Written By: Dr. Leslie Taylor
The experience of traumatic events is not uncommon, with approximately 50% of adults in the United States reporting the experience of at least one traumatic event in their lifetime[1], with 10% of women and 5% of men meeting criteria for PTSD.[2] Without treatment, PTSD can become a chronic condition associated with the onset of multiple adversities, including unemployment, profound economic losses, suicide, medical illnesses, and marital discord[3],[4]. Symptoms of PTSD include the experience unbidden intrusive memories of the event, avoidances, negative changes in thinking and mood, and changes in physical and emotional reactions.
Expert consensus guidelines point toward exposure therapies as frontline treatments for PTSD, with many patients reporting long term symptom reduction, or complete remission of their PTSD diagnosis after their completion. These therapies require patients to intentionally and repeatedly recall and engage with memories of their traumatic experiences, and may include having the patient face trauma related fears outside of session[5],[6]. This could mean listening to the sounds of busy intersection if you were in a bad car accident, or revisiting the place where the traumatic event occurred. Doing so is obviously challenging, especially given that avoidance is a core symptom PTSD. This is what we ask of trauma survivors, because when front-line trauma therapies are implemented with fidelity, they inculcate long term healing for patients. As a mental health professional, I am always humbled by the courage that patients show us when we ask them to articulate and process something that has brought them severe pain and discomfort. And for patients who have competed treatment, the transformation is palpable.
Naturally, it can be difficult to keep this group of patients engaged in treatment. The internal experience of trauma, or what is happening inside a trauma survivor after the event, is often complex and difficult to articulate in the therapy context. Moreover, depression is a common co-occurring condition among patients with PTSD, which often culminates in low motivation to engage in treatment. Given the most effective treatments require exposure (rather than avoidance), it is not surprising that depression is predictor of poor outcomes among PTSD patients. Depression is often associated with changes in brain’s reward processing system, to include the ability to feel pleasure when consuming or collecting a reward as well as the motivation to do so[7]. Convincing someone that retelling their traumatic experiences and engaging in exposure activities will result in short- and long-term benefits is especially challenging when nothing seems pleasurable, worth the effort, or rewarding, even after the effort has been made. Given the factors influencing differential responses to treatment among PTSD patients with comorbid depression are not widely known, therapy can soon become a frustrating experience for the patient as well as their mental health professional.
In an effort to increase treatment precision, researchers have begun exploring and testing a number of innovative strategies to reach PTSD patients who have not responded to front-line treatments. For example, virtual and augmented reality therapies allow for recreation of feared elements of trauma in a controlled, in-vivo environment. Although they are not considered frontline treatments, virtual and augmented reality therapies continue to garner compelling effectiveness data, especially for those patients who do not respond to frontline therapies[1]. While these findings offer helpful take-home messages in terms of what works for whom, there is still more to explore. Cognitive enhancers that facilitate the extinction of learning and memory have also been tested in relation to treating anxious emotions. D-cycloserine (DCS) is a partial N-methyl-D-aspartate agonist that can facilitate fear reduction and extinction when given before or shortly after extinction training[2]. In research trials, patients are given DCS within 60-90 minutes prior to an exposure-based treatment session [3], [4]. Studies have shown mixed effectiveness, leading researchers to review current findings and identify potential moderators of DCS augmentation for future study.[5] Another line of research has examined the role of biomarkers in fear acquisition and extinction learning, evaluating their influence on extinction learning among PTSD patients. These efforts are largely focused on anxiety disorders and PTSD, and do not widely explore the impacts of comorbid depressive disorders on outcomes.
However, a recent study[6] tested a number of hypotheses in relation to therapeutic approaches for PTSD among participants with and without comorbid depression, comparing treatment responses to virtual reality (VR) and prolonged exposure therapy (i.e., PE; a frontline treatment for PTSD) with a cognitive enhancer offered across conditions. Participants were randomized to treatment conditions (PE or VR) and to cognitive enhancer (i.e., DCS vs. placebo) condition. Participants were military service members and veterans with PTSD (N=192; n=104 reporting a comorbid depression diagnoses).
Interestingly, participants with comorbid depression improved more in the VR than PE condition and non-depressed participants improved more in the PE condition. Depressed participants improved more in the placebo condition than the DCS condition, and this was the opposite for non-depressed participants. This pattern of results could be explained through the level of engagement that VR offers depressed participants, who experience altered reward processing, and may need a higher level of stimulation to overcome negative experiences. Examination of genetic biomarkers also revealed an interesting pattern of results, in that carriers of a specific allele (i.e., FAAH A385) improved more than non-carriers, particularly in the depressed group. Participants with another variant (BDNF) show stronger response to treatment when given DCS.
Taken together, findings from this study incite fascination and hope regarding treatment of trauma survivors in terms of what works and for whom. Subsequent trials are needed to increase understanding of genomic profiles and their interaction with cognitive enhancers. Additionally, these findings also underscore the evaluation and consideration of comorbid depression among PTSD patients when selecting and implementing treatment protocols. Developing a precise understanding of how individual differences affect treatment response allows for efficient tailoring of protocols, particularly among a group of patients who have difficulty engaging in treatment and achieving benefit from them. Doing so ultimately supports healing and recovery within our families, our communities, and beyond.
[1] Eshuis, L. V., van Gelderen, M. J., van Zuiden, M., Nijdam, M. J., Vermetten, E., Olff, M., & Bakker, A. (2021). Efficacy of immersive PTSD treatments: A systematic review of virtual and augmented reality exposure therapy and a meta-analysis of virtual reality exposure therapy. Journal of psychiatric research, 143, 516–527. https://doi.org/10.1016/j.jpsychires.2020.11.030 [2] Davis, M., Ressler, K., Rothbaum, B. O., & Richardson, R. (2006). Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biological psychiatry, 60(4), 369–375. https://doi.org/10.1016/j.biopsych.2006.03.084 [3] Hofmann, S. G., Smits, J. A., Rosenfield, D., Simon, N., Otto, M. W., Meuret, A. E., Marques, L., Fang, A., Tart, C., & Pollack, M. H. (2013). D-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder. The American journal of psychiatry, 170(7), 751–758. https://doi.org/10.1176/appi.ajp.2013.12070974 [4] Andersson, E., Hedman, E., Enander, J., Radu Djurfeldt, D., Ljótsson, B., Cervenka, S., Isung, J., Svanborg, C., Mataix-Cols, D., Kaldo, V., Andersson, G., Lindefors, N., & Rück, C. (2015). D-Cycloserine vs Placebo as Adjunct to Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder and Interaction With Antidepressants: A Randomized Clinical Trial. JAMA psychiatry, 72(7), 659–667. https://doi.org/10.1001/jamapsychiatry.2015.0546 [5] Otto, M. W., Kredlow, M. A., Smits, J. A. J., Hofmann, S. G., Tolin, D. F., de Kleine, R. A., van Minnen, A., Evins, A. E., & Pollack, M. H. (2016). Enhancement of Psychosocial Treatment With D-Cycloserine: Models, Moderators, and Future Directions. Biological psychiatry, 80(4), 274–283. https://doi.org/10.1016/j.biopsych.2015.09.007 [6] Difede, J., Rothbaum, B.O., Rizzo, A.A. et al. Enhancing exposure therapy for posttraumatic stress disorder (PTSD): a randomized clinical trial of virtual reality and imaginal exposure with a cognitive enhancer. Translational Psychiatry 12, 299 (2022). https://doi.org/10.1038/s41398-022-02066-x [1] https://www.nimh.nih.gov/health/statistics/post-traumatic-stress-disorder-ptsd [2] Kessler R.C., Sonnega A., Bromet E., Hughes M., Nelson C.B. (1995). Posttraumatic stress disorder in the National Comorbidity Survey. Archives of General Psychiatry, 52, 1048–1060. [3] Kessler, R.C. (2000) Posttraumatic stress disorder: the burden to the individual and to society. Journal of Clinical Psychiatry, 61, 4–12.[4] Davidson J. R. (2000). Trauma: the impact of post-traumatic stress disorder. Journal of psychopharmacology (Oxford, England), 14(2 Suppl 1), S5–S12. https://doi.org/10.1177/02698811000142S102 [5] Foa, E.B., Hembree, E.A., Rothbaum, B.O., Rauch S. Prolonged Exposure Therapy for PTSD: Emotional Processing of Traumatic Experiences—Therapist Guide (Treatments That Work) 2nd Edition. Oxford University Press; 2019. doi:10. 1093/med-psych/9780190926939.001.0001 30.[6] Resick, P.A., Monson, C.M., Chard, K.M.: Cognitive Processing Therapy for PTSD: A Comprehensive Manual. The Guilford Press; 2017.[7] Halahakoon D.C., Kieslich, K., O’Driscoll, C., Nair, A., Lewis, G., Roiser, J.P. (2020). Reward-Processing Behavior in Depressed Participants Relative to Healthy Volunteers: A Systematic Review and Meta-analysis. JAMA Psychiatry, 77(12), 1286–1295. doi:10.1001/jamapsychiatry.2020.2139