Background

Posttraumatic stress disorder (PTSD) has been associated with exaggerated threat processing and deficits in emotion modulation circuitry. It remains unknown how neural circuits are associated with response to evidence-based treatments for PTSD.

Method

We examined associations between PTSD symptoms and indicators of neural response in key emotion processing and modulation regions. Fifty-six military Veterans with PTSD were randomly assigned to one of three evidence-based treatments (prolonged exposure, sertraline, and PE plus sertraline) in a randomized clinical trial ("PROGrESS"; 2018, Contemp Clin Trials, 64, 128-138). Twenty-seven combat-exposed controls (CCs) served as a comparison group at pretreatment. Before and after PTSD treatment, functional magnetic resonance imaging was used to assess brain activation and connectivity during the validated Shifted Attention Emotion Appraisal Task (2003, J Neurosci, 23, 5627-5633; 2013, Biol Psychiatry, 73, 1045-1053).

Results

Greater activation in emotion processing (anterior insula) and modulation (prefrontal cortex) regions and increased connectivity between attentional control (dorsolateral prefrontal cortex and superior parietal cortex) and emotion processing (amygdala) regions, at pretreatment, were associated with subsequent PTSD symptom improvement.

Conclusions

This study is one of the first to examine task-based activation and functional connectivity in a PTSD treatment trial, and provides evidence to suggest that activation in and connectivity between emotion processing and modulation regions are important predictors of treatment response.

Background

Racemic (R,S)-ketamine is a glutamatergic drug with potent and rapid acting antidepressant effects. An intranasal formulation of (S)-ketamine was recently approved by the US Food and Drug Administration (FDA) to be used in individuals with treatment-resistant depression (TRD). There are no data directly comparing outcomes on depression or other comorbidities between these two formulations of ketamine. However, recent meta-analyses have suggested that IV racemic ketamine may be more potent than IN-(S)-ketamine.

Methods

We retrospectively analyzed clinical outcomes in 15 Veterans with comorbid TRD and post-traumatic stress disorder (PTSD) who underwent ketamine treatment at the VA San Diego Neuromodulation Clinic. All Veterans included in this analysis were given at least 6 intranasal (IN)-(S)-ketamine treatments prior to switching to treatment with IV racemic ketamine.

Results

Veterans receiving ketamine treatment ( across both IN-(S)-ketamine and IV-(R,S)-ketamine) showed significant reductions in both the Patient Health Questionnaire-9 (PHQ-9), a self-report scale measuring depression symptoms (rm ANOVA F(14,42) = 12.6, p < 0.0001), and in the PTSD checklist for DSM-5 (PCL-5), a self-report scale measuring PSTD symptoms (rm ANOVA F(13,39) = 5.9, p = 0.006). Post hoc testing revealed that PHQ-9 scores were reduced by an average of 2.4 ± 1.2 compared to baseline after (S)-ketamine treatments (p = 0.1) and by an average of 5.6 ± 1 after IV-ketamine treatments (p = 0.0003) compared to pretreatment baseline scores. PCL-5 scores were reduced by an average of 4.3 ± 3.3 after IN (S)-ketamine treatments (p = 0.6) and 11.8 ± 3.5 after IV-ketamine treatments (p = 0.03) compared to pretreatment baseline scores.

Conclusions

This work suggests that off-label IV-(R,S)-ketamine could be considered a reasonable next step in patients who do not respond adequately to the FDA-approved IN-(S)-ketamine. Further double-blinded, randomized controlled trials are warranted to assess whether IV racemic ketamine is more effective than IN-(S)-ketamine.

Trauma-informed beliefs often decrease during posttraumatic stress disorder (PTSD) treatment. This may also extend to anxiety sensitivity (AS), defined as a fear of anxiety-related sensations and beliefs that anxiety is dangerous and/or intolerable. However, little is known about how AS changes during exposure-based and psychopharmacological PTSD treatments. Further, high AS may be a risk factor for diminished PTSD symptom improvement and increased treatment dropout. To better understand how AS impacts and is impacted by PTSD treatment, we conducted a secondary analysis of a randomized clinical trial with a sample of 223 veterans (87.0% male, 57.5% White) with PTSD from four U.S. sites. Veterans were randomized to receive prolonged exposure (PE) plus placebo (n = 74), sertraline plus enhanced medication management (n = 74), or PE plus sertraline (n = 75). Veterans answered questions about PTSD symptoms and AS at baseline and 6-, 12-, 24-, 36-, and 52-week follow-ups. High baseline AS was related to high levels of PTSD severity at 24 weeks across all conditions, β = .244, p = .013, but did not predict dropout from exposure-based, β = .077, p = .374, or psychopharmacological therapy, β = .009, p = .893. AS also significantly decreased across all three treatment arms, with no between-group differences; these reductions were maintained at the 52-week follow-up. These findings suggest that high AS is a risk factor for attenuated PTSD treatment response but also provide evidence that AS can be improved by both PE and an enhanced psychopharmacological intervention for PTSD.

Background

(S)-ketamine is a glutamatergic drug with potent and rapid acting effects for the treatment of depression. Little is known about the effectiveness of intranasal (S)-ketamine for treating patients with comorbid depression and post-traumatic stress disorder (PTSD).

Methods

We performed a retrospective case series analysis of clinical outcomes in 35 Veterans with co-morbid depression and PTSD who were treated with intranasal (S)-ketamine treatments at the VA San Diego Neuromodulation Clinic between Jan 2020 and March 2021. Veterans were not randomized or blinded to treatment. The primary outcome measured was a change in patient health questionnaire-9 (PHQ-9) and PTSD Checklist for DSM-5 (PCL-5) scores across the first 8 treatments (induction period) using a repeated measures analysis of variance (ANOVA). In a smaller sub-group (n = 19) of Veterans who received at least 8 additional treatments, we analyzed whether intranasal (S)-ketamine continued to show treatment effects. Finally, we performed a sub-group and correlation analyses to understand how changes in PHQ-9 and PCL-5 scores were related across treatments.

Findings

During the induction phase of treatment there was an absolute reduction of 5.1 (SEM 0.7) on the patient health questionnaire-9 (PHQ-9) rating scale for depression, from 19.8 (SEM 0.7) at treatment 1 to 14.7 (SEM 0.8) at treatment 8 (week 4) (F(7238) = 8.3, p = 1e-6, partial η² = 0.2). Five Veterans (14%) showed a clinically meaningful response (50% reduction in PHQ-9 score) at treatment 8. There was an absolute reduction of 15.5 +/- 2.4 on the patient checklist 5 (PCL-5) rating scale for PTSD, from 54.8 (SEM 2) at treatment 1 down to 39.3 (SEM 2.5) at treatment 8 (F(7238) = 15.5, p = 2e-7, partial η² = 0.31). Sixteen Veterans (46%) showed a clinically meaningful response (reduction in PCL-5 of > 30%) in PTSD. Change in PHQ-9 correlated with change in PCL-5 at treatment 8 (r = 0.47, p = 0.005), but a decrease in PTSD symptoms were observable in some individuals with minimal anti-depressant response.

Interpretations

While this is an open-label retrospective analysis, our results indicate that both depression and PTSD symptoms in Veterans with dual-diagnoses may improve with repeated intranasal (S)-ketamine treatment. The effects of (S)-ketamine on PTSD symptoms were temporally and individually distinct from those on depression, suggesting potentially different modes of action on the two disorders. This work may warrant formal randomized controlled studies on the effects of intranasal (S)-ketamine for individuals with co-morbid MDD and PTSD.

Funding

VA Center of Excellence in Stress and Mental Health, VA ORD (Career Development Award to DSR), Burroughs-Wellcome Fund Award (DSR), NIMH (EL).