Treatment Approaches for Posttraumatic Stress Disorder Derived from Basic Research on Fear Extinction.

This brief review article will describe treatment approaches for posttraumatic stress disorder (PTSD) based on findings from basic research. The focus of this review will be fear conditioning and extinction models, which provide a translational model of PTSD that can help translate basic research in non-human animals through well-controlled trials confirming the efficacy of treatment approaches in humans with PTSD such as prolonged exposure therapy. Specific cognitive aspects of fear extinction processes, including consolidation and reconsolidation, are reviewed along with behavioral and pharmacological treatment strategies based on basic research in these areas including attempts to prevent the development of PTSD as well as the treatment of chronic PTSD. Pharmacological, behavioral, and device-based augmentation strategies of PTSD treatment based in basic science findings are reviewed, including those that disrupt noradrenergic receptor processes, medications that act on NMDA receptors, physical exercise, cannabinoids, estradiol, dexamethasone, yohimbine, losartan, dopamine, and MDMA, along with the evidence for their efficacy in human clinical samples. While fear extinction provides an exciting translational opportunity to improve PTSD based on basic science findings, we review limitations and challenges of the extant literature as well as future directions.

Change in posttraumatic stress disorder-related thoughts during treatment: Do thoughts drive change when pills are involved?

Posttraumatic negative thoughts about one's self and the world are related to posttraumatic stress disorder (PTSD) symptom severity and change in cognitive behavioral treatment (CBT), but little is known about this association when CBT is delivered with medication. The current study presents a planned comparison of changes in negative posttraumatic thoughts during (a) prolonged exposure (PE) plus pill placebo (PE+PLB), (b) sertraline plus enhanced medication management (SERT+EMM), and (c) PE plus sertraline (PE+SERT) as part of a randomized clinical trial in a sample of 176 veterans. Lagged regression modeling revealed that change in posttraumatic negative thoughts was associated with PTSD symptom change in the conditions in which participants received sertraline, ds = 0.14-0.25, ps = 0.04-.001). However, contrary to previous research, the models that started with symptom change were also statistically significant, d = 0.23, p < .001, for the lagged effect of symptoms on negative thoughts about self in the SERT+EMM condition, indicating a bidirectional association between such thoughts and PTSD symptoms. In the PE+PLB condition, no significant association between posttraumatic thoughts and PTSD symptoms emerged in either direction. These results suggest that the previously demonstrated role of change in posttraumatic thoughts leading to PTSD symptom reduction in PE may be altered when combined with pill administration, either active or placebo.

Association of Prospective Risk for Chronic PTSD Symptoms With Low TNFα and IFNγ Concentrations in the Immediate Aftermath of Trauma Exposure.

OBJECTIVE: Although several reports have documented heightened systemic inflammation in posttraumatic stress disorder (PTSD), few studies have assessed whether inflammatory markers serve as prospective biomarkers for PTSD risk. The present study aimed to characterize whether peripheral immune factors measured in blood samples collected in an emergency department immediately after trauma exposure would predict later chronic development of PTSD. METHODS: Participants (N=505) were recruited from a hospital emergency department and underwent a 1.5-hour assessment. Blood samples were drawn, on average, about 3 hours after trauma exposure. Follow-up assessments were conducted 1, 3, 6, and 12 months after trauma exposure. Latent growth mixture modeling was used to identify classes of PTSD symptom trajectories. RESULTS: Three distinct classes of PTSD symptom trajectories were identified: chronic (N=28), resilient (N=160), and recovery (N=85). Multivariate analyses of covariance revealed a significant multivariate main effect of PTSD symptom trajectory class membership on proinflammatory cytokines. Univariate analyses showed a significant main effect of trajectory class membership on plasma concentrations of proinflammatory tumor necrosis factor α (TNFα) and interferon-γ (IFNγ). Concentrations of proinflammatory TNFα and IFNγ were significantly lower in individuals in the chronic PTSD class compared with those in the recovery and resilient classes. There were no significant differences in interleukin (IL) 1ß and IL-6 concentrations by PTSD symptom trajectory class. Anti-inflammatory and other cytokines, as well as chemokines and growth factor concentrations, were not associated with development of chronic PTSD. CONCLUSIONS: Overall, the study findings suggest that assessing the proinflammatory immune response to trauma exposure immediately after trauma exposure, in the emergency department, may help identify individuals most at risk for developing chronic PTSD in the aftermath of trauma.

Baroreflex dysfunction and augmented sympathetic nerve responses during mental stress in veterans with post-traumatic stress disorder.

KEY POINTS: Patients with post-traumatic stress disorder (PTSD) are at a significantly higher risk of developing hypertension and cardiovascular disease. The mechanisms underlying this increased risk are not known. Studies have suggested that PTSD patients have an overactive sympathetic nervous system (SNS) that could contribute to cardiovascular risk; however, sympathetic function has not previously been rigorously evaluated in PTSD patients. Using direct measurements of sympathetic nerve activity and pharmacological manipulation of blood pressure, we show that veterans with PTSD have augmented SNS and haemodynamic reactivity during both combat-related and non-combat related mental stress, impaired sympathetic and cardiovagal baroreflex sensitivity, and increased inflammation. Identifying the mechanisms contributing to increased cardiovascular (CV) risk in PTSD will pave the way for developing interventions to improve sympathetic function and reduce CV risk in these patients. ABSTRACT: Post-traumatic stress disorder (PTSD) is associated with increased cardiovascular (CV) risk. We tested the hypothesis that PTSD patients have augmented sympathetic nervous system (SNS) and haemodynamic reactivity during mental stress, as well as impaired arterial baroreflex sensitivity (BRS). Fourteen otherwise healthy Veterans with combat-related PTSD were compared with 14 matched Controls without PTSD.  Muscle sympathetic nerve activity (MSNA), continuous blood pressure (BP) and electrocardiography were measured at baseline, as well as during two types of mental stress:  combat-related mental stress using virtual reality combat exposure (VRCE) and non-combat related stress using mental arithmetic (MA). A cold pressor test (CPT) was administered for comparison. BRS was tested using pharmacological manipulation of BP via the Modified Oxford technique at rest and during VRCE. Blood samples were analysed for inflammatory biomarkers. Baseline characteristics, MSNA and haemodynamics were similar between the groups. In PTSD vs. Controls, MSNA (+8.2 ± 1.0 vs. +1.2 ± 1.3 bursts min-1 , P < 0.001) and heart rate responses (+3.2 ± 1.1 vs. -2.3 ± 1.0 beats min-1 , P = 0.003) were significantly augmented during VRCE.  Similarly, in PTSD vs. Controls, MSNA (+21.0 ± 2.6 vs. +6.7 ± 1.5 bursts min-1 , P < 0.001) and diastolic BP responses (+6.3 ± 1.0 vs. +3.5 ± 1.0 mmHg, P = 0.011) were significantly augmented during MA but not during CPT (P = not significant). In the PTSD group, sympathetic BRS (-1.2 ± 0.2 vs. -2.0 ± 0.3 burst incidence mmHg-1 , P = 0.026) and cardiovagal BRS (9.5 ± 1.4 vs. 23.6 ± 4.3 ms mmHg-1 , P = 0.008) were significantly blunted at rest. PTSD patients had significantly higher highly sensitive-C-reactive protein levels compared to Controls (2.1 ± 0.4 vs. 1.0 ± 0.3 mg L-1 , P = 0.047). Augmented SNS and haemodynamic responses to mental stress, blunted BRS and inflammation may contribute to an increased CV risk in PTSD.

Early adversity in chronic depression: clinical correlates and response to pharmacotherapy.

BACKGROUND: There is growing evidence suggesting that early adversity may be a marker for a distinct pathway to major depressive disorder (MDD). We examined associations between childhood adversity and a broad variety of clinical characteristics and response to pharmacotherapy in a large sample of patients with chronic forms of MDD. METHODS: Subjects included 808 patients with chronic forms of MDD (chronic MDD, double depression, or recurrent MDD with incomplete recovery between episodes and a total continuous duration of >2 years) who were enrolled in a 12-week open-label trial of algorithm-guided pharmacotherapy. Baseline assessments included a semi-structured diagnostic interview, and clinician- and self-rated measures of depressive symptoms, social functioning, depressotypic cognitions, and personality traits, and childhood adversity. Patients were re-evaluated every 2 weeks. RESULTS: A longer duration of illness; earlier onset; greater number of episodes, symptom severity, self-rated functional impairment, suicidality, and comorbid anxiety disorder; and higher levels of dysfunctional attitudes and self-criticism were each associated with multiple forms of childhood adversity. A history of maternal overcontrol, paternal abuse, paternal indifference, sexual abuse, and an index of clinically significant abuse each predicted a lower probability of remission. Among patients completing the 12-week trial, 32% with a history of clinically significant abuse, compared to 44% without such a history, achieved remission. CONCLUSIONS: These findings indicate that a history of childhood adversity is associated with an especially chronic form of MDD that is less responsive to antidepressant pharmacotherapy.