Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review

Abstract

Background The mechanisms underlying placebo effects of psychotropic drugs remain poorly understood. We carried out the first systematic review of functional neuroimaging correlates of placebo response in adults with anxiety/depressive disorders. Methods We systematically searched a large set of databases up to February 2021 based on a pre-registered protocol (PROSPERO CRD42019156911). We extracted neuroimaging data related to clinical improvement following placebo or related to placebo mechanisms. We did not perform a meta-analysis due to the small number of included studies and significant heterogeneity in study design and outcome measures. Results We found 12 relevant studies for depressive disorders and four for anxiety disorders. Activity in the ventral striatum, rostral anterior cingulate cortex and other default mode network regions, orbitofrontal cortex, and dorsolateral prefrontal cortex correlated with placebo antidepressant responses. Activity in regions of the default mode network, including posterior cingulate cortex, was associated with placebo anxiolysis. There was also evidence for possible involvement of the endogenous opioid, dopamine and serotonin systems in placebo antidepressant and anxiolytic effects. Conclusions Several brain regions and molecular systems may be involved in these placebo effects. Further adequately powered studies exploring causality and controlling for confounders are required.

Resting-state Electroencephalography Microstates Correlate with Pain Intensity in Patients with Complex Regional Pain Syndrome

“…34 In contrast, the DMN is deactivated by emotional factors (eg, depression and anxiety). 35 A previous study reported that the deactivation of the DMN is more profound when patients with chronic back pain or CRPS report higher pain intensity. 8,36 Interestingly, the microstate E was increased alongside pain alleviation following treatment in the present study.…”

Placebo stimulates neuroplasticity in depression: implications for clinical practice and research

“…There is therefore sufficient evidence from the EMBARC studies and the systematic review of Huneke et al ( 67 ) to conclude that placebo is a partially active treatment in depression through stimulation of neuroplasticity. This is the first article to suggest that neuroplasticity is generalizable to all placebo influence, not just depression, and to review evidence that placebo stimulates neuroplasticity.…”

“…The second striking finding of the EMBARC studies was that the group receiving placebo demonstrated cerebral perfusion and functional neuro-radiological change suggestive of neuroplasticity in fronto-limbic areas, albeit in slightly different brain regions to the group receiving sertraline. This unexpected finding prompted some of the EMBARC study group to conduct a systematic review ( 67 ) that sought functional neuroimaging correlates of placebo response in subjects with anxiety/depressive disorders. The 12 extracted studies for depression found that in patients where placebo induced antidepressant improvement occurred, this correlated broadly with abnormalities in the default mode network, known to mediate depression ( 36 ), with prominent additional activity in the ventral striatum, rostral anterior cingulate cortex, orbitofrontal cortex and particularly in the DLFPC.…”

Placebo effects in functional dyspepsia: Causes and implications for clinical trials

“…Specific brain regions have been associated with placebo effect in a number of psychological traits, particularly anxiety and depression. Huneke and colleagues identified responses in the dorsolateral prefrontal cortex and posterior insula, in addition to other regions 27 . This body of work suggests that there are measurable neurobiological responses to the administration of placebo therapy that operate according to plausible mechanisms, and therefore, at least in specific circumstances, the placebo effect is a real phenomenon.…”