The latent structure and longitudinal stability of cognitive heterogeneity during the early course of mood and psychosis spectrum illness has not been well-studied. We determined the presence, stability and characteristics of latent cognitive profiles underlying a transdiagnostic sample of individuals at high risk for psychosis (CHR) or with a recent onset of psychosis (ROP) or depression (ROD). The sample comprised 666 CHR, ROP or ROD individuals. Latent Profile Analysis identified transdiagnostic cognitive profiles in baseline and 11-month follow up data. Latent Transition Analysis established the stability of these profiles and their transition probabilities. Profiles were characterised across several clinical factors and those indexing functioning, neurodevelopment, stress exposure, and physical/brain health. A 3-profile model was most optimal at both timepoints, with profile equivalence metrics indicating a low likelihood of transition between them, and thus, temporal stability. The profiles were labelled 'Average Cognition', Moderately Impaired', 'Severely Impaired', with all diagnoses represented in each. No changes in cognition were observed for any profile over the follow-up despite clinical symptom improvement. The Severely Impaired profile had the lowest premorbid adjustment, brain and cognitive reserve, and the highest levels of functional impairment. A higher number and burden of recent stressful life events were reported in the Average Cognition profile. The findings suggest that stable transdiagnostic latent cognitive profiles are observable even at very early stages of manifest mood and psychotic illness. The Severely Impaired profile appears to map to indices of abnormal neurodevelopment, while the Average Cognition profile appears to represent a more stress-resilient phenotype.
Serotonergic psychedelics primarily exert their effects through activation of the serotonin (5-HT) 2A receptor (5-HT2AR). However, the full pharmacological profiles of these substances involve multiple serotonin receptor subtypes and intracellular signaling pathways. This study characterized the signaling behavior of a panel of serotonergic psychedelics using stable cell lines and a series of bioassays targeting phospholipase C (PLC) activation via inositol monophosphate (IP1) formation, phospholipase A2 (PLA2) activation, β-arrestin2 recruitment, and Gαi-protein dissociation across 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors. The results of the study indicate that IP1 formation offers the most robust and reproducible measure of 5-HT2R receptor activation and aligns most closely with human dosing data. Particularly for the 5-HT2AR, PLC-IP1 activation exhibited a strong correlation with known psychoactive doses, contrasting with assays that relied on Ca²⁺ release. The majority of psychedelics exhibited a signaling bias toward the PLC-IP1 or the PLA2-AA pathway at the 5-HT₂AR. The 5-HT2A/5-HT1A activation ratio may provide information about seizure risk and therapeutic potential. Furthermore, the low activation efficacy at the 5-HT₂BR potentially suggests reduced cardiac risk with intermittent use, and the strong activation of the 5-HT₂CR is in accordance with the reported low abuse potential of serotonergic psychedelics. This study underscores the importance of pathway-specific profiling in understanding the pharmacology of serotonergic psychedelics. It provides a framework for predicting efficacy and adverse effect potential and lays the groundwork for the rational design of next-generation psychedelics with improved safety and efficacy.
Lithium, recommended as the first-line choice for recurrence prevention in bipolar disorder, is fully effective in only about one-third of patients. It is therefore important to identify early those patients likely to benefit in the long-term. Earlier studies suggested that the response to lithium stabilization runs in families and that family history is an important predictor of treatment outcome. To overcome the limitations of the earlier studies - small sample size in particular - we carried out a multicenter study and used a standardized assessment of treatment response. Collaborating centers in Canada, Italy, and Poland recruited 92 biological relatives of 78 probands assessed for response to long term lithium monotherapy. We compared their data with those from 78 unrelated persons with bipolar disorder. The response to treatment has been quantified on a scale previously described and validated. Among the relatives of lithium responders, 69% were also good responders; in relatives of non-responders, only 22% responded to treatment (p < 0.0001). The odds of responding were 7.8 times higher in families of responders compared to non-responders (95% CI 3.0 to 20.1). The response rate in the comparison group was 31%, lower than in the responders' relatives (p < 0.0001), but not significantly different from the rate in families of non-responders (p = 0.31). Our findings support the familial nature of the response to lithium. When information about the response in relatives is available, family history of lithium response is a crucial factor to consider when selecting long term treatment.
Posttraumatic stress disorder (PTSD) is a chronic and disabling condition and identifying beneficial therapies is timely and important. We aimed to estimate the efficacy of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) compared with control on clinical and functional outcomes in PTSD. A PRISMA-compliant search (PROSPEROCRD42022353261) up to August 14, 2025, covered nine databases and manual searches to identify randomised controlled trials (RCTs). Methodological quality was assessed using the Cochrane Risk of Bias tool (RoB2), and the certainty of the evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Of 1035 records identified, 14 studies met inclusion criteria for qualitative synthesis; eight trials provided sufficient data for quantitative synthesis (k = 24). Random-effects meta-analyses indicated that MDMA-AT was associated with reductions in PTSD symptom severity (n = 298, k = 9, SMD = -1.19, 95 % CI [-1.95, -0.42]; I² = 68.8 %, τ2 = 1.02), dissociative symptoms (n = 148, k = 5, SMD = -0.37, 95 % CI [-0.70, -0.04]; I² = 0.0 %, τ2 = 0), and may improve functioning (n = 227, k = 4, SMD = -0.83, 95 % CI [-1.47, -0.19]; I² = 61.2 %, τ2 = 0.27). No clear evidence of benefit was observed for depressive symptoms. Most studies showed a high risk of bias in the measurement of the outcome, and some concerns due to deviations from the intended intervention; the overall certainty of the evidence was very low. The number of trials remains limited, with considerable heterogeneity in certain outcomes, small sample sizes, and the absence of active controls in most studies, which likely compromised blinding integrity. Current findings suggest that MDMA-AT may warrant further investigation as a potential treatment for PTSD; however, larger, higher-quality RCTs with active controls and long-term follow-up are needed to determine its efficacy.
JNJ-42165279 is a potent, selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid N-arachidonoylethanolamide (anandamide), which plays a role in regulation of fear and anxiety responses. This double-blind, randomised, placebo-controlled, phase 2a study assessed the efficacy, safety and pharmacodynamics of adjunctive treatment with JNJ-42165279 in participants with major depressive disorder (MDD) with anxious distress and inadequate response to selective serotonin reuptake inhibitors (SSRI) or serotonergic/noradrenergic reuptake inhibitors (SNRI). Eligible participants (18-64 years; N = 153) were randomised (1:1) to receive JNJ-42165279 (25 mg) or placebo orally once daily and were maintained on their current SSRI/SNRI treatment. The primary endpoint was the change from baseline at week 6 in the 17-item Hamilton Depression Rating Scale (HDRS17). The study results did not show a significant treatment effect of adjunctive JNJ-42165279 on the primary endpoint versus placebo (least square mean difference [standard error]: -0.2 [1.04]; one-sided p=0.416) in the enriched intent-to-treat population. Findings for the key secondary efficacy endpoints also did not demonstrate an additional benefit of adjunctive JNJ-42165279 treatment over placebo. Treatment with JNJ-42165279 produced substantial increases in the mean concentrations of fatty acid amides in plasma, and the plasma JNJ-42165279 and anandamide levels were strongly correlated. The safety results were consistent with the known safety profile of JNJ-42165279. Overall, adjunctive treatment with JNJ-42165279 at the dose tested did not provide significant benefit in reducing depression/anxiety symptoms versus placebo but showed no new safety signals in participants with MDD and anxious distress.
Mood stabilizers (MS) are the cornerstone of maintenance treatment for bipolar disorder. However, their mechanisms of action remain only partially understood. Increasing evidence suggests that MS may exert part of their therapeutic effects through epigenetic modulations. In this exploratory study, we investigated the effects of therapeutic concentrations of six MS - valproic acid (VPA), lithium, lamotrigine, risperidone, aripiprazole, and quetiapine - on the expression of 82 genes involved in DNA methylations and histone modifications in HeLa cells. After seven days of exposure, VPA induced the most extensive transcriptional changes, with differential expression of 17 out of 82 genes, predominantly involved in histone modifications (acetylation, methylation, phosphorylation, ubiquitination). Notably, VPA upregulated HDAC1, HDAC2, HDAC9, HDAC11, KDM5B, and PAK1 mRNA levels with fold-changes >1.3. Corresponding increased protein levels were observed only for KDM5B and PAK1. VPA also induced direct inhibition of total HDAC activity, unlike lithium and quetiapine. Lithium and quetiapine upregulated HDAC2 and ESCO1 mRNA levels. Lithium and quetiapine did not modify HDAC2 protein levels. Other MS showed no significant transcriptional effects at day 7. Overall, MS-induced transcriptional changes were mainly restricted to genes involved in histone modifications, with minimal effects on DNA methylation-related genes. These findings suggest that MS, particularly VPA, modulate the transcription of epigenetic machinery genes in HeLa cells. HDAC2 upregulation may represent a shared transcriptional response across several MS, although the absence of consistent protein-level changes warrants caution. These results are exploratory and require replication in more physiologically relevant models to determine their biological and clinical significance.
The Global OCD consortium investigated cortical and subcortical differences in the largest sample of unmedicated adults with obsessive-compulsive disorder (OCD) to date using T1-weighted MRI. We aimed to determine structural brain signatures of OCD clinical profiles, illness duration, comorbidity, and medication history. This preregistered study included 266 medication-free OCD adults and 254 healthy controls. We analyzed cortical thickness, surface area, and (sub)cortical and cerebellar volumes using FreeSurfer and voxel-based morphometry (VBM). Covariates included age, sex, IQ, and site. We found no significant differences in cortical thickness, surface area, or subcortical volumes between OCD and HC groups. However, OCD severity correlated negatively with surface area in the left lateral orbitofrontal cortex (OFC) (p(FDR)=0.008), right medial OFC (p(FDR)=0.009), and right insula (p(FDR)=0.045), supported by VBM. Regarding dimensionality, harm/aggression scores correlated negatively with right medial OFC surface area (p(FDR)=0.030), while sexual/religious scores correlated positively with hippocampal volume (p(FDR)=0.017). Compared to those without, OCD cases with comorbid depression showed smaller surface area in inferior parietal (p(FDR)=0.048) and middle temporal cortices (R:p(FDR)=0.048; L:p(FDR)=0.049). No associations were found for illness duration, onset, or medication history. In the largest prospective structural imaging study of unmedicated OCD to date, we found no significant case-control differences in cortical or subcortical morphology. Instead, structural associations were driven by clinical characteristics, including symptom severity, dimensionality, and comorbidity, supporting neuroanatomical models emphasizing the OFC and insula. The absence of case-control differences underscores the importance of studying large unmedicated samples with careful clinical characterization before concluding brain findings are related to the disorder.
Depressive episodes present a treatment challenge in bipolar disorder (BD), and an urgent need exists for novel treatment options. This review sought to revisit the results from a recent network meta-analysis (NMA) that examined treatment options for bipolar depression and to update those findings with a complementary systematic review (PROSPERO-ID: CRD42020171726). The NMA was based on the qualitative synthesis of 145 studies and the quantitative analysis of 101 studies investigating acute depression in adults with bipolar depression from inception to April 2023. A complementary systematic review was conducted using MEDLINE, OVID, EMBASE, PsychINFO, CINAHL, LILACS, Cochrane, Web of Science Core Collaboration, and Google Scholar databases from April 2023 to November 2024 to identify the most recent randomized controlled trials on the treatment of bipolar depression. Studies identified via systematic review were subjected to narrative synthesis and quality assessment was completed using revised Cochrane risk of bias tool. The original NMA showed that olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were more efficacious than placebo in reducing depressive symptoms in BD with good confidence. Several other drugs might also be efficacious, but confidence in the evidence was very low to low. The complementary systematic review identified 24 clinical trials, seven of which had published results suitable for meta-analysis; the remaining 17 studies were either ongoing or completed with no available results. Collectively, the NMA and systematic review findings can inform evidence-based care and the development of international treatment guidelines for bipolar depression.
The increased risk of atherosclerotic diseases (stroke, coronary artery disease [CAD]) observed in depression may stem from shared pathophysiology. We examined whether: 1) major depression (MD) and atherosclerotic traits share genetic risk, and 2) altered gene expression in various tissues linked to shared genetics has a potential causal role in depression etiology. Data from the largest genome-wide association studies of MD (N = 3,887,532) and 8 atherosclerotic traits (N = 26,909-1,308,460) were used in Two-Sample Mendelian randomization and colocalization to detect cross-trait causal associations and genomic loci containing shared causal variants. In shared loci, summary data-based Mendelian randomization estimated the effects of gene expression on MD etiology using expression quantitative trait loci datasets from whole blood, brain and heart tissues and atherosclerotic plaques from the Athero-Express Biobank Study. MD genetic liability increased risk of any stroke (OR=1.15, p = 9.47 × 10-8), ischemic stroke (OR=1.16, p = 1.52 × 10-7), small vessel disease (OR=1.34, p = 4.76 × 10-5) and CAD (OR=1.2, 95 %CIs=1.13-1.26, p = 3.76 × 10-22). Eight genomic regions harbored potentially shared causal variants, including one on chromosome 7 linking MD with any stroke, ischemic stroke and CAD. Altered expression of 16 genes in blood, 10 in brain, and 6 in heart was found causal for MD etiology. In atherosclerotic plaques, one gene was linked to MD at nominal significance only. Major depression and atherosclerotic diseases share genetic risk potentially acting in depression pathophysiology through expression of genes in blood, brain and heart tissues. Involvement of atherosclerotic plaques in depression etiology was not supported. Identified pathways could guide the development of new treatments to prevent depression-heightened atherosclerotic risk.
One in five people attending services with a substance use disorder (SUD) also has comorbid attention-deficit/hyperactivity disorder (ADHD). While some evidence shows that shared heritability might partly explain this frequent comorbidity, studies on this topic are scarce. Therefore, the goal of this study was to test whether ADHD and SUD have shared genetic influences. A total of 1,513 SUD treatment-seeking individuals of European ancestry were included in the study. Polygenic risk scores (PRS) were applied to test a) the association of the PRS for ADHD with multiple SUD-related phenotypes, and b) the association of the PRS for SUDs (alcohol, cocaine, cannabis, opioid, and polysubstance use disorder) with ADHD-related phenotypes. Causality between ADHD traits and SUD-related phenotypes was tested by using one-sample Mendelian randomization analyses. PRS for ADHD significantly increased the likelihood of ever using heroin (R2 = 0.7 %, p < 0.001, ß = 0.20, SE = 0.06). PRS for opioid use disorder was significantly associated with ADHD inattentive symptoms (R2 = 0.6 %, p = 0.018, ß = 0.08, SE = 0.02) and with ADHD total symptom score (R2 = 0.6 %, p = 0.025, ß = 0.07, SE = 0.02). No evidence of causal relationships were found. The findings of this study highlight the genetic contribution to the relationship between ADHD and SUDs with some indication of overlap, particularly between ADHD and opioid use disorder.
Optimising patient outcomes in treatment resistant depression (TRD) requires treatments which provide sustained remission, without relapse, and tolerability in the long term. ESCAPE-LTE (NCT04829318) was a phase IV, single-arm, 2-year (104 weeks) long-term extension of ESCAPE-TRD (NCT04338321; 32 weeks), a rater-blinded, randomised, active-controlled trial, which evaluated the safety, tolerability and efficacy of esketamine nasal spray (NS), alongside an ongoing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor, in patients with TRD. The primary endpoints were the proportion of patients who reported treatment-emergent adverse events (TEAEs) or suicidal ideation and behaviour (using the Columbia-Suicide Severity Rating Scale). Effectiveness was assessed using the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impression-Severity scale, Patient Health Questionnaire-9 and EuroQol 5-Dimension 5-Level questionnaire. Outcomes are reported from ESCAPE-TRD baseline to the end of ESCAPE-LTE (136 weeks of treatment, 138 weeks including safety follow-up). In patients who entered ESCAPE-LTE (N = 183), TEAEs and serious TEAEs were observed in 96.7% and 8.2%, respectively. 98.3% of TEAEs occurring on dosing days resolved same-day; few patients discontinued due to TEAEs during ESCAPE-LTE (3.3%). 151/160 (94.4%) patients who were non-suicidal at baseline remained non-suicidal to the end of ESCAPE-LTE. In the subgroup with remission in ESCAPE-TRD, 79.2% did not relapse or discontinue treatment throughout ESCAPE-LTE; the overall relapse rate for patients achieving remission across both studies was 6.9%. The vast majority of patients with TRD who achieved remission with esketamine NS did not relapse over 136 weeks of treatment; no new safety concerns were identified, and the safety profile was consistent with short-term studies.
Psilocybin-assisted therapies are increasingly studied for Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD), and methodological rigor requires both pharmacological evaluation and consistent reporting of non-pharmacological variables that influence therapeutic outcomes. To address this need, the ReSPCT (Reporting of Setting in Psychedelic Clinical Trials) guidelines were recently introduced, providing a 30-item framework for standardized reporting of set and setting. This study aimed to evaluate how current psilocybin clinical trial protocols incorporate these elements and to identify domains requiring improvement. We systematically searched ClinicalTrials.gov and the EU Clinical Trials Information System (CTIS) for interventional psilocybin studies targeting MDD or TRD, including protocols listing depression as a primary condition. By June 21, 2025, 13 protocols (11 Phase II and 2 Phase III) met the inclusion criteria. Each protocol was assessed using the ReSPCT checklist, yielding a total of 390 item-level assessments rated on a four-point scale. Overall, 61 of 390 entries (15.6%) demonstrated full compliance, 252 (64.6%) partial compliance, and 77 (19.7%) provided no relevant information. Procedural elements, such as medical and experimental procedures (100% compliance), focus and main activities (92.3%), number of sessions (69.2%), and dosing regimens (53.8%), were consistently reported. In contrast, contextual and equity-related domains were markedly underreported: 84.6% of protocols lacked information on cultural competence and safety, 92.3% did not describe objects or decorations, and 84.6% failed to report access to nature. These findings indicate that while procedural safeguards are well documented, critical contextual and equity-relevant aspects remain insufficiently reported. Adopting ReSPCT guidelines may improve transparency and reproducibility.
Psychiatric and neurological disorders often co-occur, complicating their assessment, management, and outcomes. No umbrella review (UR) has summarized the meta-analytic evidence on the co-occurrence of psychiatric and neurological disorders and assessed its credibility. Meta-analytic systematic reviews of observational studies documenting the prevalence and outcomes associated with the co-occurrence of neurological and psychiatric disorders, indexed from inception through August 25, 2025, and meeting established diagnostic criteria, were included. Meta-analytic prevalence and association estimates were recalculated and graded based on quantitative criteria. The AMSTAR-2 assessed the quality of the meta-analyses, while several subgroup analyses and meta-regressions aimed to explain the heterogeneity. We included 81 meta-analyses (N=42,464,788, k=2,273), yielding 166 meta-analytic estimates. Based on pre-existing meta-analytic evidence, among 90 prevalence estimates, 45 (50%) met moderate/strong credibility criteria. Strong credibility emerged in bipolar disorder for comorbid migraine (34.8%,95%CI=25.54-44.69) and chronic pain (28.9%,95%CI=16.4-43.4), in epilepsy for ADHD (22.3%,95%CI=20.3-24.4), depression (23.1%,95%CI=20.6-28.3), autism (11.1%,95%CI=9.8-12.1), and PTSD (7.7%,95%CI=5.2-11.2), in myasthenia gravis for anxiety (33%,95%CI=25.0-42.0 children), in multiple sclerosis for anxiety (36%,95%CI=30.0-42.0) and depression (27.01%,95%CI=22.80-31.68), in neuropathic chronic pain for depression (37.5%,95%CI=28.7-47.1) and anxiety (33.8%,95%CI=28.5-39.6), in neuromyelitis optica for depression (40%,95%CI=32.0-49.0), in stroke for anxiety (29.3%,95%CI=24.8-33.8) and depression (31%,95%CI=24.0-38.0 children), in dementia for depression (25.01%,95%CI=22.1-28.4). Several additional disorders were comorbid in >5%with lower credibility. No outcomes reached strong credibility criteria. The present study provides an atlas of neurological and psychiatric multimorbidity across varying levels of credibility, reinforcing the need for an integrated, multidisciplinary approach to patient care and for more research on actionable risk/protective factors and outcomes.
This retrospective cohort study aimed to compare the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus metformin for preventing type 2 diabetes mellitus (T2DM), reducing mortality, and improving body mass index (BMI) in antipsychotic-treated patients with overweight /obesity. We used data from the TriNetX Global Collaborative Network. Adults (aged ≥18 years) with overweight or obesity, antipsychotic exposure, and no prior T2DM diagnosis were identified. After propensity score matching, patients initiating GLP-1RA therapy were compared with those initiating metformin. The primary outcome was incident T2DM occurring between 1 and 5 years after treatment initiation. Secondary outcomes included all-cause mortality and BMI change. Among 9939 eligible patients, 3115 matched pairs were included. The incidence of T2DM was significantly lower in the GLP-1RA group compared with the metformin group (1.96% vs 7.26%; hazard ratio [HR]=0.34; 95% CI, 0.26-0.46; p < 0.001). All-cause mortality was also reduced in the GLP-1RA group (0.32% vs 1.96%; HR, 0.25; 95% CI, 0.13-0.49; p < 0.001). Regarding BMI change, patients receiving GLP-1RA experienced greater weight reduction than those receiving metformin. The mean (standard deviation) change in BMI was -2.66 (8.51) kg/m² in the GLP-1 group versus -1.36 (8.63) kg/m² in the metformin group (p < 0.001). In conclusion, in this large real-world cohort of antipsychotic-treated patients with overweight or obesity, GLP-1RA therapy was associated with significantly lower risks of T2DM and mortality, and greater BMI reduction compared with metformin. These findings suggest that GLP-1RAs may offer a more favorable profile against antipsychotic-induced glucose dysregulation.
Individuals with eating disorders (EDs) hold an increased risk of developing schizophrenia-spectrum disorders (SSDs). It is however unclear whether this applies to all ED subgroups. We conducted a nationwide register-based cohort study including all individuals diagnosed with EDs in Denmark between 01jan1994 and 31dec2015. We used Cox regression models to compare the risk of SSDs between individuals with and without EDs and how this risk was influenced by risk factors and time since diagnosis of ED. The cohort included 20,045 individuals with EDs and 79,720 without ED (median age [interquartile range]:19 [16-24] years; 93% female). During 1,123,372 person-years of follow-up, 1,335 (6.7%) individuals with EDs were diagnosed with SSDs, compared to 982 (1.2%) individuals without EDs. This reflected a 4-fold higher risk of any SSD among individuals with EDs (adjusted hazard ratio [aHR] 4.43; 95% confidence interval [95%CI] 4.04-4.84). Individuals with anorexia nervosa (aHR 4.56 [3.99-5.22]) and other EDs (aHR 4.99 [4.27-5.83]) had a higher risk of any SSD diagnosis compared to individuals with bulimia nervosa (aHR 3.46 [2.83-4.22]). History of previous psychiatric hospitalisation, substance abuse, alcohol abuse, male sex, and onset of ED <19 years were associated with increased risk of SSDs in individuals with EDs. The risk of any SSD diagnosis decreased over time, but persisted ≥11 years after ED diagnosis (aHR 2.23 [1.71-2.92]). In conclusion, individuals with EDs have a four-fold higher risk of developing SSDs, compared with individuals without EDs. Anorexia nervosa and other EDs entails a higher risk of a subsequent SSD diagnosis compared with bulimia nervosa.
Comorbid attention deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) is associated with poor treatment outcomes. This international multi-center observational prospective cohort study aimed to gain knowledge about predictors of treatment outcomes in adult SUD+ADHD patients. Data was collected from June 2017 to May 2021 at baseline, four weeks, three months, and nine months at twelve treatment services in nine countries. Main outcomes were: Treatment retention, ≥30% reduction from baseline to follow-up according to the adult ADHD self-report scale (ASRS-18), and self-reported substance use at three-month follow-up. A total of 137 adult females (24 %) and 441 adult males (76 %) were enrolled. Receiving stimulant treatment for ADHD was significantly associated with better treatment retention (OR: 2·4, 95% CI: 1·4-4·2), ≥30% reduction in ASRS total score (OR: 2·6, 95% CI: 1·2-6·1), and fewer heavy drinking days (IRR: 0·24, 95% CI: 0·13-0·42) at three months. Psychosocial treatment for ADHD was independently and significantly associated with fewer heavy drinking days at three months (IRR: 0·27, 95% CI: 0·14-0·51). In summary, treatment of ADHD in SUD+ADHD patients was related to improvements in ADHD-symptoms, treatment retention and fewer heavy drinking days at follow-up. These findings highlight the importance of ADHD treatment provision in this population. Future RCTs are warranted to confirm these results and should assess combinations of ADHD treatments and SUD treatments using different doses of stimulants. Trial Registration: ISRCTN (https://doi.org/10.1186/ISRCTN15998989).
Bipolar disorder (BD) involves sexual disturbances not only during affective phases but also during euthymia. Sexual dysfunctions (SD) in BD are particularly relevant, as they may negatively affect quality of life and treatment adherence. Despite their clinical impact, SD are often misdiagnosed and their characteristics remain unclear. This work aimed to review the literature on SD in patients with BD. A systematic review was conducted following PRISMA guidelines (PROSPERO ID-CRD42019130095). We included naturalistic studies of adults with BD in which sexual functioning was assessed using questionnaires/semi-structured interviews evaluating desire, arousal, orgasm, and satisfaction, or through validated diagnostic criteria. The search identified 176 eligible full-text articles, of which 37 were included, comprising 8,724 individuals with BD. The prevalence of SD varied widely (14 %-91 %) and was influenced by sample characteristics, study context, and treatment. Desire was the most frequently affected domain, and the Arizona Sexual Experiences Scale (ASEX) was the most commonly used tool. Compared to healthy controls, BD patients showed poorer sexual functioning and satisfaction. SD in BD was associated with worse quality of life, greater illness burden, and impaired psychosocial functioning. The evidence reviewed confirms that SD is a core dimension of BD, with relevant consequences for functioning and quality of life. Findings support the systematic assessment of sexual health in routine care and its integration into personalized treatment plans. Future research should clarify mechanisms and develop targeted interventions, with attention to longitudinal trajectories and the inclusion of gender and sexual minority populations.
Precision psychiatry is an approach designed to improve diagnosis and treatment of mental disorders by leveraging biological insights and developing innovative, mechanism-based treatment strategies unconstrained by current diagnostic boundaries. At its core, precision psychiatry aims to pinpoint the underlying neurobiological mechanisms responsible for the emergence and persistence of symptoms of mental health conditions. This approach strives to create diagnostic tools and therapies targeting these mechanisms, potentially addressing previously resistant aspects of mental health conditions by providing more precise symptom management and possibly altering the disease trajectory. Although still in its nascent stages, the realization of precision psychiatry will result in a more refined and biology-informed diagnostic system for mental disorders, requiring significant adaptations for clinicians, industry, patients and regulators. Identifying, validating and applying both fluid and functional biomarkers are critical steps in the development, testing and application of new precision psychiatry diagnostics and treatments. As part of the 2025 Precision Psychiatry Roadmap initiative meeting in Frankfurt, experts came together to present and discuss the current status of biomarker identification and validation, patient subtyping, and targeted interventions for stratified patient groups. This report features lecture summaries, meeting outcomes, and recommendations from both online and in-person audiences. In general, the recommendations emphasize standardization, collaboration, clinical implementation, digital innovation, long-term planning, and, importantly, patient engagement, as key priorities for advancing precision psychiatry. Despite existing challenges, there is strong optimism for the future of precision psychiatry, with continuous efforts to refine diagnostic tools and treatment strategies.
Despite significant advancements in psychopharmacology, there are inadequate treatment options for many psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia, and anxiety disorders. This review explores emerging neurobiological targets beyond conventional monoaminergic approaches, focusing on sodium channels, Neuropeptide Y (NPY), Neurokinin 1 (NK1) receptors, P2 × 7 purinergic receptors, Sigma-1 receptors, and Orexin. Recent evidence suggests that sodium channel modulators, such as evenamide, may offer therapeutic benefits for treatment-resistant schizophrenia by stabilizing glutamatergic neurotransmission. NPY-based therapies have potential in stress-related disorders, foreshadowing rapid anxiolytic and antidepressant effects through modulation of the stress response. NK1 receptor antagonists, although inconsistent in mood disorders, show promise in addiction treatment by reducing substance cravings. The P2 × 7 receptor, a key regulator of neuroinflammation, has been implicated in mood disorders, and its pharmacological inhibition may provide neuroprotective benefits. Additionally, Sigma-1 receptor agonists, including Blarcamesine and Pridopidine, have shown neuroprotective and cognitive-enhancing properties, making them attractive candidates for psychiatric and neurodegenerative disorders. Orexin receptor antagonists, such as suvorexant and seltorexant, have potential in mood disorders and substance dependence, highlighting the broader therapeutic applications of targeting the orexinergic system. While these emerging therapeutic targets hold promise, challenges remain in translating preclinical findings into effective clinical applications. Large-scale, placebo-controlled trials are necessary to establish their efficacy and safety. The identification of biomarkers for patient stratification will be critical in the hitherto elusive goal of developing precision medicine approaches. Targeted pharmacological interventions offer a path toward more effective, well-tolerated, and potentially individualized treatment options for patients with severe mental illness.
The increasing interest in the therapeutic potential of psychedelics and cannabis underscores the need to understand their long-term neuropsychological and personality effects. This cross-sectional study compared regular users of ayahuasca (n = 69), cannabis (n = 56), and non-substance users (n = 94) on a battery of neuropsychological tasks and psychological questionnaires. Participants were matched by age, education, and IQ and abstained from drug use for at least 10-30 days before assessment. No significant group differences were observed in neuropsychological performance. However, multinomial regression analyses revealed that personality traits best distinguished the user groups. Ayahuasca users exhibited significantly higher self-transcendence and lower harm avoidance and persistence, while cannabis users were associated with higher novelty seeking and impulsive nonconformity, as well as lower introvertive anhedonia. These results persisted after controlling for demographics and psychiatric history. Contrary to previous findings associating cannabis with neurocognitive impairments and psychopathology, no significant deficits were found in the abstinent cannabis users. Similarly, ayahuasca users, despite a higher lifetime prevalence of mood and anxiety disorders, showed no current psychopathological symptoms. Our findings suggest that chronic use of ayahuasca or cannabis is not associated with detectable lasting neuropsychological impairments in the executive and working memory tasks assessed in this study, and that personality characteristics-rather than cognition or psychopathology-most clearly distinguish chronic users from non-users. However, these results are based on a cross-sectional, self-selected, non-treatment-seeking sample and may therefore not be representative of all ayahuasca and cannabis users. These insights may inform future clinical applications and safety evaluations of these substances.