Katja Weimer

The placebo response in clinical trials: more questions than answers

Meta-analyses and re-analyses of trial data have not been able to answer some of the essential questions that would allow prediction of placebo responses in clinical trials. We will confront these questions with current empirical evidence. The most important question asks whether the placebo response rates in the drug arm and in the placebo arm are equal. This ‘additive model’ is a general assumption in almost all placebo-controlled drug trials but has rarely been tested. Secondly, we would like to address whether the placebo response is a function of the likelihood of receiving drug/placebo. Evidence suggests that the number of study arms in a trial may determine the size of the placebo and the drug response. Thirdly, we ask what the size of the placebo response is in ‘comparator’ studies with a direct comparison of a (novel) drug against another drug. Meta-analytic and experimental evidence suggests that comparator studies may produce higher placebo response rates when compared with placebo-controlled trials. Finally, we address the placebo response rate outside the laboratory and outside of trials in clinical routine. This question poses a serious challenge whether the drug response in trials can be taken as evidence of drug effects in clinical routine.

Placebo effects in children: a review

Of more than 155,000 PubMed citations found with the search term “placebo,” only ~9,000 (5.8%) included the terms “children” or “adolescents.” When all these papers were screened, only ~2,000 of them investigated the placebo effect per se, and of those, only ~50 (2.5%) discussed the placebo effect in children and adolescents. In this narrative review, we explore four aspects of the placebo response in children and adolescents: (i) the legal and ethical limitations and restrictions for the inclusion of children in clinical trials as well as in experimental (placebo) research that may explain the poor knowledge base; (ii) the question of whether or not the placebo effect is larger in children and adolescents as compared with adults; (iii) whether the mechanisms underlying the placebo effect are similar between children and adults; and (iv) whether mediators and moderators of the placebo effect are comparable between children and adults. We finally discuss some of the consequences from the current placebo research in adults that may affect both experimental and clinical research in children and adolescents.

Placebo effects in psychiatry: mediators and moderators

A strong placebo response in psychiatric disorders has been noted for the past 50 years and various attempts have been made to identify predictors of it, by use of meta-analyses of randomised controlled trials and laboratory studies. We reviewed 31 meta-analyses and systematic reviews of more than 500 randomised placebo-controlled trials across psychiatry (depression, schizophrenia, mania, attention-deficit hyperactivity disorder, autism, psychosis, binge-eating disorder, and addiction) for factors identified to be associated with increased placebo response. Of 20 factors discussed, only three were often linked to high placebo responses: low baseline severity of symptoms, more recent trials, and unbalanced randomisation (more patients randomly assigned to drug than placebo). Randomised controlled trials in non-drug therapy have not added further predictors, and laboratory studies with psychological, brain, and genetic approaches have not been successful in identifying predictors of placebo responses. This comprehensive Review suggests that predictors of the placebo response are still to be discovered, the response probably has more than one mediator, and that different and distinct moderators are probably what cause the placebo response within psychiatry and beyond.

Effects of short-term food deprivation on interoceptive awareness, feelings and autonomic cardiac activity.

The perception of internal bodily signals (interoception) plays a relevant role for emotion processing and feelings. This study investigated changes of interoceptive awareness and cardiac autonomic activity induced by short-term food deprivation and its relationship to hunger and affective experience. 20 healthy women were exposed to 24h of food deprivation in a controlled setting. Interoceptive awareness was assessed by using a heartbeat tracking task. Felt hunger, cardiac autonomic activity, mood and subjective appraisal of interoceptive sensations were assessed before and after fasting. Results show that short-term fasting intensifies interoceptive awareness, not restricted to food cues, via changes of autonomic cardiac and/or cardiodynamic activity. The increase of interoceptive awareness was positively related to felt hunger. Additionally, the results demonstrate the role of cardiac vagal activity as a potential index of emotion related self-regulation, for hunger, mood and the affective appraisal of interoceptive signals during acute fasting.

Prediction of placebo responses: a systematic review of the literature

Objective: Predicting who responds to placebo treatment—and under which circumstances—has been a question of interest and investigation for generations. However, the literature is disparate and inconclusive. This review aims to identify publications that provide high quality data on the topic of placebo response (PR) prediction. Methods: To identify studies concerned with PR prediction, independent searches were performed in an expert database (for all symptom modalities) and in PubMed (for pain only). Articles were selected when (a) they assessed putative predictors prior to placebo treatment and (b) an adequate control group was included when the associations of predictors and PRs were analyzed. Results: Twenty studies were identified, most with pain as dependent variable. Most predictors of PRs were psychological constructs related to actions, expected outcomes and the emotional valence attached to these events (goal-seeking, self-efficacy/-esteem, locus of control, optimism). Other predictors involved behavioral control (desire for control, eating restraint), personality variables (fun seeking, sensation seeking, neuroticism), or biological markers (sex, a single nucleotide polymorphism related to dopamine metabolism). Finally, suggestibility and beliefs in expectation biases, body consciousness, and baseline symptom severity were found to be predictive. Conclusions: While results are heterogeneous, some congruence of predictors can be identified. PRs mainly appear to be moderated by expectations of how the symptom might change after treatment, or expectations of how symptom repetition can be coped with. It is suggested to include the listed constructs in future research. Furthermore, a closer look at variables moderating symptom change in control groups seems warranted.

Placebo responses and placebo effects in functional bowel disorders.

The nature and determinants of the placebo response are widely unknown, as are the underlying psychological and biological mechanisms. Placebo response rates in functional bowel disorders (functional dyspepsia, irritable bowel syndrome) trials are similar to those in nonintestinal pain conditions and are comparable with other organic gastrointestinal diseases (duodenal ulcer, inflammatory bowel diseases). In this narrative review, different methodologies (meta-analyses, reanalyses, and experimental setups) are discussed that have been applied to the study of the placebo response in functional dyspepsia and the irritable bowel syndrome.

Rome III criteria in parents' hands: pain-related functional gastrointestinal disorders in community children and associations with somatic complaints and mental health

Objectives To determine (a) the prevalence of Rome III abdominal pain-related functional gastrointestinal disorders in a western community sample of children, (b) their associations with sociodemographic factors, and (c) whether children fulfilling Rome III abdominal pain diagnoses show higher rates of psychological distress and somatization. Methods Data were collected from parents of 6–10-year-old children who were recruited from 22 public grammar schools in Germany. A total of 1537 questionnaires were included in the analysis. Abdominal pain-related functional gastrointestinal disorders were diagnosed on the basis of questionnaire responses by Rome III criteria. Further, somatic complaints as well as emotional and behavioral problems were assessed. Results In total, 7.7% of children aged 6–10 years fulfilled the criteria for at least one Rome III abdominal pain-related functional gastrointestinal disorder according to their parents. The most prevalent diagnoses were irritable bowel syndrome (4.9%) and functional abdominal pain (2.0%). Assigned diagnoses were not associated with sociodemographic factors. We could confirm that abdominal pain-related functional disorders, especially irritable bowel syndrome, were strongly associated with somatization and emotional problems in community. Conclusion Rome III abdominal pain-related functional gastrointestinal disorders are a common health problem in children and are, even in community, strongly associated with other somatic complaints and psychological distress.

Reduction of motion sickness with an enhanced placebo instruction: an experimental study with healthy participants.

Objective Expectancy and conditioning are underlying mechanisms of placebo and nocebo responses. In previous studies with motion sickness, we could induce nocebo responses by both methods, but no placebo responses. Methods In Experiment 1, 64 volunteers (50% women, mean age = 23.5 years) were evaluated to determine the degree they realized speed changes in nauseogenic rotation. For Experiment 2, 32 volunteers (50% women, mean age = 26.0 years) were exposed to fast rotation (15 rounds per minute, or rpm) on Day 1. On Day 2, they either received a drink with a presumed effective antiemetic (actually placebo) or were told they belonged to the control group. Rotation was surreptitiously reduced (to 10 rpm). On Day 3, they were tested with the initial rotation speed. Outcome variables in both experiments were symptom ratings; additionally in Experiment 2, the number of nauseogenic head movements, tolerated rotation time, and electrogastrogram were analyzed for changes between Days 1 and 2 (expectancy plus speed reduction) and Days 1 and 3 (expectancy plus conditioning). Results In Experiment 1, a dose-response function was established for different rotation speeds, with the smallest perceived difference between 10 and 15 rpm. In Experiment 2, placebo application induced better maximal symptom rating, head movement, and rotation time at Day 2 (F = 3.097, p = .043) and Day 3 (F = 3.401, p = .031). Electrogastrogram was unaffected. Conclusions Verbal suggestions combined with a conditioning procedure are effective in reducing symptoms of motion sickness.

Mental Strain and Chronic Stress among University Students with Symptoms of Irritable Bowel Syndrome

Aim. To investigate the degree of mental strain and chronic stress in a German community sample of students with IBS-like symptoms. Methods and Materials. Following an internet-based survey about stress, this study recruited 176 German university students (23.45 ± 2.48 years; 48.3% males) with IBS-like symptoms according to Rome III and 181 students without IBS (23.55 ± 2.82 years; 50.3% males) and compared them regarding current mental strain (SCL-90-R) and the extend of chronic stress. Beyond this, IBS subtypes, IBS severity, and health care utilization were assessed. Results. Students fulfilling IBS criteria showed significantly elevated values of mental strain and chronic stress. Nearly 40% of the IBS group (versus 20% of the controls) reached a clinically relevant value on the SCL-90-R global severity scale. IBS subtypes did not differ in terms of mental distress or chronic stress. Somatization, anxiety, and the chronic stressors “work overload,” “social tension,” and “dissatisfaction with job” were most closely connected to IBS symptom severity. Regarding health care utilization, our results show that consulting a physician frequently was not associated significantly with elevated mental strain or chronic stress but with IBS symptom severity. Conclusion. Our data contribute additional evidence to the distinct association between psychological stress and IBS in community samples.

Effects of Ginger and Expectations on Symptoms of Nausea in a Balanced Placebo Design

Objective Ginger effects on (experimental) nausea have been described, but also strong placebo effects and sex differences when nausea is involved. The “balanced placebo design” has been proposed to allow better separation of drug and placebo effects. Methods Sixty-four healthy participants (32 women) were randomly assigned to receive an antiemetic ginger preparation or placebo, and half of each group was told to have received drug or placebo. They were exposed to 5×2 min body rotations to induce nausea. Subjective symptoms and behavioral (rotation tolerance, head movements) and physiological measures (electrogastrogram, cortisol) were recorded. Groups were balanced for sex of participants and experimenters. Results Ginger and the information given did not affect any outcome measure, and previous sex differences could not be confirmed. Adding the experimenters revealed a significant four-factorial interaction on behavioral but not on subjective or physiological measures Men who received placebo responded to placebo information when provided by the male experimenter, and to ginger information when provided by the female experimenter. This effect was not significant in women. Conclusion The effects of an antiemetic drug and provided information interact with psychosocial variables of participants and experimenters in reports of nausea.