The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

Background: COVID-19 containment measures and the uncertainties associated with the pandemic may have contributed to changes in mental health risks and mental health problems in university students. Due to the high burden of the disease, depression is of particular concern. However, knowledge about the prevalence of depressive symptoms in Swiss university students during the pandemic is limited. We therefore assessed the prevalence of depressive symptoms and their change during the COVID-19 pandemic in a large sample of Swiss university students. Methods: We assessed depressive symptoms in two cross-sectional cohorts of university students (n = 3571) in spring and autumn 2020 during the COVID-19 pandemic and compared them with a matched sample of the Swiss national population (n = 2328). Binary logistic regression models estimated prevalence with corresponding 95% confidence intervals (95% CI). Results: Adjusted prevalence of depressive symptoms in female (30.8% (95% CI: 28.6–33.0)) and male students (24.8% (95% CI: 21.7–28.1)) was substantially higher than in the matching female (10.9% (95% CI: 8.9–13.2)) and male (8.5% (6.6–11.0)) pre-pandemic national population. Depressive symptoms in the two consecutive student cohorts did not significantly differ. Conclusions: More than a quarter of Swiss university students reported depressive symptoms during the COVID-19 pandemic, which was substantially higher as compared to the matched general population. Universities should introduce measures to support students in such times of crisis and gain an understanding of the factors impacting mental health positively or negatively and related to university structures and procedures.

ObjectiveThe COVID-19 pandemic and government measures implemented to counter the spread of the infection may be a major stressor affecting the psychological health of university students. This study aimed to explore how anxiety symptoms changed during the pandemic.Methods676 students (76% females) at Zurich University of Applied Sciences participated in the first (T0) and second (T1) survey waves. Anxiety symptoms were assessed using the Generalized Anxiety Disorder-Scale-7 (GAD-7). Risk and protective factors (e.g., COVID-19-related variables) were examined.ResultsGAD-7 scores decreased significantly from T0 to T1 (mean change: −0.446, SE = 0.132, 95% CI: −0.706, −0.186, t = −3.371, df = 659, p = 0.001). Participants with moderate-to-severe anxiety score were 20.2 and 15.6% at T0 and T1, respectively. The following positively predicted anxiety: older age, female gender, non-Swiss nationality, loneliness, participants’ concern about their own health, and interaction between time and participants’ concern about their own health. Resilience and social support negatively predicted anxiety.ConclusionsOur findings provide information for public health measures and psychological interventions supporting the mental health of university students during the COVID-19 emergency.

BackgroundThere is ongoing controversy whether antidepressant use alters suicide risk in adults with depression and other treatment indications.MethodsSystematic review of observational studies, searching MEDLINE, PsycINFO, Web of Science, PsycARTICLES and SCOPUS for case–control and cohort studies. We included studies on depression and various indications unspecified (including off-label use) reporting risk of suicide and/or suicide attempt for adult patients using selective serotonin reuptake inhibitors (SSRI) and other new-generation antidepressants relative to non-users. Effects were meta-analytically aggregated with random-effects models, reporting relative risk (RR) estimates with 95% CIs. Publication bias was assessed via funnel-plot asymmetry and trim-and-fill method. Financial conflict of interest (fCOI) was defined present when lead authors’ professorship was industry-sponsored, they received industry-payments, or when the study was industry-sponsored.ResultsWe included 27 studies, 19 on depression and 8 on various indications unspecified (n=1.45 million subjects). SSRI were not definitely related to suicide risk (suicide and suicide attempt combined) in depression (RR=1.03, 0.70–1.51) and all indications (RR=1.19, 0.88–1.60). Any new-generation antidepressant was associated with higher suicide risk in depression (RR=1.29, 1.06–1.57) and all indications (RR=1.45, 1.23–1.70). Studies with fCOI reported significantly lower risk estimates than studies without fCOI. Funnel-plots were asymmetrical and imputation of missing studies with trim-and-fill method produced considerably higher risk estimates.ConclusionsExposure to new-generation antidepressants is associated with higher suicide risk in adult routine-care patients with depression and other treatment indications. Publication bias and fCOI likely contribute to systematic underestimation of risk in the published literature.RegistrationOpen Science Framework, https://osf.io/eaqwn/