Because extinction forms the empirical foundation of exposure therapy, strategies to enhance extinction could lead to more effective interventions for post-traumatic stress disorder (PTSD). Here, we used functional MRI to compare immediate and long-term efficacy of enhanced versus standard extinction in 54 adults with (n=32) and without (n=22) PTSD. In both control and PTSD groups, counterconditioning—an enhanced form of extinction that replaces threat with positive outcomes—was more effective than standard extinction. It reduced threat-related neural activity and promoted reinstatement of safety (extinction) patterns in the ventromedial prefrontal cortex (a region involved in learning and retrieving safety associations). However, the PTSD group continued to reinstate both threat- and safety-related neural patterns in the dorsal anterior cingulate cortex (a region involved in learning and retrieving threat associations). These findings represent novel evidence that enhanced extinction outperforms standard extinction in promoting more rapid and persistent neural representations of safety in PTSD.

OBJECTIVE:Despite its widespread use for diagnosing and assessing the severity of posttraumatic stress disorder (PTSD) among youth, psychometric evaluation of the Clinician-Administered PTSD Scale for Children and Adolescents - DSM-5 (CAPS-CA-5) is limited to Portuguese- and Japanese-translated versions. Accordingly, the present study examined the reliability, validity, and diagnostic utility of the CAPS-CA-5 in an English-speaking, U.S. sample of trauma-exposed youth enrolled in the Texas Childhood Trauma Research Network (TX-CTRN). METHOD:A total of 3,134 trauma-exposed youth and young adults aged 8-20 completed an assessment battery in English comprising semi-structured diagnostic interviews and measures of acute stress symptoms, externalizing symptoms, depressive symptoms, resilience, and suicidality. The CAPS-CA-5 was administered at baseline and one-month follow-up. RESULTS:Consistent with the original CAPS-CA, internal consistency was adequate-to-strong for the total score and all subscales except Avoidance, and test-retest reliability was strong. The CAPS-CA-5 evidenced convergent validity with a positive PTSD screen on the MINI International Neuropsychiatric Interview for Children and Adolescents and with acute stress symptoms. Externalizing symptoms, depressive symptoms, resilience, and suicidality all evidenced discriminant validity with the CAPS-CA-5. Cutoff scores were evaluated using Receiver Operating Curves and diagnostic utility was supported through the ability of the CAPS-CA-5 to differentiate categories of functional impairment, which varied by age and sex. CONCLUSIONS:This study, the first to provide psychometric support for the English version of the CAPS-CA-5 in a U.S. sample, contributes to a growing body of literature supporting the CAPS-CA-5 as a psychometrically valid PTSD interview across a range of nationalities and languages.

OBJECTIVE:Obsessive-compulsive disorder (OCD) may be associated with elevated posttraumatic stress symptoms (PTSS) among trauma-exposed youth. However, it remains unclear to what extent this association varies based on resilience and trauma type (two factors reflecting protection and risk, respectively) over time. A prior study found that OCD was not significantly associated with longitudinal changes in PTSS among trauma-exposed youth. The present study represents a follow-up to that work by examining whether this association varies based on resilience and trauma type (interpersonal vs non-interpersonal) over time. METHOD:Participants were 1179 trauma-exposed youth ages 8-20 from the Texas Childhood Trauma Research Network who had complete PTSS data at baseline and the 1-, 6-, and 12-month assessments. Generalized estimating equations examined whether longitudinal changes in PTSS varied based on trauma type and resilience. RESULTS:At baseline, expected PTSS were highest among youth with OCD and interpersonal trauma and was approximately 2.4 times as severe as among youth without OCD who reported solely non-interpersonal trauma (MR = 2.42, p < .001). PTSS remained highest in the OCD × Interpersonal Trauma profile across all four assessments. However, resilience did not significantly moderate the association between OCD and PTSS (p = .509). CONCLUSIONS:Youth with co-occurring OCD and interpersonal trauma represent a clinically important subgroup with elevated PTSS. Resilience was associated with lower PTSS and slightly greater symptom improvement over time, but did not specifically buffer against the elevated PTSS associated with OCD.

Purpose: Substantial evidence supports the effectiveness of implanted Vagus Nerve Stimulation (VNS) in the management of unipolar difficult-to-treat depression (DTD). While the treatment is included in several national and international guidelines, there is limited information to guide clinicians regarding patient selection and use of VNS in clinical practice. Patients and Methods: A group of 32 experts in the use of VNS were identified from the main countries currently providing the treatment globally. A modified Delphi technique was used to document views on 55 statements regarding the goals, patient selection, and use of VNS treatment in routine clinical practice. Statements were rated on a 9-point Likert scale from "strongly disagree" to "strongly agree". Over the course of three rounds of voting, with statements modified based on anonymous comments from panelists, consensus agreement or disagreement was deemed if at least 75% of panel members scored a statement between 7 and 9, or 1 and 3, respectively. Results: Consensus was reached by the panel on 75% of the statements covering a wide range of issues. There was agreement that the main goals for VNS are long-term management of symptoms and improvement in quality of life, that the treatment is appropriate for all ages of patients and that there are few contraindications. Conclusion: A set of expert recommendations for the use of VNS for DTD was generated. These should be of value to clinicians to ensure current best practices are followed when considering this treatment.

Interest in psychedelic therapies is booming, with hundreds of studies in process. Despite the interest, there are no approved psychedelic treatments for any psychiatric condition. Further, the one large-scale development program using MDMA that reached the FDA was disapproved by the agency for reasons that could apply to clinical trials for classical psychedelics. We review the definitions of psychedelics, the current status of psychedelic therapies, conditions targeted, compounds under investigation, and the research/clinical strategies employed. Some treatment interventions include pharmacologically assisted psychotherapy, with both benefits and challenges associated with this strategy. There is debate about whether the psychedelic experience is a required fundamental element for therapeutic potential with the induced psychedelic state, rendering blinded clinical trials challenging. We address current societal issues, such as the deregulation of formerly illegal substances in some areas, that may affect development decisions. Our review also considers regulatory issues, including alternatives to blinded trials and whether some therapeutic targets, such as adjustment disorder, may pose hurdles if current regulatory standards are applied to these trials. The interest in psychedelic treatment is considerable, although the path forward has some complexities.

Objective:To quantify associations between childhood maltreatment and emerging major depressive disorder (MDD) in adolescents/young adults with and without a first-degree family history of bipolar I disorder. Method:A total of 116 youths 14 to 21 years old were classified into a high-risk group (n = 58) based on at least 1 first-degree relative diagnosed with bipolar I disorder and a low-risk group (n = 58) based on no first- or second-degree family history of bipolar disorder. Childhood maltreatment was assessed using the Childhood Trauma Questionnaire-Short Form (CTQ-SF). Psychiatric diagnoses were established with semistructured interviews. Logistic regression tested interactions between childhood maltreatment and familial risk, controlling for age and sex, as predictors of MDD. Results:Half of participants in the high-risk group exhibited current or past MDD compared with 24% of the low-risk group. Regression models showed that each 1-point increase in CTQ-SF total score was associated with a 7% increase in the odds of MDD (odds ratio [OR] = 1.07, 95% CI 1.01-1.17, p = .004). High-risk status conferred approximately 3 times greater odds of MDD vs low-risk status (OR = 3.04, 95% CI 1.14-8.43, p = .03). Each year of age increased risk of MDD by 34% (OR = 1.34, 95% CI 1.09-1.67, p = .01). The childhood maltreatment × familial risk interaction was not significant (p > .6). Conclusion:Childhood maltreatment and familial risk for bipolar I disorder independently increase the risk of MDD. Mitigating either risk factor independently could meaningfully reduce depression risk in at-risk youth. Diversity & Inclusion Statement:We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.

A premenopausal woman in her early 40s with debilitating symptoms of posttraumatic stress disorder (PTSD) and comorbid recurrent major depressive disorder (MDD) had received a diagnosis of PTSD a decade earlier, consequent to repeated childhood sexual abuse. To alleviate her symptoms, she had previously been treated with multiple medications across several classes (selective serotonin reuptake inhibitors, benzodiazepines, mood stabilizers) and had engaged in complementary and alternative therapies, including mindfulness meditation and acupuncture. She had also engaged in multiple psychotherapy modalities, such as eye movement and desensitization reprocessing therapy, group interpersonal therapy, and dialectical behavioral therapy. Despite these sundry treatments, she had not achieved any significant or lasting symptom improvement. After providing informed consent, the patient entered an open trial of brexanolone infusion for PTSD in women. She had score of 53 on the PTSD Checklist for DSM-5 (PCL-5) (consistent with a diagnosis of PTSD) and a score of 26 on the Montgomery-& Aring;sberg Depression Rating Scale (MADRS) (suggestive of moderate depression). She endorsed symptoms of reexperiencing, negative cognitions and emotions, avoidance, and hyperarousal. At baseline, immediately before initiation of the brexanolone infusion, her PCL-5 score was 51 and her MADRS score was 16. At the conclusion of the infusion (hour 60), her PCL-5 score had declined to 27 and her MADRS score to 11. She tolerated the infusion well. Symptom improvement lasted throughout the 12-week follow-up period. At her final visit, 12 weeks after infusion, her PTSD and MDD remained in remission (PCL-5 score, 15; MADRS score, 7), and she denied any residual side effects from the treatment.

Anhedonia is a highly prevalent core pathognomonic symptom of a major depressive episode seen in major depressive disorder (MDD) and bipolar disorder. The symptom is associated with functional impairment, increased suicidality, psychiatric and somatic comorbidity, and poor therapeutic outcomes. It is an understudied and undertreated symptom, without clinically practical scales to measure its different aspects, and there are no therapies specifically designed to target anhedonia. This expert consensus aims to increase the awareness and understanding of anhedonia among healthcare professionals (HCPs) and provide consensus recommendations on the assessment, management, and treatment of anhedonia in patients with MDD. A group (N=6) of psychiatrists formed an expert consensus group that convened in a teleconference meeting in January 2024 to develop 14 consensus statements that provide an overview of the assessment, management, and treatment of anhedonia in patients with MDD. Anhedonia is a highly prevalent symptom of MDD, and it includes anticipatory, consummatory, and cognitive aspects. Several tools exist to assess the specific components of anhedonia, and the neural circuitry mediating anhedonia continues to be elucidated. The expert opinions provided by the authors aim to increase HCP awareness and understanding of anhedonia, and improve the evaluation, management, and treatment of anhedonia in patients with MDD. HCPs should routinely evaluate all aspects of anhedonia using clinical scales and welcome novel treatments that meaningfully target anhedonia. Future studies should assess the effectiveness of treatments for anhedonia and improve measurement-based initial assessment and monitoring of outcomes with comprehensive tools.

Trauma exposure has been linked to increased risk for suicide, a leading cause of death among youth. To date, most research identifying trauma as a risk factor for suicidality has been based on cross-sectional studies. To understand if trauma confers prospective risk for suicidality, this study used two-year longitudinal data from youth with trauma histories enrolled in the Texas Childhood Trauma Research Network. We analyzed data from 2606 youth assessed at baseline, including 1252 with two-year follow-up data. Analyses included youth with and without Criterion A trauma. Linear mixed effect models were estimated to disentangle the effects of trauma on between- and within-subject changes in two dimensions of suicidality, Propensity for Suicide and Suicidal Thoughts. Results demonstrated evidence for small between-person effects of cumulative trauma load and Propensity for Suicide (Posterior Median [Mdn.] = 0.16, SD = 0.03, adjusted p < .001) and Suicidal Thoughts (Mdn. = 0.10, SD = 0.03, adjusted p < .001). Unexpectedly, there was also evidence for a negative within-person effect of cumulative trauma load changes on Propensity for Suicide, with the effect falling below the threshold for a small effect (Mdn. = -0.04, SD = 0.01, adjusted p = .012). Sensitivity analyses indicated that unintentional trauma exposure may have driven the within-person effect, whereas unintentional trauma and interpersonal trauma exposure consistently demonstrated positive between-person effects. These findings demonstrate the long-term impact of trauma exposure on increased risk for suicide and suicidal thoughts in youth. Clinical implications for reducing suicidality risk in trauma-exposed youth are discussed.

The burden of depressive and bipolar disorders at the individual and societal level are extraordinary and increasing. For decades, evidence-based treatments for these conditions have been established but outcomes amongst individuals with lived experience remains suboptimal. Notwithstanding calls to close gaps between current practice and best practice, there is an absence of evidence that overall health outcomes are significantly improving. Artificial Intelligence (AI) is the cornerstone of the digital revolution. Currently, AI sources (e.g., Open Source) are widely accessed by healthcare providers and persons with lived experience for search queries and decision support. The aspiration for AI-informed medical practice is to improve health outcomes by assisting in timely diagnostic detection, illness monitoring, informing treatment selection, integrating multimodality care, decreasing barriers to access and facilitating scalability to psychosocial interventions. Against this background, rigorous evidence is still needed to empirically demonstrate transformative improvement in each of the aforementioned areas. In addition, multiple ethical, technical, scientific and economic questions are not adequately answered including aspects of confidentiality and patient engagement. This short commentary endeavors to succinctly summarize the evidentiary base as it relates to the capabilities that AI offers currently, in the near and more intermediate term. The overarching aim is to provide readers with an up-to-date understanding of what aspects of AI are currently applicable versus those that are aspirational.

Major depressive disorder (MDD) is a common and debilitating condition with limited treatment precision. While brain imaging has linked neural features to MDD diagnosis and treatment response, the underlying circuits and their early modulation by treatment remain unclear. To examine changes in functional connectivity within the first two weeks of treatment, we analyzed two independent cohorts of MDD patients receiving antidepressants or placebo. Across patients, a visual-precuneus-thalamus network showed increased functional connectivity regardless of treatment arm or clinical outcome. Placebo response involved attention and striatal systems, while drug-specific effects were localized to the amygdala, mid-cingulate, orbitofrontal cortex, and cerebellum, emerging only in a subset of medicated patients. Notably, the responses of those without drug-specific changes can be predicted with a placebo response prediction model. These early functional connectivity changes reveal common and distinct mechanisms of treatment effects, offering insights that could inform more personalized interventions for MDD.