Placebo and nocebo phenomena in schizophrenia spectrum disorders: a narrative review on current knowledge and potential future directions

Abstract

The experience of psychosis in schizophrenia spectrum disorders involves significant distress and functional impairment, contributing to immense social and economic costs. Current gold standard treatment guidelines emphasize the use of antipsychotic medications, though responses to these treatments vary widely, with the potential for detrimental side effects. However, increasing placebo responses in randomized controlled trials since the 1960s complicate the development of new medications. Elevated placebo responses are common in psychiatric populations, including those with psychosis, and are influenced by individual beliefs and prior experiences. Despite extensive research on placebo mechanisms in conditions such as depression and pain, little is known about mechanisms of these effects in psychosis. This narrative review examines the predictors and belief formation processes underlying placebo and nocebo phenomena in psychosis. We discuss features of randomized controlled trials for antipsychotic medications, individual symptom heterogeneity, and contextual factors. Findings related to placebo effects for motivation and cognition-enhancing drugs are also discussed. We then consider the possibility that theories of predictive coding and aberrant salience provide explanation for aspects of both placebo effects and schizophrenia spectrum symptoms. The role of outcome expectations broadly and in the context of reward processing is considered. We conclude with some recommendations for future placebo research in psychosis, emphasizing the diversity of placebo effects, assessment concerns, cultural considerations, and methodological aspects. Future multidisciplinary research is required to further elucidate placebo effects in schizophrenia spectrum disorders.

Keywords: Bayesian; conditioning; negative symptoms; positive symptoms; predictive coding; psychosis; randomized clinical trials (RCTs).

Figure 1.

Summary of study- and patient-centered factors influencing placebo effects in SSDs as identified by Hird et al. (2023). This meta-analysis identified several study- and patient-centered factors that may play a role in elevated placebo effects for some individuals with schizophrenia.