medications impact suicidal ideation, attempts, and completed suicides. Lithium demonstrated the strongest evidence, particularly in bipolar disorder, performing significantly better than valproate and other mood stabilizers. Ketamine/Esketamine provided rapid relief of suicidal thoughts with significant reductions within hours lasting up to a week. Single- and multi-infusion trials in major depressive disorder and cancer-related depression reported notable decreases in suicidal ideation, although long-term benefits and repeat-dosing impacts were inconsistent. Clozapine remains the only FDA-approved antipsychotic for reducing recurrent suicidal behavior in schizophrenia. InterSePT and several large cohort studies found 20–80% lower suicide attempts, hospitalizations and co-morbid depressive and insomnia symptoms compared to other treatments. The effect is dose-dependent and diminishes upon discontinuation.

Strength and weaknesses:
Strengths of the study include its comprehensive review of 49 relevant studies done over the last decade. The comparison of two well established anti suicide agents, clozapine and lithium, with the newer rapid acting agents (ketamine and esketamine) are particularly interesting. However, there are notable weaknesses of this study. The variability in the methodology used in the various studies makes a direct comparison between these agents difficult. Furthermore, most of the data comes from observational studies, few experimental studies have ever been conducted. While ketamine has the greatest number of RCTs done, the sample sizes are small. Most lithium studies were done in the United States, and most clozapine studies in Scandinavian countries, making it difficult to generalize findings. There is a lack of studies from middle and/or low-income countries. Studies based on patient registries and long follow up can have unstable results due to diagnostic criteria changes due to ICD and DSM revisions. Additionally, heterogeneity in outcome measures make cross trial comparisons challenging.

Relevance:
Even as suicide and suicidal behavior remains one of the most challenging public health issues for the US, CL psychiatrists in particular are on the forefront of the clinical management of this complex problem. Providing a broad comparison of the anti-suicide effects of two well established agents lithium and clozapine with the newer and rapid acting agents ketamine and esketamine, this study allows CL psychiatrists to review relevant evidence while formulating appropriate clinical management for suicidality.