Posttraumatic Stress Disorder Trials Research Articles

MDMA-assisted therapy for posttraumatic stress disorder: A pooled analysis of ethnoracial differences in efficacy and safety from two Phase 2 open-label lead-in trials and a Phase 3 randomized, blinded placebo-controlled trial.

Limited ethnoracial diversity in previous ±3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) trials for posttraumatic stress disorder (PTSD) has prompted questions concerning whether Black, Indigenous, and People of Color (BIPOC) also benefit from this treatment. Secondary analysis was conducted using a modified intent-to-treat sample pooled from two Phase 2 open-label trials and a Phase 3 randomized, blinded placebo-controlled trial to compare efficacy and safety of MDMA-AT for PTSD between BIPOC and non-Hispanic White participants. Four subgroups were of interest: MDMA-AT, BIPOC (n = 20); MDMA-AT, non-Hispanic White (n = 63); Placebo-assisted therapy (Placebo-AT), BIPOC (n = 17); and Placebo-AT, non-Hispanic White (n = 27). Planned comparisons tested subgroup differences in changes in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) scores from baseline to primary endpoint, controlling for study type and baseline scores. Adverse events (AEs) on the day of (day 0) to 2 days post-dosing were reported for each subgroup. In the MDMA-AT group, no significant ethnoracial difference in CAPS-5 change scores was observed. In the Placebo-AT group, BIPOC participants trended toward greater reductions in CAPS-5 scores than non-Hispanic Whites. Among non-Hispanic Whites, MDMA-AT was accompanied by significantly greater reductions in CAPS-5 scores than Placebo-AT. No treatment difference emerged among BIPOC participants. AEs were mostly rated as mild or moderate across subgroups. These findings provide preliminary support for the efficacy and safety of MDMA-AT for treating PTSD across ethnoracial groups. There was also a trend toward greater efficacy with Placebo-AT among BIPOC participants. There was an imbalance in subgroups, highlighting the need for culturally responsive recruitment strategies to diversify future studies.

Randomization tests in clinical trials with multiple imputation for handling missing data

ABSTRACT Randomization-based inference is a useful alternative to traditional population model-based methods. In trials with missing data, multiple imputation is often used. We describe how to construct a randomization test in clinical trials where multiple imputation is used for handling missing data. We illustrate the proposed methodology using Fisher’s combining function applied to individual scores in two post-traumatic stress disorder trials.

Failure of Losartan in a Clinical Trial for Posttraumatic Stress Disorder: Lack of Efficacy or Spotlight on the Power of Placebo?

Posttraumatic stress disorder (PTSD) is a debilitating disorder that affects around 8% of the U.S. population (1). PTSD is characterized by a variety of symptoms, including hyperarousal/vigilance, difficulty sleeping, and intrusive thoughts related to the traumatic event that can be extremely debilitating to the individual. The current medications for PTSD that are approved by the U.S. Food and Drug Administration are limited to selective serotonin reuptake inhibitors or norepinephrine reuptake inhibitors, which are only moderately effective and do not help the majority of patients.

The Efficacy of MDMA (3,4-Methylenedioxymethamphetamine) for Post-traumatic Stress Disorder in Humans: A Systematic Review and Meta-Analysis.

Background: 3,4-methylenedioxymethamphetamine (MDMA), known recreationally as “Molly” or “Ecstasy”, is a triple monoamine reuptake inhibitor. MDMA specifically acts as a weak 5-HT1 and 5-HT2 receptor agonist, targeting 5-HT2A, 5-HT2B, and 5-HT2C receptors. Its potential use for therapeutic purposes with these pharmacological profiles remains a controversial subject. Studies have shown the potential benefits in clinical trials for post-traumatic stress disorder (PTSD). A larger amount of data has been provided for the push in support of MDMA-assisted psychotherapy in these patients. Objective: The aim of this article is to compute a meta-analysis and conduct a systematic review of the effects of MDMA on PTSD, discussing the potential benefits and adverse events relative to dosing and stability of treatment.Methods: Articles were collected and analyzed for systematic review: 16 articles were included in the systematic review that met the criteria for the use of MDMA in the treatment of PTSD as well as assessing the safety and efficacy of the drug in human participants. Ten studies were used for the meta-analysis, with a cumulative sample size of 168 patients. The significance of the findings on dosing and efficacy of MDMA in healthy human participants was quantified based on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and PTSD symptom scores.Results: The disorders for which MDMA demonstrated a net positive or net negative effect on symptoms are presented separately. Adverse events in patients across all disease classes are presented. The therapeutic index for patients who demonstrated a benefit is also presented. An odds ratio for beneficial and adverse events is used to determine treatment-resistant patients who may benefit from clinical trials of MDMA.Discussion: Findings show promising evidence for the potential therapeutic use of MDMA alongside psychotherapy in the treatment of PTSD. The pharmacological profile of MDMA may provide direction for future drug developments to treat patients with treatment-resistant psychiatric disorders.

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms.

Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin-, brain-derived neurotrophic factor-, and early growth response-related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds. SIGNIFICANCE STATEMENT: Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.

Development of a Publicly Available Database of Randomized Controlled Trials for Posttraumatic Stress Disorder: The PTSD-Repository

To provide a single, updatable source of Posttraumatic Stress Disorder (PTSD) clinical trials to facilitate up-to-date synthesis of research findings. The database is designed to be useful for clinicians, patients, researchers, and policymakers to help improve evidence-based decision-making.

Development of the PTSD-Repository: A Publicly Available Repository of Randomized Controlled Trials for Posttraumatic Stress Disorder.

Given the extensive research on posttraumatic stress disorder (PTSD) treatment, a single, updatable repository of data from PTSD treatment studies would be useful for clinical, research, and policy stakeholders. To meet this need, we established a preliminary dataset of abstracted PTSD trial data, which serve as the basis for the PTSD Trials Standardized Data Repository (PTSD-Repository), maintained by the National Center for PTSD (NCPTSD). We followed systematic review methods to identify published randomized controlled trials (RCTs) of PTSD interventions. We consulted with a panel of experts to determine a priori inclusion criteria, ensure that we captured all relevant studies, and identify variables for abstraction. We searched multiple databases for materials published from 1980 to 2018 and reviewed reference lists of relevant systematic reviews and clinical practice guidelines. In total, 318 RCTs of PTSD interventions that enrolled almost 25,000 participants were included. We abstracted 337 variables across all studies, including study, participant, and intervention characteristics as well as results. In the present paper, we describe our methods and define data elements included in the data tables. We explain coding challenges, identify inconsistencies in reporting across study types, and discuss ways stakeholders can use PTSD-Repository data to enhance research, education, and policy. The abstracted data are currently publicly available on the NCPTSD website and can be used for future systematic reviews and identifying research gaps and as an information resource for clinicians, patients, and family members.

Associations between resting-state functional connectivity and treatment response in a randomized clinical trial for posttraumatic stress disorder.

Alterations in resting-state functional connectivity (rsFC) have been reported in posttraumatic stress disorder (PTSD). Here, we examined pre- and post-treatment rsFC during a randomized clinical trial to characterize alterations and examine predictors of treatment response. Sixty-four combat veterans with PTSD were randomly assigned to prolonged exposure (PE) plus placebo, sertraline plus enhanced medication management, or PE plus sertraline. Symptom assessment and resting-state functional magnetic resonance imaging (fMRI) scans occurred before and after treatment. Twenty-nine trauma-exposed combat veterans without PTSD served as a control group at intake. Seed-based and region of interest (ROI)-to-ROI connectivities, as well as an exploratory connectome-based approach were used to analyze rsFC patterns. Based on previously reported findings, analyses focused on Salience Network (SN) and Default-Mode Network (DMN). At intake, patients with PTSD showed greater DMN-dorsal attention network (DAN) connectivity (between ventromedial prefrontal cortex and superior parietal lobule; family-wise error corrected p = .011), greater SN-DAN connectivity (between insula and middle frontal gyrus; corrected p = .003), and a negative correlation between re-experiencing symptoms and within-DMN connectivity (between posterior cingulate cortex (PCC) and middle temporal gyrus; corrected p < .001). We also found preliminary evidence for associations between rsFC and treatment response. Specifically, high responders (≥50% PTSD symptom improvement), compared with low responders, had greater SN-DMN segregation (i.e., less pre-treatment amygdala-PCC connectivity; p = .011) and lower pre-treatment global centrality (p = .042). Our findings suggest neural abnormalities in PTSD and may inform future research examining neural biomarkers of PTSD treatment response.

Neural function during emotion processing and modulation associated with treatment response in a randomized clinical trial for posttraumatic stress disorder.

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. 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). 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. 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.

Neural correlates of emotional reactivity and regulation associated with treatment response in a randomized clinical trial for posttraumatic stress disorder

Posttraumatic Stress Disorder (PTSD) is a debilitating condition often associated with difficulty in emotion regulation, including reappraising negative emotions. This study assessed neural mechanisms associated with emotion regulation in veterans prior to and following treatment for PTSD. Participants with PTSD and combat exposed controls (CC) completed diagnostic evaluation and underwent fMRI scanning while completing Emotion Regulation Task (ERT) and Emotional Faces Assessment Task (EFAT). Participants with PTSD were randomly assigned to Prolonged Exposure plus placebo (PE+PLB), Sertraline plus enhanced medication management (SERT+EMM), or PE plus SERT (PE+SERT) and repeated diagnostic evaluation and MRI scanning following treatment. The amygdala, dmPFC, and dlPFC were examined as regions of interest. On ERT, veterans with PTSD showed significantly less dmPFC activation than CCs during reappraisal vs emotional maintenance. Within the PTSD group, results demonstrated a significant association between less activation in the dmPFC during emotion reappraisal vs maintenance trials before treatment and greater reductions in symptoms from pre- to post-treatment. During the EFAT, there were no group differences between participants with PTSD and CCs in brain activation, and no relationships between brain function and PTSD symptoms. These findings suggest that less emotional reactivity might potentially reflect less need for recruitment of prefrontal regions when reappraising negative emotion, and is an individual factor associated with better treatment outcome.

A synthetic estimator for the efficacy of clinical trials with all-or-nothing compliance.

A critical issue in the analysis of clinical trials is patients' noncompliance to assigned treatments. In the context of a binary treatment with all or nothing compliance, the intent-to-treat analysis is a straightforward approach to estimating the effectiveness of the trial. In contrast, there exist 3 commonly used estimators with varying statistical properties for the efficacy of the trial, formally known as the complier-average causal effect. The instrumental variable estimator may be unbiased but can be extremely variable in many settings. The as treated and per protocol estimators are usually more efficient than the instrumental variable estimator, but they may suffer from selection bias. We propose a synthetic approach that incorporates all 3 estimators in a data-driven manner. The synthetic estimator is a linear convex combination of the instrumental variable, per protocol, and as treated estimators, resembling the popular model-averaging approach in the statistical literature. However, our synthetic approach is nonparametric; thus, it is applicable to a variety of outcome types without specific distributional assumptions. We also discuss the construction of the synthetic estimator using an analytic form derived from a simple normal mixture distribution. We apply the synthetic approach to a clinical trial for post-traumatic stress disorder.

Solving Interpersonal Problems Correlates With Symptom Improvement in Interpersonal Psychotherapy

Interpersonal psychotherapy (IPT) research has addressed outcome more than mechanism. This study used the novel Interpersonal Psychotherapy Outcome Scale (IPOS) to test the theoretical axiom that symptomatic improvement in IPT reflects resolution of interpersonal problem areas. The IPOS rates change in focal interpersonal problem areas on a 5-point scale. Patients (N = 24) and therapists (N = 7) in a time-limited IPT outcome study of dysthymic disorder, and patients (N = 11) in an open trial for posttraumatic stress disorder, completed the IPOS at treatment termination. All responding dysthymic subjects (N = 24) and therapists (N = 21) reported interpersonal gains: dysthymic patients scored 4.39 (SD = 0.52) out of 5, therapists 4.27 (0.53). Posttraumatic stress disordered patients rated 4.75 (0.34). Patient and therapist IPOS ratings correlated with objectively measured symptomatic improvement with full or trend statistical significance. Despite methodological limitations, initial testing of the IPOS supports the theorized link between resolving interpersonal crises and improvement in IPT.

COGNITIVE BEHAVIOURAL TREATMENT OF POST TRAUMATIC STRESS DISORDER AFTER MOTOR VEHICLE ACCIDENT

Post traumatic stress disorder (PTSD) and other reactions including driving phobias and depression have in recent years been clearly identified as common motor vehicle accident (MVA) sequelae. To date, no treatment outcome data exist for PTSD following MVA beyond case study reports and one pilot investigation. The present study reports on the first randomized control trial for PTSD following MVA. Twenty volunteer participants who had motor vehicle accidents resulting in physical injury requiring medical attention and PTSD were recruited through rehabilitation service providers, other psychologists, community physicians, and lawyers. Assessments included a structured interview for diagnosis of post traumatic stress disorder (Clinician Administered PTSD Scale) by an independent rater, a range of self-report symptom questionnaires and a behavioural test wherein they had their heart rate and subjective distress measured in reaction to idiosyncratic audio descriptions of their accident. Participants were randomly assigned to eight to ten hours of individual cognitive-behavioural therapy (n=10) or to a wait list control group (n=10). Treatment included education about post-trauma reactions, relaxation training, exposure therapy with cognitive restructuring and instruction for self-directed graduated behaviour practice. Results demonstrated statistically and clinically significant treatment effects across structured interviews, self-report questionnaires and the behavioural test. Treatment gains were maintained over a 6 month follow-up using self-report questionnaires.

Comparative efficacy of treatments for post-traumatic stress disorder: a meta-analysis

A meta-analysis was conducted on 61 treatment outcome trials for post-traumatic stress disorder (PTSD). Conditions included drug therapies (TCAs, carbamazepine, MAOIs, SSRIs, and BDZs), psychological therapies (behaviour therapy, Eye-Movement Desensitization and Reprocessing (EMDR), relaxation training, hypnotherapy, and dynamic therapy), and control conditions (pill placebo, wait-list controls, supportive psychotherapies, and non-saccade EMDR control). Psychological therapies had significantly lower drop-out rates than pharmacotherapies (14% versus 32%), with attrition being uniformly low across all psychological therapies. In terms of symptom reduction, psychological therapies were more effective than drug therapies, and both were more effective than controls. Among the drug therapies, the SSRIs and carbamazepine had the greatest effect sizes, although the latter was based upon a single trial. Among the psychological therapies, behaviour therapy and EMDR were most effective, and generally equally so. The most effective psychological therapies and drug therapies were generally equally effective. Differences across treatment conditions were generally evident across symptom domains, with little matching of symptom domain to treatment type. However, SSRIs had some advantage over psychological therapies in treating depression. Follow-up results were not available for most treatments, but available data indicates that treatment effects for behaviour therapy and EMDR are maintained at 15-week follow-up. © 1998 John Wiley & Sons, Ltd.

Comparative efficacy of treatments for post‐traumatic stress disorder: a meta‐analysis

A meta-analysis was conducted on 61 treatment outcome trials for post-traumatic stress disorder (PTSD). Conditions included drug therapies (TCAs, carbamazepine, MAOIs, SSRIs, and BDZs), psychological therapies (behaviour therapy, Eye-Movement Desensitization and Reprocessing (EMDR), relaxation training, hypnotherapy, and dynamic therapy), and control conditions (pill placebo, wait-list controls, supportive psychotherapies, and non-saccade EMDR control). Psychological therapies had significantly lower drop-out rates than pharmacotherapies (14% versus 32%), with attrition being uniformly low across all psychological therapies. In terms of symptom reduction, psychological therapies were more effective than drug therapies, and both were more effective than controls. Among the drug therapies, the SSRIs and carbamazepine had the greatest effect sizes, although the latter was based upon a single trial. Among the psychological therapies, behaviour therapy and EMDR were most effective, and generally equally so. The most effective psychological therapies and drug therapies were generally equally effective. Differences across treatment conditions were generally evident across symptom domains, with little matching of symptom domain to treatment type. However, SSRIs had some advantage over psychological therapies in treating depression. Follow-up results were not available for most treatments, but available data indicates that treatment effects for behaviour therapy and EMDR are maintained at 15-week follow-up. © 1998 John Wiley & Sons, Ltd.

Complex PTSD in victims exposed to sexual and physical abuse: Results from the DSM‐IV field trial for posttraumatic stress disorder

AbstractTwo hundred thirty four participants in the DSM‐IV Posttraumatic Stress Disorder (PTSD) Field Trial who reported sexual and/or physical abuse were evaluated. Participants were categorized according to type of abuse (physical, sexual, both), duration of abuse (acute versus chronic), and onset of abuse (early versus late). Separate logistic regression analyses examined the relationship between age of onset, duration, abuse type, and the complex PTSD (CP) lifetime diagnosis for women and men. Sexually abused women, especially those who also experienced physical abuse, had a higher risk of developing CP, although CP symptoms occurred at a high base rate among physically abused women. The theoretical implications and incremental clinical usefulness of targeting CP symptoms with abused populations are discussed.

Complex PTSD in victims exposed to sexual and physical abuse: results from the DSM-IV Field Trial for Posttraumatic Stress Disorder.

Two hundred thirty four participants in the DSM-IV Posttraumatic Stress Disorder (PTSD) Field Trial who reported sexual and/or physical abuse were evaluated. Participants were categorized according to type of abuse (physical, sexual, both), duration of abuse (acute versus chronic), and onset of abuse (early versus late). Separate logistic regression analyses examined the relationship between age of onset, duration, abuse type, and the complex PTSD (CP) lifetime diagnosis for women and men. Sexually abused women, especially those who also experienced physical abuse, had a higher risk of developing CP, although CP symptoms occurred at a high base rate among physically abused women. The theoretical implications and incremental clinical usefulness of targeting CP symptoms with abused populations are discussed.