A.M. van Hemert

The association between low vitamin D and depressive disorders

It has been hypothesized that hypovitaminosis D is associated with depression but epidemiological evidence is limited. We investigated the association between depressive disorders and related clinical characteristics with blood concentrations of 25-hydroxyvitamin D [25(OH)D] in a large cohort. The sample consisted of participants (aged 18–65 years) from the Netherlands Study of Depression and Anxiety (NESDA) with a current (N=1102) or remitted (N=790) depressive disorder (major depressive disorder, dysthymia) defined according to DSM-IV criteria, and healthy controls (N=494). Serum levels of 25(OH)D measured and analyzed in multivariate analyses adjusting for sociodemographics, sunlight, urbanization, lifestyle and health. Of the sample, 33.6% had deficient or insufficient serum 25(OH)D (<50 nmol l−1). As compared with controls, lower 25(OH)D levels were found in participants with current depression (P=0.001, Cohen’s d=0.21), particularly in those with the most severe symptoms (P=0.001, Cohen’s d=0.44). In currently depressed persons, 25(OH)D was inversely associated with symptom severity (β=−0.19, s.e.=0.07, P=0.003) suggesting a dose-response gradient, and with risk (relative risk=0.90, 95% confidence interval=0.82–0.99, P=0.03) of having a depressive disorders at 2-year follow-up. This large cohort study indicates that low levels of 25(OH)D were associated to the presence and severity of depressive disorder suggesting that hypovitaminosis D may represent an underlying biological vulnerability for depression. Future studies should elucidate whether—the highly prevalent—hypovitaminosis D could be cost-effectively treated as part of preventive or treatment interventions for depression.

Unexplained physical symptoms: outcome, utilization of medical care and associated factors

The aim of the study was to investigate the recovery and frequency of physician contact in patients with unexplained physical symptoms and to identify factors associated with persistent disorder. Of 100 consecutive patients who presented with medically unexplained symptoms to a general medical out-patient clinic, 81 participated in a follow-up study. The mean follow-up time was 15.2 months (S.D. 4.0). At follow-up, many of the patients with unexplained physical symptoms reported that they had recovered (30%) or improved (46%) with regard to their presenting symptoms. Female sex and a high number of symptoms predicted a bad outcome in terms of recovery. Persistence of symptoms was not related to the duration of the symptoms, type of presenting complaint or the presence of psychiatric disorder. Forty per cent of patients with unexplained symptoms did not visit their general practitioner on their own initiative in the year following the initial visit to the clinic. Medical care utilization appeared to be associated with female sex, age, number and duration of symptoms, fatigue and psychiatric disorder, especially somatoform disorders. However, the association of a high frequency of physician contact with female sex and psychiatric disorder was not sustained after controlling for possible confounding factors.

The diagnostic and prognostic significance of the Whitely Index, the Illness Attitude Scales and the Somatosensory Amplification Scale

The aim of this study was to assess the ability of the Whitely Index, Illness Attitude Scales and Somatosensory Amplification Scale to differentiate in patients with medically unexplained physical symptoms between hypochondriacal and non-hypochondriacal patients and to examine whether the scores on these questionnaires are predictive of long-term outcome in terms of recovery of presenting symptoms and number of visits to the general practitioner. The study population consisted of 183 consecutive patients, who presented with medically unexplained physical symptoms to a general medical out-patient clinic. The Health Anxiety subscale of the Illness Attitude Scales and the Whitely Index were best in discriminating between hypochondriacal and non-hypochondriacal patients. The sensitivity and specificity of the Health Anxiety subscale of the Illness Attitude Scales were 79% and 84%, and of the Whitely Index 87% and 72%. The Whitely Index was negatively associated with recovery rate at 1 year follow-up. The Illness Behaviour subscale of the Illness Attitude Scales appeared to be predictive of the number of visits to the general practitioner. These findings might have clinical implications in helping to distinguish in patients with medically unexplained symptoms those for whom there is a high chance of persistence of the symptoms and/or of high medical care utilization.

The Reassurance Questionnaire (RQ): psychometric properties of a self-report questionnaire to assess reassurability

BACKGROUND The aim of this study was to develop a questionnaire that assessed the extent to which patients usually feel reassured by their attending physician. METHODS The study population consisted of 204 subjects from the general population, 113 general practice patients, 130 general medical out-patients and 183 general medical patients with unexplained physical symptoms participating in an intervention study on the effect of cognitive behavioural therapy. RESULTS Factor analysis yielded a one-factor solution. The internal consistency was moderate to high and the test-retest reliability was high. The convergent validity of the Reassurance Questionnaire (RQ) was satisfactory to good, but the scores on the RQ did not appear to differentiate between the general population, general practice patients and general medical out-patients. In medical out-patients with unexplained physical symptoms, the RQ discriminated well between hypochondriacal and non-hypochondriacal patients. Scores on the RQ tended to be associated with a bad outcome in terms of recovery of presenting symptoms at 1 year follow-up. There was no association between scores on the RQ and frequency of physician contact. In patients with unexplained physical symptoms treated with cognitive behavioural therapy, scores on the RQ decreased over a period of 6 months and 1 year. CONCLUSIONS The RQ was demonstrated to have psychometrically sound properties and appeared to be a useful instrument to assess reassurability in medical patients.

Somatoform disorders in consultation-liaison psychiatry: a comparison with other mental disorders

Consultation-liaison (C-L) psychiatry has an important role in the management of somatoform disorders (SD). Characteristics of SD patients in C-L psychiatry are largely unknown and are presented in this paper. We analyzed 13,314 Dutch psychiatric consultations from 1984 to 1991 and compared patients diagnosed with SD to patients with other mental disorders and to those without a mental disorder. The comparison included socio-demographic variables, consult characteristics, medical history, current somatic morbidity, information about additional diagnostic tests, hospital admission time and aftercare management. Of the 544 SD patients 39.5% (n = 215) were diagnosed with a conversion disorder that illustrates the highly selected nature of SD patients in C-L psychiatry. Employment among SD patients decreased significantly from 58% in the group aged 20-29 years to 6% in the group aged 50-59 years. This decrease was significantly larger as compared to other mental disorders and no mental disorders and was virtually unaffected by correction for potential confounding by gender. Contrary to our expectation no difference between the three groups was observed in claims for disability benefits. Of the SD patients 74.5% were referred for aftercare management, significantly more than the other two groups which is considered a promising development in C-L psychiatry.

Six-year longitudinal course and outcomes of subtypes of depression

BACKGROUND Clinical and aetiological heterogeneity have impeded our understanding of depression. AIMS To evaluate differences in psychiatric and somatic course between people with depression subtypes that differed clinically (severity) and aetiologically (melancholic v. atypical). METHOD Data from baseline, 2-, 4- and 6-year follow-up of The Netherlands Study of Depression and Anxiety were used, and included 600 controls and 648 people with major depressive disorder (subtypes: severe melancholic n = 308; severe atypical n = 167; moderate n = 173, established using latent class analysis). RESULTS Those with the moderate subtype had a significantly better psychiatric clinical course than the severe melancholic and atypical subtype groups. Suicidal thoughts and anxiety persisted longer in those with the melancholic subtype. The atypical subtype group continued to have the highest body mass index and highest prevalence of metabolic syndrome during follow-up, although differences between groups became less pronounced over time. CONCLUSIONS Course trajectories of depressive subtypes mostly ran parallel to each other, with baseline severity being the most important differentiator in course between groups.

Pathophysiology of major depressive disorder: mechanisms involved in etiology are not associated with clinical progression

Meta-analyses support the involvement of different pathophysiological mechanisms (inflammation, hypothalamic–pituitary (HPA)-axis, neurotrophic growth and vitamin D) in major depressive disorder (MDD). However, it remains unknown whether dysregulations in these mechanisms are more pronounced when MDD progresses toward multiple episodes and/or chronicity. We hypothesized that four central pathophysiological mechanisms of MDD are not only involved in etiology, but also associated with clinical disease progression. Therefore, we expected to find increasingly more dysregulation across consecutive stages of MDD progression. The sample from the Netherlands Study of Depression and Anxiety (18–65 years) consisted of 230 controls and 2333 participants assigned to a clinical staging model categorizing MDD in eight stages (0, 1A, 1B, 2, 3A, 3B, 3C and 4), from familial risk at MDD (stage 0) to chronic MDD (stage 4). Analyses of covariance examined whether pathophysiological mechanism markers (interleukin (IL)-6, C-reactive protein (CRP), cortisol, brain-derived neurotrophic factor and vitamin D) showed a linear trend across controls, those at risk for MDD (stages 0, 1A and 1B), and those with full-threshold MDD (stages 2, 3A, 3B, 3C and 4). Subsequently, pathophysiological differences across separate stages within those at risk and with full-threshold MDD were examined. A linear increase of inflammatory markers (CRP P=0.026; IL-6 P=0.090), cortisol (P=0.025) and decrease of vitamin D (P<0.001) was found across the entire sample (for example, from controls to those at risk and those with full-threshold MDD). Significant trends of dysregulations across stages were present in analyses focusing on at-risk individuals (IL-6 P=0.050; cortisol P=0.008; vitamin D P<0.001); however, no linear trends were found in dysregulations for any of the mechanisms across more progressive stages of full-threshold MDD. Our results support that the examined pathophysiological mechanisms are involved in MDD’s etiology. These same mechanisms, however, are less important in clinical progression from first to later MDD episodes and toward chronicity.

Mineralocorticoid receptor haplotype oral contraceptives and emotional information processing.

BACKGROUND Oral contraceptives (OCs) affect mood in some women and may have more subtle effects on emotional information processing in many more users. Female carriers of mineralocorticoid receptor (MR) haplotype 2 have been shown to be more optimistic and less vulnerable to depression. AIM To investigate the effects of oral contraceptives on emotional information processing and a possible moderating effect of MR haplotype. METHODS Cross-sectional study in 85 healthy premenopausal women of West-European descent. RESULTS We found significant main effects of oral contraceptives on facial expression recognition, emotional memory and decision-making. Furthermore, carriers of MR haplotype 1 or 3 were sensitive to the impact of OCs on the recognition of sad and fearful faces and on emotional memory, whereas MR haplotype 2 carriers were not. LIMITATIONS Different compounds of OCs were included. No hormonal measures were taken. Most naturally cycling participants were assessed in the luteal phase of their menstrual cycle. CONCLUSIONS Carriers of MR haplotype 2 may be less sensitive to depressogenic side-effects of OCs.

Genetic effects influencing risk for major depressive disorder in China and Europe

Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30–40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

Direct comparison of first-contact versus longitudinal register-based case finding in the same population: early evidence that the incidence of schizophrenia may be three times higher than commonly reported

BACKGROUND The incidence of schizophrenia is commonly estimated by screening for psychosis among subjects presenting to psychiatric services. This approach (using a first-contact sampling frame) cannot account for cases that did not meet criteria for schizophrenia at first contact. We compared the usual approach directly with a register-based approach (using a longitudinal sampling frame) that also includes subjects initially diagnosed with other non-schizophrenic disorders. METHOD We compared data from the Longitudinal Psychiatric Register (LPR) of The Hague over 1980-2009 with data previously collected in a first-contact study, and applied both methods to calculate the incidence of schizophrenia for subjects aged 20-54 years in the same catchment area and over the same period (October 2000 to September 2005). We reconstructed treatment pathways and diagnostic histories up to the end of 2009 and performed sensitivity analyses. RESULTS The LPR identified 843 first onsets of schizophrenia, corresponding to a treated incidence rate (IR) of 69 per 100,000 person-years [95% confidence interval (CI) 64-74]. The first-contact study identified 254 first onsets, corresponding to a treated IR of 21 per 100,000 person-years (95% CI 18-23). Two-thirds of the difference was accounted for by subjects treated for other disorders before the onset of psychosis, and by patients in older age groups. CONCLUSIONS The incidence of schizophrenia was three times higher in a longitudinal register study than in a high-quality first-contact study conducted in the same population. Risk estimates based only on first-contact studies may have been affected by selection bias.