Commentaries

Are drug and placebo effects in depression additive?

The Corona pandemic and ongoing mass vaccinations raise the question of the nocebo mechanisms involved. Since immunization is usually administered to healthy people as a preventive health measure, adverse events (AE) following immunization are less accepted and could contribute to vaccine hesitancy. Assuming that vaccinees experience nocebo responses, the aim of this meta-analysis was to investigate the effect sizes of solicited adverse events (or assumed reactogenicity) reported in placebo groups in RCTs on seasonal influenza vaccination.

Literature search via PubMed, Web of Science, and CENTRAL was conducted considering gray literature. Only RCTs with placebo groups using pharmacologically inert substances (like saline) were included. Quality was assessed using Cochrane Collaboration’s Risk of Bias Tool. Effect sizes were estimated using a random mixed effects model based on k = 31 studies covering 14,326 participants in placebo groups.

Reported solicited AEs in placebo groups showed significant effect sizes of proportions (ES_p). In k = 13 analyzed placebo groups, 35 % of the participants reported at least one solicited systemic AE (p = 0.007). The most common particular solicited systemic AEs were headache (k = 27; 17 %; p = 0.001), malaise (k = 13; 12 %; p = 0.004), and hyperhidrosis (k = 4; 12 %; p < 0.001) within one week after vaccination.

The results show significant solicited AEs in placebo groups, indicating substantial nocebo responses after vaccination. Based on the fact that most vaccination programs include similar groups of healthy people, we expect that comparable nocebo effects occur during other campaigns. Health care professionals should be aware of the nocebo response and take action to prevent or decrease the burden of adverse events following immunization. Fear of side effects must be addressed early in order to diminish vaccine hesitancy.

Prospero identifier: CRD42020156287, October 2019.

Common mental disorder is closely linked to life situations. Some individuals with depression and anxiety view their condition as disease/disorder, while others report purely situational attributions. This exploratory, cross cultural study examined the context, impact and social uses of disease attributions (DAs) in mothers experiencing perinatal distress.

Twenty-one European American (EA) and 17 South Asian (SA) mothers were recruited for the study. Mothers reporting a recent episode of distress participated in telephone interviews regarding their symptoms, experiences, and conceptual models of distress. Quantitative symptom were collected and subjected to descriptive analysis using SPSS. Qualitative interview data were analyzed using standard methods.

About half the sample made biological/disease attributions. The types of “diseases” referenced by participants differed dramatically across the two groups. SAs referenced a set of conditions understood to reflect a biological process of bodily weakening. EAs referenced psychiatric diagnoses such as ‘anxiety disorder,’ or ‘depression,’ popularly attributed to faulty brain chemistry. Compared to participants making situational attributions only, “disease attributors' reported more accommodating social networks and more treatment seeking behaviors. DAs functioned to signal distress and justify withdrawal from social roles. DAs were associated with specific symptom patterns. In both groups, DAs were closely associated with mystery and ambiguity, in keeping with the contested/problematic nature of such attributions.

More research is needed on the social context, uses, and impacts of DAs for CMD. This study sheds some light on these factors and offers questions for further exploration.

Participants in intervention studies are asked to take part in activities linked to the conduct of research, including signing consent forms and being assessed. If participants are affected by such activities through mechanisms by which the intervention is intended to work, then there is confounding. We examine how to account for research participation effects analytically.

Data from a trial of a brief alcohol intervention among Swedish university students is used to show how a proposed causal model can account for assessment effects.

The proposed model can account for research participation effects as long as researchers are willing to use existing data to make assumptions about causal influences, for instance on the magnitude of assessment effects. The model can incorporate several research processes which may introduce bias.

As our knowledge grows about research participation effects, we may move away from asking if participants are affected by study design, toward rather asking by how much they are affected, by which activities and in which circumstances. The analytic perspective adopted here avoids assuming there are no research participation effects.

Although different forms of pharmacological intervention are often prescribed for insomnia disorder, the comparative efficacies among various drugs remain unclear. We therefore conducted this study to quantitatively compare the efficacy of various pharmacotherapies for insomnia by modeling.

We searched PubMed, EMBASE and Cochrane Library databases for randomized placebo-controlled trials of insomnia medications that were conducted within a designated time period (from the inception dates to May 16, 2019). Pharmacodynamic models were established to describe the time course of changes from baseline in selected sleep parameters. Sleep quality and dropout rates were also compared by a single-arm meta-analysis.

In sum, 43 studies covering 44 trials (14,535 patients) were included in the analysis. The drugs evaluated included flurazepam, quazepam, temazepam, triazolam, eszopiclone, zaleplon, zolpidem, extended-release zolpidem, suvorexant, ramelteon and doxepin. The established models revealed eszopiclone had the highest efficacy in terms of sleep latency (SL), total sleep time (TST), and sleep quality, and was also associated with the lowest dropout rates. The effect of suvorexant on the parameter ‘wake after sleep onset’ (WASO) was significantly higher than that of the other drugs analyzed.

Each drug has its own characteristics in the treatment of insomnia, and this needs to be taken into consideration to meet individual clinical needs. These results serve as a quantitative supplement for clinical practice by reflecting the difference in efficacy of various drugs in the treatment of insomnia.

Placebo-controlled trials are the research standard to evaluate new interventions for which there is no standard of care. While lessening performance and detection bias, such design provides a direct mode of comparison against the probed intervention. Still, using placebo arms may pose new challenges to the design, conduct and analysis of clinical trials. This is particularly relevant in circumstances of non-additivity between the therapeutic and the placebo effects, if the outcome of interest has floor or ceiling effects, or when the predicted effect size of the intervention is large and leads to small sample sizes. There are several possible strategies to mitigate the confounding effects of the placebo, each relevant to specific clinical trial designs. This chapter puts into context the new challenges created by the placebo effect, discusses possible ways around them, and explores the future of the field.

Placebos are usually employed deceptively in clinical trials in order to control for non-specific effects. However, since placebos themselves have been found to cause clinically relevant changes and in some cases are indistinguishable from the verum they are tested against, this theoretically inert, but practically effective intervention has become a scientific discipline in its own right. In this review, it is argued that placebos are generic and genuine biopsychosocial interventions and as such are highly interesting candidates for a psychoneuroendocrinological perspective. Yet, despite a considerable conceptual proximity between explanatory models of placebos and their effects with psychoneuroendocrine models and findings, placebos have thus far not been subject to systematic psychoneuroendocrine examination. Consequently, it would be highly interesting and informative to make placebos the target of psychoneuroendocrine scrutiny.