Methodological flaws, conflicts of interest, and scientific fallacies : implications for the evaluation of antidepressants’ efficacy and harm

BackgroundIn current psychiatric practice, antidepressants are widely and with ever-increasing frequency prescribed to patients. However, several scientific biases obfuscate estimates of antidepressants’ efficacy and harm, and these are barely recognized in treatment guidelines. The aim of this mini-review is to critically evaluate the efficacy and harm of antidepressants for acute and maintenance treatment with respect to systematic biases related to industry funding and trial methodology.MethodsNarrative review based on a comprehensive search of the literature.ResultsIt is shown that the pooled efficacy of antidepressants is weak and below the threshold of a minimally clinically important change once publication and reporting biases are considered. Moreover, the small mean difference in symptom reductions relative to placebo is possibly attributable to observer effects in unblinded assessors and patient expectancies. With respect to trial dropout rates, a hard outcome not subjected to observer bias, no difference was observed between antidepressants and placebo. The discontinuation trials on the efficacy of antidepressants in maintenance therapy are systematically flawed, because in these studies, spontaneous remitters are excluded, whereas half of all patients who remitted on antidepressants are abruptly switched to placebo. This can cause a severe withdrawal syndrome that is easily misdiagnosed as a relapse when assessed on subjective symptom rating scales. In accordance, the findings of naturalistic long-term studies suggest that maintenance therapy has no clear benefit, and non-drug users do not show increased recurrence rates. Moreover, a growing body of evidence from hundreds of randomized controlled trials suggests that antidepressants cause suicidality, but this risk is underestimated because data from industry-funded trials are systematically flawed. Unselected, population-wide observational studies indicate that depressive patients who use antidepressants are at an increased risk of suicide and that they have a higher rate of all-cause mortality than matched controls.ConclusionThe strong reliance on industry-funded research results in an uncritical approval of antidepressants. Due to several flaws such as publication and reporting bias, unblinding of outcome assessors, concealment and recoding of serious adverse events, the efficacy of antidepressants is systematically overestimated, and harm is systematically underestimated. Therefore, I conclude that antidepressants are largely ineffective and potentially harmful

How effective are antidepressants for depression over the long term? A critical review of relapse prevention trials and the issue of withdrawal confounding

The aim of this article is to discuss the validity of relapse prevention trials and the issue of withdrawal confounding in these trials. Recommendations for long-term antidepressant treatment are based almost exclusively on discontinuation trials. In these relapse prevention trials, participants with remitted depression are randomised either to have the antidepressant abruptly discontinued and replaced by inert placebo or to continue active treatment. The drug-placebo difference in relapse rates at the end of the maintenance phase is then interpreted as a prophylactic drug effect. These trials consistently produce remarkable benefits for maintenance treatment. However, the internal validity of this trial protocol is compromised, as research has shown that abruptly stopping antidepressants can cause severe withdrawal reactions that lead to (or manifest as) depression relapses. That is, there is substantial withdrawal confounding in discontinuation trials, which renders their findings uninterpretable. It is not clear to what degree the drug-placebo separation in relapse prevention (discontinuation) trials is due to withdrawal reactions, but various estimations suggest that it is presumably the majority. A review of findings based on other methodologies, including real-world long-term effectiveness trials like STAR*D and various naturalistic cohort studies, do not indicate that antidepressants have considerable prophylactic effects. As absence of evidence does not imply evidence of absence, no definitive conclusions can be drawn from the literature. To enable a thorough risk-benefit evaluation, real-world effectiveness trials should not only focus on relapse prevention, but also assess antidepressants' long-term effects on social functioning and quality of life. Thus far, reliable long-term data on these outcome domains are lacking

The Detrimental Impact of Maladaptive Personality on Public Mental Health: A Challenge for Psychiatric Practice

Experts in personality psychology and personality disorders have long emphasised the pervasive and persistent detrimental impact of maladaptive personality traits on mental health and functioning. However, in routine psychiatric practice maladaptive personality is readily ignored and personality traits are seldom incorporated into clinical guidelines. The aim of this narrative review is to outline how pervasively personality influences public mental health and how personality thereby challenges common psychiatric practice. A comprehensive search and synthesis of the scientific literature demonstrates that maladaptive personality traits and personality disorders, in particular high neuroticism and negative affectivity, first, are risk factors for divorce, unemployment and disability pensioning; second, relate to the prevalence, incidence and co-occurrence of common mental disorders; third, impair functioning, symptom remission and recovery in co-occurring common mental disorders; and fourth, predispose to treatment resistance, non-response and poor treatment outcome. In conclusion, maladaptive personality is not only involved in the development and course of mental disorders, but also predisposes to chronicity and re-occurrence of psychopathology and reduces the efficacy of psychiatric treatments. The pernicious impact of maladaptive personality on mental health and functioning demands that careful assessment and thorough consideration of personality should be compulsory in psychiatric practice

Guidelines for the pharmacological acute treatment of major depression : conflicts with current evidence as demonstrated with the German S3-guidelines

Several international guidelines for the acute treatment of moderate to severe unipolar depression recommend a first-line treatment with antidepressants (AD). This is based on the assumption that AD obviously outperform placebo, at least in the case of severe depression. The efficacy of AD for severe depression can only be definitely clarified with individual patient data, but corresponding studies have only been available recently. In this paper, we point out discrepancies between the content of guidelines and the scientific evidence by taking a closer look at the German S3-guidelines for the treatment of depression. Based on recent studies and a systematic review of studies using individual patient data, it turns out that AD are marginally superior to placebo in both moderate and severe depression. The clinical significance of this small drug-placebo-difference is questionable, even in the most severe forms of depression. In addition, the modest efficacy is likely an overestimation of the true efficacy due to systematic method biases. There is no related discussion in the S3-guidelines, despite substantial empirical evidence confirming these biases. In light of recent data and with their underlying biases, the recommendations in the S3-guidelines are in contradiction with the current evidence. The risk-benefit ratio of AD for severe depression may be similar to the one estimated for mild depression and thus could be unfavorable. Downgrading of the related grade of recommendation would be a logical consequence

Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg depression rating scale, the gold standard clinician rating scale : a meta-analysis of randomised placebo-controlled trials

It has been claimed that efficacy estimates based on the Hamilton Depression Rating-Scale (HDRS) underestimate antidepressants true treatment effects due to the instrument's poor psychometric properties. The aim of this study is to compare efficacy estimates based on the HDRS with the gold standard procedure, the Montgomery-Asberg Depression Rating-Scale (MADRS)

Subtle scientific fallacies undermine the validity of neuroendocrinological research : do not draw premature conclusions on the role of female sex hormones

Major scientific flaws such as reporting and publication biases are well documented, even though acknowledgment of their importance appears to be lacking in various psychological and medical fields. Subtle and less obvious biases including selective reviews of the literature and empirically unsupported conclusions and recommendations have received even less attention. Using the literature on the association between transition to menopause, hormones and the onset of depression as a guiding example, I outline how such scientific fallacies undermine the validity of neuroendocrinological research. It is shown that in contrast to prominent claims, first, most prospective studies do not support the notion that the menopausal transition relates to increased risk for depression, second, that associations between hormone levels and depression are largely inconsistent and irreproducible, and, third, that the evidence for the efficacy of hormone therapy for the treatment of depression is very weak and at best inconclusive. I conclude that a direct and uniform association between female sex hormones and depression is clearly not supported by the literature and that more attention should be paid to the manifold scientific biases that undermine the validity of findings in psychological and medical research, with a specific focus on the behavioral neurosciences