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.

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.

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 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.

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.

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.

Estimates of the minimal important difference to evaluate the clinical significance of antidepressants in the acute treatment of moderate-to-severe depression.

The efficacy of antidepressants in the acute treatment of moderate-to-severe depression remains a controversial issue. The minimal important difference (MID) is relevant to judge the clinical significance of treatment effects. In this analysis paper, we discuss estimates of the MID for common depression outcome measures.For the Hamilton Depression Rating Scale 17-item Version (HDRS-17), according to both anchor-based and distribution-based approaches, MID estimates range from 3 to 8 points, and the most accurate values are likely between 3 and 5 points. For the 6-item version (HDRS-6), MID estimates range between 2 and 4 points. For both the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Beck Depression Inventory II (BDI-II), MID estimates range between 3 and 9 points, with estimates of 3-6 points likely being the most accurate. Quality of life appears to be more important to patients than core depression symptoms. We thus also evaluated the Short-Form 36 (SF-36) mental component score, a popular mental-health-related quality of life measure. Its MID estimate is likely about 5 points. By contrast, the average treatment effects of antidepressants on the HDRS-17, HDRS-6, MADRS, BDI-II and SF-36 are 2 points, 1.5 points, 3 points, 2 points and 3-5 points, respectively.In conclusion, the efficacy of antidepressants in the acute treatment of moderate-to-severe depression consistently fails to exceed the lower bound of the MID estimates for common depression outcome measures. The clinical significance of antidepressants thus remains uncertain and we call for more research on quality of life measures, which are the patients' most valued outcome domains.

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.

Swiss GPs' preferences for antidepressant treatment in mild depression: vignette-based quantitative analysis.

BACKGROUND: GPs frequently prescribe antidepressants in mild depression. The aim of this study was to examine, how often Swiss GPs recommend antidepressants in various clinical presentations of mild depression and which factors contribute to antidepressant treatment recommendations. METHODS: We conducted an online survey among Swiss GPs with within-subject effect analysis. Alternating case vignettes described a typical female case of mild depression according to International Classification of Diseases, 10th edition criteria, with and without anxiety symptoms and sleep problems. GPs indicated for each vignette their preferred treatments (several recommendations were possible). Additionally, we assessed GP characteristics, attitudes towards depression treatments, and elements of clinical decision-making. RESULTS: Altogether 178 GPs completed the survey. In the initial description of a case with mild depression, 11% (95%-CI: 7%-17%) of GPs recommended antidepressants. If anxiety symptoms were added to the same case, 29% (23%-36%) recommended antidepressants. If sleep problems were mentioned, 47% (40%-55%) recommended antidepressants, and if both sleep problems and anxiety symptoms were mentioned, 63% (56%-70%) recommended antidepressants. Several factors were independently associated with increased odds of recommending antidepressants, specifically more years of practical experience, an advanced training in psychosomatic and psychosocial medicine, self-dispensation, and a higher perceived effectiveness of antidepressants. By contrast, a higher perceived influence of patient characteristics and the use of clinical practice guidelines were associated with reduced odds of recommending antidepressants. CONCLUSIONS: Consistent with depression practice guidelines, Swiss GPs rarely recommended antidepressants in mild depression if no co-indications (i.e., sleep problems and anxiety symptoms) were depicted. However, presence of sleep problems and anxiety symptoms, many years of practical experience, overestimation of antidepressants' effectiveness, self-dispensation, an advanced training in psychosomatic and psychosocial medicine, and non-use of clinical practice guidelines may independently lead to antidepressant over-prescribing.

Prophylactic effects or withdrawal reactions? An analysis of time-to-event data from antidepressant relapse prevention trials submitted to the FDA.

BACKGROUND: Relapse prevention trials build the scientific foundation for recommendation of antidepressant continuation and maintenance therapy. However, the validity of the evidence is disputed and may be biased due to withdrawal confounding. METHODS: We analysed survival curves from all antidepressant relapse prevention trials submitted to the United States (US) Food and Drug Administration (FDA) between 1987 and 2012 for 13 approved drugs. The main outcome was the percent of the drug effect (placebo-antidepressant difference in relapse events) at any week of the maintenance phase in relation to the total drug effect at the endpoint of the randomised maintenance phase. RESULTS: Altogether, 14 studies with a mean observation period of 38.9 weeks (Kaplan-Meier estimators) were analysed. At week 3, a mean of 20.6% [95% confidence interval (CI) = 10.9-30.3%] of the total drug effect was achieved. At weeks 6 and 12, the corresponding figures were 50.3% (37.3-63.3%) and 69.0% (55.1-82.8%). No further antidepressant-placebo separation was observed as of week 24 [101.0% of total drug effect (94.6-107.3%)]. This means that censoring relapse events that occurred in the first 3, 6, 12 and 24 weeks would reduce the total drug effect at study endpoint by 20.6%, 50.3%, 69.0% and 101.0%, respectively. Assuming antidepressants had a constant prophylactic effect over 38.9 weeks, we further showed that, around week 6, the antidepressant-placebo separation was about three times larger than expected. CONCLUSION: The placebo-antidepressant separation was disproportionally large between weeks 3 and 6 of the randomised maintenance phase. The benefits of continuing antidepressants relative to abrupt/rapid discontinuation declined sharply after week 6. This indicates an excess of relapse events in the placebo arms during the early maintenance phase that may be due to withdrawal reactions caused by abrupt/rapid discontinuation of active treatment. If these early relapse events are due to a direct pharmacological effect, then antidepressants' true prophylactic long-term effects are substantially overestimated.

Suicidality and other severe psychiatric events with duloxetine: Re-analysis of safety data from a placebo-controlled trial for juvenile fibromyalgia.

BACKGROUND: In antidepressant trials for pediatric patients with depression or anxiety disorders, the risk of suicidal events and other severe psychiatric adverse events such as aggression and agitation is increased with antidepressants relative to placebo. OBJECTIVE: To examine whether largely mentally healthy adolescents treated for a non-psychiatric condition are also at increased risk of suicidality and other severe psychiatric disorders. METHODS: This is a re-analysis of a placebo-controlled duloxetine trial for juvenile fibromyalgia based on the main journal article and additional data published in the online supplementary material and on ClinicalTrials.gov. Both serious adverse events related to psychiatric disorders and adverse events leading to treatment discontinuation were defined as severe treatment-emergent psychiatric adverse events. RESULTS: We found that a significant portion of adolescents had treatment-emergent suicidal ideation and behaviour as well as other severe psychiatric adverse events with duloxetine, but no such events were recorded on placebo. The incidence of severe treatment-emergent psychiatric adverse events was statistically significantly higher with duloxetine as compared to placebo. CONCLUSIONS: Antidepressants may put adolescents at risk of suicidality and other severe psychiatric disorders even when the treatment indication is not depression or anxiety.

Suicide risk with selective serotonin reuptake inhibitors and other new-generation antidepressants in adults: a systematic review and meta-analysis of observational studies.

BACKGROUND: There is ongoing controversy whether antidepressant use alters suicide risk in adults with depression and other treatment indications. METHODS: Systematic 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. RESULTS: We 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. CONCLUSIONS: Exposure 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. REGISTRATION: Open Science Framework, https://osf.io/eaqwn/.