Psychotic experiences (PEs) and social isolation (SI) seem related during early stages of psychosis, but the temporal dynamics between the two are not clear. Literature so far suggests a self-perpetuating cycle wherein momentary increases in PEs lead to social withdrawal, which, subsequently, triggers PEs at a next point in time, especially when SI is associated with increased distress. The current study investigated the daily-life temporal associations between SI and PEs, as well as the role of SI-related and general affective distress in individuals at clinical high risk (CHR) for psychosis.

We used experience sampling methodology in a sample of 137 CHR participants. We analyzed the association between SI, PEs, and distress using time-lagged linear mixed-effects models.

SI did not predict next-moment fluctuations in PEs, or vice versa. Furthermore, although SI-related distress was not predictive of subsequent PEs, general affective distress during SI was a robust predictor of next-moment PEs.

Our results suggest that SI and PEs are not directly related on a moment-to-moment level, but a negative emotional state when alone does contribute to the risk of PEs. These findings highlight the role of affective wellbeing during early-stage psychosis development.

To address if the long-standing association between maternal infection, depression/anxiety in pregnancy, and offspring neurodevelopmental disorder (NDD) is causal, we conducted two negative-control studies.

Four primary care cohorts of UK children (pregnancy, 1 and 2 years prior to pregnancy, and siblings) born between 1 January 1990 and 31 December 2017 were constructed. NDD included autism/autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disability, cerebral palsy, and epilepsy. Maternal exposures included depression/anxiety and/or infection. Maternal (age, smoking status, comorbidities, body mass index, NDD); child (gender, ethnicity, birth year); and area-level (region and level of deprivation) confounders were captured. The NDD incidence rate among (1) children exposed during or outside of pregnancy and (2) siblings discordant for exposure in pregnancy was compared using Cox-regression models, unadjusted and adjusted for confounders.

The analysis included 410 461 children of 297 426 mothers and 2 793 018 person-years of follow-up with 8900 NDD cases (incidence rate = 3.2/1000 person years). After adjustments, depression and anxiety consistently associated with NDD (pregnancy-adjusted HR = 1.58, 95% CI 1.46–1.72; 1-year adj. HR = 1.49, 95% CI 1.39–1.60; 2-year adj. HR = 1.62, 95% CI 1.50–1.74); and to a lesser extent, of infection (pregnancy adj. HR = 1.16, 95% CI 1.10–1.22; 1-year adj. HR = 1.20, 95% CI 1.14–1.27; 2-year adj. HR = 1.19, 95% CI 1.12–1.25). NDD risk did not differ among siblings discordant for pregnancy exposure to mental illness HR = 0.97, 95% CI 0.77–1.21 or infection HR = 0.99, 95% CI 0.90–1.08.

Maternal risk appears to be unspecific to pregnancy: our study provided no evidence of a specific, and therefore causal, link between in-utero exposure to infection, common mental illness, and later development of NDD.

Psychiatric in-patients have a greatly elevated risk of suicide. We aimed to examine trends in in-patient suicide rates and determine if characteristics of in-patients who died by suicide have changed over time.

We identified all in-patients in England who died by suicide between 2009 and 2020 from the National Confidential Inquiry into Suicide and Safety in Mental Health. Suicide rates were calculated using data from Hospital Episodes Statistics.

The rate of in-patient suicide per 100 000 bed days fell by 41.9% between 2009–2011 and 2018–2020. However, since 2016 the rate has remained static with no significant fall. Rates fell in men, those aged 30–59, and those with schizophrenia and other delusional disorders or personality disorder. Rates also fell for suicide by hanging (including hanging on the ward) and jumping. No falls were seen in suicide rates among women, younger and older age groups, and those with affective disorder. There was no indication of a transfer of risk to the post-discharge period or to home treatment/crisis care. More in-patients in the latter part of the study were aged under 25, were on authorised leave, and had psychiatric comorbidity.

In-patient suicide has significantly fallen since 2009, suggesting patient safety may have improved. The recent slowdown in the fall in rates, however, highlights that renewed preventative efforts are needed. These should include a greater focus on women, younger and older patients, and those with affective disorder. Careful reviews prior to granting leave are important to ensure a safe transition into the community.

To determine whether genetic risk factors for major depression (MD) and alcohol use disorder (AUD) interact with a potent stressor – death of spouse, parent, and sibling – in predicting episodes of, respectively, MD and AUD.

MD and AUD registrations were assessed from national Swedish registries. In individuals born in Sweden 1960–1970, we identified 7586, 388 459, and 34 370 with the loss of, respectively, a spouse, parent, and sibling. We started following subjects at age 18 or the year 2002 with end of follow-up in 2018. We examined time to event – a registration for MD within 6 months or AUD within a year – on an additive scale, using the Nelson–Aalen estimator. Genetic risk was assessed by the Family Genetic Risk Score (FGRS).

In separate models controlling for the main effects of death of spouse, parent, and sibling, FGRS, and sex, significant interactions were seen in all analyses between genetic risk for MD and death of relative in prediction of subsequent MD registration. A similar pattern of results, albeit with weaker interaction effects, was seen for genetic risk for AUD and risk for AUD registration. Genetic risk for bipolar disorder (BD) and anxiety disorders (AD) also interacted with event exposure in predicting MD.

Genetic risk for both MD and AUD act in part by increasing the sensitivity of individuals to the pathogenic effects of environmental stressors. For prediction of MD, similar effects are also seen for genetic risk for AD and BD.

To investigate the association between pre-trial expectancy, suggestibility, and response to treatment in a trial of escitalopram and investigational drug, COMP360, psilocybin, in the treatment of major depressive disorder (ClinicalTrials.gov registration: NCT03429075).

We used data (n = 55) from our recent double-blind, parallel-group, randomized head-to-head comparison trial of escitalopram and investigational drug, COMP360, psilocybin. Mixed linear models were used to investigate the association between pre-treatment efficacy-related expectations, as well as baseline trait suggestibility and absorption, and therapeutic response to both escitalopram and COMP360 psilocybin.

Patients had significantly higher expectancy for psilocybin relative to escitalopram; however, expectancy for escitalopram was associated with improved therapeutic outcomes to escitalopram, expectancy for psilocybin was not predictive of response to psilocybin. Separately, we found that pre-treatment trait suggestibility was associated with therapeutic response in the psilocybin arm, but not in the escitalopram arm.

Overall, our results suggest that psychedelic therapy may be less vulnerable to expectancy biases than previously suspected. The relationship between baseline trait suggestibility and response to psilocybin therapy implies that highly suggestible individuals may be primed for response to this treatment.

We compared dissociative seizure specific cognitive behavior therapy (DS-CBT) plus standardized medical care (SMC) to SMC alone in a randomized controlled trial. DS-CBT resulted in better outcomes on several secondary trial outcome measures at the 12-month follow-up point. The purpose of this paper is to evaluate putative treatment mechanisms.

We carried out a secondary mediation analysis of the CODES trial. 368 participants were recruited from the National Health Service in secondary / tertiary care in England, Scotland, and Wales. Sixteen mediation hypotheses corresponding to combinations of important trial outcomes and putative mediators were assessed. Twelve-month trial outcomes considered were final-month seizure frequency, Work and Social Adjustment Scale (WSAS), and the SF-12v2, a quality-of-life measure providing physical (PCS) and mental component summary (MCS) scores. Mediators chosen for analysis at six months (broadly corresponding to completion of DS-CBT) included: (a) beliefs about emotions, (b) a measure of avoidance behavior, (c) anxiety and (d) depression.

All putative mediator variables except beliefs about emotions were found to be improved by DS-CBT. We found evidence for DS-CBT effect mediation for the outcome variables dissociative seizures (DS), WSAS and SF-12v2 MCS scores by improvements in target variables avoidance behavior, anxiety, and depression. The only variable to mediate the DS-CBT effect on the SF-12v2 PCS score was avoidance behavior.

Our findings largely confirmed the logic model underlying the development of CBT for patients with DS. Interventions could be additionally developed to specifically address beliefs about emotions to assess whether it improves outcomes.

Fatigue is a central feature of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), but many ME/CFS patients also report comorbid pain symptoms. It remains unclear whether these symptoms are related to similar or dissociable brain networks. This study used resting-state fMRI to disentangle networks associated with fatigue and pain symptoms in ME/CFS patients, and to link changes in those networks to clinical improvements following cognitive behavioral therapy (CBT).

Relationships between pain and fatigue symptoms and cortico-cortical connectivity were assessed within ME/CFS patients at baseline (N = 72) and after CBT (N = 33) and waiting list (WL, N = 18) and compared to healthy controls (HC, N = 29). The analyses focused on four networks previously associated with pain and/or fatigue, i.e. the fronto-parietal network (FPN), premotor network (PMN), somatomotor network (SMN), and default mode network (DMN).

At baseline, variation in pain and fatigue symptoms related to partially dissociable brain networks. Fatigue was associated with higher SMN-PMN connectivity and lower SMN-DMN connectivity. Pain was associated with lower PMN-DMN connectivity. CBT improved SMN-DMN connectivity, compared to WL. Larger clinical improvements were associated with larger increases in frontal SMN-DMN connectivity. No CBT effects were observed for PMN-DMN or SMN-PMN connectivity.

These results provide insight into the dissociable neural mechanisms underlying fatigue and pain symptoms in ME/CFS and how they are affected by CBT in successfully treated patients. Further investigation of how and in whom behavioral and biomedical treatments affect these networks is warranted to improve and individualize existing or new treatments for ME/CFS.

Although the importance of the dynamic intra-individual relationship between mother-to-infant bonding and postpartum depressive symptoms has been widely recognized, the complex interplay between them is not well understood. Furthermore, the potential role of prenatal depressive symptoms and infant temperament in this relationship remains unclear. This study aims to examine the bidirectional influence of mother-to-infant bonding on postpartum depressive symptoms within individuals and to elucidate whether prenatal depressive symptoms and infant temperament would influence deviations from stable individual states.

Longitudinal data were collected from 433 women in early pregnancy. Of these, 360 participants completed the main questionnaires measuring impaired mother-to-infant bonding and postpartum depressive symptoms at least once during the postpartum period. Data were collected at early and late pregnancy and several postpartum time points: shortly after birth and at one, four, ten, and 18 months postpartum. We also assessed prenatal depressive symptoms and infant temperament. A random-intercept cross-lagged panel model was used.

Within-individual variability in mother-to-infant bonding, especially anger and rejection, significantly predicted subsequent postpartum depressive symptoms. However, the inverse relationship was not significant. Additionally, prenatal depressive symptoms and difficult infant temperament were associated with greater within-individual variability in impaired mother-to-infant bonding and postpartum depressive symptoms.

The present study demonstrated that the within-individual relationship between mother-to-infant bonding and postpartum depressive symptoms is likely non-bidirectional. The significance of the findings is underscored by the potential for interventions aimed at improving mother-to-infant bonding to alleviate postpartum depressive symptoms, suggesting avenues for future research and practice.

Alterations in brain functional connectivity (FC) have been frequently reported in adolescent major depressive disorder (MDD). However, there are few studies of dynamic FC analysis, which can provide information about fluctuations in neural activity related to cognition and behavior. The goal of the present study was therefore to investigate the dynamic aspects of FC in adolescent MDD patients.

Resting-state functional magnetic resonance imaging data were acquired from 94 adolescents with MDD and 78 healthy controls. Independent component analysis, a sliding-window approach, and graph-theory methods were used to investigate the potential differences in dynamic FC properties between the adolescent MDD patients and controls.

Three main FC states were identified, State 1 which was predominant, and State 2 and State 3 which occurred less frequently. Adolescent MDD patients spent significantly more time in the weakly-connected and relatively highly-modularized State 1, spent significantly less time in the strongly-connected and low-modularized State 2, and had significantly higher variability of both global and local efficiency, compared to the controls. Classification of patients with adolescent MDD was most readily performed based on State 1 which exhibited disrupted intra- and inter-network FC involving multiple functional networks.

Our study suggests local segregation and global integration impairments and segregation-integration imbalance of functional networks in adolescent MDD patients from the perspectives of dynamic FC. These findings may provide new insights into the neurobiology of adolescent MDD.

Adolescence is a key developmental period for the emergence of psychopathology. Reward-related brain activity increases across adolescence and has been identified as a potential neurobiological mechanism of risk for different forms of psychopathology. The reward positivity (RewP) is an event-related potential component that indexes reward system activation and has been associated with both concurrent and family history of psychopathology. However, it is unclear whether the RewP is also associated with higher-order psychopathology subfactors and whether this relationship is present across different types of reward.

In a sample of 193 adolescent females and a biological parent, the present study examined the association between adolescent and parental psychopathology subfactors and adolescent RewP to monetary and social reward.

Results indicated that the adolescent and parental distress subfactors were negatively associated with the adolescent domain-general RewP. The adolescent and parental positive mood subfactors were negatively associated with the adolescent domain-general and domain-specific monetary RewP, respectively. Conversely, the adolescent and parental fear/obsessions subfactors were positively associated with the adolescent domain-general RewP. The associations between parental and adolescent psychopathology subfactors and the adolescent RewP were independent of each other.

The RewP in adolescent females is associated with both concurrent and parental psychopathology symptoms, suggesting that it indexes both severity and risk for higher-order subfactors.

Elucidation of the interaction of biological and psychosocial/environmental factors on opioid dependence (OD) risk can inform our understanding of the etiology of OD. We examined the role of psychosocial/environmental factors in moderating polygenic risk for opioid use disorder (OUD).

Data from 1958 European ancestry adults who participated in the Yale-Penn 3 study were analyzed. Polygenic risk scores (PRS) were based on a large-scale multi-trait analysis of genome-wide association studies (MTAG) of OUD.

A total of 420 (21.1%) individuals had a lifetime diagnosis of OD. OUD PRS were positively associated with OD (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.21–1.66). Household income and education were the strongest correlates of OD. Among individuals with higher OUD PRS, those with higher education level had lower odds of OD (OR 0.92, 95% CI 0.85–0.98); and those with posttraumatic stress disorder (PTSD) were more likely to have OD relative to those without PTSD (OR 1.56, 95% CI 1.04–2.35).

Results suggest an interplay between genetics and psychosocial environment in contributing to OD risk. While PRS alone do not yet have useful clinical predictive utility, psychosocial factors may help enhance prediction. These findings could inform more targeted clinical and policy interventions to help address this public health crisis.

Individual placement and support (IPS) is an evidence-based practice that helps individuals with mental illness gain and retain employment. IPS was implemented for young adults at a municipality level through a cross-sectoral collaboration between specialist mental healthcare, primary mental healthcare, and the government funded employment service (NAV). We investigated whether IPS implementation had a causal effect on employment outcomes for all young adults in receipt of a temporary health-related rehabilitation (work assessment allowance, WAA) welfare benefit, measured at the societal level compared to municipalities that did not implement IPS.

We used a difference in differences design to estimate the effects of IPS implementation on the outcome of workdays per year using longitudinal registry data. We estimate the average effect of being exposed to IPS implementation during four-years of implementation compared to ten control municipalities without IPS for all WAA recipients.

We found a significant, positive, causal effect on societal level employment outcomes of 5.6 (p = 0.001, 95% CI 2.7–8.4) increased workdays per year per individual, equivalent to 12.7 years of increased work in the municipality where IPS was implemented compared to municipalities without IPS. Three years after initial exposure to IPS implementation individuals worked, on average, 10.5 more days per year equating to 23.8 years of increased work.

Implementing IPS as a cross sectoral collaboration at a municipality level has a significant, positive, causal, societal impact on employment outcomes for all young adults in receipt of a temporary health-related rehabilitation welfare benefit.

To evaluate the clinical efficacy of COMPASS, a therapist-supported digital therapeutic for reducing psychological distress (anxiety/depression) in people living with long-term physical health conditions (LTCs).

A two-armed randomized-controlled trial recruiting from LTC charities. Participants with anxiety and/or depression symptoms related to their LTC(s) were randomized (concealed allocation via independent administrator) to COMPASS (access to 11 tailored modules plus five thirty-minute therapist support sessions) or standard charity support (SCS). Assessments were completed online pre-randomization, at 6- and 12-weeks post-randomization. Primary outcome was Patient Health Questionnaire Anxiety and Depression Scale; PHQ-ADS measured at 12-weeks. Analysis used intention-to-treat principles with adjusted mean differences estimated using linear mixed-effects models. Data-analyst was blinded to group allocation.

194 participants were randomized to COMPASS (N = 94) or SCS (N = 100). At 12-weeks, mean level of psychological distress was 6.82 (95% confidence interval; CI 4.55–9.10) points lower (p < 0.001) in the COMPASS arm compared with SCS (standardized mean difference of 0.71 (95% CI 0.48–0.95)). The COMPASS arm also showed moderate significant treatment effects on secondary outcomes including depression, anxiety and illness-related distress and small significant effects on functioning and quality-of-life. Rates of adverse events were comparable across the arms. Deterioration in distress at 12-weeks was observed in 2.2% of the SCS arm, and no participants in the COMPASS arm.

Compared with SCS, COMPASS digital therapeutic with minimal therapist input reduces psychological distress at post-treatment (12-weeks). COMPASS offers a potentially scalable implementation model for health services but its translation to these contexts needs further evaluating.

NCT04535778

Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP.

We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately.

Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia.

Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.

A minority of naturally cycling individuals experience clinically significant affective changes across the menstrual cycle. However, few studies have examined cognitive and behavioral constructs that may maintain or worsen these changes. Several small studies link rumination with premenstrual negative affect, with authors concluding that a tendency to ruminate amplifies and perpetuates hormone-sensitive affective symptoms. Replication in larger samples is needed to confirm the validity of rumination as a treatment target.

190 cycling individuals (M = 30.82 years; 61.1% Caucasian) were recruited for moderate perceived stress, a risk factor for cyclical symptoms. They completed the Rumination Response Scale at baseline, then reported daily affective and physical symptoms across 1–6 cycles. Multilevel growth models tested trait rumination as a predictor of baseline levels, luteal increases, and follicular decreases in symptoms.

The degree of affective cyclicity was normally distributed across a substantial range, supporting feasibility of hypothesis tests and validating the concept of dimensional hormone sensitivity. Contrary to prediction, higher brooding did not predict levels or cyclical changes of any symptom. In a subsample selected for luteal increases in negative affect, brooding predicted higher baseline negative affect but still did not predict affective cyclicity.

An individual's trait-like propensity to engage in rumination may not be a valid treatment target in premenstrual mood disorders. State-like changes in rumination should still be further explored, and well-powered prospective studies should explore other cognitive and behavioral factors to inform development of targeted psychological treatments for patients with cyclical affective symptoms.

Enlarged pituitary gland volume could be a marker of psychotic disorders. However, previous studies report conflicting results. To better understand the role of the pituitary gland in psychosis, we examined a large transdiagnostic sample of individuals with psychotic disorders.

The study included 751 participants (174 with schizophrenia, 114 with schizoaffective disorder, 167 with psychotic bipolar disorder, and 296 healthy controls) across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. Structural magnetic resonance images were obtained, and pituitary gland volumes were measured using the MAGeT brain algorithm. Linear mixed models examined between-group differences with controls and among patient subgroups based on diagnosis, as well as how pituitary volumes were associated with symptom severity, cognitive function, antipsychotic dose, and illness duration.

Mean pituitary gland volume did not significantly differ between patients and controls. No significant effect of diagnosis was observed. Larger pituitary gland volume was associated with greater symptom severity (F = 13.61, p = 0.0002), lower cognitive function (F = 4.76, p = 0.03), and higher antipsychotic dose (F = 5.20, p = 0.02). Illness duration was not significantly associated with pituitary gland volume. When all variables were considered, only symptom severity significantly predicted pituitary gland volume (F = 7.54, p = 0.006).

Although pituitary volumes were not increased in psychotic disorders, larger size may be a marker associated with more severe symptoms in the progression of psychosis. This finding helps clarify previous inconsistent reports and highlights the need for further research into pituitary gland-related factors in individuals with psychosis.

Increased autocorrelation (AR) of system-specific measures has been suggested as a predictor for critical transitions in complex systems. Increased AR of mood scores has been reported to anticipate depressive episodes in major depressive disorder, while other studies found AR increases to be associated with depressive episodes themselves. Data on AR in patients with bipolar disorders (BD) is limited and inconclusive.

Patients with BD reported their current mood via daily e-diaries for 12 months. Current affective status (euthymic, prodromal, depressed, (hypo)manic) was assessed in 26 bi-weekly expert interviews. Exploratory analyses tested whether self-reported current mood and AR of the same item could differentiate between prodromal phases or affective episodes and euthymia.

A total of 29 depressive and 20 (hypo)manic episodes were observed in 29 participants with BD. Self-reported current mood was significantly decreased during the two weeks prior to a depressive episode (early prodromal, late prodromal), but not changed prior to manic episodes. The AR was neither a significant predictor for the early or late prodromal phase of depression nor for the early prodromal phase of (hypo)mania. Decreased AR was found in the late prodromal phase of (hypo)mania. Increased AR was mainly found during depressive episodes.

AR changes might not be better at predicting depressive episodes than simple self-report measures on current mood in patients with BD. Increased AR was mostly found during depressive episodes. Potentially, changes in AR might anticipate (hypo)manic episodes.

Multimorbidity, known as the co-occurrence of at least two chronic conditions, has become of increasing concern in the current context of ageing populations, though it affects all ages. Early life risk factors of multimorbidity include adverse childhood experiences (ACEs), particularly associated with psychological conditions and weight problems. Few studies have considered related mechanisms and focus on old age participants. We are interested in estimating, from young adulthood, the risk of overweight-depression comorbidity related to ACEs while adjusting for early life confounders and intermediate variables.

We used data from the 1958 National Child Development Study, a prospective birth cohort study (N = 18 558). A four-category outcome (no condition, overweight only, depression only and, overweight-depression comorbidity) was constructed at 23, 33, and 42 years. Multinomial logistic regression models adjusting for intermediate variables co-occurring with this outcome were created. ACEs and sex interaction on comorbidity risk was tested.

In our study sample (N = 7762), we found that ACEs were associated with overweight-depression comorbidity risk throughout adulthood (RRR [95% CI] at 23y = 3.80 [2.10–6.88]) though less overtime. Comorbidity risk was larger than risk of separate conditions. Intermediate variables explained part of the association. After full-adjustment, an association remained (RRR [95% CI] at 23y = 2.00 [1.08–3.72]). Comorbidity risk related to ACEs differed by sex at 42.

Our study provides evidence on the link and potential mechanisms between ACEs and the co-occurrence of mental and physical diseases throughout the life-course. We suggest addressing ACEs in intervention strategies and public policies to go beyond single disease prevention.

One potential cause of comorbidity is the direct causal effect of one disorder – A – on risk for subsequent onset of disorder B. Could genetic risk scores be utilized to test for such an effect? If disorder A causally impacts on risk for disorder B, then genetic risk for disorder A should be lower in cases of disorder A with v. without a prior onset of B.

In all individuals (n = 905 736) born in Sweden from 1980 to 1990, from six psychiatric and drug use disorders (major depression, anxiety disorders, alcohol use disorder, drug use disorder, bipolar disorder, and schizophrenia), we formed 14 pairs of disorders A and B. In these pairs, we compared, using Cox proportional hazards models, the predictive effect of the familial-genetic risk score (FGRS) for disorder B in those who had v. had not had a prior onset of disorder A.

In all pairs, the impact of the FGRS for disorder B was significantly stronger in cases without v. with a prior history of disorder A. These effects were similar across sex, stable across levels of FGRS and not likely due to clinician bias. In many of our disorder pairs, previous clinical studies suggest a mechanism for a causal effect of disorder A on B.

Our findings provide indirect evidence that the occurrence of one psychiatric or substance use disorder often has a causal effect on risk for subsequent disorders. This mechanism may substantially contribute to the widespread comorbidity among psychiatric conditions.

Previous evidence suggests that early life complications (ELCs) interact with polygenic risk for schizophrenia (SCZ) in increasing risk for the disease. However, no studies have investigated this interaction on neurobiological phenotypes. Among those, anomalous emotion-related brain activity has been reported in SCZ, even if evidence of its link with SCZ-related genetic risk is not solid. Indeed, it is possible this relationship is influenced by non-genetic risk factors. Thus, this study investigated the interaction between SCZ-related polygenic risk and ELCs on emotion-related brain activity.

169 healthy participants (HP) in a discovery and 113 HP in a replication sample underwent functional magnetic resonance imaging (fMRI) during emotion processing, were categorized for history of ELCs and genome-wide genotyped. Polygenic risk scores (PRSs) were computed using SCZ-associated variants considering the most recent genome-wide association study. Furthermore, 75 patients with SCZ also underwent fMRI during emotion processing to verify consistency of their brain activity patterns with those associated with risk factors for SCZ in HP.

Results in the discovery and replication samples indicated no effect of PRSs, but an interaction between PRS and ELCs in left ventrolateral prefrontal cortex (VLPFC), where the greater the activity, the greater PRS only in presence of ELCs. Moreover, SCZ had greater VLPFC response than HP.

These results suggest that emotion-related VLPFC response lies in the path from genetic and non-genetic risk factors to the clinical presentation of SCZ, and may implicate an updated concept of intermediate phenotype considering early non-genetic factors of risk for SCZ.