Leveraging Single-Case Experimental Designs to Promote Personalized Psychological Treatment: Step-by-Step Implementation Protocol with Stakeholder Involvement of an Outpatient Clinic for Personalized Psychotherapy.

Our objective is to implement a single-case experimental design (SCED) infrastructure in combination with experience-sampling methods (ESM) into the standard diagnostic procedure of a German outpatient research and training clinic. Building on the idea of routine outcome monitoring, the SCED infrastructure introduces intensive longitudinal data collection, individual effectiveness measures, and the opportunity for systematic manipulation to push personalization efforts further. It aims to empower psychotherapists and patients to evaluate their own treatment (idiographic perspective) and to enable researchers to analyze open questions of personalized psychotherapy (nomothetic perspective). Organized around the principles of agile research, we plan to develop, implement, and evaluate the SCED infrastructure in six successive studies with continuous stakeholder involvement: In the project development phase, the business model for the SCED infrastructure is developed that describes its vision in consideration of the context (Study 1). Also, the infrastructure's prototype is specified, encompassing the SCED procedure, ESM protocol, and ESM survey (Study 2 and 3). During the optimization phase, feasibility and acceptability are tested and the infrastructure is adapted accordingly (Study 4). The evaluation phase includes a pilot implementation study to assess implementation outcomes (Study 5), followed by actual implementation using a within-institution A-B design (Study 6). The sustainability phase involves continuous monitoring and improvement. We discuss to what extent the generated data could be used to address current questions of personalized psychotherapy research. Anticipated barriers and limitations during the implementation processes are outlined.

Psychological Predictors of Response to Open-Label Versus Double-Blind Placebo in a Randomized Controlled Trial in Irritable Bowel Syndrome.

OBJECTIVE: There is growing evidence that open-label placebo (OLP) may be an efficacious treatment of chronic and functional conditions. However, patient-level predictors of response to OLP have not been clearly identified. The aim of this study is to evaluate the psychological predictors of response to OLP and to compare this to double-blind placebo (DBP) and no-pill control (NPC). METHODS: This study is a secondary analysis of data collected in a 6-week randomized controlled trial evaluating placebo effects in irritable bowel syndrome (IBS). The primary outcome was change in IBS severity. Hierarchical linear regression identified predictors of placebo response in general and compared them between those randomized to OLP, DBP, and NPC. Predictor variables included personality traits, generalized anxiety, depression, visceral sensitivity (a measure of symptom-specific anxiety), and pain catastrophizing. RESULTS: A total of 210 participants (mean age = 42.3 years, 73.3% female) were included. Regression models revealed that visceral sensitivity was a predictor of response to OLP and NPC but not DBP. Interestingly, the effects were opposite, with high visceral sensitivity predicting less improvement in NPC and more improvement in OLP. Pain catastrophizing was a negative predictor of response to OLP (i.e., high pain catastrophizing was associated with less improvement in OLP). Neither visceral sensitivity nor pain catastrophizing played a significant role for response to DBP. CONCLUSIONS: IBS participants who score low on the Pain Catastrophizing Scale but high on the Visceral Sensitivity Index seem to benefit particularly from OLP. Our study suggests that different psychological mechanisms may be involved in DBP and OLP interventions.

The effect of patient-centered communication on medication intake: an experimental study.

It is not only crucial to provide patients with information, but also to communicate this information in a way to enable patient participation in health decisions. Experimental studies investigating the association between the communication style of health professionals and patients' health decisions are rare, which limits causal conclusions. This study investigated the effect of a doctor's patient-centered communication style on the likelihood to take a medication.Healthy women (N = 120) were randomly allocated to one of three groups. They either received a medical consultation characterized by a patient-centered communication style (PC group) or by a doctor-centered communication style (DC group) or they received no consultation at all (control group). All participants were told that the study would investigate the effects of a 'concentration-enhancing medication'. Voluntary intake of the medication (a placebo pill) served as behavioral outcome. Participants' self-rated intention to take the medication was measured at three assessment points. Data were analyzed using a Chi-square-test and a mixed analysis of covariance.In each group, 40 participants were analyzed. Following the consultation, groups did not differ regarding the behavioral outcome, but participants' intention to take the medication was higher in the PC group compared with the control group.Our results indicate that patient-centered communication has a beneficial influence on participants' intention to take medication. Future studies should investigate the role of communication in individuals with health conditions that require a specified treatment plan and taking medication over the long-term.

Open-Label Placebo Treatment: Outcome Expectations and General Acceptance in the Lay Population.

BACKGROUND: Most physicians sometimes apply therapies without specific active ingredients. Although patients seem to judge such placebo treatments as acceptable under certain circumstances, deception is still an ethical problem. Open-label placebos (OLPs) might be a promising approach to solve this dilemma. This study compared general acceptance and outcome expectations of OLPs and deceptive placebos (DPs). METHODS: In an experimental online study, 814 participants read a case vignette of a person with insomnia receiving a pill. The participants were then randomly allocated into two groups, where the second part of the vignette described the pill as either a deceptive placebo (DP group) or as an open-label placebo (OLP group). The Credibility/Expectancy Questionnaire (CEQ) assessed outcome expectations after the first (pre-assessment) and the second (post-assessment) parts of the vignette. Treatment acceptance was measured at post-assessment. Data from 798 participants were analyzed by a mixed multivariate analysis of variance (MANOVA), t-tests, and post-hoc mediation analyses. RESULTS: The MANOVA revealed a significant group main effect and a significant time × group interaction effect. At post-assessment, outcome expectations were higher in the DP group than in the OLP group. Acceptance of the placebo treatment was also higher in the DP group than in the OLP group. Mediation analyses confirmed that higher acceptance in the DP group was mediated by higher expectations. CONCLUSIONS: When laypersons read about placebo treatment, their outcome expectations toward DPs were higher than toward OLPs. Surprisingly, the application of DPs was rated as more acceptable than OLPs. This result might be explained by indirect effects of treatment expectations.

No open-label placebo effect in insomnia? Lessons learned from an experimental trial.

BACKGROUND: Open-label placebo (OLP) treatment seems to be effective in several medical conditions but has not yet been investigated in insomnia. Furthermore, it needs to be evaluated whether providing a plausible treatment rationale is essential to obtain OLP effects. METHODS: In two consecutive nights, the sleep of patients with primary insomnia (n = 45) was assessed via subjective and objective measures. Before the second night, they received a single OLP pill that was randomly provided either with a treatment rationale (OLP+) or without (OLP-). When (M)ANOVAs did not reveal differential effects between the two OLP groups, the OLP+ group was compared post-hoc to a formerly assessed no pill control sample (NPC; n = 23). RESULTS: Neither the MANOVAs nor the ANOVAs revealed significant interaction effects of treatment group and assessment night. The OLP+ condition was superior neither to OLP- nor to NPC in improving the patients' sleep. DISCUSSION: Our findings do neither confirm the general efficacy of OLP in primary insomnia nor differential effects depending on the treatment rationale. Possible explanations lie in the dosing scheme (i.e., single OLP application), the provision of the OLP rationale by video and the experimental instead of therapeutic character of our investigation. Trials with larger samples and longer-term OLP treatment in insomnia are needed. Providing the rationale face-to-face and in a clinical setting might be additionally beneficial.

Patients' experiences treated with open-label placebo versus double-blind placebo: a mixed methods qualitative study.

BACKGROUND: There is increasing evidence suggesting that open-label placebo (OLP) is an effective treatment for several medical conditions defined by self-report. However, little is known about patients' experiences with OLP, and no studies have directly compared patients' experiences in double-blind placebo (DBP) conditions. METHODS: This study was nested in a large randomized-controlled trial comparing the effects of OLP and DBP treatments in individuals with irritable bowel syndrome (IBS). We randomly selected 33 participants for interviews concerning their experiences in the parent trial. The data were qualitatively analyzed using an iterative immersion/crystallization approach. We then compared the qualitative interview data to the quantitative IBS severity data assessed during the parent trial, using a mixed methods approach. RESULTS: Two prominent interview themes were identified: (1) the participants' feelings about their treatment allocation and (2) their reflections about the treatment. Both OLP and DBP participants mentioned hope and curiosity as major feelings driving them to engage with their treatment. However, while DBP participants tended to be more enthusiastic about their allocation, OLP participants were more ambivalent. Furthermore, OLP participants reflected more on their treatment, often involving noticeable cognitive and emotional processes of self-reflection. They offered a variety of explanations for their symptom improvement and were significantly less likely to attribute it to the treatment itself than DBP participants (Χ2 [3] = 8.28; p = .041). Similarly, the participants' retrospective narratives of symptom improvement were significantly correlated with their corresponding quantitative IBS severity scores only in DBP (p's ≤ .006) but not in OLP (p's ≥ .637). CONCLUSION: OLP and DBP participants share feelings of hope, uncertainty and curiosity but differ in the extent of conscious reflection. The counter-intuitive OLP prompts more self-examination, ambivalent feelings and active engagement compared to DBP. At the same time, OLP participants are more reluctant to attribute symptom improvement to their treatment. Our findings substantially add to the emerging picture of factors that distinguish OLP and DBP and their potential mechanisms.

Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials: A Systematic Review and Meta-analysis.

Importance: Adverse events (AEs) after placebo treatment are common in randomized clinical drug trials. Systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide especially because concern about AEs is reported to be a reason for vaccination hesitancy. Objective: To compare the frequencies of AEs reported in the placebo groups of COVID-19 vaccine trials with those reported in the vaccine groups. Data Sources: For this systematic review and meta-analysis, the Medline (PubMed) and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched systematically using medical subheading terms and free-text keywords for trials of COVID-19 vaccines published up to July 14, 2021. Study Selection: Randomized clinical trials of COVID-19 vaccines that investigated adults aged 16 years or older were selected if they assessed solicited AEs within 7 days of injection, included an inert placebo arm, and provided AE reports for both the vaccine and placebo groups separately. Full texts were reviewed for eligibility by 2 independent reviewers. Data Extraction and Synthesis: Data extraction and quality assessment were performed independently by 2 reviewers, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline and using the Cochrane risk-of-bias tool. Meta-analyses were based on random-effects models. Main Outcomes and Measures: The primary outcomes were the proportions of placebo recipients reporting overall, systemic, and local (injection-site) AEs as well as logarithmic odds ratios (ORs) to evaluate group differences. Outcomes were tested for significance using z tests with 95% CIs. Results: Twelve articles with AE reports for 45 380 participants (22 578 placebo recipients and 22 802 vaccine recipients) were analyzed. After the first dose, 35.2% (95% CI, 26.7%-43.7%) of placebo recipients experienced systemic AEs, with headache (19.3%; 95% CI, 13.6%-25.1%) and fatigue (16.7%; 95% CI, 9.8%-23.6%) being most common. After the second dose, 31.8% (95% CI, 28.7%-35.0%) of placebo recipients reported systemic AEs. The ratio between placebo and vaccine arms showed that nocebo responses accounted for 76.0% of systemic AEs after the first COVID-19 vaccine dose and for 51.8% after the second dose. Significantly more vaccine recipients reported AEs, but the group difference for systemic AEs was small after the first dose (OR, -0.47; 95% CI, -0.54 to -0.40; P < .001; standardized mean difference, -0.26; 95% CI, -0.30 to -0.22) and large after the second dose (OR, -1.36; 95% CI, -1.86 to -0.86; P < .001; standardized mean difference, -0.75; 95% CI, -1.03 to -0.47). Conclusions and Relevance: In this systematic review and meta-analysis, significantly more AEs were reported in vaccine groups compared with placebo groups, but the rates of reported AEs in the placebo arms were still substantial. Public vaccination programs should consider these high rates of AEs in placebo arms.

Placebo nasal spray protects female participants from experimentally induced sadness and concomitant changes in autonomic arousal.

BACKGROUND: To investigate the powerful placebo effects in antidepressant drug trials and their mechanisms, recent pioneering experimental studies showed that expectation manipulation combined with an active placebo attenuated induced sadness. In the present study, we aimed at extending these findings by assessing the psychophysiological response in addition to mere self-report. METHODS: One hundred and thirteen healthy female students were randomly assigned to a drug expectation group (active placebo, positive treatment expectation), placebo expectation group (active placebo, no treatment expectation), or a no-treatment group (no placebo, no treatment expectation). After placebo intake, sadness was induced by self-deprecating statements using the Velten method combined with sad music, including a rumination phase. Sadness was measured using the Positive and Negative Affect Schedule Expanded Form (PANAS-X). Heart rate and skin conductance were assessed continuously. RESULTS: After mood induction and after rumination, self-reported sadness was significantly lower, and skin conductance level was significantly higher, in the drug expectation group than in the no-treatment group. The mood induction was further accompanied by a heart rate deceleration within all groups. LIMITATIONS: Generalizability is limited by sample selectivity and focusing on sadness as a symptom of depression, exclusively. CONCLUSION: Expectation-induced placebo effects significantly influenced sadness-correlated changes in autonomic arousal, and not only subjectively reported sadness, indicating that placebo effects in the context of affect are not merely due to subjective response bias. The systematic modification of treatment expectation could be utilized in clinical practice to optimize current therapeutic approaches to improve mood regulation.

Expectation-induced placebo effect on acute sadness in women with major depression: An experimental investigation.

BACKGROUND: Meta-analyses demonstrate that placebo effects play an important role in antidepressant treatment. Expectations seem to constitute a highly relevant placebo mechanism in this context. This study investigated whether an expectation manipulation combined with the intake of an active placebo could reduce acute sadness in depressed participants following a sadness-inducing mood manipulation. METHODS: Women who suffered from a major depressive episode (N = 94) were randomly allocated to the drug expectation group (expectation to receive a fast-operating antidepressant), the placebo expectation group (expectation to receive a placebo) or the no treatment group (no expectation, no placebo). The drug expectation and the placebo expectation group received a placebo. All participants watched a sadness-inducing film. Sadness was assessed at baseline, after randomization and after placebo intake and mood induction. Data were analyzed by a 3 × 3 analysis of variance. RESULTS: There were significant between-group differences in sadness change from the baseline after mood induction. While sadness increased in the no treatment group, it did not change in the placebo expectation group. In the drug expectation group, sadness even decreased. LIMITATIONS: Only a single medication intake was simulated. Effects on acute sadness do not allow inferences about depression symptoms. CONCLUSION: This experimental study found a placebo effect on sadness in clinically depressed participants. The effects were even larger than expected. Future research must investigate placebo effects on depression symptoms as well as long-term placebo intake.