Suicide Rates and Prescription of Antidepressants.

Background: Previous ecological studies reported that increasing antidepressant prescriptions were associated with decreasing suicide rates. Aim: To determine whether antidepressant prescription prevalence is negatively associated with suicide rates (i.e., as antidepressant prescribing increases, suicide rates decrease) between 1999 and 2020. Method: The study protocol was pre-registered on the Open Science Framework (https://osf.io/978sk/). Publicly available data from the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiological Research (CDC WONDER) and Medical Expenditure Panel Survey (MEPS) were used. Results: Overall, both the antidepressant prescription prevalence and the suicide rate were increasing from 1990 to 2020 in the United States. Positive trends for both outcomes were also evident when analyses were stratified according to sex and/or race/ethnicity. Pearson's correlation analyses consistently found positive associations between antidepressant prescription prevalence and suicide rates. Limitations: Trends and their associations were examined at the population level. The results cannot clarify the causal nature of the association observed. Conclusion: The results of our analysis consistently demonstrated positive trends for both antidepressant prescription prevalence and suicide rates over time as well as positive associations between them. These findings update those from previous studies and are at odds with the notion that, at a population level, more antidepressant prescriptions would lead to lower suicide rates. However, it needs to be acknowledged that ecological studies provide insufficient evidence to infer causality.

Antidepressants use in Italy: an ecological study of national and regional trends and associated factors.

The present study aimed to (1) provide an update on trends in AD consumption both at the national and regional unit of analysis for the period 2000-2020 in Italy and (2) analyze sociodemographic and healthcare system-related factors associated with AD prescribing at the regional-population level between 2000 and 2019. Data were extracted from reports of the Italian Medicines Agency and databases of the Italian National Institute of Statistics. Linear regression and mixed models were applied to analyze trends in AD use (DDD/1000/day) and ecological factors associated with AD prescribing. Between 2000 and 2010 AD prescription rates constantly increased. Thereafter they stabilized until 2017 when a positive trend began again. There was a positive ecological association between AD prescribing and rates of hospital discharge due to affective disorders, antibiotics prescribing, public non-drug healthcare spending per capita, and Northern regions compared to Southern regions. AD consumption increased massively during the 2000s, flattened during the 2010s but thereafter increased again until 2020. The ecological correlation between healthcare provision/spending and AD consumption suggests that health-economic factors may play an important role.

Prevalence, trends, and individual patterns of long-term antidepressant medication use in the adult Swiss general population.

PURPOSE: Antidepressant use has increased in many European countries, mostly driven by longer treatment duration. The aim of this study was to provide prevalence rates of long-term users of antidepressants for the Swiss population over the last decade and to investigate associated factors for longer use. METHODS: We examined the prevalence rates of individuals with at least one prescription for antidepressants using longitudinal health claims data for 2013 to 2021. We defined short- (< one year), medium- (one-two years), and long-term users (> two years) for 2015 to 2019. We applied a binary logistic regression model to investigate the effects of population (gender, age, area of living, language, health insurance plan, and nursing home) and treatment characteristics (psychiatric or psychotherapeutic care) on long-term compared to short- and medium-term users in 2019. RESULTS: In 2021, 9% of the Swiss population (n = 770,698) received at least one antidepressant prescription, which remained stable since 2013. In 2019, the proportion of long-term users was 57.4%, with steady increase since 2015. The proportion of medium- and short-term users has decreased. Older age, being a woman, living in an urban area, living in a nursing home, being enrolled in a standard care plan, and receiving psychiatric or psychotherapeutic care were factors positively associated with being a long-term user. CONCLUSION: The proportion of long-term users in Switzerland is high and steadily increasing. Given the ongoing debate about the confounding effects of relapse and withdrawal, more research is needed to investigate longer use of antidepressants that could indicate overprescribing.

Observational studies of antidepressant use and suicide risk are selectively published in psychiatric journals.

OBJECTIVES: To investigate if observational studies showing favorable results for antidepressants on suicidal behavior (reduced risk) are preferably and more easily published in psychiatric journals and cited more often compared to studies with unfavorable results (increased risk). STUDY DESIGN AND SETTING: Prespecified secondary analysis, including 27 original studies selected through a systematic review of observational studies reporting associations between the use of newer antidepressant drugs and suicide risk. RESULTS: Independent of study quality, studies reporting favorable results were more frequently published in psychiatric than nonpsychiatric journals and were more often conducted by lead authors with financial conflicts of interest (fCOI). Within psychiatric journals, lead authors with fCOI published in journals with a higher impact factor (IF) and ranking. Within psychiatric journals, favorability of results also correlated with citation frequency, IF, and journal ranking, but these associations became weaker and inconclusive after adjusting for study quality. Results for ease of publishing were inconclusive. CONCLUSION: Studies reporting unfavorable results (increased suicide risk with antidepressant exposure) are less likely to be published in psychiatric journals. Lead authors with fCOI report more favorable results, and their studies are published in the most prestigious psychiatric journals. This may create a biased evidence base and an unbalanced dissemination and appraisal of findings within psychiatry.

Sexual attraction to visual sexual stimuli in association with steroid hormones across menstrual cycles and fertility treatment.

BACKGROUND: Steroid hormones (i.e., estradiol, progesterone, and testosterone) are considered to play a crucial role in the regulation of women's sexual desire and sexual attraction to sexual stimuli throughout the menstrual cycle. However, the literature is inconsistent, and methodologically sound studies on the relationship between steroid hormones and women's sexual attraction are rare. METHODS: This prospective longitudinal multisite study examined estradiol, progesterone, and testosterone serum levels in association with sexual attraction to visual sexual stimuli in naturally cycling women and in women undergoing fertility treatment (in vitro fertilization, IVF). Across ovarian stimulation of fertility treatment, estradiol reaches supraphysiological levels, while other ovarian hormones remain nearly stable. Ovarian stimulation hence offers a unique quasi-experimental model to study concentration-dependent effects of estradiol. Hormonal parameters and sexual attraction to visual sexual stimuli assessed with computerized visual analogue scales were collected at four time points per cycle, i.e., during the menstrual, preovulatory, mid-luteal, and premenstrual phases, across two consecutive menstrual cycles (n = 88 and n = 68 for the first and second cycle, respectively). Women undergoing fertility treatment (n = 44) were assessed twice, at the beginning and at the end of ovarian stimulation. Sexually explicit photographs served as visual sexual stimuli. RESULTS: In naturally cycling women, sexual attraction to visual sexual stimuli did not vary consistently across two consecutive menstrual cycles. While in the first menstrual cycle sexual attraction to male bodies, couples kissing, and at intercourse varied significantly with a peak in the preovulatory phase, (all p ≤ 0.001), there was no significant variability across the second cycle. Univariable and multivariable models evaluating repeated cross-sectional relationships and intraindividual change scores revealed no consistent associations between estradiol, progesterone, and testosterone and sexual attraction to visual sexual stimuli throughout both menstrual cycles. Also, no significant association with any hormone was found when the data from both menstrual cycles were combined. In women undergoing ovarian stimulation of IVF, sexual attraction to visual sexual stimuli did not vary over time and was not associated with estradiol levels despite intraindividual changes in estradiol levels from 122.0 to 11,746.0 pmol/l with a mean (SD) of 3553.9 (2472.4) pmol/l. CONCLUSIONS: These results imply that neither physiological levels of estradiol, progesterone, and testosterone in naturally cycling women nor supraphysiological levels of estradiol due to ovarian stimulation exert any relevant effect on women's sexual attraction to visual sexual stimuli.

The risks of adverse events with venlafaxine and mirtazapine versus 'active placebo', placebo, or no intervention for adults with major depressive disorder: a protocol for two separate systematic reviews with meta-analysis and Trial Sequential Analysis.

BACKGROUND: Major depressive disorder causes a great burden on patients and societies. Venlafaxine and mirtazapine are commonly prescribed as second-line treatment for patients with major depressive disorder worldwide. Previous systematic reviews have concluded that venlafaxine and mirtazapine reduce depressive symptoms, but the effects seem small and may not be important to the average patient. Moreover, previous reviews have not systematically assessed the occurrence of adverse events. Therefore, we aim to investigate the risks of adverse events with venlafaxine or mirtazapine versus 'active placebo', placebo, or no intervention for adults with major depressive disorder in two separate systematic reviews. METHODS: This is a protocol for two systematic reviews with meta-analysis and Trial Sequential Analysis. The assessments of the effects of venlafaxine or mirtazapine will be reported in two separate reviews. The protocol is reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, risk of bias will be assessed with the Cochrane risk-of-bias tool version 2, clinical significance will be assessed using our eight-step procedure, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. We will search for published and unpublished trials in major medical databases and trial registers. Two review authors will independently screen the results from the literature searches, extract data, and assess risk of bias. We will include published or unpublished randomised clinical trial comparing venlafaxine or mirtazapine with 'active placebo', placebo, or no intervention for adults with major depressive disorder. The primary outcomes will be suicides or suicide attempts, serious adverse events, and non-serious adverse events. Exploratory outcomes will include depressive symptoms, quality of life, and individual adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses. DISCUSSION: Venlafaxine and mirtazapine are frequently used as second-line treatment of major depressive disorder worldwide. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022315395.

Estimating Risk of Antidepressant Withdrawal from a Review of Published Data.

Adaptation of the brain to the presence of a drug predicts withdrawal on cessation. The outcome of adaptation is often referred to as 'physical dependence' in pharmacology, as distinct from addiction, although these terms have unfortunately become conflated in some diagnostic guides. Physical dependence to antidepressants may occur in some patients, consistent with the fact that some patients experience withdrawal effects from these medications. It is thought that longer duration of use, higher dose and specific antidepressants affect the risk of antidepressant withdrawal effects as they might cause greater adaptation of the brain. We searched PubMed for relevant systematic reviews and other relevant analyses to summarise existing data on determinants of antidepressant withdrawal incidence, severity and duration. Overall, data were limited. From survey data, increased duration of use was associated with an increased incidence and severity of withdrawal effects, consistent with some evidence from data provided by drug manufacturers. Duration of use may be related to duration of withdrawal effects but data are heterogenous and sparse. Serotonin and noradrenaline reuptake inhibitors and paroxetine are associated with higher risks than other antidepressants, though data for some antidepressants are lacking. Higher doses of antidepressant has some weak association with an increased risk of withdrawal, with some ceiling effects, perhaps reflecting receptor occupancy relationships. Past experience of withdrawal effects is known to predict future risk. Based on these data, we outline a preliminary rubric for determining the risk of withdrawal symptoms for a particular patient, which may have relevance for determining tapering rates. Given the limited scope of the current research, future research should aim to clarify prediction of antidepressant withdrawal risk, especially by examining the risk of withdrawal in long-term users of medication, as well as the severity and duration of effects, to improve the preliminary tool for predictive purposes. Further research into the precise adaptations in long-term antidepressant use may improve the ability to predict withdrawal effects for a particular patient.

Increased suicide risk among younger women in winter during full moon in northern Europe. An artifact or a novel finding?

Available evidence suggests that there is no effect of moon phases on suicidal behavior. However, a Finnish study recently reported elevated suicide rates during full-moon, but only among premenopausal women and only in winter. This could not be replicated in an Austrian study and stirred a discussion about whether the Finnish finding was false-positive or if there are unaccounted moderator variables differing between Finland and Austria. The goal of the present study was to provide another replication with data from Sweden, which is geographically more comparable to Finland than Austria. We also investigated the discussed moderator variables latitude and nightly artificial brightness. There were 48,537 suicides available for analysis. The fraction of suicides during the full-moon quarter in winter did not differ significantly from the expected 25% among premenopausal women (23.3%) and in the full sample (24.7%). The incidence risk ratios for full moon quarter in Poisson regression models were 0.96 (95% CI: 0.90-1.02) for premenopausal women and 1.01 (95% CI: 0.99-1.04) for the full sample. According to Bayes-factor analysis, the evidence supports the null-hypothesis (no association) over the alternative hypothesis (some association). We found similar results when we split the data by latitude and artificial nightly brightness, respectively. In line with the Austrian study, there was no increase of suicides in Sweden among premenopausal women in winter during full-moon. The results from the Finnish study are likely false positive, perhaps resulting from problematic but common research and publication practices, which we discuss.

The serotonin theory of depression: a systematic umbrella review of the evidence.

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.

Effect of the FDA Black Box Suicidality Warnings for Antidepressants on Suicide Rates in the USA.

Background: Some authors claimed that the US Food and Drug Administration (FDA) black box warning on treatment-emergent suicidality with antidepressants in adolescents (issued 2004) and young adults (issued 2006) led to an increase of suicides, based on the analyses of ecological data with debatable assumptions about putative changes in suicide rates. Aims: To explore if putative changes in suicide rates in adolescents and young adults at the time of the FDA warnings is a detectable signal in the data or compatible with random fluctuations. Method: We applied different changepoint analyses for adolescent and young adult suicide rates from 1981 to 2019 in the USA. Results: Changepoint analysis did not support a detrimental effect of the FDA black box warnings. The downward trend of suicides reversed several years after the warning in adolescents (2007-2009) and many years before in young adults (1999-2001). Limitations: Our analyses cannot rule out detrimental effects of the FDA warnings. However, even if there was such an effect, it was likely small and indistinguishable from random fluctuations in the available suicide data. Conclusion: There is no detectable change of trend in adolescent or young adult suicide rates in line with a detrimental effect of the FDA black box warnings on treatment-emergent suicidality.

Food preferences throughout the menstrual cycle - A computer-assisted neuro-endocrino-psychological investigation.

BACKGROUND: As eating behavior changes in relation to the menstrual cycle and weight changes with menopausal transition, ovarian hormones appear to be involved in regulating eating behavior. However, observations are contradictory and are difficult to compare, due to methodological problems related to nutritional epidemiology. To better understand the relationship between ovarian steroid hormones and eating behavior, our study evaluates women's responses to visual food cues at different points in the menstrual cycle with their specific serum estrogen/progesterone levels and women's responses in the case of strong estrogen changes in the context of fertility treatments. METHODS: We collected data from 129 women, 44 of whom received in vitro fertilization (IVF) at the Department of Reproductive Endocrinology, University Hospital Zurich. A total of 85 women with natural cycles were recruited at the University Hospital Zurich (n = 37) and at the Hannover Medical School (n = 48). Our observational study used 4 different measurement time points across the natural cycle and 2 measurement time points in women with supraphysiological estradiol levels during fertility treatments. Using a second cycle, we then tested our results for replication. At these predefined time points, women were shown pictures of 11 categories of food, with 4 items for each category and blood samples for measurement of hormone levels were taken. Food preferences registered at the time of the investigation were indicated on a visual analogue scale (0-100). RESULTS: We did not find any statistically significant association between women's serum hormone levels and the rating of visually presented food, either during the menstrual cycle or during fertility treatments after controlling for multiple testing (all p > 0.005). Ratings for fruits, vegetables, and carbohydrates showed a significant linear decline throughout the first menstrual cycle (p < 0.01), which did not replicate in the second cycle (p > 0.05). In contrast, the ratings for sweets showed a significant linear decline in both cycles (both p < 0.01), with a mean rating of 54.2 and 48.8 in the menstrual phase of the first and second cycle, respectively, to a mean rating of 47.7 and 43.4 in the premenstrual phase of the first and second cycle, respectively. During fertility treatments, no food rating showed a significant change (all p > 0.05). Mood such as negative and positive affects did not influence ratings for visual food cues neither throughout the menstrual cycles nor during fertility treatment. CONCLUSIONS: Serum levels of estradiol and progesterone do not correlate with food ratings in women, even when estradiol levels are above the physiological level of a natural menstrual cycle. Since, except for sweets, significant changes in food ratings in a first cycle did not replicate in a second menstrual cycle, significant findings from the literature based on animal or human studies focusing on a single-cycle have to be interpreted with caution.

Factors Related to Non-compliance With Non-pharmaceutical Interventions to Mitigate the Spread of SARS-CoV-2: Results From a Survey in the Swiss General Adult Population.

Background: Non-pharmaceutical interventions (NPI) play an important role in national efforts to control and contain the spread of SARS-CoV-2, but some people do not comply with these public health measures. The aim of this study was thus to describe this group of noncompliant people. Methods: A random sample of 1,157 people was drawn from the adult general population of Switzerland based on a three-stepped quota scheme considering the variables age (18-31, 32-45, 46-59, and ≥60 years), sex (male and female), and language region (German-, French-, and Italian-speaking Switzerland). We assessed a global scale of non-compliance with NPI based on several individual measures such as wearing face masks and social distancing. As predictor variables we included objective sociodemographic variables (e.g., age, sex) and easy measurable constructs (e.g., fears and worries about COVID-19, trust in medical experts). Results: Out of 14 predictor variables tested, seven were statistically significantly associated with increased non-compliance with NPI: male sex, younger age, self-identification as low-risk group, judging the consequences of an infection with SARS-CoV-2 as non-serious, less worries and fears about the pandemic, not obtaining regular information from health authorities, and not trusting in medical experts. The most parsimonious multivariable prediction model included the variables younger age, low appraisal of negative consequences, less fear and worries, not obtaining regular information from health authorities, and not trusting in medical experts. The model accounted for 27.9% of variance explained in non-compliance with NPI. Conclusion: Young adults who perceive COVID-19 as mostly harmless/inconsequential and who ignore and/or mistrust information from health authorities and medical experts, are the population most likely to be noncompliant with NPI. These findings may help to target a group of people at high risk of infection and to efficiently concentrate educational and interventional public health measures.

Longitudinal reciprocal associations between depression, anxiety, and substance use disorders over three decades of life.

BACKGROUND AND OBJECTIVE: Studies exploring longitudinal reciprocal associations between depressive, anxiety, and substance use disorders (DD, AD and SUD, respectively) over long periods of time are mainly lacking. Therefore, the aim of the present study is to test longitudinal associations (i.e. temporal dynamics) between DD, AD and SUD from young adulthood to middle adulthood. METHODS: A stratified community sample of 591 participants from the canton of Zurich, Switzerland, was interviewed with the Structured Psychopathological Interview and Rating of the Social Consequences of Psychological Disturbances for Epidemiology over seven interview waves from ages 20/21 to 49/50. Diagnostic and Statistical Manual of Mental Disorders criteria were used to evaluate the presence of DD, AD and SUD. We fitted an auto-regressive cross-lagged path analysis within a Bayesian structural equation model to test longitudinal associations. RESULTS: Regarding autoregressive effects, AD (except during young adulthood) and SUD predicted themselves over the entire time period, while DD recurrently predicted itself not consistently over time. Regarding cross-lagged effects, DD predicted SUD at different time points, and vice versa. DD predicted subsequent AD in adulthood, whereas the reverse did not happen. Female gender was associated with DD and AD at all ages while male gender was associated with SUD only in young adulthood. CONCLUSIONS: Reciprocal longitudinal associations were found between DD and SUD and DD usually preceded AD. Our results further confirm an increased risk of DD and AD in women and a higher risk of SUD in young men. Early treatment and broad psychosocial interventions should be provided in order to prevent chronicity and further maladjustment as well as interrupting the cycle of mutual reinforcement between DD and SUD.

Patterns of internalizing symptoms and disability functioning in children and adolescents.

Despite findings from previous studies, there is still little consistent knowledge regarding the co-occurrence patterns of somatic, depressive and anxiety symptoms in childhood and adolescence. Moreover, functional disability due to somatic symptoms at different concomitant levels of depression and anxiety is understudied. The present study examined the co-occurrence patterns of somatic symptoms and symptoms of depression and anxiety, in children and adolescents using two-step cluster analysis. Differences in functional disability due to somatic symptoms were tested with ANCOVA controlling for gender and age. The sample comprised 1127 Italian children and adolescents (48.7% males, n = 549) aged 8-16 years (Mage = 11.7, SD = 2.37). Data were collected using the Children Somatization Inventory-24, the Children Depression Inventory, the Screen for Child Anxiety Related Emotional Disorders, and the Functional Disability Inventory. A four-cluster solution based on the co-occurrence of internalizing symptoms best fit the data. The four clusters were labelled as follows: cluster 1: "High somatic symptoms and average depression/anxiety"; cluster 2: "High somatic symptoms and high depression/anxiety"; cluster 3: "Average somatic symptoms and above average depression/anxiety"; and cluster 4: "Low somatic symptoms and low depression/anxiety". Significant differences between the four groups according to gender and age were shown. Participants with high levels of somatic, depressive, and anxiety symptoms reported greater functional disability due to somatic symptoms than the other three groups. Our findings indicate that children and adolescents who demonstrate high symptoms of depression and anxiety also reported higher levels of disability in daily life due to somatic symptoms.