Faculty Bibliography

Bipolar disorder is associated with increased mortality from cardiovascular disease, incidence of Metabolic Syndrome (MetS), and obesity. Adverse childhood experiences (ACEs) may contribute to this increased incidence, but findings have been mixed. We aimed to determine associations between ACEs and cardiometabolic risk markers in people with bipolar disorder, and how they change during pharmacological treatment. Data was analysed from 482 participants with bipolar disorder treated for 24 weeks with lithium or quetiapine, comparing those with and without ACEs across cardiometabolic markers. At baseline, those with ACEs had higher body mass indexes but were similar on all other cardiometabolic measures. During the 24-week treatment period, those with ACEs improved slightly more on continuous metabolic syndrome score (cMetS; p = .004), waist circumference, (p = .041) high density lipoproteins (HDL) cholesterol, (p = .028) and diastolic blood pressure (p = .042) than those without ACEs. Sensitivity analysis exploring the role of ACE type revealed that change in HDL was most strongly associated with sexual abuse; higher diastolic blood pressure with emotional abuse; and increased waist circumference with emotional and physical abuse, and higher cMetS with all three ACE types. There were almost no baseline differences in cardiometabolic markers between the ACE and no ACE groups. Those with ACEs seemingly benefitted more from psychiatric treatment regarding their cardiovascular health compared to the no ACE group. Future research should explore links between ACEs and cardiovascular health in those with bipolar disorder, including benefits of psychiatric treatment, the role of specific ACE types, and longer-term outcomes.

BACKGROUND/UNASSIGNED:We evaluated whether a large language model could assist in selecting psychopharmacological treatments for adults with treatment-resistant depression. METHODS/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.

BACKGROUND:Major depressive disorder (MDD) is a leading cause of disability worldwide, with available treatments often showing limited efficacy. Recent research suggests that targeting specific subtypes of depression and understanding the underlying brain mechanisms can improve treatment outcomes. This study investigates the potential of the potassium KCNQ (Kv7) channel opener ezogabine to modulate the resting-state functional connectivity (RSFC) of the brain's reward circuitry and alleviate depressive symptoms, including anhedonia, a core feature of MDD. METHODS:A double-blind, randomized, placebo-controlled clinical trial in individuals with MDD ages 18 to 65 years compared daily dosing with ezogabine (n= 19) with placebo (n = 21) for 5 weeks. Functional magnetic resonance imaging assessed RSFC of the brain's key reward regions (ventral caudate, nucleus accumbens) at baseline and posttreatment. Clinical symptoms were measured using the Snaith-Hamilton Pleasure Scale (SHAPS), Montgomery-Åsberg Depression Rating Scale (MADRS), and other clinical symptom scales. RESULTS:Ezogabine significantly reduced RSFC between the reward seeds and the posterior cingulate cortex (PCC)/precuneus compared with placebo, which was associated with a reduction in depression severity. Improvements in anhedonia (SHAPS) and depressive symptoms (MADRS) with ezogabine compared with placebo were also associated with decreased connectivity between the reward seeds and mid/posterior cingulate regions (midcingulate cortex, PCC, precuneus). CONCLUSIONS:The findings suggest that ezogabine's antidepressant effects are mediated through modulation of striatal-mid/posterior cingulate connectivity, indicating a potential therapeutic mechanism for KCNQ-targeted drugs for MDD and anhedonia. Future studies should validate these results in larger trials.

Up to half of individuals with depression do not respond to first-line treatments, possibly due to a lack of treatment interventions informed by neurobiology. A novel therapeutic approach for depression has recently emerged from translational work targeting aberrant activity of ventral tegmental area (VTA) dopamine neurons via modulation of the KCNQ voltage-gated potassium channels. In this study, individuals with major depressive disorder (MDD) with elevated anhedonia were randomized to five weeks of the KCNQ channel opener, ezogabine (up to 900 mg/day) or placebo. Participants completed functional MRI during a monetary anticipation task and resting-state at baseline and at end-of-treatment. The clinical results were reported previously. Here, we examined VTA activity during monetary anticipation and resting-state functional connectivity between the VTA and the ventromedial prefrontal cortex (mesocortical pathway) and ventral striatum (mesolimbic pathway) at baseline and end-of-treatment. Results indicated a significant drug-by-time interaction in VTA activation during anticipation (F_(1,34) = 4.36, p = 0.044), where VTA activation was reduced from pre-to-post ezogabine, compared to placebo. Mesocortical functional connectivity was also higher in depressed participants at baseline compared to a healthy control group (t₍₅₆₎ = 2.68, p = 0.01) and associated with VTA hyper-activity during task-based functional MRI at baseline (R = 0.352, p = 0.033). Mesocortical connectivity was also reduced from pre-to-post ezogabine, compared to placebo (significant drug-by-time interaction, F_(1,33) = 4.317, p = 0.046). Together this translational work is consistent with preclinical findings highlighting VTA hyper-activity in depression, and suggesting a mechanism of action for KCNQ channel openers in normalizing this hyper-activity in individuals with both depression and anhedonia.

Subjective cognitive impairment is a key symptom of major depressive disorder (MDD). Improvement of cognitive function in patients with treatment-resistant depression (TRD) is an important treatment outcome. This study compared the impact of augmenting antidepressants with aripiprazole or repetitive transcranial magnetic stimulation (rTMS) versus switching to venlafaxine (or duloxetine for those not eligible to receive venlafaxine) on cognition in TRD patients. In a pre-defined secondary analysis of a multi-site, open-label trial, patients with TRD were randomly assigned to aripiprazole augmentation, rTMS augmentation, or switching to venlafaxine XR/duloxetine in 1:1:1 ratio and they were treated for 8 weeks. Cognition was assessed using the Cognitive and Physical Functioning Questionnaire (CPFQ). A mixed-effects model with repeated measures was conducted. Among the 258 randomized subjects with at least one post-baseline CPFQ assessment (aripiprazole n = 91; rTMS = 70;venlfaxine XR/duloxetine = 97), neither aripiprazole nor rTMS demonstrated significant differences compared to the venlafaxine XR/duloxetine switch group in cognitive outcome as measured by CPFQ scale (p > 0.025). The mean (SE) change in CPFQ scores from baseline to Week 8 was -8.04 (0.77) (aripiprazole augmentation) versus -6.70 (0.75) (venlafaxine XR/duloxetine switch), and - 8.81 (0.64) (rTMS augmentation) versus -6.72 (0.55) (venlafaxine XR/duloxetine switch). Hedge's g values were 0.21 for aripiprazole augmentation versus switching to venlafaxine XR/duloxetine and 0.33 for rTMS augmentation versus switching to venlafaxine XR/duloxetine. Although rTMS augmentation did not reach a statistically significant difference in subjective cognitive improvement, it showed a larger effect size compared to aripiprazole augmentation. Our findings signal that rTMS augmentation may offer a well-tolerated strategy for improving cognition in TRD.

The mechanisms behind comorbid symptoms of depression in persons with epilepsy (PWE) remain largely unknown. Our study aimed to learn whether seizures moderate fluctuations in depressive symptoms in PWE when controlling for preictal symptoms of depression. We enrolled 57 adult PWE admitted to the New York University (NYU) Langone Epilepsy Monitoring Unit (EMU) from 2021 to 2024. Thirty-seven participants had a seizure. Twenty of the admitted patients did not have seizures during the admission period and therefore served as controls. All participants were seizure free for > 7 days prior to participation. Upon admission, all participants completed the Montgomery-Asberg Depression Rating Scale (MADRS) to evaluate baseline mood. The MADRS was repeated acutely (4-24 h post seizure or admission) and subacutely (2-7 days post seizure or discharge) for both groups. Linear regression models revealed that individuals with higher baseline MADRS scores (indicating higher depressive symptoms) experienced worse mood acutely post-seizure, while lower baseline MADRS scores were associated with acute mood improvement (R² = 0.59, p < 0.001). Experiencing a seizure was not associated with subacute mood outcomes, which were instead driven by acute mood state (R² = 0.56, p < 0.001). In conclusion, we found that seizures exacerbate pre-ictal depressive symptoms and that post-ictal depressive symptoms persist up to 7 days after seizure resolution. This study may provide evidence for a bidirectional relationship and demonstrate a vicious cycle between depression and epilepsy.

OBJECTIVE/UNASSIGNED:receptor antagonist ondansetron. The present study employed an experimental medicine approach to test the effects of 4 weeks of high-dose ondansetron compared to placebo on SP severity and brain connectivity in a cohort of individuals with OCD and/or Tourette's disorder. METHODS/UNASSIGNED:Of 51 participants who completed the study, 27 were assigned to receive 24 mg/day of ondansetron and 24 to receive placebo. Analyses examined changes in SP severity and, for participants with OCD, overall OCD severity from baseline to final visit. Functional MRI data were collected at both visits for analysis of intrinsic functional connectivity metrics characterizing global correlation (reflecting area "hubness") and local correlation (reflecting near-neighbor coherence). RESULTS/UNASSIGNED:There were no significant differences between ondansetron and placebo in the reduction of SP or overall OCD severity in the full sample. In a subsample of participants with OCD taking concomitant serotonin reuptake inhibitors (SRIs), ondansetron was associated with a significant decrease in overall OCD severity and global connectivity of the medial sensorimotor cortex compared with placebo. Longitudinal reductions in SP severity were related to decreases in right sensorimotor hubness in both groups, and to brainstem local coherence only in participants taking ondansetron. CONCLUSIONS/UNASSIGNED:There was no effect of high-dose ondansetron on SP. However, when used as an augmentation to SRIs, ondansetron reduced overall OCD severity, which may be related to changes in the "hubness" of the sensorimotor cortex. Ondansetron's ability to modulate brainstem connectivity may underlie its variable effectiveness in reducing SP.

Disruptions in sleep are common across clinical populations, particularly those with neurological and psychiatric disorders, making restorative sleep and sustained wakefulness a public health priority. Sleep is essential for brain function, impacting cognition in addition to serving as a critical factor in memory consolidation and healthy aging. Neuromodulation via transcranial photobiomodulation (t-PBM) increases cerebral mitochondrial activity and blood flow. These effects may underlie improvements in sleep quality and wakefulness observed after t-PBM. In this systematic review, we summarize the current literature across clinical and healthy populations, which describes t-PBM's potential to improve sleep, wakefulness, and cognition. The scope of this review also includes t-PBM's effect on the brain's glymphatic system and blood flow, the potential of this strategy to augment alertness, wakefulness, and associated cognitive processes, and the suggestion for targeted t-PBM application for future research based on the underlying neurobiological mechanisms of t-PBM and wakefulness across diverse clinical populations.