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IntroductionThe ongoing coronavirus disease 2019 (COVID-19) pandemic is a globally significant crisis with a rapid spread worldwide, high rates of illness and mortality, a high degree of uncertainty, and a disruption of daily life across the sociodemographic spectrum. The clinically relevant psychological consequences of this catastrophe will be long-lasting and far-reaching. There is an emerging body of empirical literature related to the mental health aspects of this pandemic and this body will likely expand exponentially. The COVID-19 pandemic is an example of a historic catastrophe from which we can learn much and from which the field will need to archive, interpret, and synthesize a multitude of clinical and research observations.MethodsIn this commentary, we discuss situations and contexts in which a diagnosis of posttraumatic stress disorder (PTSD) may or may not apply within the context of diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) criteria.ResultsOur consensus is that a COVID-related event cannot be considered traumatic unless key aspects of DSM-5's PTSD Criterion A have been established for a specific type of COVID-19 event (e.g., acute, life-threatening, and catastrophic).ConclusionThe application of a more liberal interpretation of Criterion A will dilute the PTSD diagnosis, increase heterogeneity, confound case-control research, and create an overall sample pool with varying degrees of risk and vulnerability factors.

Key Points: Question: Is verum acupuncture delivered over 12 to 15 weeks more efficacious than sham (minimal) needling for reducing posttraumatic stress disorder (PTSD) symptoms or fear-potentiated startle response in veterans with PTSD? Findings: In this randomized clinical trial including 93 participants, verum acupuncture resulted in a larger reduction in PTSD symptom severity than sham from the beginning to the end of treatment in both the intention-to-treat and treatment-completed models, and a larger reduction in fear-potentiated startle extinction after treatment. Meaning: The findings indicate that verum acupuncture had a large pretreatment to posttreatment effect and was clinically and statistically superior to sham needling for reducing PTSD symptoms and enhancing fear extinction. This randomized clinical trial assesses the effectiveness of verum vs sham acupuncture in reducing severity of symptoms in combat-related posttraumatic stress disorder. Importance: Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates. Acupuncture is an emerging intervention with positive preliminary data for PTSD. Objective: To compare verum acupuncture with sham acupuncture (minimal needling) on clinical and physiological outcomes. Design, Setting, and Participants: This was a 2-arm, parallel-group, prospective blinded randomized clinical trial hypothesizing superiority of verum to sham acupuncture. The study was conducted at a single outpatient-based site, the Tibor Rubin VA Medical Center in Long Beach, California, with recruitment from April 2018 to May 2022, followed by a 15-week treatment period. Following exclusion for characteristics that are known PTSD treatment confounds, might affect biological assessment, indicate past nonadherence or treatment resistance, or indicate risk of harm, 93 treatment-seeking combat veterans with PTSD aged 18 to 55 years were allocated to group by adaptive randomization and 71 participants completed the intervention protocols. Interventions: Verum and sham were provided as 1-hour sessions, twice weekly, and participants were given 15 weeks to complete up to 24 sessions. Main Outcomes and Measures: The primary outcome was pretreatment to posttreatment change in PTSD symptom severity on the Clinician-Administered PTSD Scale-5 (CAPS-5). The secondary outcome was pretreatment to posttreatment change in fear-conditioned extinction, assessed by fear-potentiated startle response. Outcomes were assessed at pretreatment, midtreatment, and posttreatment. General linear models comparing within- and between-group were analyzed in both intention-to-treat (ITT) and treatment-completed models. Results: A total of 85 male and 8 female veterans (mean [SD] age, 39.2 [8.5] years) were randomized. There was a large treatment effect of verum (Cohen d, 1.17), a moderate effect of sham (d, 0.67), and a moderate between-group effect favoring verum (mean [SD] Δ, 7.1 [11.8]; t90 = 2.87, d, 0.63; P =.005) in the intention-to-treat analysis. The effect pattern was similar in the treatment-completed analysis: verum d, 1.53; sham d, 0.86; between-group mean (SD) Δ, 7.4 (11.7); t69 = 2.64; d, 0.63; P =.01). There was a significant pretreatment to posttreatment reduction of fear-potentiated startle during extinction (ie, better fear extinction) in the verum but not the sham group and a significant correlation (r = 0.31) between symptom reduction and fear extinction. Withdrawal rates were low. Conclusions and Relevance: The acupuncture intervention used in this study was clinically efficacious and favorably affected the psychobiology of PTSD in combat veterans. These data build on extant literature and suggest that clinical implementation of acupuncture for PTSD, along with further research about comparative efficacy, durability, and mechanisms of effects, is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02869646 [ABSTRACT FROM AUTHOR]

Background: Effective pharmacologic treatments for comorbid alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are lacking. Kappa (κ) opioid receptor antagonists may address this unmet need. Buprenorphine is a κ‐opioid antagonist and a partial agonist of mu (μ) opioid receptors. Whereas naltrexone blocks all μ‐mediated effects combining it with buprenorphine yields a pharmacologic net effect of opioid receptor antagonism. Because no κ‐opioid receptor antagonist it available for clinical use, we tested this combination in a proof‐of‐concept study. Methods: Consenting participants were enrolled in a Phase II, multisite, double‐blind, randomized, placebo‐controlled trial evaluating the effectiveness of sublingual (SL) buprenorphine combined with extended‐release (XR) injectable naltrexone for the treatment of comorbid AUD and PTSD. Eligible participants (n = 75) were randomized (1:1:1) to receive either buprenorphine 2 mg/day plus naltrexone‐XR (n = 35), buprenorphine 8 mg/day plus naltrexone‐XR (n = 6) or SL plus injectable placebo (n = 34) for 12 weeks. The buprenorphine 8 mg/day plus naltrexone‐XR arm was dropped early in the trial due to the negative impact of COVID‐19 on enrollment. A binary primary outcome of response at week 8 was defined as a decrease from baseline of ≥10 points on the past week Clinician‐Administered PTSD Scale (CAPS‐5) and a reduction of ≥1 of past month alcohol risk level, as defined by the World Health Organization (WHO) and measured by the Timeline Follow‐Back. Results: Based on the results of a futility analysis, enrollment was stopped prior to reaching the initial goal of 90 participants. At the week eight primary timepoint, there were no statistically significant differences between buprenorphine plus naltrexone‐XR and placebo group for the primary composite outcome (OR = 0.63; p‐value = 0.52), or the subcomponents of the PTSD outcome (OR = 0.76; p‐value = 0.69) and AUD outcome (OR = 0.17; p‐value = 0.08). The placebo arm had a significantly higher proportion of participants with ≥1 WHO risk level reduction than the buprenorphine plus naltrexone‐XR arm (OR = 0.18, p value = 0.02). Conclusions: This is the first study to evaluate the potential of κ‐opioid receptor antagonism for the treatment of comorbid AUD and PTSD. The combination of buprenorphine and naltrexone‐XR showed no significant improvement over placebo for the composite, PTSD, or alcohol measures. [ABSTRACT FROM AUTHOR]

The purpose of this study was to analyze fear extinction and reinstatement in humans using fear-potentiated startle. Participants were fear conditioned using a simple discrimination procedure with colored lights as the conditioned stimuli (CSs) and an airblast to the throat as the unconditioned stimulus (US). Participants were extinguished 24 h after fear conditioning. Upon presentation of unsignaled USs after extinction, participants displayed significant fear reinstatement. In summary, these procedures produced robust fear-potentiated startle, significant CS+/CS- discrimination, within-session extinction, and significant reinstatement. This is the first demonstration of fear extinction and reinstatement in humans using startle measures.

Background: The transition to adulthood is a period of increased risk for emergent psychopathology; emerging adults with a childhood maltreatment history are at risk for poor outcomes. Method: Using a multi-measure, transdisciplinary, cross-sectional design, this study tested whether participant-reported positive parenting, a potential resilience-promoting factor, moderated the association between clinician-rated PTSD symptom severity and a transdiagnostic maladjustment biomarker, fear-potentiated startle (FPS), in a sample of 66 emerging adults (M years = 18.83, SD = 0.89) with a maltreatment history. We hypothesized that characteristics of effective parenting would moderate the relation between PTSD symptoms and FPS. Results: Results indicated that elevated PTSD, as measured by the CAPS, was associated with a more severe startle reaction. The magnitude of the increase in startle reactivity was moderated by parenting such that those with more positive parenting (Accepting [relative to rejecting]: b = −0.42, p <.001; Psychologically-controlling [relative to autonomy-promoting]: b = 2.96, p =.004) had significantly less reactivity across the task at higher levels of PTSD symptoms. Conclusions: Emerging adults with childhood maltreatment histories, high levels of PTSD symptoms, and who perceive present-day high-quality caregiver support may cope better with novel stressors relative to youth lacking that support, potentially translating to better psychological outcomes. [ABSTRACT FROM AUTHOR]

Summary: The COVID‐19 pandemic is a rare stressor that has precipitated an accompanying mental health crisis. Prospective studies traversing the pandemic's onset can elucidate how pre‐existing disease vulnerabilities augured risk for later stress‐related morbidity. We examined how pre‐pandemic sleep reactivity predicted maladaptive stress reactions and depressive symptoms in response to, and during, the pandemic. This study is a secondary analysis of a randomised controlled trial from 2016 to 2017 comparing digital cognitive behavioural therapy for insomnia (dCBT‐I) against sleep education (N = 208). Thus, we also assessed whether dCBT‐I moderated the association between pre‐pandemic sleep reactivity and pandemic‐related distress. Pre‐pandemic sleep reactivity was measured at baseline using the Ford Insomnia Response to Stress Test. In April 2020, participants were recontacted to report pandemic‐related distress (stress reactions and depression). Controlling for the treatment condition and the degree of COVID‐19 impact, higher pre‐pandemic sleep reactivity predicted more stress reactions (β = 0.13, ± 0.07 SE, p = 0.045) and depression (β = 0.22, ± 0.07 SE, p = 0.001) during the pandemic. Further, the odds of reporting clinically significant stress reactions and depression during the pandemic were over twice as high in those with high pre‐pandemic sleep reactivity. Notably, receiving dCBT‐I in 2016–2017 mitigated the relationship between pre‐pandemic sleep reactivity and later stress reactions (but not depression). Pre‐pandemic sleep reactivity predicted psychological distress 3–4 years later during the COVID‐19 pandemic, and dCBT‐I attenuated its association with stress reactions, specifically. Sleep reactivity may inform prevention and treatment efforts by identifying individuals at risk of impairment following stressful events. [ABSTRACT FROM AUTHOR]

Background: Although the prevalence of posttraumatic stress disorder (PTSD) is twice as high in women as it is in men, the role of estrogen in the risk for PTSD is not well understood. Deficits in fear inhibition and impaired safety signal learning may be biomarkers for PTSD. We examined menstrual cycle phase and serum estradiol levels in naturally cycling women while they were undergoing a novel conditioned inhibition procedure that measured their ability to discriminate between cues representing danger versus safety and to inhibit fear in the presence of safety cues. Methods: Sample 1 included healthy participants in whom we compared inhibition of fear-potentiated startle during the follicular (lower estrogen) and luteal (higher estrogen) phases of the menstrual cycle. We used the same paradigm in a traumatized clinical population (sample 2) in whom we compared low versus high estradiol levels. Results: In both samples, we found that lower estrogen in cycling women was associated with impaired fear inhibition. Limitations: In the clinical sample, the low estradiol group was on average older than the high estradiol group owing to the random recruitment approach; we did not exclude participants based on hormonal status or menopause. Conclusion: Our results suggest that the lower estrogen state during normal menstrual cycling may contribute to risk for anxiety disorders through dysregulated fear responses., Introduction Posttraumatic stress disorder (PTSD) is a severe anxiety disorder that may develop after exposure to a traumatic event. Women have a 2-fold greater risk for PTSD than men, (1-4) [...]

Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAPl) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single sNp in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD., PACAP was first isolated from ovine hypothalamic extracts based on its ability to stimulate cyclic AMP production in anterior pituitary cells (1). It is a highly conserved member of the [...]