Nocebo in clinical trials for depression: A meta-analysis

doi:10.1016/j.psychres.2013.10.019

Psychiatry Research

Volume 215, Issue 1, 30 January 2014, Pages 82-86

https://doi.org/10.1016/j.psychres.2013.10.019 Get rights and content

Abstract

Nocebo refers to adverse events (AEs) related to negative expectations that medical treatment will likely harm instead of heal and can be assessed in placebo-controlled randomized clinical trials (RCTs). We sought to examine the AEs following placebo administration in RCTs for depression (D). After a systematic Medline search for RCTs in depression published in the last decade we assessed percentages of placebo-treated patients reporting at least one AE or discontinuing due to placebo intolerance and searched for factors influencing nocebo's extent. Data were extracted from 21 RCTs fulfilling search criteria. Of 3255 placebo-treated patients, 44.7% (95% CI: 22.3–68.3%) reported at least one AE, and 4.5% (95% CI: 3.4–5.8%) discontinued placebo treatment due to intolerance. AE rates in placebo and active drug treated patients were correlated quantitatively (r=0.915, p<0.001) and qualitatively, but not dropout rates (r=0.047). We conclude that almost one out of 20 placebo treated patients discontinued treatment due to AEs, indicating a significant nocebo in trials for depression treatment adversely affecting adherence and efficacy of current treatments in clinical practice, with additional implications for trial designing.

Introduction

Nocebo refers to adverse events (AEs) related to negative expectations that medical treatment will likely harm instead of heal (Mitsikostas et al., 2011). It includes expected AEs or, less frequently, non-specific effects that cannot be substantiated referring to pharmacological action of the treatment (Mitsikostas et al., 2011). The term nocebo (“I shall harm”) was introduced in contraposition to the term placebo (“I shall please”) by Kennedy in the early 1960s to distinguish the noxious from the pleasing effects of placebo (Kennedy, 1961, Antonaci et al., 2007). Nocebo is related to lower adherence in therapy as well as with high rates of dropouts and significant difficulty in assessing the efficacy and the safety profile of a drug in clinical trials (Barsky et al., 2002, Enck et al., 2008). There is evidence that nocebo is related to negative pretrial suggestions and previous negative experiences during treatment (Benedetti et al., 2007) along with several psychological factors including stress and anxiety (Tracey, 2010, Manchikanti et al., 2011, Elsenbruch et al., 2012). Experimental human studies showed that nocebo is mediated by limbic system after affective and cognitive evaluation (Kong et al., 2008). It would be interesting therefore to investigate nocebo in conditions characterized by limbic system dysfunction in a non-experimental setting. In this context, nocebo can be assessed in randomized controlled trials (RCTs) by estimating the prevalence of adverse effects (AEs) in placebo treated patients (Papadopoulos and Mitsikostas, 2010, Papadopoulos and Mitsikostas, 2012, Mitsikostas et al., 2012, Stathis et al., 2013). In the present study we performed a systematic meta-analysis of RCTs for depression that tested pharmaceutical treatments to estimate the magnitude of nocebo and speculate its possible consequences in clinical practice and trial design.

Section snippets

Methods

A computer-based literature search was conducted on PubMed on January 2, 2012 using key words such as depression, placebo, pharmaceutical treatment, with the limitations humans, randomized controlled trial, English language, adults (≥19 years) and date-range (2000.01.01–2012.01.01), according to the PRISMA recommendations (Moher et al., 2009). We further filtered the search for pharmacotherapy and randomized, placebo controlled trials. All selected studies that were relevant were selected for

Literature search

Twenty-two randomized placebo-controlled studies on the treatment of depression published between 2001 and 2011 were collected for analysis (Fig. 1, PRISMA CHART). To evaluate the proportion of nocebo AE we pooled data from 10 studies that contained data on the number of patients with at least one AE. Similarly, to assess the proportion of nocebo dropout rate we considered 21 papers that included these data (Appendix e-1). The descriptive of studies included in the analysis are presented in

Discussion

This meta-analysis of RCTs for treatment of depression showed that almost half of placebo treated patients experienced at least one drug related AE (44.7%) and almost one out of 20 placebo treated patients discontinued treatment because of AE (4.5%). The more AEs recorded in the active drug arm the more AEs were observed in the placebo arm. Adverse events were correlated between treatment arms (active drug and placebo) not only quantitatively but qualitatively as well: both patient groups

Authors׳ roles

Dr. Dimos D. Mitsikostas conceptualized and designed the study; he interpreted and analyzed the data and wrote the manuscript.

Dr. Nicolaos Chalarakis performed the PubMed search and the data extraction.

Dr. Leonidas Mantonakis performed the PubMed search and the data extraction. He also contributed to the data interpretation.

Acknowledgments

The authors thank Evie-Maria Delicha MSc for her contribution to the statistical analysis.

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Cited by (65)

Nocebo-associated treatment discontinuation with subcutaneous anti-osteoporotic drugs. A systematic review and meta-analysis of placebo-arm dropouts in randomized-controlled trials
2024, Maturitas
Nocebo is a concept of therapeutics referring to unpleasant symptoms attributed by a patient to a drug, due to negative anticipation. Patients receiving oral anti-osteoporotic drugs in randomized controlled trials (RCT) can experience adverse events leading to dropout, implying that nocebo contributes to treatment discontinuation for these drugs. In this study we aim to investigate the nocebo effect of subcutaneous anti-osteoporotic drugs with a higher compliance rate than orally administered drugs.
We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for double-blind trials investigating subcutaneous anti-osteoporotic drugs for osteoporosis (namely, denosumab, teriparatide, abaloparatide and romosozumab) published up to May 2023.
Dropouts due to reported adverse events in the placebo arms (“nocebo dropouts”).
Data from 17 trials were extracted. Among 10,529 placebo-treated patients the pooled nocebo-dropout percentage was 3 % for denosumab (average: 0.03; 95 % CI: 0.01–0.05), 1 % for romosozumab (average: 0.01; 95 % CI: 0.00–0.03) and 6 % for teriparatide and abaloparatide (average: 0.06; 95 % CI: 0.05–0.07). Nocebo-dropouts were significantly higher in men than women (6 % vs. 3 %, respectively, p = 0.012), in older (mean age >68 years) than in younger patients (5 % vs. 1 %, respectively, p = 0.017) and in those with more severe osteoporosis (based on the percentage of participants with prior fragility-related fractures in the study cohort) compared with patients with no prior fracture history (4 % vs. 1 %, respectively, p = 0.046).
Nocebo responses may contribute to treatment discontinuation with subcutaneous anti-osteoporotic drugs in clinical practice. Higher nocebo-related dropout rates in the higher-risk RCT population (older patients, males, those with prior fractures) show that nocebo mechanisms have the potential to hinder therapeutic efforts to specific populations who would benefit most.
Prospero registration number CRD42020212843.
Amplified gut feelings under inflammation and depressed mood: A randomized fMRI trial on interoceptive pain in healthy volunteers
2023, Brain, Behavior, and Immunity
Inflammation and depressed mood constitute clinically relevant vulnerability factors for enhanced interoceptive sensitivity and chronic visceral pain, but their putative interaction remains untested in human mechanistic studies. We tested interaction effects of acute systemic inflammation and sad mood on the expectation and experience of visceral pain by combining experimental endotoxemia with a mood induction paradigm.
The double-blind, placebo-controlled, balanced crossover fMRI-trial in N = 39 healthy male and female volunteers involved 2 study days with either intravenous administration of low-dose lipopolysaccharide (LPS, 0.4 ng/kg body weight; inflammation condition) or saline (placebo condition). On each study, day two scanning sessions were conducted in an experimentally induced negative (i.e., sad) and in a neutral mood state, accomplished in balanced order. As a model of visceral pain, rectal distensions were implemented, which were initially calibrated to be moderately painful. In all sessions, an identical series of visceral pain stimuli was accomplished, signaled by predictive visual conditioning cues to assess pain anticipation. We assessed neural activation during the expectation and experience of visceral pain, along with unpleasantness ratings in a condition combining an inflammatory state with sad mood and in control conditions. All statistical analyses were accomplished using sex as covariate.
LPS administration led to an acute systemic inflammatory response (inflammation X time interaction effects for TNF-α, IL-6, and sickness symptoms, all p <.001). The mood paradigm effectively induced distinct mood states (mood X time interaction, p <.001), with greater sadness in the negative mood conditions (both p <.001) but no difference between LPS and saline conditions. Significant main and interaction effects of inflammation and negative mood were observed for pain unpleasantness (all p <.05). During cued pain anticipation, a significant inflammation X mood interaction emerged for activation of the bilateral caudate nucleus and right hippocampus (all p_FWE < 0.05). Main effects of both inflammation and mood were observed in multiple regions, including insula, midcingulate cortex, prefrontal gyri, and hippocampus for inflammation, and midcingulate, caudate, and thalamus for mood (all p_FWE < 0.05).
Results support an interplay of inflammation and sad mood on striatal and hippocampal circuitry engaged during visceral pain anticipation as well as on pain experience. This may reflect a nocebo mechanism, which may contribute to altered perception and interpretation of bodily signals. At the interface of affective neuroscience and the gut-brain axis, concurrent inflammation and negative mood may be vulnerability factors for chronic visceral pain.
Nocebo vs Placebo Effects: Their Clinical Relevance
2022, American Journal of Medicine
The placebo effect can be defined as any improvement of illnesses or reduction of subjective symptoms that result from interventions possessing no known physical effects. By contrast, the nocebo effect refers to undesirable symptoms or illnesses that follow interventions also lacking known physical effects. It may also play a role in chronic illnesses that lack objective confirmation. Both placebo and nocebo effects can be potent and must be understood by both practitioners and researchers for proper application in clinical medicine. Individual caregivers can apply these principles to modify results in the daily care of patients.
Nocebo phenomena may be enhanced in aging: Implications for clinical practice
2021, Maturitas
Nocebo effects, denoting unfavourable outcomes after a medical intervention because of negative expectations rather than a direct pharmacologic action, are an important cause of dropout from clinical trials and non-adherence to medication, and may be especially pertinent for older adults. Several characteristics of aging individuals and their medical care have a potential to augment nocebo susceptibility, such as depression and anxiety, neurodegenerative diseases and chronic pain states, adverse healthcare experiences, generic drug use, age-related stereotypes, and strained patient-physician communication. Nocebo-related research in older adults is hindered by under-representation in clinical trials, medical complexity of geriatric patients, and lack of validated tools to accurately assess susceptibility and efficacy of preventive efforts.
Antidepressant-placebo differences for specific adverse events in major depressive disorder: A systematic review
2020, Journal of Affective Disorders
Adverse events (AEs) are known to occur while patients are treated with placebos, part of the so-called nocebo effect. Yet evidence is limited regarding the likelihood that specific AEs occurring with antidepressant treatment are or are not due to nocebo effects.
This study identified 56 placebo-controlled, randomized controlled trials (RCTs) of antidepressant monotherapy for adults with major depressive disorder that reported AE rates in sufficient detail for comparison. Poisson regression analyses compared rates of AEs according to antidepressant class weighted by study population to determine which separated from placebo. A “nocebo index” was also calculated (with 0 defined as the lowest rate and 1 or higher indicating the same or greater rate of an AE in the placebo group).
Numerous AEs did not differ statistically between antidepressant classes and placebo including worsening psychiatric symptoms, all forms of pain, weight gain and respiratory symptoms. Nevertheless, a number of AEs were significantly more common in antidepressants than placebos across multiple antidepressant classes. These were predominantly neurological, sexual and anticholinergic effects. Several AEs that separated statistically between antidepressants and placebos nevertheless had moderate nocebo indices (≥0.5). For example, dizziness in SSRIs separated significantly from placebo (OR 1.50, 95%CI 1.13–1.99) but had a nocebo index of 0.67.
This study relied on multiple RCTs with subtle design differences.
This study identified several AEs that are likely the physiological result of antidepressants and many that likely represent nocebo effects. These results should inform clinical decision making and discussions with patients.
Safety, Tolerability, and Nocebo Phenomena During Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Placebo-Controlled Clinical Trials
2020, Neuromodulation
Citation Excerpt :
In depression, the nocebo AE rate in TMS RCTs was 12.2% and the nocebo dropout rate was 2.2%. These figures are significantly lower compared to the respective figures of nocebo rates in pharmacological RCTs of depression, where the pooled estimates are 44.7% and 4.5%, respectively (9). This finding suggests that nocebo depends on the method of treatment.
The methodology used for the application of repetitive transcranial magnetic stimulation (TMS) is such that it may induce a placebo effect. Respectively, adverse events (AEs) can occur when using a placebo, a phenomenon called nocebo. The primary aim of our meta-analysis is to establish the nocebo phenomena during TMS. Safety and tolerability of TMS were also studied.
After a systematic Medline search for TMS randomized controlled trials (RCTs), we assessed the number of patients reporting at least one AE and the number of discontinuations because of AE in active and sham TMS groups.
Data were extracted from 93 RCTs. The overall pooled estimate of active TMS and placebo treated patients who discontinued treatment because of AEs was 2.5% (95% CI 1.9%-3.2%) and 2.7% (95% CI 2.0%-3.5%), respectively. The pooled estimate of active TMS and placebo treated patients experiencing at least one AE was 29.3% (95% CI 19.0%-22.6%) and 13.6% (95% CI 11.6%-15.8%), respectively, suggesting that the odds of experiencing an AE is 2.60 times higher (95% CI 1.75-3.86) in the active treatment group compared to placebo (p < 0.00001). The most common AE was headache, followed by dizziness.
Secondary meta-analyses in depression and psychotic disorders showed that the odds of experiencing an AE is 3.98 times higher (95% CI 2.14-7.40) and 2.93 times higher (95% CI 1.41-6.07), respectively, in the active treatment groups compared to placebo.
TMS is a safe and well-tolerated intervention. Nocebo phenomena do occur during TMS treatment and should be acknowledged during clinical trial design and daily clinical practice.

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Nocebo in clinical trials for depression: A meta-analysis

Abstract

Introduction

Section snippets

Methods

Literature search

Discussion

Authors׳ roles

Acknowledgments

Neuroscience

Journal of Pain

Neuron

Controlled Clinical Trials

The epidemiology of chronic syndromes that are frequently unexplained: do they have common associated factors?

International Journal of Epidemiology

Lessons from placebo effects in migraine treatment

Journal of Headache and Pain

Nonspecific medication side effects and the nocebo phenomenon

JAMA. The Journal of the American Medical Association

The combination of estimates from different experiments

Biometrics

The nocebo effect and its relevance for clinical practice

Psychosomatic Medicine

Bias in meta-analysis detected by a simple, graphical test

British Medical Journal