Faculty Bibliography

BACKGROUND:Transcranial photobiomodulation (t-PBM) with near-infrared light stimulates mitochondria and may have antidepressant effects. We evaluated dose-dependent effects of t-PBM on the hemodynamic blood-oxygenation-level-dependent (BOLD) power in major depressive disorder (MDD). METHODS:. t-PBM (808 nm) was delivered to the prefrontal cortex, bilaterally. fMRI was recorded at 3T before, during, and after t-PBM. We used mixed-effects linear regression to evaluate changes in BOLD power during stimulation, compared to sham. The analysis was repeated for the middle frontal gyrus (MFG), the prefrontal areas irradiated by t-PBM, and the entire brain cortex. RESULTS:We found similar results in the MFG, the prefrontal cortex directly irradiated, and the entire brain cortex: medium dose t-PBM was associated with a statistically significant increase in BOLD power, whereas low dose t-PBM was associated with a significant decrease in BOLD. There were no significant changes in BOLD power with the high (pulsed) t-PBM dose or with sham. Single administrations of any t-PBM dose did not result in significant changes in depression severity (versus sham). All 3 t-PBM doses were well tolerated. CONCLUSION/CONCLUSIONS:The acute effect of t-PBM on the hemodynamic BOLD power is robust, dose-dependent, bidirectional, and extends beyond the areas directly illuminated. These findings may provide a reference for future dose selection and clinical efficacy studies. CLINICALTRIALS/RESULTS:GOV: NCT04366258.

BACKGROUND:Previous studies have demonstrated that gender role nonconformity (GRNC) is associated with negative psychological consequences, but that discrimination, bullying, and homophobic stigmatization are mechanisms through which GRNC impacts psychological health. In this secondary analysis, we test the hypothesis that people reporting higher levels of GRNC will experience increased sexual dysfunction, and that social support will act as an indirect mechanism. METHODS:We analyzed data from 781 participants from the Nathan Kline Institute Rockland Sample, performed quantile regression analyses to assess the relationships among social support, GRNC, and sexual dysfunction (while controlling for age, sex, sexual orientation, and socioeconomic status) and used a mediation analysis to explore social support as a mediator of the effect of GRNC on sexual dysfunction. RESULTS:GRNC significantly positively predicted sexual dysfunction and social support significantly predicted sexual dysfunction in the opposite direction. The indirect effect of GRNC via social support was also significant, suggesting that social support is a salient mechanism through which GRNC affects sexual dysfunction. CONCLUSIONS:We concluded that GRNC significantly predicts sexual dysfunction, and that social support significantly mediates this relationship. Although GRNC is associated with negative psychological and sexual consequences, the impacts appear to be mediated by the structure and quality of social relationships.

IMPORTANCE/UNASSIGNED:Individuals with mood and psychotic disorders are at an increased risk for dementia. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of antidiabetic medications with mitochondrial and metabolic properties, may offer protective benefits. OBJECTIVE/UNASSIGNED:To evaluate whether treatment with SGLT2 inhibitors is associated with reduced risk of incident dementia and other neuropsychiatric outcomes in patients with psychiatric disorders. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study used a target trial emulation design and data from the US Department of Veterans Affairs databases from January 1, 2016, to June 1, 2024. Participants were 65 years or older with a diagnosis of major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder but without prior dementia diagnosis at baseline or history of SGLT2 inhibitor use. Analyses used marginal structural models weighted by inverse probability of treatment and censoring. INTERVENTIONS/UNASSIGNED:Initiation and noninitiation of SGLT2 inhibitor were calculated using intention-to-treat (ITT) analysis, and sustained and nonsustained use of SGLT2 inhibitor for ≥3 months were estimated using per-protocol (PP) analysis. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was incident all-cause dementia, as defined by International Classification of Diseases-coded diagnoses. Secondary outcomes were time to psychiatric emergency department (PED) visit and time to psychiatric hospitalizations. Covariates included demographic characteristics, comorbidities, psychiatric diagnoses, and medication use. RESULTS/UNASSIGNED:In total, there were 112 725 individuals in the sample, of whom 7631 (6.8%) were exposed to an SGLT2 inhibitor. The sample had a median (IQR) age of 74.1 (69.7-77.6) years and predominantly consisted of males (104 818 [92.8%]); 49.3% of the patients had obesity. In the ITT analysis, SGLT2 inhibitor use was associated with reduced odds of all-cause dementia (odds ratio [OR], 0.61; 95% CI, 0.52-0.73) and PED visits (OR, 0.80; 95% CI, 0.66-0.97) but not psychiatric hospitalizations (OR, 0.68; 95% CI, 0.44-1.04). In the PP analysis, SGLT2 inhibitor use was associated with lower odds of all-cause dementia (OR, 0.54; 95% CI, 0.40-0.73) and psychiatric hospitalizations (OR, 0.56; 95% CI, 0.31-1.00) but not PED visits (OR, 0.74; 95% CI, 0.53-1.05). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study of older adults with mood and psychotic disorders, SGLT2 inhibitor use was associated with lower risk of dementia and PED visits. The results support a neuroprotective role of SGLT2 inhibitors in a high-risk psychiatric population.

Panic provocation tests have been widely used to investigate the biological underpinnings of panic disorder (PD). However, their diagnostic specificity remains uncertain, as several agents can also induce panic-like reactions in healthy individuals. This meta-analysis estimated and compared diagnostic odds ratios (DORs) across different provocation methods. Random-effects meta-analyses were conducted using the Hartung-Knapp adjustment. Based on 123 studies including 5693 participants, sodium lactate infusion showed the highest pooled DOR (24.77, 95% CI 19.03-32.25, GRADE certainty = High), followed by isoproterenol (18.85, 95% CI 12.39-28.66, GRADE certainty = Moderate), cholecystokinin tetrapeptide (CCK-4; 15.03, 95% CI 7.83-28.84, GRADE certainty = Moderate), meta-chlorophenyl piperazine (m-CPP; 14.51, 95% CI 4.67-45.07, GRADE certainty = Low), caffeine (14.11, 95% CI 4.79-41.54, GRADE certainty = Moderate), hyperventilation (11.89, 95% CI 6.51-21.73, GRADE certainty = High), carbon dioxide inhalation (CO₂; 11.12, 95% CI 8.63-14.32, GRADE certainty = High), and yohimbine (7.87, 95% CI 1.12-55.13, GRADE certainty = Very low). Breath holding, fenfluramine and flumazenil did not demonstrate statistically significant discriminative ability. Meta-regression analysis confirmed that sodium lactate yielded significantly higher DORs than m-CPP, hyperventilation, CO₂, fenfluramine, flumazenil, and yohimbine. No substantial between-study heterogeneity or publication bias was identified across the pooled analyses. These findings suggest that provocation methods targeting acid-base balance, especially sodium lactate infusion, are associated with superior diagnostic discrimination between individuals with PD and healthy controls.

The decisional reference point, the central mechanism underlying behavioral economics, conditions our evaluations of all reinforcers. Whether a given event is experienced as positive or negative depends on this reference point. A pathological elevation of the reference point would lead a person to experience once pleasurable activities as negative reinforcers. Thus, it has been hypothesized that a reference point pathology may play a critical role in the symptomology of major depressive disorder (MDD). Here, we test the hypothesis that the reference point is pathologically elevated and dynamically inflexible in patients suffering with MDD compared to healthy controls. We find that depression is associated with a significant elevation of the reference point, and the magnitude of this elevation correlates with disease severity. The ability of patients with MDD to dynamically adjust their reference point to the environment is also dysfunctional. Our findings link the previously demonstrated treatment of depression by deep brain stimulation to modulation of the reference point in the anterior cingulate cortex and identify pathology in the dynamics of reference point setting as a potential cognitive mechanism in the disorder. Finally, these results reveal that a three-minute video game-like task measuring the reference point strongly correlates with depression severity. After further testing for clinical validity, this rapid assay may serve as a potential tool for assessing and monitoring depression.

There is a lack of consensus in the field about the indefinite use of psychostimulants for adult ADHD and the circumstances under which their deprescribing warrants consideration. To address this gap in knowledge, the American Society of Clinical Psychopharmacology (ASCP) convened a Task Force on the deprescribing of psychotropic medications, including stimulant medications for adult ADHD, which entailed a focused literature review and 2-round Delphi survey querying 45 international psychopharmacology experts on factors related to deprescribing. Consensus (≥75% agreement, defined by endorsements of "strongly agree" or "moderately agree") was reached on 10 of 11 (91%) Delphi statements. Survey responses plus literature review suggest that stimulant deprescribing may be appropriate when 1) the diagnosis of ADHD is deemed incorrect upon reevaluation unless another stimulant-responsive condition is evident; 2) cognitive complaints have other more likely etiologies for which stimulant medications are inappropriate; 3) cognitive benefits are absent; 4) stimulant medications exacerbate medical or other psychiatric comorbidities; 5) adverse effects, if present, are non-remediable; 6) stimulant medications are misused; and 7) untreated comorbid non-cannabis substance use disorders are present. Panelists just fell short of consensus in perceiving regular use of cannabis as an insufficient reason to deprescribe stimulant medications in adult ADHD patients. In sum, clinical circumstances and rationales can be identified that support decisions to deprescribe stimulant medications for adult ADHD. Deliberate stimulant misuse or abuse, comorbid medical or psychiatric contraindications, and diagnostic inaccuracy pose strong reasons to consider deprescribing stimulants, potentially in favor of alternative pharmacotherapies and psychotherapies for adult ADHD.

OBJECTIVE:Anxious depression is a negative prognostic factor linked to worse outcomes in major depressive disorder (MDD). However, its role in treatment-resistant depression (TRD) remains unclear. This secondary analysis of the ASCERTAIN-TRD trial investigates the role of anxious depression as a predictor or moderator of treatment response. METHODS:A Hamilton Depression Rating Scale Anxiety and Somatization Subscale score of at least 7 identified subjects with the anxious depressive subtype. Treatment response was evaluated based on changes in Montgomery-Asberg Depression Rating Scale scores using mixed-effects models with repeated measures and included additional terms accounting for the presence or absence of anxious depression. Two hundred fifty-three patients, who had at least one post-baseline Montgomery-Asberg Depression Rating Scale and Hamilton Depression Rating Scale score were included in the analysis. Of them, 182 subjects presented anxious and 71 nonanxious depression. RESULTS:Treatment outcomes were similar across the three treatment groups regardless of anxious MDD status (P-value > 0.5 for all comparisons) suggesting that anxious depression was not a significant predictor or moderator of treatment outcome. CONCLUSION/CONCLUSIONS:These findings indicate that anxious depression alone may be prognostic rather than predictive. These findings may be a useful guidance for clinicians, suggesting that standard TRD treatments remain applicable in the anxious MDD subtype.

Functional magnetic resonance imaging studies have reported disruptions in functional connectivity within brain networks, known as connectomes. Researchers have tested connectomes to see whether they serve as biomarkers for various psychiatric conditions. This meta-analysis aims to evaluate the diagnostic test accuracy of predictive models of connectomes derived from resting-state fMRI in diagnosing obsessive-compulsive disorder. A systematic review and meta-analysis were conducted on previous studies assessing the sensitivity, specificity, and accuracy of connectome-based diagnostic models in obsessive-compulsive disorder and healthy controls. Eight studies were identified, comprising 563 individuals with obsessive-compulsive disorder and 564 healthy controls. The results revealed robust diagnostic performance with a pooled sensitivity of 0.827 (95% CI: 0.779-0.867) and specificity of 0.794 (95% CI: 0.759-0.826). Connectome-based diagnostic models demonstrated excellent clinical utility, with an area under the curve of 87% (95% CI: 84%-90%), and significant predictive power as indicated by positive (4.15) and negative (0.21) likelihood ratios, as well as strong diagnostic odds ratio of 18.69 (95% CI: 11.84-29.49). The results highlight the potential of functional connectome-based predictive modeling as a robust tool for accurately diagnosing obsessive-compulsive disorder, with possibility of future implications for early diagnosis, monitoring treatment-related changes, involving in decision modeling, and understanding the biological mechanisms underlying obsessive-compulsive disorder.