In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis.

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.

Adult mental health outcomes of adolescent depression and co-occurring alcohol use disorder: a longitudinal cohort study.

Depression and alcohol use disorder (AUD) are frequently co-occurring in adolescence, which often goes undetected in routine care. While this may potentially compromise treatment effectiveness and lead to a less favourable long-term prognosis, few longitudinal studies have followed this group into adulthood. The aim of this study was to explore the risk for adult depression, anxiety disorders, suicidality, and AUD in adolescents with concurrent depression and AUD. The study was based on the Uppsala Longitudinal Adolescent Depression Study (ULADS), a Swedish prospective cohort study. Diagnostic interviews were conducted in adolescence (age 16-17) and adulthood (around age 30). Adolescents with concurrent depression and AUD (n = 38) were compared with peers having only depression (n = 189) or neither of the conditions (n = 144). Logistic regression was used to calculate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Adolescents with concurrent depression and AUD were more likely than their non-affected peers to experience adult depressive episodes (aOR, 5.33; 95% CI, 2.22-12.83), anxiety disorders (4.05; 1.77-9.27), suicidality (5.37; 2.28-12.66), and AUD (7.68; 2.59-22.81). Notably, 34% of adolescents with both depression and AUD subsequently experienced both these conditions as adults, compared to 7% of adolescents with only depression. Adolescents suffering only from depression were less likely than those with both conditions to experience suicidality (0.44; 0.21-0.95) and AUD in adulthood (0.18; 0.07-0.44). These findings underscore the clinical imperative to identify adolescents with this comorbidity. Recognition of the poor long-term prognosis can inform targeted interventions for this vulnerable group, ultimately improving health and well-being throughout the life course.

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium.

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis.

Adolescent depression and adult labor market marginalization: a longitudinal cohort study.

Adolescent depression is linked to adult ill-health and functional impairment, but recent research suggests that individual/contextual factors might account for this association. This study aimed to test whether the clinical heterogeneity of adolescent depression is related to marginalization from the labor market across early to middle adulthood. Data were drawn from the Uppsala Longitudinal Adolescent Depression Study, a community-based cohort initially assessed with structured clinical interviews at age 16-17. The cohort (n = 321 depressed; n = 218 nondepressed) was followed up after 2+ decades through linkage to nationwide population-based registries. Outcomes included consecutive annual data on unemployment, work disability, social welfare recipiency, and a composite marginalization measure, spanning from age 21 to 40. Longitudinal associations were examined using logistic regression analysis in a generalized estimating equations modeling framework. Subsequent depressive episodes and educational attainment in early adulthood were explored as potential pathways. The results showed that adolescent depression was associated with adult marginalization outcomes, but the strength of association varied across depressed subgroups. Adolescents with persistent depressive disorder had higher odds of all outcomes, including the composite marginalization measure (adjusted OR = 2.0, 95% CI = 1.4-2.7, p < 0.001), and this was partially (31%) mediated by subsequent depressive episodes in early adulthood. Exploratory moderation analysis revealed that entry into tertiary education mitigated the association with later marginalization, but only for adolescents with episodic major depression. In conclusion, the risk for future labor market marginalization is elevated among depressed adolescents, particularly those presenting with persistent depressive disorder. Targeted interventions seem crucial to mitigate the long-lasting impact of early-onset depression.

Adolescent depression, early psychiatric comorbidities, and adulthood welfare burden: a 25-year longitudinal cohort study.

PURPOSE: Depression at all ages is recognized as a global public health concern, but less is known about the welfare burden following early-life depression. This study aimed to (1) estimate the magnitude of associations between depression in adolescence and social transfer payments in adulthood; and (2) address the impact of major comorbid psychopathology on these associations. METHODS: This is a longitudinal cohort study of 539 participants assessed at age 16-17 using structured diagnostic interviews. An ongoing 25-year follow-up linked the cohort (n = 321 depressed; n = 218 nondepressed) to nationwide population-based registries. Outcomes included consecutive annual data on social transfer payments due to unemployment, work disability, and public assistance, spanning from age 18 to 40. Parameter estimations used the generalized estimating equations approach. RESULTS: Adolescent depression was associated with all forms of social transfer payments. The estimated overall payment per person and year was 938 USD (95% CI 551-1326) over and above the amount received by nondepressed controls. Persistent depressive disorder was associated with higher recipiency across all outcomes, whereas the pattern of findings was less clear for subthreshold and episodic major depression. Moreover, depressed adolescents presenting with comorbid anxiety and disruptive behavior disorders evidenced particularly high recipiency, exceeding the nondepressed controls with an estimated 1753 USD (95% CI 887-2620). CONCLUSION: Adolescent depression is associated with considerable public expenditures across early-to-middle adulthood, especially for those exposed to chronic/persistent depression and psychiatric comorbidities. This finding suggests that the clinical heterogeneity of early-life depression needs to be considered from a longer-term societal perspective.

Poor family relationships in adolescence as a risk factor of in-patient psychiatric care across the life course: A prospective cohort study.

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.

Parent-youth conflict as a predictor of depression in adulthood: a 15-year follow-up of a community-based cohort.

Experiencing conflictual relations with one's parents while growing up has been linked to onset, recurrence, and worse treatment outcome of adolescent depression. While this suggests that significant problems in the parent-youth relationship make depressive disorders more relentless, it is not clear whether this effect lasts into adulthood. Our aim was to examine if major and minor conflict with parents while growing up predicts depression in adulthood in youth with and without a history of depression. We utilized data from the Uppsala Longitudinal Adolescent Depression Study. This community-based cohort was assessed with structured diagnostic interviews both at age 16-17 and at follow-up 15 years later. The analyses included 382 individuals (227 with a history of child or adolescent depression; 155 peers without such a history). Binary logistic regression was used, adjusting for sex, disruptive behavior disorders, and additional family-related adversities. Among individuals with adolescent depression, major conflict with parents was strongly associated with adult depression (adjusted OR 2.28, 95% CI 1.07-4.87). While major conflict with parents was rare among non-depressed controls, a non-significant association of similar magnitude was still observed. Minor conflict, on the other hand, was not significantly associated with adult depression. Overall, conflict with parents did not predict adult anxiety disorders, substance use, suicidal behavior, somatoform disorders, or psychotic disorders. In conclusion, major parent-youth conflict during upbringing seems to be linked with an increased risk of depression in adulthood. These findings underscore the need to consider contextual/familial factors in the prevention and clinical management of early-life depression.

Parental separation in childhood as a risk factor for depression in adulthood: a community-based study of adolescents screened for depression and followed up after 15 years.

BACKGROUND: Earlier research has investigated the association between parental separation and long-term health outcomes among offspring, but few studies have assessed the potentially moderating role of mental health status in adolescence. The aim of this study was to analyze whether parental separation in childhood predicts depression in adulthood and whether the pattern differs between individuals with and without earlier depression. METHODS: A community-based sample of individuals with adolescent depression in 1991-93 and matched non-depressed peers were followed up using a structured diagnostic interview after 15 years. The participation rate was 65% (depressed n = 227; non-depressed controls n = 155). Information on parental separation and conditions in childhood and adolescence was collected at baseline. The outcome was depression between the ages 19-31 years; information on depression was collected at the follow-up diagnostic interview. The statistical method used was binary logistic regression. RESULTS: Our analyses showed that depressed adolescents with separated parents had an excess risk of recurrence of depression in adulthood, compared with depressed adolescents with non-separated parents. In addition, among adolescents with depression, parental separation was associated with an increased risk of a switch to bipolar disorder in adulthood. Among the matched non-depressed peers, no associations between parental separation and adult depression or bipolar disorder were found. CONCLUSIONS: Parental separation may have long-lasting health consequences for vulnerable individuals who suffer from mental illness already in adolescence.

Early risk factors for adult bipolar disorder in adolescents with mood disorders: a 15-year follow-up of a community sample.

BACKGROUND: We aimed to outline the early risk factors for adult bipolar disorder (BPD) in adolescents with mood disorders. METHODS: Adolescents (16-17 years old) with mood disorders (n = 287; 90 participants with hypomania spectrum episodes and 197 with major depressive disorder [MDD]) were identified from a community sample. Fifteen years later (at 30-33 years of age), mood episodes were assessed (n = 194). The risk of developing BPD (n = 22), compared with MDD (n = 104) or no mood episodes in adulthood (n = 68), was estimated via logistic regression. Adolescent mood symptoms, non-mood disorders, and family characteristics were assessed as potential risk factors. RESULTS: Among the adolescents with mood disorders, a family history of BPD was the strongest predictor of developing BPD compared with having no mood episodes in adulthood (OR = 5.94; 95% CI = 1.11-31.73), whereas disruptive disorders significantly increased the risk of developing BPD compared with developing MDD (OR = 2.94; CI = 1.06-8.12). The risk that adolescents with MDD would develop adult BPD, versus having no mood episodes in adulthood, was elevated among those with an early disruptive disorder (OR = 3.62; CI = 1.09-12.07) or multiple somatic symptoms (OR = 6.60; CI = 1.70-25.67). Only disruptive disorders significantly predicted adult BPD among adolescents with MDD versus continued MDD in adulthood (OR = 3.59; CI = 1.17-10.97). Only a few adolescents with hypomania spectrum episodes continued to have BPD as adults, and anxiety disorders appeared to increase this risk. CONCLUSIONS: Although most of the identified potential risk factors are likely general predictors of continued mood disorders, disruptive disorders emerged as specific predictors of developing adult BPD among adolescents with MDD.

Hypomania spectrum disorder in adolescence: a 15-year follow-up of non-mood morbidity in adulthood.

BACKGROUND: We investigated whether adolescents with hypomania spectrum episodes have an excess risk of mental and physical morbidity in adulthood, as compared with adolescents exclusively reporting major depressive disorder (MDD) and controls without a history of adolescent mood disorders. METHODS: A community sample of adolescents (N = 2 300) in the town of Uppsala, Sweden, was screened for depressive symptoms. Both participants with positive screening and matched controls (in total 631) were diagnostically interviewed. Ninety participants reported hypomania spectrum episodes (40 full-syndromal, 18 with brief episode, and 32 subsyndromal), while another 197 fulfilled the criteria for MDD without a history of a hypomania spectrum episode. A follow up after 15 years included a blinded diagnostic interview, a self-assessment of personality disorders, and national register data on prescription drugs and health services use. The participation rate at the follow-up interview was 71% (64/90) for the hypomania spectrum group, and 65.9% (130/197) for the MDD group. Multiple imputation was used to handle missing data. RESULTS: The outcomes of the hypomania spectrum group and the MDD group were similar regarding subsequent non-mood Axis I disorders in adulthood (present in 53 vs. 57%). A personality disorder was reported by 29% of the hypomania spectrum group and by 20% of the MDD group, but a statistically significant difference was reached only for obsessive-compulsive personality disorder (24 vs. 14%). In both groups, the risk of Axis I disorders and personality disorders in adulthood correlated with continuation of mood disorder. Prescription drugs and health service use in adulthood was similar in the two groups. Compared with adolescents without mood disorders, both groups had a higher subsequent risk of psychiatric morbidity, used more mental health care, and received more psychotropic drugs. CONCLUSIONS: Although adolescents with hypomania spectrum episodes and adolescents with MDD do not differ substantially in health outcomes, both groups are at increased risk for subsequent mental health problems. Thus, it is important to identify and treat children and adolescents with mood disorders, and carefully follow the continuing course.

Caudate nucleus volume in medicated and unmedicated patients with early- and adult-onset schizophrenia.

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.

Drug prescriptions of adults with adolescent depression in a community sample.

PURPOSE: The prescription drugs have, to our knowledge, not been much studied in epidemiological samples with long-term follow-up. Accordingly, our purpose was to analyze the use of prescription drugs in adults with adolescent depression. METHODS: A population-based cohort of adolescents (n = 2465) was screened for the presence of depressive symptoms and diagnosed according to a structured interview. Totally, 362 individuals were identified as depressed and compared with 250 non-depressed controls. The prescription drugs were evaluated at the age of 29-31 years from a register kept by the National Health and Welfare Board. RESULTS: The formerly depressed females received significantly more prescription drugs, such as antidepressants, antiepileptics, antibacterials, antimycotics, and antihistamines for systemic use as well as other drugs, compared with controls (15.6 ± 27.4 vs 8.2 ± 7.4 recipes, p < 0.001). Formerly depressed males did not differ from controls regarding prescription drugs. CONCLUSIONS: The females but not males with adolescent depression subsequently received more prescription drugs than non-depressed peers. Depressed female adolescents received more psychotropic and non-psychotropic drugs later in life compared to the non-depressed. This might be as a result of physical illnesses, different treatment-seeking behaviors, or somatizing reactions.

Prognostic significance of functional somatic symptoms in adolescence: a 15-year community-based follow-up study of adolescents with depression compared with healthy peers.

BACKGROUND: There is a lack of population-based long-term longitudinal research on mental health status and functional physical/somatic symptoms. Little is known about the long-term mental health outcomes associated with somatic symptoms or the temporal relationship between depression and such symptoms. This 15-year study followed up adolescents with depression and matched controls, screened from a population-based sample, who reported different numbers of somatic symptoms. METHODS: The total population of 16-17-year-olds in Uppsala, Sweden, was screened for depression in 1991-1993. Adolescents who screened positive and an equal number of healthy controls took part in a semi-structured diagnostic interview. In addition, 21 different self-rated somatic symptoms were assessed. Sixty-four percent of those adolescents participated in a follow-up structured interview 15 years later. RESULTS: Somatic symptoms in adolescence predicted depression and other adult mental disorders regardless of the presence of adolescent depression. In adolescents with depression, the number of functional somatic symptoms predicted, in a dose response relationship, suicidal behavior, bipolar episodes, and psychotic episodes as well as chronic and recurrent depression. Contrary to expectations, the somatic symptoms of abdominal pain and perspiration without exertion better predicted depression than all DSM-IV depressive symptoms. Abdominal pain persisted as an independent strong predictor of depression and anxiety, even after controlling for other important confounders. CONCLUSIONS: Somatic symptoms in adolescence can predict severe adult mental health disorders. The number of somatic symptoms concurrent with adolescent depression is, in a stepwise manner, linked to suicidal attempts, bipolar disorders, psychotic disorders, and recurrent and chronic depression. These findings can be useful in developing treatment guidelines for patients with somatic symptoms.

Development of an ELISA displaying similar reactivity with reduced and oxidized human Thioredoxin-1 (Trx1): The plasma level of Trx1 in early onset psychosis disorders.

The plasma level of human thioredoxin-1 (Trx1) has been shown to be increased in various somatic diseases and psychiatric disorders. However, when comparing the reported plasma levels of Trx1, a great inter-study variability, as well as variability in study outcomes of differences between patients and control subjects has been observed, ultimately limiting the possibility to make comparative analyses. Trx1 is a highly redox active protein prone to form various redox forms, e.g. dimers, oligomers or Trx1-protein complexes. We have recently shown that ELISA systems may vary in reactivity to various Trx1 redox forms. The primary aim of the present study was to develop an ELISA system with similar reactivity to various Trx1 redox forms. By evaluating a panel of novel monoclonal antibodies (mAbs), in various paired combinations, three ELISA systems were generated, with observed large variability in reactivity to various Trx1 redox forms. Importantly, an ELISA system (capture mAb MT17R6 and detection mAb MT13X3-biotin), was identified that displayed similar reactivity to oxidized and DTT reduced Trx1. The ELISA system (MT17R6/MT13X3-biotin), was subsequently used to analyze the level of Trx1 in plasma from patients (<18 years) with early onset psychosis disorders (EOP). However, no significant (p > 0.7) difference in plasma Trx1 levels between patients with EOP (n = 23) and healthy age matched controls (HC) (n = 20) were observed. Furthermore, reliable measurement was shown to be dependent on the establishment of platelet poor plasma samples, enabled by rigorous blood sample centrifugation and by efficient blocking of potentially interfering heterophilic antibodies. In conclusion, we report the design and characterization of a Trx1 ELISA system with similar reactivity to various Trx1 redox forms. Importantly, data indicated that generated ELISA systems show large variability in reactivity to various redox forms with ultimate impact on measured levels of Trx1. Overall, results from this study suggests that future studies may be strongly improved by the use of Trx1 ELISA systems with characterized specificity to various redox forms.

Association of adolescent depression with subsequent prescriptions of anti-infectives and anti-inflammatories in adulthood: A longitudinal cohort study.

New insights into how depression is linked to physical health throughout the lifespan could potentially inform clinical decision making. The aim of this study was to explore the association of adolescent depression with subsequent prescriptions of anti-infectives and anti-inflammatories in adulthood. The study was based on the Uppsala Longitudinal Adolescent Depression Study (ULADS), a Swedish prospective cohort study initiated in 1991. Depressed (n = 321) and non-depressed (n = 218) adolescents were followed prospectively using patient registries. The associations of adolescent depression (age 16-17 years) with subsequent prescription of anti-infectives and anti-inflammatories (age 30-40 years), were analysed using generalized linear models. Sub-analyses explored the impact of diagnostic characteristics in adolescence and reception of anti-depressants prescriptions in adulthood. The results suggest that females with persistent depressive disorder in adolescence have a higher rate of future prescriptions than non-depressed peers, with adjusted incidence rate ratio of 1.42 (1.06 to 1.92) for anti-infectives and 1.72 (1.10 to 2.70) for anti-inflammatories. These associations were mainly driven by those who were also prescribed antidepressants during the same period. Associations were less robust for females with episodic or subsyndromal depression in adolescence and for males. These findings emphasize the importance of integrated mental health services at the primary healthcare level.

Aberrant default mode connectivity in adolescents with early-onset psychosis: A resting state fMRI study.

Abnormal default mode network (DMN) connectivity has been found in schizophrenia and other psychotic disorders. However, there are limited studies on early onset psychosis (EOP), and their results show lack of agreement. Here, we investigated within-network DMN connectivity in EOP compared to healthy controls (HC), and its relationship to clinical characteristics. A sample of 68 adolescent patients with EOP (mean age 16.53 ± 1.12 [SD] years, females 66%) and 95 HC (mean age 16.24 ± 1.50 [SD], females 60%) from two Scandinavian cohorts underwent resting state functional magnetic resonance imaging (rsfMRI). A group independent component analysis (ICA) was performed to identify the DMN across all participants. Dual regression was used to estimate spatial maps reflecting each participant's DMN network, which were compared between EOP and HC using voxel-wise general linear models and permutation-based analyses. Subgroup analyses were performed within the patient group, to explore associations between diagnostic subcategories and current use of psychotropic medication in relation to connectivity strength. The analysis revealed significantly reduced DMN connectivity in EOP compared to HC in the posterior cingulate cortex, precuneus, fusiform cortex, putamen, pallidum, amygdala, and insula. The subgroup analysis in the EOP group showed strongest deviations for affective psychosis, followed by other psychotic disorders and schizophrenia. There was no association between DMN connectivity strength and the current use of psychotropic medication. In conclusion, the findings demonstrate weaker DMN connectivity in adolescent patients with EOP compared to healthy peers, and differential effects across diagnostic subcategories, which may inform our understanding of underlying disease mechanisms in EOP.

Poor family relationships in adolescence as a risk factor of in-patient somatic care across the life course: Findings from a 1953 cohort.

BACKGROUND: Prior research has shown that poor family relations during upbringing have long-term detrimental effects on mental health. Few previous studies have, however, focused on somatic health outcomes and studies rarely cover the life span until retirement age. The aims of the current study were, firstly, to examine the association between poor family relationships in adolescence and in-patient somatic care across the life course whilst adjusting for confounders at baseline and concurrent psychiatric in-patient care; and secondly, to compare the risks of somatic and psychiatric in-patient care across the life course. METHODS: Prospective data from the Stockholm Birth Cohort study were used, with 2636 participants born in 1953 who were followed up until 2016. Information on family relationships was collected from the participants' mothers in 1968. Annual information on in-patient somatic and psychiatric care was retrieved from official register data from 1969 to 2016. RESULTS: Poisson regressions showed that poor family relationships in adolescence were associated with an increased risk of in-patient somatic care in mid- and especially in late adulthood (ages 44-53 and 54-63 years), even when controlling for the co-occurrence of psychiatric illness and a range of childhood conditions. No statistically significant association was observed in early adulthood (ages 16-43 years), when controlling for confounders. These findings are in sharp contrast to the analyses of inpatient psychiatric care, according to which the association with poor family relations was strongest in early adulthood and thereafter attenuated across the life course. CONCLUSION: Poor family relationships in adolescence are associated with an increased risk of severe consequences for somatic health lasting to late adulthood even when controlling for confounders including in-patient psychiatric care, emphasising the potentially important role of early interventions.

Somatic symptoms as a marker for severity in adolescent depression.

AIM: This study aims to investigate the prevalence of somatic symptoms in depressed adolescents and in their healthy peers. A second aim is to investigate the correlation, in the depressed adolescents, between the number of somatic symptoms and severe concurrent symptoms, signs and life events. METHODS: The total population of 16-17 year olds - in the city of Uppsala - was screened for depression and then interviewed using a structured interview questionnaire. Depressed subjects and matched controls were identified. A total of 177 pairs were used for pair-wise analyses of somatic symptoms. Severe symptoms, signs and life events were selected for analysing their relation to depression with somatic symptoms. RESULTS: The adolescents with depressive disorders experienced considerably more somatic symptoms than their healthy controls. The duration and depth of the depression correlated with the number of somatic symptoms. There was a strong correlation between depression with many somatic symptoms and suicidal plans/thoughts, suicidal attempts, disruptive behaviour, as well as multiple stressful relationships. CONCLUSION: This study demonstrates that somatic symptoms are common in adolescent depression. Multiple somatic symptoms within depression imply a higher severity in terms of duration, depth and psychiatric comorbidity. The strong correlation with suicidal plans, suicidal attempts and disruptive behaviour is concerning.

Preclinical atherosclerosis in adolescents with psychotic or bipolar disorders investigated with carotid high-frequency ultrasound.

OBJECTIVE: Early-onset psychosis (EOP) and bipolar disorder (EOBP) (at <18 years of age), are associated with an increased future risk of cardiovascular disease (CVD) and premature death. Yet it is unknown whether the arteries show visible signs of atherosclerosis in EOP and EOBP. This study investigated whether having EOP or EOBP was associated with detectable signs of preclinical atherosclerosis. METHOD: By using 22 MHz high-frequency ultrasound, different layers of the arterial wall of the left common carotid artery (LCCA) were assessed in 77 individuals with EOP (n = 25), EOBP (n = 22), and in age-matched healthy controls (n = 30). Conventional CVD confounders were included in the analyses. RESULTS: Adolescents with EOP and EOBP, compared to controls, had a significantly thicker LCCA intima thickness (0.132 vs. 0.095 mm, p < .001) and intima/media ratio (0.24 vs. 0.17 p < .001). There was a nonsignificant intima difference between EOP and EOBP. Conventional CVD risk factors did not explain the association between EOP/EOBP and intima thickness. In the group of EOP/EOBP, there was a significant correlation between the dose of current antipsychotic medication and intima thickness; however, the correlation was attenuated to a nonsignificant level when adjusted for global function. CONCLUSIONS: Adolescents with EOP or EOBP had an increased LCCA intima thickness, interpreted as a sign of preclinical atherosclerosis. Global function of the disorders was the strongest determinant of intima thickness. The findings, if replicated, might have implications for long-term treatment of EOP and EOBP in order to reduce a future risk of CVD.

Clozapine protects adult neural stem cells from ketamine-induced cell death in correlation with decreased apoptosis and autophagy.

Adult neurogenesis, the production of newborn neurons from neural stem cells (NSCs) has been suggested to be decreased in patients with schizophrenia. A similar finding was observed in an animal model of schizophrenia, as indicated by decreased bromodeoxyuridine (BrdU) labelling cells in response to a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist. The antipsychotic drug clozapine was shown to counteract the observed decrease in BrdU-labelled cells in hippocampal dentate gyrus (DG). However, phenotypic determination by immunohistochemistry analysis could not reveal whether BrdU-positive cells were indeed NSCs. Using a previously established cell model for analysing NSC protection in vitro, we investigated a protective effect of clozapine on NSCs. Primary NSCs were isolated from the mouse subventricular zone (SVZ), we show that clozapine had a NSC protective activity alone, as evident by employing an ATP cell viability assay. In contrast, haloperidol did not show any NSC protective properties. Subsequently, cells were exposed to the non-competitive NMDA-receptor antagonist ketamine. Clozapine, but not haloperidol, had a NSC protective/anti-apoptotic activity against ketamine-induced cytotoxicity. The observed NSC protective activity of clozapine was associated with increased expression of the anti-apoptotic marker Bcl-2, decreased expression of the pro-apoptotic cleaved form of caspase-3 and associated with decreased expression of the autophagosome marker 1A/1B-light chain 3 (LC3-II). Collectively, our findings suggest that clozapine may have a protective/anti-apoptotic effect on NSCs, supporting previous in vivo observations, indicating a neurogenesis-promoting activity for clozapine. If the data are further confirmed in vivo, the results may encourage an expanded use of clozapine to restore impaired neurogenesis in schizophrenia.