The present proposal is concerned with the prediction of individual placebo responses in clinical samples. Here we part from the usual view of placebos as inert control states. On the contrary, it is hypothesized that placebo administration triggers a cascade of events activating endogenous mechanisms that promote homeostasis. This leads to the proposal that a substantial proportion of the variance in placebo responding in CNS trials can be explained by the functional variation of specific neurobiological circuits and mechanisms. We focus on the prediction of placebo effects in patients diagnosed with Major Depressive Episode (MDE), unmedicated at the time of the study. This illness was selected because of its high frequency and chronicity in the general population, but also one that presents with high placebo responses in controlled trials. Half of the subjects will also present with a diagnosis of nicotine dependence, which is expected to reduce placebo responses rates, but also affect the underlying neurobiology, increasing the generalizability of the findings. Non-problem alcohol use will be permitted and entered as a covariate in the analyses. A 3-step process is proposed. Studies using positron emission tomograph will determine the placebo-induced activation of neurotransmitter systems through to be involved in both the pathophysiology of MDE and the effects of expectations. Functional magnetic resonance imaging will be employed to determine the proportion of the variance in placebo effects explained by the function of reward, decision-making and """"""""motivation"""""""" regions. Individual variations in neurotransmitter systems and circuits involved will then be modeled by a combination of neuropsychological tests and the presence of common genetic polymorphisms regulating those regional networks. This proposal therefore addresses the predictability of the placebo effect and its underlying neurobiology. The capacity to utilize internal resources to change clinical conditions (as opposed to traditional therapies that are given or applied to the patient with little individual control) represents both a shift in paradigm and a source of """"""""noise"""""""" in clinical trials. As such, the results of the studies proposed have the potential for lasting impact in the practice of medicine at large.

Public Health Relevance

Placebo effects are a common occurrence in clinical trials. Recent data has shown that those may be caused by the effect that expectations have on specific brain mechanisms. Those brain mechanisms may then change the clinical state of the patients. This proposal examines these mechanisms in Major Depression with and without substance use to determine their predictability and application in clinical trials.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1-ERB-L (05))
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Rumsey, Judith M
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Peciña, Marta; Sikora, Magdalena; Avery, Erich T et al. (2017) Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: Implications for anhedonia, anxiety and treatment response. Eur Neuropsychopharmacol 27:977-986
Jacobs, R H; Barba, A; Gowins, J R et al. (2016) Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder. Psychol Med 46:1055-67
Sikora, Magdalena; Heffernan, Joseph; Avery, Erich T et al. (2016) Salience Network Functional Connectivity Predicts Placebo Effects in Major Depression. Biol Psychiatry Cogn Neurosci Neuroimaging 1:68-76
Peciña, Marta; Bohnert, Amy S B; Sikora, Magdalena et al. (2015) Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression. JAMA Psychiatry 72:1087-94
Elman, Igor; Zubieta, Jon-Kar; Borsook, David (2011) The missing p in psychiatric training: why it is important to teach pain to psychiatrists. Arch Gen Psychiatry 68:12-20
Mickey, Brian J; Zhou, Zhifeng; Heitzeg, Mary M et al. (2011) Emotion processing, major depression, and functional genetic variation of neuropeptide Y. Arch Gen Psychiatry 68:158-66
Stohler, Christian S; Zubieta, Jon-Kar (2010) Pain imaging in the emerging era of molecular medicine. Methods Mol Biol 617:517-37
Love, Tiffany M; Stohler, Christian S; Zubieta, Jon-Kar (2009) Positron emission tomography measures of endogenous opioid neurotransmission and impulsiveness traits in humans. Arch Gen Psychiatry 66:1124-34