Sociodemographic, clinical, and functional long-term outcomes in adolescents and young adults with mental disorders.

OBJECTIVE: To examine unfavorable sociodemographic, clinical, and functional long-term outcomes for a range of adolescent mental disorders. METHODS: A total number of 2210 adolescents and young adults (14-24 years at baseline, T0) from a representative community sample were prospectively followed up (T1-T3) over 10 years. DSM-IV mental disorders, sociodemographic, clinical, and functional outcomes were assessed using the DIA-X/M-CIDI and its embedded assessment modules. RESULTS: In (multinomial) logistic regressions adjusted for sex, age, other baseline disorders and sociodemographics, baseline anxiety, affective, substance use, somatoform and eating disorders (lifetime) predicted various unfavorable sociodemographic, clinical, and functional outcomes at T3. Particularly, strong associations were found between baseline disorders and adverse clinical outcomes at T3 (12-month diagnosis of the same/other disorder(s), drug use, suicide attempts, and help-seeking due to psychological problems). While substance use disorders were primarily associated with unfavorable sociodemographic and educational outcomes, anxiety and eating disorders were associated with unfavorable interpersonal outcomes, affective disorders with pregnancy-/childbirth-related complications and financial issues, and somatoform disorders with unfavorable educational/occupational and interpersonal outcomes. The risk of unfavorable outcomes increased with clinical severity, especially a higher number of baseline diagnoses. CONCLUSIONS: Our findings emphasize the importance of effective treatment of mental disorders to prevent unfavorable long-term outcomes in various life domains.

Symptom characteristics of depressive episodes prior to the onset of mania or hypomania.

OBJECTIVE: Depressive episodes are typically the initial presentation of bipolar disorder. The evidence as to whether depressive episodes occurring in persons who later convert to bipolar disorder are symptomatically distinct from episodes of unipolar depression remains controversial. As there are crucial differences in the therapeutic management, symptom profiles indicating subsequent bipolar conversion may aid in appropriate treatment. METHOD: A representative community sample of originally N = 3021 adolescents and young adults aged 14-24 years at baseline was assessed up to four times over 10 years. Assessment of symptoms was conducted by clinically trained interviewers using the standardized M-CIDI. Symptom profiles of depressive episodes were compared via logistic regression between subjects that subsequently developed (hypo-)manic episodes (n = 35) or remained unipolar depressive (n = 659). RESULTS: Initial depression amongst prospective converters was characterized by significantly increased suicidality (odds ratio, OR = 2.31), higher rates of feelings of worthlessness and excessive guilt (OR = 2.52), complete loss of pleasure (OR = 2.53) and diurnal variation (OR = 4.30). No differences were found for hyperphagia, hypersomnia and psychomotor alterations. CONCLUSION: Findings suggest that the symptom profile of initial depressive episodes may be useful in the identification of subjects with an elevated risk for the subsequent conversion to bipolar disorder.

Does low coping efficacy mediate the association between negative life events and incident psychopathology? A prospective-longitudinal community study among adolescents and young adults.

AIMS: To prospectively examine whether negative life events (NLE) and low perceived coping efficacy (CE) increase the risk for the onset of various forms of psychopathology and low CE mediates the associations between NLE and incident mental disorders. METHODS: A representative community sample of adolescents and young adults (N = 3017, aged 14-24 at baseline) was prospectively followed up in up to three assessment waves over 10 years. Anxiety, depressive and substance use disorders were assessed at each wave using the DSM-IV/M-CIDI. NLE and CE were assessed at baseline with the Munich Event List and the Scale for Self-Control and Coping Skills. Associations (odds ratios, OR) of NLE and CE at baseline with incident mental disorders at follow-up were estimated using logistic regressions adjusted for sex and age. RESULTS: NLE at baseline predicted the onset of any disorder, any anxiety disorder, panic disorder, agoraphobia, generalised anxiety disorder, any depression, major depressive episodes, dysthymia, any substance use disorder, nicotine dependence and abuse/dependence of illicit drugs at follow-up (OR 1.02-1.09 per one NLE more). When adjusting for any other lifetime disorder prior to baseline, merely the associations of NLE with any anxiety disorder, any depression, major depressive episodes, dysthymia and any substance use disorder remained significant (OR 1.02-1.07). Low CE at baseline predicted the onset of any disorder, any anxiety disorder, agoraphobia, generalised anxiety disorder, any depression, major depressive episodes, dysthymia, any substance use disorder, alcohol abuse/dependence, nicotine dependence and abuse/dependence of illicit drugs at follow-up (OR 1.16-1.72 per standard deviation). When adjusting for any other lifetime disorder prior to baseline, only the associations of low CE with any depression, major depressive episodes, dysthymia, any substance use disorder, alcohol abuse/dependence, nicotine dependence and abuse/dependence of illicit drugs remained significant (OR 1.15-1.64). Low CE explained 9.46, 13.39, 12.65 and 17.31% of the associations between NLE and any disorder, any depression, major depressive episodes and dysthymia, respectively. When adjusting for any other lifetime disorder prior to baseline, the reductions in associations for any depression (9.77%) and major depressive episodes (9.40%) remained significant, while the reduction in association for dysthymia was attenuated to non-significance (p-value > 0.05). CONCLUSIONS: Our findings suggest that NLE and low perceived CE elevate the risk for various incident mental disorders and that low CE partially mediates the association between NLE and incident depression. Subjects with NLE might thus profit from targeted early interventions strengthening CE to prevent the onset of depression.

Evidence that the presence of psychosis in non-psychotic disorder is environment-dependent and mediated by severity of non-psychotic psychopathology.

BACKGROUND: Evidence suggests that in affective, non-psychotic disorders: (i) environmental exposures increase risk of subthreshold psychotic experiences (PEs) and strengthen connectivity between domains of affective and subthreshold psychotic psychopathology; and (ii) PEs are a marker of illness severity. METHOD: In 3021 adolescents from the Early Developmental Stages of Psychopathology cohort, we tested whether the association between PEs and presence of DSM-IV mood disorder (MD)/obsessive-compulsive disorder (OCD) would be moderated by risk factors for psychosis (cannabis use, childhood trauma and urbanicity), using the interaction contrast ratio (ICR) method. Furthermore, we analysed whether the interaction between environment and PEs was mediated by non-psychotic psychopathology. RESULTS: The association between PEs and MD/OCD was moderated by urbanicity (ICR = 2.46, p = 0.005), cannabis use (ICR = 3.76, p = 0.010) and, suggestively, trauma (ICR = 1.91, p = 0.063). Exposure to more than one environmental risk factor increased the likelihood of co-expression of PEs in a dose-response fashion. Moderating effects of environmental exposures were largely mediated by the severity of general non-psychotic psychopathology (percentage explained 56-68%, all p < 0.001). Within individuals with MD/OCD, the association between PEs and help-seeking behaviour, as an index of severity, was moderated by trauma (ICR = 1.87, p = 0.009) and urbanicity (ICR = 1.48, p = 0.005), but not by cannabis use. CONCLUSIONS: In non-psychotic disorder, environmental factors increase the likelihood of psychosis admixture and help-seeking behaviour through an increase in general psychopathology. The findings are compatible with a relational model of psychopathology in which more severe clinical states are the result of environment-induced disturbances spreading through a psychopathology network.

Danger and loss events and the incidence of anxiety and depressive disorders: a prospective-longitudinal community study of adolescents and young adults.

BACKGROUND: There are inconclusive findings regarding whether danger and loss events differentially predict the onset of anxiety and depression. METHOD: A community sample of adolescents and young adults (n = 2304, age 14-24 years at baseline) was prospectively followed up in up to four assessments over 10 years. Incident anxiety and depressive disorders were assessed at each wave using the DSM-IV/M-CIDI. Life events (including danger, loss and respectively mixed events) were assessed at baseline using the Munich Event List (MEL). Logistic regressions were used to reveal associations between event types at baseline and incident disorders at follow-up. RESULTS: Loss events merely predicted incident 'pure' depression [odds ratio (OR) 2.4 per standard deviation, 95% confidence interval (CI) 1.5-3.9, p < 0.001] whereas danger events predicted incident 'pure' anxiety (OR 2.3, 95% CI 1.1-4.6, p = 0.023) and 'pure' depression (OR 2.5, 95% CI 1.7-3.5, p < 0.001). Mixed events predicted incident 'pure' anxiety (OR 2.9, 95% CI 1.5-5.7, p = 0.002), 'pure' depression (OR 2.4, 95% CI 1.6-3.4, p < 0.001) and their co-morbidity (OR 3.6, 95% CI 1.8-7.0, p < 0.001). CONCLUSIONS: Our results provide further evidence for differential effects of danger, loss and respectively mixed events on incident anxiety, depression and their co-morbidity. Since most loss events referred to death/separation from significant others, particularly interpersonal loss appears to be highly specific in predicting depression.

The role of behavioral inhibition and parenting for an unfavorable emotional trauma response and PTSD.

OBJECTIVE: The role of behavioral inhibition (BI) and parenting for an unfavorable emotional trauma response (DSM-IV criterion A2) and post-traumatic stress disorder (PTSD) development is unclear. METHOD: A community sample of adolescents and young adults (aged 14-24) was followed up over 10 years (N=2378). Traumatic events, criterion A2, and PTSD (according to DSM-IV-TR) were assessed using the M-CIDI. BI and parenting were assessed using the Retrospective Self-Report of Inhibition and the Questionnaire of Recalled Parenting Rearing Behavior. Multiple logistic regressions adjusted for sex, age, and number of traumata were used to examine associations of BI as well as maternal and paternal overprotection, rejection, and reduced emotional warmth with (i) criterion A2 in those with trauma (N=1794) and (ii) subsequent PTSD in those with criterion A2 (N=1160). RESULTS: Behavioral inhibition (BI; odds ratio, OR=1.32) and paternal overprotection (OR=1.27) predicted criterion A2 in those with trauma, while only BI (OR=1.53) predicted subsequent PTSD. BI and paternal emotional warmth interacted on subsequent PTSD (OR=1.32), that is, BI only predicted PTSD in those with low paternal emotional warmth. CONCLUSION: Our findings suggest that BI and adverse parenting increase the risk of an unfavorable emotional trauma response and subsequent PTSD. Paternal emotional warmth buffers the association between BI and PTSD development.

Characteristics of developmentally early alcohol use disorder symptom reports: a prospective-longitudinal community study.

BACKGROUND: There is little prospective-epidemiological information on symptoms of DSM-IV-alcohol use disorder (alcohol abuse and dependence; AUD) that may be typical for early AUD stages or the developmental periods of adolescence and early adulthood. AIMS: To investigate AUD symptoms (AUDS) cross-sectionally at three subsequent assessment waves regarding prevalence rates, symptom counts, associated drinking patterns, positive predictive values (PPV) for DSM-IV-alcohol dependence (AD), and AUDS stability over time. METHODS: N=2039 community subjects (baseline age 14-24 years) participated in a baseline and two follow-up assessment(s) over up to ten years. DSM-IV-AUDS, DSM-IV-AUD and craving were assessed with the DSM-IV/M-CIDI. RESULTS: Over the assessment waves, tolerance and much time were most and role obligations and withdrawal least frequent. Most subjects with DSM-IV-AUDS reported only one symptom (47.2-55.1%). PPV for DSM-IV-AD only exceeded 70% for activities, problem, withdrawal, and desired control; PPV were lowest for tolerance and hazardous use. For most AUDS, AUDS report compared to non-report was associated with elevated drinking frequency and amounts. Stability of baseline AUDS at four-year and ten-year follow-up did not exceed 36.4% for any symptom. CONCLUSIONS: The overall pattern of most/least frequent AUDS reported in adolescence and early adulthood resembles findings in older adults and does not suggest a developmentally specific symptom pattern. Moderate AUDS-stability and considerable remission rates indicate that AUDS in this age group are transient for a considerable proportion of subjects. However, the associations with elevated consumption indicate that AUDS reports early in life need to be taken seriously in prevention and intervention.

Dynamic changes in DNA methylation of stress-associated genes (OXTR, BDNF ) after acute psychosocial stress.

Environmentally induced epigenetic alterations are related to mental health. We investigated quantitative DNA methylation status before and after an acute psychosocial stressor in two stress-related genes: oxytocin receptor (OXTR) and brain-derived neurotrophic factor (BDNF ). The cross sectional study took place at the Division of Theoretical and Clinical Psychobiology, University of Trier, Germany and was conducted from February to August 2009. We included 83 participants aged 61-67 years. Thereof, 76 participants completed the full study procedure consisting of blood sampling before (pre-stress), 10 min after (post-stress) and 90 min after (follow-up) the Trier social stress test. We assessed quantitative DNA methylation of whole-blood cells using Sequenom EpiTYPER. Methylation status differed between sampling times in one target sequence of OXTR (P<0.001): methylation increased from pre- to post-stress (P=0.009) and decreased from post-stress to follow-up (P<0.001). This decrease was also found in a second target sequence of OXTR (P=0.034), where it lost statistical significance when blood cell count was statistically controlled. We did not detect any time-associated differences in methylation status of the examined BDNF region. The results suggest a dynamic regulation of DNA methylation in OXTR-which may in part reflect changes in blood cell composition-but not BDNF after acute psychosocial stress. This may enhance the understanding of how psychosocial events alter DNA methylation and could provide new insights into the etiology of mental disorders.

The natural course of social anxiety disorder among adolescents and young adults.

OBJECTIVE: To examine the natural course of social anxiety disorder (SAD) in the community and to explore predictors for adverse long-term outcomes. METHOD: A community sample of N = 3021 subjects aged 14-24 was followed-up over 10 years using the DSM-IV/M-CIDI. Persistence of SAD is based on a composite score reflecting the proportion of years affected since onset. Diagnostic stability is the proportion of SAD subjects still affected at follow-up. RESULTS: SAD reveals considerable persistence with more than half of the years observed since onset spent with symptoms. 56.7% of SAD cases revealed stability with at least symptomatic expressions at follow-up; 15.5% met SAD threshold criteria again. 15.1% were completely remitted (no SAD symptoms and no other mental disorders during follow-up). Several clinical features (early onset, generalized subtype, more anxiety cognitions, severe avoidance and impairment, co-occurring panic) and vulnerability characteristics (parental SAD and depression, behavioural inhibition, harm avoidance) predicted higher SAD persistence and - less impressively - diagnostic stability. CONCLUSION: A persistent course with a considerable degree of fluctuations in symptom severity is characteristic for SAD. Both consistently meeting full threshold diagnostic criteria and complete remissions are rare. Vulnerability and clinical severity indicators predict poor prognosis and might be helpful markers for intervention needs.

Do subthreshold psychotic experiences predict clinical outcomes in unselected non-help-seeking population-based samples? A systematic review and meta-analysis, enriched with new results.

BACKGROUND: The base rate of transition from subthreshold psychotic experiences (the exposure) to clinical psychotic disorder (the outcome) in unselected, representative and non-help-seeking population-based samples is unknown. METHOD: A systematic review and meta-analysis was conducted of representative, longitudinal population-based cohorts with baseline assessment of subthreshold psychotic experiences and follow-up assessment of psychotic and non-psychotic clinical outcomes. RESULTS: Six cohorts were identified with a 3-24-year follow-up of baseline subthreshold self-reported psychotic experiences. The yearly risk of conversion to a clinical psychotic outcome in exposed individuals (0.56%) was 3.5 times higher than for individuals without psychotic experiences (0.16%) and there was meta-analytic evidence of dose-response with severity/persistence of psychotic experiences. Individual studies also suggest a role for motivational impairment and social dysfunction. The evidence for conversion to non-psychotic outcome was weaker, although findings were similar in direction. CONCLUSIONS: Subthreshold self-reported psychotic experiences in epidemiological non-help-seeking samples index psychometric risk for psychotic disorder, with strong modifier effects of severity/persistence. These data can serve as the population reference for selected and variable samples of help-seeking individuals at ultra-high risk, for whom much higher transition rates have been indicated.

The association between social phobia, social anxiety cognitions and paranoid symptoms.

OBJECTIVE: Previous research suggests high levels of comorbidity between social phobia and paranoid symptoms, although the nature of this association remains unclear. METHOD: Data were derived from the Early Developmental Stages of Psychopathology study, a 10-year longitudinal study in a representative German community sample of 3021 participants aged 14-24 years at baseline. The Munich-Composite International Diagnostic Interview was used to assess social phobia and paranoid symptoms, along with data on social phobia features. Cross-sectional and longitudinal analyses were conducted. Differential associations with environmental risk factors and temperamental traits were investigated. RESULTS: Lifetime social phobia and paranoid symptoms were associated with each other cross-sectionally (OR = 1.80, 95% CI = 1.31-2.47). Lifetime paranoid symptoms were associated specifically with social anxiety cognitions. Lifetime cognitions of negative evaluation predicted later onset of paranoid symptoms, whereas onset of social phobia was predicted by cognitions of loss of control and fear/avoidance of social situations. Lifetime social phobia and paranoid symptoms shared temperamental traits of behavioural inhibition, but differed in environmental risks. CONCLUSIONS: The present study showed that paranoid symptoms and social phobia share similarities in cognitive profile and inhibited temperament. Avoidance appears to be important in the development of social phobia, whereas cannabis use and traumatic experiences may drive paranoid thinking in vulnerable individuals.

Adversity and psychosis: a 10-year prospective study investigating synergism between early and recent adversity in psychosis.

OBJECTIVE: Recent studies have suggested that early adverse events, such as childhood trauma, may promote enduring liability for psychosis whereas more recent adverse events may act as precipitants. Examination of these environmental dynamics, however, requires prospective studies in large samples. This study examines whether the association between recent adverse events and psychosis is moderated by exposure to early adversity. METHOD: A random regional representative population sample of 3021 adolescents and young adults in Munich, Germany, was assessed three times over a period of up to 10 years, collecting information on sociodemographic factors, environmental exposures, and measures of psychopathology and associated clinical relevance. Evidence of statistical non-additivity between early adversity (two levels) and more recent adversity (four levels) was assessed in models of psychotic symptoms. Analyses were a priori corrected for age, gender, cannabis use, and urbanicity. RESULTS: Early and recent adversity were associated with each other (RR = 1.32, 95% CI 1.06-1.66; P = 0.014) and displayed statistical non-additivity at the highest level of exposure to recent adversity (χ(2) = 4.59; P = 0.032). CONCLUSION: The findings suggest that early adversity may impact on later expression of psychosis either by increasing exposure to later adversity and/or by rendering individuals more sensitive to later adversity if it is severe.

The size and burden of mental disorders and other disorders of the brain in Europe 2010.

AIMS: To provide 12-month prevalence and disability burden estimates of a broad range of mental and neurological disorders in the European Union (EU) and to compare these findings to previous estimates. Referring to our previous 2005 review, improved up-to-date data for the enlarged EU on a broader range of disorders than previously covered are needed for basic, clinical and public health research and policy decisions and to inform about the estimated number of persons affected in the EU. METHOD: Stepwise multi-method approach, consisting of systematic literature reviews, reanalyses of existing data sets, national surveys and expert consultations. Studies and data from all member states of the European Union (EU-27) plus Switzerland, Iceland and Norway were included. Supplementary information about neurological disorders is provided, although methodological constraints prohibited the derivation of overall prevalence estimates for mental and neurological disorders. Disease burden was measured by disability adjusted life years (DALY). RESULTS: Prevalence: It is estimated that each year 38.2% of the EU population suffers from a mental disorder. Adjusted for age and comorbidity, this corresponds to 164.8million persons affected. Compared to 2005 (27.4%) this higher estimate is entirely due to the inclusion of 14 new disorders also covering childhood/adolescence as well as the elderly. The estimated higher number of persons affected (2011: 165m vs. 2005: 82m) is due to coverage of childhood and old age populations, new disorders and of new EU membership states. The most frequent disorders are anxiety disorders (14.0%), insomnia (7.0%), major depression (6.9%), somatoform (6.3%), alcohol and drug dependence (>4%), ADHD (5%) in the young, and dementia (1-30%, depending on age). Except for substance use disorders and mental retardation, there were no substantial cultural or country variations. Although many sources, including national health insurance programs, reveal increases in sick leave, early retirement and treatment rates due to mental disorders, rates in the community have not increased with a few exceptions (i.e. dementia). There were also no consistent indications of improvements with regard to low treatment rates, delayed treatment provision and grossly inadequate treatment. Disability: Disorders of the brain and mental disorders in particular, contribute 26.6% of the total all cause burden, thus a greater proportion as compared to other regions of the world. The rank order of the most disabling diseases differs markedly by gender and age group; overall, the four most disabling single conditions were: depression, dementias, alcohol use disorders and stroke. CONCLUSION: In every year over a third of the total EU population suffers from mental disorders. The true size of "disorders of the brain" including neurological disorders is even considerably larger. Disorders of the brain are the largest contributor to the all cause morbidity burden as measured by DALY in the EU. No indications for increasing overall rates of mental disorders were found nor of improved care and treatment since 2005; less than one third of all cases receive any treatment, suggesting a considerable level of unmet needs. We conclude that the true size and burden of disorders of the brain in the EU was significantly underestimated in the past. Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for disorders of the brain as the core health challenge of the 21st century.

Do cannabis and urbanicity co-participate in causing psychosis? Evidence from a 10-year follow-up cohort study.

BACKGROUND: Cannabis use is considered a component cause of psychotic illness, interacting with genetic and other environmental risk factors. Little is known, however, about these putative interactions. The present study investigated whether an urban environment plays a role in moderating the effects of adolescent cannabis use on psychosis risk. METHOD: Prospective data (n=1923, aged 14-24 years at baseline) from the longitudinal population-based German Early Developmental Stages of Psychopathology cohort study were analysed. Urbanicity was assessed at baseline and defined as living in the city of Munich (1562 persons per km2; 4061 individuals per square mile) or in the rural surroundings (213 persons per km2; 553 individuals per square mile). Cannabis use and psychotic symptoms were assessed three times over a 10-year follow-up period using the Munich version of the Composite International Diagnostic Interview. RESULTS: Analyses revealed a significant interaction between cannabis and urbanicity [10.9% adjusted difference in risk, 95% confidence interval (CI) 3.2-18.6, p=0.005]. The effect of cannabis use on follow-up incident psychotic symptoms was much stronger in individuals who grew up in an urban environment (adjusted risk difference 6.8%, 95% CI 1.0-12.5, p=0.021) compared with individuals from rural surroundings (adjusted risk difference -4.1%, 95% CI -9.8 to 1.6, p=0.159). The statistical interaction was compatible with substantial underlying biological synergism. CONCLUSIONS: Exposure to environmental influences associated with urban upbringing may increase vulnerability to the psychotomimetic effects of cannabis use later in life.

Adolescent development of psychosis as an outcome of hearing impairment: a 10-year longitudinal study.

BACKGROUND: It has long been acknowledged that hearing impairment may increase the risk for psychotic experiences. Recent work suggests that young people in particular may be at risk, indicating a possible developmental mechanism. METHOD: The hypothesis that individuals exposed to hearing impairment in early adolescence would display the highest risk for psychotic symptoms was examined in a prospective cohort study of a population sample of originally 3021 adolescents and young adults aged 14-24 years at baseline, in Munich, Germany (Early Developmental Stages of Psychopathology Study). The expression of psychosis was assessed at multiple time points over a period of up to 10 years, using a diagnostic interview (Munich Composite International Diagnostic Interview; CIDI) administered by clinical psychologists. RESULTS: Hearing impairment was associated with CIDI psychotic symptoms [odds ratio (OR) 2.04, 95% confidence interval (CI) 1.10-3.81], particularly more severe psychotic symptoms (OR 5.66, 95% CI 1.64-19.49). The association between hearing impairment and CIDI psychotic symptoms was much stronger in the youngest group aged 14-17 years at baseline (OR 3.28, 95% CI 1.54-7.01) than in the older group aged 18-24 years at baseline (OR 0.82, 95% CI 0.24-2.84). CONCLUSIONS: The finding of an age-specific association between hearing impairment and psychotic experiences suggests that disruption of development at a critical adolescent phase, in interaction with other personal and social vulnerabilities, may increase the risk for psychotic symptoms.

Associations between use of cocaine, amphetamines, or psychedelics and psychotic symptoms in a community sample.

OBJECTIVE: To investigate the association between use of cocaine, amphetamines, or psychedelics and psychotic symptoms. METHOD: Cumulated lifetime data from a prospective, longitudinal community study of 2588 adolescents and young adults in Munich, Germany, were used. Substance use at baseline, 4-year and 10-year follow-up and psychotic symptoms at 4-year and 10-year follow-up were assessed using the Munich-Composite International Diagnostic Interview. Data from all assessment waves were aggregated, and multinomial logistic regression analyses were performed. Additional analyses adjusted for sociodemographics, common mental disorders, other substance use, and childhood adversity (adjusted odds ratios, AOR). RESULTS: After adjusting for potential confounders, lifetime experience of two or more psychotic symptoms was associated with lifetime use of cocaine (AOR 1.94; 95% CI 1.10-3.45) and psychedelics (AOR 2.37; 95% CI 1.20-4.66). Additionally, when mood or anxiety disorders were excluded, lifetime experience of two or more psychotic symptoms was associated with use of psychedelics (AOR 3.56; 95% CI 1.20-10.61). CONCLUSION: Associations between psychotic symptoms and use of cocaine, and/or psychedelics in adolescents and young adults call for further studies to elucidate risk factors and developmental pathways.

The role of mental disorders in the risk and speed of transition to alcohol use disorders among community youth.

BACKGROUND: Among adolescents and young adults with DSM-IV alcohol use disorders (AUDs), there are inter-individual differences in the speed of transition from initial alcohol use (AU) to AUD. AUDs are highly co-morbid with other mental disorders. The factors associated with rapid transition from first AU to AUD remain unknown and the role of mental disorders in rapid transitions is unclear. Given this background we examined (1) whether prior anxiety, mood, externalizing and non-alcohol substance use disorders are related to the risk and speed of transition from first AU to DSM-IV alcohol abuse (AA) and alcohol dependence (AD) and (2) whether early age of onset of prior mental disorders (PMDs) is a promoter of rapid transition. METHOD: A total of 3021 community subjects (97.7% lifetime AU) aged 14-24 years at baseline were followed up prospectively for up to 10 years. AU and mental disorders were assessed with the DSM-IV/M-CIDI. RESULTS: Among subjects with lifetime AU, several PMDs, such as specific phobia, bipolar disorder and nicotine dependence, were associated with an increased risk of AUD independent of externalizing disorders. Associations of PMDs with the speed of transition to AUDs were mostly weak and inconsistent. Only social phobia and externalizing disorders were associated with faster transitions to AD even after adjustment for other PMDs. Earlier age of onset of PMD was not associated with rapid transition. CONCLUSIONS: Mental disorders are associated with the risk of AUD. With the possible exception of social phobia and externalizing disorders, they do not promote rapid transition, even if they occur particularly early. Future research needs to identify factors relevant to rapid transition to AUD.

TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies.

The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.

Risk factors predicting onset and persistence of subthreshold expression of bipolar psychopathology among youth from the community.

OBJECTIVE: To examine factors increasing the risk for onset and persistence of subthreshold mania and depression. METHOD: In a prospective cohort community study, the association between risk factors [a family history of mood disorders, trauma, substance use, attention-deficit/hyperactivity disorder (ADHD) and temperamental/personality traits] and onset of manic/depressive symptoms was determined in 705 adolescents. The interaction between baseline risk factors and baseline symptoms in predicting 8-year follow-up symptoms was used to model the impact of risk factors on persistence. RESULTS: Onset of manic symptoms was associated with cannabis use and novelty seeking (NS), but NS predicted a transitory course. Onset of depressive symptoms was associated with a family history of depression. ADHD and harm avoidance (HA) were associated with persistence of depressive symptoms, while trauma and a family history of depression predicted a transitory course. CONCLUSION: Different risk factors may operate during onset and persistence of subthreshold mania and depression. The differential associations found for mania and depression dimensions suggest partly different underlying mechanisms.

Evidence that bipolar disorder is the poor outcome fraction of a common developmental phenotype: an 8-year cohort study in young people.

BACKGROUND: Reported rates of bipolar syndromes are highly variable between studies because of age differences, differences in diagnostic criteria, or restriction of sampling to clinical contacts. METHOD: In 1395 adolescents aged 14-17 years, DSM-IV (hypo)manic episodes (manic and hypomanic episodes combined), use of mental health care, and five ordinal subcategories representing the underlying continuous score of (hypo)manic symptoms ('mania symptom scale') were measured at baseline and approximately 1.5, 4 and 10 years later using the Munich-Composite International Diagnostic Interview (DIA-X/M-CIDI). RESULTS: Incidence rates (IRs) of both (hypo)manic episodes and (hypo)manic symptoms (at least one DSM-IV core symptom) were far higher (714/105 person-years and 1720/10(5) person-years respectively) than traditional estimates. In addition, the risk of developing (hypo)manic episodes was very low after the age of 21 years [hazard ratio (HR) 0.031, 95% confidence interval (CI) 0.0050-0.19], independent of childhood disorders such as attention deficit hyperactivity disorder (ADHD). Most individuals with hypomanic and manic episodes were never in care (87% and 62% respectively) and not presenting co-morbid depressive episodes (69% and 60% respectively). The probability of mental health care increased linearly with the number of symptoms on the mania symptom scale. The incidence of the bipolar categories, in particular at the level of clinical morbidity, was strongly associated with previous childhood disorders and male sex. CONCLUSIONS: This study showed, for the first time, that experiencing (hypo)manic symptoms is a common adolescent phenomenon that infrequently predicts mental health care use. The findings suggest that the onset of bipolar disorder can be elucidated by studying the pathway from non-pathological behavioural expression to dysfunction and need for care.