Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial

All 16 randomised participants completed the infusion and were included in the intent‑to‑treat analysis. Baseline characteristics did not differ between groups on age, sex, race, frequency of past suicide attempts, SSI, HDRS‑17 or BDI. Most participants were taking antidepressants (13/16); other baseline medications included antipsychotics (7/16), lithium (5/16) and anticonvulsants (4/16). Primary outcome: Adjusting for baseline SSI, mean SSI at day 1 was almost 6 points lower in the ketamine group than the midazolam group. This difference corresponded to an estimated treatment effect of 5.84 (SE=3.01), t=1.94, P=0.074, 95% CI = −0.65 to 12.31, representing a trend but not meeting conventional statistical significance in this pilot sample. The number needed to treat (NNT) reported for response (SSI <4 and ≥50% reduction) was 2.2 and for remission (SSI=0) was 3.2. Depressive symptoms: HDRS‑17 scores were nearly 6 points lower at day 1 after ketamine versus midazolam, and the BDI showed an 11‑point differential reduction favouring ketamine; these differences were not statistically significant in this small sample but were described by the authors as consistent with potentially large effects. Follow‑up: Paired t‑tests indicated SSI was lower than baseline at 230 minutes, day 1, week 1 and week 5 in paired comparisons across the follow‑up weeks 1–6. The paper reports mean SSI plotted over 6 weeks for those randomised to ketamine. Neurocognition: At baseline the sample showed below‑average performance in reaction time, memory and language fluency despite above‑average estimated verbal IQ. On day 1 both groups improved in reaction time. The strongest neurocognitive finding was a correlation between memory improvement on the Selective Reminding Test and reduction in SSI after ketamine (Spearman ρ = −0.89, P=0.007, as reported in the abstract). Ketamine tended to blunt improvement in reaction time and language fluency relative to midazolam acutely. Biomarkers: In the assayed subsample serum BDNF decreased pre‑ to post‑infusion in both groups (P>0.8). However, the decrease in BDNF correlated with reduction in SSI from baseline to day 1 after ketamine (n=5, ρ=0.90, P=0.037) but not after midazolam (n=6, ρ=0.09, P=0.087). Baseline saliva cortisol and CAR did not correlate with SSI or HDRS‑17 (P>0.9), and neither baseline CAR nor treatment predicted day 1 CAR in regression models. In a subset of participants who received randomized or open‑label ketamine (n=10), plasma ketamine, norketamine and dehydronorketamine were not associated with day 1 SSI or HDRS‑17. Blinding: Participants correctly guessed their infusion at day 1 in five of seven ketamine cases and seven of nine midazolam cases; clinical assessors guessed correctly after four of seven ketamine and five of nine midazolam infusions. Safety and adverse events: There were no serious cardio‑respiratory infusion‑related adverse events. Ketamine produced transient increases in blood pressure: mean systolic BP rose 23 ± 12.8 mmHg after ketamine versus 3 ± 10.2 mmHg for midazolam (t=3.49, df=14, P=0.004), and mean diastolic BP rose 16 ± 8.8 mmHg versus 4 ± 9.6 mmHg (t=2.46, df=14, P=0.028); BP typically returned to baseline within 4–6 minutes after ketamine. Dissociative symptoms were higher immediately after ketamine (Wilcoxon P=0.001) but not different at 230 minutes or day 1. BPRS positive symptom scores were essentially zero except one case of very mild conceptual disorganisation immediately post‑infusion. Serious adverse events during months 2–6 of follow‑up included six events: four inpatient admissions for increased suicidal thoughts (three admissions for one subject), one suicide attempt by overdose in month 2, and one episode of increased suicidal ideation with preparatory behaviour occurring the evening after an open ketamine infusion; that latter participant's symptoms remitted within 24 hours, which the authors describe as possibly a delayed ketamine response. Mania and anxiety: There were no differential treatment effects at day 1 on manic symptoms (P>0.4) or anxiety (P>0.8), and no post‑infusion manic episodes were observed.

Grunebaum and colleagues conclude that a single sub‑anesthetic ketamine infusion in bipolar depressed patients with clinically significant suicidal ideation is feasible to deliver in a randomised, double‑blind design and is associated with a generally acceptable safety profile in this pilot sample. The authors note that suicidal thoughts were nearly 6 points lower at day 1 after ketamine versus midazolam when adjusted for baseline, but that this difference did not reach statistical significance, a result they attribute primarily to insufficient power in the small pilot sample despite effect sizes and NNTs consistent with large clinical effects. The investigators position their findings alongside prior ketamine trials in bipolar depression and mixed diagnostic samples, emphasising that this study uniquely required a pre‑specified level of suicidal ideation for eligibility. They highlight the concordant reductions in depressive symptom scores and the observed correlations between memory improvement and reduction in suicidal thoughts after ketamine, drawing parallels to prior work in suicidal depression linking memory change to suicidal ideation independent of overall depressive symptom change. Regarding mechanisms, the authors discuss the exploratory biomarker findings cautiously: although peripheral serum BDNF decreased across groups, the decrease correlated with SSI reduction after ketamine in a very small subsample, leaving the relevance unclear given inconsistent literature. No relationships were found for cortisol awakening response or post‑infusion plasma ketamine/metabolites with clinical outcomes in the available subsamples. Key limitations acknowledged by the authors are the small pilot sample size and the exploratory nature of biomarker and cognitive analyses. They report several serious adverse events in the follow‑up period and recommend that, given one SAE occurring close to an infusion, administering ketamine in an inpatient setting is a reasonable precaution for this population. The authors call for an adequately powered RCT to test the promising trend‑level clinical effects and for larger mechanistic studies to elucidate ketamine's neurobiological actions.