Biomarkers as predictors of CBT responsiveness in major depressive disorder: The role of heart rate variability and inflammation.

OBJECTIVE: Biological risk factors for cardiovascular disease may relate to poor treatment responsiveness in major depressive disorder (MDD). These factors encompass low-grade inflammation and autonomic dysregulation, as indexed by decreased heart rate variability (HRV) and increased heart rate (HR). This secondary analysis examined whether higher levels of inflammatory markers or autonomic alterations relate to lower responsiveness to cognitive behavioral therapy (CBT) among individuals with MDD. METHODS: Eighty antidepressant-free patients with MDD were randomly assigned to 14 weeks of CBT or waitlist (WL). Potential biological moderators at study entry included HR and HRV (24-h, daytime, nighttime) and inflammatory markers such as C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Forty non-clinical controls were involved to verify biological alterations in MDD at study entry. Depressive symptoms were assessed at baseline and at the end of treatment. RESULTS: Individuals with MDD exhibited reduced total 24-h HRV (i.e., triangular index) and daytime HRV (i.e., triangular index, HF-HRV, LF-HRV, RMSSD), as well as increased levels of inflammatory markers. Patients who received CBT exhibited stronger reductions in self- and clinician-rated depressive symptoms, compared to WL. False discovery rate-adjusted moderation analyses did not show overall moderating effects of biological measures on treatment responsiveness. However, higher CRP levels were specifically associated with poorer improvement in somatic depressive symptoms. CONCLUSIONS: There was no overall evidence for a moderating role of inflammation or autonomic features in CBT responsiveness in MDD. Higher levels of CRP might, however, specifically be associated with less improvement in somatic depressive symptoms during CBT.

Pre-treatment expectations and their influence on subjective symptom change in Crohn's disease.

BACKGROUND: Treatment expectations reportedly shape treatment outcomes, but have not been studied in the context of multimodal therapy in Crohn's disease (CD). Therefore, the current study investigated the role of treatment expectations for subjective symptom changes in CD patients who have undergone an integrative multimodal therapy program. METHODS: Validated questionnaires were completed at the start of the treatment program and post intervention. Pre-treatment expectations and experienced symptom change were assessed with the Generic Rating Scale for Previous Treatment Experiences, Treatment Expectations, and Treatment Effects (GEEE); stress levels were quantified with the Perceived Stress Scale (PSS-10) and disease specific quality of life was quantified with the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). We performed multiple linear and Bayesian regression to determine how expectations related to symptom change. RESULTS: N = 71 CD patients (66.2% female) were included. Stronger expectations regarding symptom improvement (b = 0.422, t = 3.70, p < .001) were associated with higher experienced symptom improvement. Additionally, Bayesian analysis provided strong evidence for including improvement expectations as a predictor of improvement experience (BFinclusion = 13.78). CONCLUSIONS: In line with research in other disorders, we found that positive treatment expectations were associated with experienced symptom improvement. In contrast, we found no indication that an experience of symptom worsening was associated with positive or negative baseline treatment expectations. Induction of positive expectations might be a potential avenue for improving treatment outcomes in CD therapy.

Preoperative anxiety and need for support - A qualitative analysis in 1000 patients.

OBJECTIVES: Preoperative anxiety is prevalent, emotionally distressing for many patients, and can have harmful effects on postoperative outcomes. Despite its high prevalence, there has been little research on preoperative anxiety using qualitative methods. This study's main goal was to qualitatively examine factors that may contribute to preoperative anxiety in a large sample. METHODS: In a survey, a total of 1000 patients awaiting surgery were asked open questions i) about reasons which they associate with their preoperative anxiety and ii) which coping strategies they would prefer in addition to premedication. RESULTS: The qualitative analysis indicated five overarching domains, 16 themes, and 54 subthemes of preoperative anxiety. Intra- or postoperative complications was the most common theme regarding preoperative anxiety (n = 516). Personal conversation was the most frequently desired supportive measure in addition to premedication. CONCLUSIONS: This study indicated a considerable heterogeneity of reasons associated with preoperative anxiety based on an unbiased assessment in a large sample. The study further suggests that a personal conversation is a clinically important coping strategy in addition to premedication. PRACTICE IMPLICATIONS: Providers should assess patients' preoperative anxiety and the resulting need for support individually to offer supportive measures adapted to the patients' needs.

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.

Preoperative optimization of cardiac valve patients' expectations: Study protocol of the randomized controlled ValvEx-trial.

Introduction: Complete recovery after surgery depends on psychological factors such as preoperative information, expectations, and surgery-associated anxiety. Prior studies have shown that even a short preoperative psychological intervention aiming at optimized expectations (EXPECT) can improve postoperative outcomes in coronary artery bypass patients. However, this intervention may benefit only a small subgroup of heart surgery patients since implementing preoperative psychological interventions into the daily clinical routine is difficult due to the additional time and appointments. It is unclear whether the EXPECT intervention can be shortened and whether heart valve patients would also benefit from interventions that optimize patients' expectations. The multicenter ValvEx trial aims (i) to adapt an effective preoperative psychological intervention (EXPECT) to make it brief enough to be easily integrated into the preoperative routine of heart valve patients and (ii) to examine if the adapted preoperative psychological intervention improves the subjectively perceived illness-related disability (PDI) up to 3 months after surgery. Materials and analysis: In two German university hospitals, N = 88 heart valve patients who undergo heart surgery are randomized into two groups [standard of care (SOC) vs. standard of care plus interventional expectation manipulation (SOC and EXPECT)] after baseline assessment. Patients in the EXPECT group additionally to standard of care participate in the preoperative psychological intervention (30-40 min), focusing on optimizing expectations and have two booster-telephone calls (4 and 8 weeks after the surgery, approx. 15 min). Both groups have assessments again on the evening before the surgery, 4 to 6 days, and 3 months after the surgery. Discussion: The trial demonstrates excellent feasibility in the clinical routine and a high interest by the patients. Ethics and dissemination: The Ethics Committees of the Department of Medicine of the Philipps University of Marburg and the Department of Medicine of the University of Giessen approved the study protocol. Study results will be published in peer-reviewed journals and presented at congresses. Clinical trial registration: ClinicalTrials.gov, identifier NCT04502121.

Does psychological treatment of major depression reduce cardiac risk biomarkers? An exploratory randomized controlled trial.

BACKGROUND: Depression is associated with an increased risk for cardiovascular disease (CVD). Biological cardiac risk factors are already elevated in depressed patients without existing CVD. The purpose of this exploratory trial was to examine whether treating Major Depression (MD) with cognitive behavioral therapy (CBT) is associated with improvements in cardiac risk biomarkers and whether depressive symptom severity at baseline moderates treatment effects. METHODS: Eighty antidepressant-free patients with MD were randomly assigned to CBT or waiting list (WL). Biological outcomes included long-term recordings (24-h, daytime, nighttime) of heart rate, heart rate variability (HRV), and blood pressure, as well as inflammatory markers such as C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α. A sample of 40 age- and sex-matched non-clinical controls was also involved to verify biological alterations in MD at study entry. RESULTS: Compared to WL, CBT was associated with a significant increase in overall HRV, as indexed by the 24-h and daytime HRV triangular index, as well as trend improvements in 24-h low-frequency HRV and daytime systolic blood pressure. Self-rated depressive symptom severity moderated (or tended to moderate) improvements in CBT for 24-h and daytime heart rate and several indices of HRV (especially daytime measures). Inflammatory treatment effects were not observed. CONCLUSIONS: CBT increased overall HRV in patients with MD. Initially more depressed patients showed the most pronounced cardiovascular improvements through CBT. These exploratory findings may provide new insights into the biological effects of psychological treatment against depression and must be confirmed through future research.

Pre-surgery optimization of patients' expectations to improve outcome in heart surgery: Study protocol of the randomized controlled multi-center PSY-HEART-II trial.

The PSY-HEART-I trial indicated that a brief expectation-focused intervention prior to heart surgery improves disability and quality of life 6 months after coronary artery bypass graft surgery (CABG). However, to investigate the clinical utility of such an intervention, a large multi-center trial is needed to generalize the results and their implications for the health care system. The PSY-HEART-II study aims to examine whether a preoperative psychological intervention targeting patients' expectations (EXPECT) can improve outcomes 6 months after CABG (with or without heart valve replacement). EXPECT will be compared to Standard of Care (SOC) and an intervention providing emotional support without targeting expectations (SUPPORT). In a 3-arm multi-center randomized, controlled, prospective trial (RCT), N = 567 patients scheduled for CABG surgery will be randomized to either SOC alone or SOC and EXPECT or SOC and SUPPORT. Patients will be randomized with a fixed unbalanced ratio of 3:3:1 (EXPECT: SUPPORT: SOC) to compare EXPECT to SOC and EXPECT to SUPPORT. Both psychological interventions consist of 2 in-person sessions (à 50 minute), 2 phone consultations (à 20 minute) during the week prior to surgery, and 1 booster phone consultation post-surgery 6 weeks later. Assessment will occur at baseline approx. 3-10 days before surgery, preoperatively the day before surgery, 4-6 days later, and 6 months after surgery. The study's primary end point will be patients' illness-related disability 6 months after surgery. Secondary outcomes will be patients' expectations, subjective illness beliefs, quality of life, length of hospital stay and blood sample parameters (eg, inflammatory parameters such as IL-6, IL-8, CRP). This large multi-center trial has the potential to corroborate and generalize the promising results of the PSY-HEART-I trial for routine care of cardiac surgery patients, and to stimulate revisions of treatment guidelines in heart surgery.

Baseline depressive symptoms, personal control, and concern moderate the effects of preoperative psychological interventions: the randomized controlled PSY-HEART trial.

This study examined whether baseline (3-14 days pre-surgery) levels of (i) depressive or (ii) anxiety symptoms and (iii) illness beliefs moderate the effects of additional preoperative interventions before coronary artery bypass graft surgery on (i) depressive or (ii) anxiety symptoms and (iii) illness beliefs 1 day before surgery, 1 week and 6 months after surgery. In the PSY-HEART trial, 115 patients were assessed. They were randomized into one of three groups: 1. receiving standard medical care only (SMC), additional psychological interventions: 2. aiming to optimize patients' expectations (EXPECT), or 3. focusing on emotional support. Patients with a higher baseline level of depressive symptoms receiving a preoperative psychological intervention indicated lower depressive symptoms 6 months after surgery compared to SMC. EXPECT increased personal control and concern levels in patients with low baseline personal control/concern 1 day before surgery. Brief preoperative psychological interventions can improve psychological outcomes in heart surgery patients. Baseline status may moderate these effects. The study has been approved by the medical ethics committee of the Philipps University of Marburg and has been pre-registered at www.clinicaltrials.gov (NCT01407055) on August 1, 2011.

Patients' desires for anxiolytic premedication - an observational study in adults undergoing elective surgery.

BACKGROUND: Most patients experiencing preoperative anxiety would welcome support in coping with their anxiety. Anxiolytic medication is a common way to address preoperative anxiety. However, the proportion of patients who welcome anxiolytic medication preoperatively and the preferred time of taking it have not been studied thoroughly. METHODS: Adult patients (n = 1000) scheduled to undergo elective surgery under general anesthesia were eligible to participate in this single-center observational study. Primary outcomes were the ratio of patients desiring anxiolytic medication (no/yes/on request) and the preferred time of taking it (evening before surgery/morning of day of surgery/on call to the operating room). Secondary outcomes included associations between different measures of anxiety (i.e., anxiety level according to the Amsterdam Preoperative Anxiety and Information Scale (APAIS) and anxiety status (no/yes)) and desire for anxiolytic medication (no/yes/on request). Primary outcomes were analyzed descriptively, and secondary outcomes were analyzed using multinomial logistic regressions. RESULTS: Three hundred fifty-six (35.6%) out of 1000 patients desired anxiolytic medication and 239 (23.9%) patients would welcome anxiolytic medication on request. In patients reporting anxiety (no/yes; n = 493), 228 (46.2%) stated a clear desire for anxiolytic medication (yes) and 142 (28.8%) considered anxiolytic medication (on request). Patients' preferences concerning the timing of premedication vary widely. In patients reporting a clear desire for anxiolytic medication (n = 356), the "morning of the day of surgery" was most frequently (n = 111, 31.2%) stated as the preferred time to get anxiolytic medication, followed by "on call to the operating room" (n = 51, 14.3%). All anxiety measures were significantly associated with desire for anxiolytic medication (p < 0.05). CONCLUSIONS: Given the importance of preoperative anxiety to patients, patients' desire for anxiolytic medication should be considered when discussing the pros and cons of premedication. Individualized instead of standardized prescription and timing of premedication is recommended. TRIAL REGISTRATION: German Clinical Trials Register ( DRKS 00013319 , approved 23/11/2017).

Childhood Emotional Neglect and Cardiovascular Disease: A Narrative Review.

Psychosocial factors predict the incidence and progression of cardiovascular disease (CVD). There is accumulating evidence for the importance of childhood maltreatment for the development and progression of both CVD-related risk factors and CVD. However, past research has predominantly focused on active forms of childhood maltreatment such as emotional abuse, physical abuse, and sexual abuse. At the same time, childhood neglect as a relatively silent form of childhood maltreatment received less attention. Childhood emotional neglect is the most common form of neglect. This narrative review summarizes findings on the association between childhood emotional neglect and CVD and potential underlying mechanisms. These mechanisms may involve biological factors (i.e., elevated inflammation, autonomic dysregulation, dysregulated HPA axis, and altered brain development), psychological variables and mental health (i.e., depression and anxiety), and health behaviors (i.e., eating behavior, smoking, drug use, physical activity) and interpersonal aspects. Evidence suggests that emotional neglect is associated with CVD and CVD risk factors such as obesity, diabetes, inflammation, a dysregulated stress system, altered brain development, depression and other psychological abnormalities (i.e., emotion-regulation difficulties), interpersonal difficulties, and lack of health behaviors. Specific subtypes of childhood maltreatment may be associated with CVD via different mechanisms. This review further encompasses clinical suggestions, identifies research gaps, and has implications for future studies. However, more research with better study designs is desperately needed to identify the exact underlying mechanisms and opportunities for mitigating the negative health consequences of emotional neglect to reduce the prevalence and progression of CVD.

Preoperative anxiety and its association with patients' desire for support - an observational study in adults.

BACKGROUND: Preoperative anxiety is prevalent and has harmful effects on postoperative outcomes. However, to date, it is still unclear (i) to what extent patients perceive preoperative anxiety as emotionally distressful, (ii) whether patients would welcome support from anesthesiologists in coping with their anxiety, and (iii) whether anxiety scores are useful for everyday clinical practice to determine patients' need for support. METHODS: 1082 patients scheduled to undergo elective procedures under general anesthesia were eligible for this cross-sectional study carried out at a university hospital. Preoperative anxiety, resulting in emotional distress, and patients' desire for anesthesiologists' support in coping with their anxiety were assessed dichotomously (no vs. yes) and analyzed descriptively. The intensity of anxiety was evaluated using the Amsterdam Preoperative Anxiety and Information Scale (range 4-20). Associations between the intensity of anxiety and the resulting desire for support were analyzed using logistic regression. Receiver operating characteristic analyses were performed to identify anxiety levels that best predict desire for support. RESULTS: Among the 1000 (537 female; M (SD) 57 (18) years) subjects evaluated, 493 (318 (65 %) female) reported anxiety. Anxiety was associated with emotional distress in 320 (65 %) and desire for support in 291 (59 %) patients. Increased preoperative anxiety levels were associated with higher rates of desire for support (B= 0.270; odds ratio 1.31 [95 % CI 1.22-1.41]). An anxiety score > 9 was best to predict a desire for support (sensitivity 0.861, specificity 0.724). However, desire for support was even present in some patients with lowest anxiety scores (5 or 6). CONCLUSIONS: All patients undergoing surgery should be screened for preoperative anxiety and the resulting desire for support to be able to determine who would welcome support. Anxiety scoring tools do not seem to be useful to identify these patients. By helping patients experience less preoperative anxiety, anesthesiologists may not only reduce patients' emotional distress but also have a positive impact on postoperative outcome. TRIAL REGISTRATION: German Clinical Trials Register (DRKS 00013319, 23 November 2017).

IL-8 and CRP moderate the effects of preoperative psychological interventions on postoperative long-term outcomes 6 months after CABG surgery - The randomized controlled PSY-HEART trial.

INTRODUCTION: Inflammation has been related to several somatic and psychological disorders and may moderate effects of psychological interventions. In the PSY-HEART trial patients benefitted from preoperative psychological interventions before undergoing coronary artery bypass graft surgery (CABG) and, if necessary, concomitant valvular surgery, compared to standard medical care. In this study we examined whether patients' baseline inflammatory status moderated the intervention effects. MATERIAL AND METHODS: In a prospective three-arm randomized clinical trial with 6-months follow-up, 124 patients scheduled for CABG surgery alone or concomitant with valvular surgery were randomized to (i) standard medical care only (SMC) or two preoperative psychological interventions: (ii) CBT-based optimizing expectations (EXPECT) and an (iii) an active control group focusing on emotional support (SUPPORT). Available baseline CRP- (n = 79), IL-6- (n = 78), IL-8- (n = 78) and TNF-alpha-(n = 80) parameters were considered as potential moderators (CRP as a categorical and continuous moderator). Linear mixed model analyses were calculated to test whether baseline inflammatory levels moderated intervention effects on disability, mental and physical quality of life at 6 months after surgery. RESULTS: IL-8 moderated intervention effects on patients' disability and categorical CRP moderated intervention effects on mental quality of life. Follow-up tests indicated that EXPECT (and in part SUPPORT) led to lower postoperative disability and higher mental quality of life compared to SMC in patients with low baseline inflammatory markers. EXPECT indicated higher mental quality of life compared to SUPPORT in the high CRP subgroup. Patients in the SMC group had higher mental quality of life in the high CRP subgroup compared to the low CRP subgroup. CONCLUSION: Especially for patients with a lower inflammatory baseline status preoperative psychological interventions might be helpful to optimize long-term CABG surgery outcomes.

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.

Effects of Preoperative Psychological Interventions on Catecholamine and Cortisol Levels After Surgery in Coronary Artery Bypass Graft Patients: The Randomized Controlled PSY-HEART Trial.

OBJECTIVE: The aim of the study was to examine whether preoperative psychological interventions targeting patients' expectations are capable of influencing the biological stress response after coronary artery bypass graft (CABG) surgery and could thus improve recovery after heart surgery. METHODS: Randomized controlled trial with assessments 10 days before surgery, after psychological intervention (day of hospital admission, but before surgery), postoperative (6-8 days later), and at follow-up (6 months after surgery). Eligible patients (N = 124) scheduled for elective on-pump CABG or CABG with valve replacement surgery were approached before hospital admission. Standard medical care (SMC) was compared with two additional preoperative psychological interventions: (a) an expectation manipulation intervention to optimize patients' expectations about course and outcomes or (b) supportive therapy, containing the same amount of therapeutic attention, but without specifically focusing on expectations. Postoperative plasma adrenaline, noradrenaline, and cortisol levels were a secondary outcome of our study (primary outcome patients' disability 6 months after surgery and other secondary patient-reported or clinical outcomes were reported elsewhere). RESULTS: Expectation manipulation intervention (3.68 ln pg/mL, 95% confidence interval = 3.38-3.98, p = .015) and supportive therapy (3.70 ln pg/mL, 95% confidence interval = 3.38-4.01, p = .026) led to significantly lower postoperative adrenaline levels compared with SMC (4.26 ln pg/mL, 95% confidence interval = 3.99-4.53) only. There were no treatment effects of the preoperative intervention for noradrenaline (p = .90) or cortisol (p = .30). Higher postoperative adrenaline levels predicted disability 6 months after surgery (r = .258, p = .018). CONCLUSIONS: In addition to SMC, preoperative psychological interventions seem to buffer psychobiological stress responses and could thus facilitate recovery from CABG surgery. Patients' postoperative stress responses could be an important factor for explaining trajectories of long-term outcomes. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov(NCT01407055).

Optimizing preoperative expectations leads to a shorter length of hospital stay in CABG patients: Further results of the randomized controlled PSY-HEART trial.

OBJECTIVE: To examine the effect of a preoperative expectation-optimizing psychological intervention on length of stay in the hospital and time spent in the Intensive Care Unit (ICU) in patients undergoing elective cardiac surgery. METHODS: In a randomized controlled trial, 124 patients prior to undergoing coronary artery bypass grafting (CABG) or CABG combined with heart valve surgery were randomized to either a) standard medical care alone (SMC) or an additional preoperative intervention, b) an additional expectation manipulation intervention (EXPECT) to optimize patients' expectations, or c) an additional supportive therapy (SUPPORT), containing the same amount of therapeutic attention but without a specific focus. Participants were followed-up post-operatively to assess their length of hospital stay and the time spent in the ICU. RESULTS: Patients in both psychological intervention groups spent significantly less days in the hospital then patients in the SMC group (M(EXPECT)=12.62, M(SUPPORT)=14.13, M(SMC)=17.27, p=0.028). There was a significant linear trend (F(1112)=7.68, p=0.009) showing that the more specific the intervention patients received the shorter they stayed in the hospital. The effect of the intervention on time spent in the ICU was only marginally significant (M(EXPECT)=103.76, M(SUPPORT)=103.10, M(SMC)=158.45, p=0.066). CONCLUSION: Changing patients' preoperative expectations via a psychological intervention leads to less days spent in the hospital. The psychological interventions are associated with positive cost-benefit ratios. Specific psychological mechanisms underlying the effect of our intervention remain unclear and need to be investigated further. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01407055).

Preoperative optimization of patient expectations improves long-term outcome in heart surgery patients: results of the randomized controlled PSY-HEART trial.

BACKGROUND: Placebo effects contribute substantially to outcome in most fields of medicine. While clinical trials typically try to control or minimize these effects, the potential of placebo mechanisms to improve outcome is rarely used. Patient expectations about treatment efficacy and outcome are major mechanisms that contribute to these placebo effects. We aimed to optimize these expectations to improve outcome in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: In a prospective three-arm randomized clinical trial with a 6 month follow-up, 124 patients scheduled for CABG surgery were randomized to either a brief psychological pre-surgery intervention to optimize outcome expectations (EXPECT); or a psychological control intervention focusing on emotional support and general advice, but not on expectations (SUPPORT); or to standard medical care (SMC). Interventions were kept brief to be feasible with a heart surgery environment; "dose" of therapy was identical for both pre-surgery interventions. Primary outcome was disability 6 months after surgery. Secondary outcomes comprised further clinical and immunological variables. RESULTS: Patients in the EXPECT group showed significantly larger improvements in disability (-12.6; -17.6 to -7.5) than the SMC group (-1.9; -6.6 to +2.7); patients in the SUPPORT group (-6.7; -11.8 to 1.7) did not differ from the SMC group. Comparing follow-up scores and controlling for baseline scores of EXPECT versus SUPPORT on the variable disability only revealed a trend in favor of the EXPECT group (P = 0.09). Specific advantages for EXPECT compared to SUPPORT were found for mental quality of life and fitness for work (hours per week). Both psychological pre-surgery interventions induced less pronounced increases in pro-inflammatory cytokine concentrations reflected by decreased interleukin-8 levels post-surgery compared to changes in SMC patients and lower interleukin-6 levels in patients of the EXPECT group at follow-up. Both pre-surgery interventions were characterized by great patient acceptability and no adverse effects were attributed to them. Considering the innovative nature of this approach, replication in larger, multicenter trials is needed. CONCLUSIONS: Optimizing patients' expectations pre-surgery helps to improve outcome 6 months after treatment. This implies that making use of placebo mechanisms has the potential to improve long-term outcome of highly invasive medical interventions. Further studies are warranted to generalize this approach to other fields of medicine. TRIAL REGISTRATION: Ethical approval for the study was obtained from the IRB of the Medical School, University of Marburg, and the trial was registered at ( NCT01407055 ) on July 25, 2011.