Stimulants are the first-line pharmacological treatment for ADHD and generally effective, yet 35-61% of individuals discontinue treatment within a year. We investigated the contribution of common and rare genetic variants to early stimulant discontinuation using data from 18,362 individuals with ADHD (31% female) initiating stimulants in iPSYCH, a Danish population-based case-cohort linked to national registers. Discontinuation was defined as a ≥ 180-day gap between dispensations within one year of initiation. We examined genetic differences by age groups, estimated SNP-heritability (h2SNP), conducted genome-wide association studies (GWAS), polygenic score (PGS) analyses, and assessed associations with protein truncating variants (PTV). Within one year, 7102 individuals (39%) had discontinued stimulants. Age-stratified analyses (cut-off: age 16) revealed low genetic correlation (r₉ = 0.23, 95% CI: -0.37, 0.83) between children and adolescents/adults. The h²snp for discontinuation was 0.06 (95% CI: 0.02, 0.11) overall, 0.08 (95% CI: 0.02, 0.14) in children, and 0.14 (95% CI: 0.02, 0.27) in adolescents/adults. No genome-wide significant loci were identified overall or in adolescents/adults; however, one locus (SLC5A12, chromosome 11) reached genome-wide significance in children. Ten of 36 PGSs were associated with discontinuation, with higher psychiatric risk PGSs predicting increased discontinuation, while educational attainment and BMI PGSs showed divergent effects by age. Reduced burden of dopamine-related PTVs was nominally associated with discontinuation, particularly in adolescents/adults. These findings suggest modest contributions of both common and rare variants to stimulant discontinuation in ADHD and point to potential developmental differences in genetic architecture.

Telomere length (TL) is an indicator of cellular ageing, with patients with severe mental disorders tending to have shorter telomeres than the general population. Coffee consumption may reduce oxidative stress, helping prevent biological ageing processes like telomeric shortening. The UK National Health Service advises limiting caffeine intake to 400 mg/day (4 cups of coffee). However, the role of coffee consumption and TL in psychiatric populations remains unclear. This cross-sectional study included 436 participants (schizophrenia spectrum (n=259) and affective disorders (n=177)) from the Norwegian TOP study. Leucocyte TL was measured via blood using quantitative real-time polymerase chain reaction (qPCR). Patients self-reported coffee consumption, quantified as cups per day (no coffee, 1-2, 3-4, 5+). An inverted J-shape was found between TL and coffee intake, peaking at 3-4 cups/day before declining after 4 cups (F=3.29, p=0.02). The largest TL difference was between those drinking the highest recommended dose and non-drinkers (F=6.13, p=0.01). Coffee drinkers within the recommended dose had longer TL, comparable to 5 years younger biological age, adjusted for confounders. Coffee intake within the recommended dose is linked to longer telomeres in severe mental disorders, comparable to 5 years younger biological age.

Treatment-resistant depression (TRD), defined as major depressive disorder (MDD) with multiple failed responses to antidepressant treatments, has been suggested to be heritable, but identifying its genetic component is challenging. Using a restrictive TRD definition based on antidepressant medication followed by electroconvulsive therapy (ECT), which may represent a severe subset of TRD cases, we investigated both common variants and rare copy number variations (CNVs) associated with a) TRD risk (2 062 TRD vs. 441 037 healthy controls) and b) treatment resistance in MDD (2 062 TRD vs. 38 544 non-TRD) across three Nordic countries. We observed a significant SNP-based heritability for TRD risk at 26% (SE = 5%). Genome-wide association analysis identified one locus on chromosome 3 (intronic region of SPATA16) for TRD risk and one suggestive locus for treatment resistance in MDD. TRD risk showed positive genetic correlations (rg) with other psychiatric disorders, with notably rg with bipolar disorder (0.86, SE = 0.20) and schizophrenia (0.57, SE = 0.13), as well as a negative rg with intelligence (-0.13, SE = 0.07). Analyses using PRS showed that TRD had higher common-variant burdens of various psychiatric disorders compared to non-TRD. Furthermore, TRD carried a higher CNV deletion burden in total and average lengths than healthy controls or non-TRD cases and was associated with a group of 54 known neuropsychiatric CNVs (ORs = 1.74-2.86). Given that our definition of TRD involves the use of ECT, our findings may reflect a severe form of treatment resistance. This work adds evidence on a genetic basis and provides insights into the genetic architecture of TRD, underscoring the need for further genomic research into this 'difficult-to-treat' condition.

Autism has been associated with differences in functional brain network organization. However, the exact nature of these differences across development compared to non-autistic individuals and their relationship to autism-related social cognition, remains unclear. This study first aimed to identify EEG resting-state network characteristics in autistic versus non-autistic children, adolescents, and adults. Second, we investigated associations with social cognition measures. Analyzing resting-state EEG data from the EU-AIMS Longitudinal European Autism Project, we compared network metrics (global efficiency, clustering coefficient, and small-worldness) between 344 autistic and non-autistic individuals within and across age groups in four frequency bands (delta, theta, alpha, and beta). If significant, we explored their relationships to measures of empathy (empathy quotient), complex emotion recognition [reading the mind in the eyes task (RMET)], and theory of mind (animated shapes task). Compared to their non-autistic peers, autistic adolescents showed lower alpha global efficiency, while autistic adults showed lower alpha clustering and small-worldness. No network differences were observed among children. In adolescents, higher long-range integration was tentatively associated with higher RMET scores; in those with high autistic traits, higher long-range integration related to fewer parent-reported empathic behaviors. No brain-behavior relationships were observed in adults. Our findings suggest subtle differences in network topology between autistic and non-autistic individuals, with less efficient long-range efficiency during adolescence, and less local and overall network efficiency in adulthood. Furthermore, long-range integration may play a role in complex emotion recognition and empathy difficulties associated with autism in adolescence.

Over the last decades the study of schizophrenia-spectrum disorders has been focused on early and comprehensive intervention during the first episode of psychosis (FEP), but studies in rural settings are only rare. In Greece mental healthcare in rural areas is mostly delivered by the locally-based Mobile Mental Health Units (MMHUs). The aim of the present study was to address treatment of FEP patients by the MMHUs in rural areas in Greece, focusing on patients with a first episode of schizophrenia. This is a multicenter, retrospective observational study with the participation of nine MMHUs across several areas in rural mainland and some islands of Greece. Patients of the age range of 15 to 55 years with a diagnosis of non-affective psychosis were included in the study. The study sample consisted of 216 patients, while analysis was performed for patients with a diagnosis of schizophrenia (n = 153, 70.8% of the sample). Most patients were males (n = 93, 60.8%), with a mean age at first presentation 34.9 years (Md = 34.5, SD = 11.94). The mean duration of untreated psychosis (DUP) was 7.85 months (Md = 3, IQR = 10.00) and was shorter in younger (15-25 years) patients. More than 60% of patients had been successfully engaged to treatment with the MMHUs, with a mean follow-up duration of 5.17 years (Md = 5.00, IQR = 5.00). Younger patients (26-35 years) tend to disengage from treatment, while those aged 36 to 45 years were more likely to continue follow-up. A reduction of 47.22% in hospital admissions among patients with schizophrenia was observed over follow-up of patients by the MMHUS. The most noteworthy findings of the study are the low percentage of patients seeking help from the MMHUs, compared to the expected cases and the high attendance rate of those that are examined in this context. Further research on psychosis/schizophrenia in the rural context is warranted.