Real World Effectiveness of Repeated Ketamine Infusions for Treatment Resistant Bipolar Depression

Borderline personality disorder (BPD) commonly co-occurs with major depressive disorder (MDD), and this comorbidity is associated with earlier onset, greater severity, more treatment resistance and poorer functional outcomes than MDD alone. Previous research indicates that presence of BPD worsens response to standard treatments for depression, including antidepressants, electroconvulsive therapy and psychotherapy, and there is currently no FDA-approved pharmacotherapy for BPD. Ketamine, an N-methyl-D-aspartate receptor antagonist, has established rapid antidepressant effects in treatment-resistant depression (TRD), but evidence on its effects in people with comorbid BPD is limited: a small randomized pilot of a single ketamine infusion in BPD did not show clear benefit on core symptoms, and no study had evaluated repeated ketamine infusions in this population prior to the present analysis. Danayan and colleagues set out to evaluate the real-world effectiveness of a short course of repeated intravenous ketamine infusions in adults with TRD and comorbid BPD treated in a community clinic. The study aimed to assess changes in depressive symptom severity and borderline symptom severity after four infusions over two weeks, and to compare outcomes between TRD patients with and without comorbid BPD, thereby informing whether comorbid BPD is associated with poorer response to repeated ketamine in routine clinical practice.

This is a retrospective, post hoc analysis of clinical data collected at the Canadian Rapid Treatment Centre of Excellence (CRTCE, later Braxia Health) between December 2020 and July 2022. The analysed sample comprised 100 adults with TRD who received four intravenous ketamine infusions over two weeks; 50 patients were classified as BPD-positive and 50 as BPD-negative, matched on sex and age. Inclusion required a primary diagnosis of TRD (current major depressive episode with at least two inadequate antidepressant trials) as determined by a CRTCE psychiatrist. Assignment to the BPD-positive group used both the MacLean Screening Instrument (MSI) score at baseline with a reported cut-off of 7 and clinician assessment, although the extracted text does not clearly report the citation or full rationale for that cut-off. Infusion dosing was flexible: all participants received 0.5 mg/kg for the first two infusions, with the option to increase to 0.75 mg/kg for infusions 3 and 4 if a ≥20% reduction in QIDS-SR16 had not been achieved by the second infusion. Reported dose escalations occurred in 65% of the BPD-negative group and 60% of the BPD-positive group, with no significant association between group and infusion 3 dose status (p=0.53). Outcome assessments were performed at baseline and before each subsequent infusion, with the post-infusion 4 assessment conducted a few days after the final infusion; assessments were generally within 3 days of one another. Primary and secondary measures included: Borderline Symptom List-23 (BSL-23) for BPD symptom severity (co-primary for the BPD-positive group); Quick Inventory of Depressive Symptomatology–Self Report 16-item (QIDS-SR16) for depressive severity (co-primary for between-group comparisons); QIDS-SR16 item 12 for suicidal ideation (SI); Generalised Anxiety Disorder 7-item (GAD-7); Sheehan Disability Scale (SDS) and Work Productivity and Activity Impairment (WPAI) for functioning; and the Clinician Administered Dissociative Symptoms Scale 6-item (CADSS-6) for dissociation immediately after infusions. Responders were defined as ≥50% reduction in score, partial response as 25–50% reduction, and remission as QIDS-SR16 ≤ 5. Statistical analysis used linear mixed-effects models with terms for group, infusion and group-by-infusion interaction, fitted with restricted maximum likelihood and a first-order autoregressive covariance structure; Bonferroni correction was applied for multiple comparisons, partial eta squared (η2) was reported for effect sizes, Spearman correlations assessed associations between changes in measures, and sex and age were included as covariates.

The sample comprised 50 patients classified as BPD-positive and a matched comparator group of 50 TRD patients without BPD. Medication status at baseline differed modestly: 68% of the BPD-positive sample and 84% of the BPD-negative sample were taking at least one antidepressant; small numbers were on mood stabilisers. Dose escalation to 0.75 mg/kg occurred in 60% of the BPD-positive group and 65% of the BPD-negative group. Borderline symptoms: Among 48 BPD-positive patients with BSL-23 data, baseline mean BSL-23 was 2.28 (high severity). Linear mixed modelling showed a significant main effect of infusion on BSL-23 (F(1,37.8)=29.4, p<0.0001) with a large effect size (η2=0.44). Mean BSL-23 decreased by 0.64 (SE=0.12) by post-infusion assessment; of 35 participants with sufficient categorical data, 34.3% met response criteria and an additional 22.9% showed partial response. Depressive symptoms: There was no significant group-by-infusion interaction (F(4,330.8)=0.77, p=0.55) and no main effect of group (F(1,105.6)=0.09, p=0.76), but a significant main effect of infusion on QIDS-SR16 (F(4,330.8)=18.8, p<0.0001; η2=0.185). In the BPD-positive group, mean QIDS-SR16 decreased by 5.95 (SE=1.01) from baseline to post-infusion 4, with significant reductions at each time point (Bonferroni-corrected ps<0.0001). The BPD-negative group showed a mean reduction of 3.99 (SE=0.81) to post-infusion 4, likewise with significant within-group reductions. No significant between-group differences in categorical response rates were detected. Change in BSL-23 and change in QIDS-SR16 were strongly correlated (Spearman rs(35)=0.71, p<0.0001). Suicidality: Analysis of the QIDS-SR16 suicide item found no group-by-infusion interaction (F(4,327.9)=1.1, p=0.36) and no main effect of group, but a significant main effect of infusion (F(4,327.9)=6.7, p<0.0001; η2=0.076). Mean suicide item score reductions were 0.56 (SE=0.188) in the BPD-positive group and 0.54 (SE=0.154) in the BPD-negative group. In a subgroup of 52 patients with baseline SI item scores of 2 or 3, there was a significant main effect of infusion (F(4,172.9)=11.06, p<0.0001; η2=0.204) and mean SI decreased from 2.17 to 1.20 (mean reduction 0.97, SE=0.16). Anxiety and functioning: GAD-7 scores showed a significant main effect of infusion (F(2,154.5)=13.8, p<0.0001; η2=0.15). Mean GAD-7 reductions were 4.0 (SE=1.2) in the BPD-positive group and 2.65 (SE=0.84) in the BPD-negative group, with significant within-group improvements by post-infusion 3 and 4. For SDS social subscale there was a significant infusion effect (η2=0.21): reductions from baseline to post-infusion 4 were 1.02 (SE=0.39) for BPD-positive (p=0.02) and 1.36 (SE=0.36) for BPD-negative (p=0.0005). SDS family scores also improved significantly (reductions 0.86 (SE=0.34) and 0.96 (SE=0.37) respectively). WPAI (N=40) showed a significant main effect of infusion (η2=0.31); BPD-negative patients had a statistically significant mean reduction of 1.57 (SE=0.59, p=0.02) while BPD-positive reduction of 2.03 (SE=0.86) did not reach statistical significance (p=0.07). Changes in depression severity correlated with changes in social/family functioning and work productivity in subgroup analyses. Dissociation and safety: CADSS-6 scores demonstrated a significant main effect of infusion (F(3,252.2)=5.4, p=0.001; η2=0.06) but no main effect of group or group-by-infusion interaction. Mean CADSS-6 reductions from infusion 1 to 4 were 0.81 (SE=0.6) for BPD-negative and 1.2 (SE=0.67) for BPD-positive (the latter change p=0.46). Dissociation was generally mild and no participants discontinued treatment due to dissociation. Across outcomes, there were no statistically significant between-group differences in the pattern of improvement.

Danayan and colleagues conclude that four repeated IV ketamine infusions were associated with significant reductions in depressive symptoms among TRD patients with comorbid BPD, and that the magnitude of improvement was comparable to TRD patients without BPD. The mean QIDS-SR16 shifted on average from a severe to a moderate range in the BPD-positive group. The investigators also report statistically and clinically significant reductions in BPD symptom severity (BSL-23), with mean BSL-23 improving from the high to the moderate severity classification by post-infusion 3; they note that the observed mean reduction (0.64) compares favourably with reductions reported in some dialectical behaviour therapy (DBT) trials. The authors highlight concomitant improvements in anxiety, suicidality (particularly in those with moderate/extreme baseline SI), and social, family and work functioning, and they emphasise a strong positive correlation between reductions in depressive and borderline symptoms. Dissociative effects were mild overall and tended to attenuate by the final infusion; no participants withdrew because of dissociation. Danayan and colleagues therefore suggest that ketamine may be a promising rapid-onset treatment option for this clinically complex population and might be considered as an adjunct or complement to psychotherapeutic interventions such as DBT. Key limitations acknowledged by the investigators include the retrospective, open-label design, absence of a placebo-controlled comparison, and short follow-up—endpoint assessments occurred within about a week of the final infusion. Because of these design constraints, the authors caution that causality cannot be established and the durability of effects beyond the immediate post-treatment window remains unknown. They recommend that rigorous randomised trials with larger samples and longer follow-up be conducted to assess the efficacy and tolerability of ketamine in patients with a primary diagnosis of BPD and TRD.