Faculty Bibliography

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.

Obsessive-compulsive disorder (OCD) is chronic and impairing. While OCD often involves fear of harm or bad events, many patients experience "sensory phenomena," which are aversive sensory experiences that drive repetitive behaviors regardless of specific fears. Standard treatments do not effectively address sensory phenomena, and novel approaches are needed. Transcranial magnetic stimulation (TMS) is a safe and non-invasive neuromodulation technique increasingly used in psychiatric disorders, including OCD. This work presents a data-driven approach to identifying TMS brain targets for modulating sensory urges in OCD incorporating both behavioral and clinical criteria (Study 1) for a proof-of-concept investigation (Study 2). Study 1 included 69 individuals with OCD and 23 controls who completed an urges-for-action fMRI task involving instructed eyeblink suppression as an experimental model for sensory-based urges. Data-driven conjunction analysis revealed several brain regions, including the right postcentral gyrus, that were associated with more blink suppression failure (behavioral), more severe sensory phenomena (clinical), and were hyperactivated in OCD patients compared to controls. Study 2 administered single-session inhibitory TMS on 4 returning OCD patients using individualized targets within the postcentral gyrus identified from Study 1. Compared to sham, inhibitory TMS delivered to individualized postcentral gyrus targets resulted in fewer blink suppression failures, reduced activation in the target (postcentral gyrus) and key urge-related areas (insula, mid-cingulate), and greater reduction in self-reported urge to engage in OCD-related compulsions, with medium to large effect sizes. These findings demonstrate the potential of utilizing data-driven approaches incorporating behavioral and clinical criteria to target hard-to-treat sensory phenomena in OCD.

The impact of childhood abuse on the presentation of bipolar disorder could be further elucidated by comparing the networks of affective symptoms among individuals with and with no history of childhood abuse. Data from 476 participants in the Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study were used to fit several regularised Gaussian Graphical Models. Differences in the presentation of depressive and manic symptoms were uncovered: only among participants with a history of childhood abuse, inadequacy and pessimism were central symptoms in the network of depressive symptoms, while racing thoughts was an important symptom in the network of manic symptoms. Following network theory, focusing treatments at the symptom-level and on central symptoms - like inadequacy, pessimism, and racing thoughts - could be an effective approach for managing affective symptoms among the sizeable proportion of people with bipolar disorder who have experienced childhood abuse. This study contributes a thorough investigation of the networks of affective symptoms among participants with and with no history of childhood abuse, albeit limited by the use of a binary, self-report measure of childhood abuse, thereby emphasising the importance of assessing for childhood abuse and taking needed steps towards identifying novel targets for treating bipolar disorder.

This study aimed to evaluate the dose-dependent brain temperature effects of transcranial photobiomodulation (t-PBM). Thirty adult subjects with major depressive disorder were randomized to three t-PBM sessions with different doses (low: 50 mW/cm², medium: 300 mW/cm², high: 850 mW/cm²) and a sham treatment. The low and medium doses were administered in continuous wave mode, while the high dose was administered in pulsed wave mode. A 3T MRI scanner was used to perform proton magnetic resonance spectroscopy (¹H-MRS). A voxel with a volume of 30 × 30 × 15 mm³ was placed on the left prefrontal region. Brain temperature (°C) was derived by analyzing ¹H-MRS spectrum chemical shift differences between the water (~ 4.7 ppm) and N-acetyl aspartate (NAA) (~ 2.01 ppm) peaks. After quality control of the data, the following group numbers were available for both pre- and post-temperature estimations: sham (n = 10), low (n = 11), medium (n = 10), and high (n = 8). We did not detect significant temperature differences for any t-PBM-active or sham groups post-irradiation (p-value range = 0.105 and 0.781). We also tested for potential differences in the pre-post variability of brain temperature in each group. As for t-PBM active groups, the lowest fluctuation (variance) was observed for the medium dose (σ² = 0.29), followed by the low dose (σ² = 0.47), and the highest fluctuation was for the high dose (σ² = 0.67). t-PBM sham condition showed the overall lowest fluctuation (σ² = 0.11). Our ¹H-MRS thermometry results showed no significant brain temperature elevations during t-PBM administration.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

INTRODUCTION/BACKGROUND:The use of antidepressants in major depressive disorder (MDD) has been reported to influence long-term risk of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), but studies are conflicting. METHODS:We used inverse probability weighted (IPW) Cox models with time-varying covariates in a retrospective cohort study among midlife veterans with MDD within the US Veterans Affairs healthcare system from January 1, 2000 to June 1, 2022. RESULTS:A total of 35,200 patients with MDD were identified. No associations were seen regarding the effect of being exposed to any antidepressant versus no exposure on AD/ADRD risk (events = 1,056, hazard ratio = 0.94, 95% confidence interval: 0.81 to 1.09) or the exposure to specific antidepressant classes versus no exposure. A risk reduction was observed for female patients in a stratified analysis; however, the number of cases was small. DISCUSSION/CONCLUSIONS:Our study suggests that antidepressant exposure has no effect on AD/ADRD risk. The association in female patients should be interpreted with caution and requires further attention. HIGHLIGHTS/CONCLUSIONS:We studied whether antidepressant use was associated with future dementia risk. We specifically focused on patients after their first-ever diagnosis of depression. We used IPW Cox models with time-varying covariates and a large observation window. Our study did not identify an effect of antidepressant use on dementia risk. A risk reduction was observed in female patients, but the number of cases was small.

OBJECTIVE/UNASSIGNED:Few studies have focused on medical students and residents' mental health impact on medical residency selection (MRS) performance. The authors evaluated the association of performance in MRS with depressive and anxiety symptoms and with a reported psychiatric diagnosis (rPD). METHODS/UNASSIGNED:The authors enrolled candidates after the second round of MRS examinations at a Brazilian Medical School. Performance was assessed by final grade. Depressive and anxiety symptoms were assessed by the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) and the State-Trait Anxiety Inventory (STAI). The authors performed mediation analysis and multiple linear regression analysis to investigate the impact of rPD, state and trait anxiety, and depressive symptom severity on performance. RESULTS/UNASSIGNED:515 of the 643 MRS candidates (80.1%) participated in the study. Higher age, attending a preparatory course for MRS, rPD, and the number of MRS applications that year were associated with poorer performance. In mediation analysis, trait anxiety was associated with a direct effect on performance and an indirect effect mediated by rPD. CONCLUSION/UNASSIGNED:The data suggest that psychiatric diagnosis is associated with poorer performance on MRS, regardless of current symptoms of anxiety and depression. Additionally, increased levels of trait anxiety may negatively impact performance, directly and indirectly.