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.

Major depressive disorder (MDD) is a severe and debilitating illness. Despite the available treatments, clinical outcomes remain suboptimal, and hence, it is crucial to identify predictive factors for response. This is a secondary analysis investigating the relationship between treatment preference and response to treatment in the antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) trial (NCT02977299) comparing three treatment arms [aripiprazole augmentation, repetitive transcranial magnetic stimulation (rTMS) augmentation, switching to venlafaxine XR or duloxetine] in MDD patients with treatment-resistant depression (TRD) who are currently on ongoing, stable, and adequate antidepressant therapy. Patient treatment preferences were recorded in the study entry. In total, 278 subjects were randomly assigned to one of three treatment groups: aripiprazole (n = 92), rTMS (n = 70), or venlafaxine/duloxetine (n = 98). Of these 278 subjects, 256 (92.1%) had at least one postbaseline Montgomery-Asberg Depression Rating Scale (MADRS) score and a recorded treatment preference and were included in this secondary analysis. In the total population, participants' preferences did not affect their response to treatment, and the change in MADRS score was similar among patients who received their preferred treatment, had no preference, or received treatment against their preference (P = 0.49). These results indicate that patient preference is not a significant factor that predisposes to optimal treatment outcomes.

The locus coeruleus (LC) plays important roles in sleep/wake regulation and cognitive functions. LC neurons may be particularly sensitive to neural injury and serve as an early site of accumulation pathological tau in Alzheimer's disease. Obstructive sleep apnea (OSA) creates both chronic intermittent hypoxia and sleep fragmentation as potential insults to differentially sensitive neural populations including the locus coeruleus (LC). Using high field 7T imaging in cognitively normal older adults, we demonstrate that time spent with an oxygen saturation below 90% (T90), a measure of OSA's hypoxic burden, inversely correlates with LC structural integrity and explains significant variance in LC structural integrity after controlling for age, sex, and BMI. In contrast, other sleep variables such as the apnea-hypopnea index (AHI), total sleep time, and sleep efficiency did not contribute significant variance in LC structural integrity in this model. Thus, in the diagnosis of OSA, attention to hypoxic burden variables may be important in risk stratification for LC neural injury. This observation may inform future work determining whether mitigation of the hypoxemic burden from OSA can slow deterioration in LC integrity.

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.