Objective Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. Method This randomized clinical trial tested the effect of adjunctive sub-anesthetic intravenous ketamine on clinically significant suicidal ideation in major depressive disorder (MDD). Adults (N=80) with current MDD and score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomized to ketamine or midazolam infusion. The primary outcome was Day 1 SSI score (24 hours post-infusion). Other outcomes included global depression and adverse effects. Results Reduction of SSI score was 4.96 points greater after ketamine compared with midazolam at Day 1 (95% confidence interval (CI)=2.33 to 7.59; p=0.0003; Cohen’s d=0.75). Proportion of responders (≥50% reduction in SSI) at Day 1 was 55% after ketamine and 30% after midazolam (OR=2.85 (95% CI=1.14 to 7.15); p=0.0237; NNT=4.00). Improvement in the Profile of Mood States (POMS) depression subscale was greater at Day 1 compared with midazolam treatment (Estimate=7.65 (95% CI=1.36 to 13.94), df=75, t=2.42, p=0.0178), and this effect mediated 33.6% of ketamine’s effect on SSI score. Side effects were short-lived. Benefit was sustained for up to six weeks with clinical pharmacotherapy. Conclusions Adjunctive ketamine demonstrated greater reduction of clinically significant suicidal ideation in depressed patients within 24 hours compared to midazolam, partially independent of antidepressant effect. Research is needed to understand ketamine’s mechanism of action and to develop safe, longer-term treatment.

The study demonstrated feasibility. Suicidal thoughts were lower after ketamine than after midazolam at a trend level of significance, likely due to the small pilot sample. Memory improvement and BDNF are promising biomarkers. Replication is needed in an adequately powered full-scale trial.

Social support is thought to protect against the risk of suicidal behavior in young people and late life, but less is known about the role of friendship in adults. We explored the effect of friendship on suicide attempt risk during 1-year follow-up of 132 adults presenting with major depressive episode (MDE). Items from the Social Adjustment Scale-Self-Report were used as an index of frequency and quality of recent friendship contacts. Survival methods tested associations of friendship with risk of suicide attempt, recurrent MDE, and related outcomes during follow-up. Impaired friendship predicted greater risk of suicide attempt in an unadjusted Cox model. This association was stronger for quality (p = .009) than frequency (p = .081) of friendship contacts. In the adjusted model, the effect of friendship on suicide attempts was largely explained by self-reported depression severity. Friendship has a potentially bidirectional relationship with depression, and its effect on suicidal behavior appears to occur through its relationship with depression. Future research should examine the effect of antidepressant treatment on friendship and be designed to test mediation models of relationships between friendship, depression, and suicidal behavior.

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It is unclear whether anxiety increases or decreases suicidal risk. This may contribute to the lack of guidance on which antidepressant medications are best for suicidal depressed patients who present with high anxiety. This study explored whether anxiety predicts suicidal ideation in depressed individuals treated with paroxetine or bupropion. An 8-week double-blind trial comparing controlled-release paroxetine (N=36) versus extended-release bupropion (N=38) for effect on suicidal ideation and behavior in depressed patients with suicidal ideation, past attempt, or both found an advantage for paroxetine, but anxiety effects were not investigated. This secondary analysis explored the relationship, measured at baseline and weekly, of anxiety with suicidal ideation. Anxiety severity measured weekly correlated with suicidal ideation severity irrespective of treatment (P=0.012). Patients with high baseline anxiety showed a trend toward faster reduction of suicidal ideation with paroxetine compared with bupropion treatment (standard P=0.047; bootstrap P=0.077). The latter finding, if confirmed in larger samples, could enhance choice of antidepressant medication for suicidal, depressed patients presenting with high levels of anxiety.