Publications by authors named "Brenda W J H Penninx"

620 Publications

Contributing factors to advanced brain aging in depression and anxiety disorders.

Transl Psychiatry 2021 Jul 21;11(1):402. Epub 2021 Jul 21.

Department of Psychiatry, Amsterdam University Medical Centers, Vrije Universiteit and GGZ inGeest, Amsterdam Neuroscience, Amsterdam, The Netherlands.

Depression and anxiety are common and often comorbid mental health disorders that represent risk factors for aging-related conditions. Brain aging has shown to be more advanced in patients with major depressive disorder (MDD). Here, we extend prior work by investigating multivariate brain aging in patients with MDD, anxiety disorders, or both, and examine which factors contribute to older-appearing brains. Adults aged 18-57 years from the Netherlands Study of Depression and Anxiety underwent structural MRI. A pretrained brain-age prediction model based on >2000 samples from the ENIGMA consortium was applied to obtain brain-predicted age differences (brain PAD, predicted brain age minus chronological age) in 65 controls and 220 patients with current MDD and/or anxiety. Brain-PAD estimates were associated with clinical, somatic, lifestyle, and biological factors. After correcting for antidepressant use, brain PAD was significantly higher in MDD (+2.78 years, Cohen's d = 0.25, 95% CI -0.10-0.60) and anxiety patients (+2.91 years, Cohen's d = 0.27, 95% CI -0.08-0.61), compared with controls. There were no significant associations with lifestyle or biological stress systems. A multivariable model indicated unique contributions of higher severity of somatic depression symptoms (b = 4.21 years per unit increase on average sum score) and antidepressant use (-2.53 years) to brain PAD. Advanced brain aging in patients with MDD and anxiety was most strongly associated with somatic depressive symptomatology. We also present clinically relevant evidence for a potential neuroprotective antidepressant effect on the brain-PAD metric that requires follow-up in future research.
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http://dx.doi.org/10.1038/s41398-021-01524-2DOI Listing
July 2021

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

Brain Behav Immun 2021 Jul 9. 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
July 2021

Benzodiazepines for the long-term treatment of anxiety disorders? - Authors' reply.

Lancet 2021 Jul;398(10295):120

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt-Goethe University, Frankfurt, Germany.

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http://dx.doi.org/10.1016/S0140-6736(21)00931-4DOI Listing
July 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 Jul 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 Jun 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
June 2021

Using the Power of a Giant Wisely: Confirming Inflammation in Depression.

Am J Psychiatry 2021 06;178(6):480-482

Department of Psychiatry, Amsterdam UMC, Vrije Universiteit, the Netherlands.

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http://dx.doi.org/10.1176/appi.ajp.2021.21040332DOI Listing
June 2021

Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts.

Mol Psychiatry 2021 Jun 16. Epub 2021 Jun 16.

Department of Psychiatry, University of Cambridge, Cambridge, England.

We examined whether inflammation is uniformly associated with all depressive and anxiety symptoms, and whether these associations are potentially causal. Data was from 147,478 individuals from the UK Biobank (UKB) and 2,905 from the Netherlands Study of Depression and Anxiety (NESDA). Circulating C-reactive protein (CRP) was measured in both cohorts and interleukin-6 (IL-6) in NESDA. Genetic instruments for these proteins were obtained from published GWAS and UKB. Depressive and anxiety symptoms were assessed with self-report questionnaires. In NESDA, neurovegetative (appetite, sleep, psychomotor) symptoms were disaggregated as increased vs. decreased. In joint analyses, higher CRP was associated with depressive symptoms of depressed mood (OR = 1.06, 95% CI = 1.05-1.08), altered appetite (OR = 1.25, 95%CI = 1.23-1.28), sleep problems (OR = 1.05, 95%CI = 1.04-1.06), and fatigue (OR = 1.12, 95% CI = 1.11-1.14), and with anxiety symptoms of irritability (OR = 1.06, 95% CI = 1.05-1.08) and worrying control (OR = 1.03, 95% CI = 1.02-1.04). In NESDA, higher IL-6 was additionally associated with anhedonia (OR = 1.30, 95% CI = 1.12-1.52). Higher levels of both CRP (OR = 1.27, 95% CI = 1.13-1.43) and IL-6 (OR = 1.26, 95% CI = 1.07-1.49) were associated with increased sleep. Higher CRP was associated with increased appetite (OR = 1.21, 95% CI = 1.08-1.35) while higher IL-6 with decreased appetite (OR = 1.45, 95% CI = 1.18-1.79). In Mendelian Randomisation analyses, genetically predicted higher IL-6 activity was associated with increased risk of fatigue (estimate = 0.25, SE = 0.08) and sleep problems (estimate = 0.19, SE = 0.07). Inflammation was associated with core depressive symptoms of low mood and anhedonia and somatic/neurovegetative symptoms of fatigue, altered sleep and appetite changes. Less consistent associations were found for anxiety. The IL-6/IL-6R pathway could be causally linked to depression. Experimental studies are required to further evaluate causality, mechanisms, and usefulness of immunotherapies for depressive symptoms.
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http://dx.doi.org/10.1038/s41380-021-01188-wDOI Listing
June 2021

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Metabolomics dissection of depression heterogeneity and related cardiometabolic risk.

Psychol Med 2021 Jun 3:1-10. Epub 2021 Jun 3.

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

Background: A recent hypothesis postulates the existence of an 'immune-metabolic depression' (IMD) dimension characterized by metabolic dysregulations. Combining data on metabolomics and depressive symptoms, we aimed to identify depressions associated with an increased risk of adverse metabolic alterations.

Method: Clustering data were from 1094 individuals with major depressive disorder in the last 6 months and measures of 149 metabolites from a 1H-NMR platform and 30 depressive symptoms (IDS-SR30). Canonical correlation analyses (CCA) were used to identify main independent metabolite-symptom axes of variance. Then, for the replication, we examined the association of the identified dimensions with metabolites from the same platform and cardiometabolic diseases in an independent population-based cohort (n = 6572).

Results: CCA identified an overall depression dimension and a dimension resembling IMD, in which symptoms such as sleeping too much, increased appetite, and low energy level had higher relative loading. In the independent sample, the overall depression dimension was associated with lower cardiometabolic risk, such as (i.e. per s.d.) HOMA-1B -0.06 (95% CI -0.09 - -0.04), and visceral adipose tissue -0.10 cm2 (95% CI -0.14 - -0.07). In contrast, the IMD dimension was associated with well-known cardiometabolic diseases such as higher visceral adipose tissue 0.08 cm2 (95% CI 0.04-0.12), HOMA-1B 0.06 (95% CI 0.04-0.09), and lower HDL-cholesterol levels -0.03 mmol/L (95% CI -0.05 - -0.01).

Conclusions: Combining metabolomics and clinical symptoms we identified a replicable depression dimension associated with adverse metabolic alterations, in line with the IMD hypothesis. Patients with IMD may be at higher cardiometabolic risk and may benefit from specific treatment targeting underlying metabolic dysregulations.
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http://dx.doi.org/10.1017/S0033291721001471DOI Listing
June 2021

Genetic underpinnings of sociability in the general population.

Neuropsychopharmacology 2021 Aug 30;46(9):1627-1634. Epub 2021 May 30.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Levels of sociability are continuously distributed in the general population, and decreased sociability represents an early manifestation of several brain disorders. Here, we investigated the genetic underpinnings of sociability in the population. We performed a genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank. Subsequently we performed gene-wide and functional follow-up analyses. Robustness analyses were performed in the form of GWAS split-half validation analyses, as well as analyses excluding neuropsychiatric cases. Using genetic correlation analyses as well as polygenic risk score analyses we investigated genetic links of our sociability score to brain disorders and social behavior outcomes. Individuals with autism spectrum disorders, bipolar disorder, depression, and schizophrenia had a lower sociability score. The score was significantly heritable (SNP h of 6%). We identified 18 independent loci and 56 gene-wide significant genes, including genes like ARNTL, DRD2, and ELAVL2. Many associated variants are thought to have deleterious effects on gene products and our results were robust. The sociability score showed negative genetic correlations with autism spectrum, disorders, depression, schizophrenia, and two sociability-related traits-loneliness and social anxiety-but not with bipolar disorder or Alzheimer's disease. Polygenic risk scores of our sociability GWAS were associated with social behavior outcomes within individuals with bipolar disorder and with major depressive disorder. Variation in population sociability scores has a genetic component, which is relevant to several psychiatric disorders. Our findings provide clues towards biological pathways underlying sociability.
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http://dx.doi.org/10.1038/s41386-021-01044-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280100PMC
August 2021

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

Psychoneuroendocrinology 2021 Aug 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 Aug 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
August 2021

Educational attainment does not influence brain aging.

Proc Natl Acad Sci U S A 2021 May;118(18)

Center for Lifespan Changes in Brain and Cognition, University of Oslo, 0317 Oslo, Norway;

Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.
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http://dx.doi.org/10.1073/pnas.2101644118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106299PMC
May 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

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

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
April 2021

Effects of dietary interventions on depressive symptom profiles: results from the MooDFOOD depression prevention study.

Psychol Med 2021 Apr 7:1-10. Epub 2021 Apr 7.

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

Background: Dietary interventions did not prevent depression onset nor reduced depressive symptoms in a large multi-center randomized controlled depression prevention study (MooDFOOD) involving overweight adults with subsyndromal depressive symptoms. We conducted follow-up analyses to investigate whether dietary interventions differ in their effects on depressive symptom profiles (mood/cognition; somatic; atypical, energy-related).

Methods: Baseline, 3-, 6-, and 12-month follow-up data from MooDFOOD were used (n = 933). Participants received (1) placebo supplements, (2) food-related behavioral activation (F-BA) therapy with placebo supplements, (3) multi-nutrient supplements (omega-3 fatty acids and a multi-vitamin), or (4) F-BA therapy with multi-nutrient supplements. Depressive symptom profiles were based on the Inventory of Depressive Symptomatology.

Results: F-BA therapy was significantly associated with decreased severity of the somatic (B = -0.03, p = 0.014, d = -0.10) and energy-related (B = -0.08, p = 0.001, d = -0.13), but not with the mood/cognition symptom profile, whereas multi-nutrient supplementation was significantly associated with increased severity of the mood/cognition (B = 0.05, p = 0.022, d = 0.09) and the energy-related (B = 0.07, p = 0.002, d = 0.12) but not with the somatic symptom profile.

Conclusions: Differentiating depressive symptom profiles indicated that food-related behavioral interventions are most beneficial to alleviate somatic symptoms and symptoms of the atypical, energy-related profile linked to an immuno-metabolic form of depression, although effect sizes were small. Multi-nutrient supplements are not indicated to reduce depressive symptom profiles. These findings show that attention to clinical heterogeneity in depression is of importance when studying dietary interventions.
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http://dx.doi.org/10.1017/S0033291721000337DOI Listing
April 2021

Diet, Obesity, and Depression: A Systematic Review.

J Pers Med 2021 Mar 3;11(3). Epub 2021 Mar 3.

Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, UK.

Background: Obesity and depression co-occur in a significant proportion of the population. Mechanisms linking the two disorders include the immune and the endocrine system, psychological and social mechanisms. The aim of this systematic review was to ascertain whether weight loss through dietary interventions has the additional effect of ameliorating depressive symptoms in obese patients.

Methods: We systematically searched three databases (Pubmed, Medline, Embase) for longitudinal clinical trials testing a dietary intervention in people with obesity and depression or symptoms of depression.

Results: Twenty-four longitudinal clinical studies met the eligibility criteria with a total of 3244 included patients. Seventeen studies examined the effects of calorie-restricted diets and eight studies examined dietary supplements (two studies examined both). Only three studies examined people with a diagnosis of both obesity and depression. The majority of studies showed that interventions using a calorie-restricted diet resulted in decreases in depression scores, with effect sizes between ≈0.2 and ≈0.6. The results were less clear for dietary supplements.

Conclusions: People with obesity and depression appear to be a specific subgroup of depressed patients in which calorie-restricted diets might constitute a promising personalized treatment approach. The reduction of depressive symptoms may be related to immunoendocrine and psychosocial mechanisms.
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http://dx.doi.org/10.3390/jpm11030176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999659PMC
March 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

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BMC Med 2021 Mar 18;19(1):69. Epub 2021 Mar 18.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.

Methods: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.

Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.

Conclusions: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
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http://dx.doi.org/10.1186/s12916-021-01939-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971964PMC
March 2021

The association between genetically determined ABO blood types and major depressive disorder.

Psychiatry Res 2021 May 24;299:113837. Epub 2021 Feb 24.

Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.

ABO blood types and their corresponding antigens have long been assumed to be related to different human diseases. So far, smaller studies on the relationship between mental disorders and blood types yielded contradicting results. In this study we analyzed the association between ABO blood types and lifetime major depressive disorder (MDD). We performed a pooled analysis with data from 26 cohorts that are part of the MDD working group of the Psychiatric Genomics Consortium (PGC). The dataset included 37,208 individuals of largely European ancestry of which 41.6% were diagnosed with lifetime MDD. ABO blood types were identified using three single nucleotide polymorphisms in the ABO gene: rs505922, rs8176746 and rs8176747. Regression analyses were performed to assess associations between the individual ABO blood types and MDD diagnosis as well as putative interaction effects with sex. The models were adjusted for sex, cohort and the first ten genetic principal components. The percentage of blood type A was slightly lower in cases than controls while blood type O was more prominent in cases. However, these differences were not statistically significant. Our analyses found no evidence of an association between ABO blood types and major depressive disorder.
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http://dx.doi.org/10.1016/j.psychres.2021.113837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071927PMC
May 2021

Changes in peripheral blood compounds following psychopharmacological treatment in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: a meta-analysis.

Psychol Med 2021 03 3;51(4):538-549. Epub 2021 Mar 3.

Parnassia Academy, Parnassia Psychiatric Institute, Kiwistraat 43, 2552 DHThe Hague, the Netherlands.

Background: This meta-analysis on peripheral blood compounds in drug-naïve first-episode patients with either schizophrenia or major depressive disorder (MDD) examined which compounds change following psychopharmacological treatment.

Methods: The Embase, PubMed and PsycINFO databases were systematically searched for longitudinal studies reporting measurements of blood compounds in drug-naïve first-episode schizophrenia or MDD.

Results: For this random-effects meta-analysis, we retrieved a total of 31 studies comprising 1818 schizophrenia patients, and 14 studies comprising 469 MDD patients. Brain-derived neurotrophic factor (BDNF) increased following treatment in schizophrenia (Hedges' g (g): 0.55; 95% confidence interval (CI) 0.39-0.70; p < 0.001) and MDD (g: 0.51; CI 0.06-0.96; p = 0.027). Interleukin (IL)-6 levels decreased in schizophrenia (g: -0.48; CI -0.85 to -0.11; p = 0.011), and for MDD a trend of decreased IL-6 levels was observed (g: -0.39; CI -0.87 to 0.09; p = 0.115). Tumor necrosis factor alpha (TNFα) also decreased in schizophrenia (g: -0.34; CI -0.68 to -0.01; p = 0.047) and in MDD (g: -1.02; CI -1.79 to -0.25; p = 0.009). Fasting glucose levels increased only in schizophrenia (g: 0.26; CI 0.07-0.44; p = 0.007), but not in MDD. No changes were found for C-reactive protein, IL-1β, IL-2 and IL-4.

Conclusions: Psychopharmacological treatment has modulating effects on BDNF and TNFα in drug-naïve first-episode patients with either schizophrenia or MDD. These findings support efforts for further research into transdiagnostic preventive strategies and augmentation therapy for those with immune dysfunctions.
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http://dx.doi.org/10.1017/S0033291721000155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020491PMC
March 2021

Sociodemographic, Health and Lifestyle, Sampling, and Mental Health Determinants of 24-Hour Motor Activity Patterns: Observational Study.

J Med Internet Res 2021 02 17;23(2):e20700. Epub 2021 Feb 17.

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

Background: Analyzing actigraphy data using standard circadian parametric models and aggregated nonparametric indices may obscure temporal information that may be a hallmark of the circadian impairment in psychiatric disorders. Functional data analysis (FDA) may overcome such limitations by fully exploiting the richness of actigraphy data and revealing important relationships with mental health outcomes. To our knowledge, no studies have extensively used FDA to study the relationship between sociodemographic, health and lifestyle, sampling, and psychiatric clinical characteristics and daily motor activity patterns assessed with actigraphy in a sample of individuals with and without depression/anxiety.

Objective: We aimed to study the association between daily motor activity patterns assessed via actigraphy and (1) sociodemographic, health and lifestyle, and sampling factors, and (2) psychiatric clinical characteristics (ie, presence and severity of depression/anxiety disorders).

Methods: We obtained 14-day continuous actigraphy data from 359 participants from the Netherlands Study of Depression and Anxiety with current (n=93), remitted (n=176), or no (n=90) depression/anxiety diagnosis, based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Associations between patterns of daily motor activity, quantified via functional principal component analysis (fPCA), and sociodemographic, health and lifestyle, sampling, and psychiatric clinical characteristics were assessed using generalized estimating equation regressions. For exploratory purposes, function-on-scalar regression (FoSR) was applied to quantify the time-varying association of sociodemographic, health and lifestyle, sampling, and psychiatric clinical characteristics on daily motor activity.

Results: Four components of daily activity patterns captured 77.4% of the variability in the data: overall daily activity level (fPCA1, 34.3% variability), early versus late morning activity (fPCA2, 16.5% variability), biphasic versus monophasic activity (fPCA3, 14.8% variability), and early versus late biphasic activity (fPCA4, 11.8% variability). A low overall daily activity level was associated with a number of sociodemographic, health and lifestyle, and psychopathology variables: older age (P<.001), higher education level (P=.005), higher BMI (P=.009), greater number of chronic diseases (P=.02), greater number of cigarettes smoked per day (P=.02), current depressive and/or anxiety disorders (P=.05), and greater severity of depressive symptoms (P<.001). A high overall daily activity level was associated with work/school days (P=.02) and summer (reference: winter; P=.03). Earlier morning activity was associated with older age (P=.02), having a partner (P=.009), work/school days (P<.001), and autumn and spring (reference: winter; P=.02 and P<.001, respectively). Monophasic activity was associated with older age (P=.005). Biphasic activity was associated with work/school days (P<.001) and summer (reference: winter; P<.001). Earlier biphasic activity was associated with older age (P=.005), work/school days (P<.001), and spring and summer (reference: winter; P<.001 and P=.005, respectively). In FoSR analyses, age, work/school days, and season were the main determinants having a time-varying association with daily motor activity (all P<.05).

Conclusions: Features of daily motor activity extracted with fPCA reflect commonly studied factors such as the intensity of daily activity and preference for morningness/eveningness. The presence and severity of depression/anxiety disorders were found to be associated mainly with a lower overall activity pattern but not with the time of the activity. Age, work/school days, and season were the variables most strongly associated with patterns and time of activity, and thus future epidemiological studies on motor activity in depression/anxiety should take these variables into account.
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http://dx.doi.org/10.2196/20700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929740PMC
February 2021

Depressive and anxiety disorders in concert-A synthesis of findings on comorbidity in the NESDA study.

J Affect Disord 2021 04 5;284:85-97. Epub 2021 Feb 5.

Amsterdam UMC, Vrije Universiteit Amsterdam, Psychiatry, Amsterdam Public Health, Amsterdam, The Netherlands & GGZ inGeest Specialized Mental Health Care, Research and Innovation, Amsterdam, the Netherlands; GGZ inGeest Specialized Mental Health Care, Research and Innovation, Oldenaller 1, 1081 HJ Amsterdam, the Netherlands. Electronic address:

Background: Comorbidity of depressive and anxiety disorders is common and remains incompletely comprehended. This paper summarizes findings from the Netherlands Study of Depression and Anxiety (NESDA) regarding prevalence, temporal sequence, course and longitudinal patterns; sociodemographic, vulnerability and neurobiological indicators; and functional, somatic and mental health indicators of comorbidity.

Methods: Narrative synthesis of earlier NESDA based papers on comorbidity (n=76).

Results: Comorbidity was the rule in over three-quarter of subjects with depressive and/or anxiety disorders, most often preceded by an anxiety disorder. Higher severity and chronicity characterized a poorer comorbidity course. Over time, transitions between depressive and anxiety disorders were common. Consistent comorbidity risk indicators in subjects with depressive and anxiety disorders were childhood trauma, neuroticism and early age of onset. Psychological vulnerabilities, such as trait avoidance tendencies, were more pronounced in comorbid than in single disorders. In general, there were few differences in biological markers and neuroimaging findings between persons with comorbid versus single disorders. Most functional, somatic, and other mental health indicators, ranging from disability to cardiovascular and psychiatric multimorbidity, were highest in comorbid disorders.

Limitations: The observational design of NESDA limits causal inference. Attrition was higher in comorbid relative to single disorders.

Conclusions: As compared to single disorders, persons with comorbid depressive and anxiety disorders were characterized by more psychosocial risk determinants, more somatic and other psychiatric morbidities, more functional impairments, and poorer outcome. These results justify specific attention for comorbidity of depressive and anxiety disorders, particularly in treatment settings.
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http://dx.doi.org/10.1016/j.jad.2021.02.004DOI Listing
April 2021

The long-lasting impact of childhood trauma on adult chronic physical disorders.

J Psychiatr Res 2021 04 27;136:87-94. Epub 2021 Jan 27.

GGZinGeest, Oldenaller 1, 1081 HJ, Amsterdam, the Netherlands; Department of Psychiatry and Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, de Boelelaan 1105, 1081, HV, the Netherlands. Electronic address:

Background: It is unclear if childhood trauma (CT) is an independent risk factor of adult chronic physical disorders or whether its impact is (also) due to underlying poorer mental health.

Methods: Data were obtained from baseline measurements among 13,489 respondents of the Netherlands Mental Health Survey and Incidence Study-1 and -2, cohort studies of the Dutch general population aged 18-64 years. We used a childhood trauma questionnaire measuring emotional, psychological, physical or sexual trauma before the age of 16. Lifetime mood, anxiety and substance use disorders were assessed with the Composite International Diagnostic Interview version 1.1 and 3.0. A standard self-report checklist was used to assess a broad range of chronic physical disorders treated by a medical doctor in the previous 12 months.

Results: Respondents with a history of CT (N = 4054) suffered significantly more often from digestive (OR: 1.89-2.95), musculoskeletal (OR: 1.21-1.75) and respiratory disorders (OR: 1.39-1.91) and migraine (OR: 1.42-1.66). We found indirect associations between CT and digestive, musculoskeletal and respiratory disorders through lifetime mood (54%, 52% and 48% respectively), anxiety (44%, 55% and 44% respectively) and substance use disorders (33%, 23% and 38% respectively). Mood (69%) and anxiety disorders (67%) also impacted the relationship with migraine.

Conclusions: CT predicts the development of adult physical disorders, even after controlling for sociodemographic and lifestyle factors. This association is substantially influenced by mental health disorders. Treatment programs for CT should include interventions aimed at enhancing both mental and physical health.
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http://dx.doi.org/10.1016/j.jpsychires.2021.01.031DOI Listing
April 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

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

Childhood Trauma in Adult Depressive and Anxiety Disorders: An Integrated Review on Psychological and Biological Mechanisms in the NESDA Cohort.

J Affect Disord 2021 03 28;283:179-191. Epub 2021 Jan 28.

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

Background: Childhood trauma (CT) has adverse consequences on mental health across the lifespan. The understanding of how CT increases vulnerability for psychiatric disorders is growing. However, lack of an integrative approach to psychological and biological mechanisms of CT hampers further advancement. This review integrates CT findings across explanatory levels from a longitudinal adult cohort - the Netherlands Study of Depression and Anxiety (NESDA).

Methods: We reviewed all studies (k = 37) from the NESDA cohort (n = 2981) published from 2009 to 2020 containing CT findings related to psychopathology and potential psychological and biological mechanisms of CT.

Results: CT was associated with a higher risk of anxiety and depressive disorders with the strongest associations in the comorbid group. CT predicted the onset of these disorders, recurrence, and poorer outcomes (more comorbidity and chronicity). CT was associated with maladaptive personality characteristics and cognitions (e.g., higher neuroticism and negative self-associations), mild stress systems dysregulations (heightened levels of cortisol and inflammation), advanced biological aging (increased epigenetic aging and telomere attrition), poorer lifestyle (higher smoking rate and body mass index), somatic health decline (e.g., increased metabolic syndrome dysregulations), and brain alterations (e.g., reduced mPFC volume and increased amygdala reactivity).

Limitations: Literature review of one cohort using mixed analytical approaches.

Conclusion: CT impacts the functioning of the brain, mind, and body, which together may contribute to a higher vulnerability for affective disorders. It is essential to employ an integrative approach combining different sources of data to understand the mechanisms of CT better.
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http://dx.doi.org/10.1016/j.jad.2021.01.054DOI Listing
March 2021

The day-to-day bidirectional longitudinal association between objective and self-reported sleep and affect: An ambulatory assessment study.

J Affect Disord 2021 03 27;283:165-171. Epub 2021 Jan 27.

Amsterdam UMC, Vrije Universiteit, Department of Psychiatry, Amsterdam Public Health Research Institute, The Netherlands.

Background: Ambulatory assessments offer opportunities to evaluate daily dynamics of sleep and momentary affect using mobile technologies. This study examines day-to-day bidirectional associations between sleep and affect using mobile monitoring, and evaluates whether these associations differ between people without and with current or remitted depression/anxiety.

Methods: Two-week ecological momentary assessment (EMA) and actigraphy data of 359 participants with current (n = 93), remitted (n = 176) or no (n = 90) CIDI depression/anxiety diagnoses were obtained from the Netherlands Study of Depression and Anxiety. Objective sleep duration (SD) and efficiency were obtained from actigraphy data. Self-reported SD, sleep quality (SQ), positive affect (PA) and negative affect (NA) were assessed by electronic diaries through EMA.

Results: A bidirectional longitudinal association was found between self-reported SQ and affect, while no association was found for self-reported SD and objective SD and efficiency. Better SQ predicted affect the same day (higher PA: b = 0.035, p < 0.001; lower NA: b = -0.022, p < 0.001), while lower NA on the preceding day predicted better SQ (b = -0.102, p = 0.001). The presence of current depression/anxiety disorders moderated the association between better SQ and subsequent lower NA; it was stronger for patients compared to controls (p = 0.003).

Limitations: Observational study design can only point to areas of interest for interventions.

Conclusions: This 2-week ambulatory monitoring study shows that, especially among depression/anxiety patients, better self-reported SQ predicts higher PA and lower NA the same day, while lower NA predicts better self-reported SQ. The value of mobile technologies to monitor and potentially intervene in patients to improve their affect should be explored.
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http://dx.doi.org/10.1016/j.jad.2021.01.052DOI Listing
March 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

Associations between depression, lifestyle and brain structure: A longitudinal MRI study.

Neuroimage 2021 05 4;231:117834. Epub 2021 Feb 4.

Department of Psychiatry, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, Vrije Universiteit Amsterdam, The Netherlands. Electronic address:

Background: Depression has been associated with decreased regional grey matter volume, which might partly be explained by an unhealthier lifestyle in depressed individuals which has been ignored by most earlier studies. Also, the longitudinal nature of depression, lifestyle and brain structure associations is largely unknown. This study investigates the relationship of depression and lifestyle with brain structure cross-sectionally and longitudinally over up to 9 years.

Methods: We used longitudinal structural MRI data of persons with depression and/or anxiety disorders and controls (N = 347, N = 609). Cortical thickness of medial orbitofrontal cortex (mOFC), rostral anterior cingulate cortex (rACC) and hippocampal volume were derived using FreeSurfer. Using Generalized Estimating Equations, we investigated associations of depression and lifestyle (Body mass index (BMI), smoking, alcohol consumption, physical activity and sleep duration) with brain structure and change in brain structure over 2 (n = 179) and 9 years (n = 82).

Results: Depression status (B = -.053, p = .002) and severity (B = -.002, p = .002) were negatively associated with rACC thickness. mOFC thickness was negatively associated with BMI (B = -.004, p < .001) and positively with moderate alcohol consumption (B = .030, p = .009). All associations were independent of each other. No associations were observed between (change in) depression, disease burden or lifestyle factors with brain change over time.

Conclusions: Depressive symptoms and diagnosis were independently associated with thinner rACC, BMI with thinner mOFC, and moderate alcohol consumption with thicker mOFC. No longitudinal associations were observed, suggesting that regional grey matter alterations are a long-term consequence or vulnerability indicator for depression but not dynamically or progressively related to depression course trajectory.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117834DOI Listing
May 2021

Obesity and atypical depression symptoms: findings from Mendelian randomization in two European cohorts.

Transl Psychiatry 2021 02 4;11(1):96. Epub 2021 Feb 4.

Institute of Primary Care and Public Health (Unisante), University of Lausanne, Lausanne, Switzerland.

Studies considering the causal role of body mass index (BMI) for the predisposition of major depressive disorder (MDD) based on a Mendelian Randomization (MR) approach have shown contradictory results. These inconsistent findings may be attributable to the heterogeneity of MDD; in fact, several studies have documented associations between BMI and mainly the atypical subtype of MDD. Using a MR approach, we investigated the potential causal role of obesity in both the atypical subtype and its five specific symptoms assessed according to the Statistical Manual of Mental Disorders (DSM), in two large European cohorts, CoLaus|PsyCoLaus (n = 3350, 1461 cases and 1889 controls) and NESDA|NTR (n = 4139, 1182 cases and 2957 controls). We first tested general obesity measured by BMI and then the body fat distribution measured by waist-to-hip ratio (WHR). Results suggested that BMI is potentially causally related to the symptom increase in appetite, for which inverse variance weighted, simple median and weighted median MR regression estimated slopes were 0.68 (SE = 0.23, p = 0.004), 0.77 (SE = 0.37, p = 0.036), and 1.11 (SE = 0.39, p = 0.004). No causal effect of BMI or WHR was found on the risk of the atypical subtype or for any of the other atypical symptoms. Our findings show that higher obesity is likely causal for the specific symptom of increase in appetite in depressed participants and reiterate the need to study depression at the granular level of its symptoms to further elucidate potential causal relationships and gain additional insight into its biological underpinnings.
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http://dx.doi.org/10.1038/s41398-021-01236-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862438PMC
February 2021