Faculty Bibliography

Anhedonia is a salient transdiagnostic psychiatric symptom associated with increased illness severity and chronicity. Anhedonia is also present to varying degrees in non-clinical cohorts. Here, we sought to examine factors influencing expression of anhedonia. Participants (N = 335) were recruited through the Nathan Kline Institute-Rockland Sample, an initiative to deeply phenotype a large community sample across the lifespan. Utilizing a data-driven approach, we evaluated associations between anhedonia severity, indexed by Snaith-Hamilton Pleasure Scale (SHAPS), and 20 physical, developmental, and clinical measures, including Structured Clinical Interview for DSM-IV, Beck Depression Inventory, State-Trait Anxiety Inventory, NEO Five-Factor Inventory-3 (NEO-FFI-3), BMI, Hemoglobin A1C, and demography. Using a bootstrapped AIC-based backward selection algorithm, seven variables were retained in the final model: NEO-FFI-3 agreeableness, extraversion, and openness to experience; BMI; sex; ethnicity; and race. Though median SHAPS scores were greater in participants with psychiatric diagnoses (18.5) than those without (17.0) (U = 12238.5, z = 2.473, p = 0.013), diagnosis and symptom measures were not retained as significant predictors in the final robust linear model. Participants scoring higher on agreeableness, extraversion, and openness to experience reported significantly lower anhedonia. These results demonstrate personality as a mild-to-moderate but significant driver of differences in experiencing pleasure in a community sample.

OBJECTIVE/UNASSIGNED:) receptor, for the treatment of major depressive disorder. METHODS/UNASSIGNED:Patients 18-64 years of age with severe major depressive disorder were enrolled in this randomized, double-blind, placebo-controlled trial. Patients self-administered zuranolone 50 mg or placebo once daily for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15. Safety and tolerability were assessed by incidence of adverse events. RESULTS/UNASSIGNED:Of 543 randomized patients, 534 (266 in the zuranolone group, 268 in the placebo group) constituted the full analysis set. Compared with patients in the placebo group, patients in the zuranolone group demonstrated a statistically significant improvement in depressive symptoms at day 15 (least squares mean change from baseline HAM-D score, -14.1 vs. -12.3). Numerically greater improvements in depressive symptoms for zuranolone versus placebo were observed by day 3 (least squares mean change from baseline HAM-D score, -9.8 vs. -6.8), which were sustained at all visits throughout the treatment and follow-up periods of the study (through day 42, with the difference remaining nominally significant through day 12). Two patients in each group experienced a serious adverse event; nine patients in the zuranolone group and four in the placebo group discontinued treatment due to adverse events. CONCLUSIONS/UNASSIGNED:Zuranolone at 50 mg/day elicited a significantly greater improvement in depressive symptoms at day 15, with a rapid time to effect (day 3). Zuranolone was generally well tolerated, with no new safety findings compared with previously studied lower dosages. These findings support the potential of zuranolone in treating adults with major depressive disorder.

Novel treatment strategies that refract existing treatment algorithms for depressive disorders are being sought. Abnormal brain bioenergetic metabolism may represent an alternative, therapeutically targetable neurobiological basis for depression. A growing body of research points to endogenous ketones as candidate neuroprotective metabolites with the potential to enhance brain bioenergetics and improve mood. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally approved for the treatment of diabetes, induce ketogenesis and are associated with mood improvement in population-based studies. In this column, we highlight the rationale for the hypothesis that ketogenesis induced by SGLT2 inhibitors may be an effective treatment for depressive disorders.

Adiponectin is a protein hormone that is produced and secreted primarily by adipose tissue. The levels of adiponectin in those with eating disorders, obesity, and healthy controls have been extensively studied. However, the general picture of the differences in adiponectin levels across the mentioned conditions is still unclear and fragmented. In this study, we pooled previous studies and performed a network meta-analysis to gain a global picture of comparisons of adiponectin levels across eating disorders, obesity, constitutional thinness, and healthy controls. Electronic databases were searched for anorexia nervosa, avoidant restrictive food intake disorder, binge-eating disorder, bulimia nervosa, healthy controls, night eating syndrome, obesity, and constitutional thinness in studies where adiponectin levels were measured. A total of 4262 participants from 50 published studies were included in the network meta-analysis. Adiponectin levels were significantly higher in participants with anorexia nervosa than in healthy controls (Hedges' g = 0.701, p < 0.001). However, adiponectin levels in constitutionally thin participants were not significantly different from those of healthy controls (Hedges' g = 0.470, p = 0.187). Obesity and binge-eating disorder were associated with significantly lower adiponectin levels compared to those of healthy controls (Hedges' g = -0.852, p < 0.001 and Hedges' g = -0.756, p = 0.024, respectively). The disorders characterized by excessive increases or decreases in BMI were associated with significant changes in adiponectin levels. These results suggest that adiponectin may be an important marker of severely disequilibrated homeostasis, especially in fat, glucose, and bone metabolisms. Nonetheless, an increase in adiponectin may not simply be associated with a decrease in BMI, as constitutional thinness is not associated with a significant increase in adiponectin.

BACKGROUND:Patients with schizophrenia show reduced NMDA glutamate receptor-dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination. METHODS:Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each. In AudRem, participants indicated which paired tone was higher in pitch. The primary outcome was plasticity improvement, operationalized as change in pitch threshold between AudRem tones [(test tone Hz - reference tone Hz)/reference tone Hz] between the initial plateau pitch threshold (mean of trials 20-30 of treatment visit 1) to pitch threshold at the end of visit(s). Target engagement was assessed by electroencephalography outcomes, including mismatch negativity (pitch primary). RESULTS:There was a significant overall treatment effect for plasticity improvement (p = .014). Plasticity improvement was largest within the 80 and 100 mg/kg groups (p < .001, d > 0.67), while 120 mg/kg and placebo-treated participants showed nonsignificant within-group changes. Plasticity improvement was seen after a single treatment and was sustained on subsequent treatments. Target engagement was demonstrated by significantly larger mismatch negativity (p = .049, d = 1.0) for the 100 mg/kg dose versus placebo. CONCLUSIONS:Our results demonstrate sufficient proof of principle for continued development of both the d-serine+AudRem combination and our target engagement methodology. The ultimate utility is dependent on the results of an ongoing larger, longer study of the combination for clinically relevant outcomes.

Major depressive disorder (MDD) is considered a global crisis. Conventional treatments for MDD consist of pharmacotherapy and psychotherapy, although a significant number of patients with depression respond poorly to conventional treatments and are diagnosed with treatment-resistant depression (TRD). Transcranial photobiomodulation (t-PBM) therapy uses near-infrared light, delivered transcranially, to modulate the brain cortex. The aim of this review was to revisit the antidepressant effects of t-PBM, with a special emphasis on individuals with TRD. A search on PubMed and ClinicalTrials.gov tracked clinical studies using t-PBM for the treatment of patients diagnosed with MDD and TRD.

INTRODUCTION:Major depressive disorder (MDD) is one of the leading causes of disability worldwide. However, many patients do not achieve an adequate clinical improvement with pharmacotherapies targeting monoamine receptors, and the onset of therapeutic benefit typically lags by 4-6 weeks. There is a significant need for mechanistically novel treatments with more rapid efficacy. Combinations of dextromethorphan, an oral N-methyl-D-aspartate (NMDA) receptor antagonist, can potentially fill this gap. AREAS COVERED:US Clinical Trials registration was systematically searched for studies examining the effects of dextromethorphan in mood disorders. Results were gathered via a PubMed search, adding also press releases, and poster presentations. Two case reports and eight clinical trials were identified for the treatment of MDD or treatment resistant depression (TRD); we also reviewed additional studies in bipolar disorder. EXPERT OPINION:Clinical studies show that the combinations of dextromethorphan with quinidine or bupropion have been effective in decreasing depressive symptomatology in MDD. However, dextromethorphan studies in adults with TRD or with bipolar depression have shown mixed results. The combination of dextromethorphan and bupropion is a well-tolerated, safe, and efficacious treatment option for adults with MDD. Additional studies analyzing the effects of dextromethorphan and bupropion for TRD and bipolar depression are needed.

We report on the rationale and design of an ongoing National Institute of Mental Health (NIMH) sponsored R61-R33 project in major depressive disorder (MDD). Current treatments for MDD have significant limitations in efficacy and side effect burden. There is a critical need for device-based treatments in MDD that are efficacious, well-tolerated, and easy to use. This project focuses on the adjunctive use of the transcranial photobiomodulation (tPBM) with near-infrared (NIR) light for the treatment of MDD. tPBM with NIR light penetrates robustly into the cerebral cortex, stimulating the mitochondrial respiratory chain, and also significantly increases cerebral blood flow (CBF). In the R61 phase, we will conduct target engagement studies to demonstrate dose-dependent effects of tPBM on the prefrontal cortex (PFC) CBF, using the increase in fMRI blood-oxygenation-level-dependent (BOLD) signal levels as our Go/No-go target engagement biomarker. In the R33 phase, we will conduct a randomized clinical trial of tPBM vs. sham in MDD to establish the target engagement and evaluate the association between changes in the biomarker (BOLD signal) and changes in clinical symptoms, while also collecting important information on antidepressant effects, safety, and tolerability. The study will be done in parallel at New York University/the Nathan Kline Institute (NYU/NKI) and at Massachusetts General Hospital (MGH). The importance of this study is threefold: 1. it targets MDD, a leading cause of disability worldwide, which lacks adequate treatments; 2. it evaluates tPBM, which has a well-established safety profile and has the potential to be safe in at-home administration; and 3. it uses fMRI BOLD changes as a target engagement biomarker. If effects are confirmed, the present study will both support short-term clinical development of an easy to scale device for the treatment of MDD, while also validating a biomarker for the development of future, novel modulation strategies.