Studies comparing cases with controls to uncover the causes of psychiatric disorders are common in biological research. The validity of these studies depends upon adherence to the methodological principles underlying the case-control design. However, these principles are often violated. One common practice that violates these principles is the use of well controls. In this paper we describe the bias that it can cause and discuss why the use of well controls leads to invalidity in case-control studies.

Using hypothetical numerical examples we illustrate the consequences of using well controls.

The results illustrate that the use of well controls can cause substantial bias. In no instance does the use of well controls improve validity.

We conclude that the use of well controls is an unhealthy practice in psychiatric research.

National Guard troops are at increased risk for post-traumatic stress disorder (PTSD); however, little is known about risk and resilience in this population.

The Readiness and Resilience in National Guard Soldiers Study is a prospective, longitudinal investigation of 522 Army National Guard troops deployed to Iraq from March 2006 to July 2007. Participants completed measures of PTSD symptoms and potential risk/protective factors 1 month before deployment. Of these, 81% (n=424) completed measures of PTSD, deployment stressor exposure and post-deployment outcomes 2–3 months after returning from Iraq. New onset of probable PTSD ‘diagnosis’ was measured by the PTSD Checklist – Military (PCL-M). Independent predictors of new-onset probable PTSD were identified using hierarchical logistic regression analyses.

At baseline prior to deployment, 3.7% had probable PTSD. Among soldiers without PTSD symptoms at baseline, 13.8% reported post-deployment new-onset probable PTSD. Hierarchical logistic regression adjusted for gender, age, race/ethnicity and military rank showed that reporting more stressors prior to deployment predicted new-onset probable PTSD [odds ratio (OR) 2.20] as did feeling less prepared for deployment (OR 0.58). After accounting for pre-deployment factors, new-onset probable PTSD was predicted by exposure to combat (OR 2.19) and to combat's aftermath (OR 1.62). Reporting more stressful life events after deployment (OR 1.96) was associated with increased odds of new-onset probable PTSD, while post-deployment social support (OR 0.31) was a significant protective factor in the etiology of PTSD.

Combat exposure may be unavoidable in military service members, but other vulnerability and protective factors also predict PTSD and could be targets for prevention strategies.

Social dysfunction is a hallmark symptom of schizophrenia which commonly precedes the onset of psychosis. It is unclear if social symptoms in clinical high-risk patients reflect depressive symptoms or are a manifestation of negative symptoms.

We compared social function scores on the Social Adjustment Scale-Self Report between 56 young people (aged 13–27 years) at clinical high risk for psychosis and 22 healthy controls. The cases were also assessed for depressive and ‘prodromal’ symptoms (subthreshold positive, negative, disorganized and general symptoms).

Poor social function was related to both depressive and negative symptoms, as well as to disorganized and general symptoms. The symptoms were highly intercorrelated but linear regression analysis demonstrated that poor social function was primarily explained by negative symptoms within this cohort, particularly in ethnic minority patients.

Although this study demonstrated a relationship between social dysfunction and depressive symptoms in clinical high-risk cases, this association was primarily explained by the relationship of each of these to negative symptoms. In individuals at heightened risk for psychosis, affective changes may be related to a progressive decrease in social interaction and loss of reinforcement of social behaviors. These findings have relevance for potential treatment strategies for social dysfunction in schizophrenia and its risk states and predict that antidepressant drugs, cognitive behavioral therapy and/or social skills training may be effective.

Generalizability of antidepressant efficacy trials (AETs) to daily practice is questioned because of their very stringent patient selection. This study aims to determine eligibility for AETs of out-patients suffering from major depression in a routine out-patient setting and investigates influence of eligibility on treatment outcome.

Data collection (n=1653) was performed through routine outcome monitoring by independent trained research nurses. The Mini-International Neuropsychiatric Interview Plus and the Dimensional Assessment of Personality Pathology, short Dutch version were used for diagnostic assessment and personality pathology screening. The Montgomery–Asberg Depression Rating Scale (MADRS) was used for assessment of baseline severity and treatment outcome. Eligibility was assessed by stepwise application of commonly used exclusion criteria. Influence of eligibility on treatment outcome was investigated in a subsample of the 1653 patients who had at least one follow-up assessment (n=626). Eligible and non-eligible patients were compared on proportion of response (50% reduction) and remission on MADRS (MADRS⩽10).

Altogether, 17–25% of the patients were eligible for AETs. The most common reasons for exclusion would be ‘not meeting minimum baseline severity’ and ‘presence of co-morbid Axis I disorder’. Eligible and non-eligible patients did not differ in treatment outcome. Only ‘meeting the minimum baseline severity’ is associated with remission.

The majority of ‘real life’ out-patients are not eligible for AETs. However, the influence of eligibility on treatment outcome seems to be small. This suggests that stringent patient selection by eligibility criteria is not the major reason for lack of generalizability of AETs. Exclusion of less severely depressed patients from the analyses resulted in better treatment outcome. Milder depression is highly prevalent in daily practice and more research into treatment effectiveness in milder depression is warranted.

The peak in age of onset of psychotic disorders such as schizophrenia during puberty and early adulthood suggests a relationship between the expression of psychopathology and the changes in the brain and body that take place during this dynamic maturational period, including a dramatic increase in circulating oestrogens and androgens. This study examined levels of salivary testosterone and oestradiol in adolescents with prepsychotic, prodromal symptoms, as this may mediate risk for psychosis by having an impact on brain development.

In 21 male adolescents with prodromal symptoms and 21 male non-clinical controls levels of testosterone and oestradiol were measured in saliva. Tanner pubertal stage and prodromal symptoms were also assessed.

Levels of testosterone were significantly lower in adolescents with prodromal symptoms as compared with non-clinical controls. No group differences in oestradiol were found. In the total sample, level of testosterone was significantly correlated with age and Tanner pubertal stage.

Our observations are in line with current hypotheses stressing the role of neuroendocrine factors during adolescence in the expression of psychotic symptoms. From a developmental perspective, susceptibility to psychotic disorders increases during adolescence. Our data suggest that testosterone might, in part, mediate this increased vulnerability. Further research is needed to assess the mediating, neural, mechanisms through which testosterone may have an impact on the development of psychotic symptoms. In the search for early risk markers for psychosis, studying neuroendocrine factors might increase our understanding of ‘at-risk’ developmental pathways.

Although long working hours are common in working populations, little is known about the effect of long working hours on mental health.

We examined the association between long working hours and the onset of depressive and anxiety symptoms in middle-aged employees. Participants were 2960 full-time employees aged 44 to 66 years (2248 men, 712 women) from the prospective Whitehall II cohort study of British civil servants. Working hours, anxiety and depressive symptoms, and covariates were measured at baseline (1997–1999) followed by two subsequent measurements of depressive and anxiety symptoms (2001 and 2002–2004).

In a prospective analysis of participants with no depressive (n=2549) or anxiety symptoms (n=2618) at baseline, Cox proportional hazard analysis adjusted for baseline covariates showed a 1.66-fold [95% confidence interval (CI) 1.06–2.61] risk of depressive symptoms and a 1.74-fold (95% CI 1.15–2.61) risk of anxiety symptoms among employees working more than 55 h/week compared with employees working 35–40 h/week. Sex-stratified analysis showed an excess risk of depression and anxiety associated with long working hours among women [hazard ratios (HRs) 2.67 (95% CI 1.07–6.68) and 2.84 (95% CI 1.27–6.34) respectively] but not men [1.30 (0.77–2.19) and 1.43 (0.89–2.30)].

Working long hours is a risk factor for the development of depressive and anxiety symptoms in women.

Designed as state measures to monitor treatment response, symptoms of anxiety and depression (SxAnxDep) also have trait-like characteristics. No comprehensive etiologic model for SxAnxDep has illuminated the inter-relationship between their state- and trait-like characteristics, while including key predictor variables.

In a prospective three-wave study of 2395 female twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD), we examined, using structural equation modeling, how genes, childhood and past-year environmental stressors, personality and episodes of major depression (MD) and generalized anxiety disorder (GAD) influence SxAnxDep.

The best-fit model, which explained 68–74% of the variance in SxAnxDep, revealed two etiologic pathways. Stable levels of SxAnxDep resulted largely from neuroticism, which in turn was influenced by genetic and early environment risk factors. Occasion-specific influences resulted from stressful events mediated through episodes of MD or GAD. These two pathways, which had approximately equal influences on levels of SxAnxDep, were substantially correlated because the genetic, early environmental and personality factors that impacted on stable symptom levels also predisposed to event exposure and disorder onset. No significant interaction was seen between the two pathways.

SxAnxDep in women in the general population arise from two inter-related causal pathways. The first, the ‘trait-like’ pathway, reflects genetic and early environmental risk factors, and is mediated largely through personality. The second pathway is mediated through episodes of MD and GAD, and is the result of both recent environmental adversities and trait-like factors that influence event exposure and the probability of disorder onset.

Previous research reported that childhood adversity predicts juvenile- onset but not adult-onset depression, but studies confounded potentially genuine differences in adversity with differences in the recency with which adversity was experienced. The current study paper took into account the recency of risk when testing for differences among child-, adolescent- and young adult-onset depressions.

Up to nine waves of data were used per subject from two cohorts of the Great Smoky Mountains Study (GSMS; n=1004), covering children in the community aged 9–16, 19 and 21 years. Youth and one of their parents were interviewed using the Child and Adolescent Psychiatric Assessment (CAPA) between ages 9 and 16; these same youth were interviewed using the Young Adult Psychiatric Assessment (YAPA) at ages 19 and 21. The most common psychosocial risk factors for depression were assessed: poverty, life events, parental psychopathology, maltreatment, and family dysfunction.

Consistent with previous research, most childhood psychosocial risk factors were more strongly associated with child-onset than with adolescent-/adult-onset depression. When potentially genuine risk differences among the depression-onset groups were disentangled from differences due to the recency of risk, child- and young adult-onset depression were no longer different from one another. Adolescent-onset depression was associated with few psychosocial risk factors.

There were no differences in putative risk factors between child- and young adult-onset depression when the recency of risk was taken into account. Adolescent-onset depression was associated with few psychosocial risk factors. It is possible that some adolescent-onset depression cases differ in terms of risk from child- and young adult-onset depression.

Cognitive impairment, particularly in memory and executive function, is a core feature of psychosis. Moreover, psychosis is characterized by a more prominent history of stress exposure, and by dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. In turn, stress exposure and abnormal levels of the main HPA axis hormone cortisol are associated with cognitive impairments in a variety of clinical and experimental samples; however, this association has never been examined in first-episode psychosis (FEP).

In this study, 30 FEP patients and 26 controls completed assessment of the HPA axis (cortisol awakening response and cortisol levels during the day), perceived stress, recent life events, history of childhood trauma, and cognitive function. The neuropsychological battery comprised general cognitive function, verbal and non-verbal memory, executive function, perception, visuospatial abilities, processing speed, and general knowledge.

Patients performed significantly worse on all cognitive domains compared to controls. In patients only, a more blunted cortisol awakening response (that is, more abnormal) was associated with a more severe deficit in verbal memory and processing speed. In controls only, higher levels of perceived stress and more recent life events were associated with a worse performance in executive function and perception and visuospatial abilities.

These data support a role for the HPA axis, as measured by cortisol awakening response, in modulating cognitive function in patients with psychosis; however, this association does not seem to be related to the increased exposure to psychosocial stressors described in these patients.

Acute stress disorder involves prominent symptoms of threat avoidance. Preliminary cross-sectional data suggest that such threat-avoidance symptoms may also manifest cognitively, as attentional threat avoidance. Confirming these findings in a longitudinal study might provide insights on risk prediction and anxiety prevention in traumatic exposures.

Attention-threat bias and post-traumatic symptoms were assessed in soldiers at two points in time: early in basic training and 23 weeks later, during advanced combat training. Based on random assignment, the timing of the repeat assessment occurred in one of two schedules: for a combat simulation group, the repeat assessment occurred immediately following a battlefield simulation exercise, and for a control group, the assessment occurred shortly before this exercise.

Both groups showed no threat-related attention bias at initial assessments. Following acute stress, the combat simulation group exhibited a shift in attention away from threat whereas the control group showed no change in attention bias. Stronger threat avoidance in the combat simulation group correlated with severity of post-traumatic symptoms. Such an association was not found in the control group.

Acute stress may lead some individuals to shift their attention away from threats, perhaps to minimize stress exposure. This acute attention response may come at a psychological cost, given that it correlates with post-traumatic stress disorder (PTSD) symptoms. Further research is needed to determine how these associations relate to full-blown PTSD in soldier and civilian populations.

The aim of this study was to develop empirically validated criteria for the diagnoses of clinically relevant somatization.

This study was performed in a population-representative cohort consisting of 461 males (47.8%) and 503 females (52.2%), with an average age of 55.8 years (s.d.=11.1). Somatization, anxiety and depression were derived from the Composite International Diagnostic Interview. Mplus was used to perform confirmative factor analyses on the current DSM-IV symptom groups; on alternative symptom clusters previously suggested; and to perform latent class analysis in order to define an empirically derived cut-off for somatization.

The existence of symptom groups as described in DSM-IV was not supported by our data, whereas a differentiation between cardiopulmonary, musculoskeletal, gastrointestinal and general somatic symptoms did fit our data. Latent class analysis revealed two classes characterized by few (n=859) and many (n=105) symptoms. The class of subjects could be approached by a simple cut-off of four functional symptoms (sensitivity 79%, specificity 98%, positive predictive value 82%, negative predictive value 97%) regardless of the number of organ systems involved.

This study in a large population-representative cohort suggests that a simple symptom count can be used as a dimensional diagnosis of somatization. In those instances in which a categorical diagnosis is preferred, a simple cut-off of four out of 43 functional symptoms best fitted our data. We did not find any added value for incorporating the number of symptom clusters into the diagnostic criteria.

Some personality characteristics have previously been associated with an increased risk for psychiatric disorder. Longitudinal studies are required in order to tease apart temporary (state) and enduring (trait) differences in personality among individuals with bipolar disorder (BD). This study aimed to determine whether there is a characteristic personality profile in BD, and whether associations between BD and personality are best explained by state or trait effects.

A total of 2247 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder study completed the NEO Five-Factor Inventory administered at study entry, and at 1 and 2 years.

Personality in BD was characterized by high neuroticism (N) and openness (O), and low agreeableness (A), conscientiousness (C) and extraversion (E). This profile was replicated in two independent samples, and openness was found to distinguish BD from major depressive disorder. Latent growth modeling demonstrated that manic symptoms were associated with increased E and decreased A, and depressed symptoms with higher N and lower E, A, C and O. During euthymic phases, high N and low E scores predicted a future depression-prone course.

While there are clear state effects of mood on self-reported personality, personality variables during euthymia predict future course of illness. Personality disturbances in extraversion, neuroticism and openness may be enduring characteristics of patients with BD.

Paranoia is an unregarded but pervasive attribute of human populations. In this study we carried out the most comprehensive investigation so far of the demographic, economic, social and clinical correlates of self-reported paranoia in the general population.

Data weighted to be nationally representative were analysed from the Adult Psychiatric Morbidity Survey in England (APMS 2007; n=7281).

The prevalence of paranoid thinking in the previous year ranged from 18.6% reporting that people were against them, to 1.8% reporting potential plots to cause them serious harm. At all levels, paranoia was associated with youth, lower intellectual functioning, being single, poverty, poor physical health, poor social functioning, less perceived social support, stress at work, less social cohesion, less calmness, less happiness, suicidal ideation, a great range of other psychiatric symptoms (including anxiety, worry, phobias, post-traumatic stress and insomnia), cannabis use, problem drinking and increased use of treatment and services.

Overall, the results indicate that paranoia has the widest of implications for health, emotional well-being, social functioning and social inclusion. Some of these concomitants may contribute to the emergence of paranoid thinking, while others may result from it.

The suicide rate is higher in prisoners compared with the general population. The aim was to describe the characteristics of and longitudinal trends in prisoner suicides in England and Wales.

A case series was ascertained from the Safer Custody and Offender Policy Group at the Ministry of Justice and included a 9-year (1999–2007) national census of prisoner suicides. Questionnaires were completed by prison staff on sociodemographic, custodial, clinical and service-level characteristics of the suicides.

There was a fall in the number of prison suicides and a decline in the proportion of young prisoner (18–20 years) suicides over time. Females were over-represented. Upward trends were found in prisoners with a history of violence and with previous mental health service contact. A downward trend was found in those with a primary psychiatric diagnosis of drug dependence. Drug dependence was found to be significant in explaining suicides within the first week of custody.

The findings provide an important insight to aid a target set in the National Suicide Prevention Strategy in England to reduce suicides in the prisoner population by 20% and highlight an important area for policy development in mental health services. Examining trends identified subgroups that may require improved mental healthcare and recognized those that appeared to be having their treatment needs more adequately met. Evidence suggests that targeted suicide prevention strategies for subgroups of prisoners are required.

Deficits in face emotion recognition (FER) in schizophrenia are well documented, and have been proposed as a potential intermediate phenotype for schizophrenia liability. However, research on the relationship between psychosis vulnerability and FER has mixed findings and methodological limitations. Moreover, no study has yet characterized the relationship between FER ability and level of psychosis-proneness. If FER ability varies continuously with psychosis-proneness, this suggests a relationship between FER and polygenic risk factors.

We tested two large internet samples to see whether psychometric psychosis-proneness, as measured by the Schizotypal Personality Questionnaire-Brief (SPQ-B), is related to differences in face emotion identification and discrimination or other face processing abilities.

Experiment 1 (n=2332) showed that psychosis-proneness predicts face emotion identification ability but not face gender identification ability. Experiment 2 (n=1514) demonstrated that psychosis-proneness also predicts performance on face emotion but not face identity discrimination. The tasks in Experiment 2 used identical stimuli and task parameters, differing only in emotion/identity judgment. Notably, the relationships demonstrated in Experiments 1 and 2 persisted even when individuals with the highest psychosis-proneness levels (the putative high-risk group) were excluded from analysis.

Our data suggest that FER ability is related to individual differences in psychosis-like characteristics in the normal population, and that these differences cannot be accounted for by differences in face processing and/or visual perception. Our results suggest that FER may provide a useful candidate intermediate phenotype.

Despite international concern about unregulated predictive genetic testing, there are surprisingly few data on both the determinants of community interest in such testing and its psychosocial impact.

A large population-based public survey with community-dwelling adults (n=1046) ascertained through random digit dialling. Attitudes were assessed by structured interviews.

The study found strong interest in predictive genetic testing for a reported susceptibility to depression. Once the benefits and disadvantages of such testing had been considered, there was significantly greater interest in seeking such a test through a doctor (63%) compared to direct-to-consumer (DTC; 40%) (p<0.001). Personal history of mental illness [odds ratio (OR) 2.58, p<0.001], self-estimation of being at higher than average risk for depression (OR 1.92, p<0.001), belief that a genetic component would increase rather than decrease stigma (OR 1.62, p<0.001), and endorsement of benefits of genetic testing (OR 3.47, p<0.001) significantly predicted interest in having such a test.

Despite finding attitudes that genetic links to mental illness would increase rather than decrease stigma, we found strong community acceptance of depression risk genotyping, even though a predisposition to depression may only manifest upon exposure to stressful life events. Our results suggest that there will be a strong demand for predictive genetic testing.