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.

Major Depressive Disorder (MDD) affects millions globally, with approximately 30% of patients experiencing treatment-resistant depression (TRD). While ketamine has emerged as a rapid-acting intervention, response rates remain variable, underscoring the need to refine precision medicine approaches for ketamine treatment. Network theories of mental health disorders have been promoted as framework for better conceptualizing the structure of symptoms, as well as affording potential insights to bolster personalized treatment approaches. This study sought to leverage a network analytic approach to compare the symptom architecture and density of TRD patients who responded to ketamine treatment versus those who did not. In the current study, 447 patients receiving acute-phase intravenous ketamine or intranasal esketamine at the MGH Ketamine Clinic were included. Gaussian graphical models were estimated using the graphical LASSO method to derive pre- and post-treatment symptom networks (11 nodes) using the QIDS-SR-16. Network density and node centrality were compared between responders and non-responders using permutation-based Network Comparison Tests (NCT). Pre-treatment network density was significantly higher in non-responders (global strength = 4.03) compared to responders (global strength = 1.06; p < 0.01). Following treatment, the responder group showed a significant increase in network strength (to 2.66; p < 0.01), while non-responders showed a significant decrease (to 2.59; p < 0.05). Thus, patients with sparsely connected symptom networks at baseline appear more likely to benefit from ketamine, potentially because their symptoms are more amenable to reorganization. Pre-treatment network density serves as a potential correlate of treatment outcomes of ketamine for TRD.

Deficits in dopamine function cause alterations in episodic memory. Converging evidence implicates dopamine in postencoding hippocampal mechanisms inferred to support long-term memory, though there is a lack of direct evidence in humans. We address this gap using pharmacological functional MRI (fMRI) and positron emission tomography (PET). Using a motivated reward encoding task on and off oral methylphenidate, we tested whether individual differences in baseline dopamine ([11C]raclopride PET D2/3 receptor density) relate to drug-induced changes in hippocampal postencoding processes. Our study focused on healthy older adults, who are among those most vulnerable to memory decline and may benefit from pharmacologically enhancing dopamine. We found that methylphenidate administration was associated with improved memory performance relative to placebo for both high and low reward conditions. Older adults with high receptor density showed greater persistence of hippocampal multivoxel patterns into postencoding rest and stronger hippocampus-midbrain resting-state connectivity following encoding while on methylphenidate. These findings support the view that enhanced dopaminergic tone, verified through PET, directly modulates hippocampal postencoding dynamics in humans. Substantial variation in neurobiological effects was associated with individual differences in baseline dopamine function as older adults with high dopamine receptor density profiles showed preferential benefit of drug on hippocampal function, though these insights are qualified by null associations between memory performance and postencoding hippocampal activity. Individuals with lower dopamine receptor profiles showed preferential benefit of reward incentives suggesting altered sensitivity to extrinsic motivational factors depending on endogenous dopamine function.

OBJECTIVE:This study evaluated the long-term comparative effectiveness and safety of esketamine versus injectable ketamine and esketamine versus oral antidepressants for major depressive disorder (MDD). METHODS:This emulated target trial utilized observational data from a cohort of U.S. adults with MDD between 2018 and 2024. Patients were categorized into those receiving esketamine, injectable R,S-ketamine, and those with treatment-resistant depression (TRD) prescribed at least two classes of oral antidepressants. Esketamine initiators were matched to injectable R,S-ketamine initiators and to patients receiving oral antidepressants using propensity scores based on clinical and demographic factors. Outcomes included suicidal ideation or attempt, neuropsychiatric, and cardiovascular outcomes. Cox proportional hazards regression was used to estimate the risk of outcomes. RESULTS:A total of 4505 esketamine initiators, 197,694 injectable R,S-ketamine initiators, and 887,220 patients receiving oral antidepressant were included. After propensity score matching, compared with injectable R,S-ketamine initiators, esketamine initiators were associated with higher risks of suicidal ideation (HR = 1.24, 95% CI = 1.06-1.46), generalized anxiety disorder (HR = 1.55, 95% CI = 1.37-1.74), insomnia (HR = 1.25, 95% CI = 1.07-1.46), and cardiac arrest (HR = 1.57, 95% CI = 1.21-2.20). Compared with patients with TRD receiving oral antidepressants, esketamine initiators were associated with lower risks of suicidal ideation (HR = 0.89, 95% CI = 0.83-0.96), suicide attempt (HR = 0.71, 95% CI = 0.56-0.90), and generalized anxiety disorder (HR = 0.82, 95% CI = 0.74-0.91), but a higher risk of cardiac arrest (HR = 2.09, 95% CI = 1.50-2.91). CONCLUSION:Injectable R,S-ketamine demonstrated a more favorable safety and effectiveness profile than esketamine, whereas esketamine was associated with greater effectiveness but a higher risk of cardiac arrest compared with oral antidepressants. Head-to-head clinical trials are needed to validate these findings.

Clinical efficacy of deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) remains limited by the absence of objective neural biomarkers to guide targeting, programming, and longitudinal optimization of therapy. Using sensing-enabled DBS devices, we analyzed intracranial local field potentials recorded longitudinally from thirteen patients with treatment-refractory OCD implanted in the ventral capsule/ventral striatum (VC/VS). We identify the periodic component of alpha-band activity (7-14 Hz) as a robust electrophysiological correlate of OCD symptom severity. At the initial clinical evaluation, periodic alpha power explained inter-individual variance in symptom severity, and within individuals it tracked longitudinal symptom fluctuations during chronic treatment. Spatial mapping localized the source of this periodic alpha activity to the anterior external globus pallidus (GPe), aligning with stimulation contacts selected as therapeutically optimal during clinical monopolar review. Together, these findings identify anterior GPe alpha oscillations as a state-dependent and spatially specific biomarker of OCD severity, with direct implications for electrophysiology-informed DBS programming and the development of adaptive neuromodulation strategies.

Background Depression treatments aim to minimize symptom burden and optimize quality of life (QoL) and psychosocial function. Objective Compare the effects of adjunctive versus sham vagus nerve stimulation (VNS) on QoL and function in markedly treatment-resistant depression (TRD). Methods In this multicenter, double-blind, sham-controlled trial, 493 adults with TRD and ≥4 adequate but unsuccessful antidepressant treatment trials (current episode) were randomized to active (n = 249) or sham (n = 244) VNS (plus treatment as usual) over a 12-month observation period. Quarterly outcomes included QoL with the Q-LES-Q, Mini-Q-LES-Q, and EQ-5D-5L, and function with the WHODAS 2.0 and Work Productivity and Activity Impairment Questionnaire (WPAI) item 6. Differences between treatment groups in change in scores from baseline and percentage of time with a meaningful response in Q-LES-Q, Mini-Q-LES-Q, and WPAI item 6 scores were analyzed. Results Active VNS was superior to sham in mean change in scores from baseline in the Mini-Q-LES-Q (P = 0.050) and WPAI item 6 (health condition's effect on regular activities [P = 0.050]) used as continuous variables, with a similar trend for Q-LES-Q (P = 0.061). Active VNS was superior to sham in time spent in clinically meaningful benefit (categorical analyses) using the Q-LES-Q (P = 0.029), Mini-Q-LES-Q (P = 0.011), and WPAI item 6 (P = 0.039). The WHODAS 2.0 (P = 0.304) and EQ-5D visual analog scale (P = 0.125) failed to reveal between-group differences. Conclusion Active VNS was superior to sham VNS in improving QoL and psychosocial function in patients with TRD. VNS has a broader therapeutic impact than symptom improvement alone in patients with marked psychosocial impairment.

Background:We evaluated whether a large language model could assist in selecting psychopharmacological treatments for adults with treatment-resistant depression. Methods:We generated 20 clinical vignettes reflecting treatment-resistant depression among adults based on distributions drawn from electronic health records. Each vignette was evaluated by 2 expert psychopharmacologists to determine and rank the 5 best next-step pharmacologic interventions, as well as contraindicated or poor next-step treatments. Vignettes were then presented in random order, permuting gender and race, to a large language model (Qwen 2.5:7B), augmented with a synopsis of published treatment guidelines. Model output was compared to expert rankings, as well as to those of a convenience sample of community clinicians and an additional group of expert clinicians. Results:The augmented model prioritized the expert-designated optimal choice for 114/320 vignettes (35.6 %, 95 % CI 30.6 %-41.0 %; Cohen's kappa = 0.34, 95 % CI 0.28-0.39). There were no vignettes for which any of the model choices were among the poor or contraindicated treatments. Results were not meaningfully different when gender or race of the vignette was permuted to examine risk for bias. A sample of community clinicians identified the optimal treatment choice for 12/91 vignettes (13.2 %, 95 % CI: 7.7-21.6 %; Cohen's kappa = 0.10, 95 % CI 0.03-0.18), while an additional group of expert psychopharmacologists identified optimal treatment for 9/140 (6.4 %, 95 %CI: 3.4-11.8 %; Cohen's kappa = 0.03, 95 % CI 0.01-0.08). Conclusion:An augmented language model demonstrated moderate agreement with expert recommendations and avoided contraindicated treatments, suggesting potential as a tool for supporting complex psychopharmacologic decision-making in treatment-resistant depression.

The Probabilistic Reward Task (PRT) probes the impact of Major Depressive Disorder (MDD) on reinforcement learning (RL), but MDD also affects decision-making. We acquired PRT data from depressed adults twice, fit the data with decision-making and RL models, and studied model psychometrics.

Ketamine is effective as a treatment for treatment-resistant depression (TRD). Previous studies have demonstrated that depressed populations present altered electroencephalographic (EEG) power spectra and active auditory oddball (AAO) P300 event-related potential (ERP) components, suggesting aberrant cortical functioning. Moreover, studies have shown ketamine produces post-dose short-term EEG power spectra changes associated with an anti-depressant response. This exploratory study utilizes EEG to investigate the short and long-term impact of ketamine treatment on resting-state and AAO electrophysiological signals.

The neurobiological mechanisms underlying the placebo phenomenon in patients with major depressive disorder (MDD) remain largely unknown. The progressive rise in rates of placebo responses within clinical trials over the past two decades may impede the detection of a true signal and thus present a major obstacle in new treatment development. Understanding the mechanisms would have several important implications, including (1) identifying biomarkers of placebo responders (thereby identifying those individuals who could benefit therapeutically from such interventions), (2) opening new avenues for manipulating such mechanisms to maximize symptom reduction, and (3) refining treatments with approaches that decrease (in clinical trials) or increase (in clinical practice) the placebo response. Here we investigated the research question: is the dopaminergic system one of the neurobiological underpinnings of the placebo response within MDD? Inspired by preclinical and clinical findings that have implicated dopamine in the occurrence, prediction, and expectation of reward, we hypothesized that dopaminergic activity in the mesolimbic system is a critical mediator of placebo response in MDD. To test this hypothesis, we designed a double-blind, placebo-controlled, sequential parallel comparison design clinical trial aimed at maximizing placebo antidepressant response. We integrated behavioral, imaging, and hemodynamic probes of mesocorticolimbic dopaminergic pathways within the context of manipulations of psychological constructs previously linked to placebo responses (e.g., expectation of improvement). The aim of this manuscript is to present the rationale of the study design and to demonstrate how a cross-modal methodology may be utilized to investigate the role of reward circuitry in placebo response in MDD.

Despite decades of research on yoga and depression, subjective experiences of participants in these studies have rarely been reported, and never in individuals receiving heated yoga for depression. We examined patient-reported qualitative findings from an 8-week randomized controlled trial of heated yoga for depression. Eighty medically healthy participants with moderate-to-severe depression were randomized to 8 weeks of at least twice-weekly heated yoga classes, derived from Bikram yoga, or a waitlist control. Fifty-seven participants received a clinician-administered exit interview at intervention completion/study withdrawal. The exit interview assessed: (1) how participants felt immediately following the heated yoga sessions (acute effects), (2) what they liked or found helpful about heated yoga over the 8-week intervention (positive effects), and (3) what they disliked/did not find helpful over the 8-week intervention (negative effects). Qualitative data were analyzed using thematic analysis. Acute improvements in depressive symptoms (i.e., immediately following yoga) were the most commonly reported (n = 44, 77.2%), followed by overall positive effects on depressive symptoms (i.e., over the course of the 8-week intervention; n = 33, 57.9%), including improvements in sleep (n = 10, 17.5%), energy (n = 13, 22.8%), mood (n = 18, 31.6%), motivation (n = 2, 3.5%), and concentration/decision-making (n = 5, 8.8%). Overall negative effects (i.e., over the course of the 8-week intervention) included dislike of various aspects of the intervention (n = 19, 33.3%), such as instruction (n = 7, 12.3%), difficulty (n = 7, 12.3%), repetitiveness (n = 3, 5.3%), class length (n = 2, 3.5%), and boredom (n = 7, 12.3%). Most participants reported both overall positive and negative effects (n = 37, 64.9%). Of the rest, 19 (33.3%) reported only overall positive effects, and 1 (1.8%) reported only overall negative effects. Most participant experiences were positive. Negative effects were less common and primarily involved dislike of different aspects of the heated yoga. The findings support strong acceptability and subjective improvement in depressive symptoms in depressed individuals.

The Probabilistic Reward Task (PRT) is widely used to investigate the impact of Major Depressive Disorder (MDD) on reinforcement learning (RL), and recent studies have used it to provide insight into decision-making mechanisms affected by MDD. The current project used PRT data from unmedicated, treatment-seeking adults with MDD to extend these efforts by: (1) providing a more detailed analysis of standard PRT metrics—response bias and discriminability—to better understand how the task is performed; (2) analyzing the data with two computational models and providing psychometric analyses of both; and (3) determining whether response bias, discriminability, or model parameters predicted responses to treatment with placebo or the atypical antidepressant bupropion. Analysis of standard metrics replicated recent work by demonstrating a dependency between response bias and response time (RT), and by showing that reward totals in the PRT are governed by discriminability. Behavior was well-captured by the Hierarchical Drift Diffusion Model (HDDM), which models decision-making processes; the HDDM showed excellent internal consistency and acceptable retest reliability. A separate “belief” model reproduced the evolution of response bias over time better than the HDDM, but its psychometric properties were weaker. Finally, the predictive utility of the PRT was limited by small samples; nevertheless, depressed adults who responded to bupropion showed larger pre-treatment starting point biases in the HDDM than non-responders, indicating greater sensitivity to the PRT’s asymmetric reinforcement contingencies. Together, these findings enhance our understanding of reward and decision-making mechanisms that are implicated in MDD and probed by the PRT.

Importance Bipolar disorder affects approximately 8 million adults in the US and approximately 40 million individuals worldwide. Observations Bipolar disorder is characterized by recurrent episodes of depression and mania or hypomania. Bipolar depressive episodes are similar to major depressive episodes. Manic and hypomanic episodes are characterized by a distinct change in mood and behavior during discrete time periods. The age of onset is usually between 15 and 25 years, and depression is the most frequent initial presentation. Approximately 75% of symptomatic time consists of depressive episodes or symptoms. Early diagnosis and treatment are associated with a more favorable prognosis. Diagnosis and optimal treatment are often delayed by a mean of approximately 9 years following an initial depressive episode. Long-term treatment consists of mood stabilizers, such as lithium, valproate, and lamotrigine. Antipsychotic agents, such as quetiapine, aripiprazole, asenapine, lurasidone, and cariprazine, are recommended, but some are associated with weight gain. Antidepressants are not recommended as monotherapy. More than 50% of patients with bipolar disorder are not adherent to treatment. Life expectancy is reduced by approximately 12 to 14 years in people with bipolar disorder, with a 1.6-fold to 2-fold increase in cardiovascular mortality occurring a mean of 17 years earlier compared with the general population. Prevalence rates of metabolic syndrome (37%), obesity (21%), cigarette smoking (45%), and type 2 diabetes (14%) are higher among people with bipolar disorder, contributing to the risk of early mortality. The annual suicide rate is approximately 0.9% among individuals with bipolar disorder, compared with 0.014% in the general population. Approximately 15% to 20% of people with bipolar disorder die by suicide. Conclusions and Relevance Bipolar disorder affects approximately 8 million adults in the US. First-line therapy includes mood stabilizers, such as lithium, anticonvulsants, such as valproate and lamotrigine, and atypical antipsychotic drugs, such as quetiapine, aripiprazole, asenapine, lurasidone, and cariprazine.

Recent observations suggest a role of the volume of the cerebral ventricle volume, corpus callosum (CC) segment volume, in particular that of the central-anterior part, and choroid plexus (CP) volume for treatment resistance of major depressive disorder (MDD). An increased CP volume has been associated with increased inflammatory activity and changes in the structure of the ventricles and corpus callosum. We attempt to replicate and confirm that these imaging markers are associated with clinical outcome in subjects from the EMBARC study, as implied by a recent pilot study. The EMBARC study is a placebo controlled randomized study comparing sertraline vs. placebo in patients with MDD to identify biological markers of therapy resistance. Association of baseline volumes of the lateral ventricles (LVV), choroid plexus volume (CPV) and volume of segments of the CC with treatment response after 4 weeks treatment was evaluated. 171 subjects (61 male, 110 female) completed the 4 week assessments; gender and age were taken into account for this analyses. As previously reported, no treatment effect of sertraline vs. placebo was observed, therefore the study characterized prognostic markers of response in the pooled population. Change in depression severity was identified by the ratio of the Hamilton-Depression rating scale 17 (HAMD-17) at week 4 divided by the HAMD-17 at baseline (HAMD-17 ratio). Volumes of the lateral ventricles and choroid plexi were positively correlated with the HAMD-17 ratio, indication worse outcome with larger ventricles and choroid plexus volumes, whereas the volume of the central-anterior corpus callosum was negatively correlated with the HAMD-17 ratio. Responders (n = 54) had significantly smaller volumes of the lateral ventricles and CP compared to non-responders (n = 117), whereas the volume of mid-anterior CC was significantly larger compared to non-responders (n = 117), confirming our previous findings. In an exploratory way associations between enlarged LVV and CPV and signs of lipid dysregulation were observed. In conclusion, we confirmed that volumes of lateral ventricles, choroid plexi and the mid-anterior corpus callosum are associated with clinical improvement of depression and may be indicators of metabolic/inflammatory activity.

Objective: To evaluate feasibility, acceptability, and preliminary efficacy of heated yoga to treat moderate-to-severe depression. Design: An 8-week randomized controlled trial (RCT) of heated yoga versus waitlist control was conducted from March 2017 to August 2019. Methods: Participants in the yoga condition were asked to attend heated yoga classes at 2 community heated yoga studios at least twice weekly. We assessed acceptability and feasibility using exit interview and attendance data, respectively. The primary intervention efficacy outcome variable was change in the Inventory of Depressive Symptomatology-Clinician Rated (IDS-CR) score from baseline to post-intervention (week 8). Results: We randomized 80 participants and included 65 (mean [± SD] age 32.7 [± 11.7] years; 81.5% female) in the analyses (yoga n = 33, waitlist n = 32). The mean IDS-CR score at baseline was 35.6 (± 7.9) for the full sample, 36.9 (± 8.8) for yoga participants, and 34.4 (± 6.7) for waitlist participants. Participants attended an average of 10.3 (± 7.1) total classes over the 8-week intervention period. Yoga participants had a significantly greater pre- to post-intervention reduction in IDS-CR scores than waitlist participants (Cohen d = 1.04, P < .001). More yoga participants (59.3%; n = 16) than waitlist participants (6.3%; n = 2) evidenced larger treatment responses (IDS-CR ≥ 50% decrease in symptoms). Participants rated the heated yoga and its aftereffects positively in exit interviews. Conclusions: Approximately 1 heated yoga session per week (mean of 10.3 classes over 8 weeks) was associated with significantly greater reduction in depression symptoms than a waitlist control. Participants rated heated yoga positively. Taken together, results suggest feasibility, acceptability, and preliminary efficacy for patients with depression and warrant further research using active control conditions. Trial Registration: ClinicalTrials.gov identifier: NCT02607514.