Refractory Post-traumatic Stress Disorder Research Articles

5-MeO-DMT for post-traumatic stress disorder: a real-world longitudinal case study

Psychedelic therapy is, arguably, the next frontier in psychiatry. It offers a radical alternative to longstanding, mainstays of treatment, while exciting a paradigm shift in translational science and drug discovery. There is particular interest in 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)—a serotonergic psychedelic—as a novel, fast-acting therapeutic. Yet, few studies have directly examined 5-MeO-DMT for trauma- or stress-related psychopathology, including post-traumatic stress disorder (PTSD). Herein, we present the first longitudinal case study on 5-MeO-DMT for chronic refractory PTSD, in a 23-year-old female. A single dose of vaporized bufotoxin of the Sonoran Desert Toad (Incilius alvarius), containing an estimated 10−15 mg of 5-MeO-DMT, led to clinically significant improvements in PTSD, with next-day effects. This was accompanied by marked reductions in hopelessness and related suicide risk. Improvements, across all constructs, were sustained at 1-, 3-, 6-, and 12-months follow-up, as monitored by a supporting clinician. The subject further endorsed a complete mystical experience, hypothesized to underly 5-MeO-DMT’s therapeutic activity. No drug-related, serious adverse events occurred. Together, results showed that 5-MeO-DMT was generally tolerable, safe to administer, and effective for PTSD; however, this was not without risk. The subject reported acute nausea, overwhelming subjective effects, and late onset of night terrors. Further research is warranted to replicate and extend these findings, which are inherently limited, non-generalizable, and rely on methods not clinically accepted.

Repetitive Transcranial Magnetic Stimulation (rTMS) in Post-Traumatic Stress Disorder: Study Protocol of a Nationwide Randomized Controlled Clinical Trial of Neuro-Enhanced Psychotherapy "TraumaStim".

The use of high-frequency Transcranial Magnetic Stimulation (HF-rTMS) of the right dorsolateral prefrontal cortex (DLPFC) in treating Post-traumatic Stress Disorder (PTSD) is currently regarded as a level B intervention (probable effectiveness). HF-rTMS has attracted interest as a neuromodulation therapeutic method for PTSD. Prolonged exposure and reactivation therapy are also regarded as first-line treatments for PTSD. Randomized controlled clinical studies examining the effectiveness of several HF-rTMS sessions coupled with psychotherapy have not yet been completed. In total, 102 patients with refractory PTSD will be randomly assigned (1:1) to reactivation therapy, in addition to either active HF-rTMS (20 Hz) or sham HF-rTMS, for 12 sessions in a nationwide, multicenter, double-blind controlled trial. The impact on PTSD symptoms and neurocognitive functioning will be assessed. The primary outcome is the PTSD severity score measured based on the Clinician-Administered PTSD Scale (CAPS-5) at one month. If this additional therapy is successful, it may strengthen the case for regulatory authorities to approve this additional technique of treating PTSD. Additionally, it expands the field of neurostimulation-assisted psychotherapy.

Traumatic memory retrieval followed by electroconvulsive therapy as a treatment for posttraumatic stress disorder: A pilot study

Delivering electroconvulsive therapy (ECT) during the reconsolidation of traumatic memories may enhance the treatment efficacy in posttraumatic stress disorder (PTSD). To test this, 14 patients with severe and refractory PTSD were randomly allocated to receive ECT sessions either after retrieving the traumatic (n=8) or a neutral (n=6) memory. We found that delivering ECT after retrieving the traumatic memory enhanced the improvement of PTSD symptoms and the reduction of subjective reactivity to the traumatic memory. Reduction in anxiety and mood symptoms and physiological reactivity to the traumatic memory were observed in the sample as a whole regardless of memory retrieval.

Application of Deep Brain Stimulation in Refractory Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a mental disorder that produces crippling anxiety and occurs in response to an extreme, traumatic stressor. Compared to the prevalence of PTSD in the general population, the prevalence of PTSD in at-risk populations (e.g., army veterans, those affected by environmental calamities, and others) can reach up to threefold. The conventional treatment of PTSD involves using SSRIs (serotonin reuptake inhibitors) and other anti-depressants along with psychotherapy such as debriefing and CBT (cognitive behavioral therapy). Due to increasing resistance to conventional treatment, more novel treatment options, such as stellate ganglion block shots and neuromodulation, are being explored. These neuromodulation techniques include transcranial magnetic stimulation (TMS), transcranial direct current stimulation (TDS), and deep brain stimulation (DBS). The rationale behind employing these techniques in refractory PTSD is the altered neurocircuitry seen in PTSD patients, which can be visualized on imaging. Studies involving the use of DBS for PTSD primarily target specific areas in the brain: the amygdala, the prefrontal cortex, the hippocampus, and the hypothalamus. This article aims to provide a brief overview of the various neuromodulation techniques currently employed in the management of treatment-resistant PTSD and an in-depth review of the available literature on animal models in which DBS for PTSD has been researched. We also shed light on the human clinical trials conducted for the same.

Effects of transcranial direct current stimulation (tDCS) in "Kiss nightclub fire" patients with post-traumatic stress disorder (PTSD): A phase II clinical trial.

Considered the second biggest tragedy with fatal victims caused by fire, the Kiss nightclub fire tragedy that occurred in the interior of southern Brazil brought several problems to survivors. It is reported that 30-40% of victims of disasters can develop post-traumatic stress disorder. Application of repetitive transcranial magnetic stimulation has shown promising results in the treatment of post-traumatic stress disorder. Transcranial direct current stimulation similar to repetitive transcranial magnetic stimulation, a neuromodulation technique, has shown promise in treatment of neuropsychiatric disorders. A clinical trial was conducted from March 2015 to July 2016 in "KISS nightclub fire" disaster patients diagnosed with post-traumatic stress disorder without complete remission of symptoms, over 18 years, and who maintained pharmacological treatment. Treatment was given using electrodes as cathode (right dorsolateral prefrontal cortex) and anode (contralateral deltoid muscle); a current of 2 mA was used for 25 cm² area (0.08 mA/cm² current density); 30 min once a day for 10 days continuously. Patients assessed pre- and post-intervention, 30 days' and 90 days' post-intervention. Post-Traumatic Stress Disorder Checklist, Civilian version, Montreal Cognitive Assessment, and Hamilton Depression and Anxiety Rating Scale were used. One hundred forty-five subjects were screened and eight analyzed; 87.5% were female; 30.88 ± 7.74 years were of mean age. Post-intervention results: no cognitive impairment (Montreal Cognitive Assessment), 60% reduction in Hamilton Depression Rating Scale (moderate depression turns normal) (p < 0.001), 54.39% Hamilton Anxiety Rating Scale reduction (moderate-to-severe symptoms turn into mild symptoms) (p < 0.001), and 20% Post-Traumatic Stress Disorder Checklist, Civilian version scale decrease (high severity post-traumatic stress disorder symptoms turn moderate to moderately high severity) (p < 0.001). Post-traumatic stress disorder symptoms improvement was maintained 30-days post-intervention (Post-Traumatic Stress Disorder Checklist, Civilian version, p = 0.025) and improvement in symptoms of depression (Hamilton Depression Rating Scale, p = 0.006) and anxiety (Hamilton Anxiety Rating Scale, p = 0.028) in 90 days post-intervention. Despite decrease over time, improvement in post-traumatic stress disorder, depression and anxiety symptoms was maintained throughout the first month after treatment. Transcranial direct current stimulation adjuvant can be an alternative treatment to refractory post-traumatic stress disorder, either as monotherapy or as treatment enhancement strategy. They can also be an option for patients who do not want or do not tolerate pharmacological management.

Post-traumatic stress disorder: a psychiatric disorder requiring urgent attention.

Post-traumatic stress disorder (PTSD) is a severe and heterogenous psychiatric disorder that was first defined as a mental disorder in 1980. Currently, the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and the International Classification of Diseases 11th Edition (ICD-11) offer the most widely accepted diagnostic guidelines for PTSD. In both diagnostic categories, experiencing a traumatic event (TE) is the necessary criterion for diagnosing PTSD. The TEs described in the DSM-5 include actual or threatened death, serious injury, sexual violence, and other extreme stressors, either directly or indirectly. More than 70% of adults worldwide are exposed to a TE at least once in their lifetime, and approximately 10% of individuals develop PTSD after experiencing a TE. The important features of PTSD are intrusion or re-experiencing fear memories, pervasive sense of threat, active avoidance, hyperarousal symptoms, and negative alterations of cognition and mood. Individuals with PTSD have high comorbidities with other psychiatric diseases, including major depressive disorder, generalized anxiety disorder, and substance use disorder. Multiple lines of evidence suggest that the pathophysiology of PTSD is complex, involving abnormal neural circuits, molecular mechanisms, and genetic mechanisms. A combination of both psychotherapy and pharmacotherapy is used to treat PTSD, but has limited efficacy in patients with refractory PTSD. Because of the high prevalence, heavy burden, and limited treatments, PTSD is a psychiatric disorder that requires urgent attention. In this review, we summarize and discuss the diagnosis, prevalence, TEs, pathophysiology, and treatments of PTSD and draw attention to its prevention.

MDMA-Assisted Therapy for Treatment-Resistant Posttraumatic Stress Disorder (PTSD) – One step further toward a patient-centered treatment pathway

IntroductionPTSD is a chronic, debilitating condition with limited treatment efficacy. Accessing traumatic memories often leads to overwhelming distress, impacting treatment process. Current approved pharmacological treatments have exhibited small to moderate effects when compared with placebo. Evidence suggests 3,4,-methylene-dioxymethamphetamine(MDMA)-assisted psychotherapy as a viable option for refractory PTSD.ObjectivesComprehensive review of early clinical research, proposed mechanisms, safety and emerging therapeutic models.MethodsEligible studies will be identified through strategic search of MEDLINE.ResultsPre-clinical and imaging studies suggest memory reconsolidation and fear extinction as candidate psychological and neurological mechanisms, involving MDMA’s combined effects of increasing serotonergic activity, as well the release of oxytocin and brain-derived neurotrophic factor in key memory and emotional circuits. Resulting reduction in amygdala and insula activation and increasing connectivity between the amygdala and hippocampus may create a “tolerance window” of neuroplasticity for emotional engagement and reprocessing of traumatic memories during psychotherapy. Early clinical trials report impressive and durable reduction in PTSD symptoms, with a safety profile comparable to that of SSRIs. A recently completed randomized, double-blind, placebo-controlled phase 3 trial reported full remission of PTSD symptoms in 67% of patients at 2 months, with no increase in suicidality, cardiovascular events or abuse behavior. Emerging treatment models underline the importance of unmedicated therapeutic sessions for preparation for the experience and subsequent integration as essential for full benefit and safety of the clinical context.ConclusionsThe psychological impact associated with the COVID-19 pandemic is an reminder of the emotional and economic burden associated with PTSD. MDMA-assisted therapy may be a breakthrough approach meriting further multidisciplinary investment and clinical research.DisclosureNo significant relationships.

Psychological Adaptive Mechanism Maturity Predicts Good Outcomes in Treatment for Refractory PTSD.

Background: Post-traumatic Stress Disorder (PTSD) severity follows a bell-shaped curve ranging from mild to severe. Those in the severe range often receive the most intensive treatments, including targeted residential rehabilitation stays. These are expensive and welcome ways to improve their effectiveness. We hypothesized that positive change among subjects treated in a 45-day residential rehabilitation format would be associated with the maturity levels of measurable Psychological Adaptive Mechanisms (PAMs), alternately ego defense mechanisms.Methods: In this association study, adult male patients (N = 115) with a history of combat related PTSD treated in a residential rehabilitation setting completed the Defense Style Questionnaire (DSQ) on admission, as well as the Post-Traumatic Stress Disorder Checklist-Military Version (PCL-M) and the Mississippi Scale for Combat-Related Post-traumatic Stress Disorder (M-PTSD) on admission and again at discharge. This allowed prospectively calculated change scores on each of the PTSD measures for each patient. The change scores allowed association testing with averaged admission DSQ scores using Pearson's correlation probability with significance held at p < 0.05.Results: As hypothesized, averaged individual Mature scores on the DSQ were associated with improved change scores on both the PCL-M (p = 0.03) and the M-PTSD (p = 0.04). By contrast neither averaged DSQ Neurotic or Immature scores associated significantly with either PTSD scale change scores.Conclusion: These results, the first of their kind to our knowledge, suggest that patients presenting with predominantly Mature level PAMs are likely to benefit from residential rehabilitation treatment of PTSD. By contrast, those presenting with Neurotic or Immature PAMs predominantly are less likely to encounter positive change in this type of treatment. Although residential treatment is often reserved for the most refractory PTSD cases, it appears that those endorsing Mature level PAMs will make use of residential treatment whereas other forms of treatment may be better suited to those with Neurotic and Immature adjustment mechanisms.

Broad-spectrum Cannabis oil alleviates behavioral symptoms associated with stress-related anxiety and depression in mice

Background: Posttraumatic stress disorder (PTSD) is a psychiatric condition that manifests through a broad range of symptoms and shares several phenotypes with anxiety and depression. Refractory PTSD affects 10 – 30% of the patients and highlights the need for alternative pharmacotherapy. The suggested involvement of the endocannabinoid system (ECS) with the emotional processes has enlightened the use of Cannabis sp. Then, this study aimed to evaluate the therapeutic effects of a broad-spectrum Cannabis oil on anxiety- and depressive-like behaviors triggered by stressors from combined nature. In addition, this study investigated the effect of the oil on central cannabinoid receptor 1 and serum levels of cytokines, chemokines, and growth factors. Methods: Mice were randomized into five groups (vehicle; Cannabis oil; fluoxetine; single oral dose) and submitted to acute restraint and chronic unpredictable stress. Then, they were behaviorally assessed in the elevated plus-maze test (EPMT), forced swimming test (FST), splash test (ST), and open field test (OFT). The tetrad cannabinoid assay evaluated the central effect of the oil. Serum biomarkers levels were measured by a multiplex bead-based assay. Results: Cannabis oil (0.1 mg/kg, p.o.) significantly reduced the anxiety-like behavior in EPMT in the acute restraint stress model (p &lt; 0.05) as compared to vehicle. Moreover, compared to the vehicle, Cannabis oil significantly reverted the despair and anhedonic-like behaviors in FST (p &lt; 0.05) and ST (p &lt; 0.05), respectively, in chronically stressed mice. Yet, compared to vehicle, therapy with Cannabis oil did not induce cannabinoid-tetrad (p &lt; 0.0001); downregulated granulocyte-macrophage colony-stimulating factor (GM-CSF; p &lt; 0.01) and advanced glycation end-products (RAGE; p &lt; 0.0001); and upregulated vascular endothelial growth factor (VEGF; p &lt; 0.01) serum levels. Conclusion: Altogether, our data suggest the potential of the broad-spectrum Cannabis oil to improve symptoms related to anxiety and depression caused by traumatic events.

Combining Ketamine and Internet-Based Cognitive Behavioral Therapy for the Treatment of Posttraumatic Stress Disorder: Protocol for a Randomized Controlled Trial.

BackgroundOver one third of patients with posttraumatic stress disorder (PTSD) do not respond to current interventions. Ketamine presents a potential treatment option; however, its effects are temporary. Administering ketamine alongside psychotherapy is one potential means of prolonging its effects; however, only a few studies have investigated this treatment method to date, and none have tested ketamine with internet-based or electronically delivered cognitive behavioral therapy (e-CBT).ObjectiveThis open-label randomized controlled trial aims to assess the efficacy of a combined treatment method of subanesthetic intravenous ketamine and e-CBT for treating patients with PTSD.MethodsIn total, 20 patients with refractory PTSD recruited from a community clinic will be randomly assigned to either an experimental group (n=10), receiving a combination of ketamine and therapist-administered e-CBT over 14 weeks, or a waitlist control group (n=10), receiving the experimental treatment after 14 weeks. Both groups will be assessed for the symptoms of PTSD and comorbid disorders before treatment, at two midway points, and at the end of the experiment.ResultsPTSD symptoms of participants in the experimental group are expected to improve significantly more than those of participants in the waitlist control group (P=.05) with a large effect size (η2=0.14).ConclusionsThis is the first study to assess the relationship between e-CBT and ketamine and their combined ability to treat refractory PTSD. If successful, this study will open web-based, asynchronous therapeutic options for patients with PTSD and will provide new insights into the functional role of glutamate in trauma-related disorders as well as in learning, memory, and fear extinction.Trial RegistrationClinicalTrials.gov NCT04771767; https://clinicaltrials.gov/ct2/show/NCT04771767.International Registered Report Identifier (IRRID)PRR1-10.2196/30334

The potential use of N-methyl-3,4-methylenedioxyamphetamine (MDMA) assisted psychotherapy in the treatment of eating disorders comorbid with PTSD

Despite advances in the field, eating disorders (EDs) remain very challenging disorders to treat, especially when comorbid with posttraumatic stress disorder (PTSD). N-methyl-3,4-methylenedioxyamphetamine (MDMA)-assisted psychotherapy for treatment refractory PTSD shows great promise, with two-thirds of participants achieving full remission at 1 year or more at follow-up. PTSD is a common comorbidity associated with EDs, and patients with EDs and PTSD (ED-PTSD) are reported to have higher severities of illness, greater comorbidities, higher treatment dropouts, and poorer outcomes. We hypothesize that MDMA-assisted psychotherapy will be efficacious in the ED-PTSD population for both ED and PTSD symptoms. The rationales for and proposed mechanisms of MDMA-assisted psychotherapy for ED-PTSD are considered from neurobiological, psychological and social perspectives. MDMA is associated with unique psychopharmacological effects, including: 1) reduced fear, 2) enhanced wellbeing, 3) increased sociability/extroversion, 4) reduced self-criticism, 5) increased compassion for self/others, 6) increased interpersonal trust, and 7) alert state of consciousness. These anxiolytic and prosocial effects may counteract avoidance and hyperarousal in the context of psychotherapy for those with ED-PTSD. Other clinical features of EDs that may be amenable to MDMA-assisted psychotherapy include body image distortion, cognitive rigidity, and socio-emotional processing difficulties. To illustrate its potential, personal accounts of individuals with ED-PTSD symptoms reporting benefit from MDMA adjunctive to psychotherapy are described. In addition, the possible risks and challenges in conducting this work are addressed, and future implications of this proposal are discussed.

Acute Effects and the Dreamy State Evoked by Deep Brain Electrical Stimulation of the Amygdala: Associations of the Amygdala in Human Dreaming, Consciousness, Emotions, and Creativity.

Accurate localization of complex human experiences such as emotions, dreaming, creativity, and consciousness to specific cerebral structures or neural networks has remained elusive despite technological advances. We report the use of acute deep brain stimulation (DBS) to evoke behavioral and emotional effects by applying electrical stimulation (ES) at various voltage strengths to the basolateral and central subnuclei of the amygdala in addition to the head of hippocampus (HC) for two subjects with medically refractory post-traumatic stress disorder (PTSD). Our results suggest that the amygdala could be a node in a neural network responsible for the generation of complex vivid mental imagery and integrated sensory experiences similar to John Hughlings Jackson’s “dreamy state” and “double consciousness,” which have been classically associated with temporal lobe epilepsy during uncinate seizures. That we were able to elicit similar vivid, dynamic, complex, bizarre, and original mental imagery with ES in non-epileptic subjects suggests that Jackson’s seizure related “dreamy state” and “double consciousness” may arise from heightened innate brain mechanisms with the amygdala acting as a node in the neural network responsible for physiologic dreaming and creative functions. Furthermore, our subjects experienced different emotions with different stimulation strengths at various electrode contacts. Our results suggest that higher voltage stimulation of the amygdala and HC at 4–5 V leads to predominantly negative responses and 2–4 V stimulation showed inversely coupled positive and negative responses of the amygdala in either hemisphere which may imply hemispheric dominance of emotional valences without relation to handedness. Due to the unique and complex responses dependent on location and strength of stimulation, we advise that all patients receiving DBS of the amygdala undergo acute stimulation mapping in a monitored setting before selecting therapeutic parameters for chronic stimulation.

Mapping of acute Deep Brain Stimulation (DBS) effects in two patients with refractory post-traumatic stress disorder

Introduction: We report the behavioral effects of acute stimulation in 2 patients who underwent placement of bilateral amygdala deep brain stimulation (DBS) electrodes for the treatment of severe refractory post-traumatic stress disorder.

DBS in Treatment of Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition for which pharmacological therapy is not always solvable. Various treatments have been suggested and deep brain stimulation (DBS) is currently under investigation for patients affected by PTSD. We review the neurocircuitry and up-to-date clinical concepts which are behind the use of DBS in posttraumatic stress disorder (PTSD). The role of DBS in treatment-refractory PTSD patients has been investigated relying on both preclinical and clinical studies. DBS for PTSD is in its preliminary phases and likely to provide hope for patients with medical refractory PTSD following the results of randomized controlled studies.

Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy prolong the therapeutic effects of single ketamine infusion on post-traumatic stress disorder and comorbid depression: a pilot randomized, placebo-controlled, crossover clinical trial

Background and objectives: Trauma memories lay at the core in etiopathogenesis of post-traumatic stress disorder (PTSD). Using pharmacological and cognitive behavioral treatments that specifically target trauma memories can improve the outcome. Ketamine has been shown to rapidly improve symptoms in PTSD and comorbid depression, but unfortunately these effects are short-lived. Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy is a type of mindfulness based cognitive behavioral therapy that targets the trauma memories. TIMBER psychotherapy in combination with (R,S)-ketamine are increasingly used to treat PTSD and comorbid depression. This study aims to determine if the combination of (R,S)-ketamine chemotherapy and TIMBER psychotherapy would produce a positive synergistic response in patients with PTSD. Design: This is a randomized, placebo-controlled, cross-over clinical study. Methods: Because response to ketamine alone is short-lived, this study combined TIMBER with a single infusion of 0.5 mg/kg (R,S)-ketamine to sustain its therapeutic effects. Ten patients with chronic and refractory PTSD were randomly assigned to two groups (n = 5 each): TIMBER-K group patients received ketamine infusion in combination with 12 TIMBER sessions (3 sessions in the first week followed by 9 sessions conducted on a weekly basis) and TIMBER-P group patients received placebo (normal saline infusion) in combination with 12 TIMBER sessions. The patients in the TIMBER-P group were switched to those in the TIMBER-K group after they experienced a sustained relapse. Outcome measures: PTSD Checklist (PCL), Clinician Administered PTSD Scale for DSM-IV (CAPS), the 17-item Hamilton Rating Scale for Depression (Ham-D-17, clinician rated), Beck Anxiety Inventory (BAI), and Montreal Cognitive Assessment (MoCA) at baseline and 8 hours after infusion were used to investigate if ketamine selectively affected trauma memories leaving the general memory intact. The mindfulness interventions in TIMBER were personalized based on subject's scores on Assessment Scale for Mindfulness Interventions which was administered at baseline, and after 5 sessions and 9 sessions (completion) of TIMBER. In this study, scores on CAPS and PCL scales were the primary outcome measures. Results: In the acute phase trial ( first 3 months after infusion), nine out of 10 subjects showed robust response in primary outcome measures (PCL and CAPS scores for PTSD) and in the secondary outcome measures (Ham-D-17 and Beck Anxiety Inventory for depression and anxiety respectively) with a sustained response of 31.78 ± 18.29 days. The TIMBER-K group had a more sustained response (33 ± 22.98 days) compared to the TIMBER-P group (25 ± 16.8 days, P = 0.545). After switch from TIMBER-P group to TIMBER-K, patients experienced significantly prolonged response (49 vs. 25 days, P = 0.028). There were no intolerable side effects or dropouts during the 18-month follow-up period. Conclusion: TIMBER psychotherapy augmented with low dose (R,S)-ketamine prolongs the therapeutic effects of the later and may be a valuable treatment option for PTSD. Trial registration: ClinicalTrials.gov identifier: NCT02766192

Nonconventional interventions for chronic post-traumatic stress disorder: Ketamine, repetitive trans-cranial magnetic stimulation (rTMS), and alternative approaches

ABSTRACTIt is alarming that only 59% of those who have post-traumatic stress disorder (PTSD) respond to selective serotonin reuptake inhibitors. Many existing treatments, both pharmacological and nonpharmacological, do not directly target trauma memories that lay at the core of the PTSD pathogenesis. Notable exceptions are medications like ketamine and propranolol and trauma-focused psychotherapies like eye-movement desensitization and reprocessing therapy (developed by Shapiro) and Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) for trauma memories (developed by Pradhan). Although the antidepressant effects of ketamine are no longer news, ketamine’s effects on treatment refractory PTSD (TR-PTSD) is a recent concept. As TR-PTSD has a marked public health burden and significant limitations in terms of treatment interventions, a thorough assessment of current strategies is required. Research to bring clarity to the underlying pathophysiology and neurobiology of TR-PTSD delineating the chemical, structural, and circuitry abnormalities will take time. In the interim, in the absence of a 1-size-fits-all therapeutic approach, pragmatically parallel lines of research can be pursued using the pharmacological and nonpharmacological treatments that have a strong theoretical rationale for efficacy. This article aims to review the current literature on interventions for PTSD, most notably ketamine, trans-cranial magnetic stimulation treatment, yoga and mindfulness interventions, and TIMBER. We present an outline for their future use, alone as well as in combination, with a hope of providing additional insights as well as advocating for developing more effective therapeutic intervention for this treatment-resistant and debilitating condition.

3,4-Methylenedioxymethamphetamine's (MDMA's) Impact on Posttraumatic Stress Disorder.

Review the current literature assessing the role of 3,4-methylenedioxymethamphetamine (MDMA) on posttraumatic stress disorder (PTSD). OVID MEDLINE search (1960-February 2014) using the terms MDMA, 3,4-methylenedioxymethamphetamine, Molly, and Ecstasy crossed with posttraumatic stress disorder with backwards citation tracking using references from procured articles. English language studies assessing MDMA in patients with PTSD. Three randomized controlled trials (RCTs) were conducted along with follow-up open-label and extension evaluations. In the 3 RCTs, therapy with MDMA-assisted psychotherapy is promising, with reductions in PTSD rating scale scores (Clinician-Administered PTSD Scale, Severity of Symptoms Scale for PTSD Scale), although 2 of 3 trials did not show significant results, and all three had methodological limitations. The direction of effect for all trials was toward benefit in patients who were refractory to other PTSD therapies; the percentage reductions on rating scores ranged from 23% to 68%; and in 1 trial, the effect was sustained over a long period of time. MDMA ingestion without sustained psychotherapy over a 6- to 8-hour period is unlikely to be beneficial; trying to prolong the duration of effect with supplemental dosing is unlikely to provide additional benefits; and there are adverse effects on blood pressure and heart rate that should be appreciated. These studies used unadulterated MDMA with known and reproducible potency, which may not happen with street purchase of the product. MDMA-assisted psychotherapy may be an effective therapy in refractory PTSD but needs further evaluation to determine its place in contemporary therapy.

Use of Stellate Ganglion Block for Refractory Post-Traumatic Stress Disorder: A Review of Published Cases

Introduction: The lifetime prevalence of post-traumatic stress disorder (PTSD) is estimated to be 7.3% in the U.S. population, 10-20% among active duty service members and 35-40% among veterans. Overall success rates of evidence-based therapies for PTSD are low, leading clinicians to explore new therapeutic options. This study evaluated all published articles on the use of stellate ganglion block (SGB) as an adjunctive therapy for treatmentrefractory PTSD. Methods: EMBASE, PubMed, PsychINFO and Cochrane databases were searched using keyword combinations including stellate ganglion block, SGB, post-traumatic stress disorder, and PTSD. Articles were restricted to English language with no date delimiter. Twelve publications were identified, seven of which were eliminated due to lack of case data, duplicate patient sample, or descriptive reports with no standardized PTSD symptom assessment. Twenty-four cases from five articles were examined further by two independent evaluators who extracted data on sociodemographic and clinical characteristics including PTSD symptoms, comorbidities, and treatment history. Interrater reliability showed complete agreement (κ=1.0). Results: Cases were predominantly male (n=21, 88%) and active duty military (n=14, 58%) or veterans (n=8, 33%) with combat-related PTSD. The average age was 40.5 years (±10.0 SD). All cases had received >1 year of psychotherapy and pharmacotherapy before SGB. Seventeen cases (71%) received one SGB, seven (29%) received multiple SGBs. Clinically meaningful improvements were observed in 75% (n=18) of cases after SGB, with significant differences in mean PTSD scores pre- (69.5 ± 26.6) and post-SGB (34.2 ± 32.5) across cases (p<0.001). The effect size was relatively large (d=1.2). On average, PTSD improved by 50.4% (± 30.9 SD; range: 6.3-98.4) for cases with one SGB and 69.0% (± 28.0 SD; range: 9.2-93.5) for cases with multiple SGBs. Conclusions: Most patients with treatment-refractory PTSD experienced rapid improvement after SGB. Robust clinical trials are needed to determine SGB’s treatment efficacy for PTSD.

Randomized Controlled Trial of Accelerated Resolution Therapy (ART) for Symptoms of Combat-Related Post-Traumatic Stress Disorder (PTSD)

Therapies for post-traumatic stress disorder (PTSD) endorsed by the Department of Defense and Veterans Administration are relatively lengthy, costly, and yield variable success. We evaluated Accelerated Resolution Therapy (ART) for the treatment of combat-related psychological trauma. A randomized controlled trial of ART versus an Attention Control (AC) regimen was conducted among 57 U.S. service members/veterans. After random assignment, those assigned to AC were offered crossover to ART, with 3-month follow-up on all participants. Self-report symptoms of PTSD and comorbidities were analyzed among study completers and by the intention-to-treat principle. Mean age was 41 ± 13 years with 19% female, 54% Army, and 68% with prior PTSD treatment. The ART was delivered in 3.7 ± 1.1 sessions with a 94% completion rate. Mean reductions in symptoms of PTSD, depression, anxiety, and trauma-related guilt were significantly greater (p < 0.001) with ART compared to AC. Favorable results for those treated with ART persisted at 3 months, including reduction in aggression (p < 0.0001). Adverse treatment-related events were rare and not serious. ART appears to be a safe and effective treatment for symptoms of combat-related PTSD, including refractory PTSD, and is delivered in significantly less time than therapies endorsed by the Department of Defense and Veterans Administration.

Self-Care Mindfulness Approaches for Refractory Posttraumatic Stress Disorder

PSYCHIATRIC ANNALS 43:7 | JULY 2013 Current first-line posttraumatic stress disorder (PTSD) therapies include trauma-focused cognitive behavioral psychotherapies, stress inoculation training such as prolonged exposure, and pharmacotherapies.1 In recent years, however, the evidence base for mindfulness interventions has been rapidly expanding, as reflected in the 2010 Veterans Administration (VA)/ Department of Defense (DoD) Clinical Practice Guideline for Management of PTSD, and the 2011 systematic review by the VA evidence-based synthesis program.1 Although the guidelines do not recommend any mindfulness approaches as first-line treatments for PTSD, they are known to facilitate the patient’s engagement in care, address hyperarousal symptoms, and comorbid conditions. Mindfulness-based approaches are increasingly employed to treat a variety of psychological, psychiatric, and physical problems, including anxiety, depression, PTSD, sleep difficulties, and chronic pain.2 A 2012 survey of 125 VA-specialized PTSD treatment programs indicated that 88% offered mindfulness practices including yoga and meditation.3,4 Deployment to a war zone in Iraq or Afghanistan is associated with a threefold increase in new-onset PTSD.5 Since PTSD appears to be a risk factor for suicidal behavior, and often co-occurs with depression, anxiety, substance use disorders, and chronic pain, associated long-term personal and societal costs are high.6-8 Considering the high prevalence, and chronic debilitating nature of PTSD among US service members and veterans, the development of cost-effective self-management of this condition carries great public health importance.9 Engaging patients in collaborative care and educating them on how to self-manage their chronic diseases has been shown to lead to increased levels of functioning, reduced pain, improved health outcomes, and decreased health care costs.10 Additionally, it supports the patientcentered partnership model of care, where responsibility shifts from the physician to the patient. Recent metaanalysis and efficacy data suggest that self-help interventions are accepted and effective for patients with PTSD and anxiety disorders.11 They are useful in decreasing avoidance behavior, frequency of intrusive symptoms, anxiety, and depressive symptoms; they also have been shown to increase coping and selfefficacy skills.12 On Aug. 31, 2012, President Obama signed an executive order that directs the DoD, the VA, the Department of Health and Human Services, and the Department of Education to develop strategies Self-Care Mindfulness Approaches for Refractory Posttraumatic Stress Disorder