Suicidal behavior is common among people with bipolar disorder and is the leading cause of death in this group, with rates remaining high despite standard treatments like lithium, antidepressants, and psychotherapy. A review of PubMed identified few studies on acute suicidality and lithium or clozapine, but 14 studies on ketamine, esketamine, or glutamate-related treatments. Glutamatergic abnormalities are present in both bipolar disorder and suicide. The NMDA antagonist ketamine and its S-enantiomer esketamine appear to decrease acute suicidality, possibly by rapidly remodeling glutamate activity. Intranasal esketamine or subcutaneous ketamine, and possibly other glutamate receptor modulators, may improve suicidal behavior in unipolar and bipolar depression, suggesting glutamatergic modulators could reduce acute suicidality and mortality in bipolar disorder.
In patients with treatment-resistant depression receiving intranasal esketamine (56 mg) alongside another antidepressant, those taking antidepressants that inhibit cytochrome-P450 isoforms (paroxetine, fluoxetine, duloxetine, venlafaxine) had significantly higher serum esketamine levels 20 minutes after dosing and over 72 hours compared to patients on sertraline, citalopram, escitalopram, or vortioxetine. Salivary esketamine levels were several-fold higher than serum levels at all time points and showed high variability. These pharmacokinetic differences did not affect clinical outcomes, but changes in systolic blood pressure positively correlated with serum esketamine levels, suggesting dose reduction may be warranted for patients with cardiovascular comorbidity on those CYP450-inhibiting antidepressants. Small subgroup sizes limit strong conclusions.