Does Certainty of Genuine Treatment Increase the Drug Response in Alzheimer's Disease Patients: A Meta-Analysis and Critical Discussion (vol 84, pg 1821, 2021)

Background: Non-specific treatment effects, such as expectations, contribute to the effectiveness of pharmacological treatments across diseases. However, the contribution of expectancy, i.e., certainty of receiving treatment, in patients with Alzheimer's disease (AD) is unknown. Objective: The aim is to investigate whether certainty of receiving a genuine treatment influences the response to active treatment in AD patients. Methods: The efficacy of active treatments in open-label trials, where patients are certain of receiving treatment (100% certainty), was compared to the same active treatments in randomized controlled trials (RCT), where patients are uncertain of receiving treatment or placebo (50% certainty). Results: In the seven open-label trials, there was no significant difference between post- and pre-treatment scores (difference in means = 0.14, 95% CI [-0.51; 0.81], p = 0.66). In the eight RCT trials, there was a significant difference between post- and pre-treatment (difference in means = -0.91, 95% CI [-1.43; -0.41], p < 0.001). There was a statistically significant difference between open-label and RCT trials (difference =1.06, 95% CI [0.23; 1.90], p = 0.001). Conclusion: Patients with AD did not benefit from certainty of receiving genuine treatment. This could be due to the nature/progression of the disease, but it could also be related to an order effect in the practice of running AD trials, where RCTs are conducted prior to open label. These findings have implications for the understanding of non-specific treatment effects in AD patients as well as for the design of clinical trials that test pharmacological treatments in AD.