Prevalence of multimorbidity in people with and without severe mental illness: a systematic review and meta-analysis.

BACKGROUND: People with severe mental illness, such as schizophrenia-spectrum disorder and bipolar disorder, face poorer health outcomes from multiple chronic illnesses. Physical multimorbidity, the coexistence of two or more chronic physical conditions, and psychiatric multimorbidity, the coexistence of three or more psychiatric disorders, are both emerging concepts useful in conceptualising disease burden. However, the prevalence of physical and psychiatric multimorbidity in this cohort is unknown. This study aimed to estimate the absolute prevalence of both physical and psychiatric multimorbidity in people with severe mental illness, and also compare the odds of physical multimorbidity prevalence against people without severe mental illness. METHODS: We searched CINAHL, EMBASE, PubMed, and PsycINFO from inception until Feb 15, 2024, for observational studies that measured multimorbidity prevalence. To be included, studies had to have an observational study design, be conducted in an adult population (mean age ≥18 years) diagnosed with either schizophrenia-spectrum disorder or bipolar disorder, and include a measurement of occurrence of either physical multimorbidity (≥2 physical health conditions) or psychiatric multimorbidity (≥3 psychiatric conditions total, including the severe mental illness). From control studies, a random-effects meta-analysis compared odds of physical multimorbidity between people with and without severe mental illness. Absolute prevalence of physical and psychiatric multimorbidity in people with severe mental illness was also calculated. Sensitivity and meta-regression analyses tested an array of demographic, diagnostic, and methodological variables. FINDINGS: From 11 144 citations we included 82 observational studies featuring 1 623 773 individuals with severe mental illness (specifically schizophrenia-spectrum disorder or bipolar disorder), of which 21 studies featured 13 235 882 control individuals without severe mental illness (descriptive data for the entire pooled cohorts were not available for numbers of males and females, age, and ethnicity). This study did not feature involvement of people with lived experience. The odds ratio (OR) of physical multimorbidity between people with and without severe mental illness was 2·40 (95% CI 1·57-3·65, k=11, p=0·0009). This ratio was higher in younger severe mental illness populations (mean age ≤40 years, OR 3·99, 95% CI 1·43-11·10) compared with older populations (mean age >40 years, OR 1·55, 95% CI 0·96-2·51; subgroup differences p=0·0013). For absolute prevalence, 25% of those with severe mental illness have physical multimorbidity (95% CI 0·19-0·32, k=29) and 14% have psychiatric multimorbidity (95% CI 0·08-0·23, k=21). INTERPRETATION: This is the first meta-analysis to estimate physical alongside psychiatric multimorbidity prevalence, showing that these are common in people with schizophrenia-spectrum disorder and bipolar disorder. The greater burden of physical multimorbidity in people with severe mental illness compared with those without is higher for younger cohorts, reflecting a need for earlier intervention. Our findings speak to the utility of multimorbidity for characterising the disease burden associated with severe mental illness, and the importance of facilitating integrated physical and mental health care. FUNDING: None.

Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

An Unhealthy Dietary Pattern during Pregnancy is Associated with Neurodevelopmental Disorders in Childhood and Adolescence.

Despite the high prevalence of neurodevelopmental disorders, there are a lack of clinical studies examining the impact of pregnancy diet on child neurodevelopment. This observational clinical study examined the associations between pregnancy dietary patterns and neurodevelopmental diagnoses, as well as their symptoms, in a prospective cohort of 10-year-old children (n=508). Data-driven dietary patterns were derived from self-reported food frequency questionnaires. An Unhealthy dietary pattern in pregnancy (per SD change) was significantly associated with attention deficit hyperactivity disorder (ADHD) OR 1.66 [1.21 - 2.27], p=0.002 and autism diagnosis OR 2.22 [1.33 - 3.74], p=0.002 and associated symptoms p<0.001. Findings for ADHD were validated in two large (n=656, n=348), independent mother-child cohorts via blood metabolome modelling. Objective metabolite scores, assessed at five timepoints in mothers and children in two independent mother-child cohorts, indicated that the strongest association with ADHD was during early-to mid-pregnancy. These results provide evidence for targeted prenatal dietary interventions to prevent neurodevelopmental disorders in children.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Rationale and Study Design of the Largest Global Prospective Cohort Study of Clinical High Risk for Psychosis.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

Required elements for an educational programme for lay exercise instructors in charge of community-based exercise targeting young adults with schizophrenia spectrum disorders - A stakeholder focus group study.

BACKGROUND: Exercise plays a crucial role in addressing the increased cardiometabolic morbidity and premature mortality in people with schizophrenia spectrum disorders. When delivered in community-based settings, exercise may also reduce loneliness, while promoting overall physical activity behaviours. Skilled instructors are essential to deliver effective community-based exercise; however, knowledge about their roles and required training is lacking. We aim to explore various stakeholders' perspectives regarding lay exercise instructors' roles, and the required elements in an educational programme supporting the delivery of community-based exercise for young adults with SSD. METHODS: We used semi-structured homogeneous focus groups with representatives from different stakeholder groups (i.e., including representatives of clinical staff within mental health, physiotherapists, exercise instructors, young adults with schizophrenia spectrum disorders, and relatives of individuals with schizophrenia spectrum disorders) targeted or affected by a community-based exercise intervention. Data were analysed using qualitative content analysis. RESULTS: We conducted six focus groups comprising a total of 30 individuals representing five different stakeholder groups The analysis identified three categories: (i) awareness and understanding of mental illness, i.e., providing basic knowledge to dispel common myths and stigma regarding mental illness (ii) protecting youth identity, i.e., supporting the feeling of being more than just a patient, and (iii) promoting exercise as a shared activity, i.e., a communal pursuit, fostering personal growth among participants, their peers and the instructors. CONCLUSIONS: An educational programme for lay exercise instructors delivering community-based exercise targeting young adults with SSD should empower the instructors to assume the role of guardians of an inclusive exercise culture. Educational elements identified were adapted and integrated into an educational programme implemented and evaluated as a part of the Vega trial. Our results may be transferable to the education of lay workers in mental health care where the aim is to facilitate sustainable, recreational, community-based activities.

Functional Connectivity Between Auditory and Medial Temporal Lobe Networks in Antipsychotic-Naïve Patients With First-Episode Schizophrenia Predicts the Effects of Dopamine Antagonism on Auditory Verbal Hallucinations.

Background: Understanding how antipsychotic medication ameliorates auditory verbal hallucinations (AVHs) through modulation of brain circuitry is pivotal for understanding the pathophysiology of psychosis and for predicting treatment response. Methods: This case-control study included examinations at baseline and at follow-up after 6 weeks. Initially, antipsychotic-naïve patients with first-episode schizophrenia who were experiencing AVHs were recruited together with healthy control participants. Antipsychotic treatment with the relatively selective D2 receptor antagonist amisulpride was administered as monotherapy. Functional connectivity measured by resting-state functional magnetic resonance imaging between networks of interest was used to study the effects of D2 blockade on brain circuitry and predict clinical treatment response. Hallucinations were rated with the Positive and Negative Syndrome Scale. Results: Thirty-two patients experiencing AVHs and 34 healthy control participants were scanned at baseline. Twenty-two patients and 34 healthy control participants were rescanned at follow-up. Connectivity between the auditory network and the medial temporal lobe network was increased in patients at baseline (p = .002) and normalized within 6 weeks of D2 blockade (p = .018). At baseline, the connectivity between these networks was positively correlated with ratings of hallucinations (t = 2.67, p = .013). Moreover, baseline connectivity between the auditory network and the medial temporal lobe network predicted reduction in hallucinations (t = 2.34, p = .032). Conclusions: Functional connectivity between the auditory network and the medial temporal lobe predicted response to initial antipsychotic treatment. These findings demonstrate that connectivity between networks involved in auditory processing, internal monitoring, and memory is associated with the clinical effect of dopamine antagonism.

Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

Long-term outcomes with haloperidol versus placebo in acutely admitted adult ICU patients with delirium.

PURPOSE: We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo. METHODS: We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values. RESULTS: At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of - 6.4%-points (95% confidence interval [CI] - 12.8%-points to - 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI - 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI - 9.3 to 17.5; P = 0.142) for EQ VAS. CONCLUSIONS: In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL.

High-dose vitamin D3 supplementation in pregnancy and risk of neurodevelopmental disorders in the children at age 10: A randomized clinical trial.

BACKGROUND: Vitamin D deficiency in pregnancy may increase the risk of autism and attention deficit hyperactivity disorder (ADHD). OBJECTIVE: The objective of this study was to estimate the effect of vitamin D3 supplementation in pregnancy on risk of autism and ADHD. DESIGN: This randomized clinical trial was part of the COpenhagen Prospective Study on Neuro-PSYCHiatric Development (COPYCH) project nested within the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort comprising a population-based sample of 700 healthy mother-child pairs enrolled at week 24 of pregnancy. Maternal 25-hydroxy-vitamin D (25(OH)D) was measured at inclusion and 623 mothers were randomized 1:1 to either high-dose (2800 IU/d) or standard dose (400 IU/d) vitamin D3 until 1 wk postpartum (315 received high-dose, 308 standard dose). At age 10, diagnoses and symptom load of autism and ADHD, respectively, were established using the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. RESULTS: The psychopathologic evaluation was completed by 591 children aged 10 y, and 16 children (2.7%) were diagnosed with autism and 65 (11.0%) with ADHD. Hereof, 496 children participated in the vitamin D3 trial (246 received high-dose, 250 standard dose). Of these, 12 children (2.4%) were diagnosed with autism and 58 (11.7%) with ADHD. Higher maternal preintervention 25(OH)D levels were associated with a decreased risk of autism [odd ratio (OR) per 10 nmol/L: 0.76 (0.59,0.97); P = 0.034], lower autistic symptom load [ß per 10 nmol/L: -0.03 (-0.05,0.00); P = 0.024), and decreased risk of ADHD diagnosis (OR per 10 nmol/L: 0.88 (0.78,0.99); P = 0.033]. High-dose vitamin D3 supplementation was not associated with risk of autism or ADHD. CONCLUSIONS: Higher maternal preintervention 25(OH)D was associated with a decreased risk of autism, lower autistic symptom load, and decreased risk of ADHD diagnosis, but high-dose vitamin D3 supplementation in pregnancy had no effect on risk of autism and ADHD. This trial was registered at clinicaltrials.gov as NCT00856947.

Minor tranquillizers for short-term treatment of newly onset symptoms of anxiety and distress: a systematic review with network meta-analysis of randomized trials.

Unspecific symptoms of anxiety and distress are frequently encountered in patients in both general practice and acute psychiatric services. Minor tranquillizers may be a treatment option when non-pharmacological interventions are insufficient or unavailable. We conducted a systematic review with network meta-analysis of the evidence for short-term (1-4 weeks) pharmacological treatment of newly onset symptoms of anxiety and distress. We searched the PsycInfo, MEDLINE, EMBASE and Cochrane Library databases and extracted data following a predefined hierarchy of outcomes. We assessed risk of bias using the Cochrane Risk of Bias tool and the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation framework (GRADE). We included 34 randomized trials comprising a total of 7044 patients with adjustment disorders or anxiety spectrum disorders. The network meta-analysis showed that regarding the critical outcome symptoms of anxiety within 1-4 weeks benzodiazepines (SMD - 0.58, 95% CI - 0.77 to - 0.40), quetiapine (SMD - 0.51, 95% CI - 0.90 to - 0.13) and pregabalin (SMD - 0.58, 95% CI - 0.87 to - 0.28) all performed better than placebo with no statistically significant difference between the drugs. Data on other important outcomes were inconsistently reported. Adverse effects varied, but overall, it was uncertain whether adverse effects differed between interventions. The evidence regarding the risk of dependence was uncertain, but dependence may be a concern in susceptible individuals even with short-term treatment. Overall, the certainty of the evidence according to GRADE was rated as low to very low across outcomes. Despite the limitations in the evidence, the results of this review can inform treatment guidelines, supporting clinicians in the choice of minor tranquillizer in this prevalent and help-seeking, clinically heterogeneous population.

Dimensional profiling of psychopathology in children and adolescents based on the K-SADS-PL and an analysis of the construct validity of two ADHD symptom dimensions.

OBJECTIVES: The traditional view on psychiatric disorders as categorical and distinct is being challenged by perspectives emphasizing the relevance of dimensional and transdiagnostic assessment. However, most diagnostic instruments are based on a categorical view with a threshold-approach to disease classification. METHODS: We here describe algorithms for dimensionalizing the psychopathological ratings of the widely used diagnostic interview for children and adolescents, the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL). We further evaluate the criterion-related construct validity of the dimensionalized attention-deficit/hyperactivity disorder (ADHD) scales using Rasch models in a sample of 590 children (mean age 10.29 (.36), 49% girls). RESULTS: The algorithms generate scores of current symptom load, i.e., the sum of clinician-rated symptoms within each disorder assessed with the interview. We found support for counting symptoms of inattention and hyperactivity/impulsivity, respectively, but not for a single combined ADHD scale. CONCLUSIONS: The algorithms constitute an initial step in creating a framework for clinician-rated dimensional analyses of symptoms derived from the K-SADS-PL, but future studies are needed to further evaluate the construct validity of the remaining scales and the reliability and clinical utility of the method. We believe that our proposed algorithms offer a novel method of dimensional psychopathological assessment, which can be applied in multiple branches of child and adolescent psychiatry.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Maternal inflammation during pregnancy is associated with risk of ADHD in children at age 10.

INTRODUCTION: Maternal inflammation during pregnancy may affect early neurodevelopment in offspring as suggested by preclinical and register data. However, clinical evidence for risk of aberrant neurodevelopment later in childhood is scarce. In the population-based COPSAC2010 mother-child cohort, we investigated associations between maternal inflammation levels during pregnancy and the risk of a diagnosis of ADHD as well as the load of ADHD symptoms in the children at age 10. METHODS: The COPSAC2010 cohort consists of 700 mother-child pairs followed prospectively since pregnancy week 24.Maternal high-sensitivity C-Reactive Protein (hs-CRP) level at week 24 of gestation was investigated in relation to child neurodevelopment by age 10 using logistic and linear regression models with extensive confounder adjustment, including socioeconomic status and maternal polygenic risk of ADHD. The children completed a comprehensive examination of neurodevelopment including categorical (i.e., diagnostic) and dimensional (i.e., symptom load) psychopathology using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) and parental rated ADHD-Rating Scale (ADHD-RS). RESULTS: A total of 604 (86 %) of the 700 children in the COPSAC2010 cohort participated in the COPSYCH visit at age 10. Sixty-five (10.8 %) fulfilled a research diagnosis of ADHD (16 girls and 49 boys). Higher maternal hs-CRP level in pregnancy at week 24 (median 5.4 mg/L) was significantly associated with increased risk for a diagnosis of ADHD, adjusted OR 1.40, 95 %CI (1.16-1.70), p = 0.001. Additionally, higher maternal hs-CRP was associated with increased ADHD symptom load in the entire cohort, reflected by ADHD-RS raw scores. DISCUSSION: These clinical data demonstrated a robust association of prenatal maternal inflammation assessed by hs-CRP with a diagnosis of ADHD by age 10. Moreover, maternal inflammation was associated with ADHD symptom load in the complete cohort. Identifying inflammation as an important marker will provide a potential target for future increased awareness and prevention during pregnancy thereby ultimately improving neurodevelopmental outcomes in children.

The Trajectory of Prefrontal GABA Levels in Initially Antipsychotic-Naïve Patients With Psychosis During 2 Years of Treatment and Associations With Striatal Cerebral Blood Flow and Outcome.

BACKGROUND: GABAergic (gamma-aminobutyric acidergic) function in the prefrontal cortex seems dysfunctional in patients with first-episode psychosis, but the impact of longer-term treatment and relationship to clinical outcomes and striatal activity are unknown. METHODS: A longitudinal study of 39 antipsychotic-naïve and benzodiazepine-free patients with psychosis (22.4 ± 5.4 years, 64% women) and 54 matched healthy control participants (HCs) (22.2 ± 4.3 years, 61% women) who were followed up after 6 weeks (28 patients, 51 HCs), 6 months (17 patients, 47 HCs), and 2 years (21 patients, 43 HCs) was completed. GABA levels in the dorsal anterior cingulate cortex and striatal resting cerebral blood flow were assessed on a 3T magnetic resonance scanner at all visits. RESULTS: GABA levels in the dorsal anterior cingulate cortex were significantly lower in patients at baseline and after 6 weeks but not after 6 months or 2 years. Analyses of groups separately revealed decreased GABA levels after 2 years in HCs but stable levels in patients. Treatment increased striatal resting cerebral blood flow after 6 weeks and 6 months but not after 2 years. GABA levels were negatively associated with striatal resting cerebral blood flow in both groups at all visits. Last, lower baseline GABA levels in patients were related to less functional improvement after 2 years. CONCLUSIONS: The findings suggest a different trajectory of GABA levels and striatal perfusion in first-episode patients over 2 years of antipsychotic treatment compared with HCs and indicate a downregulatory role of prefrontal GABAergic function on the striatum. Moreover, abnormally low prefrontal GABA level at illness onset may be a marker for a more severe prognosis.

Management of dyslipidaemia in individuals with severe mental illness: a population-based study in the Greater Copenhagen Area.

Background: Severe mental illness (SMI) is associated with increased cardiovascular risk. Dyslipidaemia is a potentially modifiable risk factor, which may be inadequately managed in patients with SMI. Objectives: To assess management of dyslipidaemia in patients with SMI versus healthy controls (HCs) in 2005 and 2015. Design and methods: Using Danish registers, we identified adult patients with SMI in the Greater Copenhagen Area (schizophrenia spectrum disorders or bipolar disorder) with ⩾1 general practitioner contact in the year before 2005 and 2015, respectively, and HCs without SMI matched on age and gender (1:5). Outcomes were lipid-profile measurements, presence of dyslipidaemia and redemption of lipid-lowering pharmacotherapy. Differences in outcomes between patients with SMI and controls were measured with multivariable logistic regression. Results: We identified 7217 patients with SMI in 2005 and 9939 in 2015. After 10 years, patients went from having lower odds of lipid measurements to having higher odds of lipid measurements compared with HCs [odds ratio (OR)2005 0.70 (99% confidence interval (CI) 0.63-0.78) versus OR2015 1.34 (99% CI 1.24-1.44); p2005versus2015 < 0.01]. Patients had higher odds of dyslipidaemia during both years [OR2005 1.43 (99% CI 1.10-1.85) and OR2015 1.23 (99% CI 1.08-1.41)]. Patients went from having lower odds of receiving lipid-lowering pharmacotherapy to having higher odds of receiving lipid-lowering pharmacotherapy [OR2005 0.77 (99% CI 0.66-0.89) versus OR2015 1.37 (99% CI 1.24-1.51); p2005versus2015 < 0.01]. However, among persons at high cardiovascular risk, patients had lower odds of receiving lipid-lowering pharmacotherapy during both years, including subsets with previous acute coronary syndrome [OR2005 0.30 (99% CI 0.15-0.59) and OR2015 0.44 (99% CI 0.24-0.83)] and ischaemic stroke or transient ischaemic attack (TIA) [OR2005 0.43 (99% CI 0.26-0.69) and OR 2015 0.61 (99% CI 0.41-0.89)]. Conclusion: These results imply an increased general awareness of managing dyslipidaemia among patients with SMI in the primary prophylaxis of cardiovascular disease. However, secondary prevention with lipid-lowering drugs in patients with SMI at high cardiovascular risk may be lacking.

Treatment of schizotypal disorder: a protocol for a systematic review of the evidence and recommendations for clinical practice.

INTRODUCTION: Schizotypal disorder is associated with a high level of disability at an individual level and high societal costs. However, clinical recommendations for the treatment of schizotypal disorder are scarce and based on limited evidence. This review aims to synthesise the current evidence on treatment for schizotypal disorder making recommendations for clinical practice. METHODS AND ANALYSIS: This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic literature search will be performed in PsychArticles, Embase, Medline and Cochrane Central Register of Controlled Trials. Additionally, we will search for relevant articles manually. Inclusion criteria are published studies including individuals diagnosed with schizotypal personality disorder according to Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, or schizotypal disorder according to International Classification of Diseases (ICD) criteria. We will include interventional studies comprising any pharmacological and non-pharmacological treatment trials for patients with schizotypal disorder, and all relevant outcome measures will be reported. Risk of bias will be assessed by Cochrane risk-of-bias tools. Data will be synthesised using narrative or thematic analysis and, if suitable, through meta-analysis. ETHICS AND DISSEMINATION: No original data will be collected as part of this study and ethics approval is, therefore, not applicable. The results will be disseminated through peer-reviewed publication and presented at international scientific meetings. We will aim at submitting the final paper for publication within 4 months of completion of analyses. Furthermore, this systematic review will inform clinicians and researchers on the current state of evidence on treatment for schizotypal disorder. Findings may guide proposals for further research and potentially guide recommendations for clinical practice using the Grading of Recommendations Assessment, Development and Evaluation. PROSPERO REGISTRATION NUMBER: CRD42022375001.

Influence of psychopathology and metabolic parameters on quality of life in patients with first-episode psychosis before and after initial antipsychotic treatment.

The impact of psychological and physical health on quality of life (QoL) in patients with early psychosis remain relatively unexplored. We evaluated the predictive value of psychopathological and metabolic parameters on QoL in antipsychotic-naïve patients with first-episode psychosis before and after initial antipsychotic treatment. At baseline, 125 patients underwent assessments of psychopathology, prevalence of metabolic syndrome (MetS), and QoL. After 6 weeks of antipsychotic monotherapy, 89 patients were re-investigated. At baseline, the prevalence of MetS was 19.3% (n = 22). After 6 weeks, body weight (1.3 kg, p < 0.001) and body mass index (0.4 kg/m2, p < 0.001) increased, and four additional patients developed MetS. Multivariate linear regression revealed that positive and negative symptoms, and to some degree waist circumference, were predictors of QoL at both time points. Our findings suggest that in the earliest stages of antipsychotic treatment, metabolic side-effects may be less influential on QoL than psychopathological severity.

Perspectives of professional experts in relation to the development of community-based exercise for young adults with schizophrenia: a qualitative study.

Physical activity is a key modifiable factor in protecting physical and mental health in people with severe mental illness including schizophrenia. Therefore, early promotion of physical activity is recommended and programmes supporting long-term maintenance of physically active behaviour are warranted. This study aimed to explore the perspectives of professional experts in relation to the development of a sustainable community-based exercise programme tailored to young adults with schizophrenia and intended to promote change and adoption of physical activity. We conducted 9 semistructured interviews with 11 clinical and professional experts. Qualitative content analysis, as described by Graneheim and Lundman, was applied to analyse data. We identified four categories: (1) living a physical active life with schizophrenia, (2) exercise as promotor of personal recovery, (3) prescribing safe and relevant exercise and (4) instructors' qualifications and formation. When developing sustainable community-based exercise programmes tailored to young adults with schizophrenia, developers should ensure instructors' qualifications and provide an exercise protocol. In addition, developers should consider providing an inclusive and recovery-oriented exercise environment.

COVID-19 lockdown, genetic ADHD susceptibility, and mental health in 10- year-old children.

Previous studies report that the COVID-19 lockdown had an impact on the mental health of the pediatric population. In this study, we harness the deep neuropsychiatric phenotyping of the population-based COPSAC2010 (n = 700) cohort at age 10 to study the impact of the COVID-19 lockdown on mental health outcomes with focus on the role of the genetic vulnerability to attention-deficit/hyperactivity disorder (ADHD), in the form of polygenic risk scores (PRS). A total of 593 children were examined between 2019 and 2021, resulting in two groups of different children, those evaluated before the lockdown (n = 230) and those evaluated after (n = 363). Children assessed after the lockdown presented higher odds of being diagnosed with ADHD and had significantly higher scores in most neuropsychiatric scales, particularly in subscales pertaining to behavior and attention problems. We observed a significant interaction between the lockdown and ADHD PRS on several neuropsychiatric dimensions, with a large post-lockdown increase in children with a high PRS, while there was little to no pre-post difference in children with low PRS. These results indicate mental health consequences of the lockdown in children and suggest that genetically susceptible individuals are more affected by such stressors in childhood.

Promising translatable pharmacological interventions for body weight management in individuals with severe mental illness - a narrative review.

INTRODUCTION: Psychotropic medications, especially antipsychotics, have been consistently shown to cause weight gain in individuals with severe mental illness (SMI), a population inherently challenged by poor physical health. Consequently, compared to the general population, this contributes to an increased cardiometabolic burden, including the risk of type 2 diabetes, dyslipidemia, and hypertension. Furthermore, comorbid obesity leads to treatment nonadherence, decreased quality of life, and increased risk of relapse, posing a challenge in the management of mental health. To address this, emerging agents investigated in the general population with potential to mitigate weight gain were explored to assess translatability to the SMI population. AREAS COVERED: A literature search was conducted including agents approved for the management of obesity in the general population, along with upcoming agents under investigation in phase III trials with weight loss properties. EXPERT OPINION: Metformin and topiramate along with lifestyle interventions are commonly prescribed for weight gain in individuals with SMI; however, their weight loss potential is modest at best. This review identified tirzepatide and cagrilintide-semaglutide among others as promising agents for adjunctive pharmacological management of weight gain.