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1.  Reconsidering the prognosis of major depressive disorder across diagnostic boundaries: full recovery is the exception rather than the rule 
BMC Medicine  2017;15:215.
Background
Major depressive disorder (MDD) is often handled as an episodic and isolated disorder, resulting in an optimistic view about its prognosis. Herein, we test the idea that the prognosis of MDD changes if we vary the perspective in terms of (1) a longer time frame and (2) a broader diagnostic conceptualisation including dysthymia, (hypo)mania and anxiety disorders as relevant outcomes.
Methods
Patients with current MDD at baseline (n = 903) and available 2-, 4-, and/or 6-year follow-up assessments were selected from the Netherlands Study of Depression and Anxiety, a psychiatric cohort study. Combining psychiatric DSM-IV-based diagnoses and life-chart data, patient course trajectories were classified as (1) recovered (no diagnoses at 2-year follow-up or thereafter), (2) recurrent without chronic episodes, (3) recurrent with chronic episodes or (4) consistently chronic since baseline. A chronic episode was defined as having a current diagnosis at the follow-up assessment and consistent symptoms over 2 years. Proportions of course trajectories were provided moving from a short, narrow perspective (2-year follow-up, considering only MDD diagnosis) to a long, broad perspective (6-year follow-up, including MDD, dysthymia, (hypo)mania and anxiety diagnoses).
Results
With the short, narrow perspective, the recovery rate was 58% and 21% had a chronic episode. However, in the long, broad perspective the recovery rate was reduced to 17%, while 55% of the patients experienced chronic episodes.
Conclusions
Results from a long and rigorous follow-up in a large cohort suggests that most MDD patients have an unfavourable prognosis. Longer follow-up and broader diagnostic conceptualisation show that the majority of patients have a disabling and chronic disorder. Conceptualising and handling MDD as a narrowly defined and episodic disorder may underestimate the prognosis of the majority of depressed patients and, consequently, the type of care that is appropriate.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-017-0972-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-017-0972-8
PMCID: PMC5725897  PMID: 29228943
Major depressive disorder; Affective disorder; Anxiety disorder; Course; Prognosis; Longitudinal; Comorbidity
2.  The association between herpes virus infections and functional somatic symptoms in a general population of adolescents. The TRAILS study 
PLoS ONE  2017;12(10):e0185608.
Background
FSS have been suggested to follow activation of the immune system, triggered by herpes virus infections. The aim of this study was to find out whether herpes virus infections were associated with the experience of FSS in adolescents, and whether this association was mediated by hsCRP, as a general marker of immune activation.
Methods
This study was performed in TRAILS, a large prospective population cohort of 2230 adolescents (mean age: 16.1 years, SD = .66, 53.4% girls). FSS were assessed using the somatic complaints subscale of the Youth Self-Report. FSS were analyzed as total scores and divided in two group clusters based on previous studies in this cohort. Levels of hsCRP and antibody levels to the herpes viruses HSV1, HSV2, CMV, EBV and HHV6 were assessed in blood samples at age 16. Also a value for pathogen burden was created adding the number of viruses the adolescents were seropositive for. Multiple regression analysis with bootstrapping was used to analyze the association between viral antibodies and pathogen burden, hsCRP and FSS scores.
Results
Antibody levels and pathogen burden were not associated with FSS total scores or FSS scores in both symptom groups. hsCRP was associated with the total FSS score (B = .02, 95% CI: .004 to .028, p = .01) and FSS score in the symptom group of headache and gastrointestinal complaints (B = .02, 95% CI: .001 to .039, p = .04).
Conclusion
Our study showed no association between herpes virus infections and FSS in general or specific FSS symptom clusters. A role for inflammatory processes in FSS development was supported by the significant association we found between hsCRP levels and FSS, especially in the symptom group of headache and gastrointestinal complaints.
doi:10.1371/journal.pone.0185608
PMCID: PMC5646771  PMID: 29045430
3.  Mouse repeated electroconvulsive seizure (ECS) does not reverse social stress effects but does induce behavioral and hippocampal changes relevant to electroconvulsive therapy (ECT) side-effects in the treatment of depression 
PLoS ONE  2017;12(9):e0184603.
Electroconvulsive therapy (ECT) is an effective treatment for depression, but can have negative side effects including amnesia. The mechanisms of action underlying both the antidepressant and side effects of ECT are not well understood. An equivalent manipulation that is conducted in experimental animals is electroconvulsive seizure (ECS). Rodent studies have provided valuable insights into potential mechanisms underlying the antidepressant and side effects of ECT. However, relatively few studies have investigated the effects of ECS in animal models with a depression-relevant manipulation such as chronic stress. In the present study, mice were first exposed to chronic social stress (CSS) or a control procedure for 15 days followed by ECS or a sham procedure for 10 days. Behavioral effects were investigated using an auditory fear conditioning (learning) and expression (memory) test and a treadmill-running fatigue test. Thereafter, immunohistochemistry was conducted on brain material using the microglial marker Iba-1 and the cholinergic fibre marker ChAT. CSS did not increase fear learning and memory in the present experimental design; in both the control and CSS mice ECS reduced fear learning and fear memory expression. CSS induced the expected fatigue-like effect in the treadmill-running test; ECS induced increased fatigue in CSS and control mice. In CSS and control mice ECS induced inflammation in hippocampus in terms of increased expression of Iba-1 in radiatum of CA1 and CA3. CSS and ECS both reduced acetylcholine function in hippocampus as indicated by decreased expression of ChAT in several hippocampal sub-regions. Therefore, CSS increased fatigue and reduced hippocampal ChAT activity and, rather than reversing these effects, a repeated ECS regimen resulted in impaired fear learning-memory, increased fatigue, increased hippocampal Iba-1 expression, and decreased hippocampal ChAT expression. As such, the current model does not provide insights into the mechanism of ECT antidepressant function but does provide evidence for pathophysiological mechanisms that might contribute to important ECT side-effects.
doi:10.1371/journal.pone.0184603
PMCID: PMC5598988  PMID: 28910337
4.  Persistence and Subtype Stability of ADHD Among Substance Use Disorder Treatment Seekers 
Journal of attention disorders  2016;1087054716629217.
Objective
To examine ADHD symptom persistence and subtype stability among substance use disorder (SUD) treatment seekers.
Method
In all, 1,276 adult SUD treatment seekers were assessed for childhood and adult ADHD using Conners’ Adult ADHD Diagnostic Interview for Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; CAADID). A total of 290 (22.7%) participants met CAADID criteria for childhood ADHD and comprise the current study sample.
Results
Childhood ADHD persisted into adulthood in 72.8% (n = 211) of cases. ADHD persistence was significantly associated with a family history of ADHD, and the presence of conduct disorder and antisocial personality disorder. The combined subtype was the most stable into adulthood (78.6%) and this stability was significantly associated with conduct disorder and past treatment of ADHD.
Conclusion
ADHD is highly prevalent and persistent among SUD treatment seekers and is associated with the more severe phenotype that is also less likely to remit. Routine screening and follow-up assessment for ADHD is indicated to enhance treatment management and outcomes.
doi:10.1177/1087054716629217
PMCID: PMC5002258  PMID: 26922805
ADHD; subtypes; persistence; substance related disorders
5.  Psychometric properties of the Dresden Body Image Questionnaire: A multiple-group confirmatory factor analysis across sex and age in a Dutch non-clinical sample 
PLoS ONE  2017;12(7):e0181908.
Background
Body image has implications for psychosocial functioning and quality of life and its disturbance is reported in a broad range of psychiatric disorders. In view of the lack of instruments in Dutch measuring body image as a broad concept, we set out to make an instrument available that reflects the multidimensional character of this construct by including more dimensions than physical appearance. The Dresden Körperbildfragebogen (DBIQ, Dresden Body Image Questionnaire) particularly served this purpose. The DBIQ consists of 35 items and five subscales: body acceptance, sexual fulfillment, physical contact, vitality, and self-aggrandizement. The main objective of the present study was to evaluate the psychometric properties of the Dutch translation of the Dresden Body Image Questionnaire (DBIQ-NL) in a non-clinical sample.
Methods
The psychometric properties of the DBIQ-NL were examined in a non-clinical sample of 988 respondents aged between 18 and 65. We investigated the subscales' internal consistency and test-retest reliability. In order to establish construct validity we evaluated the association with a related construct, body cathexis, and with indices of self-esteem and psychological wellbeing. The factor structure of the DBIQ-NL was examined via confirmatory factor analysis (CFA). The equivalence of the measurement model across sex and age was evaluated by multiplegroup confirmatory factor analyses.
Results
Confirmatory factor analyses showed a structure in accordance with the original scale, where model fit was improved significantly by moving one item to another subscale. Multiple group confirmatory factor analysis across sex and age demonstrated partial strong invariance. Internal consistency was good with little overlap between the subscales. Temporal reliability and construct validity were satisfactory.
Conclusion
Results indicate that the DBIQ-NL is a reliable and valid instrument for non-clinical subjects. This provides a sound basis for further investigation of the DBIQ-NL in a clinical sample.
doi:10.1371/journal.pone.0181908
PMCID: PMC5528876  PMID: 28746387
6.  Childhood trauma exposure in substance use disorder patients with and without ADHD 
Addictive behaviors  2016;65:118-124.
Background
Childhood trauma exposure (CTE) is frequently reported by those with substance use disorders (SUDs). SUDs also frequently co-occur with attention deficit hyperactivity disorder (ADHD).
Objective
To investigate the role of childhood trauma exposure (CTE) in the presence and the persistence of ADHD in treatment seeking SUD patients.
Method
Data was derived from the International ADHD in Substance Use Disorder Prevalence (IASP) study. A structured interview was administered to 1274 treatment-seeking SUD patients aged 18 to 65.
Results
CTE was present in 53.5% of the patients and comorbid adult ADHD in 14.1%. CTE was significantly associated with ADHD: the prevalence of adult ADHD with and without CTE was 19.4% and 8.5% (OR adjusted for age, gender, main substance of abuse, BPD, and ASPD 1.91 [95%CI 1.29–2.81]). CTE was not associated with the severity of adult ADHD or with the persistence of childhood ADHD into adulthood.
Conclusions
CTE is common in SUD patients and associated with adult ADHD but not with the persistence of childhood ADHD into adulthood. These findings suggest that the increased rate of adult ADHD in SUD patients with CTE is not the consequence of a negative effect of CTE on the persistence of childhood ADHD into adulthood, but a direct expression of the high rate of childhood ADHD in SUD patients with CTE.
doi:10.1016/j.addbeh.2016.10.016
PMCID: PMC5518307  PMID: 27816036
Childhood trauma; Substance use disorders; Comorbidity; ADHD
7.  Social exclusion and psychopathology in an online cohort of Moroccan-Dutch migrants: Results of the MEDINA-study 
PLoS ONE  2017;12(7):e0179827.
Introduction
Migration is seen as a risk factor for developing psychiatric symptoms and experiencing social exclusion. In the Netherlands, the Moroccan-Dutch population is the second largest migrant group. 70% of all young Moroccan-Dutch people meet each other in the online community www.marokko.nl. Within this community, we investigated the association between experiences of social exclusion and self-reported depressive symptoms and psychotic experiences.
Materials and methods
Participants were recruited via the website www.marokko.nl. They completed an online survey, with screening instruments for depressive symptoms (K10) and psychotic experiences (PQ-16), measures of social exclusion (perceived discrimination, social defeat and social support), and questions about demographical information. With regression analysis the association between social exclusion and psychiatric symptoms was investigated.
Results
We included 267 participants; 87% were female. 27% of the sample has received mental healthcare in the past. Over 50% of these people screened positive for depressive symptoms and psychotic experiences. Perceived discrimination and social defeat were significantly associated with psychotic experiences and social defeat was associated with depressive symptoms. Social support and higher education were associated with less depressive symptoms and psychotic experiences.
Discussion
Our findings suggest that the online environment allows for epidemiological research and early symptom detection. Levels of psychopathology were high in our sample. This suggests that a part of this young ethnic minority population might not get adequate mental healthcare. Since this population can be reached through Internet, the online environment may therefore also offer an appropriate setting for intervention, to increase resilience towards social exclusion.
doi:10.1371/journal.pone.0179827
PMCID: PMC5503196  PMID: 28692653
8.  Negative body experience in women with early childhood trauma: associations with trauma severity and dissociation 
ABSTRACT
Background: A crucial but often overlooked impact of early life exposure to trauma is its far-reaching effect on a person’s relationship with their body. Several domains of body experience may be negatively influenced or damaged as a result of early childhood trauma.
Objective: The aim of this study was to investigate disturbances in three domains of body experience: body attitude, body satisfaction, and body awareness. Furthermore, associations between domains of body experience and severity of trauma symptoms as well as frequency of dissociation were evaluated.
Method: Body attitude was measured with the Dresden Body Image Questionnaire, body satisfaction with the Body Cathexis Scale, and body awareness with the Somatic Awareness Questionnaire in 50 female patients with complex trauma and compared with scores in a non-clinical female sample (n = 216). Patients in the clinical sample also filled out the Davidson Trauma Scale and the Dissociation Experience Scale.
Results: In all measured domains, body experience was severely affected in patients with early childhood trauma. Compared with scores in the non-clinical group, effect sizes in Cohen’s d were 2.7 for body attitude, 1.7 for body satisfaction, and 0.8 for body awareness. Associations between domains of body experience and severity of trauma symptoms were low, as were the associations with frequency of dissociative symptoms.
Conclusions: Early childhood trauma in women is associated with impairments in self-reported body experience that warrant careful assessment in the treatment of women with psychiatric disorders.
doi:10.1080/20008198.2017.1322892
PMCID: PMC5475325
Early childhood trauma; body experience; body attitude; body satisfaction; body awareness; dissociation
9.  Design of the Lifestyle Interventions for severe mentally ill Outpatients in the Netherlands (LION) trial; a cluster randomised controlled study of a multidimensional web tool intervention to improve cardiometabolic health in patients with severe mental illness 
BMC Psychiatry  2017;17:107.
Background
The cardiometabolic health of persons with a severe mental illness (SMI) is alarming with obesity rates of 45-55% and diabetes type 2 rates of 10-15%. Unhealthy lifestyle behaviours play a large role in this. Despite the multidisciplinary guideline for SMI patients recommending to monitor and address patients’ lifestyle, most mental health care professionals have limited lifestyle-related knowledge and skills, and (lifestyle) treatment protocols are lacking. Evidence-based practical lifestyle tools may support both patients and staff in improving patients’ lifestyle. This paper describes the Lifestyle Interventions for severe mentally ill Outpatients in the Netherlands (LION) trial, to investigate whether a multidimensional lifestyle intervention using a web tool can be effective in improving cardiometabolic health in SMI patients.
Methods/Design
The LION study is a 12-month pragmatic single-blind multi-site cluster randomised controlled trial. 21 Flexible Assertive Community Treatment (ACT) teams and eight sheltered living teams of five mental health organizations in the Netherlands are invited to participate. Per team, nurses are trained in motivational interviewing and use of the multidimensional web tool, covering lifestyle behaviour awareness, lifestyle knowledge, motivation and goal setting. Nurses coach patients to change their lifestyle using the web tool, motivational interviewing and stages-of-change techniques during biweekly sessions in a) assessing current lifestyle behaviour using the traffic light method (healthy behaviours colour green, unhealthy behaviours colour red), b) creating a lifestyle plan with maximum three attainable lifestyle goals and c) discussing the lifestyle plan regularly. The study population is SMI patients and statistical inference is on patient level using multilevel analyses. Primary outcome is waist circumference and other cardiometabolic risk factors after six and twelve months intervention, which are measured as part of routine outcome monitoring using standard protocols. Secondary outcomes include depressive and negative symptoms, cost-effectiveness, and barriers and facilitators in intervention implementation.
Discussion
Adequate health care should target both mental health and lifestyle behaviours in SMI patients. This trial contributes by studying a 12-month multidimensional lifestyle intervention as a potential evidence based (nursing) tool for targeting multiple lifestyle behaviours in SMI patients.
Trial registration
Nederlands Trialregister NTR3765 (trialregister.nl; registered 21 December 2012).
doi:10.1186/s12888-017-1265-7
PMCID: PMC5361714  PMID: 28327086
Severe mental illness; Cardiometabolic health; Physical activity; Diet; Intervention; e-health; Web tool; Community-dwelling patients; Outpatients
10.  Mental disorders as networks of problems: a review of recent insights 
Purpose
The network perspective on psychopathology understands mental disorders as complex networks of interacting symptoms. Despite its recent debut, with conceptual foundations in 2008 and empirical foundations in 2010, the framework has received considerable attention and recognition in the last years.
Methods
This paper provides a review of all empirical network studies published between 2010 and 2016 and discusses them according to three main themes: comorbidity, prediction, and clinical intervention.
Results
Pertaining to comorbidity, the network approach provides a powerful new framework to explain why certain disorders may co-occur more often than others. For prediction, studies have consistently found that symptom networks of people with mental disorders show different characteristics than that of healthy individuals, and preliminary evidence suggests that networks of healthy people show early warning signals before shifting into disordered states. For intervention, centrality—a metric that measures how connected and clinically relevant a symptom is in a network—is the most commonly studied topic, and numerous studies have suggested that targeting the most central symptoms may offer novel therapeutic strategies.
Conclusions
We sketch future directions for the network approach pertaining to both clinical and methodological research, and conclude that network analysis has yielded important insights and may provide an important inroad towards personalized medicine by investigating the network structures of individual patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s00127-016-1319-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s00127-016-1319-z
PMCID: PMC5226976  PMID: 27921134
Comorbidity; Early warning signals; Mental disorders; Network analysis; Treatment
11.  Major depressive disorder subtypes to predict long-term course 
Depression and anxiety  2014;31(9):765-777.
Background
Variation in course of major depressive disorder (MDD) is not strongly predicted by existing subtype distinctions. A new subtyping approach is considered here.
Methods
Two data mining techniques, ensemble recursive partitioning and Lasso generalized linear models (GLMs) followed by k-means cluster analysis, are used to search for subtypes based on index episode symptoms predicting subsequent MDD course in the World Mental Health (WMH) Surveys. The WMH surveys are community surveys in 16 countries. Lifetime DSM-IV MDD was reported by 8,261 respondents. Retrospectively reported outcomes included measures of persistence (number of years with an episode; number of with an episode lasting most of the year) and severity (hospitalization for MDD; disability due to MDD).
Results
Recursive partitioning found significant clusters defined by the conjunctions of early onset, suicidality, and anxiety (irritability, panic, nervousness-worry-anxiety) during the index episode. GLMs found additional associations involving a number of individual symptoms. Predicted values of the four outcomes were strongly correlated. Cluster analysis of these predicted values found three clusters having consistently high, intermediate, or low predicted scores across all outcomes. The high-risk cluster (30.0% of respondents) accounted for 52.9-69.7% of high persistence and severity and was most strongly predicted by index episode severe dysphoria, suicidality, anxiety, and early onset. A total symptom count, in comparison, was not a significant predictor.
Conclusions
Despite being based on retrospective reports, results suggest that useful MDD subtyping distinctions can be made using data mining methods. Further studies are needed to test and expand these results with prospective data.
doi:10.1002/da.22233
PMCID: PMC5125445  PMID: 24425049
Epidemiology; Depression; Anxiety/Anxiety Disorders; Suicide/Self Harm; Panic Attacks
12.  Does CRP predict outcome in bipolar disorder in regular outpatient care? 
Background
The association between inflammation and the course of mood disorders is receiving increased attention. This study aims to investigate whether a sub-group of patients with BD can be identified for which a higher CRP (C-reactive protein) level at baseline is associated with an unfavorable prognosis.
Methods
This is a historic cohort study using CRP at baseline, with 15-month follow-up of mood status and medication. Cross-sectional analyses include boxplots, one-way ANOVA, receiver operating characteristics (ROC) curve and Chi square test, and the longitudinal analysis using multivariate Cox-regression.
Results
Eighty-four bipolar disorder patients were included in the analyses. Cross-sectionally, no statistically significant difference was found in CRP distribution across mood states (p = 0.372) or rapid cycling state (p = 0.656). Also, no CRP cut-off level was distinguished between euthymic and non-euthymic patients according to the ROC curve (p = 0.449, AUC = 0.452, 95 % CI 0.327, 0.576), and a literature-derived cut-off value (3 mg/L) again demonstrated no difference (p = 0.530). Longitudinally, no association was found between CRP and prognosis of disease neither in euthymic [−2 log likelihood = 120.460; CRP: p = 0.866, B = −0.011, OR = 0.989 (95 % CI 0.874–1.120)] nor non-euthymic patients [(−2 log likelihood = 275.028; CRP: p = 0.802, B = 0.010, OR = 1.010 (95 % CI 0.937–1.088)]. Medication use did not affect these associations.
Conclusions
We found no statistically significant association between CRP and a more unfavorable BD prognosis, suggesting that the application of CRP as a practical biomarker to predict outcome in a naturalistic outpatient care setting is not as straightforward as it may seem.
Electronic supplementary material
The online version of this article (doi:10.1186/s40345-016-0055-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s40345-016-0055-3
PMCID: PMC4949199  PMID: 27430576
C-reactive protein; Bipolar disorder; Inflammation; Biological markers; Prognosis; Historic cohort
13.  Testing a machine-learning algorithm to predict the persistence and severity of major depressive disorder from baseline self-reports 
Molecular psychiatry  2016;21(10):1366-1371.
Heterogeneity of major depressive disorder (MDD) illness course complicates clinical decision-making. While efforts to use symptom profiles or biomarkers to develop clinically useful prognostic subtypes have had limited success, a recent report showed that machine learning (ML) models developed from self-reports about incident episode characteristics and comorbidities among respondents with lifetime MDD in the World Health Organization World Mental Health (WMH) Surveys predicted MDD persistence, chronicity, and severity with good accuracy. We report results of model validation in an independent prospective national household sample of 1,056 respondents with lifetime MDD at baseline. The WMH ML models were applied to these baseline data to generate predicted outcome scores that were compared to observed scores assessed 10–12 years after baseline. ML model prediction accuracy was also compared to that of conventional logistic regression models. Area under the receiver operating characteristic curve (AUC) based on ML (.63 for high chronicity and .71–.76 for the other prospective outcomes) was consistently higher than for the logistic models (.62–.70) despite the latter models including more predictors. 34.6–38.1% of respondents with subsequent high persistence-chronicity and 40.8–55.8% with the severity indicators were in the top 20% of the baseline ML predicted risk distribution, while only 0.9% of respondents with subsequent hospitalizations and 1.5% with suicide attempts were in the lowest 20% of the ML predicted risk distribution. These results confirm that clinically useful MDD risk stratification models can be generated from baseline patient self-reports and that ML methods improve on conventional methods in developing such models.
doi:10.1038/mp.2015.198
PMCID: PMC4935654  PMID: 26728563
14.  Risk Factors for Borderline Personality Disorder in Treatment Seeking Patients with a Substance Use Disorder: An International Multicenter Study 
European addiction research  2015;21(4):188-194.
Borderline personality disorder (BPD) and substance use disorders (SUDs) often co-occur, partly because they share risk factors. In this international multicenter study, risk factors for BPD were examined for SUD patients. In total, 1,205 patients were comprehensively examined by standardized interviews and questionnaires on psychiatric diagnosis and risk factors, and it was found that 1,033 (85.7%) had SUDs without BPD (SUD) and 172 (14.3%) had SUD with BPD (SUD + BPD). SUD + BPD patients were significantly younger, more often females and more often diagnosed with comorbid adult attention deficit/hyperactivity disorder. SUD + BPD patients did not differ from SUD patients on most risk factors typical for SUD such as maternal use of drugs during pregnancy or parents having any SUD. However, SUD + BPD patients did have a higher risk of having experienced emotional and physical abuse, neglect, or family violence in childhood compared to SUD patients, suggesting that child abuse and family violence are BPD-specific risk factors in patients with SUDs.
doi:10.1159/000371724
PMCID: PMC4869722  PMID: 25832736
Risk factors; Substance use disorder; Borderline personality disorder; Comorbidity
15.  The Facts About Sexual (Dys)function in Schizophrenia: An Overview of Clinically Relevant Findings 
Schizophrenia Bulletin  2015;41(3):674-686.
A limited number of studies have evaluated sexual functioning in patients with schizophrenia. Most patients show an interest in sex that differs little from the general population. By contrast, psychiatric symptoms, institutionalization, and psychotropic medication contribute to frequently occurring impairments in sexual functioning. Women with schizophrenia have a better social outcome, longer lasting (sexual) relationships, and more offspring than men with schizophrenia. Still, in both sexes social and interpersonal impairments limit the development of stable sexual relationships. Although patients consider sexual problems to be highly relevant, patients and clinicians not easily discuss these spontaneously, leading to an underestimation of their prevalence and contributing to decreased adherence to treatment. Studies using structured interviews or questionnaires result in many more patients reporting sexual dysfunctions. Although sexual functioning can be impaired by different factors, the use of antipsychotic medication seems to be an important factor. A comparison of different antipsychotics showed high frequencies of sexual dysfunction for risperidone and classical antipsychotics, and lower frequencies for clozapine, olanzapine, quetiapine, and aripiprazole. Postsynaptic dopamine antagonism, prolactin elevation, and α1-receptor blockade may be the most relevant factors in the pathogenesis of antipsychotic-induced sexual dysfunction. Psychosocial strategies to treat antipsychotic-induced sexual dysfunction include psychoeducation and relationship counseling. Pharmacological strategies include lowering the dose or switching to a prolactin sparing antipsychotic. Also, the addition of a dopamine agonist, aripiprazole, or a phosphodiesterase-5 inhibitor has shown some promising results, but evidence is currently scarce.
doi:10.1093/schbul/sbv001
PMCID: PMC4393701  PMID: 25721311
antipsychotic; sexual dysfunction;  schizophrenia; dopamine; prolactin; negative symptoms
16.  Feedback-informed treatment in emergency psychiatry; a randomised controlled trial 
BMC Psychiatry  2016;16:110.
Background
Immediate patient feedback has been shown to improve outcomes for patients in mild distress but it is unclear whether psychiatric patients in severe distress benefit equally from feedback. This study investigates the efficacy of an immediate feedback instrument in the treatment of patients with acute and severe psychosocial or psychiatric problems referred in the middle of a crisis.
Methods
A naturalistic mixed diagnosis sample of patients (N = 370) at a Psychiatric Emergency Centre was randomised to a Treatment-as-Usual (TAU) or a Feedback (FB) condition. In the FB condition, feedback on patient progress was provided on a session-by-session basis to both therapists and patients. Outcomes of the two treatment conditions were compared using repeated measures MANCOVA, Last Observation Carried Forward and multilevel analysis.
Results
After 3 months, symptom improvement in FB (ES 0.60) did not significantly differ from TAU (ES 0.71) (p = 0.505). After 6 weeks, FB patients (ES 0.31) actually improved less than TAU patients (0.56) (p = 0.019).
Conclusions
Patients with psychiatric problems and severe distress seeking emergency psychiatric help did not benefit from direct feedback.
Trial registration
Dutch Trial Register, NTR3168, date of registration 1-9-2009
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-016-0811-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12888-016-0811-z
PMCID: PMC4837581  PMID: 27095106
Patient feedback; Randomised controlled trial; Crisis intervention; Efficacy; Outcome monitoring
17.  Depression in context of low neuroticism is a risk factor for stroke 
Neurology  2014;83(19):1692-1698.
Objective:
Depression predicts stroke; however, meta-analyses show significant heterogeneity. We hypothesize that the risk of depression on incident stroke is conditional upon the relative contribution of vascular disease and of neuroticism in the underlying pathways to depression in a specific patient. We examined whether depression increases stroke in persons with low neuroticism and without preexisting cardiac disease.
Methods:
This was a population-based cohort study with 9-year follow-up (n = 2,050; ≥55 years, 52% female). The incidence of stroke was determined by self-report data as well as data from general practitioners and death certificates. Neuroticism was measured using the Dutch Personality Questionnaire and depression using the Center for Epidemiologic Studies–Depression scale. All data were analysed by Cox proportional hazards regression.
Results:
A total of 117 incident cases of stroke occurred during follow-up. Among persons with a history of cardiac disease (n = 401), depression predicted incident stroke independent of neuroticism level with a hazard ratio (HR) of 1.05 (95% confidence interval [CI] 1.01–1.10) (p = 0.02). In persons without cardiac disease (n = 1,649), depression and neuroticism interacted significantly in predicting incident stroke (p = 0.028). Stratified analyses showed that depression predicted incident stroke in those with low neuroticism, HR 1.05 (95% CI 1.00–1.09) (p = 0.033), but not in those with high neuroticism, HR 1.01 (95% CI 0.96–1.05) (p = 0.82).
Conclusions:
In persons without preexistent cardiac disease, depression is only predictive for future stroke in absence of high neuroticism. This might be explained by the hypothesis that late-life depression in context of low neuroticism is a marker of subclinical vascular disease.
doi:10.1212/WNL.0000000000000955
PMCID: PMC4239832  PMID: 25274852
18.  Empathic accuracy and oxytocin after tryptophan depletion in adults at risk for depression 
Psychopharmacology  2015;233:111-120.
Rationale
Major depressive disorder (MDD) has been associated with disturbances in social functioning and in the brain serotonin system. Reduced levels of serotonin may negatively influence social functioning, for example by impairing the recognition of facial emotion expressions.
Objectives
The present study investigated the effect of acute tryptophan depletion (ATD), which reduces brain serotonin, on a related component of social functioning, empathic accuracy (EA), and oxytocin levels.
Methods
Individuals with (FH+) and without (FH−) a family history of MDD participated in a randomized, double-blind, crossover study. On two separate test days, participants ingested tryptophan-deficient and nutritionally balanced amino acid mixtures. Six hours later, they performed an EA task, which involved watching videos of people recounting autobiographical emotional events. While watching, participants continuously rated how these people felt during the recounting. Mood state was repeatedly assessed using the Positive Affect and Negative Affect Schedule and a series of visual analogue scales. Blood samples obtained at baseline and 5 h after mixture ingestion were assessed for tryptophan and oxytocin levels.
Results
ATD decreased circulating levels of tryptophan and oxytocin. Nevertheless, there were no significant effects of ATD on EA or mood in either FH group.
Conclusions
While previous studies have shown that acute reductions in brain serotonin alter the recognition of facial emotion expressions in never-depressed individuals, the present study suggests that empathic abilities may remain unaffected.
Electronic supplementary material
The online version of this article (doi:10.1007/s00213-015-4093-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00213-015-4093-9
PMCID: PMC4700075  PMID: 26462806
Serotonin; Empathy; Cognition; Ecological validity; Major depressive disorder; Oxytocin
19.  The Network Structure of Symptoms of the Diagnostic and Statistical Manual of Mental Disorders 
PLoS ONE  2015;10(9):e0137621.
Although current classification systems have greatly contributed to the reliability of psychiatric diagnoses, they ignore the unique role of individual symptoms and, consequently, potentially important information is lost. The network approach, in contrast, assumes that psychopathology results from the causal interplay between psychiatric symptoms and focuses specifically on these symptoms and their complex associations. By using a sophisticated network analysis technique, this study constructed an empirically based network structure of 120 psychiatric symptoms of twelve major DSM-IV diagnoses using cross-sectional data of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, second wave; N = 34,653). The resulting network demonstrated that symptoms within the same diagnosis showed differential associations and indicated that the strategy of summing symptoms, as in current classification systems, leads to loss of information. In addition, some symptoms showed strong connections with symptoms of other diagnoses, and these specific symptom pairs, which both concerned overlapping and non-overlapping symptoms, may help to explain the comorbidity across diagnoses. Taken together, our findings indicated that psychopathology is very complex and can be more adequately captured by sophisticated network models than current classification systems. The network approach is, therefore, promising in improving our understanding of psychopathology and moving our field forward.
doi:10.1371/journal.pone.0137621
PMCID: PMC4569413  PMID: 26368008
20.  Depression and anxiety in patients with and without same-sex attraction: differences in clinical expression, lifestyle factors, and vulnerability indicators 
Brain and Behavior  2015;5(9):e00363.
Background
The aim of this study was to compare clinical expressions (severity and loneliness), lifestyle factors (substance use), and vulnerability indicators (stressful childhood experiences) in patients with any same-sex attraction versus heterosexual patients diagnosed with depression and/or anxiety disorder. Little is known about this, even though it is now well documented that depression and anxiety are more prevalent among persons with same-sex attraction.
Method
Data, derived from the Netherlands Study of Depression and Anxiety (NESDA), allowed us to compare patients with a same-sex (n = 122) and an exclusively opposite-sex (n = 1658) attraction. Persons with same-sex attraction included persons who were attracted to both sexes. Data were collected by means of the Composite International Diagnostic Interview and paper-and pencil questionnaires.
Results
Seven percent of the patients reported any same-sex orientation. Clinical expression of depression and anxiety did not differ in relation to sexual attraction. Regarding substance use, same-sex attracted women reported more drug use than heterosexual women (drug use: 16.2% vs. 6.6%, P = 0.003). Regarding stressful childhood experiences, men with any same-sex attraction reported more sexual abuse during childhood than men with a heterosexual orientation (20.4% vs. 8.5%, P = 0.005).
Conclusions
For women with same-sex attraction substance use (especially illicit drug use) might be a coping mechanism to deal with existing symptoms or with the minority stressors they have to deal with; for same-sex attracted men stressful childhood experiences might reflect an aspect of etiology.
doi:10.1002/brb3.363
PMCID: PMC4589810  PMID: 26445702
Anxiety disorders; clinical expression; depressive disorders; risk factors; same-sex attraction
21.  Commentary: “Consistent Superiority of Selective Serotonin Reuptake Inhibitors Over Placebo in Reducing Depressed Mood in Patients with Major Depression” 
doi:10.3389/fpsyt.2015.00117
PMCID: PMC4543778  PMID: 26347663
selective serotonin reuptake inhibitors; major depressive disorder; network analysis; antidepressants; symptomics
22.  Disturbances in Hypothalamic-Pituitary-Adrenal Axis and Immunological Activity Differentiating between Unipolar and Bipolar Depressive Episodes 
PLoS ONE  2015;10(7):e0133898.
Introduction
Differentiating bipolar depression (BD) from unipolar depression (UD) is difficult in clinical practice and, consequently, accurate recognition of BD can take as long as nine years. Research has therefore focused on the discriminatory capacities of biomarkers, such as markers of the hypothalamic-pituitary-adrenal (HPA) axis or immunological activity. However, no previous study included assessments of both systems, which is problematic as they may influence each other. Therefore, this study aimed to explore whether cortisol indicators and inflammatory markers were a) independently associated with and/or b) showed effect modification in relation to a lifetime (hypo)manic episode in a large sample of depressed patients.
Methods
Data were derived from the Netherlands Study of Depression and Anxiety and comprised 764 patients with a DSM-IV depressive disorder at baseline, of which 124 (16.2%) had a lifetime (hypo)manic episode at the 2-year assessment, or a more recent episode at the 4-year or 6-year assessment. Baseline cortisol awakening response, evening cortisol and diurnal cortisol slope were considered as cortisol indicators, while baseline C-reactive Protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α) were included as inflammatory markers.
Results
In depressed men and women, none of the cortisol indicators and inflammatory markers were (independently) associated with a (hypo)manic episode. However, effect modification was found of diurnal cortisol slope and CRP in relation to a (hypo)manic episode. Further analyses showed that depressed men with high levels of diurnal cortisol slope and CRP had an increased odds (OR=10.99, p=.001) of having a (hypo)manic episode. No significant differences were found in women.
Conclusion
Our findings suggest that the combination of high diurnal cortisol slope and high CRP may differentiate between UD and BD. This stresses the importance of considering HPA-axis and immunological activity simultaneously, but more research is needed to unravel their interrelatedness.
doi:10.1371/journal.pone.0133898
PMCID: PMC4510385  PMID: 26196286
23.  Risk of Criminal Victimisation in Outpatients with Common Mental Health Disorders 
PLoS ONE  2015;10(7):e0128508.
Background
Crime victimisation is a serious problem in psychiatric patients. However, research has focused on patients with severe mental illness and few studies exist that address victimisation in other outpatient groups, such as patients with depression. Due to large differences in methodology of the studies that address crime victimisation, a comparison of prevalence between psychiatric diagnostic groups is hard to make. Objectives of this study were to determine and compare one-year prevalence of violent and non-violent criminal victimisation among outpatients from different diagnostic psychiatric groups and to examine prevalence differences with the general population.
Method
Criminal victimisation prevalence was measured in 300 outpatients living in Amsterdam, The Netherlands. Face-to-face interviews were conducted with outpatients with depressive disorder (n = 102), substance use disorder (SUD, n = 106) and severe mental illness (SMI, n = 92) using a National Crime Victimisation Survey, and compared with a matched general population sample (n = 10865).
Results
Of all outpatients, 61% reported experiencing some kind of victimisation over the past year; 33% reported violent victimisation (3.5 times more than the general population) and 36% reported property crimes (1.2 times more than the general population). Outpatients with depression (67%) and SUD (76%) were victimised more often than SMI outpatients (39%). Younger age and hostile behaviour were associated with violent victimisation, while being male and living alone were associated with non-violent victimisation. Moreover, SUD was associated with both violent and non-violent victimisation.
Conclusion
Outpatients with depression, SUD, and SMI are at increased risk of victimisation compared to the general population. Furthermore, our results indicate that victimisation of violent and non-violent crimes is more common in outpatients with depression and SUD than in outpatients with SMI living independently in the community.
doi:10.1371/journal.pone.0128508
PMCID: PMC4489091  PMID: 26132200
24.  Evidence for a Shared Etiological Mechanism of Psychotic Symptoms and Obsessive-Compulsive Symptoms in Patients with Psychotic Disorders and Their Siblings 
PLoS ONE  2015;10(6):e0125103.
The prevalence of obsessive-compulsive disorder in subjects with psychotic disorder is much higher than in the general population. The higher than chance co-occurrence has also been demonstrated at the level of subclinical expression of both phenotypes. Both extended phenotypes have been shown to cluster in families. However, little is known about the origins of their elevated co-occurrence. In the present study, evidence for a shared etiological mechanism was investigated in 3 samples with decreasing levels of familial psychosis liability: 987 patients, 973 of their unaffected siblings and 566 healthy controls. The association between the obsessive-compulsive phenotype and the psychosis phenotype c.q. psychosis liability was investigated. First, the association was assessed between (subclinical) obsessive-compulsive symptoms and psychosis liability. Second, in a cross-sib cross-trait analysis, it was examined whether (subclinical) obsessive-compulsive symptoms in the patient were associated with (subclinical) psychotic symptoms in the related unaffected sibling. Evidence was found for both associations, which is compatible with a partially shared etiological pathway underlying obsessive-compulsive and psychotic disorder. This is the first study that used a cross-sib cross-trait design in patients and unaffected siblings, thus circumventing confounding by disease-related factors present in clinical samples.
doi:10.1371/journal.pone.0125103
PMCID: PMC4465647  PMID: 26061170
25.  Inflammatory and Metabolic Dysregulation and the 2-Year Course of Depressive Disorders in Antidepressant Users 
Neuropsychopharmacology  2014;39(7):1624-1634.
Scarce evidence suggests that inflammatory and metabolic dysregulation predicts poor response to antidepressants, which could result in worse depression outcome. This study prospectively examined whether inflammatory and metabolic dysregulation predicted the 2-year course of depressive disorders among antidepressant users. Data were from the Netherlands Study of Depression and Anxiety, including 315 persons (18–65 years) with a current depressive disorder (major depressive disorder, dysthymia) at baseline according to the DSM-IV criteria and using antidepressants. Inflammatory (C-reactive protein, interleukin-6 (IL-6), tumor-necrosis factor-α) and metabolic (waist circumference, triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure, fasting glucose) factors were measured at baseline. Primary outcome for course of depression was indicated by whether or not a DSM-IV depressive disorder diagnosis was still/again present at 2-year follow-up, indicating chronicity of depression. Elevated IL-6, low HDL cholesterol, hypertriglyceridemia, and hyperglycemia were associated with chronicity of depression in antidepressant users. Persons showing ⩾4 inflammatory or metabolic dysregulations had a 1.90 increased odds of depression chronicity (95% CI=1.12–3.23). Among persons who recently (ie, at most 3 months) started antidepressant medication (N=103), having ⩾4 dysregulations was associated with a 6.85 increased odds of depression chronicity (95% CI=1.95–24.06). In conclusion, inflammatory and metabolic dysregulations were found to predict a more chronic course of depressive disorders among patients using antidepressants. This could suggest that inflammatory and metabolic dysregulation worsens depression course owing to reduced antidepressant treatment response and that alternative intervention treatments may be needed for depressed persons with inflammatory and metabolic dysregulation.
doi:10.1038/npp.2014.9
PMCID: PMC4023159  PMID: 24442097
Antidepressants; Biological Psychiatry; Depression; Unipolar/Bipolar; Eating/Metabolic Disorders; Epidemiology; inflammation; prospective cohort; inflammation; metabolic syndrome; depression; antidepressants; prospective cohort

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