Pharmacological Mechanism of Ketamine in Suicidal Behavior Based on Animal Models of Aggressiveness and Impulsivity: A Narrative Review

Abstract

Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures to prevent acting out also remain limited. Drugs shown to reduce the risk of suicide (antidepressants, lithium, or clozapine) necessitate a long delay of onset. To date, no treatment is indicated for the treatment of suicidality. Ketamine, a glutamate NMDA receptor antagonist, is a fast-acting antidepressant with significant effects on suicidal ideation in the short term, while its effects on suicidal acts still need to be demonstrated. In the present article, we reviewed the literature on preclinical studies in order to identify the potential anti-suicidal pharmacological targets of ketamine. Impulsive–aggressive traits are one of the vulnerability factors common to suicide in patients with unipolar and bipolar depression. Preclinical studies in rodent models with impulsivity, aggressiveness, and anhedonia may help to analyze, at least in part, suicide neurobiology, as well as the beneficial effects of ketamine/esketamine on reducing suicidal ideations and preventing suicidal acts. The present review focuses on disruptions in the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation, and/or the HPA axis in rodent models with an impulsive/aggressive phenotype, because these traits are critical risk factors for suicide in humans. Ketamine can modulate these endophenotypes of suicide in human as well as in animal models. The main pharmacological properties of ketamine are then summarized. Finally, numerous questions arose regarding the mechanisms by which ketamine may prevent an impulsive–aggressive phenotype in rodents and suicidal ideations in humans. Animal models of anxiety/depression are important tools to better understand the pathophysiology of depressed patients, and in helping develop novel and fast antidepressant drugs with anti-suicidal properties and clinical utility.

The Patient’s Perspective on the Effects of Intranasal Esketamine in Treatment-Resistant Depression

“…The efficacy of anti-inflammatory treatments in reducing anhedonia seems to support the involvement of inflammation in the pathophysiology of such dimension [59,60]. Also, suicide pathogenesis has been associated with neuroinflammation [61] with a specific interrelationship that goes beyond the underlying psychiatric illness, such as major depression [62]. However, the brain-derived neurotrophic factor (BDNF) has been reported among the underlying mechanisms of the association between suicidality and depression [63].…”

Explorando Abordagens Terapêuticas Baseadas em Evidências para a Prevenção do Suicídio

“…Essas pesquisas recentes fornecem um panorama abrangente das estratégias atuais e emergentes na prevenção do suicídio, destacando a necessidade contínua de explorar abordagens inovadoras e baseadas em evidências. Nguyen et al (2023) oferecem uma perspectiva valiosa sobre o mecanismo farmacológico da cetamina no comportamento suicida com base em modelos animais de agressividade e impulsividade. Esta revisão narrativa destaca a importância de compreender os mecanismos subjacentes ao efeito anti-suicida da cetamina, especialmente em relação aos aspectos comportamentais como agressividade e impulsividade.…”