Journal of Psychopharmacology

Background: The incidence of antidepressant withdrawal reactions in longer-term users and the influence of dosage is insufficiently understood. Objectives: Informed by neuropharmacological models and user surveys, this study examined symptom change during tapering and if increases were specifically associated with reductions below 75% of the minimum effective dose. Design: This was a prospective longitudinal cohort study with seven assessments over six months. Methods: Altogether 32 Swiss adult primary care patients who were on antidepressants for at least six months and in stable remission were assessed at baseline (week 0) before they started tapering and after 2, 4, 6, 8, 16, and 26 weeks. Withdrawal symptoms were measured repeatedly using an adapted version of the Discontinuation-Emergent Signs and Symptoms Scale (DESS) and the main outcome was intra-individual symptom change during intervals. Antidepressant dose was standardized relative to the minimum effective dose in the treatment of depressive and anxiety disorders. Results: Across intervals, reductions below 75% of the minimum effective dose were associated with symptom increases, while reductions above that threshold or no reductions were associated with symptom decreases. After adjusting for potential confounders, the rate of clinically relevant symptom increases contingent on dose reductions below 75% of the minimum effective dose was 33%, as compared to 13% during intervals with no dose reductions (OR=3.2, 1.4 to 7.4). We thus estimated that 60% of the risk of clinically relevant symptom increases was attributable to pharmacological withdrawal effects. The adjusted incidence rates for clinically relevant and severe withdrawal reactions were 32% and 11%, respectively. Conclusions: Consistent with neuropharmacological research findings, we found that antidepressant withdrawal symptoms emerge mostly following reductions below 75% of the minimum effective dose, affecting about one-third of patients. Even small reductions may trigger clinically relevant withdrawal reactions in this lowest dose-range, stressing the need for personalized tapering plans.

BackgroundThe mechanisms underlying pharmacological treatments for stimulant use disorders are poorly understood. This study examined whether changes in craving, depressive symptoms, and/or impulsivity mediate treatment effect in pharmacotherapy with combined naltrexone and bupropion for methamphetamine use disorder. MethodsThe study was based on secondary analysis of data from the Accelerated Development of Additive Pharmacotherapy Treatment for methamphetamine disorder (ADAPT-2) trial which randomized adults with methamphetamine use disorder to combined treatment with injectable naltrexone (380 mg every three weeks) plus oral bupropion (450 mg daily) versus placebo. A total of 403 adults with methamphetamine use disorder participated in the first Stage; 225 of first Stage participants in the placebo arm who did not respond to treatment were re-randomized in the second Stage. Mediation effects were examined using longitudinal multi-level structural equation modeling. ResultsNaltrexone-bupropion treatment was associated with decreases in drug use, craving, depressive symptoms, and impulsivity. The indirect effect of treatment through change in craving was significant (self-reported use=-0.21, 95% Credible Interval [CrI]=-0.35, -0.09; drug screen-ascertained use=-0.36, 95% CrI=-0.63, -0.16). Change in craving mediated 56% of the treatment effect on self-reported use and 45% of the effect on drug screen-ascertained use. Estimates for mediated effects for depressive symptoms and impulsivity were smaller in magnitude and non-significant. ConclusionReduction in craving mediates the effect of naltrexone-bupropion pharmacotherapy in methamphetamine use disorder. Craving may serve as a surrogate measure of treatment efficacy in short-term trials and help identify promising candidate medications to be tested in larger and longer-term trials. Trial RegistrationClinicalTrials.gov number: NCT03078075.

BackgroundLauric acid (LA) is a medium-chain saturated fatty acid found in several foods, including vegetable oils and seeds. Previous studies have demonstrated that LA exhibits neuroprotective, antioxidant, and anti-inflammatory properties in experimental models of neuropsychiatric disorders. Therefore, the present study aimed to investigate the behavioral and neurochemical effects of LA in a corticosterone-induced murine model of depression. MethodsMale Swiss mice received corticosterone (CORT; 20 mg/kg, subcutaneously) for 23 consecutive days, while the control group received vehicle only. During the last nine days of the experimental protocol, the animals received the respective treatments by oral gavage: LA (10 or 20 mg/kg), fluvoxamine (FLUV; 50 mg/kg), or vehicle, administered 1 hour after CORT injection. One hour after treatment administration, the animals were subjected to the behavioral tests: Forced Swimming Test (FST), Tail Suspension Test (TST), and Open Field Test (OFT). At the end of the experimental protocol, the animals were euthanized, and the prefrontal cortex (PFC), hippocampus (HPC), and striatum (STR) were collected for neurochemical analyses. ResultsChronic CORT treatment significantly increased immobility time in the FST and TST, characterizing depressive-like behavior. Treatment with LA reversed these behavioral alterations, showing an effect similar to that observed in the FLUV-treated group. In the OFT, LA did not promote significant changes in locomotor activity, suggesting the absence of psychostimulant effects. Regarding neurochemical analyses, LA treatment did not reduce malondialdehyde (MDA) or nitrite/nitrate (NO2-/NO3-) levels, nor did it alter reduced glutathione (GSH) levels in the evaluated brain regions. ConclusionThe results demonstrated that LA treatment was able to reverse corticosterone-induced behavioral alterations in mice, indicating a potential antidepressant-like effect. Furthermore, the observed effects were not associated with nonspecific locomotor alterations. Although LA did not promote significant changes in the evaluated neurochemical markers, these findings reinforce its potential as a therapeutic agent for depressive disorders and highlight the need for further studies to elucidate its mechanisms of action and possible clinical applicability.

Current treatments for opioid use disorder (OUD) have major barriers to access. As such, researching new potential therapies for OUD is important to public health. Previous research has implicated glucagon-like peptide-1 (GLP-1) receptor agonists in decreasing the use of addictive substances by animals. In this study, female Wistar rats (N=32) were surgically implanted with jugular catheters and trained to self-administer fentanyl at a fixed-ratio 1 (FR1) schedule of reinforcement for 21 sessions under short- (ShA; 1 hour) or long-access (LgA; 8 hours) conditions. Next, the animals received injections of semaglutide (0.1 mg/kg, s.c.) or saline (0.9% NaCl, s.c.) prior to another FR1 session. The animals underwent a progressive ratio (PR) schedule of reinforcement while receiving saline (i.v.) or fentanyl (0.625-10 {micro}g/kg/inf, i.v.) and semaglutide (0.1 mg/kg, s.c.) or saline (s.c.). Next, the animals underwent a semaglutide (0-0.1 mg/kg, s.c.) dose response procedure at FR1 and a single dose of fentanyl (2.5 {micro}g/kg/inf, i.v.). Following drug discontinuation, spontaneous locomotor activity and withdrawal-like symptoms were measured. Semaglutide dose-dependently decreased fentanyl rewards under ShA and LgA conditions (p<0.05). Under a PR, semaglutide significantly decreased breakpoint (p<0.05), suggesting semaglutide decreases motivation to self-administer fentanyl. Semaglutide-treated ShA animals displayed significantly less withdrawal-like behavior (p<0.05) but not LgA animals. Overall, these findings suggest semaglutide may modulate motivation to seek opioid reward and could be useful in the development of pharmacotherapies to address OUD.

Social withdrawal is a key component of the negative symptom domain of schizophrenia, and pharmacological blockade of the N-methyl-D-aspartate receptor (NMDAR) is widely used to model schizophrenia-relevant phenotypes in animals. However, findings on social behaviour are inconsistent across paradigms and laboratories. We therefore conducted a systematic review and meta-analysis to synthesise the effects of dizocilpine, ketamine, and phencyclidine on social interaction and social preference, to evaluate whether clinically approved antipsychotics modify these outcomes, and to examine locomotor activity measured within the same social tests to aid interpretation. We searched Embase, PubMed and Web of Science without language or date restrictions. Controlled in vivo studies in laboratory animals administering an eligible NMDAR antagonist and reporting social interaction and/or social preference outcomes were included. Two reviewers independently screened records, extracted data and assessed risk of bias. Effect sizes were computed as standardised mean differences and synthesised using correlated multilevel random-effects models with cluster-robust variance estimation. In total, 264 studies met the inclusion criteria. Overall, NMDAR antagonists were associated with reduced social interaction and reduced social preference relative to controls, although the social preference literature appeared vulnerable to small-study effects and imprecision. Locomotor activity measured during social interaction tests tended to be higher following NMDAR antagonists, whereas during social preference no consistent overall change was observed. In animals exposed to NMDAR antagonists, antipsychotics increased social behaviour, but these changes commonly co-occurred with reduced locomotion during social interaction tests, suggesting that improvements in social measures may partly reflect altered behavioural competition and time allocation rather than selective restoration of social functioning. Taken together, the evidence supports an overall link between NMDAR antagonism and reduced social behaviour, but the strength and interpretability of this signal depend on the paradigm and are constrained by heterogeneity and limitations in reporting.

Serotonergic psychedelics induce altered states of consciousness characterised by profound changes in emotional experience. Although psychedelics modulate autonomic arousal, sympathetic engagement during their affective effects remains poorly characterised. We recorded cardiac, electrodermal, and respiratory activity in 19 participants following inhalation of 20 or 40 mg of freebase N,N-dimethyltryptamine (DMT) under a semi-naturalistic blinded design, alongside time-resolved retrospective phenomenological reports. DMT induced robust increases across all autonomic markers, integrated into a multimodal index that selectively tracked subjective emotional intensity. Dose-dependent divergence followed modality-specific profiles: heart rate and respiratory differences emerged within the first 2 min post-inhalation, whereas electrodermal activity diverged only during the later phase, with higher doses showing prolonged autonomic engagement. DMT thus produces a transient sympathetic activation co-varying with emotional arousal, followed by gradual disengagement accompanied by pleasantness and bliss. By combining time- and cost-effective peripheral physiological measures with time-resolved phenomenological reports, this work contributes to the objective characterisation of psychedelic-induced affective states and provides a methodological basis for future biomarker research in clinical applications.

Mental illness poses a substantial global burden, yet existing psychotherapies and psychopharmacologies often produce limited outcomes. Psychedelic assisted therapies have emerged as potential transdiagnostic interventions. In particular, 3,4 methylenedioxymethamphetamine assisted therapy (MDMA AT) has generated interest for its rapid psychological effects and potential to enhance psychotherapy outcomes. However, the incremental efficacy of MDMA AT relative to control interventions across transdiagnostic outcomes remains unclear. Further, there have been emerging concerns regarding harm reporting quality in MDMA AT clinical trials. We conducted a systematic review and meta analysis of MDMA AT randomized controlled trials. Eleven publications representing eight controlled trials with 10 analyzed subgroups (n = 295 participants) were included in meta-analyses. Two additional secondary publications were included for harm reporting syntheses (k = 13 total). Across 114 extracted effect sizes, MDMA AT demonstrated a significant moderate-to-large incremental reduction in psychopathology relative to controls (g = 1.03, 95% CI [0.46, 1.60]), though heterogeneity was high (I squared = 76%). Incremental effects were larger versus inert placebos (g = 1.27) than active controls (g = 0.75). Symptom specific analyses indicated strong incremental effects for trauma reduction (g=1.46 [95% CI: 0.67, 2.25]) and smaller non-significant effects for depression (g=0.51 [95% CI: -0.06, 1.08]). Harm reporting quality synthesis showed only 23% of publications met high-quality reporting standards. Overall, MDMA AT demonstrates potential transdiagnostic efficacy, but small samples, confounding factors, and mediocre harm reporting highlight the need for larger more transparent clinical trials.

In a single-blind randomized controlled trial, we investigated the effectiveness of real-time fMRI neurofeedback delivered in 7 runs over three sessions across two weeks in N = 65 patients with alcohol use disorder. The intervention targeted modulation of ventral striatal cue reactivity to alcohol-related cues as well as enhancement of prefrontal control mechanisms in the right inferior frontal gyrus. The study design incorporate three experimental groups that either were instructed to downregulate a ventral striatum signal, upregulate the right inferior frontal gyrus, or upregulate negative functional connectivity between these two structures. In two active control groups participants were instructed to either up- or downregulate the primary auditory cortex. We did not find an effect of ventral striatal downregulation or negative connectivity feedback, and a reduced striatal activation in the right inferior frontal gyrus upregulation group was accompanied by concurrent lower activation in the target structure, suggesting that our intended modulation approaches were not effective. Identified problems that might have contributed to this unexpected outcome might have been the use of continuous feedback presentation that potentially confuses regulation target and reward processing in the ventral striatum, counterintuitive regulation directions, a lack of explicit strategy guidance and transparency about the targeted process, and generally the difficulty to recruit a sufficient number of eligible voluntary participants for a well-powered study with a complex design. These insights emphasize the complex challenges of real-time fMRI neurofeedback interventions for the treatment of substance use disorders and could provide guidance for the development of more effective future approaches.

Trauma-focused psychotherapies for post-traumatic stress disorder (PTSD) require waking re-engagement with traumatic memories, driving high dropout. We tested whether trauma-linked auditory cues delivered during slow-wave sleep are feasible. Of 13 patients who provided written informed consent, 6 (100% female) completed overnight Sound Exposure during Sleep (SES); none of the adverse events observed during overnight stimulation were judged by the study team to be attributable to the auditory intervention, and slow-wave sleep was preserved. Two sequential protocol versions were used: Version A (n = 2; capped at SUDs 30-40) and a no-ceiling amendment (Version B, n = 4). Post-hoc exploratory analyses (not powered for efficacy) showed Version B reduced subjective distress (mean difference -65.5%, 95% CI -104.2 to -26.7; nominal p = 0.012) and PCL-5 intrusion (-7.0; nominal p = 0.015). Findings are exploratory and require sham-controlled confirmation. Trial registration: jRCT1030230706.

BackgroundNon-suicidal self-injury (NSSI) represents a growing public health concern, particularly in adolescents. Emotion dysregulation is central to prevailing NSSI models, yet it remains unclear whether acceptance-based emotion regulation (ER) and its underlying neural processes are disrupted in naturalistic, dynamic contexts. MethodsPre-registered neuroimaging trial in recently diagnosed and treatment-naive adolescents with NSSI (n=25) and healthy controls (n=25) using an ER paradigm with dynamic video clips and concomitant functional magnetic resonance imaging. Behavioral, neural activity, and connectivity indices during emotion reactivity and acceptance-based regulation were compared between groups. ResultsAdolescents with NSSI experienced elevated negative feelings during neutral clips, reflecting heightened baseline negativity. In comparison to controls, they displayed reduced temporal and ventrolateral prefrontal engagement during emotional reactivity, but increased engagement of regions implicated in both emotion reactivity (right amygdala, insula) and ER (right dlPFC, dmPFC, vlPFC) when utilizing acceptance. Higher activation in the right dlPFC was positively associated with difficulties in accessing ER strategies in everyday life. Adolescents with NSSI showed reduced functional connectivity between the right amygdala and left dlPFC. ConclusionsAdolescents with NSSI exhibited a baseline negativity bias and altered neural engagement during both negative emotional reactivity and acceptance-based regulation, characterized by increased activation and reduced amygdala-dlPFC connectivity. These findings highlight atypical emotion processing in real-life contexts in individuals with NSSI. Targeting acceptance-based regulation and prefrontal-limbic circuitry may represent a promising intervention approach for adolescents with NSSI.

BackgroundEvidence suggests steeper accelerating opioid-related overdose, and non-medical use rates, in middle aged men in recent years compared with younger cohorts. Little is known about whether this is driven by age-related differences in the effects of opioids compared with socio-cultural factors driving non-medical consumption. Rodent models can be useful for dissociating biological from psychosocial factors, however, only minimal evidence exists on the effects of opioids in middle-age rats. ObjectiveTo determine if the anti-nociceptive and rewarding effects of opioids differ between adult and middle-age rats. MethodsFemale and male Wistar rats were obtained in early adulthood and examined across 4 to 11 months of age for nociceptive responses to heroin (0-1.56 mg/kg, s.c.) using a warm-water tail withdrawal assay. Subgroups (N=8 per group) were initiated on intravenous self-administration (IVSA) of heroin at either 5 months or 12 months of age. ResultsAnti-nociceptive effects of heroin did not differ across age. Female rats that initiated IVSA in early adulthood or middle-age obtained significantly more infusions of heroin than male rats of the same age during acquisition, and in dose-substitution under a FR1 schedule. Male, but not female, rats that initiated IVSA in middle age self-administered less heroin then rats that initiated in early adulthood; this was observed in acquisition and in dose-substitution. DiscussionThis study shows that opioid reward is diminished in middle aged male rats. It also found that middle age rats can be used effectively to model opioid-related outcomes, including drug seeking using the IVSA procedure.

Background and PurposeWhile inflammation has been generally considered to exacerbate symptoms of schizophrenia, some clinical observations suggest that acute inflammation may alleviate positive symptoms. However, animal models often use excessive inflammatory stimuli, and the effects of acute inflammation--comparable to levels observed in patients--remain unknown. Experimental ApproachTo address this, we examined whether acute inflammation induced under relatively mild, clinically relevant conditions suppresses behavioural sensitization in methamphetamine (METH)-sensitized mice, a model of psychostimulant-induced psychosis with relevance to certain aspects of positive symptoms of schizophrenia. We used a repeated METH (1 mg/kg) sensitized model to evaluate the effects of acute inflammation on behavioural sensitization. Acute inflammation was induced via two methods using either lipopolysaccharides (LPS; 1 g/kg) to mimic peripheral immune activation or restraint stress (RS; single 2-h exposure) to model the neuroinflammation induced by psychological stress. LPS doses were adjusted with reference to the magnitude of peripheral cytokine elevation reported in patients, and RS was applied in short single sessions to avoid excessive inflammation. Key ResultsBoth LPS and RS significantly suppressed behavioural sensitization, without inducing other behavioural abnormalities. This suppression was dependent on toll-like receptor-4 activation. LPS-mediated suppression involved cyclooxygenase-2, whereas RS-mediated suppression was linked to the microglia-derived tumour necrosis factor-. LPS did not alter, whereas RS significantly reduced the striatal extracellular dopamine levels. Conclusion and ImplicationsThese findings suggest that acute inflammation suppresses behavioural sensitization through distinct mechanisms depending on the inflammatory trigger, providing a framework for understanding how inflammation may influence psychosis-related processes, with potential relevance to schizophrenia.

RationaleCholinergic signalling is critical for attentional control and signal detection, yet the contribution of specific acetylcholine receptor (AChR) subtypes remains poorly understood. Although the 7 nicotinic AChR (nAChR) holds promise as a target for cognition-enhancing therapy, clinical findings to date have been inconsistent. ObjectiveTo investigate the effects of putative cognitive enhancing drugs, including those targeting cholinergic transmission and 7 nAChRs on a visual signal detection task (SDT). MethodsMale and female Sprague Dawley rats were trained on an SDT. Cholinergic transmission was probed systemically with nicotinic and muscarinic receptor antagonists (mecamylamine and scopolamine), a cholinesterase inhibitor (galantamine), an M4-AChR positive allosteric modulator (PAM; VU0467154), an 7 nAChR antagonist (MLA), an 7 nAChR PAM (CCMI), and an 7 nAChR partial agonist (SSR-180,711). Dopaminergic transmission was probed using the catechol-O-methyltransferase (COMT) inhibitor, tolcapone. A novel, trial-level signal detection theory-based generalised linear mixed-effects model (SDT-GLMM) was used to index response bias and perceptual sensitivity (d'), the latter reflecting subjects ability to discriminate signal from noise. ResultsMecamylamine profoundly impaired SDT performance across all measures. Galantamine significantly improved d' at moderate doses but not when a distractor was present. MLA uniquely produced dose-dependent improvements in d' that were preserved under distraction. In contrast, positive allosteric modulation and agonism of 7 nAChRs impaired task performance. Scopolamine, VU0467154, and tolcapone had no consistent or interpretable effects on signal detection. ConclusionsThis work demonstrates that 7 nAChR modulation bidirectionally and dose-dependently regulates perceptual sensitivity, irrespective of attentional distraction. These findings have implications for targeted cognitive enhancement in disorders of attention.

Electroencephalographic (EEG) microstates provide a compact framework for characterizing the temporal organization of large-scale brain activity, yet their sensitivity to altered brain states remains insufficiently explored. In this study, we applied broadband and frequency-resolved EEG microstate analysis to resting-state EEG data from two publicly available datasets acquired under markedly different altered-state conditions: psilocybin microdosing and acute inhaled N,N-dimethyltryptamine (DMT). The aim was to determine whether narrowband microstate analysis reveals structured alterations in resting-state brain dynamics beyond those captured by broadband analysis alone. Psilocybin microdosing was associated with relatively subtle effects, including reduced global field power and frequency-specific alterations in delta- and theta-band microstate parameters, while no significant broadband spatiotemporal changes were observed. In contrast, acute inhaled DMT was associated with broader microstate alterations spanning broadband, delta, theta, and alpha activity, indicating more extensive reorganization of temporal microstate expression. Across both datasets, a descriptive overlap was observed in the delta band, where microstate C showed increased duration and microstate D showed decreased occurrence. Given the substantial differences between datasets in dose, route of administration, temporal dynamics, and study context, these overlapping effects should be interpreted cautiously. Overall, the findings support frequency-resolved EEG microstate analysis as a useful approach for characterizing altered resting-state brain dynamics and for detecting frequency-specific effects that may be obscured in broadband summaries.

Background: Participants in the ReINVEST randomised placebo-controlled trial of sertraline, conducted among men with high trait impulsivity and histories of violent offending, received structured clinical contact throughout the trial, including psychiatric assessments, nursing consultations, crisis support, and referrals to mental health and external services. We estimated the effect of placebo trial participation, compared with non-participation after baseline and single-blind run-in, on violent and domestic-violence reoffending. Methods: This prespecified secondary analysis included men from the ReINVEST trial pathway who completed baseline assessment and entered the single-blind run-in phase but did not proceed to randomisation, to inform the counterfactual. Violent and domestic-violence offences were identified from linked administrative records over 12- and 24-month follow-up periods. The adjusted difference in offending was estimated using two independent analytical approaches accounting for baseline differences. Additional analyses examined whether the effect varied by baseline clinical and criminal-history characteristics, whether pre-randomisation external referrals explained selection into placebo participation, and whether post-randomisation external referrals accounted for any part of the estimated effect. Results: Placebo trial participation was associated with lower offending across both outcome domains and follow-up periods. Placebo-standardised mean count differences for violent offending were -0.19 (95% confidence interval [CI] -0.38, -0.04) at 12 months and -0.22 (95% CI -0.51, -0.05) at 24 months. Corresponding differences for domestic-violence offending were -0.37 (95% CI -0.81, -0.14) at 12 months and -0.49 (95% CI -0.92, -0.22) at 24 months. The association was more apparent among men with a documented psychiatric history and, for domestic-violence offending, among those with higher baseline anger, irritability and aggression. Pre-randomisation referrals did not explain selection into placebo participation or materially alter the estimates. Post-randomisation referrals were observed in both groups, remained more common in the placebo group, and did not account for the observed association. Conclusion: Placebo participation in this trial involved sustained clinical contact and psychosocial support beyond exposure to inactive medication, and these non-pharmacological components may have contributed to lower reoffending. In placebo-controlled trials involving populations with high psychiatric morbidity and limited continuity of coordinated care, the clinical content of placebo participation should be explicitly characterised in trial design and interpretation.

Background: Hydrogen sulfide (H2S) is an endogenous gasotransmitter synthesised in the central nervous system (CNS) primarily by cystathionine {beta}-synthase (CBS) and cystathionine {gamma}-lyase (CSE). Pre-clinical studies consistently implicates H2S deficiency in the pathophysiology of depression through disruption of synaptic plasticity, neuroinflammation, oxidative stress, and brain-derived neurotrophic factor (BDNF) signalling. Yet, we still lack direct clinical evidence quantifying circulating H2S in patients with Major Depressive Disorder (MDD), particularly from South Asian populations. In this study, we measured serum H2S levels in drug-naive patients with MDD and compared them with healthy controls at a tertiary care center in eastern India. We examined the associations between serum H2S and depression severity as assessed by the 17-item Hamilton Depression Rating Scale (HAM-D-17). This institution-based, cross-sectional analytical study was conducted at North Bengal Medical College and Hospital (NBMCH), West Bengal, India, over 12 months. Fifty drug-naive patients fulfilling DSM-5 criteria for MDD and fifty age- and sex-matched healthy controls were enrolled by consecutive sampling. We quantified serum H2S using the spectrophotometric methylene blue method and depression severity was assessed using HAM-D-17. Statistical analyses included independent-samples t-test, chi-square test, and linear regression. Serum H2S was markedly and significantly lower in MDD patients (0.068 {+/-} 0.044 {micro}mol/L) compared with healthy controls (0.524 {+/-} 0.272 {micro}mol/L; p < 0.001), representing an approximately 7.7-fold reduction. HAM-D-17 scores were significantly higher in MDD patients (28.94 {+/-} 12.78) than in controls (3.96 {+/-} 2.31; p < 0.001). Linear regression across the combined cohort revealed a significant negative association between serum H2S and HAM-D score (R{superscript 2} = 0.287; y = 24.64 - 26.84x; p < 0.001), indicating that higher serum H2S was associated with lower depression severity. Within the MDD group alone, the regression was weak (R{superscript 2} = 0.061), consistent with a floor effect. Within the control group alone, the regression was strong (R{superscript 2} = 0.772). No significant associations were found between serum H2S and any sociodemographic variable in either group. Drug-naive MDD patients exhibited substantially reduced serum H2S levels compared with healthy controls, and lower H2S was associated with greater depression severity. These findings provide direct clinical evidence from an Indian population supporting the H2S deficiency hypothesis of depression and suggest that the CBS/CSE-H2S axis may represent a novel biomarker and therapeutic target in MDD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/26352330v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1ce64f6org.highwire.dtl.DTLVardef@1465ca2org.highwire.dtl.DTLVardef@6bba64org.highwire.dtl.DTLVardef@9a1411_HPS_FORMAT_FIGEXP M_FIG C_FIG

Young people with major depressive disorder (MDD) exhibit altered thermoregulation, which has also been linked to vigilance and sustained attention. However, whether peripheral skin temperature is associated with cognitive vulnerability around sleep onset is unknown. We examined the relationship between the distal-proximal skin temperature gradient (DPG) and vigilance in 38 young people with MDD (20.1{+/-}3.7 years, 65.9% female) using an in-laboratory protocol spanning 4h before, to 2h after, habitual sleep time. Participants were classified into DPGwarm and DPGcold subgroups based on being above or below median DPG before sleep onset. Linear mixed models adjusted for age and sex examined psychomotor vigilance task performance across timepoints. The DPGwarm subgroup (n=19) showed significantly worse performance than DPGcold (n=19) across the evening for mean reaction time (RT), reciprocal reaction time, number of lapses, and fastest 10% of RT (all p[&le;]0.003). Significant GroupxTime interactions were observed for mean RT (F(3,90.4)=5.00, p=0.003) and lapses (F(3,93.6)=6.73, p<0.001), with DPGwarm participants showing progressively worse performance approaching sleep onset. At 2h post-habitual sleep onset, DPGwarm participants exhibited slower RT ({Delta}=129ms, p<0.001) and nearly four times more lapses (14.9 vs 4.1, p<0.001). Performance decrements were not accompanied by differences in melatonin timing, subjective sleepiness or mood, suggesting DPG may index cognitive vulnerability independently. Of note, younger age was associated with greater vigilance decrements. These findings demonstrate that elevated peripheral skin temperature before sleep onset is associated with reduced vigilance in young people with MDD, and may therefore have potential utility as a non-invasive thermoregulatory biomarker of cognitive vulnerability.

AimsTo examine the longitudinal dynamic interactions of craving and drug use in the course of treatment of stimulant use disorders. DesignCross-lagged residual dynamic structural equation modeling (R-DSEM) was used to examine the reciprocal (bidirectional) longitudinal associations between craving and drug use. SettingPooled data from 11 randomized controlled trials of pharmacotherapies for methamphetamine and cocaine use disorders in the United States sponsored by the National Institute on Drug Abuse. Participants1,936 adults with cocaine or methamphetamine use disorder. MeasurementsCraving was measured using Brief Substance Craving Scale (BSCS), drug use was measured using Timeline Followback and urine drug screen (UDS). FindingsCraving and stimulant drug use were dynamically associated over time (within-person association). Daily craving significantly predicted drug use in subsequent days (estimate=0.092, 95% credible interval [CrI]=0.081, 0.103 for self-reported drug use and estimate=0.081, 95% CrI=0.069, 0.095 for UDS-ascertained drug use). In turn, drug use predicted subsequent craving (estimate=0.361, 95% CrI=0.325, 0.398 and estimate=0.060, 95% CrI=0.028, 0.094, respectively). There was substantial between-person heterogeneity in these cross-lagged effects, as reflected in the coefficients of variation ranging from 0.78 to 2.88. ConclusionsThere is a bidirectional interaction between stimulant drug craving and drug use. The heterogeneity in the interaction of craving with stimulant drug use may partly explain between-person variability in responses to anti-craving medications in treatment of stimulant use disorders.

The ability to adjust to changing environments (cognitive flexibility) and optimal decision-making are pivotal brain functions that govern successful human behavior. Anxiety and depressive disorders are strongly pervasive psychiatric conditions across the lifespan that profoundly disrupt mechanisms of attention, working memory, and decision-making. Although existing task evidence documents impaired decision-making and flexibility outcomes for both anxiety and depression, there is a growing need to systematically evaluate the role of anxiety and depression and to quantitatively compare the effects of these disorders on these domains. In the present study, we conducted a meta-analysis of anxiety and depression on decision-making and cognitive flexibility. We utilized a random-effects approach, given that a large amount of between-subject heterogeneity was anticipated. Given the scope of this meta-analysis, we used the machine learning tool asReview to more efficiently conduct a meta-analytic search. Across all outcomes, results showed anxiety and depression were associated with reduced cognitive flexibility and decision-making. These effect sizes were then tested for significance using a fixed-effects (plural) model. Subgroup analyses revealed no significant differences between anxiety and depression for either decision-making or flexibility outcomes, consistent with a transdiagnostic perspective. Results are contextualized in light of the biopsychosocial model and potential transdiagnostic factors.

RationalePrenatal alcohol exposure (PAE) can result in Fetal Alcohol Spectrum Disorder (FASD), which consists of a group of diagnosable medical conditions that can include an increased risk for anxiety disorders and/or alcohol misuse, and sensory issues, such as increased mechanical sensitivity. ObjectiveThis study investigated how a single moderate PAE on gestational day 12 (G12) alters anxiety-like behavior, ethanol (EtOH) intake, and mechanical sensitivity across the lifespan of Sprague Dawley rats. MethodsPregnant dams were exposed to vaporized EtOH or room air (control) for 6 hours (BECs [~]108 mg/dL). Testing in male and female offspring began at three different ages: juveniles ([~]postnatal day (P) 25), adolescents ([~]P45) and adults ([~]P80). ResultsThe greatest PAE effects were observed in adolescent animals, with alterations in anxiety-like behaviors demonstrated in the light-dark box and elevated plus maze. Additionally, adolescent female animals consumed more sweetened EtOH compared to males. However, PAE adolescent animals consuming less sweetened EtOH compared to their counterparts, which was also observed in adult PAE females. Interestingly, this effect is reversed in juvenile and adolescent males when tested with unsweetened EtOH, with juvenile females consuming more EtOH also. Finally, PAE and air animals exhibited increased mechanical sensitivity following post-natal EtOH consumption across all ages. ConclusionThese data demonstrate that there are age- and sex-specific effects of PAE on anxiety-like behaviors, EtOH intake, and mechanical sensitivity that are more distinct in adolescent animals.