Working with patients' treatment expectations - what we can learn from homeopathy.

The usual homeopathic remedy, "globules," does not contain any pharmacologically active ingredient. However, many patients and practitioners report beneficial effects of homeopathic treatment on various health outcomes. Experimental and clinical research of the last two decades analyzing the underlying mechanisms of the placebo effect could explain this phenomenon, with patients' treatment expectations as the predominant mechanism. Treatment expectations can be optimized through various factors, such as prior information, communication, and treatment context. This narrative review analyses how homeopathy successfully utilizes these factors. Subsequently, it is discussed what evidence-based medicine could learn from homeopathic practice to optimize treatment expectations (e.g., using an empathic, patient-centered communication style, deliberately selecting objects in practice rooms, or using clear treatment rituals and salient contextual stimuli) and thereby treatment effectiveness. Homeopathic remedy does not work beyond the placebo effect but is recommended or prescribed as an active treatment by those who believe in it. Thus, practitioners need to understand the manner in which homeopathy (as an example of inert treatment) works and are advised to reintegrate its underlying effective placebo mechanisms into evidence-based medicine. This promises to increase treatment efficacy, tolerability, satisfaction, and compliance with evidence-based treatments, and addresses the desires patients are trying to satisfy in homeopathy in an ethical, fully informed way that is grounded in evidence-based medicine.

Hype or hope? High placebo response in major depression treatment with ketamine and esketamine: a systematic review and meta-analysis.

Background: Ketamine and esketamine offer a novel approach in the pharmacological treatment of major depressive disorder (MDD). This meta-analysis aimed to investigate the placebo response in double-blind, randomized controlled studies (RCTs) on patients with MDD receiving ketamine or esketamine. Methods: For this systematic review and meta-analysis Medline (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), PsycInfo and Embase databases were systematically searched for citations published up to March 17, 2023. A total number of 5017 abstracts was identified. Quality of the included trials was assessed with the Cochrane risk-of-bias tool. The meta-analysis was performed using a restricted maximum likelihood model. This study is registered with PROSPERO, number CRD42022377591. Results: A total number of 14 studies and 1100 participants (593 in the medication group and 507 in the placebo group) meeting the inclusion criteria were selected. We estimated the pooled effect sizes of the overall placebo (d pl = -1.85 [CI 95%: -2.9 to -0.79] and overall treatment (dtr = -2.57; [CI 95% -3.36 to -1.78]) response. The overall placebo response accounts for up to 72% of the overall treatment response. Furthermore, we performed subgroup analysis of 8 studies for the for the 7 days post-intervention timepoint. Seven days post-intervention the placebo response (d pl 7d = -1.98 [CI 95%: -3.26 to -0.69]) accounts for 66% of the treatment response (d tr 7d = - 3.01 [CI 95%, -4.28 to -1.74]). Conclusion: Ketamine and esketamine show large antidepressant effects. However, our findings suggest that the placebo response plays a significant role in the antidepressant response and should be used for the benefit of the patients in clinical practice. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022377591.

The role of the communicated treatment rationale on treatment outcome: study protocol for a randomized controlled trial.

BACKGROUND: Placebo effects are a well-established phenomenon in the treatment of depression. However, the mechanism underlying these effects are not fully understood. Treatment expectations are considered one explanation for why placebos work. Treatment expectations are likely to be affected by clinician-patient interactions. This study aims to investigate the role of the communicated treatment rationale in modulating treatment expectations and its effects on the treatment outcomes of a pharmacological and a psychological active placebo intervention for depression. In this study, treatment expectations are modulated by presenting illness models that are either congruent or incongruent with the treatment intervention that follows. METHODS: This 2 × 2 randomized controlled trial will involve patients with major depression. Participants will either receive a biological or a psychological illness model from a clinician. Following this, they are randomly assigned to receive either a pharmacological or a psychological active placebo intervention. The illness model and the treatment are either congruent or incongruent with each other, resulting in four groups. In addition, a natural course control group will be included. DISCUSSION: This study will provide insights into the mechanism of expectation modulation in active placebo treatments for major depression. The results may provide insights for clinicians to improve their communication with patients by focusing on treatment expectations. By identifying the factors that contribute to placebo effects, this study has the potential to improve the effectiveness of existing depression treatments and reduce the burden of this highly prevalent mental health condition. TRIAL REGISTRATION: This trial has been registered prospectively at ClinicalTrials.gov under the identifier: NCT04719663. Registered on January 22, 2021.

Psychological Factors Predict Higher Odds and Impairment of Post-COVID Symptoms: A Prospective Study.

OBJECTIVE: The causes of the long-term persistence of symptoms after a severe acute respiratory syndrome coronavirus 2 infection (i.e., post-COVID syndrome) remain elusive. Although previous research identified demographic and medical risk factors for the development of post-COVID, the present prospective study is the first to investigate the role of psychological factors. METHODS: The interview and survey data of polymerase chain reaction-positive participants ( n = 137; 70.8% female) were assessed in the acute, subacute (3 months after symptom onset), and chronic phases (6 months after symptom onset) of COVID. RESULTS: After controlling for medical (body mass index, disease score) and demographic factors (sex, age), psychosomatic symptom burden (measured by the Somatic Symptom Disorder-B Criteria Scale) predicted higher odds and magnitude of COVID-related symptom impairment in the post-COVID phases. Fear of COVID-related health consequences (measured by the Fear of COVID Scale) also predicted higher odds of reporting any COVID symptoms in the subacute and chronic phases, whereas it only predicted a higher magnitude of COVID-related symptom impairment in the subacute phase. In subsequent exploratory analyses, we found that other psychological factors were associated with an overall increase (i.e., chronic stress and depression) or decrease (i.e., trait positive affect) in the odds and magnitude of COVID-related symptom impairment. CONCLUSIONS: We conclude that psychological factors can fuel or temper the experience in post-COVID syndrome, opening new possibilities for psychological interventions. TRIAL REGISTRATION: The study protocol was preregistered in the Open Science Framework ( https://osf.io/k9j7t ).

Associations between indices of 24-hour heart rate variability and inflammation in individuals with major depressive disorder.

Biological cardiac risk factors, including reduced heart rate variability (HRV) and inflammation, are already prominent in patients with major depressive disorder (MDD) without existing cardiovascular disease. Although inverse relations between HRV and inflammation have been found across several populations, little work has been done concerning MDD. The present work thus intended to examine whether measures of HRV indices based on 24-h electrocardiograph recordings (24-h, daytime, nighttime) relate to levels of circulating inflammatory markers such as C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α in eighty antidepressant-free individuals with MDD. A sample of 40 age- and sex-matched non-clinical controls was also involved to verify biological alterations in MDD. Individuals with MDD exhibited reduced total 24-h HRV (i.e., triangular index) and reduced daytime HRV (i.e., triangular index, HF-HRV, LF-HRV, RMSSD), as well as increased levels of all inflammatory markers. Multivariate analyses adjusted for age, sex, body mass index, and smoking revealed robust inverse associations of total 24-h HRV (i.e., triangular index) and daytime HRV (i.e., Triangular index, HF-HRV, LF-HRV, RMSSD) with IL-6. An attenuated daytime HRV may relate to higher circulating levels of IL-6 in the context of MDD. These findings show that biological cardiac risk factors may act in concert in MDD.

Expectation focused and frequency enhanced cognitive behavioural therapy for patients with major depression (EFFECT): a study protocol of a randomised active-control trial.

INTRODUCTION: The effectiveness of psychotherapy in depression is subject of an ongoing debate. The mechanisms of change are still underexplored. Research tries to find influencing factors fostering the effect of psychotherapy. In that context, the dose-response relationship should receive more attention. Increasing the frequency from one to two sessions per week seems to be a promising start. Moreover, the concept of expectations and its influence in depression can be another auspicious approach. Dysfunctional expectations and the lack of their modification are central in symptom maintenance. Expectation focused psychological interventions (EFPI) have been investigated, primarily in the field of depression. The aim of this study is to compare cognitive behavioural therapy (CBT) once a week with an intensified version of CBT (two times a week) in depression as well as to include a third proof-of-principle intervention group receiving a condensed expectation focused CBT. METHODS AND ANALYSIS: Participants are recruited through an outpatient clinic in Germany. A current major depressive episode, diagnosed via structured clinical interviews should present as the main diagnosis. The planned randomised-controlled trial will allow comparisons between the following treatment conditions: CBT (one session/week), condensed CBT (two sessions/week) and EFPI (two sessions/week). All treatment arms include a total dose of 24 sessions. Depression severity applies as the outcome variable (Beck Depression Inventory II, Montgomery Asberg Depression Rating Scale). A sample size of n=150 is intended. ETHICS AND DISSEMINATION: The local ethics committee of the Department of Psychology, Philipps-University Marburg approved the study (reference number 2020-68 v). The final research article including the study results is intended to be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry (DRKS00023203).

Effects of a video-based positive side-effect information framing: An online experiment.

OBJECTIVE: Despite the public health value of vaccines, vaccination uptake rates are stagnating. Expected adverse events following immunization are a major source of concern and play a role in the emergence of vaccine hesitancy. Since nocebo mechanisms are involved in the perception of adverse reactions, positive side-effect communication is warranted. The aim of the present study was to compile a comprehensive communication strategy that minimizes expectations of nocebo effects while respecting the informed consent procedure. METHOD: In a randomized 2 × 2 between-subject design, 652 participants received information about COVID-19 or influenza vaccination using either standard side-effect messaging or messaging enriched with proven elements of expectation-optimizing framing. A physician presented information online via video. Moderation analyses were conducted to examine effects among particular subpopulations. Expected adverse event ratings following an imagined immunization, cost-benefit ratios of the vaccination, and future vaccination intentions were assessed. RESULTS: Information content ratings were equally high in each group. Positive framing significantly decreased adverse event expectations in the COVID-19 information group and raised the cost-benefit ratio in the influenza condition, indicating higher benefits than cost expectations. Moderation analysis revealed that the framed side-effect communication lowered the expected COVID-19 vaccination uptake willingness in individuals with strong anti-vaccination attitudes. CONCLUSIONS: Facing the ongoing coronavirus mass vaccinations, positive information frames have a small but significant impact on vaccination concerns while upholding informed consent. Although intervention trials are still pending, this approach could help decrease vaccine hesitancy by reducing fearful expectations. However, it seems that it should not be used without considering vaccination attitudes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Exploring the path of persisting dysfunctional expectations-Development of the immunization scale IMS.

Objectives: Persistent dysfunctional expectations seem to be core features of mental disorders. The aim of this study was to develop a questionnaire that assesses mechanisms responsible for the consistency of dysfunctional expectations. Processes before (i.e., assimilation) and after (i.e., immunization) expectation-violating experiences have been considered. Design: The Immunization Scale (IMS) is constructed and validated with the help of an explorative (EFA) and confirmatory factor analysis (CFA) in two conducted studies. Materials and methods: For the first study, the initially formulated 75-item version was completed online by 230 (range 18-69) participants from a convenience sample. For the second study, 299 (range 18-62) participants completed the reduced scale at the first measurement point, 75 participants thereof also 1 month later. For validity and reliability analyses, participants in both studies provided demographic information, the Beck Depression Inventory (BDI-II), the Depressive Expectation Scale (DES), the Beck Anxiety Inventory (BAI), and the German version of the Acceptance and Action Questionnaire (FAH-II). Results: The initial 75 items were reduced to 23 items. The EFA revealed three main factors, namely, negative expectations, assimilation, and cognitive immunization. The three-factor structure could be confirmed in study 2 by the CFA. Reliability measures showed an excellent internal consistency for the entire IMS. A very good test-retest reliability was found. Significant correlations resulted between the IMS and DES, BDI-II, BAI, and FAH-II, the highest for DES and FAH-II. Conclusion: Psychometric properties of the IMS are promising. Future studies should verify the reliability and validity measures in other population samples. The IMS can be very useful in expectation research, especially in the examination of expectation-focused therapy.

Supporting Relatives Prior to Caregiver Burden-Preventive E-Mental Health Short Intervention for Family Members of Individuals with Parkinsonism in an Early Phase of the Disease: Protocol for a Feasibility Study.

Research on support for relatives of patients with Parkinsonism has mainly focused on caregivers, while preventive offers for non-caregiving relatives are lacking. Thus, the aim of this multicenter pilot study is to develop and assess the feasibility of a preventive psychosocial support program for relatives of patients with Parkinsonism. It specifically focuses on family members of patients who are in an early phase of the disease, are not currently caregiving, and have not yet developed distress symptoms. It includes a telemedicine-based, 6-week preventive psychological short intervention (PPSI). The main objective of this feasibility mixed-methods study is to specify the demand for an early, low-threshold, and low-cost short intervention and to collect feedback based on qualitative and quantitative data of N = 20 relatives. Secondary objectives are an evaluation of the effects of the intervention and an analysis of the study design. Future directions are to further develop the PPSI using these data. This study can serve as a basis for future randomized controlled studies on this intervention, which might fill an important gap in clinical supply.

Optimising the efficacy of a stress-reducing psychological intervention using placebo mechanisms: A randomized controlled trial.

This study examined whether i) brief videos aiming to optimise outcome expectations would augment the efficacy of progressive muscle relaxation (PMR) and ii) whether participants' characteristics would moderate these effects. Sixty-eight healthy subjects randomized to one of three experimental manipulations before undergoing a single PMR session either watched i) a video displaying a neutral expert, ii) a video with a warm expert, or iii) were part of an active control condition. Constrained linear mixed models indicated increased relaxation and decreased stress levels for all participants after the PMR session. The primary outcome was the change of perceived relaxation/stress from pre to post. Participants with high neuroticism and trait anxiety indicated an augmented PMR's efficacy and increased outcome expectations when watching the warm expert video compared to the control group or the less warm expert. Brief videos displaying an expert aiming to optimise outcome expectations regarding a brief stress-reducing psychological intervention may boost or decrease an intervention's efficacy. Effects may depend on the viewer's personality and the (video) expert's communication style. Trial Registration: The study protocol was approved by the local Ethics Committee of the University of Marburg, Germany. This study was registered at www.clinicaltrials.gov (NCT03330431).

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.

Does Health Literacy Make a Difference? Comparing the Effect of Conventional Medicine Versus Homeopathic Prescribing on Treatment Credibility and Expectancy.

OBJECTIVE: While homeopathic remedies are often used to treat non-specific complaints such as headaches, empirical evidence suggests their treatment effect is due to the placebo effect. Low health literacy seems to be connected to higher use of complementary and alternative medicine (CAM). The aim of this study was to examine what people with occasional headaches expect from conventional medicine or homeopathic remedies and if health literacy interacts with this expectation. METHODS: In this experimental study, n = 582 participants with occasional headaches were randomized to read one of two vignettes, which described the prescription of either conventional medicine or a homeopathic remedy. Subsequently, the participants were asked to rate treatment credibility and expectancy with regard to their assigned vignette. Health literacy was assessed as a potential moderator. RESULTS: Participants in the conventional medicine group rated treatment credibility and expectancy higher than in the homeopathic remedy group. Moderation analysis revealed that when being offered conventional medicine, participant reports of treatment credibility and expectancy decreased with lower health literacy, while these outcomes increased with lower health literacy for homeopathic remedies. DISCUSSION: People with occasional headaches estimate the effectiveness of conventional medication properly. However, health care professionals should pay special attention to patients with low health literacy, as they might need more time and information to give their informed consent.

Psychological Preparation for Cardiac Surgery.

PURPOSE OF REVIEW: To review the current state of preoperative psychological preparation to improve outcomes after cardiac surgery. RECENT FINDINGS: Preoperative psychosocial factors are associated with short- and long-term outcomes after cardiac surgery. There are several approaches to optimize patients' preoperative psychological status with promising effects on postoperative outcomes (e.g., less complications, improved quality of life). Preoperative psychological preparation often aims to improve patients' knowledge or social support and to modify and optimize expectations and illness beliefs. Preoperative psychological preparation is gaining importance for cardiac surgery. However, patients' psychological status still does not get as much attention as it deserves. Preoperative psychological preparation seems to have positive effects on postoperative outcomes. Since overall evidence is still weak, further studies are warranted to understand which intervention works best for whom and why.

A meta-analysis of heart rate variability in major depression.

BACKGROUND: Major depression (MD) is a risk factor for cardiovascular disease. Reduced heart rate variability (HRV) has been observed in MD. Given the predictive value of HRV for cardiovascular health, reduced HRV might be one physiological factor that mediates this association. METHODS: The purpose of this study was to provide up-to-date random-effects meta-analyses of studies which compare resting-state measures of HRV between unmedicated adults with MD and controls. Database search considered English and German literature to July 2018. RESULTS: A total of 21 studies including 2250 patients and 1982 controls were extracted. Significant differences between patients and controls were found for (i) frequency domains such as HF-HRV [Hedges' g = -0.318; 95% CI (-0.388 to -0.247)], LF-HRV (Hedges' g = -0.195; 95% CI (-0.332 to -0.059)], LF/HF-HRV (Hedges' g = 0.195; 95% CI (0.086-0.303)] and VLF-HRV (Hedges' g = -0.096; 95% CI (-0.179 to -0.013)), and for (ii) time-domains such as IBI (Hedges' g = -0.163; 95% CI (-0.304 to -0.022)], RMSSD (Hedges' g = -0.462; 95% CI (-0.612 to -0.312)] and SDNN (Hedges' g = -0.266; 95% CI (-0.431 to -0.100)]. CONCLUSIONS: Our findings demonstrate that all HRV-measures were lower in MD than in healthy controls and thus strengthens evidence for lower HRV as a potential cardiovascular risk factor in these patients.

Decreasing the Burden of Side Effects Through Positive Message Framing: an Experimental Proof-of-Concept Study.

PURPOSE: Informing patients about treatment side effects increases the occurrence and intensity of side effects. Since the obligatory informed consent procedure in drug treatments requires transparency and nocebo research suggests that the informed consent of a drug leads to an increased occurrence of the mentioned side effects, the aim of this proof of concept study was to determine the effect of two different framings of informed consent on the occurrence, intensity, and perceived threat of side effects. METHODS: Healthy male participants (n = 80) were randomized to one of two framing groups. The positive framing group was informed that the common side effect dizziness was a sign that the drug had started to work, while the neutral framing group was told that dizziness is an unpleasant but well-known side effect. Side effects were measured after the administration of metoprolol, an antihypertensive agent. Post hoc moderator analyses investigated the effect of pre-existing negative beliefs about the general harm of medication on the framing manipulation. RESULTS: Metoprolol-specific drug-attributed side effects were rated significantly less threatening in the positive framing group. The between-group effect size (Cohen's d) was small (d = 0.38, p = 0.049). Exploratory post hoc moderator analyses suggest that participants who believed that medication is a source of harmful effects benefited from positive framing, compared to neutral framing of drug-attributed side effects. CONCLUSIONS: Positive framing was partially effective in decreasing specific side effect measures, particularly among participants with a tendency to believe that medicine is harmful. Informed consent procedures should therefore be personalized, focusing on patients with negative treatment beliefs.

It's all a matter of necessity and concern: A structural equation model of adherence to antihypertensive medication.

OBJECTIVE: Hypertension is often treated pharmacologically, yet adherence is poor. Beliefs about antihypertensive medicine, i.e., the necessity-concern framework (NCF), are valuable for explaining adherence. Therefore, a model structure is transferred from hypercholesterolemia to hypertension, assuming a mediating role of the NCF. METHODS: Patients with hypertension (n=273) were surveyed online about demographics, health- and treatment-related factors, control beliefs, necessity and concern beliefs about their medication, and adherence. The data were analyzed using structural equation modeling (SEM). RESULTS: Necessity was positively (ß=0.26, p=0.009) and concern was negatively (ß=-0.51, p=0.020) associated with adherence. The NCF mediated the influence of background variables on adherence. Necessity was associated with comorbidity (ß=-0.36, p<0.001), treatment time (ß=0.19, p=0.004), emotionally supportive doctor-patient communication (ß=0.12, p=0.045), side effects (ß=0.16, p=0.013), personal control (ß=-0.13, p=0.022), and treatment control (ß=0.29, p<0.001). Concern was associated with side effects (ß=0.38, p<0.001) and beliefs about medicine in general being harmful (ß=0.61, p<0.001). The model fit was acceptable (RMSEA=0.61). CONCLUSION: The transferred adherence model with the necessity-concern framework as a mediating factor was confirmed in hypertension, explaining more variance than previous approaches (23%). PRACTICE IMPLICATIONS: A personalized, emotionally supportive doctor-patient communication could be key to addressing beliefs about medicine and therefore to increasing adherence.

Effect of placebo groups on blood pressure in hypertension: a meta-analysis of beta-blocker trials.

Hypertension is often treated pharmacologically. Since there is evidence that the cardiovascular system is sensitive to placebo mechanisms, our aim was to conduct an effect size analysis of placebo groups in double-blinded randomized controlled parallel-group drug trials using beta-blockers to treat hypertensive patients. A comprehensive literature search via PubMed, PsycINFO, PSYNDEX, PQDT OPEN, OpenGREY, ISI Web of Knowledge, and the WHO International Clinical Trials Registry Platform provided the basis of our meta-analysis. Effect sizes were estimated using a random-effects model based on 23 studies covering a total of 11,067 participants. Main outcomes were systolic blood pressure (sBP) and diastolic blood pressure (dBP). Blood pressure was lowered in placebo groups with significant and robust effect sizes (Hedges' g). The estimates for sBP (-0.27, P < .001) and dBP (-0.49, P < .001) can be interpreted as small to moderate. The placebo response accounted for 34% of the drug response for sBP and 47% of the drug response for dBP. Our moderator analyses indicated that a higher study quality and more study site visits were marginally associated with a higher placebo response. In light of these strong placebo responses, placebo mechanisms need to be considered in order to improve antihypertensive treatment.