COVID-19 risk, course and outcome in people with mental disorders: a systematic review and meta-analyses.

AIMS: It has been suggested that people with mental disorders have an elevated risk to acquire severe acute respiratory syndrome coronavirus 2 and to be disproportionally affected by coronavirus disease 19 (COVID-19) once infected. We aimed to analyse the COVID-19 infection rate, course and outcome, including mortality and long COVID, in people with anxiety, depressive, neurodevelopmental, schizophrenia spectrum and substance use disorders relative to control subjects without these disorders. METHODS: This study constitutes a preregistered systematic review and random-effects frequentist and Bayesian meta-analyses. Major databases were searched up until 27 June 2023. RESULTS: Eighty-one original articles were included reporting 304 cross-sectional and prospective effect size estimates (median n per effect-size = 114837) regarding associations of interest. Infection risk was not significantly increased for any mental disorder that we investigated relative to samples of people without these disorders. The course of COVID-19, however, is relatively severe, and long COVID and COVID-19-related hospitalization are more likely in all patient samples that we investigated. The odds of dying from COVID-19 were high in people with most types of mental disorders, except for those with anxiety and neurodevelopmental disorders relative to non-patient samples (pooled ORs range, 1.26-2.57). Bayesian analyses confirmed the findings from the frequentist approach and complemented them with estimates of the strength of evidence. CONCLUSIONS: Once infected, people with pre-existing mental disorders are at an elevated risk for a severe COVID-19 course and outcome, including long COVID and mortality, relative to people without pre-existing mental disorders, despite an infection risk not significantly increased.

SARS-CoV-2 susceptibility and COVID-19 illness course and outcome in people with pre-existing neurodegenerative disorders: systematic review with frequentist and Bayesian meta-analyses.

BACKGROUND: People with neurodegenerative disease and mild cognitive impairment (MCI) may have an elevated risk of acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and may be disproportionally affected by coronavirus disease 2019 (COVID-19) once infected. AIMS: To review all eligible studies and quantify the strength of associations between various pre-existing neurodegenerative disorders and both SARS-CoV-2 susceptibility and COVID-19 illness course and outcome. METHOD: Pre-registered systematic review with frequentist and Bayesian meta-analyses. Systematic searches were executed in PubMed, Web of Science and preprint servers. The final search date was 9 January 2023. Odds ratios (ORs) were used as measures of effect. RESULTS: In total, 136 primary studies (total sample size n = 97 643 494), reporting on 268 effect-size estimates, met the inclusion criteria. The odds for a positive SARS-CoV-2 test result were increased for people with pre-existing dementia (OR = 1.83, 95% CI 1.16-2.87), Alzheimer's disease (OR = 2.86, 95% CI 1.44-5.66) and Parkinson's disease (OR = 1.65, 95% CI 1.34-2.04). People with pre-existing dementia were more likely to experience a relatively severe COVID-19 course, once infected (OR = 1.43, 95% CI 1.00-2.03). People with pre-existing dementia or Alzheimer's disease were at increased risk for COVID-19-related hospital admission (pooled OR range: 1.60-3.72). Intensive care unit admission rates were relatively low for people with dementia (OR = 0.54, 95% CI 0.40-0.74). All neurodegenerative disorders, including MCI, were at higher risk for COVID-19-related mortality (pooled OR range: 1.56-2.27). CONCLUSIONS: Our findings confirm that, in general, people with neurodegenerative disease and MCI are at a disproportionally high risk of contracting COVID-19 and have a poor outcome once infected.

Linguistic Analysis of Online Domestic Violence Testimonies in the Context of COVID-19.

Worldwide, an increase in cases and severity of domestic violence (DV) has been reported as a result of social distancing measures implemented to decrease the spreading of the Coronavirus Disease (COVID-19). As one's language can provide insight in one's mental health, this pre-registered study analyzed word use in a DV online support group, aiming to investigate the impact of the COVID-19 pandemic on DV victims in an ex post facto research design. Words reflecting social support and leisure activities were investigated as protective factors against linguistic indicators of depression in 5,856 posts from the r/domesticviolence subreddit and two neutral comparison subreddits (r/changemyview & r/femalefashionadvice). In the DV support group, the average number of daily posts increased significantly by 22% from pre- to mid-pandemic. Confirmatory analysis was conducted following a registered pre-analysis plan. DV victims used significantly more linguistic indicators of depression than individuals in the comparison groups. This did not change with the onset of COVID-19. The use of negative emotion words was negatively related to the use of social support words (Spearman's rho correlation coefficient [rho] = -0.110) and words referring to leisure activities (rho = -0.137). Pre-occupation with COVID-19 was associated with the use of negative emotion words (rho = 0.148). We conclude that language of DV victims is characterized by indicators of depression and this characteristic is stable over time. Concerns with COVID-19 could contribute to negative emotions, whereas social support and leisure activities could function to some degree as protective factors. A potential weakness of this study is its cross-sectional design and the lack of experimental control. Future studies could make use of natural language processing and other advanced methods of linguistic analysis to learn about the mental health of DV victims.

The incubus phenomenon: Prevalence, frequency and risk factors in psychiatric inpatients and university undergraduates.

Background: The incubus phenomenon is a paroxysmal sleep-related disorder characterized by the visuotactile sensation of a person or entity exerting pressure on one's thorax during episodes of sleep paralysis and (apparent) wakefulness. This terrifying phenomenon is relatively unknown even though a previous meta-analysis indicated a lifetime prevalence of 0.11 for individuals in the general population and of 0.41 for selected at-risk groups, including people diagnosed with schizophrenia and students. Since the studies reviewed did not always make a strict distinction between the incubus phenomenon and isolated sleep paralysis, we carried out a cross-sectional study in a contemporary patient and student sample to attain current, more detailed data on the incubus phenomenon. Materials and methods: In a cross-sectional design, we used the Waterloo Unusual Sleep Experience Questionnaire (WUSEQ) to screen patients with severe psychiatric disorders and university undergraduates to establish and compare prevalence rates, frequencies of occurrence, and risk factors for the incubus phenomenon. Results: Having interviewed 749 people, comprising 606 students and 143 patients with a schizophrenia spectrum or related disorder who had been acutely admitted to a secluded nursing ward, we computed a reported lifetime prevalence of 0.12 and 0.09, respectively, which rates were not statistically different. In both groups, the phenomenon was more common in people with a non-Western European background. Risk factors noted for the students were the use of psychotropic medication and the lifetime presence of an anxiety disorder, eating disorder, or sleeping disorder. We found no associations with age or gender in either group. Conclusion: The 0.09 and 0.12 lifetime prevalence rates we recorded for the incubus phenomenon in students and psychiatric inpatients is substantially lower than the 0.41 found in an earlier meta-analysis. We tentatively attribute this difference to an overgeneralization in previous studies but also discuss alternative explanations. The elevated prevalence among non-Western European participants may well be due to the fact that the topic continues to be part of the cultural and religious heritage of many non-Western countries.

Forced swim stressor: Trends in usage and mechanistic consideration.

The acquired immobility response during the "forced swim test (FST)" is not a rodent model of depression, but the test has some validity in predicting a compound's antidepressant potential. Nevertheless, 60% of the about 600 papers that were published annually the past 2 years label the rodent's immobility response as depression-like behaviour, but the relative contribution per country is changing. When the Editors-in-Chief of 5 journals publishing most FST papers were asked for their point of view on labelling immobility as depression-like behaviour and despair, they responded that they primarily rely on the reviewers regarding scientific merit of the submission. One Editor informs authors of the recent NIMH notice (https://grants.nih.gov/grants/guide/notice-files/NOT-MH-19-053.html) which encourages investigators to use animal models "for" addressing neurobiological questions rather than as model "of" specific mental disorders. The neurobiological questions raised by use of the FST fall in two categories. First, research on the role of endocrine and metabolic factors, with roots in the 1980s, and with focus on the bottom-up action of glucocorticoids on circuits processing salient information, executive control and memory consolidation. Second, recent findings using novel technological and computational advances that have allowed great progress in charting top-down control in the switch from active to passive coping with the inescapable stressor executed by neuronal ensembles of the medial prefrontal cortex via the peri-aquaductal grey. It is expected that combining neural top-down and endocrine bottom-up approaches will provide new insights in the role of stress-coping and adaptation in pathogenesis of mental disorders.

The Effects of Physical Exercise on Functional Outcomes in the Treatment of ADHD: A Meta-Analysis.

Objective: An increasing number of studies suggest possible beneficial effects of exercise in alleviating ADHD functional outcomes. The current study provides a quantitative meta-analysis of the available studies investigating this relationship. Method: Studies reporting on the effects of physical exercise on motor skills and executive functions in children with ADHD were identified through Cochrane, PsycInfo, PubMed, Web of Science databases. Ten publications were selected. Random-effects model was used to calculate effect sizes. Results: There was a significant effect of exercise on ADHD functional outcomes (g = 0.627). Longer exercise intervention duration was consistently associated with larger effect sizes. Effect sizes were not related to exercise intensity, mean age of participants, or gender distribution. Conclusion: Results suggest that exercise has a modest positive impact on ADHD functional outcomes, such as executive functions and motor skills, with longer interventions yielding better results.

Anxiety in Children with Selective Mutism: A Meta-analysis.

This study evaluates the current conceptualization of selective mutism (SM) as an anxiety disorder in the DSM-5 using a meta-analytic approach. In the absence of any systematic assessment of anxiety in the field of SM, we pooled prevalence data of comorbid anxiety disorders in a random-effects meta-analysis. On the basis of 22 eligible studies (N = 837), we found that 80% of the children with SM were diagnosed with an additional anxiety disorder, notably social phobia (69%). However, considerable heterogeneity was present, which remained unexplained by a priori specified moderators. The finding that SM is often diagnosed in combination with anxiety disorders, indicates that these disorders are not discrete, separable categories. Moreover, this finding does not help to elucidate the relation between SM and anxiety as an etiological mechanism or symptomatic feature. Broadening our research strategies regarding the assessment of anxiety is paramount to clarify the role of anxiety in SM, and allow for proper classification.

Coping with the forced swim stressor: Current state-of-the-art.

The forced swim test (FST) for rodents does not model despair or helplessness. It also is not a read-out for depression, anxiety, psychomotor retardation or autism, because these are anthropomorphic interpretations of the rodent's acquired immobility. Rather, the transition from swimming to immobility allows to examine the mechanistic underpinning of coping with inescapable stressors. However, in a recent detailed analysis of the FST application over the past 40 years, we noted a dramatic surge in the use of this test to phenotype animals as 'depressed'. As a follow up to that report, we now present an analysis of the use of the FST over the past three years. This literature analysis shows that the popularity of the FST is still increasing and that the majority of researchers qualifies the rodent's floating response as depressive-like behavior. However, over the past few years we also note a trend to interpret immobility rather as the expression of a coping strategy. In view of this result, we have sent a poll to the relevant authors to learn how consistent they are in naming FST behavior. Remarkably, we find a dramatic inverse correlation between their first qualification of acquired immobility as depressive-like behavior towards their current interpretation as coping strategy. In this contribution we have embedded our literature analysis and poll results in an update on the management of coping with inescapable stressors by processing in prefrontal cortical circuitry and glucocorticoid feedback.

The SMILES trial: do undisclosed recruitment practices explain the remarkably large effect?

The SMILES trial showed substantial improvement of depressive symptoms following seven consultations on healthy dieting. The very large effect size on depression reduction seems remarkable and we suggest that selectively induced expectancy and a loss of blinding have contributed to the observed effect.

Prevalence Rates of the Incubus Phenomenon: A Systematic Review and Meta-Analysis.

BACKGROUND: The incubus phenomenon is a paroxysmal sleep-related disorder characterized by compound hallucinations experienced during brief phases of (apparent) wakefulness. The condition has an almost stereotypical presentation, characterized by a hallucinated being that exerts pressure on the thorax, meanwhile carrying out aggressive and/or sexual acts. It tends to be accompanied by sleep paralysis, anxiety, vegetative symptoms, and feelings of suffocation. Its prevalence rate is unknown since, in prior analyses, cases of recurrent isolated sleep paralysis with/without an incubus phenomenon have been pooled together. This is unfortunate, since the incubus phenomenon has a much greater clinical relevance than isolated sleep paralysis. METHODS: PubMed, Embase, and PsycINFO were searched for prevalence studies of the incubus phenomenon, and a meta-analysis was performed. RESULTS: Of the 1,437 unique records, 13 met the inclusion criteria, reporting on 14 (k) independent prevalence estimates (total N = 6,079). The pooled lifetime prevalence rate of the incubus phenomenon was 0.19 [95% confidence interval (CI) = 0.14-0.25, k = 14, N = 6,079] with heterogeneous estimates over different samples. In selected samples (e.g., patients with a psychiatric disorder, refugees, and students), prevalence rates were nearly four times higher (0.41, 95% CI = 0.25-0.56, k = 4, n = 1,275) than in the random samples (0.11, 95% CI = 0.08-0.14, k = 10, n = 4,804). This difference was significant (P < 0.001). CONCLUSION: This review and meta-analysis yielded a lifetime prevalence of the incubus phenomenon in the general population of 0.11 and, in selected samples, of 0.41. This is slightly higher than the prevalence rates in previous analyses that included cases of recurrent isolated sleep paralysis without an incubus phenomenon. Based on the condition's robust clinical presentation and the relatively high prevalence rates, we advocate inclusion of the incubus phenomenon as a diagnostic category in major classifications such as the International Classification of Diseases and Related Health Problems and the Diagnostic and Statistical Manual of Mental Disorders. Recommendations are also made for clinical practice and future research.

The association of childhood maltreatment with depression and anxiety is not moderated by the oxytocin receptor gene.

BACKGROUND: The oxytocin receptor (OXTR) gene may be involved in resilience or vulnerability towards stress, and hence in the development of stress-related disorders. There are indications that OXTR single nucleotide polymorphisms (SNPs) interact with early life stressors in predicting levels of depression and anxiety. To replicate and extend these findings, we examined whether three literature-based OXTR SNPs (rs2254298, rs53576, rs2268498) interact with childhood maltreatment in the development of clinically diagnosed depression and anxiety disorders. METHODS: We included 2567 individuals from the Netherlands Study of Depression and Anxiety. This sample consisted of 387 healthy controls, 428 people with a current or past depressive disorder, 243 people with a current or past anxiety disorder, and 1509 people with both lifetime depression and anxiety diagnoses. Childhood maltreatment was measured with both an interview and via self-report. Additional questionnaires measured depression and anxiety sensitivity. RESULTS: Childhood maltreatment was strongly associated with both lifetime depression and anxiety diagnoses, as well as with depression and anxiety sensitivity. However, the OXTR SNPs did not moderate these associations nor had main effects on outcomes. CONCLUSIONS: The three OXTR gene SNPs did not interact with childhood maltreatment in predicting lifetime depression and anxiety diagnoses or sensitivity. This stresses the importance of replication studies with regard to OXTR gene variants in general populations as well as in clearly established clinical samples.

C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis.

BACKGROUND: Inflammatory processes and neural-immune interactions have been implicated in the pathogenesis of psychiatric conditions, but studies in bipolar disorder are inconclusive so far. We aimed to investigate whether peripheral concentrations of C-reactive protein (CRP), an acute-phase response protein of inflammatory activity, are increased in bipolar disorder across the mood spectrum. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, the Cochrane Library, Scopus, and Web of Knowledge from database inception to Aug 14, 2016, for studies that measured serum and plasma CRP concentrations in adult patients with bipolar disorder (as defined by DSM-IV-TR) and healthy controls. We extracted data from published reports. We did three between-group meta-analyses comparing CRP concentrations in patients in mania, depression, or euthymia, with those in healthy controls (cross-sectional studies), and two within-group meta-analyses comparing changes in CRP concentrations before and after treatment of an index manic or depressive episode (longitudinal studies). We used Hedges' adjusted g to calculate effect sizes and pooled results using random-effect models. We also did meta-regression analyses by mood state to investigate possible moderators of CRP concentrations. FINDINGS: We identified 27 studies representing 2161 patients with bipolar disorder and 81 932 healthy controls. Compared with healthy individuals, CRP concentrations were moderately increased in people with bipolar disorder during depression (g 0·67, 95% CI 0·23 to 1·11; p=0·003) and euthymia (0·65, 0·40 to 0·90; p<0·0001) and more substantially increased during mania (0·87, 0·58 to 1·15; p<0·0001). The extent of the increases in CRP concentrations in mania and depression was not related to symptom severity (p=0·256 for mania and p=0·626 for depression). CRP concentrations were moderately decreased after resolution of an index manic episode (-0·36, -0·66 to -0·05; p=0·022) and slightly decreased after resolution of an index depressive episode (-0·18, -0·30 to -0·07; p=0·002). INTERPRETATION: CRP concentrations are increased in bipolar disorder regardless of mood state, but are higher during mania than in depression and euthymia, suggesting an increased inflammatory burden in mania. FUNDING: None.

Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies.

BACKGROUND: The neurotrophic hypothesis postulates that mood disorders such as bipolar disorder (BD) are associated with a lower expression of brain-derived neurotrophic factor (BDNF). However, its role in peripheral blood as a biomarker of disease activity and of stage for BD, transcending pathophysiology, is still disputed. In the last few years an increasing number of clinical studies assessing BDNF in serum and plasma have been published. Therefore, it is now possible to analyse the association between BDNF levels and the severity of affective symptoms in BD as well as the effects of acute drug treatment of mood episodes on BDNF levels. METHODS: We conducted a systematic review and meta-analysis of all studies on serum and plasma BDNF levels in bipolar disorder. RESULTS: Through a series of meta-analyses including a total of 52 studies with 6,481 participants, we show that, compared to healthy controls, peripheral BDNF levels are reduced to the same extent in manic (Hedges' g = -0.57, P = 0.010) and depressive (Hedges' g = -0.93, P = 0.001) episodes, while BDNF levels are not significantly altered in euthymia. In meta-regression analyses, BDNF levels additionally negatively correlate with the severity of both manic and depressive symptoms. We found no evidence for a significant impact of illness duration on BDNF levels. In addition, in plasma, but not serum, peripheral BDNF levels increase after the successful treatment of an acute mania episode, but not of a depressive one. CONCLUSIONS: In summary, our data suggest that peripheral BDNF levels, more clearly in plasma than in serum, is a potential biomarker of disease activity in BD, but not a biomarker of stage. We suggest that peripheral BDNF may, in future, be used as a part of a blood protein composite measure to assess disease activity in BD.

Immobility in the forced swim test is adaptive and does not reflect depression.

The forced swim test is based on the progressive immobility a rodent displays when immersed in a beaker filled with water from where no escape is possible. While the test was originally designed to identify the antidepressant potential of drugs, over the past decade a rapidly growing number of publications (more than 2000) portray this immobility response anthropomorphically as a measure for depression and despair. This is incorrect. The response to the forced swim stressor should be considered for what it shows: a switch from active to passive behavior in the face of an acute stressor, aligned to cognitive functions underlying behavioral adaptation and survival.

Workplace Bullying and Mental Health: A Meta-Analysis on Cross-Sectional and Longitudinal Data.

BACKGROUND: A growing body of research has confirmed that workplace bullying is a source of distress and poor mental health. Here we summarize the cross-sectional and longitudinal literature on these associations. METHODS: Systematic review and meta-analyses on the relation between workplace bullying and mental health. RESULTS: The cross-sectional data (65 effect sizes, N = 115.783) showed positive associations between workplace bullying and symptoms of depression (r = .28, 95% CI = .23-.34), anxiety (r = .34, 95% CI = .29-.40) and stress-related psychological complaints (r = .37, 95% CI = .30-.44). Pooling the literature that investigated longitudinal relationships (26 effect sizes, N = 54.450) showed that workplace bullying was related to mental health complaints over time (r = 0.21, 95% CI = 0.13-0.21). Interestingly, baseline mental health problems were associated with subsequent exposure to workplace bullying (r = 0.18, 95% CI = 0.10-0.27; 11 effect sizes, N = 27.028). LIMITATIONS: All data were self-reported, raising the possibility of reporting- and response set bias. CONCLUSIONS: Workplace bullying is consistently, and in a bi-directional manner, associated with reduced mental health. This may call for intervention strategies against bullying at work.

Association between smoking, nicotine dependence, and BDNF Val66Met polymorphism with BDNF concentrations in serum.

INTRODUCTION: Nicotine use is associated with the upregulation of brain-derived neurotrophic factor (BDNF) in serum. An association between smoking and the BDNF Val(66)Met polymorphism has also been found. The aim of this study is to examine the levels of serum BDNF in never-smokers, former smokers, and current smokers-with and without nicotine dependence-and to examine the interaction of the polymorphism and smoking status with serum BDNF. METHODS: We used baseline serum and gene data of BDNF on 2,088 participants from the Netherlands Study of Depression and Anxiety (NESDA) to investigate smoking-BDNF association while controlling for potential confounding variables. Nicotine dependence was assessed with the Fagerstrom Test for Nicotine Dependence (FTND). RESULTS: Smokers with and without nicotine dependence had higher levels of serum BDNF than former and never-smokers. Nicotine dependence and number of cigarettes smoked per day did not add to the prediction of serum BDNF; however, total number of smoking years was a significant predictor of serum BDNF. There was no association of BDNF Val(66)Met, nor an interaction of this polymorphism and smoking status, with serum BDNF. CONCLUSIONS: Current smoking and higher number of smoking years are associated with higher levels of serum BDNF, and this is independent of the BDNF genotype. Nicotine dependence itself is not associated with a further increase or decrease of serum BDNF. Longitudinal investigations that address changes in serum BDNF in incident smokers and/or in quitters may be useful to understand the association of smoking with BDNF.

Association between serum brain-derived neurotrophic factor and plasma interleukin-6 in major depressive disorder with melancholic features.

Inflammatory processes as well as attenuation of brain-derived neurotrophic factor (BDNF) availability are involved in the pathophysiology of major depressive disorder (MDD). Although it is generally presumed that these two systems interact negatively in the brain, preclinical and human in vitro studies have shown synergistic rather than antagonistic interactions in the periphery. We therefore examined the association between serum levels of BDNF and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in patients with MDD (n=1070) and non-depressed controls (n=379) from the Netherlands Study of Depression and Anxiety. We used multiple regression analyses with serum BDNF as the dependent variable and we specifically tested the presence of BDNF-cytokine associations in DSM-IV-assigned melancholic MDD patients, identified by the Inventory of Depressive Symptomatology. After adjustment for sociodemographics, sampling variability, lifestyle indicators, somatic diseases and medication use, BDNF levels were predicted by the interaction between MDD diagnosis and IL-6 (p-interaction=.006). Stratified analyses showed that BDNF levels are indeed positively associated with IL-6 levels in MDD patients (ß=.07, p=.02), but not in non-depressed controls (ß=-.07, p=.23). When further stratified for melancholic and non-melancholic MDD (p-interaction=.005), IL-6 emerged as a robust positive predictor of BDNF only in the melancholic sample (ß=.21, p=.01), wherein serum BDNF levels were accordingly enhanced. Post-hoc exploratory analyses verified an accentuated positive association of BDNF levels with leucocyte counts in melancholia. No significant associations emerged between BDNF and TNF-α. Overall, our cross-sectional approach may have disclosed an allostatic, BDNF-inducing component of peripheral immunity and/or an immunotrophic function of peripheral BDNF. Both scenarios may warrant further exploration, as they could inform new research concepts towards immune-based antidepressive treatment strategies.

Serum BDNF concentrations show strong seasonal variation and correlations with the amount of ambient sunlight.

Earlier findings show seasonality in processes and behaviors such as brain plasticity and depression that in part are regulated by Brain-Derived Neurotrophic Factor (BDNF). Based on this we investigated seasonal variation in serum BDNF concentrations in 2,851 persons who took part in the Netherlands Study of Depression and Anxiety (NESDA). Analyses by month of sampling (monthly n's >196) showed pronounced seasonal variation in serum BDNF concentrations (P<.0001) with increasing concentrations in the spring-summer period (standardized regression weight (ß) = 0.19, P<.0001) and decreasing concentrations in the autumn-winter period (ß = -0.17, P<.0001). Effect sizes [Cohen's d] ranged from 0.27 to 0.66 for monthly significant differences. We found similar seasonal variation for both sexes and for persons with a DSM-IV depression diagnosis and healthy control subjects. In explorative analyses we found that the number of sunshine hours (a major trigger to entrain seasonality) in the week of blood withdrawal and the 10 weeks prior to this event positively correlated with serum BDNF concentrations (Pearson's correlation coefficients ranged: 0.05-0.18) and this could partly explain the observed monthly variation. These results provide strong evidence that serum BDNF concentrations systematically vary over the year. This finding is important for our understanding of those factors that regulate BDNF expression and may provide novel avenues to understand seasonal dependent changes in behavior and illness such as depression. Finally, the findings reported here should be taken into account when designing and interpreting studies on BDNF.