Addiction Biology

Background: Substance use disorders (SUDs), including alcohol and drug dependence, and smoking, pose a public health threat with their high prevalence and comorbidity with other diseases, and contribution to mortality. SUDs are highly correlated, and their genetic background is shared to some degree. Objectives: We aimed to investigate the genetic associations of previously reported loci for a wide range of SUDs in an unstudied Ukrainian population. Methods: We collected data from 595 individuals (339 women, 253 men), including 321 participants from two rehab centres. Based on clinical review and questionnaire data we defined drug dependence, alcohol dependence, alcohol abuse, binge drinking, smoking, opiate, amphetamine, cannabis, and hallucinogen use, along with several intermediary alcohol use and smoking variables considering the amount of use and the level of dependence. We genotyped COMT-rs4680, ADH1B-ADH1C-rs1789891, and HTR2A-rs6313, and applied logistic and ordered logistic regression assuming an additive inheritance model, controlling for the recruitment group, other substance uses, age, and sex, in the association analyses. Results: We replicate (P<0.05) the associations at COMT-rs4680 with smoking status (OR[95% CI]=1.56[1.01-2.41], P=0.047) and heaviness (1.37[1.04-1.80], P=0.026), and at ADH1B-ADH1C-rs1789891 and HTR2A-rs6313 with alcohol dependence (1.69[1.03-2.76], P=0.038 and 0.66[0.47-0.92, P=0.016], respectively). Furthermore, we provide evidence for an association at HTR2A-rs6313 with hallucinogen use (0.58[0.35-0.98], P=0.040). Conclusion: In this study on multiple SUDs we shed light on the genetic background of SUDs in Ukrainians and provide further evidence that variation at COMT is mainly associated with smoking, at ADH1B-ADH1C with alcohol-related variables, whereas HTR2A is a more general SUD-associated locus.

Regular cannabis use has been associated with alterations in reward-related neural processes, yet findings remain inconsistent and the relationship between neural activity and behavioural performance is not fully understood. The present study aimed to characterise neural and behavioural correlates of reward processing in regular cannabis users (CU) compared with matched non-users (NU) using the Monetary Incentive Delay Task (MIDT). Firstly, we assessed behavioural performance through reaction times, accuracy and monetary earnings to determine whether potential neural alterations were reflected in task performance. Secondly, focusing on reward-related brain regions, we examined group differences in BOLD functional MRI activity during anticipation and outcome phases separately for monetary win and loss conditions. Finally, we explored the association between behavioural performance and neural activation. Our findings indicate that regular cannabis use is associated with altered engagement of key nodes within the mesocorticolimbic circuit during both anticipatory and outcome phases of reward processing, accompanied by impaired behavioural performance. Particularly, compared with NU, CU showed (I) lower striatal activity during anticipation of monetary win and higher ventral striatum and frontal pole activity during anticipation of monetary loss; (II) greater VTA activation during outcome of successful monetary win and loss avoidance and lower frontal pole activity during outcome of unsuccessful loss avoidance; (III) impaired behavioural performance, reflected in lower monetary rewards and a trend towards slower reaction times and reduced accuracy; (IV) disrupted brain-behaviour coupling. Results from this study may help inform future research on the neurobiological mechanisms underlying changes in reward function and the resultant behavioural consequences of cannabis use.

BackgroundPersistent automatic approach tendencies toward alcohol cues that resist goal-directed control are a key feature of harmful alcohol use, yet the causal neural mechanisms underlying this imbalance remain poorly understood. Converging evidence implicates the frontoparietal network (FPN) in actively regulating alcohol approach-avoidance behavior, but whether its constituent nodes make dissociable causal contributions has not been established. MethodsIn a within-subject, active-sham counterbalanced design, inhibitory continuous theta burst stimulation (cTBS) was applied to right dorsolateral prefrontal cortex (rDLPFC) and right posterior parietal cortex (rPPC) in separate groups of non-clinical alcohol users (rDLPFC: n = 29; rPPC: n = 28), followed by an Alcohol Approach-Avoidance Task. ResultsActive rDLPFC cTBS selectively slowed down alcohol push responses, whereas rPPC suppression produced a bidirectional action-specific shift in response to alcohol cues, where pull responses accelerated, and push slowed simultaneously. Suppression of either node shifted automatic tendencies toward greater alcohol approach through mechanistically distinct routes. ConclusionThese dissociable profiles indicate that rDLPFC is causally necessary for effortful top-down avoidance control, while rPPC supports the priority-based selection of alcohol cue-driven actions. These findings provide the first node-specific causal evidence for functional specialization within the FPN in the context of automatic tendencies towards alcohol. Alcohol avoidance emerges as an active, prefrontal-dependent process, whereas priority-based regulation emerges as a parietal-dependent process, together indicating rDLPFC and rPPC as mechanistically independent targets for intervention in maladaptive alcohol approach behavior.

There is a dearth of information on how different cocktails sweetened with different sugars impact brain activity. Glucose enters the brain faster and in greater concentration than fructose and directly affects neuronal activity of melanin-concentrating hormone (MCH) neurons. MCH signaling promotes both glucose drinking and alcohol intake by integrating central and sensory inputs, but it is currently unknown how MCH neuronal activity relates to sweetened cocktail drinking. This study sought to investigate the relationship between MCH activity and sugar-sweetened alcoholic cocktail drinking. We also sought to compare MCH neuronal responses to the sugar solutions without alcohol as well as their response to sensory stimuli. In female and male rats, we used fiber photometry to monitor MCH neurons in response to sensory stimuli and during drinking of 10% glucose, 10% fructose, and glucose or fructose cocktails with 1.25% or 10% alcohol. We found that MCH activity rises in response to a variety of sensory stimuli and peaks before the start of drinking for all cocktails, before returning to baseline near the start of drinking. The cocktail type impacted the dynamics of MCH activity, where increased alcohol concentration resulted in earlier MCH activity for fructose but not glucose cocktails. Finally, we found that peak MCH activity during drinking is correlated with approach behavior for all sugar and cocktail types. These findings suggest that glucose and alcohol may interact to directly influence MCH activity. Further, MCH neurons may regulate cocktail drinking in response to sugar type and alcohol concentration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/719280v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@b992c3org.highwire.dtl.DTLVardef@1526895org.highwire.dtl.DTLVardef@1504c6dorg.highwire.dtl.DTLVardef@c990fc_HPS_FORMAT_FIGEXP M_FIG C_FIG New and noteworthyFiber photometry was used to monitor lateral hypothalamic melanin-concentrating hormone (MCH) neurons in male and female rats during sensory stimuli and drinking of glucose, fructose, or glucose- or fructose-sweetened alcoholic cocktails. Subsecond-scale changes in MCH activity occurred after stimuli. Peak MCH activity during drinking was correlated with approach behavior. Alcohol concentration only impacted MCH activity with fructose cocktails. We discuss the implications of MCH dynamics towards brain function, associative learning, and alcohol use disorder.

Objectives: Non-suicidal self-injury (NSSI) and self-harming sexual behaviours share functional and behavioural overlaps. However, the relationship between NSSI and problematic sexual behaviour (PSB) remains underexplored. This study aimed to investigate the association between NSSI and PSB in two cohorts - a non-clinical university cohort and a clinical PSB patient cohort. Methods: Data were collected from 2,189 university participants and 477 clinical PSB patients. NSSI was assessed via self-report, and PSB was measured with the Sexual Addiction Screening Test-Revised (SAST-R) Core. The four core addictive dimensions of PSB: relationship disturbance, loss of control, preoccupation, and affect disturbance, were also evaluated. Logistic regression analyses were conducted to examine the association between PSB (presence/absence and severity) and NSSI, looking at effects of gender and contributions of addictive dimensions of PSB. Results: Rates of NSSI were similar in the university (7.1%) and patient (5.7%) cohorts; stratified by gender, a higher proportion of women PSB patients had NSSI compared to in the university cohort (29.3% vs 9.3%). In the university group, who had milder PSB than patients, PSB was associated with NSSI (OR=2.11, p<0.001); a significant gender by PSB interaction was found showing that women with PSB were over four times more likely to have NSSI than men without PSB (OR=4.44, p=0.037). In contrast, PSB severity was not associated with NSSI in PSB patients (OR=1.10, p=0.25). Associations of the addictive dimensions of PSB with NSSI were observed only in the subgroup of university women, in the 'preoccupation' dimension (p<0.001). Conclusions: Our findings highlight gender-specific patterns in the association between PSB and NSSI, suggesting the need for further research and possibly targeted prevention and intervention strategies in women.

Objectives: To evaluate the effectiveness and cultural feasibility of family-supervised disulfiram as a first-line treatment for alcohol use disorder (AUD) in Sri Lanka, and to compare its clinical outcomes with standard therapy delivered at a tertiary psychiatric unit. Design: Single-blind Randomized Controlled Trial known as ETAT-RCT (Efficacy of Two Alcohol Treatments) was conducted under routine clinical setup with three parallel groups: family-supervised disulfiram, locally developed psychosocial intervention, and routine treatment. Allocation was independently concealed; assessors were blinded. Analyses followed an intention-to-treat approach using repeated-measures ANOVA (group x time). This paper reports the disulfiram (test) versus routine treatment (control) comparison; the psychosocial intervention will be reported separately. Setting: University Psychiatry Unit, National Hospital of Sri Lanka, Colombo (UPU, NHSLC). Participants: Patients aged [&ge;]14 years with AUD presenting to the unit were recruited consecutively without inducements. Planned allocation ratio was 1:1:1 with 31 participants per arm; key exclusions were lifetime psychotic disorder and current contraindication to disulfiram. Randomisation: Participants were randomised into each treatment arm using an independent concealed paper-based allocation system. Intervention: (1) family-supervised disulfiram, with psychoeducation/support only - DT arm, (2) a locally developed denormalization focused psychosocial programme - PT arm, and (3) standard therapy (motivational/cognitive/behavioural input; naltrexone permitted; no disulfiram/denormalisation) - ST arm. Outcome measures: Primary outcome was Alcohol Use Disorders Identification Test (AUDIT) score at 12 months. Key secondary outcomes were past 30 day alcohol use via Timeline Follow-Back (TLFB); alcohol biomarkers [ALT (alanine aminotransferase), {gamma}-GT (gamma-glutamyl transferase), MCV (mean corpuscular volume)]; locally developed measures of addiction-relevant cognitive, affective, behavioural factors [AARSU (Attitude Assessment Related to Substance Use), BARSU (Behaviour Assessment Related to Substance Use)]; and Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Outcomes were assessed at baseline, 6, and 12 months. Results: Participants in DT (n=33) and ST (n=38) were comparable at baseline. Both groups showed clinically and statistically significant improvement in AUDIT scores over 12 months (DT: F=39.90, p<0.001; ST: F=49.90, p<0.001), with no group x time interaction (F<0.001, p=0.98). Biomarkers and AARSU, and BARSU and Q-LES-Q-SF to a lesser degree, mirrored the AUDIT pattern. TLFB did not change significantly over time in either arm (p>0.05). In moderator analyses, improvement in AUDIT was not moderated by baseline motivation (F=0.20, p=0.89) but was moderated by baseline AUD severity (F=7.70, p=0.007). No serious adverse events were attributed to disulfiram. Adherence to supervised dosing was generally high during periods of supervision but intermittent overall. Conclusions: In this pilot RCT, family-supervised disulfiram achieved 12-month outcomes comparable to standard therapy in a tertiary Sri Lankan setting. Improvements were independent of baseline motivation and varied by baseline AUD severity. These findings may support family-supervised disulfiram as a culturally feasible first-line option in Sri Lanka; larger, adequately powered multicentre trials are warranted to confirm effectiveness and scalability. Trial registration: SLCTR/2014/021

Affective biases are important neuropsychological mechanisms by which emotions modulate cognition, behaviour and the subjective experience of mood. Previous studies have shown that the rapid-acting antidepressant, ketamine, and serotonergic psychedelic, psilocybin, modulate affective biases in a translational rat model. Both treatments differ from conventional, delayed onset antidepressants in being able to attenuate negatively biased memories and facilitate re-learning with a more positive affective valence. Psilocybin, but not ketamine, also positively biased new experiences, an effect similar to conventional antidepressants. This study used the different affective bias test protocols, in adult male rats, to investigate the effects of acute treatment with the serotonergic psychedelics N,N-DMT, LSD and 5-MeO-DMT, and MDMA. These drugs have different pharmacology in relation to their effects on serotonin receptor subtypes and we hypothesised this may influence their modulation of affective biases. When comparing the ability to attenuate a negatively biased memory, only MDMA had specific effects although for all drugs tested, retrieval of the FG7142-induced negative affective bias was more variable and less robust statistically. LSD attenuated the negative bias at higher doses but had non-specific effects on memory retrieval. At 24hrs post treatment only N,N-DMT had a sustained effect and none of the treatments facilitated re-learning with a more positive affective valence. However, like psilocybin and conventional antidepressants, N,N-DMT positively biased new experiences. These findings suggest there are divergent affective bias modulating effects associated with different psychedelics which may be relevant to their antidepressant effects.

Obsessive compulsive disorder (OCD) is significantly heritable, but only a fraction of the contributory genetic variation has been identified, and the molecular etiology involved remains obscure. Identifying rare contributory variants of large effect would be an important milestone in helping to elucidate the mechanisms involved. Analysis of densely affected pedigrees is a potentially useful strategy to bypass the sample size challenges of standard case-control approaches. Here we performed whole genome sequencing (WGS) of 25 individuals across two multiplex OCD pedigrees. We prioritised rare variants using a Bayesian inference approach which incorporates variant pathogenicity and co-segregation with OCD. In the first pedigree, we identified a highly deleterious missense variant in NPY5R, carried by the majority of affected individuals. This gene is brain-expressed and has previously been implicated in panic disorder and internet addiction GWAS studies. In the second pedigree, we identified a large deletion of DLGAP1 and a missense variant in MAPK8IP3, that perfectly co-segregated in a specific branch of the family: both genes have previously been implicated in OCD and autism. Both genes contribute to a protein interaction network including ERBB4 and RAPGEF1 which we had previously identified in a large Tourette Syndrome pedigree. Our analysis suggests that both energy homeostasis and downstream signalling from the post-synaptic density may both be important avenues for future research.

Alternative-splicing events (ASE) increase transcriptomic variability and play key roles in biological functions. The contribution of ASE to bipolar disorder (BD) remains largely unexplored. We performed a Transcriptome-Wide Alternative-Splicing Analysis (TWASA) to identify ASEs and genes potentially involved in BD. The study comprised 635 individuals: a discovery sample (DS) of 31 individuals from eight multiplex BD families (16 BD cases; 15 unaffected relatives), and a replication sample (RS) of 604 subjects (372 BD cases; 232 controls). Sequencing was conducted on RNA from lymphoblastoid cell lines (DS) and whole blood (RS). TWASA was performed using VAST-TOOLS (VT), rMATS (RM), and MAJIQ/MOCCASIN (MCC). Gene-set association analyses of genes containing ASEs were performed across six psychiatric disorders. Novel ASE (nASE) were investigated in the DS using FRASER. Limited gene overlap was observed across TWASA tools. MCC identified 2,031 complex ASEs involving 1,508 genes, showing the strongest genetic association with BD across psychiatric phenotypes. Prioritization of MCC-identified ASE genes yielded 441 candidates, including DOCK2 as top candidate from the DS. Replication was obtained for 98 genes, five with an identical ASE, and four (RBM26, QKI, ANKRD36, and TATDN2) showing a concordant percentage-spliced-in direction with the DS. Finally, 578 nASE were identified in the DS, with no evidence of familial segregation or differences in ASE types. This first TWASA in BD reveals tool-specific variability, complex ASE for genes specifically associated with BD, and novel candidate genes for BD. Alternative transcript isoform abundance may represent a mechanism contributing to BD pathophysiology.

Background: The etiology and nosological status of seasonal affective disorder (SAD) as a specifier of depressive episodes versus a transdiagnostic disorder are the subject of debate. In this study, we investigated the underlying etiology of SAD and dimensional seasonality by examining their association with latitude and genetic risk for a range of traits, and investigated gene-environment interactions. Methods: This study included 12,460 adults aged 18-90 with a history of depression from the Australian Genetics of Depression Study. Regression models included predictors for latitude (distance from equator) and polygenic scores for eight traits; major depressive disorder, bipolar disorder, anxiety disorders, chronotype, sleep duration, body mass index, vitamin D levels, and educational attainment. Outcomes were SAD status and general seasonality score. Results: SAD was positively associated with latitude (OR[95%CI] = 1.05[1.03-1.06], padjusted<0.001), and there was nominal evidence of additive and multiplicative interactions between chronotype genetic risk and latitude (OR = 0.99[0.99-0.99], padjusted=0.381; OR=0.98[0.97-0.99], padjusted=0.489). General seasonality score was associated with latitude (IRR=1.01[1.01-1.01], padjusted 0.001) and genetic risk for major depressive disorder (IRR =1.02[1.01-1.03], padjusted<0.001), bipolar disorder (IRR=1.02[1.01-1.03], padjusted=0.001), anxiety disorders (IRR=1.03[1.01-1.04], padjusted<0.001), vitamin D levels (OR=0.89[0.80-0.95], padjusted=0.048), and educational attainment (IRR=0.97[0.96-0.99], padjusted<0.001). Conclusions: These findings enhance understanding of SAD etiology, highlighting contributions of psychiatric genetic risk and geographic measures on seasonal behavior, and support examining seasonality as a continuous dimension.

Schizophrenia frequently follows a chronic relapsing-remitting course, comprising alternating episodes with and without psychotic symptoms (hereafter: psychosis and psychotic remission). One potential neurobiological correlate of this course is aberrant dopamine synthesis and storage (DSS) in the striatum, which can be estimated by 18F-DOPA positron emission tomography (PET). We hypothesised that striatal DSS in patients with schizophrenia decreases from psychosis to psychotic remission, with lower striatal DSS in patients during psychotic remission compared to healthy subjects. Additionally, we explored whether striatal DSS is associated with psychotic relapse after remission. 18F-DOPA PET scans and clinical assessments were conducted in 28 patients with schizophrenia at two timepoints, first during psychosis and second during early psychotic remission 6 weeks to 12 months after the first timepoint, as well as in 21 healthy controls, assessed twice in a comparable time interval. The averaged influx constant kicer as proxy for DSS was calculated for striatal subregions (i.e., nucleus accumbens, caudate, and putamen) using voxel-wise Patlak modelling with a cerebellar reference region. Mixed-effects models and post hoc analyses were used to test for longitudinal changes in kicer and cross-sectional group differences. An exploratory clinical follow-up 12 months after the second scan was conducted to assess psychotic relapse, and post hoc ANCOVAs were used to test for differences in kicer at each session between relapsing and non-relapsing patients. Kicer in both caudate and nucleus accumbens significantly changed from psychosis to psychotic remission compared to healthy controls, with a significant longitudinal decrease of caudate kicer in patients. Furthermore, kicer in both caudate and accumbens was significantly lower in patients during early psychotic remission compared to controls. At the exploratory clinical follow-up, 32% of patients had experienced a psychotic relapse; they showed higher caudate kicer compared to non-relapsing patients during psychosis, with no difference during psychotic remission. These findings provide evidence for the link between striatal, particularly caudate, DSS and the relapsing-remitting course of psychotic symptoms in schizophrenia, with lower caudate DSS during early psychotic remission. Data suggest altered striatal dopamine synthesis together with impaired DSS dynamics along the course of psychotic symptoms in schizophrenia.

D-Aspartate (D-Asp) is an endogenous D-amino acid that exhibits a pronounced developmental peak in the mammalian brain, suggesting a potential regulatory role in glutamatergic signaling and neurodevelopment. Disruption of D-Asp homeostasis has been associated with neuropsychiatric disorders characterized by early-life circuit vulnerability, including schizophrenia and autism spectrum disorders. However, its functional impact to hippocampal physiology remains incompletely defined. Here, we investigated how constitutive D-Asp depletion affects synaptic function in the hippocampal CA1 region of Ddo-knock-in (Ddo-KI) mice, in which zygotic overexpression of the D-Asp-degrading enzyme, D-aspartate oxidase (DASPO), results in embryonic and persistent D-Asp deficiency. Electrophysiological recordings were performed in acute hippocampal slices from male and female mice at postnatal day 30 (P30) and day 60 (P60). Basal synaptic transmission, assessed through paired-pulse ratio and spontaneous excitatory/inhibitory events, was unaltered between genotypes, indicating preserved presynaptic release probability and overall excitation/inhibition balance. In contrast, NMDA receptor (NMDAR)-dependent synaptic plasticity was selectively altered, as theta-burst stimulation induced significantly greater long-term potentiation (LTP) in juvenile P30 Ddo-KI mice, whereas this difference was no longer observed at P60. Consistently, patch-clamp recordings revealed a reduced AMPAR/NMDAR ratio in P30 Ddo-KI males, suggesting an increased relative contribution of NMDAR-mediated currents. Importantly, acute bath application of exogenous D-Asp restored LTP to wild-type levels, demonstrating rapid reversibility and supporting a model of homeostatic receptor rebalancing rather than irreversible circuit alterations. Biochemical assays confirmed significantly increased DASPO activity and reduced D-Asp levels in Ddo-KI mice. However, these parameters remained stable between P30 and P60, indicating that the age-dependent plasticity phenotype is unlikely to arise from progressive biochemical changes. Together, these findings indicate that developmental D-Asp deficiency induces a transient, juvenile-specific alteration characterized by enhanced NMDAR-dependent synaptic plasticity, which can be rapidly normalized upon D-Asp re-exposure.

This updated systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and obesity related complications. Medline and Embase were searched up to 21 November 2025 for randomized controlled trials comparing OMMs versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and 3 years, anthropometric, metabolic, mental health and quality of life outcomes, cardiovascular morbidity and mortality, remission of obesity related complications, serious adverse events and all cause mortality. Sixty six RCTs (66 comparisons) were identified: orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5) and phentermine/topiramate (2), enrolling 63,909 patients (34,861 and 29,048 with active compound and placebo, respectively). All OMMs showed significantly greater TBWL% versus placebo; tirzepatide and semaglutide exceeded 10% TBWL and showed the most favourable glycaemic effects. Semaglutide reduced major adverse cardiovascular events and all cause mortality. In dedicated complication specific trials, semaglutide and tirzepatide showed benefit on heart failure related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome and semaglutide with knee osteoarthritis pain remission. Tirzepatide and semaglutide were associated with improvements in metabolic dysfunction-associated steatohepatitis remission, and semaglutide with improvement in liver fibrosis. No OMMs were associated with an increased risk of serious adverse events. These updated results reinforce the need to individualize OMMs selection according to weight loss efficacy, complication profile and safety.

Chronic pain and nicotine use frequently co-occur, and individuals with chronic pain often experience greater difficulty quitting. Therefore, we examined nicotine withdrawal behaviors and analgesic-like effects in pain-naive and chronic pain conditions. Adult male and female rats underwent chronic constriction injury or sham surgery. After pain establishment, rats received twice-daily subcutaneous nicotine (0.3 or 0.7 mg/kg) or saline for 14 days. 24 h after the final injection, withdrawal was assessed, including physical signs and anxiety-like behavior. Depressive-like responses were evaluated at 72 h. Pain sensitivity and nicotines analgesic-like effects were assessed throughout. Chronic pain increased physical signs of withdrawal in both sexes, with greater effects in females. It also induced anxiety-like behavior in controls of both sexes. In rats with comorbid chronic pain and withdrawal, anxiety-like behavior was further enhanced in males, whereas females showed variable responses across assays, with increases or decreases depending on the test. Chronic pain induced depressive-like behavior in males but not in females. During withdrawal, depressive-like responses in males with chronic pain were not greater than those in the chronic pain alone group, while chronic nicotine exposure reduced depressive-like behavior in females. Nicotine produced acute analgesic-like effects that diminished over time in both pain-naive and chronic pain conditions, indicating tolerance. In pain-naive rats, repeated nicotine exposure induced mechanical hypersensitivity. Chronic pain intensified nicotine withdrawal severity in a nicotine concentration- and sex-dependent manner. These findings highlight the importance of considering pain status and sex when developing effective cessation strategies, particularly for individuals with comorbid chronic pain. SummaryChronic pain exacerbates nicotine withdrawal severity. Chronic nicotine exposure induces pain hypersensitivity and tolerance to analgesic effects. These effects vary by nicotine concentration and sex.

Background: Early adolescence is a common period of onset for depressive symptoms. In part, this may reflect a developmental manifestation of individual's genetic propensities as they undergo physiological and hormonal changes and interact with new environments. Many commonly proposed mechanisms assume direct effects of an individual's own genes on emerging variation in their depressive symptomatology. However, estimates of genetic influence based on analyses in unrelated individuals capture not only direct genetic effects but also genetic effects from parents and other biologically related family members. Aim: In data from the Norwegian Mother, Father and Child Cohort (MoBa), we used linear mixed models to distinguish developmentally-stable and adolescence-specific direct and parental indirect genetic effects. We examined effects of polygenic scores for major depressive disorder (MDD), ADHD, anxiety disorders, and educational attainment (EA) on depressive symptoms, which were assessed by maternal reports at ages 8 and 14. Results: Children's own MDD polygenic scores showed adolescence-specific effects on depressive symptoms ( b_PGS*wave=0.041, [95% CI: 0.017, 0.065]). Developmentally-stable direct effects from children's polygenic scores for MDD (b=0.016, [0.006, 0.039]), ADHD (b=0.024, [0.008, 0.041]) and EA (b=-0.02, [ -0.038, -0.002]) were also evident. The only evidence of indirect genetic effects was a stable effect of maternal EA polygenic scores (b=0.04, [0.024, 0.054]). Conclusion: Direct genetic effects linked to genetic liability to MDD accounted for emerging variation in depressive symptoms in adolescence. These results imply that specific etiological mechanisms related to MDD may become particularly relevant for depressive symptoms during early adolescence compared to at earlier ages.

GLP-1 receptor agonists have reshaped obesity therapeutics, but their impact on neuropsychiatric outcomes remains poorly characterized. From 29 million patients in a large federated data platform across the USA, including 489,785 semaglutide treated patients, we conducted an observational study integrating longitudinal neuropsychiatric outcomes. From this population, we assembled a cohort of 63,215 patients with baseline neuropsychiatric conditions before treatment initiation and evaluated 24 incident neuropsychiatric outcomes. In propensity-matched comparator analyses, during the 2 year time-period from treatment initiation, semaglutide was associated with broadly lower neuropsychiatric event risk than metformin, SGLT2 inhibitors, and DPP-4 inhibitors. Within the semaglutide-treated cohort, higher attained dose during the first two years after the first prescription ("pre-landmark period") was associated with significantly lower incidence during the following two years ("post-landmark period") of diagnostic codes associated with substance-related disorders (P<0.001), mood disorders (P<0.001), anxiety- and stress-related disorders (P<0.001), CNS atrophies (P<0.001), neuromuscular disorders (P=0.013), eating/sleep/behavioral disorders (P=0.022), and personality/impulse-control disorders (P=0.028). Consistent with previous clinical trials, the post-landmark incidence of dementia or CNS degenerative diseases was similar between the high-dose and low-dose semaglutide cohorts (P=0.15). For most neuropsychiatric diagnoses, post-landmark incidence was strongly associated with the maximum attained semaglutide dose during the pre-landmark period, but incident cognitive symptoms and speech/language symptoms were more closely linked to the pre-landmark weight-loss magnitude (p<0.001 and p<0.003, respectively). Bulk and single-cell transcriptomic analyses demonstrated GLP1R expression in CNS tissues (hypothalamus, caudate, putamen, nucleus accumbens, cerebellum) and peripheral nerves. Age-associated heterogeneity in GLP1R expression was evident in several of these compartments including the caudate nucleus, suggesting dynamic changes in the availability of the neurobiological substrate for semaglutide response. Together, these data support a model in which semaglutide confers a sustained, dose-dependent, weight loss-independent benefit across multiple neuropsychiatric conditions via direct CNS target engagement. This observational study motivates prospective clinical studies and mechanistic analyses to clarify the impact of GLP-1 receptor agonists on human neuropsychiatric pathways and disease processes.

Catatonia is a severe psychomotor syndrome that occurs across psychiatric diagnoses and is increasingly conceptualized as reflecting neurodevelopmental vulnerability. The anterior cingulate cortex (ACC) plays a central role in motor initiation and cognitive-affective integration and displays substantial interindividual variability in its sulcal morphology, which is established prenatally and remains stable across life. In this MRI study, we examined whether ACC sulcal patterns represent a structural trait marker of catatonia. We analyzed high-resolution T1-weighted images from a hospital-based cohort comprising patients with catatonia (N = 109), psychiatric patients without catatonia (N = 323), and healthy controls (N = 91). The presence of the paracingulate sulcus (PCS) in each hemisphere was determined through blinded visual inspection, and regression analyses tested associations with diagnostic group, adjusting for age, sex, scanner type, intracranial volume, and benzodiazepine and antipsychotic exposure. Patients with catatonia exhibited a significantly reduced prevalence of the left PCS and diminished hemispheric asymmetry compared with both non-catatonic patients and healthy controls. These effects were independent of whether catatonia occurred within psychotic or mood disorders. PCS size did not differ across groups, and sulcal pattern did not correlate with catatonia severity among affected individuals. The findings demonstrate that ACC sulcal deviations are specifically associated with catatonia across diagnostic categories, supporting a neurodevelopmental etiology and reinforcing ACC involvement in its pathophysiology. Early-determined sulcal morphology may represent a trait-level marker contributing to vulnerability for catatonia, with implications for early identification, risk stratification, and targeted intervention strategies.

BackgroundThe severity of positive psychotic symptoms largely defines emerging psychosis syndromes. However, depressive and negative symptoms are strongly psychologically and biologically interlinked. A transdiagnostic exploration of symptom severity across early illness syndromes could enhance the understanding of shared common factors and future trajectories of mental illness. We aimed to identify subgroups based on the severity of positive, negative, and depressive symptoms and assess relationships with: 1) premorbid functioning, 2) longitudinal illness course, 3) genetic risk, and 4) brain volume differences. MethodsWe analysed 749 participants from a multisite, naturalistic, longitudinal (18 months) cohort study of: clinical high risk for psychosis (n=147), recent onset psychosis (n=161), and healthy controls (n=286), and recent onset depression (n=155). Participants were stratified into subgroups based on severity of baseline positive, negative, and depression symptoms. Baseline and longitudinal differences between groups for clinical, functioning, and polygenic risk scores (schizophrenia, depression, cross-disorder) were assessed with ANOVAs and linear mixed models. Voxel-based morphometry was used to examine whole-brain grey matter volume differences. Discovery findings were replicated in a held-out sample (n=610). ResultsParticipants were stratified into no (n=241), mild (n=50), moderate (n=182), and severe symptom (n=254) subgroups. The mean (SD) age was 25.3 (6.0) and 344 (47.3%) were male. Symptom severity was associated with poorer premorbid functioning and illness trajectory, greater genetic risk, and lower brain volume. Findings were not confounded by the original study groups or symptoms and were largely replicated. Conclusions and relevanceTransdiagnostic symptom severity is linked to shared aetiologies, prognoses, and biological markers across diagnoses and illness stages. Such commonalities could guide therapeutic selection and future research aiming to detect unique contributions to specific psychopathologies.

Scratching provides transient relief from itch, yet the neural circuit mechanisms that transform scratching into itch relief remain poorly understood. Midbrain dopaminergic neurons and their downstream targets in the lateral shell of the nucleus accumbens (NAc LaSh) are implicated in itch-scratch processing. Previous studies show that pharmacological manipulation of dopamine D1 and D2 receptors in the NAc LaSh alters scratching behavior, but the specific contributions of D1R- and D2R-expressing neurons during acute and chronic itch remain unclear. Here, we show that NAc LaShD1R and D2R neurons bidirectionally regulate scratching behavior across itch states. NAc LaShD1R neurons activity promotes scratching bouts, whereas NAc LaShD2R neurons preferentially facilitate scratch termination. Anterograde viral tracing revealed distinct brain-wide projection patterns of NAc LaShD1R and D2R neurons, which we functionally tested using projection-specific optogenetic manipulations. We found that NAc LaShD2R neurons terminate scratching by inhibiting neurons in the lateral parabrachial nucleus (LPBN), a key hub for itch processing. Furthermore, dopamine levels in the NAc LaSh were elevated during chronic itch compared with acute itch, suggesting enhanced dopaminergic signaling contributes to persistent scratching. Together, these findings identify circuit mechanisms linking reward pathways to itch regulation.

ImportanceBlood-based biomarkers hold promise for psychiatric diagnosis and prognosis, yet clinical translation is constrained by poor reproducibility. Psychiatric biomarker studies are typically small, and demographic, behavioral, and temporal covariates often go undetected or cannot be adequately modeled. This may lead to residual confounding and unstable associations. ObservationsLeveraging UK Biobank data (N=~500,000), we systematically quantified how technical, demographic, behavioral, and temporal covariates influence 29 blood biomarkers commonly measured in research studies in psychiatry. Variance analyses showed substantial differences across biomarkers. Technical factors explained 1-6% and demographic factors explained 5-15% of the variance, with pronounced age-by-sex interactions for lipids and sex hormones. Behavioral covariates, particularly body mass index (BMI) and smoking, strongly influenced inflammatory markers. Temporal factors introduced systematic confounding. Chronotype was associated with blood collection time, multiple biomarkers exhibited marked diurnal rhythms (including testosterone, triglycerides, and immune markers), and inflammatory markers showed seasonal peaks in winter. In association analysis of biomarkers with major depression, bipolar disorder and schizophrenia, covariate adjustments attenuated or eliminated a substantial proportion of the biomarker-disorder associations, with BMI emerging as the dominant confounder. These findings demonstrate that such confounding structures exist and can be characterized in large cohorts, though specific biomarker-disorder relationships require validation in clinical samples. Conclusions and RelevancePoor reproducibility of biomarkers may not only stem from insufficient biological signal but also from inconsistent handling of confounders. We propose a systematic framework distinguishing technical factors (to be removed), demographic factors (addressed through adjustment or stratification), temporal factors (ideally controlled at design stages), and behavioral factors (requiring explicit causal reasoning). Associations robust to multiple adjustment strategies should be prioritized for clinical biomarker development. Standardized collection protocols, comprehensive covariate measurement, and transparent reporting across models are essential to improve reproducibility and identify biomarkers that reflect genuine illness-related pathophysiology.