The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications.

Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.

Inhibition of 5-HT alleviates PTSD-like behaviors and promotes hippocampal neuroplasticity by modulating hippocampal autophagy in rats.

5-Hydroxytryptamine (5-HT) plays a substantial role in mitigating depression and anxiety. However, the potential effects of 5-HT against posttraumatic stress disorder (PTSD) and its underlying mechanisms remain unclear. Elevated plus maze test evaluates anxiety-related behaviors, and the open field test is used to assess overall activity levels and anxiety. Inflammatory cytokine levels were determined using ELISA. The levels of 5-HT and dopamine were measured using HPLC. mRNA and protein levels were examined by PCR and Western blot, respectively. Rats exposed to single prolonged stress (SPS) exhibited typical PTSD-like phenotypes, with decreased levels of 5-HT in the hippocampus and significant reductions in its downstream targets, brain-derived neurotrophic factor (BDNF) and TrkB. In addition, it was discovered that the autophagy signaling pathway might be involved in regulating hippocampal BDNF in rats exposed to SPS. Subsequent treatment with an intracerebral injection of sh-SERT significantly inhibited anxiety and cognitive dysfunction in rats. Moreover, sh-SERT treatment was observed to substantially reverse the increase in autophagy signaling protein expression and consequently improve the expression of BDNF and TrkB proteins, which had been reduced. The current study demonstrates that sh-SERT exhibits significant anti-PTSD effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity.NEW & NOTEWORTHY The study demonstrated that sh-SERT exhibits significant anti-posttraumatic stress disorder (PTSD) effects, potentially mediated in part through the reduction of cellular autophagy to enhance hippocampal synaptic plasticity.

Decoding neural reactivation of threat during fear learning, extinction, and recall in a randomized clinical trial of L-DOPA among women with PTSD.

BACKGROUND: Laboratory paradigms are widely used to study fear learning in posttraumatic stress disorder (PTSD). Recent basic science models demonstrate that, during fear learning, patterns of activity in large neuronal ensembles for the conditioned stimuli (CS) begin to reinstate neural activity patterns for the unconditioned stimuli (US), suggesting a direct way of quantifying fear memory strength for the CS. Here, we translate this concept to human neuroimaging and test the impact of post-learning dopaminergic neurotransmission on fear memory strength during fear acquisition, extinction, and recall among women with PTSD in a re-analysis of previously reported data. METHODS: Participants (N = 79) completed a context-dependent fear acquisition and extinction task on day 1 and extinction recall tests 24 h later. We decoded activity patterns in large-scale functional networks for the US, then applied this decoder to activity patterns toward the CS on day 1 and day 2. RESULTS: US decoder output for the CS+ increased during acquisition and decreased during extinction in networks traditionally implicated in human fear learning. The strength of US neural reactivation also predicted individuals skin conductance responses. Participants randomized to receive L-DOPA (n = 43) following extinction on day 1 demonstrated less US neural reactivation on day 2 relative to the placebo group (n = 28). CONCLUSION: These results support neural reactivation as a measure of memory strength between competing memories of threat and safety and further demonstrate the role of dopaminergic neurotransmission in the consolidation of fear extinction memories.

Cannabidiol ameliorates PTSD-like symptoms by inhibiting neuroinflammation through its action on CB2 receptors in the brain of male mice.

Post-traumatic stress disorder (PTSD) is a debilitating mental health disease related to traumatic experience, and its treatment outcomes are unsatisfactory. Accumulating research has indicated that cannabidiol (CBD) exhibits anti-PTSD effects, however, the underlying mechanism of CBD remains inadequately investigated. Although many studies pertaining to PTSD have primarily focused on aberrations in neuronal functioning, the present study aimed to elucidate the involvement and functionality of microglia/macrophages in PTSD while also investigated the modulatory effects of CBD on neuroinflammation associated with this condition. We constructed a modified single-prolonged stress (SPS) mice PTSD model and verified the PTSD-related behaviors by various behavioral tests (contextual freezing test, elevated plus maze test, tail suspension test and novel object recognition test). We observed a significant upregulation of Iba-1 and alteration of microglial/macrophage morphology within the prefrontal cortex and hippocampus, but not the amygdala, two weeks after the PTSD-related stress, suggesting a persistent neuroinflammatory phenotype in the PTSD-modeled group. CBD (10 mg/kg, i.p.) inhibited all PTSD-related behaviors and reversed the alterations in both microglial/macrophage quantity and morphology when administered prior to behavioral assessments. We further found increased pro-inflammatory factors, decreased PSD95 expression, and impaired synaptic density in the hippocampus of the modeled group, all of which were also restored by CBD treatment. CBD dramatically increased the level of anandamide, one of the endocannabinoids, and cannabinoid type 2 receptors (CB2Rs) transcripts in the hippocampus compared with PTSD-modeled group. Importantly, we discovered the expression of CB2Rs mRNA in Arg-1-positive cells in vivo and found that the behavioral effects of CBD were diminished by CB2Rs antagonist AM630 (1 mg/kg, i.p.) and both the behavioral and molecular effects of CBD were abolished in CB2Rs knockout mice. These findings suggest that CBD would alleviate PTSD-like behaviors in mice by suppressing PTSD-related neuroinflammation and upregulation and activation of CB2Rs may serve as one of the underlying mechanisms for this therapeutic effect. The present study offers innovative experimental evidence supporting the utilization of CBD in PTSD treatment from the perspective of its regulation of neuroinflammation, and paves the way for leveraging the endocannabinoid system to regulate neuroinflammation as a potential therapeutic approach for psychiatric disorders.

Paradoxical effect of anti-inflammatory drugs on IL-6 mRNA expression in patients with PTSD during treatment.

The pathophysiology of posttraumatic stress disorder (PTSD) is associated with the activation of the innate immune system, including cytokines like interleukin 6 (IL-6). However, the role of IL-6 in the etiology and treatment of PTSD still remains elusive. We conducted a prospective controlled trial to investigate the development of IL-6 during psychosomatic treatment in individuals with PTSD in comparison with individuals without PTSD. We assessed IL-6 mRNA expression before and after 2 months of psychosomatic treatment in individuals with and without PTSD. Severities of PTSD and depressive symptoms were assessed in parallel. Linear mixed regression was applied for statistical analysis, including the factors diagnosis PTSD and pre-post treatment after subgrouping for intake of anti-inflammatory drugs. The development of IL-6 mRNA expression during treatment was affected by the use of anti-inflammatory drugs. In the subgroup without intake of anti-inflammatory drugs, no significant statistical treatment effect in individuals with and without PTSD emerged. In the subgroup of individuals taking anti-inflammatory drugs, a significant interaction effect of the factors pre-post treatment and diagnosis PTSD was observed. Whereas IL-6 mRNA expression in individuals without PTSD decreased according to amelioration of symptoms, IL-6 mRNA expression in individuals with PTSD increased significantly during treatment, in opposite direction to symptom severity. Anti-inflammatory drugs might affect IL-6 mRNA expression in individuals with PTSD in a paradoxical way. This study offers a further piece of evidence that IL-6 could be involved in the pathophysiology of PTSD and PTSD-specific immunologic molecular mechanisms.

A Pilot Randomized Control Trial of the Striving Towards EmPowerment and Medication Adherence (STEP-AD) Intervention for Black Women Living with HIV.

Black women living with HIV (BWLWH) face adversities associated with lower HIV medication adherence, viral non-suppression, and mental health symptoms (e.g., post-traumatic stress disorder) such as trauma/violence, racism, HIV-related discrimination/stigma, and gender-related stressors. We developed the first intervention based in cognitive behavioral therapy and culturally congruent coping for BWLWH to increase medication adherence and decrease PTSD symptoms by enhancing resilience, self-care, engagement in care, and coping for trauma, racism, HIV-related discrimination/stigma, and gender-related stressors. A pilot randomized control trial was conducted with BWLWH and histories of trauma who were at risk for their HIV viral load remaining or becoming detectable (i.e., below 80% medication adherence, detectable viral load in the past year, and/or missed HIV-related appointments). 119 BWLWH were assessed at baseline and 70 met inclusion criteria, completed one session of Life-Steps adherence counseling, and were randomized to either nine sessions of STEP-AD (Striving Towards EmPowerment and Medication Adherence) or ETAU (enhanced treatment as usual consisting of biweekly check-ins). Women completed a post intervention follow up assessment (3 months post baseline) and 3-month post intervention follow-up (6 months post baseline). Via STATA the difference-in-difference methodology with mixed models compared STEP-AD to ETAU on changes in outcomes over time. BWLWH in STEP-AD compared to E-TAU had significantly higher ART adherence (estimate = 9.36 p = 0.045) and lower likelihood of being clinically diagnosed with PTSD (OR = .07, estimate = - 2.66, p = 0.03) as well as borderline significance on higher CD4 count (estimate = 161.26, p = 0.05). Our findings suggest preliminary efficacy of STEP-AD in improving ART adherence, mental health, and immune function.

Psychedelic Therapy: A Primer for Primary Care Clinicians-3,4-Methylenedioxy-methamphetamine (MDMA).

BACKGROUND: After becoming notorious for its use as a party drug in the 1980s, 3,4-methylenedioxy-methampetamine (MDMA), also known by its street names "molly" and "ecstasy," has emerged as a powerful treatment for post-traumatic stress disorder (PTSD). AREAS OF UNCERTAINTY: There are extensive data about the risk profile of MDMA. However, the literature is significantly biased. Animal models demonstrating neurotoxic or adverse effects used doses well beyond the range that would be expected in humans (up to 40 mg/kg in rats compared with roughly 1-2 mg/kg in humans). Furthermore, human samples often comprise recreational users who took other substances in addition to MDMA, in uncontrolled settings. THERAPEUTIC ADVANCES: Phase III clinical trials led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have shown that MDMA-assisted psychotherapy has an effect size of d = 0.7-0.91, up to 2-3 times higher than the effect sizes of existing antidepressant treatments. 67%-71% of patients who undergo MDMA-assisted psychotherapy no longer meet the diagnostic criteria for PTSD within 18 weeks. We also describe other promising applications of MDMA-assisted psychotherapy for treating alcohol use disorder, social anxiety, and other psychiatric conditions. LIMITATIONS: Thus far, almost all clinical trials on MDMA have been sponsored by a single organization, MAPS. More work is needed to determine whether MDMA-assisted therapy is more effective than existing nonpharmacological treatments such as cognitive behavioral therapy. CONCLUSIONS: Phase III trials suggest that MDMA is superior to antidepressant medications for treating PTSD. Now that MAPS has officially requested the Food and Drug Administration to approve MDMA as a treatment for PTSD, legal MDMA-assisted therapy may become available as soon as 2024.

Early pharmacological interventions for prevention of post-traumatic stress disorder (PTSD) in individuals experiencing acute traumatic stress symptoms.

BACKGROUND: Acute traumatic stress symptoms may develop in people who have been exposed to a traumatic event. Although they are usually self-limiting in time, some people develop post-traumatic stress disorder (PTSD), a severe and debilitating condition. Pharmacological interventions have been proposed for acute symptoms to act as an indicated prevention measure for PTSD development. As many individuals will spontaneously remit, these interventions should balance efficacy and tolerability. OBJECTIVES: To assess the efficacy and acceptability of early pharmacological interventions for prevention of PTSD in adults experiencing acute traumatic stress symptoms. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trial Register (CCMDCTR), CENTRAL, MEDLINE, Embase and two other databases. We checked the reference lists of all included studies and relevant systematic reviews. The search was last updated on 23 January 2023. SELECTION CRITERIA: We included randomised controlled trials on adults exposed to any kind of traumatic event and presenting acute traumatic stress symptoms, without restriction on their severity. We considered comparisons of any medication with placebo, or with another medication. We excluded trials that investigated medications as an augmentation to psychotherapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Using a random-effects model, we analysed dichotomous data as risk ratios (RR) and calculated the number needed to treat for an additional beneficial/harmful outcome (NNTB/NNTH). We analysed continuous data as mean differences (MD) or standardised mean differences (SMD). Our primary outcomes were PTSD severity and dropouts due to adverse events. Secondary outcomes included PTSD rate, functional disability and quality of life. MAIN RESULTS: We included eight studies that considered four interventions (escitalopram, hydrocortisone, intranasal oxytocin, temazepam) and involved a total of 779 participants. The largest trial contributed 353 participants and the next largest, 120 and 118 participants respectively. The trials enrolled participants admitted to trauma centres or emergency departments. The risk of bias in the included studies was generally low except for attrition rate, which we rated as high-risk. We could meta-analyse data for two comparisons: escitalopram versus placebo (but limited to secondary outcomes) and hydrocortisone versus placebo. One study compared escitalopram to placebo at our primary time point of three months after the traumatic event. There was inconclusive evidence of any difference in terms of PTSD severity (mean difference (MD) on the Clinician-Administered PTSD Scale (CAPS, score range 0 to 136) -11.35, 95% confidence interval (CI) -24.56 to 1.86; 1 study, 23 participants; very low-certainty evidence), dropouts due to adverse events (no participant left the study early due to adverse events; 1 study, 31 participants; very low-certainty evidence) and PTSD rates (RR 0.59, 95% CI 0.03 to 13.08; NNTB 37, 95% CI NNTB 15 to NNTH 1; 1 study, 23 participants; very low-certainty evidence). The study did not assess functional disability or quality of life. Three studies compared hydrocortisone to placebo at our primary time point of three months after the traumatic event. We found inconclusive evidence on whether hydrocortisone was more effective in reducing the severity of PTSD symptoms compared to placebo (MD on CAPS -7.53, 95% CI -25.20 to 10.13; I2 = 85%; 3 studies, 136 participants; very low-certainty evidence) and whether it reduced the risk of developing PTSD (RR 0.47, 95% CI 0.09 to 2.38; NNTB 14, 95% CI NNTB 8 to NNTH 5; I2 = 36%; 3 studies, 136 participants; very low-certainty evidence). Evidence on the risk of dropping out due to adverse events is inconclusive (RR 3.19, 95% CI 0.13 to 75.43; 2 studies, 182 participants; low-certainty evidence) and it is unclear whether hydrocortisone might improve quality of life (MD on the SF-36 (score range 0 to 136, higher is better) 19.70, 95% CI -1.10 to 40.50; 1 study, 43 participants; very low-certainty evidence). No study assessed functional disability. AUTHORS' CONCLUSIONS: This review provides uncertain evidence regarding the use of escitalopram, hydrocortisone, intranasal oxytocin and temazepam for people with acute stress symptoms. It is therefore unclear whether these pharmacological interventions exert a positive or negative effect in this population. It is important to note that acute traumatic stress symptoms are often limited in time, and that the lack of data prevents the careful assessment of expected benefits against side effects that is therefore required. To yield stronger conclusions regarding both positive and negative outcomes, larger sample sizes are required. A common operational framework of criteria for inclusion and baseline assessment might help in better understanding who, if anyone, benefits from an intervention. As symptom severity alone does not provide the full picture of the impact of exposure to trauma, assessment of quality of life and functional impairment would provide a more comprehensive picture of the effects of the interventions. The assessment and reporting of side effects may facilitate a more comprehensive understanding of tolerability.

Cognitive processing therapy (CPT) versus individual drug counseling (IDC) for PTSD for veterans with opioid use disorder maintained on buprenorphine.

BACKGROUND AND OBJECTIVES: There are high rates of comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD). Evidence-based trauma-focused psychotherapies such as Cognitive Processing Therapy (CPT) are a first-line treatment for PTSD. Veterans with OUD are treated primarily in substance use disorder (SUD) clinics where the standard of care is drug counseling; they often do not have access to first-line PTSD treatments. This study tested whether CPT can be conducted safely and effectively in veterans with comorbid OUD treated with buprenorphine. METHODS: This 12-week, 2-site, randomized clinical trial (RCT) included open-label randomization to two groups: (a) CPT versus (b) Individual Drug Counselling (IDC) in veterans with PTSD and comorbid OUD who were maintained on buprenorphine (N = 38). RESULTS: Veterans randomized to either IDC (n = 18) or CPT (n = 20) showed a significant reduction in self-reported PTSD symptoms over time as measured by the PTSD checklist (PCL-5) but there were no treatment group differences; there was some indication that reduction in PTSD symptoms in the CPT group were sustained in contrast to the IDC group. Recruitment was significantly impacted by COVID-19 pandemic, so this study serves as a proof-of-concept pilot study. DISCUSSION AND CONCLUSIONS: Veterans with OUD and PTSD can safely and effectively participate in evidence-based therapy for PTSD; further work should confirm that trauma-focused treatment may be more effective in leading to sustained remission of PTSD symptoms than drug counseling. SCIENTIFIC SIGNIFICANCE: This is the first study to evaluate CPT for PTSD in the context of buprenorphine treatment for OUD.

The crosstalk between subjective fibromyalgia, mental health symptoms and the use of over-the-counter analgesics in female Syrian refugees: a cross-sectional web-based study.

Suboptimal fibromyalgia management with over-the-counter analgesics leads to deteriorated outcomes for pain and mental health symptoms especially in low-income countries hosting refugees. To examine the association between the over-the-counter analgesics and the severity of fibromyalgia, depression, anxiety and PTSD symptoms in a cohort of Syrian refugees. This is a cross-sectional study. Fibromyalgia was assessed using the patient self-report survey for the assessment of fibromyalgia. Depression was measured using the Patient Health Questionnaire-9, insomnia severity was measured using the insomnia severity index (ISI-A), and PTSD was assessed using the Davidson trauma scale (DTS)-DSM-IV. Data were analyzed from 291. Among them, 221 (75.9%) reported using acetaminophen, 79 (27.1%) reported using non-steroidal anti-inflammatory drugs (NSAIDs), and 56 (19.2%) reported receiving a prescription for centrally acting medications (CAMs). Fibromyalgia screening was significantly associated with using NSAIDs (OR 3.03, 95% CI 1.58-5.80, p = 0.001). Severe depression was significantly associated with using NSAIDs (OR 2.07, 95% CI 2.18-3.81, p = 0.02) and CAMs (OR 2.74, 95% CI 1.30-5.76, p = 0.008). Severe insomnia was significantly associated with the use of CAMs (OR 3.90, 95% CI 2.04-5.61, p < 0.001). PTSD symptoms were associated with the use of CAMs (ß = 8.99, p = 0.001) and NSAIDs (ß = 10.39, p < 0.001). Improper analgesics are associated with poor fibromyalgia and mental health outcomes, prompt awareness efforts are required to address this challenge for the refugees and health care providers.

Progesterone Attenuates the Stress Response in Individuals with Alcohol Dependence and Post-Traumatic Stress Disorder - A Pilot Study.

OBJECTIVE: Evidence from laboratory studies suggests that progesterone may be effective in reducing stress and craving, and may improve cognitive performance in smokers and individuals with cocaine dependence. The objective of this study was to examine if progesterone would attenuate stress-induced craving, anxiety, affect and physiological measures, as well as improve stress-induced cognitive performance (processing speed and selective attention) in individuals diagnosed with alcohol use disorder (AUD) and post traumatic stress disorder (PTSD). METHODS: This laboratory study included (n = 13) participants who were diagnosed with current AUD and PTSD who were randomly assigned to recive either progesterone (200mg bid) or placebo in identical looking capsules for 3 days. On the fourth day they completed a laboratory session. In the morning of the test session, they received the last dose of medication and completed the rest of the laboratory procedures. The procedures included presentation in random order of personalized trauma and neutral scripts with relaxation in between. Main outcomes included measure of craving, anxiety, affect and cognitive performance. RESULTS: Consistent with other research, trauma scripts produced significantly greater increases in craving, anxiety and negative affect when compared with neutral scripts. Progesterone significantly reduced stress-induced symptoms of craving, anxiety, fear, anger and sadness but had no effect on positive emotions (joy, relaxation). Progesterone was effective in ameliorating stress-induced decreases in cognitive performance. CONCLUSIONS: The findings from this study demonstrate that progesterone can be effective in reducing stress-induced craving, anxiety and negative affect in a laboratory setting in individuals with comorbid AUD and PTSD. Interestingly, progesterone also improved cognitive performance. These findings require replication in a larger clinical trial and may have implications for treatment among individuals with AUD and PTSD.This study was registered as NCT02187224, at www.clinicaltrials.gov.

Sertraline versus venlafaxine combined with psychotherapy in trauma-affected refugees - a follow-up study on a pragmatic randomised trial.

BACKGROUND: Research on long-term pharmacotherapy for trauma-affected refugees is scarce. The purpose of this follow-up study of a randomised trial was to investigate the effects of sertraline compared to venlafaxine in combination with psychotherapy, 6 and 18 months after end of trial. METHOD: The primary outcome was PTSD symptoms, measured by the Harvard Trauma Questionnaire (HTQ). The secondary outcomes included: Hopkins Symptom Checklist-25 (HSCL-25), somatisation items of the Symptoms Checklist-90 (SCL), pain on a visual analogue scale, well-being on the WHO-5, Sheehan Disability Scale, Hamilton Depression and Anxiety scales and Global Assessment of Functioning. Moreover, the shorter version of the Recent Life Events (IRLE) was adopted to obtain information regarding the patients' treatment and life events between the follow-up periods. RESULTS: Out of 195 patients eligible for intention-to-treat analyses during trial, 116 participated in the 6-month follow-up and 97 participated in the 18-month follow-up. The results of our intention-to-treat analyses revealed no significant long-term differences between the groups on the primary outcome assessing PTSD symptoms (HTQ). For the secondary outcomes significant differences were found at the 18-month follow-up in favour of venlafaxine assessing symptoms of anxiety, depression and somatisation (HSCL-25 and SCL), although only in intention-to-treat and not per-protocol analyses. CONCLUSIONS: No conclusions could be drawn due to conflicting results between our intention-to-treat and per-protocol analyses.

Astroglial Dysfunctions in Mood Disorders and Rodent Stress Models: Consequences on Behavior and Potential as Treatment Target.

Astrocyte dysfunctions have been consistently observed in patients affected with depression and other psychiatric illnesses. Although over the years our understanding of these changes, their origin, and their consequences on behavior and neuronal function has deepened, many aspects of the role of astroglial dysfunction in major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) remain unknown. In this review, we summarize the known astroglial dysfunctions associated with MDD and PTSD, highlight the impact of chronic stress on specific astroglial functions, and how astroglial dysfunctions are implicated in the expression of depressive- and anxiety-like behaviors, focusing on behavioral consequences of astroglial manipulation on emotion-related and fear-learning behaviors. We also offer a glance at potential astroglial functions that can be targeted for potential antidepressant treatment.

[Pharmacological treatment of posttraumatic stress disorder]. / Pharmakologische Behandlung der Posttraumatischen Belastungsstörung.

In addition to trauma-focussed psychotherapy, pharmacological treatment is often unavoidable, especially in patients with severe posttraumatic stress disorder (PTSD). As long as comorbid disorders do not dictate the pharmacotherapy approach, sertraline and paroxetine, along with other off-label prescribable substances approved in Germany, can be used for the treatment of PTSD. Venlafaxine, in particular, has shown good effectiveness in studies, whereas risperidone has shown lower effectiveness in augmentation. Overall, only a small to medium effect size is to be expected for all substances. Psychopharmacotherapy plays an important role in addressing sleep disorders, which are highly prevalent in PTSD. Treatment of trauma-related nightmares can be attempted with doxazosin or clonidine. In contrast, there are limited empirical data available for sleep disorders associated with PTSD, but the pharmacological treatment of insomnia can provide some guidance.

Temporal sequencing of change in trauma-related beliefs and therapeutic alliance during prolonged exposure and sertraline for chronic PTSD.

OBJECTIVE: Changes in trauma-related beliefs and therapeutic alliance have been found to temporally precede symptom reduction; however, it is likely these processes do not act in isolation but rather in interactive ways. METHODS: The present study examined the temporal relationships between negative posttraumatic cognitions (PTCI) and therapeutic alliance (WAI) in 142 patients who were part of a randomized trial comparing prolonged exposure (PE) to sertraline for chronic PTSD. RESULTS: Using time-lagged mixed regression models, improvements in the therapeutic alliance predicted subsequent improvements in trauma-related beliefs (d = 0.59), an effect accounted for by between-patient variability (d = 0.64) compared to within-patient variability (d = .04) giving weaker support to the causal role of alliance on outcome. Belief change did not predict improvements in alliance and neither model was moderated by treatment type. CONCLUSION: Findings suggest alliance may not be an independent driver of cognition change and point to the need for additional study of the impact of patient characteristics on treatment processes.

Heparin as a Potential Therapeutic Substance for Post-Traumatic Stress Disorder.

In sexually mature male Wistar rats with modeled post-traumatic stress disorder, personalized characteristics of neurobiological reactions in the population of predator-induced stress-resilient and stress-susceptible heparinized animals were determined. Characteristics of the systemic response of immune mechanisms, hypothalamic-pituitary-adrenal axis, behavioral manifestations, as well as basic properties of the CNS (excitation/inhibition) are presented. The study demonstrated encouraging positive results of the course administration of unfractionated heparin at a dose below the therapeutic and prophylactic doses. The inclusion of heparin drugs into the clinical practice for the treatment of post-traumatic stress disorder will not require large-scale clinical trials, because many effects of heparin as a nonspecific adaptogen are well studied. Moreover, these properties were confirmed at a higher technological level during the COVID-19 pandemic.

Prospective associations of psychedelic treatment for co-occurring alcohol misuse and posttraumatic stress symptoms among United States Special Operations Forces Veterans.

This study evaluated prospective associations of ibogaine and 5-MeO-DMT treatment for risky alcohol use and post-traumatic stress disorder (PTSD) symptoms among United States (US) Special Operations Forces Veterans (SOFV). Data were collected during standard clinical operations at pre-treatment and 1-month (1 m), 3-months (3 m), and 6-months (6 m) post-treatment in an ibogaine and 5-MeO-DMT treatment program in Mexico. Of the 86 SOFV that completed treatment, 45 met criteria for risky alcohol use at pre-treatment (mean age = 44; male = 100%; White = 91%). There was a significant reduction in alcohol use from pre-treatment (M = 7.2, SD = 2.3) to 1 m (M = 3.6; SD = 3.5) post-treatment, which remained reduced through 6 m (M = 4.0; SD = 2.9; p < .001, partial eta squared = .617). At 1 m, 24% were abstinent, 33% were non-risky drinking, and 42% were risky drinkers. At 6 m, 16% were abstinent, 31% were non-risky drinking, and 53% were risky drinkers. There were no differences between responders (abstinent/non-risky drinkers) and non-responders (risky drinkers) in demographics/clinical characteristics. However, there were significant and very large differences between responders and non-responders in PTSD symptom (p < .01, d = -3.26) and cognitive functioning change (p < .01, d = -0.99). Given these findings, future clinical trials should determine whether psychedelic-assisted therapy holds promise for individuals with complex trauma and alcohol misuse who have not been successfully treated with traditional interventions.

Sodium aescinate improve behavioral performance by inhibiting dorsal raphe nucleus NLRP3 inflammasome in Post-traumatic stress disorder Rat Model.

Growing evidence suggest that NLRP3 inflammasome activation in hippocampus and amygdala is involved in the pathophysiology of PTSD. Our previous studies have demonstrated that apoptosis of dorsal raphe nucleus (DRN) contributes to the pathological progression of PTSD. Recent studies by others have shown that in brain injury sodium aescinate (SA) has a protective effect on neurons by inhibiting inflammatory response pathways, thereby relieving symptoms. Here, we extend the therapeutic effects of SA to PTSD rats. We found that PTSD was associated with significant activation of the NLRP3 inflammasome in DRN, whereas administration of SA significantly inhibited DRN NLRP3 inflammasome activation and reduced DRN apoptosis level. SA also improved learning and memory ability and reduced anxiety and depression level in PTSD rats. In addition, NLRP3 inflammasome activation in DRN of PTSD rats impaired mitochondria function by inhibiting ATP synthesis and increasing ROS production, whereas SA can effectively reverse the pathological progression of mitochondria. We recommend SA as a new candidate for the pharmacological treatment of PTSD.

Age-related impairment in fear memory extinction is restored by ketamine in middle-aged mice.

Posttraumatic stress disorder (PTSD), a disabling and chronic condition after exposure to an extreme traumatic event, affects approximately 8% of the population worldwide. However, the underlying mechanisms of PTSD are not clear. The ability to manage fear memories is critical for PTSD. Differences in stress responsiveness and coping strategies by age represent an important starting point for the understanding and prevention of PTSD. However, we do not know whether the ability to cope with fear memories is decreased in middle-aged mice. To investigate this, we compared fear memory extinction among different age groups of mice. We found that middle-aged mice exhibited impaired fear memory extinction, which was accompanied by sustained enhanced long-term potentiation (LTP) induction in the extinction process. Most interestingly, ketamine treatment restored the impaired fear memory extinction in middle-aged mice. Moreover, ketamine could ameliorate the increased LTP during the extinction process through a presynaptic mechanism. Altogether, our results indicated that middle-aged mice were unable to extinguish fear memories, which could be treated with ketamine via presynaptic-mediated synaptic plasticity in middle-aged mice, suggesting that ketamine administration may be a new strategy for the treatment of PTSD.