The Placebo Effect

The Placebo Effect is the tendency of any medication or treatment, even an inert or ineffective one, to exhibit results simply because the recipient believes that it will work.

• The response rates for placebo in antidepressant clinical trials ranges between 30% to 40%.
• In patients with mild depression the placebo response rate is closer to 50% and often indistinguishable from the response rate to antidepressants.^[1]

• Children and adolescents can have even higher rates of placebo response (up to 46% response on placebo for depression, compared to a mean medication response of 59%). This rate has also been increasing over time.^[2]

• The placebo effect is thought to be mediated by the interplay between unconscious conditioning and conscious expectations.

• The neurotransmitter dopamine is also the salience and “excitement” neurotransmitter in the brain, while catechol-O-methyltransferase (COMT) is an enzyme that breaks down monoamine and dopamine.
  • Individuals with the Val/Val polymorphism of COMT are particularly effective at breaking down dopamine, and thus lower dopamine levels and the lowest placebo response.
  • Individuals with the Met/Met polymorphism are not as good at breaking down dopamine, and thus have the high levels of dopamine, and in general have a greater placebo response.
  • Individual with the Val/Met heterozygotes polymorphism have an intermediate placebo response.^[3]
• Interestingly, COMT has also been found to be linked to schizophrenia as well.

• The nocebo effect is the opposite of the placebo effect, where patient is experiences with harmful side effects or worsening of symptoms due to negative psychological expectations of a treatment. The amygdala is thought to mediate the nocebo effect.

• The placebo effect in healthcare is pervasive, and occur in all aspects of medicine. For example, placebo effects can be clinically meaningful and can rival the effects of active medication in patients with asthma.^[4]

• Clinicians that exhibit more empathy, as perceived by patients with the common cold, have significantly shorter duration and severity of illness, and have marked immune system changes.^[5]. The effects of a practitioner on a patient's response can have dramatic impacts.^[6]

• Psychiatrists in particular are aware of the placebo effect, and may prescribe sub-therapeutic doses of medications.^[7]

• Weimer, K., Gulewitsch, M. D., Schlarb, A. A., Schwille-Kiuntke, J., Klosterhalfen, S., & Enck, P. (2013). Placebo effects in children: a review. Pediatric research, 74(1), 96-102.

• Sinyor, M., Cheung, C. P., Abraha, H. Y., Lanctôt, K. L., Saleem, M., Liu, C. S., ... & Schaffer, A. (2020). Antidepressant-placebo differences for specific adverse events in major depressive disorder: A systematic review. Journal of Affective Disorders, 267, 185-190.

• The Number Needed to Treat (NNT) can be a misleading figure when one factors in the placebo response. The NNT can be very misleading in a randomized placebo-controlled trial, because the placebo response also contributes to the NNT in the active medication arm, and not just the placebo arm!^[8][9]

• When wines are marketed as more “expensive,” individuals are inclined to report increased pleasantness as well.^[10]