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Bipolar disorder is heterogeneous in phenomenology, illness trajectory, and response to treatment. Despite evidence for the efficacy of multimodal-ity interventions, the majority of persons affected by this disorder do not achieve and sustain full syndromal recovery. It is eagerly anticipated that combining datasets across various information sources (e.g., hierarchical "multi-omic" measures, electronic health records), analyzed using advanced computational methods (e.g., machine learning), will inform future diagnosis and treatment selection. In the interim, identifying clinically meaningful subgroups of persons with the disorder having differential response to specific treatments at point-of-care is an empirical priority. This paper endeavours to synthesize salient domains in the clinical characterization of the adult patient with bipolar disorder, with the overarching aim to improve health outcomes by informing patient management and treatment considerations. Extant data indicate that characterizing select domains in bipolar disorder provides actionable information and guides shared decision making. For example, it is robustly established that the presence of mixed features - especially during depressive episodes - and of physical and psychiatric comorbidities informs illness trajectory, response to treatment, and suicide risk. In addition, early environmental exposures (e.g., sexual and physical abuse, emotional neglect) are highly associated with more complicated illness presentations, inviting the need for developmentally-oriented and integrated treatment approaches. There have been significant advances in validating subtypes of bipolar disorder (e.g., bipolar I vs. II disorder), particularly in regard to pharmacological interventions. As with other severe mental disorders, social functioning, interpersonal/family relationships and internalized stigma are domains highly relevant to relapse risk, health outcomes, and quality of life. The elevated standardized mortality ratio for completed suicide and suicidal behaviour in bipolar disorder invites the need for characterization of this domain in all patients. The framework of this paper is to describe all the above salient domains, providing a synthesis of extant literature and recommendations for decision support tools and clinical metrics that can be implemented at point-of-care.

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

BackgroundNovel technologies make it possible to incorporate pharmacogenetic testing into the medical management of depression. However, previous studies indicate that there may be a subset of subjects who have concerns about genetic testing and may be psychologically vulnerable. If so, pharmacogenetic testing in depressed subjects could negatively impact their mental health and undermine treatment goals.MethodsIn this study, we developed a standardized instrument to assess motivations and attitudes around pharmacogenetic testing in a cohort of 170 depressed Veterans participating in a multi-center clinic trial.ResultsTesting reveals that subjects were largely positive about the use of genetic testing to guide pharmacological treatment and help plan their future. Most subjects showed only modest concerns about the impact on family, inability to cope with the results, and fear of discrimination. The severity of depression did not predict the concern expressed about negative outcomes. However, non-Caucasian subjects were more likely on average to endorse concerns about poor coping and fear of discrimination.ConclusionsThese data indicate that while the overall risk is modest, some patients with depression may face psychosocial challenges in the context of pharmacogenetic testing. Future work should identify factors that predict distress and aim to tailor test results to different populations.

BackgroundAccess to healthcare delivery programs and systems is a primary correlate to the overall health and well-being of Veterans and the general population. Participation in clinical research is a gateway to novel therapies that are intended to address current global health issues. Meeting or exceeding recruitment goals in clinical research is one of the key determinants of the timely and successful completion of a study. The travel and time burdens experienced by study participants are often considered barriers to their enrollment into clinical research. The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) established a consortium of nine VA medical centers (VAMCs) called the Network of Dedicated Enrollment Sites (NODES). The NODES program provides study site-level expertise and innovative approaches that address challenges to clinical research execution. In alignment with our mission, our program developed an approach to increase study participant access to clinical research through implementing "Mobile Recruitment (MoRe)" units. This manuscript describes the utility and challenges associated with employing this strategy to address three common barriers to clinical research participation: 1) research participant travel burden, 2) participant access to study opportunities, and 3) low participant enrollment.MethodsA plan to introduce the Mobile Recruitment (MoRe) unit as a recruitment strategy was piloted for a high-volume, observational cohort study and mega biobank in the VA health care system, the "Million Veteran Program (MVP)". MoRe is a recruitment strategy for CSP research integrating mobile technology and atypical research recruitment locations. Recruitment locations include primary or main VA hospitals and their assigned VA Community-Based Outpatient Clinics (CBOCs). Each Node site (n = 9) received components of the MoRe unit including a laptop, printer, portable cart with storage space, cooler/ice packs for specimen storage and transport. Each site's usage of these components varied based on its respective needs. Activities focused on both VA main facilities and CBOC facilities for recruitment.ResultsSeven of the nine Node sites compared the effectiveness of the MoRe unit on MVP study enrollment outcomes over three-time points: pre-intervention period, intervention period, and post-intervention period. The utilization of MoRe in the intervention period demonstrated a 36.9% increase in enrollment compared to the previous six months (pre-intervention period). There was a 2% enrollment increase at the six-month post-intervention period as compared to the intervention period. When comparing the pre-intervention period to the post-intervention period (duration of eighteen months), enrollment increased by 38.9%.ConclusionFive of the seven sites experienced an increase in enrollment during the intervention and post-intervention periods. The two sites without an increase in enrollment experienced various extenuating factors. Characteristics of sites using MoRe included the ability to utilize a smaller, unconventional space, i.e. not a traditional clinical research exam space for recruitment. MoRe was utilized in hospital laboratory space, CBOCs, primary care clinics, and other subspecialty clinics that allowed recruitment activities but did not have dedicated space to offer the research teams for that purpose. This initiative successfully demonstrated the benefit of deploying the unit, proving its utility in cases in where there was a lack of space or alternative workstations for research activities. The implementation of MoRe by NODES as a recruitment strategy for MVP may be transferable to other VA clinical research studies, as well as to other healthcare settings executing similar clinical research activities.

Mechanistically targeted behavioral interventions are a much-needed strategy for improving outcomes in depression, especially for vulnerable populations with comorbidities such as obesity. Such interventions may change behavior and outcome by changing underlying neural circuit function. However, it is unknown how these circuit-level modifications unfold over intervention and how individual differences in early circuit-level modifications may explain the heterogeneity of treatment effects. We addressed this need within a clinical trial of problem-solving therapy for participants with depression symptoms and comorbid obesity, focusing on the cognitive control circuit as a putative neural mechanism of action. Functional magnetic resonance imaging was applied to measure the cognitive control circuit activity at five time points over 24 months. Compared with participants who received usual care, those receiving problem-solving therapy showed that attenuations in cognitive control circuit activity were associated with enhanced problem-solving ability, which suggests that this circuit plays a key role in the mechanisms of problem-solving therapy. Attenuations in circuit activity were also associated with improved depression symptoms. Changes in cognitive control circuit activity at 2 months better predicted changes in problem-solving ability and depression symptoms at 6, 12, and 24 months, with predictive improvements ranging from 17.8 to 104.0%, exceeding baseline demographic and symptom characteristics. Our findings suggest that targeting the circuit mechanism of action could enhance the prediction of treatment outcomes, warranting future model refinement and improvement to pave the way for its clinical application. Editor's summary: Behavioral intervention therapies can improve symptoms of depression but do not work for all patients. To identify brain circuit changes that might underlie treatment response, Zhang et al. performed a longitudinal fMRI imaging study on patients with depression and comorbid obesity who received either problem-solving therapy (I-CARE) or usual care (U-CARE). They found that decreased cognitive control circuit activity measured at different time points over 24 months correlated with better treatment outcomes. A predictive model based on control circuit changes at 2 months outperformed a standard model based on demographic and clinical parameters. These results suggest an approach that could support treatment outcome predictions for depression, but further optimization and validation are needed. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

ImportanceLess than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant.ObjectiveTo determine the relative effectiveness and safety of 3 common alternate treatments for MDD.Design, setting, and participantsFrom December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks.InterventionsSwitch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase).Main outcomes and measuresThe primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects.ResultsAmong 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain.Conclusions and relevanceAmong a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.Trial registrationclinicaltrials.gov Identifier: NCT01421342.

Key Points: Question: Will a single psychedelic dose of psilocybin with psychotherapy demonstrate evidence for efficacy and/or safety in drug-free, treatment-resistant participants with bipolar II depression? Findings: In this nonrandomized open-label trial of 15 individuals with bipolar II depression, most participants met remission criteria on the Montgomery-Åsberg Depression Rating Scale 3 weeks after a single 25-mg psilocybin dose, and most remained in remission 12 weeks postdose with no increase in mania/hypomania symptoms or suicidality. Meaning: The findings suggest efficacy and safety of psilocybin in bipolar II depression and support further study of psychedelics in this population. This open-label nonrandomized open-label trial evaluates the safety and efficacy of single-dose psilocybin with psychotherapy for depressive episodes in individuals with bipolar disorder. Importance: Bipolar II disorder (BDII) is a debilitating condition frequently associated with difficult-to-treat depressive episodes. Psilocybin has evidence for rapid-acting antidepressant effects but has not been investigated in bipolar depression. Objective: To establish the safety and efficacy of psilocybin in patients with BDII in a current depressive episode. Design, Setting, and Participants: This was a 12-week, open-label nonrandomized open-label trial conducted at Sheppard Pratt Hospital. Participants aged 18 to 65 years with BDII, a current depressive episode longer than 3 months, and documented insufficient benefit with at least 2 pharmacologic treatments during the current episode were invited to participate. Of 70 approached, 19 met inclusion criteria and were enrolled. The trial was conducted between April 14, 2021, and January 5, 2023. Interventions: A single dose of synthetic psilocybin, 25 mg, was administered. Psychotropic medications were discontinued at least 2 weeks prior to dosing. Therapists met with patients for 3 sessions during pretreatment, during the 8-hour dosing day, and for 3 integration sessions posttreatment. Main Outcomes and Measures: The primary outcome measure was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Secondary measures included MADRS scores 12 weeks posttreatment, the self-rated Quick Inventory of Depression Symptoms-Self Rating (QIDS-SR), and the self-rated Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), each completed at baseline and all subsequent visits. Safety measures included the Columbia Suicide Severity Rating Scale (CSSRS) and the Young Mania Rating Scale (YMRS) completed at each visit. Results: Of the 15 participants in this study (6 male and 9 female; mean [SD] age, 37.8 [11.6] years), all had lower scores at week 3, with a mean (SD) change of −24.00 (9.23) points on the MADRS, (Cohen d = 4.08; 95% CI, −29.11 to −18.89; P <.001). Repeat measures analysis of variance showed lower MADRS scores at all tested posttreatment time points, including the end point (Cohen d = 3.39; 95% CI, −33.19 to −16.95; adjusted P <.001). At week 3, 12 participants met the response criterion (50% decrease in MADRS), and 11 met remission criterion (MADRS score ≤10). At the study end point, 12 patients met both response and remission criteria. QIDS-SR scores and Q-LES-Q-SF scores demonstrated similar improvements. YMRS and CSSRS scores did not change significantly at posttreatment compared to baseline. Conclusions and Relevance: The findings in this open-label nonrandomized open-label trial suggest efficacy and safety of psilocybin with psychotherapy in BDII depression and supports further study of psychedelics in this population. [ABSTRACT FROM AUTHOR]

Introduction: This study explored the current knowledge, attitudes, and clinical practices regarding psychedelics among mental health professionals in California, where state legislation to decriminalize psychedelics has been proposed. Method: Two hundred thirty‐seven mental health providers (74% female; mean age 54; 83% White; 46% psychologists) completed a 37‐item online survey between November 2021 and February 2022, disseminated through local and state‐wide professional organizations in California. Results: Providers endorsed limited knowledge about the risks and benefits of psychedelic use (M = 4.7 and 5.4, respectively, with 10 = high knowledge) and inadequate knowledge to counsel patients on use (45%). Gaps in knowledge related to psychedelic drug scheduling and current use in clinical research were identified. Providers expressed support for additional psychedelic research (97%), approval of recreational (66%) and medical (91%) psychedelic use, belief in the potential therapeutic benefits of psychedelics (89%), and concerns about safety (33%) and potential psychiatric risks (27%). Results indicated that most providers discuss psychedelic use with patients (73%), yet many do not feel comfortable addressing the effects of use (49%). There were significant correlations between knowledge and attitudes towards psychedelics (r = 0.2, p =.006; r = 0.31, p <.001) and attitudes and clinical practices (r = 0.34, p <.001). Conclusions: Findings suggest that providers are interested in psychedelic‐assisted treatments and hold favourable attitudes towards the therapeutic use of psychedelics yet lack the knowledge to appropriately counsel patients, highlighting the need for additional provider education about psychedelics. [ABSTRACT FROM AUTHOR]