Gender differences in the association between adverse childhood experiences and premature mortality: A prospective population study.

BACKGROUND: Birth cohort studies have shown that adverse childhood experiences (ACEs) are associated with all-cause mortality. The effect of ACEs on premature mortality among working-age people is less clear and may differ between the genders. OBJECTIVE: In this prospective population study, we investigated the association of ACEs with all-cause mortality in a working-age population. PARTICIPANTS AND METHODS: In a representative Finnish population study, Health 2000, individuals aged 30 to 64 years were interviewed in 2000, and their deaths were registered until 2020. At baseline, the participants (n = 4981, 2624 females) completed a questionnaire that included 11 questions on ACEs and questions on tobacco smoking, alcohol abuse, self-reported health and sufficiency of income. All-cause mortality was analysed by Cox regression analysis. RESULTS: Of the ACEs, financial difficulties, parental unemployment and individual's own chronic illness were associated with mortality. High number (4+) of ACEs was significantly associated with all-cause mortality in females (HR 2.11, p < 0.001), not in males. Poor health behaviour, self-reported health and low income were the major predictors of mortality in both genders. When the effects of these factors were controlled, childhood family conflicts associated with mortality in both genders. CONCLUSIONS: Among working-age people, females seem to be sensitive to the effects of numerous adverse childhood experiences, exhibiting higher premature all-cause mortality. Of the individual ACEs, family conflicts may increase risk of premature mortality in both genders. The effect of ACEs on premature mortality may partly be mediated via poor adult health behaviour and low socioeconomic status. WHAT IS ALREADY KNOWN: In birth cohort studies, adverse childhood experiences (ACEs) have been associated with all-cause mortality. In working-age people, the association of ACEs with premature mortality is less clear and may differ between the genders. WHAT THIS STUDY ADDS: In working-age people, high number of ACEs associate with all-cause premature mortality in females, not in males. The effect of ACEs on premature mortality may partly be mediated via poor adult health behaviour, self-reported health and low socioeconomic status.

Seasonal variation in D2/3 dopamine receptor availability in the human brain.

PURPOSE: Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized. METHODS: Based on a historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. Daylength at the time of scanning was used as a predictor for brain regional non-displaceable binding of the radiotracer, while controlling for age and sex. RESULTS: Daylength was negatively correlated with availability of D2/3 dopamine receptors in the striatum. The largest effect was found in the left caudate, and based on the primary sample, every 4.26 h (i.e., one standard deviation) increase of daylength was associated with a mean 2.8% drop (95% CI -0.042 to -0.014) of the receptor availability. CONCLUSIONS: Seasonally varying D2/3 receptor signaling may also underlie the seasonality of mood, feeding, and motivational processes. Our finding suggests that in future studies of brain dopamine signaling, especially in high-latitude regions, the effect of seasonality should be considered.

Distinct multimodal biological and functional profiles of symptom-based subgroups in recent-onset psychosis.

Symptom heterogeneity characterizes psychotic disorders and hinders the delineation of underlying biomarkers. Here, we identify symptom-based subtypes of recent-onset psychosis (ROP) patients from the multi-center PRONIA (Personalized Prognostic Tools for Early Psychosis Management) database and explore their multimodal biological and functional signatures. We clustered N = 328 ROP patients based on their maximum factor scores in an exploratory factor analysis on the Positive and Negative Syndrome Scale items. We assessed inter-subgroup differences and compared to N = 464 healthy control (HC) individuals regarding gray matter volume (GMV), neurocognition, polygenic risk scores, and longitudinal functioning trajectories. Finally, we evaluated factor stability at 9- and 18-month follow-ups. A 4-factor solution optimally explained symptom heterogeneity, showing moderate longitudinal stability. The ROP-MOTCOG (Motor/Cognition) subgroup was characterized by GMV reductions within salience, control and default mode networks, predominantly throughout cingulate regions, relative to HC individuals, had the most impaired neurocognition and the highest genetic liability for schizophrenia. ROP-SOCWD (Social Withdrawal) patients showed GMV reductions within medial fronto-temporal regions of the control, default mode, and salience networks, and had the lowest social functioning across time points. ROP-POS (Positive) evidenced GMV decreases in salience, limbic and frontal regions of the control and default mode networks. The ROP-AFF (Affective) subgroup showed GMV reductions in the salience, limbic, and posterior default-mode and control networks, thalamus and cerebellum. GMV reductions in fronto-temporal regions of the salience and control networks were shared across subgroups. Our results highlight the existence of behavioral subgroups with distinct neurobiological and functional profiles in early psychosis, emphasizing the need for refined symptom-based diagnosis and prognosis frameworks.

Long-term benzodiazepine use and risk of labor market marginalization in Finland: A cohort study with 5-year follow-up.

BACKGROUND: Benzodiazepines and related drugs (BZDRs) are widely used in the treatment of anxiety and sleep disorders, but cognitive adverse effects have been reported in long-term use, and these may increase the risk of labor market marginalization (LMM). The aim of this study was to investigate whether the risk of LMM is associated with new long-term BZDR use compared to short-term use. METHODS: This register-based nationwide cohort study from Finland included 37,703 incident BZDR users aged 18-60 years who initiated BZDR use in 2006. During the first year of use, BZDR users were categorized as long-term users (≥180 days) versus short-term users based on PRE2DUP method. The main outcome was LMM, defined as receipt of disability pension, long-term sickness absence (>90 days), or long-term unemployment (>180 days). The risk of outcomes was analyzed with Cox regression models, adjusted with sociodemographic background, somatic and psychiatric morbidity, other types of medication and previous sickness absence. RESULTS: During 5 years of follow-up, long-term use (34.4%, N = 12,962) was associated with 27% (adjusted Hazard Ratio, aHR 1.27, 95% CI 1.23-1.31) increased risk of LMM compared with short-term use. Long-term use was associated with 42% (aHR 1.42, 95% CI 1.34-1.50) increased risk of disability pension and 26% increased risk of both long-term unemployment and long-term sickness absence. CONCLUSIONS: These results indicate that long-term use of BZDRs is associated with increased risk of dropping out from labor market. This may be partly explained by cognitive adverse effects of prolonged BZDR use, which should be taken into account when prescribing BZDRs.

Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders.

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants' past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23-1.43], p = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia (n = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden (p = 1.00e-04 and p = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories.

Alterations in type 2 dopamine receptors across neuropsychiatric conditions: A large-scale PET cohort.

PURPOSE: Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls. METHODS: Here, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (D2R) availability using [11C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls, and subjects with Parkinson's disease (PD), antipsychotic-naïve schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in D2R availability. We also analyzed the interregional correlation in D2R availability within each group. RESULTS: Subjects with PD showed the clearest decline in D2R availability. Overall, the groups showed high interregional correlation in D2R availability, while this pattern was weaker in violent offenders. Subjects with schizophrenia, pathological gambling, depression, or overweight did not show clear changes in either the regional receptor availability or the interregional correlation. CONCLUSION: We conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also how coupled regions are across people. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region coupling might be disrupted in violence.

Polygenic risk for depression predicting temperament trajectories over 15 years - A general population study.

BACKGROUND: A great number of case-control and population-based studies have shown that depression patients differ from healthy controls in their temperament traits. We investigated whether polygenic risk for depression predicts trajectories of temperament traits from early adulthood to middle age. METHODS: Participants came from the population-based Young Finns Study (n = 2212). The calculation for Polygenic risk for depression (PRS) was based on the most recent genome-wide association study. Temperament traits of Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were assessed with the Temperament and Character Inventory in 1997, 2001, 2007, and 2012 (participants being 24-50-year-olds). As covariates, we used depressive symptoms as assessed by a modified version of the Beck Depression Inventory, psychosocial family environment from parent-filled questionnaires, and socioeconomic factors from adulthood. RESULTS: High PRS predicted higher Persistence from early adulthood to middle age (p = 0.003) when controlling for depressive symptoms, psychosocial family environment, and socioeconomic factors. PRS did not predict trajectories of Novelty Seeking (p = 0.063-0.416 in different models) or Reward Dependence (p = 0.531-0.736). The results remained unaffected when participants with diagnosed affective disorders were excluded. Additionally, we found an interaction between PRS and depressive symptoms when predicting the Harm Avoidance subscale Anticipatory Worry, indicating that the association of Anticipatory Worry with depressive symptoms is stronger in individuals with higher (vs. lower) PRS. LIMITATIONS: There was some attrition due to the long follow-up. CONCLUSIONS: High polygenic risk for major depression may predict differences in temperament trajectories among those who have not developed any severe affective disorders.

Polygenic risk for schizophrenia, social dispositions, and pace of epigenetic aging: Results from the Young Finns Study.

Schizophrenia is often regarded as a disorder of premature aging. We investigated (a) whether polygenic risk for schizophrenia (PRSsch ) relates to pace of epigenetic aging and (b) whether personal dispositions toward active and emotionally close relationships protect against accelerated epigenetic aging in individuals with high PRSsch . The sample came from the population-based Young Finns Study (n = 1348). Epigenetic aging was measured with DNA methylation aging algorithms such as AgeAccelHannum , EEAAHannum , IEAAHannum , IEAAHorvath , AgeAccelHorvath , AgeAccelPheno , AgeAccelGrim , and DunedinPACE. A PRSsch was calculated using summary statistics from the most comprehensive genome-wide association study of schizophrenia to date. Social dispositions were assessed in terms of extraversion, sociability, reward dependence, cooperativeness, and attachment security. We found that PRSsch did not have a statistically significant effect on any studied indicator of epigenetic aging. Instead, PRSsch had a significant interaction with reward dependence (p = 0.001-0.004), cooperation (p = 0.009-0.020), extraversion (p = 0.019-0.041), sociability (p = 0.003-0.016), and attachment security (p = 0.007-0.014) in predicting AgeAccelHannum , EEAAHannum , or IEAAHannum . Specifically, participants with high PRSsch appeared to display accelerated epigenetic aging at higher (vs. lower) levels of extraversion, sociability, attachment security, reward dependence, and cooperativeness. A rather opposite pattern was evident for those with low PRSsch . No such interactions were evident when predicting the other indicators of epigenetic aging. In conclusion, against our hypothesis, frequent social interactions may relate to accelerated epigenetic aging in individuals at risk for psychosis. We speculate that this may be explained by social-cognitive impairments (perceiving social situations as overwhelming or excessively arousing) or ending up in less supportive or deviant social groups.

Polygenic risk for schizophrenia predicting social trajectories in a general population sample.

BACKGROUND: We investigated (a) whether polygenic risk for schizophrenia predicts different trajectories of social development among those who have not developed psychoses and (b) whether possible associations are PRSSCZ-specific or evident also for any polygenic risk for mental disorders, e.g. for major depression. METHODS: Participants came from the population-based Young Finns Study (n = 2377). We calculated a polygenic risk score for schizophrenia (PRSSCZ) and for major depression (PRSDEP). Diagnoses of psychotic disorders were derived from the hospital care register. Social development from adolescence to middle age was measured by (a) perceived social support from friends, family, and a close other, (b) perceived sociability, and (c) family structure (partnership status, number of children, age of first-time parenthood). RESULTS: Among those without manifest psychoses, high PRSSCZ predicted lower experienced support from friends (B = -0.04, p = 0.009-0.035) and family (B = -0.04, p = 0.009-0.035) especially after early adulthood, and also lower perceived sociability (B = -0.05, p = 0.010-0.026). PRSSCZ was not related to family structure. PRSDEP did not predict any domain of social development. CONCLUSIONS: Individuals at high PRSSCZ (not converted to psychosis) seem to experience a lower preference to be with others over being alone. Individuals with high (v. low) PRSSCZ seem to have a similar family structure in terms of partnership status or number of children but, nevertheless, they experience less support from their family. Among those not converted to psychosis in a typical age period, high PRSSCZ may predict a 'later risk phase' and reduced functional resilience when approaching middle age.

Sense of mastery in first-episode psychosis-a one-year follow-up study.

Introduction: A sense of mastery refers to beliefs about having control over one's life and has been found to protect health and buffer the effect of stressful experiences. Methods: We investigated sense of mastery in first-episode psychosis (FEP) patients and population controls at baseline and at one-year follow-up. Pearlin and Schooler's Sense of Mastery scale was completed by 322 participants at baseline and by 184 participants at follow-up. Results: People having experienced FEP reported lower mastery than controls at both time points, but a modest increase was seen in patients at follow-up. The strongest correlates of high baseline mastery in FEP were lower depressive symptoms and higher perceived social support, whereas positive or negative psychotic symptoms did not associate with mastery. Current depressive symptoms also correlated with mastery at the follow-up point, and change in depressive symptoms correlated with change in mastery. Higher mastery at treatment entry predicted remission of psychotic symptoms one year later. Sense of mastery was also found to mediate the association of perceived social support with depressive symptoms. Discussion: The usefulness of mastery measures should be further tested for estimations of patient prognosis in early psychosis.

Childhood family environment predicting psychotic disorders over a 37-year follow-up - A general population cohort study.

BACKGROUND: Childhood adverse effects and traumatic experiences increase the risk for several psychiatric disorders. We now investigated whether prospectively assessed childhood family environment per se contributes to increased risk for psychotic disorders in adulthood, and whether these family patterns are also relevant in the development of affective disorders. METHODS: We used the Young Finns Data (n = 3502). Childhood family environment was assessed in 1980/1983 with previously constructed risk scores: (1) disadvantageous emotional family atmosphere (parenting practices, parents' life satisfaction, parents' mental disorder, parents' alcohol intoxication), (2) adverse socioeconomic environment (overcrowded apartment, home income, parent's employment, occupational status, educational level), and (3) stress-prone life events (home movement, school change, parental divorce, death, or hospitalization, and child's hospitalization). Psychiatric diagnoses (ICD-10 classification) over the lifespan were collected up to 2017 from the national registry of hospital care. Non-affective psychotic disorder and affective disorder groups were formed. RESULTS: Frequent stress-prone life events predicted higher likelihood of non-affective psychotic disorders (OR = 2.401, p = 0.001). Adverse socioeconomic environment or emotional family atmosphere did not predict psychotic disorders. Only disadvantageous emotional family atmosphere predicted modestly higher likelihood of affective disorders (OR = 1.583, p = 0.013). CONCLUSIONS: Our results suggest that childhood family environment and atmosphere patterns as such contribute to the risk for developing adulthood mental disorders with relative disorder specificity. The results emphasize the importance of both individual and public health preventive initiatives, including family support interventions.

The heterogeneity of attenuated and brief limited psychotic symptoms: association of contents with age, sex, country, religion, comorbidities, and functioning.

Introduction: The Attenuated Psychosis Symptoms (APS) syndrome mostly represents the ultra-high-risk state of psychosis but, as does the Brief Intermittent Psychotic Symptoms (BIPS) syndrome, shows a large variance in conversion rates. This may be due to the heterogeneity of APS/BIPS that may be related to the effects of culture, sex, age, and other psychiatric morbidities. Thus, we investigated the different thematic contents of APS and their association with sex, age, country, religion, comorbidity, and functioning to gain a better understanding of the psychosis-risk syndrome. Method: A sample of 232 clinical high-risk subjects according to the ultra-high risk and basic symptom criteria was recruited as part of a European study conducted in Germany, Italy, Switzerland, and Finland. Case vignettes, originally used for supervision of inclusion criteria, were investigated for APS/BIPS contents, which were compared for sex, age, country, religion, functioning, and comorbidities using chi-squared tests and regression analyses. Result: We extracted 109 different contents, mainly of APS (96.8%): 63 delusional, 29 hallucinatory, and 17 speech-disorganized contents. Only 20 contents (18.3%) were present in at least 5% of the sample, with paranoid and referential ideas being the most frequent. Thirty-one (28.5%) contents, in particular, bizarre ideas and perceptual abnormalities, demonstrated an association with age, country, comorbidity, or functioning, with regression models of country and obsessive-compulsive disorders explaining most of the variance: 55.8 and 38.3%, respectively. Contents did not differ between religious groups. Conclusion: Psychosis-risk patients report a wide range of different contents of APS/BIPS, underlining the psychopathological heterogeneity of this group but also revealing a potential core set of contents. Compared to earlier reports on North-American samples, our maximum prevalence rates of contents were considerably lower; this likely being related to a stricter rating of APS/BIPS and cultural influences, in particular, higher schizotypy reported in North-America. The various associations of some APS/BIPS contents with country, age, comorbidities, and functioning might moderate their clinical severity and, consequently, the related risk for psychosis and/or persistent functional disability.

Polygenic liabilities underlying job stress and exhaustion over a 10-year follow-up: A general population study.

We investigated whether individuals, who have a high polygenic loading for schizophrenia and major depression (PGL) but have not developed the respective disorders, are still susceptible to experience milder forms of ill-being in terms of job strain or exhaustion. We used the population-based Young Finns Study data (n = 928). PGL was assessed with a cumulative score of the polygenic risk scores for schizophrenia and depression. Participants (24-49-year-olds) evaluated their exhaustion levels and perceived job characteristics over a 10-year follow-up (2001, 2007, 2011). Participants with diagnosed psychotic or affective disorders were excluded. We found that high PGL did not predict less favorable perceptions of job environment (job strain, demands, control, satisfaction, social support at work) but high PGL predicted a higher trajectory of exhaustion in early adulthood and middle age. Additionally, high (vs. low) PGL predicted a stronger increase in exhaustion at increased levels of job strain. These findings remained after controlling for sex, socioeconomic factors, health behaviors, and cognitive performance. In conclusion, individuals with high PGL may have an elevated liability to experience exhaustion especially in early adulthood and middle age (despite they perceive their job environment similarly than others), and especially and at high levels of job strain.

Structural and Functional Brain Patterns Predict Formal Thought Disorder's Severity and Its Persistence in Recent-Onset Psychosis: Results From the PRONIA Study.

BACKGROUND: Formal thought disorder (FThD) is a core feature of psychosis, and its severity and long-term persistence relates to poor clinical outcomes. However, advances in developing early recognition and management tools for FThD are hindered by a lack of insight into the brain-level predictors of FThD states and progression at the individual level. METHODS: Two hundred thirty-three individuals with recent-onset psychosis were drawn from the multisite European Prognostic Tools for Early Psychosis Management study. Support vector machine classifiers were trained within a cross-validation framework to separate two FThD symptom-based subgroups (high vs. low FThD severity), using cross-sectional whole-brain multiband fractional amplitude of low frequency fluctuations, gray matter volume and white matter volume data. Moreover, we trained machine learning models on these neuroimaging readouts to predict the persistence of high FThD subgroup membership from baseline to 1-year follow-up. RESULTS: Cross-sectionally, multivariate patterns of gray matter volume within the salience, dorsal attention, visual, and ventral attention networks separated the FThD severity subgroups (balanced accuracy [BAC] = 60.8%). Longitudinally, distributed activations/deactivations within all fractional amplitude of low frequency fluctuation sub-bands (BACslow-5 = 73.2%, BACslow-4 = 72.9%, BACslow-3 = 68.0%), gray matter volume patterns overlapping with the cross-sectional ones (BAC = 62.7%), and smaller frontal white matter volume (BAC = 73.1%) predicted the persistence of high FThD severity from baseline to follow-up, with a combined multimodal balanced accuracy of BAC = 77%. CONCLUSIONS: We report the first evidence of brain structural and functional patterns predictive of FThD severity and persistence in early psychosis. These findings open up avenues for the development of neuroimaging-based diagnostic, prognostic, and treatment options for the early recognition and management of FThD and associated poor outcomes.

Cohort profile: SUPER-Finland - the Finnish study for hereditary mechanisms of psychotic disorders.

PURPOSE: SUPER-Finland is a large Finnish collection of psychosis cases. This cohort also represents the Finnish contribution to the Stanley Global Neuropsychiatric Genetics Initiative, which seeks to diversify genetic sample collection to include Asian, Latin American and African populations in addition to known population isolates, such as Finland. PARTICIPANTS: 10 474 individuals aged 18 years or older were recruited throughout the country. The subjects have been genotyped with a genome-wide genotyping chip and exome sequenced. A subset of 897 individuals selected from known population sub-isolates were selected for whole-genome sequencing. Recruitment was done between November 2015 and December 2018. FINDINGS TO DATE: 5757 (55.2%) had a diagnosis of schizophrenia, 944 (9.1%) schizoaffective disorder, 1612 (15.5%) type I or type II bipolar disorder, 532 (5.1 %) psychotic depression, 1047 (10.0%) other psychosis and for 530 (5.1%) self-reported psychosis at recruitment could not be confirmed from register data. Mean duration of schizophrenia was 22.0 years at the time of the recruitment. By the end of the year 2018, 204 of the recruited individuals had died. The most common cause of death was cardiovascular disease (n=61) followed by neoplasms (n=40). Ten subjects had psychiatric morbidity as the primary cause of death. FUTURE PLANS: Compare the effects of common variants, rare variants and copy number variations (CNVs) on severity of psychotic illness. In addition, we aim to track longitudinal course of illness based on nation-wide register data to estimate how phenotypic and genetic differences alter it.

Functional Characterization of Six SLCO1B1 (OATP1B1) Variants Observed in Finnish Individuals with a Psychotic Disorder.

Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2',7'-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.

Metabolic trajectories in childhood and adolescence: Effects on risk for schizophrenia.

Abnormal glucose and lipid metabolism is common in antipsychotic-naive first-episode patients with schizophrenia, but it is unclear whether these changes can already be seen in premorbid or prodromal period, before the first psychotic episode. We examined insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride trajectories in children and adolescents (9-18 years old), who were later diagnosed with schizophrenia, any non-affective psychosis (NAP) or affective disorder (AD). The study population consisted of a general population-based cohort "The Cardiovascular Risk in Young Finns Study", started in 1980 (n = 3596). Psychiatric diagnoses were derived from the Health Care Register up to the year 2018. Multivariate statistical analysis indicated no significant differences in insulin or lipid levels in children and adolescents who later developed schizophrenia (n = 41) compared to the cohort control group (n = 3202). In addition, no changes in these parameters were seen in the NAP (n = 74) or AD (n = 156) groups compared to the controls, but lower triglyceride levels in childhood/adolescence associated with earlier diagnosis of psychotic disorder in the NAP group. Taken together, our results do not support any gross-level insulin or lipid changes during childhood and adolescence in individuals with later diagnosis of schizophrenia-spectrum disorder. Since changes in glucose and lipid metabolism can be observed in neuroleptic-naive patients with schizophrenia, we hypothesize that the more marked metabolic changes develop during the prodrome closer to the onset of the first psychotic episode. The findings have relevance for studies on developmental hypotheses of schizophrenia.

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex.

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning: Dementia Praecox Revisited.

Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2 = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2 = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

Extrapyramidal symptoms predict cognitive performance after first-episode psychosis.

Extrapyramidal (EP) symptoms such as tremor, rigidity, and bradykinesia are common side effects of most antipsychotics, and may associate with impaired performance in neurocognitive testing. We studied EP symptoms in first-episode psychosis (FEP; n = 113). Cognitive testing and EP symptoms (three items of the Simpson-Angus Scale) were assessed at baseline and follow-up (mean follow-up time 12 months). Mild EP symptoms were present at treatment onset in 40% of the participants. EP symptoms were related with lower performance in neurocognitive testing at baseline and at follow-up, especially among those with nonaffective psychotic disorder, and especially in tasks requiring speed of processing. No associations between EP symptoms and social cognition were detected. In linear regression models, when positive and negative symptom levels and chlorpromazine equivalents were accounted for, baseline EP symptoms were associated with worse baseline global neurocognition and visuomotor performance. Baseline EP symptoms also longitudinally predicted global, verbal, and visuomotor cognition. However, there were no cross-sectional associations between EP symptoms and cognitive performance at follow-up. In sum, we found both cross-sectional and longitudinal associations between EP symptoms and neurocognitive task performance in the early course of psychosis. Those without EP symptoms at the start of treatment had higher baseline and follow-up neurocognitive performance. Even mild EP symptoms may represent early markers of long-term neurocognitive impairment.