Nocebo effects with antidepressant clinical drug trial placebos

doi:10.1016/j.genhosppsych.2007.01.010

General Hospital Psychiatry

Volume 29, Issue 3, May–June 2007, Pages 275-277

https://doi.org/10.1016/j.genhosppsych.2007.01.010 Get rights and content

Abstract

We describe an individual who experienced unusual negative effects while taking a placebo during a clinical drug trial. A 26-year-old male took 29 inert capsules, believing he was overdosing on an antidepressant. Subsequently, he experienced hypotension requiring intravenous fluids to maintain an adequate blood pressure until the true nature of the capsules was revealed. The adverse symptoms then rapidly abated. The nocebo effect (undesirable symptoms following administration of an inert substance that the patient believes to be an active drug) may have significant negative impacts on certain patients. Further research is warranted to better understand this phenomenon.

Section snippets

Case report

Mr. A, a 26-year-old male, presented to the receiving clerk of an emergency department stating, “Help me, I took all my pills” and then collapsed. As he fell, he dropped an empty prescription bottle. Assessment and treatment were initiated immediately. Mr. A was conscious but appeared drowsy and lethargic. He related that he had taken all of his medication, which he said was a new experimental drug for depression. The label confirmed that the bottle contained capsules to be taken as part of a

Discussion

Mr. A's hypotension appears to have occurred as a result of the placebo overdose. Although other causes of hypotension cannot be entirely excluded, this would be the most likely explanation in view of his otherwise normal history, physical examination and laboratory studies at the time of presentation, particularly normal blood urea nitrogen (BUN), creatinine, electrolytes and hematocrit, suggesting a normovolemic state. The nature of placebo and nocebo effects are poorly understood, with some

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Empirical evidence consistently shows that discordance, also called dissociation or discrepancy, between actual physiological (mainly visceral) events and their perceived counterparts is substantial. On the one hand, we typically do not perceive actual visceral events occurring in our bodies; on the other hand, sometimes we do perceive bodily changes that do not really take place. This narrative review presents the available empirical findings on the discordance, and summarizes possible explanations that approach the phenomenon from the viewpoint of evolution, cognitive development, and predictive processing. Also, the role of top-down factors, such as expectations and experiences is discussed. Finally, practically relevant consequences of the discordance are presented using the examples of mind-body practices, the placebo and nocebo phenomenon, and medically unexplained symptoms. It is concluded that the discordance between actual and perceived body changes can have a negative impact on health, mainly through issues with adherence and other behavioral factors. The existence of actual-perceived discordance should be taught and demonstrated in the elementary and high school, as well as in many areas of higher education.
The association between placebo arm inclusion and adverse event rates in antidepressant randomized controlled trials: An examination of the Nocebo Effect
2021, Journal of Affective Disorders
Citation Excerpt :
A placebo control is used to isolate the effects of the active medication as it is well established that treatment with an inert substance can elicit both positive and negative outcomes in subjects (Požgain et al., 2014). Although the use of placebo-controls separates non-specific treatment effects from more direct pharmacological actions, a body of research suggests that the inclusion of a placebo arm and the number of active treatment arms both have meaningful effects on efficacy and tolerability outcomes (Reeves et al., 2007; Rutherford et al., 2010; Sinyor et al., 2010; Trivedi and Rush, 1994). Antidepressant response is known to be attenuated in subjects with lower expectations (Krell et al., 2004) and one factor that may influence expectations is the possibility of receiving a placebo.
Antidepressant efficacy is influenced by patient expectations and, in randomized controlled trials (RCTs), the probability of receiving a placebo. It is unclear whether tolerability demonstrates a similar pattern. This study aimed to determine whether study design influences adverse event (AE) rates in antidepressant trials for subjects receiving active treatment or placebo.
RCTs comparing one antidepressant to another antidepressant, placebo, or both in major depressive disorder (MDD) (1996-2018) were retrieved from Medline and PsycINFO. Clinicaltrials.gov was searched for unpublished trials. Of 1,997 studies screened, 77 trials were included. Studies were classified as drug-drug, drug-drug-placebo, or drug-placebo based on design and overall number of subjects experiencing any AE was recorded. Subgroup meta-analysis of proportions and meta-regression techniques were used to compare AE rates across study designs in patients receiving active antidepressant treatment and placebo.
Among the actively treated, AE rates were lower in drug-drug trials (58.5%) compared to drug-drug-placebo (75.7%) and drug-placebo (76.4%) (the model reported coefficients for percent differences between AE rates of different study designs were B=17.0, p<0.001 and B=17.8, p<0.001, respectively). AE rates in patients receiving placebo were not different between study designs.
The present study is limited by the diverse range of study populations, variability in reporting of AEs, and specific antidepressants employed in the included trials.
The inclusion of a placebo arm in the study design was unexpectedly associated with higher rates of AEs among patients receiving active medication in antidepressant trials. This observation has important implications for interpretation of trial tolerability findings.
Nocebo in multiple sclerosis trials: A meta-analysis on oral and newer injectable disease-modifying treatments
2019, Multiple Sclerosis and Related Disorders
Citation Excerpt :
In the early 1960s, Kennedy introduced the term nocebo, which refers to the adverse events (AEs) following the administration of an active or inert substance (Kennedy, 1961). Unlike placebo, nocebo is detrimental for clinical research and practice, complicating the assessment of the side effect profile of drugs (Reeves et al., 2007) and sometimes leading to drug discontinuation (Preston et al., 2000). Furthermore, it adversely affects drug adherence while also increasing the cost of care.
Nocebo phenomena are linked to decreased adherence to treatments in clinical practice as well as difficulty in assessing the adverse effect profile in clinical trials.
To estimate the incidence and severity of nocebo responses in clinical trials of oral and newer injectable disease-modifying treatments (DMTs) for relapsing multiple sclerosis (MS).
Meta-analysis of the incidence of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited adverse events (AEs) in randomized, placebo-controlled MS trials published between 2005 and 2018. Nocebo severity was estimated as a percentage of placebo-treated patients who discontinued the treatment due to drug-related AEs.
The pooled incidence of nocebo was 89% (95% CI: 88%–90%) in trials for oral DMTs (cladribine, fingolimod, teriflunomide and dimethyl fumarate) and 66% (95% CI: 51%–80%) in trials of newer injectable DMTs (biosimilar glatiramer acetate 20 mg, innovator glatiramer acetate 40 mg and pegylated interferon beta). The pooled nocebo severity was 8% (95% CI: 5%–12%) for oral treatments and 2% (95% CI: 0–2%) for newer injectable DMTs.
Oral DMTs may be associated with a higher incidence and greater nocebo severity than newer injectables.
Nocebo effect
2019, FMC Formacion Medica Continuada en Atencion Primaria
The Power of Labeling in Nocebo Effects
2018, International Review of Neurobiology
Nocebo effects comprise two broad types: primary nocebo effects, in which overall treatment efficacy is reduced; and nocebo side effects, which result in the increased experience of unpleasant secondary side effects. An important factor in generating nocebo effects of both types is the patient's expectations of how well a treatment will work, and how likely it is to cause side effects. One source of negative expectations is the presence of generic—as opposed to brand name—labeling. A medicine's labeling is likely to be one of the first aspects of a treatment that is encountered by a patient, and perhaps the most common labeling information on pharmaceuticals is the labeling that identifies the drug as being made by the originator brand manufacturer, or as a generic copy. Although generic medicines are pharmaceutically equivalent to their brand name counterparts, generics are often viewed with distrust and perceived to be inferior to branded medicines. Negative perceptions of generic pharmaceuticals may contribute to reduced treatment efficacy via enhanced primary nocebo effects, and increased nocebo side effects. This chapter reviews evidence for the role of brand and generic labeling in treatment outcomes across a range of contexts—most often laboratory research assessing pain outcomes, as well as the influence of related factors including price, familiarity, and treatment switches. Although increasing evidence suggests that labeling of medicines can shape nocebo effects, interventions to improve perceptions of generics do not necessarily translate into more positive treatment outcomes.
Nocebos in Daily Clinical Practice. The Potential Side Effects of the Treatment Context and the Patient-Doctor Interaction on Pain in Clinical Populations
2013, Placebo and Pain: From Bench to Bedside
Nocebo effects are extremely common in clinical practice, and they are induced by a patient’s negative expectancies about a treatment outcome. They may occur after an inert treatment, or after the administration of a pharmacologically active substance, and modulate the treatment outcome. Nocebo effects in clinical practice manifest themselves in the deterioration of a pre-existing symptomatology or in the development of new symptoms that are often considered as nonspecific side effects and are ascribed to the medical regimen. Nocebo responses can be induced by components of the therapeutic encounter, e.g. the communication of the diagnosis, information about the treatment, the disclosure of risks and benefits of the treatment, or the verbal interaction during the treatment. This chapter reviews empirical evidence from clinical populations that documents nocebo effects in the different stages of the therapeutic process. Based on this review, it suggests strategies for the minimization of nocebo effects in clinical practice.

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View full text

Case ReportNocebo effects with antidepressant clinical drug trial placebos

Abstract

Section snippets

Case report

Discussion

Prev Med

Prev Med

Drug-related information generates placebo and nocebo responses that modify the drug response

Psychosom Med

The interaction of psychologic stimuli and pharmacologic agents on airway reactivity

Psychosom Med

A double-blind study of symptom provocation to determine food sensitivity

N Engl J Med

Placebo effects mediated by endogenous opioid activity on μ-opioid receptors

J Neurosci

Placebo and nocebo responses, cortisol, and circulating beta-endorphin

Psychosom Med

Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease

Science

Conditioned immunomodulation: research needs and directions

Brain Behav Immun

Case Report
Nocebo effects with antidepressant clinical drug trial placebos