Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors

Abstract

Despite the continuous advancement in neurosciences as well as in the knowledge of human behaviors pathophysiology, currently suicide represents a puzzling challenge. The World Health Organization (WHO) has established that one million people die by suicide every year, with the impressive daily rate of a suicide every 40 s. The weightiest concern about suicidal behavior is how difficult it is for healthcare professionals to predict. However, recent evidence in genomic studies has pointed out the essential role that genetics could play in influencing person’s suicide risk. Combining genomic and clinical risk assessment approaches, some studies have identified a number of biomarkers for suicidal ideation, which are involved in neural connectivity, neural activity, mood, as well as in immune and inflammatory response, such as the mammalian target of rapamycin (mTOR) signaling. This interesting discovery provides the neurobiological bases for the use of drugs that impact these specific signaling pathways in the treatment of suicidality, such as ketamine. Ketamine, an N-methyl-d-aspartate glutamate (NMDA) antagonist agent, has recently hit the headlines because of its rapid antidepressant and concurrent anti-suicidal action. Here we review the preclinical and clinical evidence that lay the foundations of the efficacy of ketamine in the treatment of suicidal ideation in mood disorders, thereby also approaching the essential question of the understanding of neurobiological processes of suicide and the potential therapeutics.

Understanding the Complex of Suicide in Depression: from Research to Clinics

“…14,[55][56][57][58][59][60] Indeed, the recently investigated and interesting role of glutamatergic involvement may play a significant role, given recent antisuicidal findings with NMDA antagonist esketamine. 180,181 Further evidences appear to emerge at the genetic and epigenetic level, with a series of supposed proximal and distal suicide risk factors associated with various endophenotypes implicated in suicidality amongst MDD subjects. Therefore, assessing suicidality amongst MDD subjects requires a multidimensional approach, which takes into account suicidality factors at every level, preclinical, neurobiological, neurochemical, clinical and psychopathological.…”

Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction

“…In clinical studies, a single dose of ketamine induced rapid and long-lasting antidepressant response [25,26]. What is very important and unique is that ketamine or its enantiomer (S)-ketamine was also effective in the treatment of resistant depression [25][26][27][28] and MDD with suicidal ideations [29][30][31]. Moreover, ketamine and other NMDAR antagonists such as Ro and MK-801 reversed behavioral abnormalities in animal models of depression [32,33].…”

Ketamine in Major Depressive Disorder: Mechanisms and Future Perspectives

“…The antidepressant effects of ketamine through the glutamate pathway has been reported to exert anti-suicidal effect by preclinical studies. 89 Although most pharmacological studies on depression exclude individuals with imminent risk of suicide, several ketamine studies have included patients with a moderate level of suicidal ideation. In many case series and open-label studies, ketamine infusion consistently reduced suicidal ideation.…”