Statistically significant antidepressant-placebo differences on subjective symptom-rating scales do not prove that the drugs work : effect Size and method bias matter!

Following the publication of a recent meta-analysis by Cipriani et al., various opinion leaders and news reports claimed that the effectiveness of antidepressants has been definitely proven. E.g., Dr. Pariante, spokesperson for the Royal College of Psychiatrists, stated that this study “finally puts to bed the controversy on antidepressants, clearly showing that these drugs do work in lifting mood and helping most people with depression” (https://www.theguardian.com/science/2018/feb/21/the-drugs-do-work-antidepressants-are-effective-study-shows). We surely would embrace drug treatments that effectively help most people with depression, but based on work that has contested the validity of mostly industry-sponsored antidepressant trials we remain skeptical about antidepressants' clinical benefits. The most recent meta-analysis indeed concludes that antidepressants are more effective than placebo but also acknowledges that risk of bias was substantial and that the mean effect size of d = 0.3 was modest. Unfortunately, no clarification is given what this effect size means and whether it can be expected to be clinically significant in real-world routine practice. In this opinion paper we therefore ponder over how the reported effect size of d = 0.3 relates to clinical significance and how method bias undermines its validity, in order that the public, clinicians, and patients can judge for themselves whether antidepressants clearly work in most people with depression

Long-term outcomes of trials in the National Institute for Health and Care Excellence depression guideline

The forthcoming National Institute for Health and CareExcellence depression guideline reviews short-term outcomesfor long-term depression. We present effect sizes for long-termoutcomes in trials that report these data. Psychological therapiesbecome more effective, whereas antidepressants becomeless effective over the long term. We review other forms oflongitudinal research that support these findings

Statistically Significant Antidepressant-Placebo Differences on Subjective Symptom-Rating Scales Do Not Prove That the Drugs Work: Effect Size and Method Bias Matter!

Following the publication of a recent meta-analysis by Cipriani et al., various opinion leaders and news reports claimed that the effectiveness of antidepressants has been definitely proven. E.g., Dr. Pariante, spokesperson for the Royal College of Psychiatrists, stated that this study “finally puts to bed the controversy on antidepressants, clearly showing that these drugs do work in lifting mood and helping most people with depression” (https://www.theguardian.com/science/2018/feb/21/the-drugs-do-work-antidepressants-are-effective-study-shows). We surely would embrace drug treatments that effectively help most people with depression, but based on work that has contested the validity of mostly industry-sponsored antidepressant trials we remain skeptical about antidepressants' clinical benefits. The most recent meta-analysis indeed concludes that antidepressants are more effective than placebo but also acknowledges that risk of bias was substantial and that the mean effect size of d = 0.3 was modest. Unfortunately, no clarification is given what this effect size means and whether it can be expected to be clinically significant in real-world routine practice. In this opinion paper we therefore ponder over how the reported effect size of d = 0.3 relates to clinical significance and how method bias undermines its validity, in order that the public, clinicians, and patients can judge for themselves whether antidepressants clearly work in most people with depression

Establishing the substantive interpretation of the GFP by considering evidence from research on personality disorders and Animal Personality

In research on individual differences, various structural models aim at providing a comprehensive description of personality. These models assume multiple, mostly independent personality dimensions. More recently, the so-called General Factor of Personality (GFP) has become a proliferous, but contentious, topic. The notion of the GFP is based on the observations that personality dimensions are not independent, but in fact show consistent inter-correlations, leading to a relevant proportion of shared variance among them (Figueredo et al., 2006). The GFP seems to capture the socially desirable ends of personality scales, and, in terms of the Big Five model, high-GFP individuals score relatively high on openness, conscientiousness, extraversion (mainly the sociability-facet), agreeableness, and emotional stability (Rushton and Irwing, 2009; van der Linden et al., 2010a). Some authors have suggested that the GFP simply reflects methodological artifacts (Ashton et al., 2009; Backstrom et al., 2009; Hopwood et al., 2011b; Pettersson et al., 2012). However, much of this criticism has been addressed (Rushton and Erdle, 2010; Loehlin, 2012; Dunkel and van der Linden, 2014; van der Linden et al., 2014a). The objective of the present work is not to reiterate these issues, as they have been discussed extensively elsewhere (Irwing, 2013; van der Linden et al., 2016). Instead, we contend that criticism mostly offered within the specialty of personality psychology misses the bigger picture. More specific, evidence in favor of the GFP as a substantive and theoretically coherent construct has been provided in other research fields long before it became a contentious issue in personality psychology. Here we introduce two lines of evidence that may further corroborate the substantive interpretation of the GFP, specifically, findings from personality pathology as well as from animal personality. Looking at the GFP from a different perspective may help to overcome the current debates within personality psychology. In the following we will first briefly introduce work on the GFP and its theoretical foundation as social effectiveness. Afterwards we outline research from psychiatric nosology and animal ecology and discuss these in context

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

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

Predictors of employment for people with mental illness : results of a multicenter randomized trial on the effectiveness of placement budgets for supported employment

Background: Individual placement and support (IPS) has proven to be effective for vocational outcomes in people with mental illness. The original concept of IPS requires temporally unlimited provision of support. Using limited placement budgets and investigating factors that predict their effectiveness may inform decisions about resource allocation. Methods: A range of patient characteristics were tested as predictors of employment outcomes in participants who attended six outpatient psychiatric clinics in Switzerland between June 2010 and May 2011. Overall, 116 patients with the full spectrum of psychiatric conditions were randomly assigned and started an IPS intervention, which was provided by three different placement budgets. Support lasted 2 years for those who found a job, and outcomes were repeatedly assessed over 3 years. The intervention ended for those who failed to find competitive employment by the time their placement budget had run out. Results: Of the 15 variables tested, only Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) scores were predictors for obtaining work (for ≥1 day) and for maintaining it over a longer period (>3 months). Higher GAF and lower CGI scores increased the odds of obtaining employment and keeping it for at least 3 months. Functional role impairment, quality of life, self-esteem, or education level did not predict employment. Conclusion: Our data suggest that, if time-restricted budgets are offered to a wide range of patients, such as those included in this study, better functioning and lower symptom severity at baseline are predictive of better employment outcomes (finding and maintaining work) on the first (competitive) labor market in Switzerland. It remains to be investigated whether this holds true under different environmental factors. Clinical Trial Registration: ISRCTN, trial number: ISRCTN89670872

Lack of associations between female hormone levels and visuospatial working memory, divided attention and cognitive bias across two consecutive menstrual cycles

Background: Interpretation of observational studies on associations between prefrontal cognitive functioning and hormone levels across the female menstrual cycle is complicated due to small sample sizes and poor replicability. Methods: This observational multisite study comprised data of n = 88 menstruating women from Hannover, Germany, and Zurich, Switzerland, assessed during a first cycle and n = 68 re-assessed during a second cycle to rule out practice effects and false-positive chance findings. We assessed visuospatial working memory, attention, cognitive bias and hormone levels at four consecutive time-points across both cycles. In addition to inter-individual differences we examined intra-individual change over time (i.e., within-subject effects). Results: Estrogen, progesterone and testosterone did not relate to inter-individual differences in cognitive functioning. There was a significant negative association between intra-individual change in progesterone and change in working memory from pre-ovulatory to mid-luteal phase during the first cycle, but that association did not replicate in the second cycle. Intra-individual change in testosterone related negatively to change in cognitive bias from menstrual to pre-ovulatory as well as from pre-ovulatory to mid-luteal phase in the first cycle, but these associations did not replicate in the second cycle. Conclusions: There is no consistent association between women’s hormone levels, in particular estrogen and progesterone, and attention, working memory and cognitive bias. That is, anecdotal findings observed during the first cycle did not replicate in the second cycle, suggesting that these are false-positives attributable to random variation and systematic biases such as practice effects. Due to methodological limitations, positive findings in the published literature must be interpreted with reservation

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

Mitochondria as a Target of Environmental Toxicants

Enormous strides have recently been made in our understanding of the biology and pathobiology of mitochondria. Many diseases have been identified as caused by mitochondrial dysfunction, and many pharmaceuticals have been identified as previously unrecognized mitochondrial toxicants. A much smaller but growing literature indicates that mitochondria are also targeted by environmental pollutants. We briefly review the importance of mitochondrial function and maintenance for health based on the genetics of mitochondrial diseases and the toxicities resulting from pharmaceutical exposure. We then discuss how the principles of mitochondrial vulnerability illustrated by those fields might apply to environmental contaminants, with particular attention to factors that may modulate vulnerability including genetic differences, epigenetic interactions, tissue characteristics, and developmental stage. Finally, we review the literature related to environmental mitochondrial toxicants, with a particular focus on those toxicants that target mitochondrial DNA. We conclude that the fields of environmental toxicology and environmental health should focus more strongly on mitochondri