Logo: to the web site of Uppsala University

IMPORTANCE Mental health problems in early life are associated with labor market marginalization, especially in youths with persistent internalizing and externalizing problems. However, previous research has not adjusted for familial (genetic and shared environmental) factors.

OBJECTIVE To examine associations of early-life internalizing and externalizing problems with adulthood unemployment and work disability, adjusting for familial factors.

DESIGN, SETTING, AND PARTICIPANTS This population-based prospective cohort study included Swedish twins whowere born in 1985-1986 and surveyed at 4 consecutivewaves across childhood and adolescence until 2005. Through linkage to nationwide registries, participants were followed up from 2006 to 2018. Data analyses were conducted between September 2022 and April 2023.

EXPOSURES Internalizing and externalizing problems, assessed with the Child Behavior Checklist. Participants were differentiated regarding duration of internalizing and externalizing problems (persistent, episodic, and noncases).

MAIN OUTCOMES AND MEASURES Unemployment (180 days or more of being unemployed) and work disability (60 days or more of being sickness absent or disability pensioned) during follow-up. Cox proportional hazards regression models were calculated to obtain cause-specific hazard ratios (HRs) with 95% CIs in the whole cohort and exposure-discordant twin pairs.

RESULTS Of 2845 participants, 1464 (51.5%) were female. Incident unemployment was experienced by 944 (33.2%) and incidentwork disability by 522 (18.3%) participants. Compared with noncases, persistent internalizing problemswere associated with unemployment (HR, 1.56; 95% CI, 1.27-1.92) and work disability (HR, 2.32; 95% CI, 1.80-2.99). Similarly, compared with noncases, persistent externalizing problems were associated with unemployment (HR, 1.87; 95% CI, 1.55-2.26) andwork disability (HR, 2.38; 95% CI, 1.87-3.03). Persistent cases had overall higher risks of adverse outcomes than episodic cases. After adjustment for familial factors, associations with unemployment were no longer statistically significant, whereas associations with work disability remained or were only slightly reduced.

CONCLUSIONS AND RELEVANCE In this cohort study of young Swedish twins, familial factors explained the associations between early-life persistent internalizing and externalizing problems and unemployment; such factors were comparatively less important for the association with work disability. This suggests nonshared environmental factors may be important for the risk of future work disability among young individuals with persistent internalizing and externalizing problems.

Background: Depression and anxiety are associated with increased risk of sickness absence (SA), yet the developmental patterns of SA remain unclear. We aimed to identify trajectories of SA in young adults with depression and/or anxiety, accounting for sociodemographic and occupational factors.

Methods: Longitudinal study of 1445 twin individuals with elevated depressive/anxiety symptoms in late adolescence or young adulthood (age range: 19-30), assessed in Swedish surveys completed in 2005. Through linkage to nationwide registries, individuals were prospectively followed from 2006 to 2018. The outcome included consecutive annual days of SA, which were analyzed using group-based trajectory modeling. Multinomial logistic regression estimating odds ratios (OR) with 95 % confidence intervals (CI) was used to examine associations of age, sex, and educational level with the resulting SA trajectories.

Results: Four distinct SA trajectories were identified in the total sample: 'high-increasing' (6 %), 'low-increasing' (12 %), 'high-decreasing' (13 %), and 'low-constant' (69 %). Increasing age was associated with higher odds of belonging to the low-increasing trajectory (OR = 1.07, 95 % CI = 1.02-1.12). Women had higher odds of belonging to the low-increasing trajectory (OR = 1.67, 95 % CI = 1.10-2.53), compared with men. Higher education was associated with lower odds of belonging to high-increasing (OR = 0.34, 95 % CI = 0.22-0.54) and high-decreasing (OR = 0.59, 95 % CI = 0.43-0.81) trajectories, compared with lower education. Few differences were observed in analyses stratified by occupational sector.

Limitations: Information on potential confounders (e.g., psychiatric comorbidity, work-environment factors) was not available.

Conclusions: Among young adults with prior depression/anxiety, close to every fifth showed rising SA trajectories over time. This calls for targeted strategies to improve public mental health already at young ages.

Background: Previous research has shown that poor family relations in childhood are associated with adverse mental health in adulthood. Yet, few studies have followed the offspring until late adulthood, and very few have had access to register-based data on hospitalisation due to psychiatric illness. The aim of this study was to examine the association between poor family relations in adolescence and the likelihood of in-patient psychiatric care across the life course up until age 55. Methods: Data were derived from the Stockholm Birth Cohort study, with information on 2638 individuals born in 1953. Information on family relations was based on interviews with the participants' mothers in 1968. Information on in-patient psychiatric treatment was derived from administrative registers from 1969 to 2008. Binary logistic regression was used. Results: Poor family relations in adolescence were associated with an increased risk of later in-patient treatment for a psychiatric diagnosis, even when adjusting for other adverse conditions in childhood. Further analyses showed that poor family relations in adolescence were a statistically significant predictor of in-patient psychiatric care up until age 36-45, but that the strength of the association attenuated over time. Conclusions: Poor family relationships during upbringing can have serious negative mental-health consequences that persist into mid-adulthood. However, the effect of poor family relations seems to abate with age. The findings point to the importance of effective interventions in families experiencing poor relationships.

The caudate nucleus is a part of the striatum, and striatal hyperdopaminergia is considered central to the pathophysiology of schizophrenia. How caudate volume is affected in schizophrenia and what role antipsychotics play remains unclear. In early-onset schizophrenia (EOS), where psychosis emerges during a neurodevelopmentally critical phase, the caudate may exhibit a heightened vulnerability to the effects of antipsychotic medications. We hypothesized effects of both antipsychotic medication use and age of onset on caudate in schizophrenia. We included adult patients with EOS (n = 83) and adult-onset schizophrenia (AOS) (n = 246), adult healthy controls (HC, n = 774), adolescent patients with non-affective psychosis (n = 56) and adolescent HC (n = 97). We obtained T1-weighted MRI scans using a 1.5T Siemens scanner and General Electric 3T scanners. In our main analysis, we tested for main and interaction effects of diagnosis and current antipsychotic medication use on caudate volume. Adult patients with EOS (p < 0.001) and AOS (p = 0.002) had both larger caudate than HC. Age of onset (EOS/AOS) interacted with antipsychotic use (p = 0.004) which was associated with larger caudate in EOS (p < 0.001) but not in AOS (p = 0.654). Conversely, among medicated patients only, EOS had larger caudate than AOS (p < 0.001). No other subcortical structures showed differences between medicated EOS and AOS. Medicated adolescent patients with non-affective psychosis and medicated adult patients with EOS showed similar caudate volumes. The results may indicate a schizophrenia-related and a medication-induced caudate increase, the latter restricted to patients with EOS and possibly occurring already in adolescence shortly after disease onset.

BACKGROUND: Emotion dysregulation (ED) is common in attention-deficit/hyperactivity disorder (ADHD) and often results in adverse outcomes. However, ED has been suggested as a transdiagnostic construct, why the specific association between ADHD and ED when adjusting for other mental health conditions needs further investigation. It is also important to determine the aetiological basis of the association between ADHD and ED to inform the theoretical conceptualization of ADHD.

METHOD: This study used a co-twin control design, including a sample of dizygotic (DZ) and monozygotic (MZ) twins (N = 389; 45.8% females, age = 8-31 years, MZ twin pairs 57.6%). ED was assessed using the dysregulation profile from the parent-rated Child Behaviour Checklist and its adult version. Regression analyses were used across individuals and within the pairs, while adjusting for diagnoses of autism, intellectual disability, other neurodevelopmental conditions and affective conditions.

RESULTS: ADHD was significantly associated with ED, even when adjusting for age, sex, attention problems and other mental health conditions, and was the diagnosis most strongly associated with ED. Within-pair analyses revealed that twins with ADHD had higher levels of ED compared to their co-twin without ADHD. This association remained within DZ twins and was non-significant in the MZ subsample, with non-overlapping confidence intervals between the DZ and MZ estimates.

CONCLUSION: ADHD is strongly and in part independently linked to ED, stressing the importance of early detection and treatment of emotional difficulties within this group. The findings from the within-pair analyses indicate a genetic influence on the association between ADHD and ED.

Autism spectrum disorder (ASD) is a neurodevelopmental condition diagnosed in approximately 2% of children. Reliance on the emergence of clinically observable behavioral patterns only delays the mean age of diagnosis to approximately 4 years. However, neural pathways critical to language and social functions develop during infancy, and current diagnostic protocols miss the age when therapy would be most effective. We developed non-invasive ASD biomarkers using mass spectrometry analyses of elemental metabolism in single hair strands, coupled with machine learning. We undertook a national prospective study in Japan, where hair samples were collected at 1 month and clinical diagnosis was undertaken at 4 years. Next, we analyzed a national sample of Swedish twins and, in our third study, participants from a specialist ASD center in the US. In a blinded analysis, a predictive algorithm detected ASD risk as early as 1 month with 96.4% sensitivity, 75.4% specificity, and 81.4% accuracy (n = 486; 175 cases). These findings emphasize that the dynamics in elemental metabolism are systemically dysregulated in autism, and these signatures can be detected and leveraged in hair samples to predict the emergence of ASD as early as 1 month of age.

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age=16.6 years, interquartile range (IQR)=2.14, 46.4% females) and 265 adolescent healthy controls (median age=16.2 years, IQR=2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d=0.37), posterior corona radiata (d=0.32), and superior fronto-occipital fasciculus (d=0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

Autism is a neurodevelopmental condition associated with atypical social communication, cognitive, and sensory faculties. Recent advances in exposure biology suggest that biomarkers of elemental uptake and metabolism measured in hair samples can yield an effective signal predictive of autism diagnosis. Here, we investigated if elemental biomarkers in hair were associated with functional connectivity in regions of the default mode network (DMN) previously linked to autism. In a study sample which included twin pairs with concordant and discordant diagnoses for autism, our analysis of hair samples and neuroimaging data supported two general findings. First, independent of autism diagnosis, we found a broad pattern of association between elemental biomarkers and functional connectivity in the DMN, which primarily involved dynamics in zinc metabolism. Second, we found that associations between the DMN and elemental biomarkers, particularly involving phosphorus, calcium, manganese, and magnesium, differed significantly in autistic participants from control participants. In sum, these findings suggest that functional dynamics in elemental metabolism relate broadly to persistent patterns of functional connectivity in the DMN, and that these associations are altered in the emergence of autism.

Atypical regulation of inflammation has been proposed in the etiology of autism spectrum disorder (ASD); however, measuring the temporal profile of fetal inflammation associated with future ASD diagnosis has not been possible. Here, we present a method to generate approximately daily profiles of prenatal and early childhood inflammation as measured by developmentally archived C-reactive protein (CRP) in incremental layers of deciduous tooth dentin. In our discovery population, a group of Swedish twins, we found heightened inflammation in the third trimester in children with future ASD diagnosis relative to controls (n = 66; 14 ASD cases; critical window: -90 to -50 days before birth). In our replication study, in the US, we observed a similar increase in CRP in ASD cases during the third trimester (n = 47; 23 ASD cases; -128 to -21 days before birth). Our results indicate that the third trimester is a critical period of atypical fetal inflammatory regulation in ASD.

Background: Personality style can partly be described as the way an individual controls and regulates emotions and can be divided into over- and undercontrol. Studies have indicated that personality style may impact the onset, clinical presentation, and recovery from an eating disorder (ED). Furthermore, symptoms of anxiety and depression are common in patients with EDs. However, the association between self-control levels and anxiety/depression symptoms in patients with EDs remains unknown. The main aim of this study was to assess how levels of self-control relate to anxiety/depression symptoms in patients with EDs, with a secondary, exploratory aim to assess the stability of self-control during treatment.

Methods: Patients were recruited from the outpatient ED clinic at the Uppsala University Hospital, between October 2014 and December 2019. In total, 227 patients (age: 25.4, SD: 7.1) were included at the start of their treatment, with 14 participants also completing post-treatment measurements. Self-control was assessed with the Ego Undercontrol scale (EUC-13), anxiety/depression symptoms with the Hopkins Symptoms Checklist (HSCL-25), and ED diagnosis and symptoms with the Eating Disorder Examination Interview (EDE-I) and Questionnaire (EDE-Q), respectively.

Result: sA quadratic regression (n = 227) showed that levels of self-control accounted for about four percent of the variance in degree of global anxiety/depressive symptoms. Anxiety/depression symptoms were better explained by ED symptoms (R-2 = 0.24). Visualizations in boxplots revealed a tendency for extreme values of both over- and undercontrol to be associated with higher levels of depression, whereas symptoms of anxiety increased with increasing undercontrol. In the exploratory analyses (n = 14) levels of self-control remained more stable than symptoms of anxiety and depression, which decreased significantly during ED treatment.

Conclusions: Our results indicated that anxiety/depression symptoms, in patients with EDs, were not strongly correlated with levels of self-control, but rather with ED symptoms. However, extreme values of both over- and undercontrol showed a tendency to be associated with higher levels of depression symptoms, whereas anxiety symptoms increased with increasing levels of undercontrol. Future studies could benefit from considering both over- and undercontrol as potentially dysfunctional.

Using a three-wave (mean age 14.4, 17.4, and 20.4 years) longitudinal design (N = 1,834; 55.6% females), we set out to map direct and indirect effects of adolescent peer victimization and mental health on academic achievement in early adulthood, and the buffering effect of positive family relations. Data was collected in Sweden 2012 to 2018. We found concurrent (βs = .13–.28) but no longitudinal transactional effects between peer victimization and symptoms of depression, anxiety, and conduct disorder (CD). Peer victimization, depression, and CD had longitudinal direct effects on poorer academic achievement in early adulthood (βs = .09–.11). Positive family relations did not moderate the effects. The results indicate that prevention and interventions against peer victimization and poor mental health may contribute to a higher proportion of individuals graduating from high school.

We examined perceived stress and sleep problems in adolescent ADHD and whether this varies as a function of ADHD presentation and sex. Further, we mapped structural associations between ADHD symptoms, comorbid symptoms, perceived stress, and sleep problems. Participants were 306 adolescents aged 13-19 years (66.8% females, 193 had an ADHD diagnosis, 113 were controls). Parents rated ADHD symptoms, all other constructs were self-rated. Adolescents with ADHD had elevated levels of perceived stress and sleep problems. Girls with ADHD reported the highest levels of perceived stress. Emotional symptoms mediated the effect of inattention whereas conduct problems mediated the effect of hyperactivity/impulsivity on stress and sleep. Perceived stress and sleep problems should be considered when mapping ADHD-related problems. Comorbid symptoms are potential intervention targets that may increase treatment response.

Acceptance and Commitment Therapy has gained preliminary evidence for paediatric chronic pain. Several studies show that psychological flexibility/inflexibility is a process driving treatment change in ACT for chronic pain. The literature supporting psychological flexibility as a change process in ACT is typically based on selfreport. The aim of the present study was to investigate psychological flexibility (i.e. acceptance, defusion, values formulation and committed action) as in-treatment behaviour during internet-delivered Acceptance and Commitment Therapy for paediatric chronic pain, by having two independent observers rating patient written statements. The sample was self-recruited and consisted of 28 girls between ages 13 and 17 years. Results showed that psychological flexibility could be operationalised as in-treatment behaviours and reliably assessed using observer ratings. Also, data illustrated a within subject variability in ratings of acceptance and defusion, with a considerable difference in degree of acceptance or defusion evoked by different experiential exercises. Furthermore, analyses showed that a higher average degree of acceptance in patient statements during the early phase of treatment was related to larger treatment effects. Defusion, values formulation and committed action showed no significant influence on outcome. Results should be interpreted with caution due to the small sample size.

Digitally delivered behavioral interventions for chronic pain have been encouraging with effects similar to face-to-face treatment. Although many chronic pain patients benefit from behavioral treatment, a substantial proportion do not improve. To contribute to more knowledge about factors that predict treatment effects in digitally delivered behavioral interventions for chronic pain, the present study analyzed pooled data (N = 130) from three different studies on digitally delivered Acceptance and Commitment Therapy (ACT) for chronic pain. Longitudinal linear mixed-effects models for repeated measures were used to identify variables with significant influence on the rate of improvement in the main treatment outcome pain interference from pre- to post-treatment. The variables were sorted into six domains (demographics, pain variables, psychological flexibility, baseline severity, comorbid symptoms and early adherence) and analysed in a stepwise manner. The study found that shorter pain duration and higher degree of insomnia symptoms at baseline predicted larger treatment effects. The original trials from which data was pooled are registered at clinicaltrials.gov (registration number: NCT03105908 and NCT03344926).

Depressive symptoms are associated with altered pupillary responses during learning and reward prediction as well as with changes in neurometabolite levels, including brain concentrations of choline, glutamate and gamma-aminobutyric acid (GABA). However, the full link between depressive symptoms, reward-learning-related pupillary responses and neurometabolites is yet to be established as these constructs have not been assessed in the same individuals. The present pilot study, investigated these relations in a sample of 24 adolescents aged 13 years. Participants completed the Revised Child Anxiety and Depression Scale (RCADS) and underwent a reward learning task while measuring pupil dilation and a single voxel dorsal anterior cingulate cortex (dACC) MEGA-PRESS magnetic resonance spectroscopy scan assessing choline, glutamate and GABA concentrations. Pupil dilation was related to prediction errors (PE) during learning, which was captured by a prediction error-weighted pupil dilation response index (PE-PDR) for each individual. Higher PE-PDR scores, indicating larger pupil dilations to negative prediction errors, were related to lower depressive symptoms and lower dACC choline concentrations. Dorsal ACC choline was positively associated with depressive symptoms, whereas glutamate and GABA were not related to PE-PDR or depressive symptoms. The findings support notions of cholinergic involvement in depressive symptoms and cholinergic influence on reward-related pupillary response, suggesting that pupillary responses to negative prediction errors may hold promise as a biomarker of depressive states.

Emotion regulation (ER) is a source of risk and resilience for psychological development and everyday functioning. Despite extensive research on various early contextual predictors of child ER capacity, few studies have integrated them into the same study. Therefore, our longitudinal study investigated the joint and independent contributions of several prominent contextual predictors of child ER capacity. We followed typically developing children and their caregivers (N = 118, 47% girls) at three time points (children ages 10, 12, and 18 months). At 10 months, mothers reported household chaos, social support, and parenting stress, and maternal sensitivity was observed and coded with the Ainsworth's Maternal Sensitivity Scales. At 12 months, child-mother attachment security was assessed using the Strange Situation Procedure. Finally, at 18 months, child ER was obtained with a Laboratory Temperament Assessment Battery frustration task. Correlational analyses revealed that household chaos and maternal sensitivity were significantly positively associated with child ER. Multiple regression analyses showed independent effects of household chaos and maternal sensitivity on child ER. Our partly counterintuitive results underscore the significance of cumulative risk and protective factors for ER development and suggest that household chaos and maternal sensitivity may contribute uniquely to better ER in typical toddlerhood.

Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.

Psychotic-like experiences (PLEs), such as delusions and hallucinations, are regarded to occur along a spectrum and to be present also in non-help-seeking individuals from the general population. However, it remains unclear whether the occurrence of PLEs is a unique risk factor for future PLEs or a symptom of general psychopathology. In this study, we investigated whether PLEs during adolescence predict future PLEs in adulthood. A community-based cohort of 1146 young adolescents (mean age, 14.38 years) were assessed and then reassessed 6 years later (mean age, 20.15 years). Participants reported PLEs experienced in the past year, as well as symptoms of depression, anxiety, attention-deficit/hyperactivity disorder, and conduct problems. We adjusted the analysis for other forms of psychopathology and sex differences. Participants who reported PLEs in adulthood had higher ratings for all preceding and co-occurring symptoms of psychopathology. In the adjusted logistic regression model, having PLEs and, to a smaller degree, anxiety during adolescence predicted PLEs in early adulthood. The association between baseline and future PLEs did not differ between males and females, although females were more likely to report PLEs during adolescence. Participants with persistent PLEs reported more hallucinations during adolescence than those with transient symptoms. Our findings suggest that the early occurrence of PLEs is an important and independent predictor of future PLEs and should be monitored to identify individuals with a high risk of future psychopathology and to enable early interventions.