EXAMINING THE IMPACT OF TRAUMA ON KETAMINE'S EFFICACY IN BIPOLAR I/II DEPRESSION: A SECONDARY ANALYSIS FROM A RANDOMIZED, MIDAZOLAM-CONTROLLED TRIAL

Background

Childhood trauma and comorbid post-traumatic stress disorder (PTSD) are highly prevalent in bipolar disorder (BD) and are consistently associated with greater illness severity and poorer response to pharmacological treatments. However, it remains unclear whether childhood trauma or PTSD comorbidity moderate response to ketamine, and whether ketamine may exert therapeutic effects on trauma-related symptoms independent of depressive symptoms.

Methods

Adults with treatment resistant bipolar I/II depression (TRBD; n=63) were randomized to receive four infusions over two weeks of either ketamine (0.5-0.75 mg/kg) or midazolam (0.02-0.03 mg/kg). Depressive symptoms were measured using the MontgomeryÅsberg Depression Rating Scale (MADRS), and PTSD symptoms using the PTSD Checklist for DSM-5 (PCL-5) at baseline, Day 14, and Day 28. Comorbid PTSD was defined as a PCL-5 score ≥33 with symptom endorsement consistent with DSM-5 cluster criteria. Childhood trauma was assessed with the Childhood Trauma Questionnaire (CTQ) and operationalized as total trauma severity (CTQ total score), trauma subtype severity (CTQ subscale scores), and maltreatment load (count of trauma subtypes meeting moderate-to-severe thresholds). Linear mixed-effects models examined whether trauma variables or baseline PTSD status moderated antidepressant response. Additional models assessed PTSD symptom trajectories in participants with comorbid PTSD, adjusting for depressive symptom change, including exploratory analyses by PTSD symptom cluster.

Results

Greater childhood trauma severity (F(1, 74.05) = 6.01, p = .017) and maltreatment load (F(1, 70.85) = 4.41, p = .039) were significantly associated with higher depressive symptom severity. However, no significant treatment × time × trauma interactions emerged for total trauma severity (F(2, 118.61) = 0.44, p = .644), maltreatment load (F(2, 116.24) = 0.06, p = .941), or any trauma subtype (all p > .05), indicating that childhood trauma did not moderate antidepressant response to ketamine versus midazolam. Similarly, PTSD comorbidity did not moderate antidepressant response (F(2, 152.24) = 0.144, p = .866), though baseline PTSD status was associated with greater overall MADRS severity (F(1, 187.97) = 4.98, p = .027). Among participants with comorbid PTSD (n = 27), a significant treatment x time interaction emerged for total PCL-5 scores (F(2, 44.59) = 6.19, p = .004), with ketamine-treated participants showing significantly greater reductions in PTSD symptoms compared to midazolam by Day 28 (mean difference = -13.04, 95% CI [−22.87, −3.21], p = .010). This effect remained significant after adjusting for concurrent changes in MADRS scores (F(2, 41.93) = 6.52, p = .003). Clusterspecific analyses showed significant treatment × time effects for intrusion (F(2, 38.45) = 4.52, p = .017), avoidance (F(2, 41.04) = 10.23, p = < .001), and negative alterations in cognition/mood (F(2, 44.36)= 3.36, p = .044), but not hyperarousal (F(2, 43.23) = 2.33, p = .110).

Significance

Compared to midazolam, ketamine demonstrated superior antidepressant efficacy in TRBD patients regardless of childhood trauma history or comorbid PTSD. Importantly, ketamine also led to sustained reductions in PTSD symptoms that were independent of depressive symptom improvement. These findings highlight the therapeutic potential of intravenous ketamine for trauma-exposed individuals with TRBD.