Emotion-related impulsivity and suicidal ideation and behavior in schizophrenia spectrum disorder: a pilot fMRI study.

Introduction: Suicidal ideation and behavior (SIB) are serious problems in people with schizophrenia spectrum disorders (SSD). Nevertheless, relatively little is known about the circuitry underlying SIB in SSD. Recently, we showed that elevated emotional impulsivity (urgency) was associated with SIB in SSD. Here we examined brain activity in people with SSD and elevated SIB. Methods: We tested 16 people with SSD who had low SIB and 14 people with high SIB on a task in which emotion regulation in response to affective pictures was implicitly manipulated using spoken sentences. Thus, there were neutral pictures preceded by neutral statements (NeutNeut condition), as well as negative pictures preceded by either negative (NegNeg) or neutral (NeutNeg) statements. After each picture, participants rated how unpleasant each picture was for them. The latter two conditions were compared to the NeutNeut condition. We compared the emotion-regulated condition (NeutNeg) to the unregulated condition (NeutNeut). Statistics were threshold using threshold free cluster enhancement (TFCE). Results: People in the low SIB group showed higher activation in this contrast in medial frontal gyrus, right rostral anterior cingulate, bilateral superior frontal gyrus/DLPFC, and right middle cingulate gyrus, as well as right superior temporal gyrus. Discussion: This study provides clues to the neural basis of SIB in SSD as well as underlying mechanisms.

Antidepressant exposure and long-term dementia risk in a nationwide retrospective study on US veterans with midlife major depressive disorder.

INTRODUCTION: 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: 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: 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.

Association of performance in medical residency selection with a psychiatric diagnosis, and depressive and anxiety symptoms.

OBJECTIVE: 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: 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: 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: 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.

Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

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.

Personality characteristics, not clinical symptoms, are associated with anhedonia in a community sample: A preliminary investigation.

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.

Efficacy of Transcranial Photobiomodulation on Depressive Symptoms: A Meta-Analysis.

Background: Transcranial photobiomodulation (tPBM) is a novel, noninvasive, device-based intervention, which has been tested as a possible treatment for various neurological and psychiatric conditions. Recently, it has been investigated as an innovative treatment for major depressive disorder (MDD). There have been several animal and clinical studies that evaluated the underlying mechanism and the efficacy of its antidepressant effects, but results have been conflicting. Objective: Thus, we conducted the first meta-analysis on effects of tPBM on depressive symptoms. Materials and methods: Thirty original articles on tPBM were retrieved, eight of them met criteria for inclusion to a random effects meta-analysis. Results: tPBM appeared effective in decreasing depressive symptom severity regardless of diagnosis (Hedges' g = 1.415, p < 0.001, k = 8), but a significant heterogeneity has been found. The meta-analysis of single-arm studies (baseline to endpoint changes) limited to participants with MDD has supported the significant effect of tPBM in reducing the depression severity, without a significant heterogeneity (Hedges' g = 1.142, 95% confidence interval = 0.780-1.504, z = 6.19, p < 0.001, k = 5). However, the meta-analysis of the few double-blind, sham-controlled studies in MDD has not supported the statistically significant superiority of tPBM over sham (Hedges' g = 0.499, p = 0.211, k = 3), although a sample size bias is likely present. Conclusions: Overall, this meta-analysis provides weak support for the promising role of tPBM in the treatment of depressive symptoms. Dose finding studies to determine optimal tPBM parameters followed by larger, randomized, sham-controlled studies will be needed to fully demonstrate the antidepressant efficacy of tPBM.

Using latent profile analyses to classify subjects with anhedonia based on reward-related measures obtained in the FAST-MAS study.

BACKGROUND: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments. METHODS: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups. Measures included ventral striatal activation during the Monetary Incentive Delay task, response bias in the Probabilistic Reward Task, reward valuation scores from the Effort-Expenditure for Rewards Task, and scores from reward-related self-report measures. RESULTS: Two subgroups were identified, which differed on self-report measures of reward. Participants in the subgroup reporting more anhedonia also reported more depression and had greater illness severity and functional impairments. Graphs of change with treatment showed a trend for the less severe subgroup to demonstrate higher response to KOR antagonist treatment on the neuroimaging measure, probabilistic reward task, and ratings of functioning; the subgroup with greater severity showed a trend for higher treatment response on reward-related self-report measures. LIMITATIONS: The main limitations include the small sample size and exploratory nature of analyses. CONCLUSIONS: Evidence of possible dissociation between self-reported measures of anhedonia and other measures with respect to treatment response emerged. These results highlight the importance for future research to consider severity of self-reported reward-related deficits and how the relationship across measurement methods may vary with severity.

Protocol Report on the Transcranial Photobiomodulation for Alzheimer's Disease (TRAP-AD) Study.

BACKGROUND: Alzheimer's disease's (AD) prevalence is projected to increase as the population ages and current treatments are minimally effective. Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light penetrates into the cerebral cortex, stimulates the mitochondrial respiratory chain, and increases cerebral blood flow. Preliminary data suggests t-PBM may be efficacious in improving cognition in people with early AD and amnestic mild cognitive impairment (aMCI). METHODS: In this randomized, double-blind, placebo-controlled study with aMCI and early AD participants, we will test the efficacy, safety, and impact on cognition of 24 sessions of t-PBM delivered over 8 weeks. Brain mechanisms of t-PBM in this population will be explored by testing whether the baseline tau burden (measured with 18F-MK6240), or changes in mitochondrial function over 8 weeks (assessed with 31P-MRSI), moderates the changes observed in cognitive functions after t-PBM therapy. We will also use changes in the fMRI Blood-Oxygenation-Level-Dependent (BOLD) signal after a single treatment to demonstrate t-PBM-dependent increases in prefrontal cortex blood flow. CONCLUSION: This study will test whether t-PBM, a low-cost, accessible, and user-friendly intervention, has the potential to improve cognition and function in an aMCI and early AD population.

The Impact of Post-Stroke Depressive Symptoms on Cognitive Performance in Women and in Men: A 4 Month Prospective Study.

Background: Depressive symptoms have been associated with cognitive impairment after stroke, and women may be specifically affected. Objective: The aim of this study was to investigate gender-specific characteristics in the relationship between changes in depression severity and changes in cognitive performance after stroke. Methods: We prospectively evaluated 73 patients without a previous history of depression in the first and fourth months after a first ischemic stroke. The severity of depressive symptoms was assessed using the 31-item version of the Hamilton Rating Scale for Depression, and executive function, attention, working memory, and verbal fluency were assessed using a neuropsychological battery. Results: We included 46 (63.0%) men and 27 (36.9%) women, with mean ages of 55.2 (SD ± 15.1) and 46.8 (SD ± 14.7) years, respectively. We found significant improvement in the digit span forward and Stroop dots from month 1 to month 4 post stroke for both men and women. Women, but not men, presented a correlation between changes in phonemic verbal fluency and changes in the 31-item version of the Hamilton Rating Scale for Depression scores. Improvement in depression was correlated with improvement in verbal fluency, and worsening in depression was correlated with worsening in verbal fluency. Conclusions: Our results suggest that women might be more vulnerable to the relationship between depressive symptoms and cognitive performance, and improvement of depression may be necessary for women's improvement in phonemic verbal fluency from the first to the fourth month after a stroke. We did not adjust the results for multiple comparisons. Thus, our findings might be considered preliminary, and confirmatory studies, also focusing on specific characteristics of women that could explain these differences, are warranted.

Sodium-Glucose Cotransporter-2 Inhibitors in Depression.

ABSTRACT: 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.

Zuranolone for the Treatment of Adults With Major Depressive Disorder: A Randomized, Placebo-Controlled Phase 3 Trial.

OBJECTIVE: This study assessed the efficacy and safety of a 14-day treatment course of once-daily zuranolone 50 mg, an investigational oral positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, for the treatment of major depressive disorder. METHODS: 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: 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: 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.

Comparison of Adiponectin Levels in Anorexia Nervosa, Bulimia Nervosa, Binge-Eating Disorder, Obesity, Constitutional Thinness, and Healthy Controls: A Network Meta-Analysis.

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.

Photobiomodulation: An Emerging Treatment Modality for Depression.

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.

Combinations of dextromethorphan for the treatment of mood disorders - a review of the evidence.

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.

Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine.

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.

Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes.

OBJECTIVE: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. METHODS: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. RESULTS: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. CONCLUSION: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.