Suicide remains difficult to predict despite advances in neuroscience. The World Health Organization reports one million suicide deaths annually, with one every 40 seconds. Recent genomic studies suggest genetics influence suicide risk. Combining genomic and clinical assessments has identified biomarkers for suicidal ideation involved in neural connectivity, mood, and immune response, including the mammalian target of rapamycin (mTOR) signaling pathway. This provides a neurobiological basis for drugs like ketamine, an NMDA antagonist, which has shown rapid antidepressant and anti-suicidal effects. This review examines preclinical and clinical evidence for ketamine's efficacy in treating suicidal ideation in mood disorders, addressing the neurobiological processes of suicide and potential therapeutics.
Abnormalities in glutamatergic neurotransmission are hypothesized to play a role in mood disorders, prompting investigation of NMDA receptor modulators for Major Depressive Disorder (MDD). Intranasal esketamine, an NMDA receptor antagonist, has been developed for treatment-resistant depression (TRD) and for rapidly reducing depressive symptoms, including suicidal ideation, in MDD patients at imminent suicide risk. A systematic review of literature up to October 2019 found that intravenous esketamine elicits rapid and sustained antidepressant effects in refractory patients. Phase II studies showed intranasal esketamine had rapid onset and persistent efficacy in TRD and MDD patients at suicide risk, though phase III data had discrepancies.
A systematic review of 41 brain MRI studies involving 1,396 people with treatment-resistant depression and 587 healthy controls identified neural correlates of ketamine's antidepressant effects. Ketamine (0.5 mg/kg racemic or 0.25 mg/kg S-ketamine, infused intravenously over 40 minutes, given one to six times over two weeks) rapidly reduces depressive symptoms. Meaningful brain-based markers of treatment response were found in limbic, salience, fronto-parietal, default-mode, and subcortical networks. Features in limbic, salience, and fronto-parietal networks may help predict which patients with treatment-resistant depression will respond better to ketamine, particularly for relief of anhedonia, thought rumination, and suicidal ideation.