Publications by authors named "Erik J Giltay"

220 Publications

Lessons learned from two clinical trials on nutritional supplements to reduce aggressive behaviour.

J Eval Clin Pract 2022 Jan 17. Epub 2022 Jan 17.

Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.

Background: Setting up and conducting a randomised controlled trial (RCT) has many challenges-particularly trials that include vulnerable individuals with behavioural problems or who reside in facilities that focus on care as opposed to research. These populations are underrepresented in RCTs.

Approach: In our paper, we describe the challenges and practical lessons learned from two RCTs in two care settings involving long-stay psychiatric inpatients and people with intellectual disabilities. We describe five main difficulties and how these were overcome: (1) multisite setting, (2) inclusion of vulnerable participants, (3) nutritional supplements and placebos, (4) assessment of behavioural outcomes, and (5) collecting bio samples.

Conclusions: By sharing these practical experiences, we hope to inform other researchers how to optimally design their trials, while avoiding and minimising the difficulties that we encountered, and to facilitate the implementation of a trial. Both trials were registered in the Clinical Trials Register (RCT A: NCT02498106; RCT B: NCT03212092).
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http://dx.doi.org/10.1111/jep.13653DOI Listing
January 2022

The Role of Kynurenines in Cognitive Dysfunction in Bipolar Disorder.

Neuropsychobiology 2021 Dec 9:1-8. Epub 2021 Dec 9.

Faculty of Medicine and Health Sciences, Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp, Antwerp, Belgium.

Introduction: Chronic low-grade inflammation is suggested to play a pathophysiological role in bipolar disorder (BD) and its related cognitive dysfunctions. Although kynurenine (KYN) pathway metabolites are key inflammatory mediators, studies investigating the association between KYN metabolism and cognition in BD are scarce. We aimed to explore the relationship between KYN metabolism and cognitive functioning across different mood states in BD.

Methods: Sixty-seven patients with BD (35 depressed and 32 [hypo] manic) and 29 healthy controls were included. Cognitive functioning was assessed at 3 time intervals (baseline, 4, and 8 months) assessing processing speed, sustained attention, verbal memory, working memory, and response inhibition. Plasma samples for quantification of 3-hydroxykynurenine, quinolinic acid, and kynurenic acid (KYNA) were concurrently provided. Linear mixed models were used for statistical analysis.

Results: The manic group showed deficits in all assessed cognitive domains with the exception of verbal memory at all test moments. The bipolar depression group showed deficits in the processing speed at all test moments. Throughout the whole follow-up period, KYNA was significantly lower in both patient groups than in controls. Only in the bipolar depression group, low KYNA was associated with worse global cognitive functioning (B = 0.114, p = 0.02) and slower processing speed in particular (B = 0.139, p = 0.03).

Conclusion: Only in the bipolar depression group, lower KYNA was associated with worse cognitive functioning. Future large-scale longitudinal studies are warranted to confirm the role of KYN metabolites in cognitive impairment in patients with BD and the possible therapeutic implications of this relationship.
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http://dx.doi.org/10.1159/000520152DOI Listing
December 2021

The 9-year clinical course of depressive and anxiety disorders: New NESDA findings.

J Affect Disord 2021 12 4;295:1269-1279. Epub 2021 Sep 4.

Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands.

Background: In longitudinal research, switching between diagnoses should be considered when examining patients with depression and anxiety. We investigated course trajectories of affective disorders over a nine-year period, comparing a categorical approach using diagnoses to a dimensional approach using symptom severity.

Method: Patients with a current depressive and/or anxiety disorder at baseline (N = 1701) were selected from the Netherlands Study of Depression and Anxiety (NESDA). Using psychiatric diagnoses, we described 'consistently recovered,' 'intermittently recovered,' 'intermittently recurrent', and 'consistently chronic' at two-, four-, six-, and nine-year follow-up. Additionally, latent class growth analysis (LCGA) using depressive, anxiety, fear, and worry symptom severity scores was used to identify distinct classes.

Results: Considering the categorical approach, 8.5% were chronic, 32.9% were intermittently recurrent, 37.6% were intermittently recovered, and 21.0% remained consistently recovered from any affective disorder at nine-year follow-up. In the dimensional approach, 66.6% were chronic, 25.9% showed partial recovery, and 7.6% had recovered.

Limitations: 30.6% of patients were lost to follow-up. Diagnoses were rated by the interviewer and questionnaires were completed by the participant.

Conclusions: Using diagnoses alone as discrete categories to describe clinical course fails to fully capture the persistence of affective symptoms that were observed when using a dimensional approach. The enduring, fluctuating presence of subthreshold affective symptoms likely predisposes patients to frequent relapse. The commonness of subthreshold symptoms and their adverse impact on long-term prognoses deserve continuous clinical attention in mental health care as well further research.
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http://dx.doi.org/10.1016/j.jad.2021.08.108DOI Listing
December 2021

Diet quality among people with intellectual disabilities and borderline intellectual functioning.

J Appl Res Intellect Disabil 2021 Oct 26. Epub 2021 Oct 26.

Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands.

Background: We sought to assess diet quality among people with intellectual disabilities or borderline intellectual functioning, living in residential facilities or receiving day care.

Methods: We measured diet quality using the Dutch Healthy Diet Food Frequency Questionnaire (DHD) and compared this between participants with (n = 151) and controls without intellectual disabilities (n = 169). Potential correlates of diet quality were explored.

Results: We found lower mean diet quality among people with intellectual disabilities (M = 80.9) compared to controls (M = 111.2; mean adjusted difference -28.4; 95% CI [-32.3, -24.5]; p < .001). Participants with borderline intellectual functioning and mild intellectual disabilities had lower diet quality and higher body mass index than individuals with severe to profound intellectual disabilities. Being female was a predictor of better diet quality.

Conclusions: Overall, we found that diet quality was low in the sample of people with intellectual disabilities or borderline intellectual functioning.
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http://dx.doi.org/10.1111/jar.12958DOI Listing
October 2021

Diet quality among people with intellectual disabilities and borderline intellectual functioning.

J Appl Res Intellect Disabil 2021 Oct 26. Epub 2021 Oct 26.

Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands.

Background: We sought to assess diet quality among people with intellectual disabilities or borderline intellectual functioning, living in residential facilities or receiving day care.

Methods: We measured diet quality using the Dutch Healthy Diet Food Frequency Questionnaire (DHD) and compared this between participants with (n = 151) and controls without intellectual disabilities (n = 169). Potential correlates of diet quality were explored.

Results: We found lower mean diet quality among people with intellectual disabilities (M = 80.9) compared to controls (M = 111.2; mean adjusted difference -28.4; 95% CI [-32.3, -24.5]; p < .001). Participants with borderline intellectual functioning and mild intellectual disabilities had lower diet quality and higher body mass index than individuals with severe to profound intellectual disabilities. Being female was a predictor of better diet quality.

Conclusions: Overall, we found that diet quality was low in the sample of people with intellectual disabilities or borderline intellectual functioning.
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http://dx.doi.org/10.1111/jar.12958DOI Listing
October 2021

Basal and LPS-stimulated inflammatory markers and the course of anxiety symptoms.

Brain Behav Immun 2021 11 9;98:378-387. Epub 2021 Sep 9.

Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.

A cross-sectional relationship between low-grade inflammation -characterized by increased blood levels of C-reactive protein (CRP) and pro-inflammatory cytokines- and anxiety has been reported, but the potential longitudinal relationship has been less well studied. We aimed to examine whether basal and lipopolysaccharide (LPS-)induced levels of inflammatory markers are associated with anxiety symptom severity over the course of nine years. We tested the association between basal and LPS-induced inflammatory markers with anxiety symptoms (measured with the Beck's Anxiety Inventory; BAI, Fear Questionnaire; FQ and Penn's State Worry Questionnaire; PSWQ) at 5 assessment waves over a period up nine years. We used multivariate-adjusted mixed models in up to 2867 participants of the Netherlands Study of Depression and Anxiety (NESDA). At baseline, 43.6% of the participants had a current anxiety disorder, of which social phobia (18.5%) was most prevalent. Our results demonstrated that baseline inflammatory markers were significantly associated with several outcomes of anxiety at baseline over nine subsequent years. BAI subscale of somatic (arousal) symptoms of anxiety, and FQ subscale of agoraphobia demonstrated the strongest effects with standardized beta-coefficients of up to 0.14. The associations were attenuated by 25%-30% after adjusting for the presence of (comorbid) major depressive disorder (MDD), but remained statistically significant. In conclusion, we found that participants with high levels of inflammatory markers have on average high levels of anxiety consisting of physical arousal and agoraphobia, which tended to persist over a period of nine years, albeit with small effect sizes. These associations were partly driven by co-morbid depression.
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http://dx.doi.org/10.1016/j.bbi.2021.09.001DOI Listing
November 2021

Oral contraceptives, depressive and insomnia symptoms in adult women with and without depression.

Psychoneuroendocrinology 2021 11 12;133:105390. Epub 2021 Aug 12.

OLVG Hospital, Department of Psychiatry and Medical Psychology, Amsterdam, The Netherlands; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands; Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A⁎STAR), Singapore.

Background: Worldwide, oral contraceptive (OC) use is a very common form of birth control, although it has been associated with symptoms of depression and insomnia. Insomnia is a risk factor for major depressive disorder (MDD) but may also be a symptom of the disorder. Despite the large number of women who use OC, it is yet unknown whether women with previous or current diagnosis of depression are more likely to experience more severe depressive and insomnia symptoms during concurrent OC use than women without diagnosis of depression.

Aim: This study examined associations between OC use and concurrent symptoms of depression (including atypical depression) and insomnia as well as between OC and prevalences of concurrent dysthymia and MDD. Participants were adult women with and without a history of MDD or dysthymia. We hypothesized that OC use is associated with concurrent increased severity of depressive symptoms and insomnia symptoms, as well as with an increased prevalence of concurrent diagnoses of dysthymia and MDD. We also hypothesized that a history of MDD or dysthymia moderates the relationship between OC use and depressive and insomnia symptoms.

Methods: Measurements from premenopausal adult women from the Netherlands Study of Depression and Anxiety (NESDA) were grouped, based on whether participants were using OC or naturally cycling (NC). OC use, timing and regularity of the menstrual cycle were assessed with a structured interview, self-reported symptoms of depression (including atypical depression), insomnia with validated questionnaires, and MDD and dysthymia with structured diagnostic interviews.

Results: We included a total of 1301 measurements in women who reported OC use and 1913 measurements in NC women (mean age 35.6, 49.8% and 28.9% of measurements in women with a previous depression or current depression, respectively). Linear mixed models showed that overall, OC use was neither associated with more severe depressive symptoms (including atypical depressive symptoms), nor with higher prevalence of diagnoses of MDD or dysthymia. However, by disentangling the amalgamated overall effect, within-person estimates indicated increased depressive symptoms and depressive disorder prevalence during OC use, whereas between-person estimated indicated lower depressive symptoms and prevalence of depressive disorders. OC use was consistently associated with more severe concurrent insomnia symptoms, in the overall estimates as well as in the within-person and between-person estimates. Presence of current or previous MDD or dysthymia did not moderate the associations between OC use and depressive or insomnia symptoms.

Discussion: The study findings showed consistent associations between OC use and more severe insomnia symptoms, but no consistent associations between OC and depressive symptoms or diagnoses. Instead, post-hoc analyses showed that associations between OC and depression differed between within- and between person-estimates. This indicates that, although OC shows no associations on the overall level, some individuals might experience OC-associated mood symptoms. Our findings underscore the importance of accounting for individual differences in experiences during OC use. Furthermore, it raises new questions about mechanisms underlying associations between OC, depression and insomnia.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105390DOI Listing
November 2021

Association between adolescent oral contraceptive use and future major depressive disorder: a prospective cohort study.

J Child Psychol Psychiatry 2021 Jul 12. Epub 2021 Jul 12.

Department of Psychology, University of British Columbia, Vancouver, BC, Canada.

Background: Because of the widespread use of oral contraceptives (OCs) and the devastating effects of depression both on an individual and a societal level, it is crucial to understand the nature of the previously reported relationship between OC use and depression risk. Insight into the impact of analytical choices on the association is important when interpreting available evidence. Hence, we examined the association between adolescent OC use and subsequent depression risk in early adulthood analyzing all theoretically justifiable models.

Methods: Data from the prospective cohort study TRacking Adolescents' Individual Lives Survey, among women aged 13-25 years were used. Adolescent OC use (ages 16-19 years) was used as a predictor and major depressive disorder (MDD) in early adulthood (ages 20-25 years), as assessed by the Diagnostic and Statistical Manual of Mental Disorders-IV oriented Lifetime Depression Assessment Self-Report and the Composite International Diagnostic Interview, was used as an outcome. A total of 818 analytical models were analyzed using Specification Curve Analysis in 534 adolescent OC users and 191 nonusers.

Results: Overall, there was an association of adolescent OC use and an episode of MDD in early adulthood [median odds ratio (OR)  = 1.41; OR  = 1.08; OR  = 2.18, p < .001], which was driven by the group of young women with no history of MDD (OR  = 1.72; OR  = 1.21; OR  = 2.18, p < .001).

Conclusions: In summary, adolescent OC use was associated with a small but robust increased risk for experiencing an episode of MDD, especially among women with no history of MDD in adolescence. Understanding the potential side effects of OCs will help women and their doctors to make informed choices when deciding among possible methods of birth control.
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http://dx.doi.org/10.1111/jcpp.13476DOI Listing
July 2021

Dynamic time warp analysis of individual symptom trajectories in depressed patients treated with electroconvulsive therapy.

J Affect Disord 2021 10 2;293:435-443. Epub 2021 Jul 2.

Department of Psychiatry, Leiden University Medical Center (LUMC), the Netherlands. Electronic address:

Background: Although electroconvulsive therapy (ECT) effectively improves severity scores of depression, its effects on its individual symptoms has scarcely been studied. We aimed to study which depressive symptom trajectories dynamically cluster together in individuals as well as groups of patients during ECT using Dynamic Time Warp (DTW) analysis.

Methods: We analysed the standardized weekly scores on the 25-item abbreviated version of the Comprehensive Psychopathological Rating Scale (CPRS) in depressed patients before and during their first six weeks of ECT treatment. DTW analysis was used to analyse the (dis)similarity of time series of items scores at the patient level (300 'DTW distances' per patient) as well as on the group level. Hierarchical cluster, network, and Distatis analyses yielded symptom dimensions.

Results: We included 133 patients, 64.7% female, with an average age of 60.4 years (SD 15.1). Individual DTW distance matrices and networks revealed marked differences in hierarchical and network clusters among patients. Based on cluster analyses of the aggregated matrices, four symptom clusters emerged. In patients who reached remission, the average DTW distance between their symptoms was significantly smaller than non-remitters, reflecting denser symptom networks in remitters than non-remitters (p=0.04).

Limitations: The assessments were done only weekly during the first six weeks of ECT treatment. The use of individual items of the abbreviated CPRS may have led to measurement error as well as floor and ceiling effects.

Conclusion: DTW offers an efficient new approach to analyse symptom trajectories within individuals as well as groups of patients, aiding personalized medicine of psychopathology.
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http://dx.doi.org/10.1016/j.jad.2021.06.068DOI Listing
October 2021

The association between plasma tryptophan catabolites and depression: The role of symptom profiles and inflammation.

Brain Behav Immun 2021 10 9;97:167-175. Epub 2021 Jul 9.

Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC/Vrije Universiteit, Amsterdam, The Netherlands.

Background: Tryptophan catabolites ("TRYCATs") produced by the kynurenine pathway (KP) may play a role in depression pathophysiology. Studies comparing TRYCATs levels in depressed subjects and controls provided mixed findings. We examined the association of TRYCATs levels with 1) the presence of Major Depressive Disorder (MDD), 2) depressive symptom profiles and 3) inflammatory markers.

Methods: The sample from the Netherlands Study of Depression and Anxiety included participants with current (n = 1100) or remitted (n = 753) MDD DSM-IV diagnosis and healthy controls (n = 642). Plasma levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KynA), quinolinic acid (QA), C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured. Atypical/energy-related symptom (AES), melancholic symptom (MS) and anxious-distress symptom (ADS) profiles were derived from questionnaires.

Results: After adjustment for age, sex, education, smoking status, alcohol consumption and chronic diseases, no significant differences in TRYCATs were found comparing MDD cases versus controls. The MS profile was associated (q < 0.05) with lower KynA (β = -0.05), while AES was associated with higher KYN (β = 0.05), QA (β = 0.06) and TRP (β = 0.06). Inflammatory markers were associated with higher KYN (CRP β = 0.12, IL-6 β = 0.08, TNF β = 0.10) and QA (CRP β = 0.21, IL-6 β = 0.12, TNF β = 0.18). Significant differences against controls emerged after selecting MDD cases with high (top 30%) CRP (KYN d = 0.20, QA d = 0.33) and high TNF (KYN d = 0.24; QA d = 0.39).

Conclusions: TRYCATs levels were related to specific clinical and biological features, such as atypical symptoms or a proinflammatory status. Modulation of KP may potentially benefit a specific subset of depressed patients. Clinical studies should focus on patients with clear evidence of KP dysregulations.
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http://dx.doi.org/10.1016/j.bbi.2021.07.007DOI Listing
October 2021

Temporal relationships between happiness and psychiatric disorders and their symptom severity in a large cohort study: the Netherlands Study of Depression and Anxiety (NESDA).

BMC Psychiatry 2021 07 10;21(1):344. Epub 2021 Jul 10.

Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands.

Background: Notwithstanding the firmly established cross-sectional association of happiness with psychiatric disorders and their symptom severity, little is known about their temporal relationships. The goal of the present study was to investigate whether happiness is predictive of subsequent psychiatric disorders and symptom severity (and vice versa). Moreover, it was examined whether changes in happiness co-occur with changes in psychiatric disorder status and symptom severity.

Methods: In the Netherlands Study of Depression and Anxiety (NESDA), happiness (SRH: Self-Rated Happiness scale), depressive and social anxiety disorder (CIDI: Composite Interview Diagnostic Instrument) and depressive and anxiety symptom severity (IDS: Inventory of Depressive Symptomatology; BAI: Beck Anxiety Inventory; and FQ: Fear Questionnaire) were measured in 1816 adults over a three-year period. Moreover, we focused on occurrence and remittance of 6-month recency Major Depressive Disorder (MDD) and Social Anxiety Disorders (SAD) as the two disorders most intertwined with subjective happiness.

Results: Interindividual differences in happiness were quite stable (ICC of .64). Higher levels of happiness predicted recovery from depression (OR = 1.41; 95% CI = 1.10-1.80), but not social anxiety disorder (OR = 1.31; 95%CI = .94-1.81), as well as non-occurrence of depression (OR = 2.41; 95%CI = 1.98-2.94) and SAD (OR = 2.93; 95%CI = 2.29-3.77) in participants without MDD, respectively SAD at baseline. Higher levels of happiness also predicted a reduction of IDS depression (sr = - 0.08; 95%CI = -0.10 - -0.04), and BAI (sr = - 0.09; 95%CI = -0.12 - -0.05) and FQ (sr = - 0.06; 95%CI = -0.09 - -0.04) anxiety symptom scores. Conversely, presence of affective disorders, as well as higher depression and anxiety symptom severity at baseline predicted a subsequent reduction of self-reported happiness (with marginal to small sr values varying between -.04 (presence of SAD) to -.17 (depression severity on the IDS)). Moreover, changes in happiness were associated with changes in psychiatric disorders and their symptom severity, in particular with depression severity on the IDS (sr = - 0.46; 95%CI = -.50 - -.42).

Conclusions: Results support the view of rather stable interindividual differences in subjective happiness, although level of happiness is inversely associated with changes in psychiatric disorders and their symptom severity, in particular depressive disorder and depression severity.
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http://dx.doi.org/10.1186/s12888-021-03346-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272268PMC
July 2021

Common and specific determinants of 9-year depression and anxiety course-trajectories: A machine-learning investigation in the Netherlands Study of Depression and Anxiety (NESDA).

J Affect Disord 2021 10 24;293:295-304. Epub 2021 Jun 24.

University of Groningen, University Medical Center Groningen, Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion regulation (ICPE), Groningen, The Netherlands.

Background: Given the strong relationship between depression and anxiety, there is an urge to investigate their shared and specific long-term course determinants. The current study aimed to identify and compare the main determinants of the 9-year trajectories of combined and pure depression and anxiety symptom severity.

Methods: Respondents with a 6-month depression and/or anxiety diagnosis (n=1,701) provided baseline data on 152 sociodemographic, clinical and biological variables. Depression and anxiety symptom severity assessed at baseline, 2-, 4-, 6- and 9-year follow-up, were used to identify data-driven course-trajectory subgroups for general psychological distress, pure depression, and pure anxiety severity scores. For each outcome (class-probability), a Superlearner (SL) algorithm identified an optimally weighted (minimum mean squared error) combination of machine-learning prediction algorithms. For each outcome, the top determinants in the SL were identified by determining variable-importance and correlations between each SL-predicted and observed outcome (ρ) were calculated.

Results: Low to high prediction correlations (ρ: 0.41-0.91, median=0.73) were found. In the SL, important determinants of psychological distress were age, young age of onset, respiratory rate, participation disability, somatic disease, low income, minor depressive disorder and mastery score. For course of pure depression and anxiety symptom severity, similar determinants were found. Specific determinants of pure depression included several types of healthcare-use, and of pure-anxiety course included somatic arousal and psychological distress.

Limitations: Limited sample size for machine learning.

Conclusions: The determinants of depression- and anxiety-severity course are mostly shared. Domain-specific exceptions are healthcare use for depression and somatic arousal and distress for anxiety-severity course.
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http://dx.doi.org/10.1016/j.jad.2021.06.029DOI Listing
October 2021

Efficacy of combined oral contraceptives for depressive symptoms and overall symptomatology in premenstrual syndrome: pairwise and network meta-analysis of randomized trials.

Am J Obstet Gynecol 2021 12 2;225(6):624-633. Epub 2021 Jul 2.

Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Objective: Combined oral contraceptives are often considered a treatment option for women with premenstrual syndrome or premenstrual dysphoric disorder also seeking contraception, but evidence for this treatment is scarce. We aimed to determine (1) the level of evidence for the efficacy of combined oral contraceptives in managing premenstrual depressive symptoms and overall premenstrual symptomatology and (2) the comparative efficacy of combined oral contraceptives (the International Prospective Register of Systematic Reviews registration number CRD42020205510).

Data Sources: We searched Cochrane Central Register of Controlled Trials, PubMed, Web of Science, PsycINFO, EMCare, and Embase from inception to June 3, 2021.

Study Eligibility Criteria: All randomized clinical trials that evaluated the efficacy of combined oral contraceptives in women with premenstrual syndrome or premenstrual dysphoric disorder were considered eligible for inclusion in this meta-analysis.

Study Appraisal And Synthesis Methods: A random effect Bayesian pairwise and network meta-analysis was conducted with change in premenstrual depressive symptoms and overall premenstrual symptomatology between baseline and 3 cycles as outcome. Certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach.

Results: Of 3664 records, 9 eligible trials were included that studied 1205 women with premenstrual syndrome or premenstrual dysphoric disorder (mean age per study range, 24.6-36.5 years). The pairwise meta-analysis revealed that combined oral contraceptives were more efficacious than placebo in treating overall premenstrual symptomatology (standardized mean difference, 0.41; 95% credible interval, 0.17-0.67), but not premenstrual depressive symptoms specifically (standardized mean difference, 0.22; 95% credible interval, -0.06 to 0.47). However, none of the combined oral contraceptives were more effective than each other in reducing premenstrual depressive symptoms and overall premenstrual symptomatology.

Conclusion: Combined oral contraceptives may improve overall premenstrual symptomatology in women with premenstrual syndrome or premenstrual dysphoric disorder, but not premenstrual depressive symptoms. There is no evidence for one combined oral contraceptive being more efficacious than any other.
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http://dx.doi.org/10.1016/j.ajog.2021.06.090DOI Listing
December 2021

Hormonal contraceptive use and depressive symptoms: systematic review and network meta-analysis of randomised trials.

BJPsych Open 2021 Jun 8;7(4):e110. Epub 2021 Jun 8.

Department of Psychiatry, University Medical Center Leiden, The Netherlands.

Background: Observational studies suggest that hormonal contraceptive use may increase depressive symptoms in women, but it is unclear whether the effect is causal.

Aims: To quantitatively examine the evidence from randomised clinical trials for the link between hormonal contraceptive use and depressive symptoms.

Method: We performed a systematic review and network meta-analysis of randomised clinical trials comparing women randomised to any form of a hormonal contraceptive with women randomised to any other form of a (non-)hormonal contraceptive or placebo. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, PsycINFO, EMCare and EMBASE, from inception to 1 May 2020. Certainty of the evidence was assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. A random-effect Bayesian network meta-analysis was conducted, with change in depressive symptoms between baseline and three cycles as outcome.

Results: This review identified 3492 records, of which 14 trials were eligible and 12 could be included in the network meta-analysis. These trials included 5833 participants (mean age per study range: 16.8-32.4 years) and compared 10 different interventions. Compared with placebo, hormonal contraceptive use did not cause worsening of depressive symptoms (standardised mean difference: median, -0.04; range, -0.17 [95% credible interval -0.46 to 0.13] to 0.13 [95% credible interval -0.28 to 0.56]).

Conclusions: This study suggests that hormonal contraceptive use does not lead to an increase in depressive symptoms in adult women. Future studies should include first-time users, to confirm the results in young women.
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http://dx.doi.org/10.1192/bjo.2021.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220855PMC
June 2021

Tryptophan Catabolites in Bipolar Disorder: A Meta-Analysis.

Front Immunol 2021 19;12:667179. Epub 2021 May 19.

Faculty of Medicine and Health Sciences, Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp, Antwerp, Belgium.

Objective: Tryptophan catabolites (TRYCATs) are implicated in the pathophysiology of mood disorders by mediating immune-inflammation and neurodegenerative processes. We performed a meta-analysis of TRYCAT levels in bipolar disorder (BD) patients compared to healthy controls.

Methods: A systematic literature search in seven electronic databases (PubMed, Embase, Web of Science, Cochrane, Emcare, PsycINFO, Academic Search Premier) was conducted on TRYCAT levels in cerebrospinal fluid or peripheral blood according to the PRISMA statement. A minimum of three studies per TRYCAT was required for inclusion. Standardized mean differences (SMD) were computed using random effect models. Subgroup analyses were performed for BD patients in a different mood state (depressed, manic). The methodological quality of the studies was rated using the modified Newcastle-Ottawa Quality assessment Scale.

Results: Twenty-one eligible studies were identified. Peripheral levels of tryptophan (SMD = -0.44; < 0.001), kynurenine (SMD = - 0.3; = 0.001) and kynurenic acid (SMD = -.45; = < 0.001) were lower in BD patients versus healthy controls. In the only three eligible studies investigating TRP in cerebrospinal fluid, tryptophan was not significantly different between BD and healthy controls. The methodological quality of the studies was moderate. Subgroup analyses revealed no significant difference in TRP and KYN values between manic and depressed BD patients, but these results were based on a limited number of studies.

Conclusion: The TRYCAT pathway appears to be downregulated in BD patients. There is a need for more and high-quality studies of peripheral and central TRYCAT levels, preferably using longitudinal designs.
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http://dx.doi.org/10.3389/fimmu.2021.667179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170319PMC
October 2021

Plasma androgens and the presence and course of depression in a large cohort of men.

Psychoneuroendocrinology 2021 08 19;130:105278. Epub 2021 May 19.

Department of Psychiatry, University of Groningen / University Medical Center Groningen, 9700 RB, PO Box 30.001 (CC 43), Groningen, The Netherlands. Electronic address:

Background: Hypoandrogenic men showed a higher prevalence of major depressive disorder (MDD), which could be ascribed to overlapping symptoms such as sexual dysfunction, or additionally to core emotional symptoms such as sadness and anhedonia. We examined whether androgen levels 1) differ between men with and without MDD cross-sectionally, 2) are associated with an elevated risk for onset of MDD prospectively, and 3) associate with all individual MDD symptoms, or only with hypogonadism overlapping symptoms.

Methods: In 823 men (mean age 43.5 years), baseline plasma levels of total testosterone, 5α-dihydrotestosterone (5α-DHT), and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulphate (DHEAS) and sex hormone binding globulin with radioimmunoassay, whereas free testosterone was calculated. MDD status was assessed at baseline and after two years using structured interviews and individual MDD symptoms were self-rated at baseline, and after one and two years.

Results: None of the androgen levels were associated with current or onset (incidence or recurrence) of MDD. Free testosterone was only inversely associated with interest in sex. Also, androstenedione and DHEAS were positively associated with some individual MDD symptoms, and 5α-DHT levels showed non-linear associations (both with low and high levels) with MDD symptom severity and several individual MDD symptoms.

Conclusions: These results support the idea that circulating androgens synthesised by the testes are of limited clinical relevance to MDD in adult men, but levels of androstenedione, DHEAS and 5α-DHT may be associated with some individual MDD symptoms.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105278DOI Listing
August 2021

Metabolomic profiles discriminating anxiety from depression.

Acta Psychiatr Scand 2021 08 25;144(2):178-193. Epub 2021 May 25.

Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Amsterdam, the Netherlands.

Objective: Depression has been associated with metabolomic alterations. Depressive and anxiety disorders are often comorbid diagnoses and are suggested to share etiology. We investigated whether differential metabolomic alterations are present between anxiety and depressive disorders and which clinical characteristics of these disorders are related to metabolomic alterations.

Methods: Data were from the Netherlands Study of Depression and Anxiety (NESDA), including individuals with current comorbid anxiety and depressive disorders (N = 531), only a current depression (N = 304), only a current anxiety disorder (N = 548), remitted depressive and/or anxiety disorders (N = 897), and healthy controls (N = 634). Forty metabolites from a proton nuclear magnetic resonance lipid-based metabolomics panel were analyzed. First, we examined differences in metabolites between disorder groups and healthy controls. Next, we assessed whether depression or anxiety clinical characteristics (severity and symptom duration) were associated with metabolites.

Results: As compared to healthy controls, seven metabolomic alterations were found in the group with only depression, reflecting an inflammatory (glycoprotein acetyls; Cohen's d = 0.12, p = 0.002) and atherogenic-lipoprotein-related (e.g., apolipoprotein B: Cohen's d = 0.08, p = 0.03, and VLDL cholesterol: Cohen's d = 0.08, p = 0.04) profile. The comorbid group showed an attenuated but similar pattern of deviations. No metabolomic alterations were found in the group with only anxiety disorders. The majority of metabolites associated with depression diagnosis were also associated with depression severity; no associations were found with anxiety severity or disease duration.

Conclusion: While substantial clinical overlap exists between depressive and anxiety disorders, this study suggests that altered inflammatory and atherogenic-lipoprotein-related metabolomic profiles are uniquely associated with depression rather than anxiety disorders.
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http://dx.doi.org/10.1111/acps.13310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361773PMC
August 2021

Cohort profile of the longitudinal Netherlands Study of Depression and Anxiety (NESDA) on etiology, course and consequences of depressive and anxiety disorders.

J Affect Disord 2021 05 17;287:69-77. Epub 2021 Mar 17.

Department of Psychiatry, Amsterdam Public Health, Amsterdam University Medical Center, Vrije Universiteit, and GGZ InGeest Specialized Mental Health Care, Amsterdam, The Netherlands (Oldenaller 1, 1081 HJ Amsterdam, The Netherlands).

Introduction: The Netherlands Study of Depression and Anxiety (NESDA, www.nesda.nl) is a longitudinal, multi-site, naturalistic, case-control cohort study set up to examine the etiology, course and consequences of depressive and anxiety disorders. This paper presents a cohort profile of NESDA.

Methods And Results: The NESDA sample recruited initially 2329 persons with a remitted or current DSM-IV based depressive (major depressive disorder, dysthymia) and/or anxiety disorder (panic disorder, social phobia, agoraphobia, generalized anxiety disorder), 367 of their siblings and 652 healthy controls, yielding a total of 3348 participants. Half-day face-to-face assessments of participants started in 2004 and since then have been repeated six times over a period of 9 years. A 13-year follow-up assessment is ongoing, at what time we also recruit offspring of participants. Retention rates are generally high, ranging from 87.1% (after 2 years) to 69.4% (after 9 years). Psychiatric diagnostic interviews have been administered at all face-to-face assessments, as was monitoring of clinical characteristics, psychosocial functioning and somatic health. Assessed etiological factors include e.g. early and current environmental risk factors, psychological vulnerability and resilience factors as well as (neuro)biology through hypothesis-driven biomarker assessments, genome-wide and large-scale '-omics' assessments, and neuroimaging assessments.

Limitations: The naturalistic design allows research into course and consequences of affective disorders but is limited in treatment response interpretation.

Conclusions: NESDA provides a strong research infrastructure for research into depressive and/or anxiety disorders. Its data have been used for many scientific papers describing either NESDA-based analyses or joint collaborative consortia-projects, and are in principle available to researchers outside the NESDA consortium.
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http://dx.doi.org/10.1016/j.jad.2021.03.026DOI Listing
May 2021

Predicting the 9-year course of mood and anxiety disorders with automated machine learning: A comparison between auto-sklearn, naïve Bayes classifier, and traditional logistic regression.

Psychiatry Res 2021 05 24;299:113823. Epub 2021 Feb 24.

Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands.

Background: Predicting the onset and course of mood and anxiety disorders is of clinical importance but remains difficult. We compared the predictive performances of traditional logistic regression, basic probabilistic machine learning (ML) methods, and automated ML (Auto-sklearn).

Methods: Data were derived from the Netherlands Study of Depression and Anxiety. We compared how well multinomial logistic regression, a naïve Bayes classifier, and Auto-sklearn predicted depression and anxiety diagnoses at a 2-, 4-, 6-, and 9-year follow up, operationalized as binary or categorical variables. Predictor sets included demographic and self-report data, which can be easily collected in clinical practice at two initial time points (baseline and 1-year follow up).

Results: At baseline, participants were 42.2 years old, 66.5% were women, and 53.6% had a current mood or anxiety disorder. The three methods were similarly successful in predicting (mental) health status, with correct predictions for up to 79% (95% CI 75-81%). However, Auto-sklearn was superior when assessing a more complex dataset with individual item scores.

Conclusions: Automated ML methods added only limited value, compared to traditional data modelling when predicting the onset and course of depression and anxiety. However, they hold potential for automatization and may be better suited for complex datasets.
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http://dx.doi.org/10.1016/j.psychres.2021.113823DOI Listing
May 2021

Plasma androgens and the presence and course of depression in a large cohort of women.

Transl Psychiatry 2021 02 12;11(1):124. Epub 2021 Feb 12.

University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands.

Major depressive disorder (MDD) has a higher prevalence in women with supraphysiologic androgen levels. Whether there is also an association between depression and androgen levels in the physiological range, is unknown. This study examined if women with current MDD have higher androgen levels compared to women who have never had MDD, and if androgen levels are associated with onset and remission of MDD. In 1659 women (513 current MDD, 754 remitted MDD, and 392 never MDD), baseline plasma levels of total testosterone, 5α-dihydrotestosterone, and androstenedione were determined with liquid chromatography-tandem mass spectrometry, and dehydroepiandrosterone-sulfate and sex hormone binding globulin (SHBG) with radioimmunoassays. Free testosterone was calculated. MDD status was assessed at baseline, and at 2 and 4 years follow-up. Women were aged between 18 and 65 years (mean age 41) with total testosterone levels in the physiological range (geometric mean 0.72 nmol/L [95% CI 0.27-1.93]). After adjusting for covariates and multiple testing, women with current MDD had a higher mean free testosterone than women who never had MDD (adjusted geometric mean 8.50 vs. 7.55 pmol/L, p = 0.0005), but this difference was not large enough to be considered clinically meaningful as it was consistent with statistical equivalence. Levels of other androgens and SHBG did not differ and were also statistically equivalent between the groups. None of the androgens or SHBG levels predicted onset or remission of MDD. Our findings support the idea that plasma androgens within the physiological range have no or only limited effects on depressive disorders in women.
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http://dx.doi.org/10.1038/s41398-021-01249-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881099PMC
February 2021

An integrated approach to understand biological stress system dysregulation across depressive and anxiety disorders.

J Affect Disord 2021 03 27;283:139-146. Epub 2021 Jan 27.

Department of Psychiatry (GGZ inGeest), Amsterdam UMC (location VUmc), Vrije University, Amsterdam Public Health and Amsterdam Neuroscience Research Institutes, Amsterdam, the Netherlands.

Background: Affective disorders involve dysregulation of major biological stress systems (hypothalamic-pituitary-adrenal (HPA)-axis, immune system, autonomic nervous system (ANS)). Suchdysregulationshave rarely beensimultaneously examined across different stress systems.

Methods: In the Netherlands Study of Depression and Anxiety (n=2789), we investigated whether current or remitted depressive and/or anxiety disorders (based on the CIDI semi-structured interview), including specific symptom profiles, were associated with separate markers and cumulative indexes of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), immune system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period).

Results: Depressive andanxiety disorderswere significantlyassociated with changes in three biological stress systemsincluding HPA-axis hyperactivity, increased inflammatory activity, and a higher ANS tone, particularly for integrative and cumulative indexes of these stress systems (pFDR <.05) vs. controls. The strongest associations were seen with current disorders andcumulative indexes of the HPA-axis (β=.124, pFDR=.001), the immune system (β =.057, pFDR=.032), and total cumulative index across stress systems (β=.102, pFDR=.004). Atypical, energy-related depression severity was linked to immune system markers (pFDR<0.001), melancholic depression severity to HPA-axis markers (pFDR=.032), and anxiety arousal severity to both HPA-axis and immune system markers (pFDR<0.05). Findings were partially explained by poorer lifestyle, more chronic diseases,or (especially for ANS-function) antidepressant use.

Limitations: Cross-sectional analyses limit examination of temporal associations.

Conclusion: Patients withdepressive and anxiety disorders showed consistent dysregulation across biological stress systems, particularly for current episodes.To understand stress system functionality in affective disorders, an integrated approach capturing cumulative stress indices within and across biological stress systems is important.
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http://dx.doi.org/10.1016/j.jad.2021.01.051DOI Listing
March 2021

Anger and cluster B personality traits and the conversion from unipolar depression to bipolar disorder.

Depress Anxiety 2021 06 27;38(6):671-681. Epub 2021 Jan 27.

Department of Mood Disorders, Mental Health Care PsyQ Kralingen, Rotterdam, The Netherlands.

Introduction: Feelings of anger and irritability are prominent symptoms of bipolar disorder (BD) that may occur during hypomanic, depressive and, especially, during mixed mood states. We aimed to determine whether such constructs are associated with the conversion to BD in subjects with a history of unipolar depression.

Methods: Data were derived from the depressed participants of Netherlands Study of Depression and Anxiety with 9 years of follow-up. Hypomania was ascertained using the Composite International Diagnostic Interview at 2, 4, 6, and 9 years follow-up. Cross-sectionally, we studied the association between prevalent hypomania and anger related constructs with the "Spielberger Trait Anger subscale," the "Anger Attacks" questionnaire, the cluster B personality traits part of the "Personality Disorder Questionnaire," and "aggression reactivity." Prospectively, we studied whether aggression reactivity predicted incident hypomania using Cox regression analyses.

Results: Cross-sectionally, the bipolar conversion group (n = 77) had significantly higher scores of trait anger and aggression reactivity, as well as a higher prevalence on "anger attacks," "antisocial traits," and "borderline traits" compared to current (n = 349) as well as remitted (n = 1159) depressive patients. In prospective analyses in 1744 participants, aggression reactivity predicted incident hypomania (n = 28), with a multivariate-adjusted hazard ratio of 1.4 (95% confidence interval: 1.02-1.93; p = .037).

Conclusion: Anger is a risk factor for conversion from unipolar depression to BD. In addition, patients who converted to BD showed on average more anger, agitation and irritability than people with a history of unipolar depression who had not converted.
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http://dx.doi.org/10.1002/da.23137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248435PMC
June 2021

Predictors of irritability symptoms in mildly depressed perimenopausal women.

Psychoneuroendocrinology 2021 04 7;126:105128. Epub 2021 Jan 7.

Connors Center for Women's Health and Gender Biology / Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Thorn 1117, MA 02115, United States. Electronic address:

Objective: Irritability is a highly burdensome complaint, commonly, but not universally, linked with depressive symptoms. While increased variability in estradiol has been associated with depressive symptoms during perimenopause, more insight is needed into reproductive hormone dynamics and other factors that predispose perimenopausal women to irritable mood.

Methods: Among 50 mildly depressed perimenopausal women (mean (SD) age 48.4 (3.9) years), severity of irritability symptoms (on Symptom Questionnaire Hostility subscale, range 0-23) was assessed weekly for eight weeks, concurrent with potential predictors. Associations between these were examined using generalized estimating equating models.

Results: Most women (82.0%) reported having moderate to severe irritability at least once. However, the severity of irritability was highly variable from week-to-week (between-subject mean coefficient of variation [CV] 72.9% and within-subject mean CV 63.7%). In multivariate analyses, less variable serum estradiol levels (standardized β within-person CV -0.23 95%CI [-0.32, -0.14], p < 0.001), greater depression severity (0.45 [0.35, 0.56], p < 0.001), younger age (-0.23, [-0.28, -0.09], p < 0.001), and more frequent vasomotor symptoms (0.14 [0.05, 0.23], p = 0.002) were associated with more irritability. Depression severity explained the largest portion of the variance in irritability, but still not more than 20.3%. Neither crude values, weekly change in, or variability of progesterone or FSH levels were associated with irritability.

Conclusions: Irritability was highly prevalent among mildly depressed perimenopausal women. In contrast to depressive symptoms, decreased rather than increased variability in estradiol levels was associated with more irritability. This highlights that irritable mood can be disentangled from depressive symptoms in perimenopausal women and might be linked with different estradiol dynamics.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105128DOI Listing
April 2021

The role of depressive symptoms and symptom dimensions in actigraphy-assessed sleep, circadian rhythm, and physical activity.

Psychol Med 2021 Jan 12:1-7. Epub 2021 Jan 12.

Department of Psychiatry, Amsterdam UMC, Vrije Universiteit, Amsterdam Public Health research institute, Amsterdam, The Netherlands.

Background: Considering the heterogeneity of depression, distinct depressive symptom dimensions may be differentially associated with more objective actigraphy-based estimates of physical activity (PA), sleep and circadian rhythm (CR). We examined the association between PA, sleep, and CR assessed with actigraphy and symptom dimensions (i.e. mood/cognition, somatic/vegetative, sleep).

Methods: Fourteen-day actigraphy data of 359 participants were obtained from the Netherlands Study of Depression and Anxiety. PA, sleep, and CR estimates included gross motor activity (GMA), sleep duration (SD), sleep efficiency (SE), relative amplitude between daytime and night-time activity (RA) and sleep midpoint. The 30-item Inventory of Depressive Symptomatology was used to assess depressive symptoms, which were categorised in three depression dimensions: mood/cognition, somatic/vegetative, and sleep.

Results: GMA and RA were negatively associated with higher score on all three symptom dimensions: mood/cognition (GMA: β = -0.155, p < 0.001; RA: β = -0.116, p = 0.002), somatic/vegetative (GMA: β = -0.165, p < 0.001; RA: β = -0.133, p < 0.001), sleep (GMA: β = -0.169, p < 0.001; RA: β = -0.190, p < 0.001). The association with sleep was more pronounced for two depression dimensions: longer SD was linked to somatic/vegetative (β = 0.115, p = 0.015) dimension and lower SE was linked to sleep (β = -0.101, p = 0.011) dimension.

Conclusion: As three symptom dimensions were associated with actigraphy-based low PA and dampened CR, these seem to be general indicators of depression. Sleep disturbances appeared more linked to the somatic/vegetative and sleep dimensions; the effectiveness of sleep interventions in patients reporting somatic/vegetative symptoms may be explored, as well as the potential of actigraphy to monitor treatment response to such interventions.
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http://dx.doi.org/10.1017/S0033291720004870DOI Listing
January 2021

The mental health impact of the COVID-19 pandemic on people with and without depressive, anxiety, or obsessive-compulsive disorders: a longitudinal study of three Dutch case-control cohorts.

Lancet Psychiatry 2021 02 8;8(2):121-129. Epub 2020 Dec 8.

Department of Psychiatry, Amsterdam Public Health, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, Netherlands; Geestelijke gezondheidszorg (GGZ) InGeest Specialized Mental Health Care, Amsterdam, Netherlands.

Background: The impact of the COVID-19 pandemic on mental health in people with pre-existing mental health disorders is unclear. In three psychiatry case-control cohorts, we compared the perceived mental health impact and coping and changes in depressive symptoms, anxiety, worry, and loneliness before and during the COVID-19 pandemic between people with and without lifetime depressive, anxiety, or obsessive-compulsive disorders.

Methods: Between April 1 and May 13, 2020, online questionnaires were distributed among the Netherlands Study of Depression and Anxiety, Netherlands Study of Depression in Older Persons, and Netherlands Obsessive Compulsive Disorder Association cohorts, including people with (n=1181) and without (n=336) depressive, anxiety, or obsessive-compulsive disorders. The questionnaire contained questions on perceived mental health impact, fear of COVID-19, coping, and four validated scales assessing depressive symptoms, anxiety, worry, and loneliness used in previous waves during 2006-16. Number and chronicity of disorders were based on diagnoses in previous waves. Linear regression and mixed models were done.

Findings: The number and chronicity of disorders showed a positive graded dose-response relation, with greater perceived impact on mental health, fear, and poorer coping. Although people with depressive, anxiety, or obsessive-compulsive disorders scored higher on all four symptom scales than did individuals without these mental health disorders, both before and during the COVID-19 pandemic, they did not report a greater increase in symptoms during the pandemic. In fact, people without depressive, anxiety, or obsessive-compulsive disorders showed a greater increase in symptoms during the COVID-19 pandemic, whereas individuals with the greatest burden on their mental health tended to show a slight symptom decrease.

Interpretation: People with depressive, anxiety, or obsessive-compulsive disorders are experiencing a detrimental impact on their mental health from the COVID-19 pandemic, which requires close monitoring in clinical practice. Yet, the COVID-19 pandemic does not seem to have further increased symptom severity compared with their prepandemic levels.

Funding: Dutch Research Council.
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http://dx.doi.org/10.1016/S2215-0366(20)30491-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831806PMC
February 2021

Assessment of Factors Associated With Long-term Posttraumatic Stress Symptoms Among 56 388 First Responders After the 2011 Great East Japan Earthquake.

JAMA Netw Open 2020 09 1;3(9):e2018339. Epub 2020 Sep 1.

Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands.

Importance: First responders are at risk for developing symptoms of posttraumatic stress disorder (PTSD). Little is known about the risk factors for developing PTSD during a years-long period after complex mass disasters.

Objective: To explore the long-term course of PTSD symptoms and to identify risk factors and their relative association with PTSD among first responders dispatched to the 2011 Japanese earthquake, tsunami, and nuclear disaster.

Design, Setting, And Participants: This 6-year, large, prospective cohort study was part of a continuous longitudinal study of Japan Ground Self-Defense Force first responders. The data were collected at 1, 6, 12, 24, 36, 48, 60, and 72 months after mission completion from 2011 to 2017. Of approximately 70 000 eligible participants, 56 388 were enrolled in this study. Data were analyzed from 2017 to 2020.

Exposures: Stress exposures owing to personal or professional disaster experience (eg, duties with body recovery or radiation exposure risk) and working conditions (eg, deployment length, postdeployment overtime work).

Main Outcomes And Measures: The Impact of Event Scale-Revised score assessed PTSD symptoms; scores of at least 25 were defined as probable PTSD. Cox proportional hazards regression models assessed the risk factors for incidence of probable PTSD.

Results: Among the 56 388 participants, 97.1% were men, and the median age at enrollment was 34 (range, 18-63) years. A probable PTSD rate was 2.7% at 1 month and showed a downward trend in the first year and a subsequent plateau. The cumulative incidence of probable PTSD was 6.75%. The severity of PTSD symptoms demonstrated a high degree of rank-order stability over time. Rather than professional disaster experience, sociodemographic factors and working conditions were independently associated with the incidence of probable PTSD: personal experience of the disaster (hazard ratio [HR], 1.96; 95% CI, 1.72-2.24), deployment length of at least 3 months (HR vs <1 month, 1.75; 95% CI, 1.52-2.02), increased age (HR for ≥46 vs ≤25 years, 2.28; 95% CI, 1.79-2.92), and postdeployment overtime work of at least 3 months (HR vs little to none, 1.61; 95% CI, 1.39-1.87).

Conclusions And Relevance: Given these findings, in the future, first responders' PTSD symptoms might be mitigated by shortening deployment length, avoiding postdeployment overtime work, and paying special attention to the needs of personnel with personal experience of the disaster or older age. Efforts to alleviate responders' initial symptoms will be required.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.18339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525349PMC
September 2020

Comorbidity between depression and anxiety: assessing the role of bridge mental states in dynamic psychological networks.

BMC Med 2020 09 29;18(1):308. Epub 2020 Sep 29.

Department of Psychiatry, Interdisciplinary Center for Psychopathology and Emotion regulation (ICPE), University Medical Center Groningen (UMCG), University of Groningen, PO Box 30.001, 9700 RB, Groningen, the Netherlands.

Background: Comorbidity between depressive and anxiety disorders is common. A hypothesis of the network perspective on psychopathology is that comorbidity arises due to the interplay of symptoms shared by both disorders, with overlapping symptoms acting as so-called bridges, funneling symptom activation between symptom clusters of each disorder. This study investigated this hypothesis by testing whether (i) two overlapping mental states "worrying" and "feeling irritated" functioned as bridges in dynamic mental state networks of individuals with both depression and anxiety as compared to individuals with either disorder alone, and (ii) overlapping or non-overlapping mental states functioned as stronger bridges.

Methods: Data come from the Netherlands Study of Depression and Anxiety (NESDA). A total of 143 participants met criteria for comorbid depression and anxiety (65%), 40 participants for depression-only (18.2%), and 37 for anxiety-only (16.8%) during any NESDA wave. Participants completed momentary assessments of symptoms (i.e., mental states) of depression and anxiety, five times a day, for 2 weeks (14,185 assessments). First, dynamics between mental states were modeled with a multilevel vector autoregressive model, using Bayesian estimation. Summed average lagged indirect effects through the hypothesized bridge mental states were compared between groups. Second, we evaluated the role of all mental states as potential bridge mental states.

Results: While the summed indirect effect for the bridge mental state "worrying" was larger in the comorbid group compared to the single disorder groups, differences between groups were not statistically significant. The difference between groups became more pronounced when only examining individuals with recent diagnoses (< 6 months). However, the credible intervals of the difference scores remained wide. In the second analysis, a non-overlapping item ("feeling down") acted as the strongest bridge mental state in both the comorbid and anxiety-only groups.

Conclusions: This study empirically examined a prominent network-approach hypothesis for the first time using longitudinal data. No support was found for overlapping mental states "worrying" and "feeling irritable" functioning as bridge mental states in individuals vulnerable for comorbid depression and anxiety. Potentially, bridge mental state activity can only be observed during acute symptomatology. If so, these may present as interesting targets in treatment, but not prevention. This requires further investigation.
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http://dx.doi.org/10.1186/s12916-020-01738-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523307PMC
September 2020

The incidence and economic impact of aggression in closed long-stay psychiatric wards.

Int J Psychiatry Clin Pract 2021 Nov 21;25(4):430-436. Epub 2020 Sep 21.

Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.

Objective: Aggressive behaviour is highly prevalent in long-term psychiatric inpatient care. We aimed to estimate the overall incidence of aggression, the time staff took to handle aggression incidents, and the weighted average financial costs thereof.

Methods: A random sampling procedure was conducted at long-term psychiatric inpatient care facilities. Nurses were asked to recall all incidents (i.e., verbal, physical towards objects, self, or others) of their shift. For the time spent on each type of incident, staff were monitored in real-time. Estimated costs were calculated by the time spent multiplied by hourly wages in addition to material-related costs.

Results: Incidence rates were 90 incidents per patient year. The average time spent per incident was 125 min but differed for each type of incident. Almost 80% of this time was consumed by nursing staff. The average cost per aggression incident was €78; extrapolated per patient year, the total costs were approximately €7000.

Conclusions: The current study found a high rate of aggression incidents in closed long-stay psychiatric wards. Reports of aggression on these types of wards are scarce. Nevertheless, aggression seems to have a severe impact on invested time and related costs, which suggests a need for aggression-prevention and de-escalating programs.Key pointsAggression incidents are highly prevalent and are accompanied by high costs.The effect of aggression incidents on the workload for staff members is high, especially for nursing staff.Studies across countries on the incidence and the costs of aggression among psychiatric inpatients are needed to help model the effects of (new) strategies for aggression reduction.
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http://dx.doi.org/10.1080/13651501.2020.1821894DOI Listing
November 2021

Childhood trauma and dysregulation of multiple biological stress systems in adulthood: Results from the Netherlands Study of Depression and Anxiety (NESDA).

Psychoneuroendocrinology 2020 11 20;121:104835. Epub 2020 Aug 20.

Department of Psychiatry (GGZ inGeest), Amsterdam UMC (location VUmc), Vrije University, Amsterdam Public Health and Amsterdam Neuroscience Research Institutes, Amsterdam, the Netherlands. Electronic address:

Background: Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. Although dysregulated biological stress systems may underlie the enduring effect of CT, the relation between CT and separate and cumulative activity of the major stress systems, namely, the hypothalamic-pituitary-adrenal (HPA)-axis, the immune-inflammatory system, and the autonomic nervous system (ANS), remains inconclusive.

Methods: In the Netherlands Study of Depression and Anxiety (NESDA, n = 2778), we determined whether self-reported CT (as assessed by the Childhood Trauma Interview) was associated with separate and cumulative markers of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), the immune-inflammatory system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period) in adulthood.

Results: Almost all individuals with CT (n = 1330) had either current or remitted depressive and/or anxiety disorder (88.6%). Total-sample analyses showed little evidence for CT being significantly associated with the separate or cumulative stress systems' activity in adulthood. These findings were true for individuals with and without depressive and/or anxiety disorders. To maximize contrast, individuals with severe CT were compared to healthy controls without CT. This yielded slight, but significantly higher levels of cortisol awakening response (AUCg, β = .088, p =  .007; AUCi, β = .084, p =  .010), cumulative HPA-axis markers (β = .115, p =  .001), C-reactive protein (β = .055, p = .032), interleukin-6 (β = .053, p =  .038), cumulative inflammation (β = .060, p =  .020), and cumulative markers across all systems (β = .125, p =  .0003) for those with severe CT, partially explained by higher rates of smoking, body mass index, and chronic diseases.

Conclusion: While our findings do not provide conclusive evidence on CT directly dysregulating stress systems, individuals with severe CT showed slight indications of dysregulations, partially explained by an unhealthy lifestyle and poorer health.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104835DOI Listing
November 2020

Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression.

Transl Psychiatry 2020 07 15;10(1):235. Epub 2020 Jul 15.

Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.

Multiple studies show an association between inflammatory markers and major depressive disorder (MDD). People with chronic low-grade inflammation may be at an increased risk of MDD, often in the form of sickness behaviors. We hypothesized that inflammation is predictive of the severity and the course of a subset of MDD symptoms, especially symptoms that overlap with sickness behavior, such as anhedonia, anorexia, low concentration, low energy, loss of libido, psychomotor slowness, irritability, and malaise. We tested the association between basal and lipopolysaccharide (LPS)-induced inflammatory markers with individual MDD symptoms (measured using the Inventory of Depressive Symptomatology Self-Report) over a period of up to 9 years using multivariate-adjusted mixed models in 1147-2872 Netherlands Study of Depression and Anxiety (NESDA) participants. At baseline, participants were on average 42.2 years old, 66.5% were women and 53.9% had a current mood or anxiety disorder. We found that basal and LPS-stimulated inflammatory markers were more strongly associated with sickness behavior symptoms at up to 9-year follow-up compared with non-sickness behavior symptoms of depression. However, we also found significant associations with some symptoms that are not typical of sickness behavior (e.g., sympathetic arousal among others). Inflammation was not related to depression as a unified syndrome but rather to the presence and the course of specific MDD symptoms, of which the majority were related to sickness behavior. Anti-inflammatory strategies should be tested in the subgroup of MDD patients who report depressive symptoms related to sickness behavior.
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http://dx.doi.org/10.1038/s41398-020-00920-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363825PMC
July 2020
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