Cornelis L. Mulder

A Genome-Wide Association Study of Depressive Symptoms

BACKGROUND Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). CONCLUSIONS The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

Anxiety disorders and salivary cortisol levels in older adults: a population-based study

CONTEXT The hypothalamic-pituitary-adrenal (HPA) axis is one of the bodys main systems that controls response to stress. It acts through the hormone cortisol. While the dysregulation of cortisol has been associated with anxiety disorders, the evidence is inconsistent. Moreover, only a few small studies have assessed this relationship in older adults. OBJECTIVE To determine whether in adults aged 65 years and over there is a difference in daily cortisol pattern between those with and without an anxiety disorder. METHODS The study population comprised 1788 older adults from a population-based cohort. The Munich version of the Composite International Diagnostic Interview was used to diagnose anxiety disorders (generalized anxiety disorder, social phobia, specific phobia, agoraphobia and panic disorder). The cortisol awakening response and total cortisol secretion over the day were calculated from cortisol levels in four saliva samples taken over the course of one day (at awakening, 30min after awakening, at 1700h, at bedtime). RESULTS Older adults with an anxiety disorder (n=145, median duration since first symptoms 41 years) had a lower cortisol awakening response (p=0.02) than those without such a disorder (n=1643). This association was most prominent in those with generalized anxiety disorder (p=0.008), but was not associated with the extent of chronicity of anxiety disorders. CONCLUSION Older adults from the general population with long-lasting anxiety disorders had a lower cortisol awakening response than those without. This is consistent with the notion that chronic anxiety may result in downregulation of HPA-axis activity. Longitudinal studies are needed to confirm this mechanism.

Meta-analysis of genome-wide association studies of anxiety disorders

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat–response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case–control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10−8); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.

The PCLO gene and depressive disorders: replication in a population-based study

Previous genome-wide association analysis revealed a new putative candidate gene for major depression: the PCLO gene. Replication in one population-based cohort did not yield genome-wide significance and further replication efforts in clinical studies were unsuccessful. We aimed to validate the association of single-nucleotide polymorphism (SNP) rs2522833 in the PCLO gene with depression in the Rotterdam Study, a prospective population-based cohort of elderly persons. In the Rotterdam Study, we identified 579 persons with a broad depression phenotype (depressive syndromes) of whom 178 cases with DSM-defined depressive disorder. The control group consisted of 912 persons free of depression during the follow-up period and in their histories. Logistic regression analysis showed an association between rs2522833 and depressive disorders (P = 0.0025). However, no association between the broader depressive syndrome group and this SNP was observed (P = 0.20). A meta-analysis combining all studies from the original publication and our study yielded a P-value of 2.16 x 10(-3) for the association between SNP rs2522833 and depressive disorders. However, as in the previous publication, high heterogeneity between studies was observed. Thus, a meta-analysis with the findings from three population-based studies was performed. This demonstrated a genome-wide significant P-value (P = 1.93 x 10(-9)). In conclusion, this study provides additional evidence for an association between PCLO and depressive disorders in a population-based study; no association with a broader syndromal phenotype was observed.

Evaluation of behavioral changes and subjective distress after exposure to coercive inpatient interventions

BackgroundThere is a lack of evidence to underpin decisions on what constitutes the most effective and least restrictive form of coercive intervention when responding to violent behavior. Therefore we compared ratings of effectiveness and subjective distress by 125 inpatients across four types of coercive interventions.MethodsEffectiveness was assessed through ratings of patient behavior immediately after exposure to a coercive measure and 24 h later. Subjective distress was examined using the Coercion Experience Scale at debriefing. Regression analyses were performed to compare these outcome variables across the four types of coercive interventions.ResultsUsing univariate statistics, no significant differences in effectiveness and subjective distress were found between the groups, except that patients who were involuntarily medicated experienced significant less isolation during the measure than patients who underwent combined measures. However, when controlling for the effect of demographic and clinical characteristics, significant differences on subjective distress between the groups emerged: involuntary medication was experienced as the least distressing overall and least humiliating, caused less physical adverse effects and less sense of isolation. Combined coercive interventions, regardless of the type, caused significantly more physical adverse effects and feelings of isolation than individual interventions.ConclusionsIn the absence of information on individual patient preferences, involuntary medication may be more justified than seclusion and mechanical restraint as a coercive intervention. Use of multiple interventions requires significant justification given their association with significant distress.

Reconstructing continuity of care in mental health services: a multilevel conceptual framework.

Continuity of mental health care is a key issue in the organization and evaluation of services for patients with disabling chronic conditions. Over many years, health services researchers have been exploring the conceptual boundaries between continuity of care and other service characteristics. On the basis of papers published over the past decade, we argue that while conceptual consensus is growing, there is room to improve continuity measures, and the development of practical interventions is still at an early stage. There is growing consensus that continuity of care is a multidimensional concept. We identified four core elements: continuous care; care of an individual patient; cross-boundary care; and care recorded objectively. These elements help clarify conceptual boundaries, and incorporate measurement guidelines. With reference to these core elements, we define types of continuity of care, including informational continuity, management continuity, relational continuity and contact continuity. In order to improve continuity of care, better understanding is needed of the complex inter-relationship of core elements and types of continuity. A multilevel perspective on continuity of care can guide research to develop and evaluate new interventions. Achieving continuity of care is hindered by the lack of standard measures and administrative data appropriate to assessing continuity. Account should be taken not only of the nature of the patient population, but also of local conditions. To address these topics and identify best practices, research should be multidisciplinary and take a comparative, naturalistic form.

Methodological issues in monitoring the use of coercive measures

PURPOSE In many European countries, initiatives have emerged to reduce the use of seclusion and restraint in psychiatric institutions. To study the effects of these initiatives at a national and international level, consensus on definitions of coercive measures, assessment methods and calculation procedures of these coercive measures are required. The aim of this article is to identify problems in defining and recording coercive measures. The study contributes to the development of consistent comparable measurements definitions and provides recommendations for meaningful data-analyses illustrating the relevance of the proposed framework. METHODS Relevant literature was reviewed to identify various definitions and calculation modalities used to measure coercive measures in psychiatric inpatient care. Figures on the coercive measures and epidemiological ratios were calculated in a standardized way. To illustrate how research in clinical practice on coercive measures can be conducted, data from a large multicenter study on seclusion patterns in the Netherlands were used. RESULTS Twelve Dutch mental health institutes serving a population of 6.57 million inhabitants provided their comprehensive coercion measure data sets. In total 37 hospitals and 227 wards containing 6812 beds were included in the study. Overall seclusion and restraint data in a sample of 31,594 admissions in 20,934 patients were analyzed. Considerable variation in ward and patient characteristics was identified in this study. The chance to be exposed to seclusion per capita inhabitants of the institutes catchment areas varied between 0.31 and 1.6 per 100.000. Between mental health institutions, the duration in seclusion hours per 1000 inpatient hours varied from less than 1 up to 18h. The number of seclusion incidents per 1000 admissions varied between 79 up to 745. The mean duration of seclusion incidents of nearly 184h may be seen as high in an international perspective. CONCLUSION Coercive measures can be reliably assessed in a standardized and comparable way under the condition of using clear joint definitions. Methodological consensus between researchers and mental health professionals on these definitions is necessary to allow comparisons of seclusion and restraint rates. The study contributes to the development of international standards on gathering coercion related data and the consistent calculation of relevant outcome parameters.

Criminal Victimisation in People with Severe Mental Illness : A Multi-Site Prevalence and Incidence Survey in the Netherlands

Background Although crime victimisation is as prevalent in psychiatric patients as crime perpetration (and possibly more so), few European figures for it are available. We therefore assessed its one-year prevalence and incident rates in Dutch severely mentally ill outpatients, and compared the results with victimisation rates in the general population. Method This multisite epidemiological survey included a random sample of 956 adult severely mentally ill outpatients. Data on victimisation were obtained using the victimisation scale of the Dutch Crime and Victimisation Survey, which assesses crime victimisation over the preceding 12 months. Comparison data were derived from the nationwide survey on safety and victimisation in the Netherlands. Prevalence and incident rates were weighted for sex, age, ethnicity and socioeconomic status, and compared with a general population sample matched by region (N = 38,227). Results In the past year, almost half of the severely mentally ill outpatients (47%) had been victim of a crime. After control for demographic differences, prevalence rates of overall and specific victimisation measures were significantly higher in severely mentally ill outpatients than in the general population. The relative rates were especially high for personal crimes such as violent threats (RR = 2.12, 95% CI: 1.72–2.61), physical assaults (RR = 4.85, 95% CI: 3.69–6.39) and sexual harassment and assaults (RR = 3.94, 95% CI: 3.05–5.09). In concordance, severely mentally ill outpatients reported almost 14 times more personal crime incidents than persons from the general population (IRR = 13.68, 95% CI: 12.85–14.56). Conclusion Crime victimisation is a serious problem in Dutch severely mentally ill outpatients. Mental-healthcare institutions and clinicians should become aware of their patients’ victimisation risk, and should implement structural measures to detect and prevent (re-)victimisation.

Patients’ Preference and Experiences of Forced Medication and Seclusion

This study examined patients’ preferences for coercive methods and the extent to which patients’ choices were determined by previous experience, demographic, clinical and intervention-setting variables. Before discharge from closed psychiatric units, 161 adult patients completed a questionnaire. The association between patients’ preferences and the underlying variables was analyzed using logistic regression. We found that patients’ preferences were mainly defined by earlier experiences: patients without coercive experiences or who had had experienced seclusion and forced medication, favoured forced medication. Those who had been secluded preferred seclusion in future emergencies, but only if they approved its duration. This suggests that seclusion, if it does not last too long, does not have to be abandoned from psychiatric practices. In an emergency, however, most patients prefer to be medicated. Our findings show that patients’ preferences cannot guide the establishment of international uniform methods for managing violent behaviour. Therefore patients’ individual choices should be considered.

Consumer-Providers in Assertive Community Treatment Programs: Associations With Client Outcomes

OBJECTIVE This study examined whether employing mental health consumers as consumer-providers in assertive community treatment teams can enhance outcomes for clients with severe mental illness. METHODS In a prospective longitudinal study, presence of consumer-providers and outcomes of 530 clients with severe mental illness in 20 outpatient teams were assessed at baseline and at one-year and two-year follow-ups. Measures included the Health of the Nation Outcome Scales (HoNOS), the Camberwell Assessment of Need Short Assessment Schedule (CANSAS), the Working Alliance Scale, the number of hospital days, and the number of days of homelessness. Multilevel regression was used with the independent variables consumer-provider presence, time of measurement, and their interaction. RESULTS A positive association was found between consumer-provider presence and improvements in functioning on the HoNOS (p = .020), met needs in relation to personal recovery (p=.044), unmet needs in relation to personal recovery (p = .008), and number of homeless days (p<.001). A negative association was found for consumer-provider presence and the number of hospital days (p = .019). CONCLUSIONS Consumer-providers are important participants in outpatient teams serving clients with severe mental illnesses, although integrating these providers as part of a team is a slow process.