Major depressive disorder (MDD) is a leading cause of disability worldwide, with many patients experiencing inadequate response to standard antidepressants. Dysregulation of N-methyl-D-aspartate (NMDA) receptor activity is implicated in the pathophysiology of MDD. Satoprodil (BI 1569912), an oral NMDA subunit GluN2B-selective negative allosteric modulator, was evaluated for safety and efficacy in MDD in two multicenter, randomized, placebo-controlled Phase II dose-finding trials as an adjunctive or monotherapy. In each trial, patients (18-65 years old) were randomized 2:1:1:2 to placebo or satoprodil (5 mg, 10 mg, or 20 mg) once-daily for 6 weeks, with ongoing antidepressant treatment in the adjunctive trial. Primary endpoint was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6 (both trials). Safety and tolerability were also assessed. In the adjunctive trial (N = 243; 60.9% female), the adjusted mean (standard error [SE]) change in MADRS total score at Week 6 was: placebo, -12.0 (1.1); satoprodil 5 mg, -7.8 (1.6); satoprodil 10 mg, -11.9 (1.6) and satoprodil 20 mg, -12.3 (1.2). In the monotherapy trial (N = 225; 54.2% female), the adjusted mean (SE) change in MADRS total score at Week 6 was: placebo, -10.3 (1.4); satoprodil 5 mg, -13.6 (2.1); satoprodil 10 mg, -10.6 (2.0) and satoprodil 20 mg, -10.0 (1.4). In patients with MDD, satoprodil (all doses) over 6-weeks was well tolerated but did not reduce depressive symptoms beyond placebo in either trial in a relevant manner. These trials provide the most comprehensive clinical evidence to date on GluN2B-selective modulation in MDD and will inform future research on glutamatergic pathways.
We found menstrual cycle effects on white matter microstructure and craving in women with substance use disorder. Axial diffusivity was higher in the luteal phase and negatively correlated with craving in the follicular phase. Exploratory correlations with ovarian hormones highlight menstrual cycle-sensitive white matter dynamics in addiction.
Social hierarchy influences behavior, resource access, and health, but the neural mechanisms underlying individual differences in social competition remain incompletely understood. Using a novel competitive platform test and assessment of region-specific activation in male and female mice, we found a range of social hierarchies as determined by time on platform, revealing greater behavioral complexity than previously described and improved stability in females. We also measured motivated behavior and saw reduced platform acquisition attempts over testing days as well as rank-dependent differences in platform co-occupancy, which were seen primarily amongst lower ranks. We found no association between rank and medial prefrontal cortex (mPFC) activation, but found a positive correlation between lateral habenula (LHb) activation and rank. Social dominance was magnified in a group setting compared to paired matchups with similar motivation and co-occupancy behavior between ranks. There was no association between rank and mPFC activation in a group setting, but the LHb was again positively correlated with rank. Collectively, these findings demonstrate that the competitive platform task captures individual differences in social competition, motivation, and resource-sharing behavior under an aversive stimulus and identify the LHb as a neural correlate of performance in this behavioral context. These results highlight the complexity of social interactions in both sexes and provide insight into neural mechanisms that contribute to competitive social behavior.
Brain-derived neurotrophic factor (BDNF) exon VI promoter is implicated in mediating activity-induced synthesis of hippocampal BDNF. BDNF is implicated in (R,S)-ketamine’s antidepressant effects, but its role in (R,S)-ketamine-mediated prophylaxis is unknown. Using BDNF-e6 mice, in which promoter VI-driven BDNF production is disrupted, we tested its necessity for (R,S)-ketamine’s prophylactic effects.
Evidence of heterogeneity in the trajectory of psychosis is abundant. Here, we applied group-based trajectory modeling on positive symptoms and collected resting state fMRI data of 81 medication-naïve first episode psychosis (FEP) patients during a 16-week antipsychotic drug (APD) trial. Data from 131 healthy controls (HCs) were also acquired during the trial for comparison. Three major trajectory subgroups were identified and labeled as Fast (50.6%), Delay (35.8%), and Partial responders (13.6%). Logistic regressions revealed that Fast responders (vs. Partial) showed significantly lower psychopathology symptoms prior to treatment and lower APD dosage after the trial. Moreover, Delay responders showed significant increases in executive control network resting state functional connectivity (ECN FC) during the trial towards a normalization (using HCs as reference), while Fast and Partial responders to a lesser extent. These changes were associated with treatment response (reduction in positive symptoms after the trial). Future work should harness the potential of ECN FC to inform the mechanism of delayed responses with the potential to start unraveling psychotic heterogeneity which has hampered our ability to identify new treatment strategies and lead to better clinical outcomes. (Clinical trial registration: Trajectories of Treatment Response as Window into the Heterogeneity of Psychosis: A Longitudinal Multimodal Imaging Study, NCT03442101 https://clinicaltrials.gov/ct2/show/NCT03442101 . Glutamate, Brain Connectivity and Duration of Untreated Psychosis (DUP), NCT02034253 https://clinicaltrials.gov/ct2/show/NCT02034253 ).
Anoctamin 2 (ANO2, TMEM16B) is a calcium-activated chloride channel best known for its role in sensory neurons, yet its expression in multiple brain regions associated with dopamine-related signaling, including the prefrontal cortex, striatum, substantia nigra, ventral tegmental area, and cerebellum, suggests broader functions in central neural circuits. However, the contribution of ANO2 to dopamine-related neural function and behavior remains undefined. To address this question, we generated ANO2-deficient mice using CRISPR-Cas9-mediated gene editing and examined their behavioral and neurochemical phenotypes. ANO2 knockout mice exhibited age-dependent hyperactivity, impaired inhibitory behavioral control, altered aversive/risk-related responses, and selective motor coordination deficits, while spatial learning and memory were preserved. Neurochemically, ANO2 deficiency resulted in reduced tyrosine hydroxylase expression and phosphorylation, decreased dopamine levels despite unchanged dopamine transporter expression, region- and subtype-dependent dopamine receptor alterations, and reduced downstream signaling markers across cortico-striatal and cerebellar circuits. These changes suggest impaired dopamine biosynthesis and altered dopamine-related signaling rather than broad disruption of dopaminergic neuronal identity. Together, these findings identify ANO2 as a potential modulator of dopamine-related signaling and inhibitory behavioral control, expanding current understanding of calcium-activated chloride channel function in neural circuits relevant to behavioral domains implicated in neuropsychiatric disorders.
Reward processing deficits are a well-established mechanism underlying anhedonia, a core symptom of Major Depressive Disorder (MDD). Given the role of dopamine in mesocorticolimbic reward pathways, this study examined whether a single low dose of amisulpride (100 mg), which is thought to enhance dopaminergic transmission through presynaptic D2/3 autoreceptor blockade, modulates brain activation during the anticipation of social rewards. A total of 58 participants with MDD and 57 healthy controls (HCs) participated in a double-blind, placebo-controlled, randomized trial. They received either amisulpride or placebo before completing a Social Incentive Delay task during functional magnetic resonance imaging (fMRI). Neural activation was examined in the ventral and dorsal striatum, pallidum, ventral tegmental area (VTA), anterior insula, and ventromedial prefrontal cortex. Anhedonia was assessed using self-report measures. Behaviorally, participants responded faster to reward than no-reward cues, with no significant differences between groups (MDD vs. HCs) or treatment conditions (amisulpride vs. placebo). On a neural level, amisulpride enhanced VTA activation during the anticipation of social rewards compared to no-reward cues. Relative to HCs, participants with MDD showed reduced right putamen activity when anticipating highly rewarding cues, which was not significantly affected by amisulpride. Within the MDD-amisulpride group, exploratory analyses revealed positive associations between anhedonia severity and activity in the putamen, VTA, and anterior insula, and higher striatal activity correlated with faster responses to highly rewarding cues. These findings suggest that while amisulpride enhances VTA activity during the anticipation of social rewards, core striatal deficits in MDD remain, underscoring both the potential and limitations of dopaminergic modulation in addressing social anhedonia.
The PACt-MD study demonstrated that combined cognitive remediation (CR) and transcranial direct current stimulation (tDCS) slows global cognitive decline in individuals with mild cognitive impairment (MCI) or remitted major depressive disorder (rMDD) over a median follow-up of four years. Prefrontal theta-gamma coupling (TGC), measured via electroencephalography (EEG), is a marker of prefrontal cortical function and may index cognitive compensation, the mechanism thought to underlie CR+tDCS effects. This secondary analysis investigated whether baseline TGC influenced the efficacy of CR+tDCS, hypothesizing that participants with high baseline TGC-indicating better prefrontal function-would benefit more from CR+tDCS than those with low baseline TGC. TGC was assessed during an N-back task at baseline in 260 participants (mean age=71.9, SD = 6.0) and dichotomized by median split into high vs low groups. Cognition was evaluated two months post-baseline and annually up to six years. Baseline TGC significantly moderated the effects of CR+tDCS on global cognition (χ²=12.46, p = 0.006), verbal memory (χ²=16.93, p = 0.0007), and executive function (χ²=18.57, p = 0.0003). In the high-TGC group, global cognition declined more slowly with active CR+tDCS compared to sham. No such difference was observed in the low-TGC group. Lower baseline TGC may reflect reduced capacity for cognitive compensation, limiting CR+tDCS effectiveness in at-risk older adults. Higher TGC may identify those most likely to benefit from this intervention. ClinicalTrials.gov Identifier: NCT02386670.
We previously demonstrated that male progeny of cocaine-experienced sires resisted cocaine, expressed as delayed acquisition of cocaine self-administration. Here, we sought to determine whether this phenotype extended to another psychostimulant, methamphetamine (meth). Sires self-administered meth or cocaine or received yoked-saline infusions for 60 days, after which they were mated to naïve females. Some behaviors previously altered in cocaine-sired male rats, including object memory and anxiety-like behavior, were not influenced by paternal meth taking. In contrast to cocaine resistance in cocaine-sired male rats, meth-sired male offspring demonstrated increased susceptibility to meth taking, with no effect in females. Single nuclei RNA- and ATAC-sequencing of the nucleus accumbens was used to identify molecular drivers of phenotypes in cocaine- and meth-sired offspring. Sequencing results revealed unique profiles of gene expression and open chromatin in offspring nucleus accumbens. Differential gene expression in cocaine-resistant, cocaine-sired offspring and meth-susceptible, meth-sired offspring illuminates potential novel treatment targets for psychostimulant use disorders.
Comorbid depressive symptoms are highly prevalent in patients with chronic colitis, posing a major clinical challenge because pain and depression often fail to respond to the same treatment. However, the neural mechanisms underlying this comorbidity remain poorly understood. Using a dextran sulfate sodium (DSS)-induced chronic colitis mouse model, we identified depression-resilient and depression-susceptible phenotypes and uncovered a critical role for the posterior insular cortex glutamatergic (pICGlu) projection to the anteroventral bed nucleus of the stria terminalis (avBNST) in regulating both depressive-like behaviors and visceral hypersensitivity. Bidirectional chemogenetic manipulation of pICGlu neurons and optogenetic modulation of the pICGlu-avBNST circuit revealed dissociable control of affective and sensory processing: activation alleviated depressive-like behaviors but enhanced visceral pain sensitivity, whereas inhibition produced the opposite effects. Furthermore, genetic and pharmacological manipulation of CB1R signaling influenced depression-like behaviors and visceral hypersensitivity in chronic colitis. Together, these findings identify the pICGlu-avBNST circuit and support a role for CB1R signaling in the affective and sensory abnormalities associated with chronic colitis, with mechanistic studies performed in male mice.
Problematic alcohol use frequently emerges during adolescence and young adulthood, yet few objective markers reliably capture risk or track early changes in drinking behavior. Reactivity to uncertain threat (U-threat) has been identified as a potential neurobiological risk factor for alcohol misuse; however, no study has examined within-subjects changes in reactivity to U-threat as a function of drinking frequency. Thus, it remains unclear whether reactivity to U-threat reflects a stable vulnerability marker or a dynamic process that tracks within-person changes in alcohol use. To address this gap, youth ages 16-19 (N = 134) in the early stages of alcohol involvement completed startle and neuroimaging versions of the No-Predictable-Unpredictable (NPU) threat task at baseline and 6-month follow-up. Participants were classified into three groups based on changes in binge drinking frequency (decreased, stable, increased). Repeated-measures ANOVAs examined group × time effects on startle potentiation and activation of the anterior insula (aINS) and dorsal anterior cingulate cortex (dACC) during U-threat. Results revealed a significant group × time interaction for startle: youth who increased binge drinking showed heightened startle reactivity to U-threat over time, whereas those who decreased or maintained drinking showed no change. No significant interactions emerged for aINS or dACC activation. Findings indicate that behavioral reactivity to U-threat is associated with short-term changes in binge drinking, suggesting that startle potentiation may reflect a within-person correlate of risk. These results highlight exaggerated U-threat reactivity as a promising psychophysiological target for early detection and intervention.
Functional magnetic resonance imaging (fMRI) is widely used to investigate brain function. However, interpretation of the blood oxygen level-dependent (BOLD) signal is complicated by the fact that it reflects both neuronal activity and vascular physiology. This problem is especially relevant in neuropsychopharmacology research because pharmacological and psychiatric effects on brain function are often accompanied by physiological shifts. Here, we discuss recent evidence for an approach to disentangling neuronal and physiological components of the BOLD signal that enhances the interpretability and clinical utility of fMRI. Converging findings suggest that the systemic low-frequency oscillation (sLFO), a major component of the global signal, indexes cardiovascular manifestations of arousal rather than neuronal function. As such, retaining the sLFO in fMRI data can substantially distort functional connectivity estimates, leading to the misinterpretation of physiological fluctuations in arousal as neuronal effects. At the same time, the sLFO itself tracks physiological arousal level, behavioral performance, drug craving, pharmacological modulation, and large-scale brain network organization. Collectively, we suggest that when interpreting fMRI data, sLFO-indexed physiological arousal should both be modeled and considered separately, as extracting this signal from fMRI data provides dual benefits: a cleaner neuronal signal and a complementary index of behaviorally relevant physiology.
