Nocebo Responses in Brain Diseases: A Systematic Review of the Current Literature

Abstract

Placebo is an intervention with no therapeutic effect that is used as a control in randomized controlled trials (RCTs). Placebo effects and responses can produce a beneficial effect that cannot be attributed to the properties of the intervention itself, since it is usually inactive, and should, therefore, be due to the patient's expectations about treatment (placebo effects), or confounding factors such as natural history, co-interventions, biases, among other co-factors (placebo responses). However, adverse events (AEs) may occur when using a placebo intervention, a phenomenon that is called nocebo. Like placebo, the nocebo effect is a cognitive and idiosyncratic phenomenon with specific biological bases, controlled by distinctive neurotransmitters within mapped brain areas most likely located within the network of the limbic system. Nocebo responses has been found to be very prevalent in various neurological conditions, in particular, in many brain disorders including headache, Parkinson's disease, Alzheimer's disease, depression, epilepsy, multiple sclerosis and motor neuron disease. Pooled AE rates in the placebo groups (nocebo AE rates) vary from 25% in the symptomatic treatment for multiple sclerosis RCTs to almost 80% in motor neuron disease RCTs. Pooled dropout rates because of AEs in the placebo groups (i.e., nocebo dropout rates) vary from 2% in multiple sclerosis RCTs to almost 10% in PD RCTs. Across all brain disorders, the nature of AEs reported in the placebo-treated subjects mirrors those reported by active drug-treated subjects, suggesting that awareness of drug side-effect profiles might have influenced patient expectations and, thus, nocebo responses. Unexplored brain diseases where nocebo should be studied further include mental disorders (i.e., schizophrenia and bipolar disorder), vascular disorders (i.e., acute ischemic stroke, vascular dementia), degenerative disorders (i.e., frontotemporal dementia, Lewy body dementia) and other systemic atrophies of the brain (i.e., hereditary ataxias).