PSYCHOTHERAPY VERSUS PHARMACOTHERAPY FOR POSTTRAUMATIC STRESS DISORDER: SYSTEMIC REVIEW AND META-ANALYSES TO DETERMINE FIRST-LINE TREATMENTS.

BACKGROUND: Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as first-line treatment. Direct head-to-head comparisons are lacking. METHODS: Systemic review of Medline, EMBASE, PILOTS, Cochrane Central Register of Controlled Trials, PsycINFO, and Global Health Library was conducted without language restrictions. Randomized clinical trials ≥8 weeks in duration using structured clinical interview-based outcome measures, active-control conditions (e.g. supportive psychotherapy), and intent-to-treat analysis were selected for analyses. Independent review, data abstraction, and bias assessment were performed using standardized processes. Study outcomes were grouped around conventional follow-up time periods (3, 6, and 9 months). Combined effect sizes were computed using meta-analyses for medication versus control, medication pre-/posttreatment, psychotherapy versus control, and psychotherapy pre-/posttreatment. RESULTS: Effect sizes for trauma-focused psychotherapies (TFPs) versus active control conditions were greater than medications versus placebo and other psychotherapies versus active controls. TFPs resulted in greater sustained benefit over time than medications. Sertraline, venlafaxine, and nefazodone outperformed other medications, although potential for methodological biases were high. Improvement following paroxetine and fluoxetine treatment was small. Venlafaxine and stress inoculation training (SIT) demonstrated large initial effects that decreased over time. Bupropion, citalopram, divalproex, mirtazapine, tiagabine, and topiramate failed to differentiate from placebo. Aripiprazole, divalproex, guanfacine, and olanzapine failed to differentiate from placebo when combined with an antidepressant. CONCLUSIONS: Study findings support use of TFPs over nontrauma-focused psychotherapy or medication as first-line interventions. Second-line interventions include SIT, and potentially sertraline or venlafaxine, rather than entire classes of medication, such as SSRIs. Future revisions of CPGs should prioritize studies that utilize active controls over waitlist or treatment-as-usual conditions. Direct head-to-head trials of TFPs versus sertraline or venlafaxine are needed.

A Quantitative Framework to Identify and Prioritize Opportunities in Biomedical Product Innovation: A Proof-of-Concept Study.

Importance: Prioritization and funding for health initiatives, including biomedical innovation, may not consistently target unmet public health needs. Objective: To (1) develop a quantitative, databased framework to identify and prioritize opportunities for biomedical product innovation investments based on a multicriteria decision-making model (MCDM) that includes comprehensive measures of public health burden and health care costs, and (2) pilot test the model. Design, Setting, and Participants: The Department of Health and Human Services (HHS) convened public and private experts to develop a model, select measures, and complete a longitudinal pilot study to identify and prioritize opportunities for investment in biomedical product innovations that have the greatest public health benefit. Cross-sectional and longitudinal data (2012-2019) for 13 pilot medical disorders were obtained from the Institute for Health Metrics Global Burden of Disease database (IHME GBD) and the National Center for Health Statistics (NCHS). Main Outcome Measures: The main outcome measure was an overall gap score reflecting high public health burden (composite measure of mortality, prevalence, years lived with disability, and health disparities), or high health care costs (composite measure of total, public, and out-of-pocket health spending) relative to low biomedical innovation. Sixteen innovation metrics were selected to reflect the pipeline of biomedical products from research and development to market approval. A higher score indicates a greater gap. Normalized composite scores were calculated for public health burden, cost, and innovation investment using the MCDM Technique for Order of Preference by Similarity to Ideal Solution method. Results: Among the 13 conditions tested in the pilot study, diabetes (0.61), osteoarthritis (0.46), and drug-use disorders (0.39) had the highest overall gap score reflecting high public health burden, or high health care costs relative to low biomedical innovation in these medical disorders. Chronic kidney disease (0.05), chronic obstructive pulmonary disease (0.09), and cirrhosis and other liver diseases (0.10) had the least amount of biomedical product innovation despite similar public health burden and health care cost scores. Conclusions: In this cross-sectional pilot study, we developed and implemented a data-driven, proof-of-concept model that can help identify, quantify, and prioritize opportunities for biomedical product innovation. Quantifying the relative alignment between biomedical product innovation, public health burden, and health care cost may help identify and prioritize investments that can have the greatest public health benefit.

Impaired Lymphatic Drainage and Interstitial Inflammatory Stasis in Chronic Musculoskeletal and Idiopathic Pain Syndromes: Exploring a Novel Mechanism.

A normal functioning lymphatic pump mechanism and unimpaired venous drainage are required for the body to remove inflammatory mediators from the extracellular compartment. Impaired vascular perfusion and/or lymphatic drainage may result in the accumulation of inflammatory substances in the interstitium, creating continuous nociceptor activation and related pathophysiological states including central sensitization and neuroinflammation. We hypothesize that following trauma and/or immune responses, inflammatory mediators may become entrapped in the recently discovered interstitial, pre-lymphatic pathways and/or initial lymphatic vessels. The ensuing interstitial inflammatory stasis is a pathophysiological state, created by specific pro-inflammatory cytokine secretion including tumor necrosis factor alpha, interleukin 6, and interleukin 1b. These cytokines can disable the local lymphatic pump mechanism, impair vascular perfusion via sympathetic activation and, following transforming growth factor beta 1 expression, may lead to additional stasis through direct fascial compression of pre-lymphatic pathways. These mechanisms, when combined with other known pathophysiological processes, enable us to describe a persistent feed-forward loop capable of creating and maintaining chronic pain syndromes. The potential for concomitant visceral and/or vascular dysfunction, initiated and maintained by the same feed-forward inflammatory mechanism, is also described.

Characteristics and correlates of U.S. clinicians prescribing buprenorphine for opioid use disorder treatment using expanded authorities during the COVID-19 pandemic.

BACKGROUND: To determine how clinicians with a DATA waiver to prescribe buprenorphine for opioid use disorder (OUD) adapted during the COVID-19 pandemic to emergency authorities, including use of telehealth to prescribe buprenorphine, the challenges faced by clinicians, and strategies employed by them to manage patients with OUD. METHODS: From June 23, 2020 to August 19, 2020, we conducted an electronic survey of U.S. DATA-waivered clinicians. Descriptive statistics and multivariable logistic regression were used for analysis. RESULTS: Among 10,238 respondents, 68 % were physicians, 25 % nursing-related providers, and 6% physician assistants; 28 % reported never prescribing or not prescribing in the 12 months prior to the survey. Among the 72 % of clinicians who reported past 12-month buprenorphine prescribing (i.e. active practitioners during the pandemic) 30 % reported their practice setting closed to in-person visits during COVID-19; 33 % reported remote prescribing to new patients without an in-person examination. The strongest predictors of remote buprenorphine prescribing to new patients were prescribing buprenorphine to larger numbers of patients in an average month in the past year and closure of the practice setting during the pandemic; previous experience with remote prescribing to established patients prior to COVID-19 also was a significant predictor. Among clinicians prescribing to new patients without an in-person examination, 5.5 % reported difficulties with buprenorphine induction, most commonly withdrawal symptoms. CONCLUSIONS: Telehealth practices and prescribing to new patients without an in-person examination were adopted by DATA-waivered clinicians during the first six months of COVID-19. Permanent adoption of these authorities may enable expanded access to buprenorphine treatment.

Randomized Controlled Trial of Riluzole Augmentation for Posttraumatic Stress Disorder: Efficacy of a Glutamatergic Modulator for Antidepressant-Resistant Symptoms.

OBJECTIVE: Current pharmacologic treatments for posttraumatic stress disorder (PTSD) have shown limited efficacy, prompting a call to investigate new classes of medications. The current study investigated the efficacy of glutamate modulation with riluzole augmentation for combat-related PTSD symptoms resistant to treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: A randomized, double-blind, placebo-controlled, parallel trial was conducted at Walter Reed National Military Medical Center and Syracuse VA Medical Center between December 2013 and November 2017. Veterans and active duty service members with combat-related PTSD (per the Clinician Administered PTSD Scale [CAPS]) who were not responsive to SSRI or SNRI pharmacotherapy were randomized to 8-week augmentation with a starting dose of 100 mg/d of riluzole (n = 36) or placebo (n = 38) and assessed weekly for PTSD symptoms, anxiety, depression, disability, and side effects. RESULTS: Intent-to-treat analyses (N = 74) of the primary outcome (CAPS for DSM-IV) showed no significant between-group difference in change in overall PTSD symptoms (F = 0.64, P = .422), with a small effect size (d = 0.25). There was clinically significant within-group improvement in overall PTSD symptoms in both groups, with a greater mean (SD) decrease in CAPS score in the riluzole group (-21.1 [18.9]) than in the placebo group (-16.7 [17.2]). Exploratory analyses of PTSD symptom clusters showed significantly greater improvement on hyperarousal symptoms in the riluzole group as measured by the PTSD Checklist-Specific-Subscale D (d = 0.48) and near-significant findings on the CAPS Subscale D. Riluzole augmentation was not superior to placebo on change in depression, anxiety, or disability severity. CONCLUSIONS: Although preliminary, the exploratory findings of this study offer some evidence that riluzole augmentation of an SSRI or SNRI may selectively improve PTSD hyperarousal symptoms without changes in overall PTSD symptoms, depression, anxiety, or disability. Additional investigation of the mechanism of the efficacy of riluzole for hyperarousal symptoms is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02155829.

Reward circuitry in resilience to severe trauma: an fMRI investigation of resilient special forces soldiers.

Enhanced brain reward function could contribute to resilience to trauma. Reward circuitry in active duty, resilient special forces (SF) soldiers was evaluated using functional magnetic resonance imaging during a monetary incentive delay task. Findings in this group of resilient individuals revealed unique patterns of activation during expectation of reward in the subgenual prefrontal cortex and nucleus accumbens area, regions pivotal to reward processes.

Low cortisol, high DHEA, and high levels of stimulated TNF-alpha, and IL-6 in women with PTSD.

Posttraumatic stress disorder (PTSD) has been associated with hypothalamic-pituitary-adrenal (HPA) axis and immune function alterations; however, few studies have simultaneously investigated these systems in participants with PTSD. In this study, HPA axis and immune function in 26 women with PTSD with and without major depressive disorder was compared to 24 traumatized controls and to 21 nontraumatized controls. Posttraumatic stress disorder was associated with low cortisol and higher levels of DHEA and greater production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) compared to traumatized and healthy controls. Women with PTSD and depression exhibited greater production of IL-6 and higher levels of dehydroepiandrosterone (DHEA) than those with PTSD, but without depression. These findings suggest dysregulated HPA axis and immune function in women with PTSD, and that comorbid depression may contribute to these abnormalities.

Association between level of emotional intelligence and severity of anxiety in generalized social phobia.

Generalized social phobia (GSP) is characterized by a marked fear of most social situations. It is associated with an anomalous neural response to emotional stimuli, and individuals with the disorder frequently show interpretation bias in social situations. From this it might be suggested that GSP involves difficulty in accurately perceiving, using, understanding and managing emotions. Here we applied the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) to medication-free GSP (n=28) and no pathology (n=21) individuals. Patients with GSP performed within the normal range on the measure however severity of social anxiety significantly correlated with emotional intelligence (EI). Specifically, there was a negative correlation between social anxiety severity and Experiential (basic-level emotional processing) EI. In contrast, there was no significant correlation between social anxiety severity and Strategic (higher-level conscious emotional processing) EI. These results suggest that EI may index emotional processing systems that mitigate the impact of systems causally implicated in GSP.

Altered cerebral benzodiazepine receptor binding in post-traumatic stress disorder.

Agonists of the γ-aminobutyric acid (GABA) type A benzodiazepine (BZD) receptor exert anxiolytic effects in anxiety disorders, raising the possibility that altered GABA-ergic function may play a role in the pathophysiology of anxiety disorders, such as post-traumatic stress disorder (PTSD). However, few neuroimaging studies have assessed the function or binding potential of the central GABAA BZD receptor system in PTSD. Therefore, our aim was to compare the BZD receptor binding potential between PTSD patients and healthy controls. Twelve medication-free participants with a current diagnosis of PTSD and 15 matched healthy controls underwent positron emission tomography (PET) imaging using [11C] flumazenil. Structural magnetic resonance imaging (MRI) scans were obtained and co-registered to the PET images to permit co-location of neuroanatomical structures in the lower resolution PET image data. Compared to healthy controls, PTSD patients exhibited increased BZD binding in the caudal anterior cingulate cortex and precuneus (p's < 0.05). Severity of PTSD symptoms positively correlated with BZD binding in the left mid- and anterior insular cortices. This study extends previous findings by suggesting that central BZD receptor system involvement in PTSD includes portions of the default mode and salience networks, along with insular regions that support interoception and autonomic arousal.

Choosing the lesser of two evils, the better of two goods: specifying the roles of ventromedial prefrontal cortex and dorsal anterior cingulate in object choice.

The ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortices (ACd) are considered important for reward-based decision making. However, work distinguishing their individual functional contributions has only begun. One aspect of decision making that has received little attention is that making the right choice often translates to making the better choice. Thus, response choice often occurs in situations where both options are desirable (e.g., choosing between mousse au chocolat or crème caramel cheesecake from a menu) or, alternatively, in situations where both options are undesirable. Moreover, response choice is easier when the reinforcements associated with the objects are far apart, rather than close together, in value. We used functional magnetic resonance imaging to delineate the functional roles of the vmPFC and ACd by investigating these two aspects of decision making: (1) decision form (i.e., choosing between two objects to gain the greater reward or the lesser punishment), and (2) between-object reinforcement distance (i.e., the difference in reinforcements associated with the two objects). Blood oxygen level-dependent (BOLD) responses within the ACd and vmPFC were both related to decision form but differentially. Whereas ACd showed greater responses when deciding between objects to gain the lesser punishment, vmPFC showed greater responses when deciding between objects to gain the greater reward. Moreover, vmPFC was sensitive to reinforcement expectations associated with both the chosen and the forgone choice. In contrast, BOLD responses within ACd, but not vmPFC, related to between-object reinforcement distance, increasing as the distance between the reinforcements of the two objects decreased. These data are interpreted with reference to models of ACd and vmPFC functioning.

Effects of antidepressant treatment on neural correlates of emotional and neutral declarative verbal memory in depression.

BACKGROUND: Multiple studies have documented deficits in verbal declarative memory function in depression that improve with resolution of symptoms; imaging studies show deficits in anterior cingulate function in depression, a brain area that mediates memory. No studies to date have examined neural correlates of emotionally valenced declarative memory using affectively negative (sad) verbal material that is clinically relevant to understanding depression. Also no studies have examined the effects of treatment on neural correlates of verbal declarative memory. The purpose of this study was to examine the effects of treatment with antidepressants on verbal declarative memory in patients with depression. METHODS: Subjects with (N=18) and without (N=9) mid-life major depression underwent positron emission tomography (PET) imaging during verbal declarative memory tasks with both neutral paragraph encoding compared to a control condition, and emotional (sad) word pair retrieval compared to a control condition. Imaging was repeated in 13 subjects with depression after treatment with antidepressants. RESULTS: Patients with untreated depression had a failure of anterior cingulate activation relative to controls during retrieval of emotional word pairs. Antidepressant treatment resulted in increased anterior cingulate function compared to the untreated baseline for both neutral and emotional declarative memory. LIMITATIONS: Limitations include a small sample size and variety of antidepressants used. CONCLUSIONS: These results are consistent with alterations in anterior cingulate function that are reversible with treatment in patients with depression. These findings may have implications for understanding the mechanism of action of antidepressants in the treatment of depression.

Sex differences in diencephalon serotonin transporter availability in major depression.

BACKGROUND: Major depression is more prevalent in women than men. The present study evaluated if previous findings that demonstrated decreased 5-hydroxytryptamine (5-HT) transporter availability in depressed patients would be confirmed in a larger sample and also evaluated sex differences. METHODS: Depressed (n = 32) and healthy subjects (n = 32), including 16 pairs of women and men, participated in an iodine-123-2 beta-carbomethoxy-3beta-(4-iodophenyltropane) ([(123)I]beta-CIT) single photon emission computed tomography (SPECT) and a magnetic resonance imaging (MRI) scan. Participants were administered [(123)I]beta-CIT (225.7 +/- 3.7 MBq) and imaged 23.0 +/- 1.6 hours later. Statistical analyses included analysis of variance and a regression analysis of the main and interactive effects of age, sex, and depression. RESULTS: Overall, depressed patients demonstrated 12% lower diencephalon and no change in striatal or brainstem [(123)I]beta-CIT uptake. Significant age by sex, sex by depression, and age by sex by depression interactions were noted due to 22% lower diencephalon [(123)I]beta-CIT uptake in depressed women compared with less than a 1% decrease in depressed men. CONCLUSIONS: As observed previously, diencephalon 5-HT transporter availability is decreased in depressed patients. However, the decrease appears to be sex-specific and age-dependent. These findings suggest that serotonergic mechanisms mediating depressed mood differ between men and women in an age-dependent manner and may explain why young women respond better to treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants.

Hydrocortisone impairs hippocampal-dependent trace eyeblink conditioning in post-traumatic stress disorder.

Trace eyeblink conditioning is a hippocampal-dependent associative learning task that could help evaluate hippocampal function in Post-traumatic stress disorder (PTSD). Since preclinical research has demonstrated that trace eyeblink conditioning can be pharmacologically manipulated by glucocorticoids, this task may shed light on glucocorticoid sensitivity in PTSD. This study assessed baseline and hydrocortisone-mediated changes in trace eyeblink conditioning in patients with PTSD and in healthy controls. A total of 12 patients with PTSD and 12 age- and sex-matched healthy controls participated in a trace eyeblink test 6 h following intravenous administration of 30 mg of hydrocortisone. Spontaneous blink rates were similar between PTSD patients and healthy controls. There was no significant difference in the mean conditioned response between PTSD subjects and healthy controls under placebo conditions. Following hydrocortisone administration, only the PTSD patients demonstrated a significant reduction in conditioned response in contrast to healthy subjects who did not demonstrate any change. Patients with PTSD had increased glucocorticoid sensitivity in the focal brain regions mediating trace eyeblink conditioning.

Alterations in stress reactivity after long-term treatment with paroxetine in women with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is typically accompanied by both acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but studies have also used a challenge model to assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. The purpose of this article was to assess the effect of long-term treatment with the selective reuptake inhibitor (SSRI), paroxetine, on stress reactivity in patients with PTSD. We assessed diurnal salivary cortisol and urinary cortisol as well as cortisol, heart rate, and behavioral responses to a standardized cognitive stress challenge, in 13 female patients with chronic PTSD before and after 12 months of paroxetine treatment. Treatment resulted in a significant decrease in PTSD symptoms. Twenty-four-hour urinary cortisol was lower compared to base line after successful treatment. Treatment resulted in a decrease of salivary cortisol levels on all time points on a diurnal curve. Despite similar stress perception, cortisol response to the cognitive stress challenge resulted in a 26.5% relative decrease in stress-induced salivary cortisol with treatment. These results suggest that successful treatment with SSRI in chronic PTSD is associated with a trend for a decrease in baseline diurnal cortisol and with reduced cortisol reactivity to stress.

The Emerging Role of Mindfulness Meditation as Effective Self-Management Strategy, Part 1: Clinical Implications for Depression, Post-Traumatic Stress Disorder, and Anxiety.

Mindfulness-based interventions (MBIs) have been increasingly utilized in the management of mental health conditions. This first review of a two-part series evaluates the efficacy, mechanism, and safety of mindfulness meditation for mental health conditions frequently seen after return from deployment. Standard databases were searched until August 4, 2015. 52 systematic reviews and randomized clinical trials were included. The Strength of Recommendation (SOR) Taxonomy was used to assess the quality of individual studies and to rate the strength of evidence for each clinical condition. Adjunctive mindfulness-based cognitive therapy is effective for decreasing symptom severity during current depressive episode, and for reducing relapse rate in recovered patients during maintenance phase of depression management (SOR moderate [SOR B]). Adjunctive mindfulness-based stress reduction is effective for improving symptoms, mental health-related quality of life, and mindfulness in veterans with combat post-traumatic stress disorder (PTSD) (SOR B). Currently, there is no sufficient data to recommend MBIs for generalized anxiety disorder (SOR B). MBIs are safe, portable, cost-effective, and can be recommended as an adjunct to standard care or self-management strategy for major depressive disorder and PTSD. Future large, well-designed randomized clinical trials in service members and veterans can help plan for the anticipated increase in demand for behavioral health services.

The Emerging Role of Mindfulness Meditation as Effective Self-Management Strategy, Part 2: Clinical Implications for Chronic Pain, Substance Misuse, and Insomnia.

Mindfulness-based interventions have been increasingly utilized in the management of chronic pain since 1982. This second review of a two-part series evaluates the efficacy, mechanism, and safety of mindfulness meditation for chronic pain, substance use disorder, tobacco use disorder, and insomnia frequently co-occurring after return from deployment. Standard databases were searched until August 4, 2015. 72 relevant systematic reviews and clinical trials met the inclusion criteria. The Strength of Recommendation Taxonomy was used to assess the quality of individual studies and to rate the strength of recommendation (SOR) for each clinical condition. Mindfulness-based interventions effectively and durably reduce pain intensity, improve functional status, pain-related psychological consequences, quality of life (SOR B). They can also be utilized as an adjunctive intervention aimed at improving health-related quality of life in individuals with substance use disorders interested in self-management strategies (SOR B). Mindfulness training for smokers used adjunctively with pharmacotherapy shows efficacy in maintaining abstinence comparable to that of the current standard of care (SOR B). Future large, well-designed randomized clinical trials using active controls in service members and veterans with co-occurring pain and psychological health conditions are necessary to provide more precise clinical guidance.

No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder.

OBJECTIVE: Serotonin type 1A receptors (5HT1ARs) have been shown to be affected by stress in experimental animals and related to anxiety and depression in humans. In the present study, the authors sought an association between 5HT1AR binding and posttraumatic stress disorder (PTSD). METHOD: Using positron emission tomography and the radioligand [18F]FCWAY, the authors compared 5HT1AR binding between patients with PTSD and healthy subjects. RESULTS: No significant differences in 5HT1AR distribution volume, binding potential, or tracer delivery were found. CONCLUSIONS: 5HT1AR expression may not be altered in patients with PTSD.

Smaller head of the hippocampus in Gulf War-related posttraumatic stress disorder.

Reductions in hippocampal volume and impairment in short-term verbal memory have been reported in Vietnam combat veterans with posttraumatic stress disorder (PTSD) and in women with abuse-related PTSD. The present investigation evaluated hippocampal volume and memory in Gulf War veterans. This research is timely given the ongoing war in Iraq and the anticipated high rates of PTSD among returning combat soldiers. Fourteen veterans with PTSD related to traumatic experiences during the Gulf War (1990-1991), 23 deployed veterans without PTSD, 22 non-deployed reservists and 29 healthy civilians were studied. Volumes of the hippocampus, temporal lobe, and whole brain were measured on coronal MRI scans, and hippocampal mediated memory function was evaluated. The head of the hippocampus was the only subregion that was significantly smaller in Gulf War veterans with PTSD than in healthy civilians. Deployed veterans with PTSD, deployed veterans without PTSD, and non-deployed reservists had significantly smaller whole hippocampal volume and lower scores on immediate and delayed verbal and visual retrieval compared with healthy civilians.