A pilot randomized controlled trial of ketamine in Borderline Personality Disorder

The study enrolled adult outpatients aged 20–64 years with major depressive disorder (DSM‑5) who had an inadequate response to at least two antidepressants and presented with prominent suicidal ideation (defined as a score ≥4 on MADRS item 10). Eligible participants were randomised to receive a single intravenous infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The researchers implemented an add‑on design: participants continued their usual psychotropic medications during the study period rather than being tapered off other treatments. Clinical assessments focused on depressive and suicidal symptoms. Depressive symptoms were measured with the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline, 40, 80 and 240 minutes postinfusion, and on Days 2, 3, 5, 7 and 14. Treatment response was defined as at least one MADRS score showing ≥50% reduction at Day 2 or Day 3. Suicidal symptoms were assessed using the Columbia‑Suicide Severity Rating Scale Ideation Severity Subscale (CSSRS‑ISS) at baseline, 240 minutes, and Days 2, 3, 5, 7 and 14; and with the self‑report Positive and Negative Suicide Ideation Inventory (PANSI) at baseline, 240 minutes, and Days 2, 3, 7 and 14. Level of treatment refractoriness was classified using the Maudsley Staging Method (MSM) and grouped as low (≤7), moderate (8–10) or high (≥11). The investigators prespecified exploratory subgroup analyses to examine whether treatment refractoriness (low/moderate vs high), duration of the current depressive episode (<24 vs ≥24 months) and number of prior failed antidepressants (≤4 vs >4) modified clinical trajectories. Statistical analyses used generalised estimating equations (GEE) with treatment group as the between‑patient factor and time as the within‑patient factor, including interactions; additional analyses truncated follow‑up at <7 days to examine short‑term antisuicidal effects. Two‑tailed P < .05 was considered significant. Analyses were performed in SPSS version 17.

Of 90 outpatients screened, six were excluded (three for hypertension, one for type 2 diabetes mellitus, two declined consent), leaving 84 participants who were randomised to a single infusion of ketamine or midazolam. Baseline characteristics were similar between groups for age, sex, BMI, age at illness onset, history of suicide attempt and treatment refractoriness. The midazolam group had a slightly higher mean baseline total MADRS score (38.26 ± 3.83 vs 35.83 ± 4.53; p = .010). Baseline suicidal measures (MADRS item 10, CSSRS‑ISS, PANSI subscales) and psychiatric comorbidities did not differ between groups. A greater proportion of participants receiving ketamine met the predefined treatment response criterion (35.7% vs 11.9%; p = .020). GEE analyses found a significant antidepressant effect for ketamine versus midazolam on total MADRS scores up to Day 14 (p = .035). When stratified by treatment refractoriness, the antidepressant effect was present in participants with low or moderate refractoriness (p = .004) but not in those with high refractoriness (p = .371). The antidepressant effect was also observed specifically in patients whose current depressive episode had lasted <24 months (p = .015) and in those with ≤4 failed antidepressant treatments (p = .023); no significant benefit was seen for episodes ≥24 months (p = .329) or >4 failed treatments (p = .167). More patients in the ketamine arm achieved full remission of suicidal ideation (CSSRS‑ISS = 0) from Day 2 (n = 14 vs 4; p = .015) through Day 5 (n = 11 vs 3; p = .038) compared with midazolam. GEE models identified significant antisuicidal effects for ketamine on the CSSRS‑ISS (p = .040) and MADRS item 10 (p = .023) at least up to Day 5. The antisuicidal benefit was seen in low/moderate refractoriness (CSSRS‑ISS p = .001; MADRS item 10 p < .001) but not in high refractoriness. Antisuicidal effects were confined to participants with current episode <24 months and to those with ≤4 failed antidepressants (CSSRS‑ISS p = .042 and p = .027; MADRS item 10 p = .005 and p < .001 respectively). On the PANSI scales, the negative suicide ideation subscale (PANSI‑NSI) showed a between‑group difference favouring ketamine up to Day 7 (p = .039), whereas the protective subscale (PANSI‑PSI) did not differ between groups (p = .077). Adverse effects that were more frequent with ketamine during infusion included derealisation (n = 29 vs 7; p < .001), dizziness (n = 24 vs 5; p < .001) and crying (n = 6 vs 0; p = .026); these effects resolved by 80 minutes postinfusion. There were three serious events of attempted suicide by drug overdose during follow‑up: one in the ketamine group (Day 10) and two in the midazolam group (Days 8 and 12); all required hospitalisation for crisis intervention.

Y. and colleagues interpret their findings as indicating that a single low‑dose ketamine infusion produced an antidepressant effect that persisted for up to 14 days in this outpatient sample with treatment‑resistant depression and prominent suicidal ideation, while the measurable antisuicidal effects (clinician‑rated and self‑reported) were shorter lived, attenuating after approximately 5–7 days. They emphasise that treatment timing and degree of refractoriness moderated benefit: participants with low or moderate refractoriness, those whose current depressive episode had lasted <24 months, and those with ≤4 prior failed antidepressant treatments showed both antidepressant and antisuicidal responses, whereas those with high refractoriness, longer current episodes (≥24 months) or >4 failed treatments did not. The authors situate these results within prior literature that links treatment refractoriness, episode duration and number of prior treatment failures to subsequent treatment response. They note congruence with previous findings that patients with lower refractoriness benefit more from other modalities (for example, neurostimulation) and with their own prior small study in very highly refractory patients that showed no ketamine effect. Regarding suicidal ideation, the pattern on PANSI subscales led the authors to suggest that ketamine's antisuicidal effect in this trial was driven primarily by reductions in negative suicide‑related ideation rather than by increases in protective or positive ideation. The trial was conducted in an outpatient setting with frequent in‑person follow‑up in the first week (Days 2, 3, 5 and 7). The authors observe three serious suicide attempts across both arms and note that their findings are consistent with previous work reporting no main effect of treatment setting (inpatient v. outpatient) on ketamine's antisuicidal impact. They propose two clinical recommendations based on their data: (1) to optimise timing of ketamine treatment with respect to illness course and prior treatment history, especially for patients whose episode duration is ≥12 but <24 months or who have failed >2 but ≤4 antidepressants; and (2) to consider biweekly ketamine infusions for suicide prevention because the antisuicidal effect appears to last only about 5 days. The authors acknowledge key limitations: the add‑on design (concomitant medications were not discontinued), and the administration of only a single ketamine infusion per participant. They state that the add‑on design was chosen for ethical reasons and for ecological validity, but that repeated‑dose studies are necessary to determine whether sustained antidepressant and antisuicidal benefits can be achieved in more severely ill patients.

Y. and colleagues conclude that a single low‑dose ketamine infusion produced a sustained antidepressant effect for up to 14 days in outpatients with treatment‑resistant depression and prominent suicidal ideation, whereas measurable antisuicidal benefits were shorter, attenuating after about 5–7 days. The authors highlight that clinical response was concentrated among patients with lower or moderate treatment refractoriness, shorter current episodes (<24 months) and fewer prior antidepressant failures (≤4), and they recommend consideration of timing and possibly biweekly dosing for suicide prevention. They call for further research using repeated infusions to evaluate sustained effects and to clarify optimal use in patients with more severe refractoriness.