Our knowledge of the comorbidity of mood disorders depends heavily on their diagnostic classification, which is currently in a state of flux.

A diagnostic specifier for bipolarity was developed and applied to data collected on major depression in several studies: Zurich Study, EDSP Study Munich, NCS-R Study USA, and Bridge Study (Vieta et al. 2010).

In all four studies, about 40% of DSM-IV major depressive disorder diagnoses were re-classified as sub-threshold bipolar II disorders, resulting in a major change in comorbidity. The comorbidity of major depression with substance use disorder (SUD) (especially alcohol use) and panic disorder shifted substantially towards an association with hidden bipolar depression. The highest comorbidity was found in bipolar-I disorders. Pure and preponderantly manic or hypomanic subjects seem to be protected against comorbidity with anxiety disorders but are at risk for SUD.

The current classification of mood disorders over-estimates a diagnosis of pure depression. New data suggest that 40% to 50% of all subjects with mood disorders are bipolars. This has a considerable impact on comorbidity, treatment and future research. Self-assessment instruments for the detection of hypomania are recommendable.

There has been increasing evidence that chronic low-grade inflammation is associated with mood disorders. However, the findings have been inconsistent because of heterogeneity across studies and methodological limitations. Our aim is to prospectively evaluate the bi-directional associations between inflammatory markers including interleukin (IL)-6, tumor necrosis factor (TNF)-α and high sensitivity C-reactive protein (hsCRP) with mood disorders.

The sample consisted of 3118 participants (53.7% women; mean age: 51.0, s.d. 8.8 years), randomly selected from the general population, who underwent comprehensive somatic and psychiatric evaluations at baseline and follow-up (mean follow-up duration = 5.5 years, s.d. 0.6). Current and remitted mood disorders including bipolar and major depressive disorders (MDD) and its subtypes (atypical, melancholic, combined atypical and melancholic, and unspecified) were based on semi-structured diagnostic interviews. Inflammatory biomarkers were analyzed in fasting blood samples. Associations were tested by multiple linear and logistic regression models.

Current combined MDD [β = 0.29, 95% confidence interval (CI) 0.03–0.55] and current atypical MDD (β = 0.32, 95% CI 0.10–0.55) at baseline were associated with increased levels of hsCRP at follow-up. There was little evidence for inflammation markers at baseline predicting mood disorders at follow-up.

The prospective unidirectional association between current MDD subtype with atypical features and hsCRP levels at follow-up suggests that inflammation may be a consequence of this condition. The role of inflammation, particularly hsCRP that is critically involved in cardiovascular diseases, warrants further study. Future research that examines potential influences of medications on inflammatory processes is indicated.

Studies have indicated that the association of urbanicity at birth and during upbringing with schizophrenia may be driven by familial factors such as genetic liability. We used a population-based nested case–control study to assess whether polygenic risk score (PRS) for schizophrenia was associated with urbanicity at birth and at age 15, and to assess whether PRS and parental history of mental disorder together explained the association between urbanicity and schizophrenia.

Data were drawn from Danish population registries. Cases born since 1981 and diagnosed with schizophrenia between 1994 and 2009 were matched to controls with the same sex and birthdate (1549 pairs). Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of a separate, large meta-analysis.

Those with higher PRS were more likely reside in the capital compared with rural areas at age 15 [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01–1.40], but not at birth (OR 1.09, 95% CI 0.95–1.26). Adjustment for PRS produced almost no change in relative risks of schizophrenia associated with urbanicity at birth, but slightly attenuated those for urban residence at age 15. Additional adjustment for parental history led to slight attenuation of relative risks for urbanicity at birth [incidence rate ratio (IRR) for birth in capital = 1.54, 95% CI 1.18–2.02; overall p = 0.016] and further attenuation of relative risks for urbanicity at age 15 (IRR for residence in capital = 1.32, 95% CI 0.97–1.78; overall p = 0.148).

While results regarding urbanicity during upbringing were somewhat equivocal, genetic liability as measured here does not appear to explain the association between urbanicity at birth and schizophrenia.

There is growing interest in the role of childhood adversities, including parental death and separation, in the etiology of psychotic disorders. However, few studies have used prospectively collected data to specifically investigate parental separation across development, or assessed the importance of duration of separation, and family characteristics.

We measured three types of separation not due to death: maternal, paternal, and from both parents, across the ages of 1–15 years among a cohort of 985 058 individuals born in Denmark 1971–1991 and followed to 2011. Associations with narrowly and broadly defined schizophrenia and bipolar disorder in the psychiatric register were assessed in terms of separation occurrence, age of separation, and number of years separated. Interactions with parental history of mental disorder were assessed.

Each type of separation was associated with all three outcomes, adjusting for age, sex, birth period, calendar year, family history of mental disorder, urbanicity at birth and parental age. Number of years of paternal separation was positively associated with both schizophrenia and bipolar disorder. Associations between separation from both parents and schizophrenia were stronger when separation occurred at later ages, while those with bipolar disorder remained stable across development. The first occurrence of paternal separation appeared to increase risk more when it occurred earlier in childhood. Associations differed according to parental history of mental disorder, although in no situation was separation protective.

Effects of parental separation may differ by type, developmental timing and family characteristics. These findings highlight the importance of considering such factors in studies of childhood adversity.

There are only a small number of prospective studies that have systematically evaluated standardised diagnostic criteria for mental disorder for more than a decade. The aim of this study is to present the approximated overall and sex-specific cumulative incidence of mental disorder in the Zurich cohort study, a prospective cohort study of 18–19 years olds from the canton of Zurich, Switzerland, who were followed through age 50.

A stratified sample of 591 participants were interviewed with the Structured Psychopathological Interview and Rating of the Social Consequences of Psychological Disturbances for Epidemiology, a semi-structured interview that uses a bottom-up approach to assess the past-year presence of 15 psychiatric syndromes. Seven interview waves took place between 1979 and 2008. Approximated cumulative incidence was estimated using Kaplan–Meier methods.

Rates of mental disorder were considerably higher than those generally reported in cross-sectional surveys. We found rates ranging from 32.5% for major depressive disorder to 1.2% for Bipolar I disorder. The cumulative probability of experiencing any of the mental disorders assessed by age 50 was 73.9%, the highest reported to date. We also found that rates differed by sex for most disorders, with females generally reporting higher rates of mood, anxiety and phobic disorder, and males reporting higher rates of substance- and alcohol-related disorders.

These findings confirm those of other long-term prospective studies that indicate the nearly universal nature of disturbances of emotion and behaviour across the life span. Greater community awareness of the normative nature of these experiences is warranted. An important area of future research is study long-term course and stability to determine who among those with such disturbances suffer from chronic disabling mental disorders. Such longitudinal studies may aid in directing services and intervention efforts where they are most needed.

Threshold and subthreshold forms of generalized anxiety disorder (GAD) are highly prevalent and impairing conditions among adults. However, there are few general population studies that have examined these conditions during the early life course. The primary objectives of this study were to: (1) examine the prevalence, and sociodemographic and clinical characteristics of threshold and subthreshold forms of GAD in a nationally representative sample of US youth; and (2) test differences in sociodemographic and clinical characteristics between threshold and subthreshold forms of the disorder.

The National Comorbidity Survey-Adolescent Supplement is a nationally representative face-to-face survey of 10 123 adolescents 13 to 18 years of age in the continental USA.

Approximately 3% of adolescents met criteria for threshold GAD. Reducing the required duration from 6 months to 3 months resulted in a 65.7% increase in prevalence (5.0%); further relaxing the uncontrollability criterion led to an additional 20.7% increase in prevalence (6.1%). Adolescents with all forms of GAD displayed a recurrent clinical course marked by substantial impairment and co-morbidity with other psychiatric disorders. There were few significant differences in sociodemographic and clinical characteristics between threshold and subthreshold cases of GAD. Results also revealed age-related differences in the associated symptoms and clinical course of GAD.

Findings demonstrate the clinical significance of subthreshold forms of GAD among adolescent youth, highlighting the continuous nature of the GAD construct. Age-related differences in the associated symptoms and clinical course of GAD provide further support for criteria that capture variation in clinical features across development.

Identifying depressive subtypes is an important tool in reducing the heterogeneity of major depressive disorder. However, few studies have examined the stability of putative subtypes of depression over time.

The sample included 488 persons from the Netherlands Study of Depression and Anxiety (NESDA) who had major depressive disorder at baseline and at the 2-year follow-up assessment. A latent transition analysis (LTA) was applied to examine the stability of depressive subtypes across time-points. Differences in demographic, clinical, psychosocial and health correlates between subtypes were evaluated in a subsample of persons with stable subtypes.

Three subtypes were identified at each time-point: a moderate subtype (prevalence T0 39%, T1 42%), a severe typical subtype (T0 30%, T1 25%), and a severe atypical subtype (T0 31%, T1 34%). The LTA showed 76% stability across the 2-year follow-up, with the greatest stability in the severe atypical class (79%). Analyses of correlates in the stable subtypes showed a predominance of women and more overweight and obesity in the severe atypical subtype, and a greater number of negative life events and higher neuroticism and functioning scores in the severe typical subtype.

Subtypes of major depressive disorder were found to be stable across a 2-year follow-up and to have distinct determinants, supporting the notion that the identified subtypes are clinically meaningful.

Research on the structure of co-morbidity among common mental disorders has largely focused on current prevalence rather than on the development of co-morbidity. This report presents preliminary results of the latter type of analysis based on the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A).

A national survey was carried out of adolescent mental disorders. DSM-IV diagnoses were based on the Composite International Diagnostic Interview (CIDI) administered to adolescents and questionnaires self-administered to parents. Factor analysis examined co-morbidity among 15 lifetime DSM-IV disorders. Discrete-time survival analysis was used to predict first onset of each disorder from information about prior history of the other 14 disorders.

Factor analysis found four factors representing fear, distress, behavior and substance disorders. Associations of temporally primary disorders with the subsequent onset of other disorders, dated using retrospective age-of-onset (AOO) reports, were almost entirely positive. Within-class associations (e.g. distress disorders predicting subsequent onset of other distress disorders) were more consistently significant (63.2%) than between-class associations (33.0%). Strength of associations decreased as co-morbidity among disorders increased. The percentage of lifetime disorders explained (in a predictive rather than a causal sense) by temporally prior disorders was in the range 3.7–6.9% for earliest-onset disorders [specific phobia and attention deficit hyperactivity disorder (ADHD)] and much higher (23.1–64.3%) for later-onset disorders. Fear disorders were the strongest predictors of most other subsequent disorders.

Adolescent mental disorders are highly co-morbid. The strong associations of temporally primary fear disorders with many other later-onset disorders suggest that fear disorders might be promising targets for early interventions.

Although mental disorders have been shown to predict subsequent substance disorders, it is not known whether substance disorders could be cost-effectively prevented by large-scale interventions aimed at prior mental disorders. Although experimental intervention is the only way to resolve this uncertainty, a logically prior question is whether the associations of mental disorders with subsequent substance disorders are strong enough to justify mounting such an intervention. We investigated this question in this study using simulations to estimate the number of substance disorders that might be prevented under several hypothetical intervention scenarios focused on mental disorders.

Data came from the National Comorbidity Survey Replication (NCS-R), a nationally representative US household survey that retrospectively assessed lifetime history and age of onset of DSM-IV mental and substance disorders. Survival analysis using retrospective age-of-onset reports was used to estimate associations of mental disorders with subsequent substance dependence. Simulations based on the models estimated effect sizes in several hypothetical intervention scenarios.

Although successful intervention aimed at mental disorders might prevent some proportion of substance dependence, the number of cases of mental disorder that would have to be treated to prevent a single case of substance dependence is estimated to be so high that this would not be a cost-effective way to prevent substance dependence (in the range 76–177 for anxiety-mood disorders and 40–47 for externalizing disorders).

Treatment of prior mental disorders would not be a cost-effective way to prevent substance dependence. However, prevention of substance dependence might be considered an important secondary outcome of interventions for early-onset mental disorders.

The ‘gateway’ pattern of drug initiation describes a normative sequence, beginning with alcohol and tobacco use, followed by cannabis, then other illicit drugs. Previous work has suggested that ‘violations’ of this sequence may be predictors of later problems but other determinants were not considered. We have examined the role of pre-existing mental disorders and sociodemographics in explaining the predictive effects of violations using data from the US National Comorbidity Survey Replication (NCS-R).

The NCS-R is a nationally representative face-to-face household survey of 9282 English-speaking respondents aged 18 years and older that used the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) to assess DSM-IV mental and substance disorders. Drug initiation was estimated using retrospective age-of-onset reports and ‘violations’ defined as inconsistent with the normative initiation order. Predictors of violations were examined using multivariable logistic regressions. Discrete-time survival analysis was used to see whether violations predicted progression to dependence.

Gateway violations were largely unrelated to later dependence risk, with the exception of small increases in risk of alcohol and other illicit drug dependence for those who initiated use of other illicit drugs before cannabis. Early-onset internalizing disorders were predictors of gateway violations, and both internalizing and externalizing disorders increased the risks of dependence among users of all drugs.

Drug use initiation follows a strong normative pattern, deviations from which are not strongly predictive of later problems. By contrast, adolescents who have already developed mental health problems are at risk for deviations from the normative sequence of drug initiation and for the development of dependence.