Placebo Effects in the Treatment of Depression: Cognitive and Neural Mechanisms

Studies of the neural mechanisms underlying placebo effects in antidepressant clinical trials largely have been limited to demonstrating objective differences in brain activity between responders and non-responders to placebo. This 8 week Placebo-controlled and Open groups study employs a novel antidepressant trial design with integrated functional magnetic resonance imaging (fMRI) to manipulate patient expectancy and examine its neural mediators.

The placebo effect represents a potent treatment for Major Depressive Disorder (MDD)-placebo response in acute randomized controlled trials (RCTs) of antidepressant medications averages 30%, and meta-analyses have estimated the proportion of medication response attributable to placebo to be 50-75%. Patient expectancy is the mechanism of placebo effects in antidepressant RCTs and has been positively associated with medication response. Determining how expectancy alters the course of MDD could lead to methods of optimizing placebo effects and improving the treatment of MDD. In addition, investigating the neurobiology of placebo effects has the potential to elucidate the pathophysiology of MDD and the mechanisms of action of antidepressant treatments. Brain regions implicated in expectancy and placebo effects comprise prefrontal cortical (PFC) areas, amygdala, insular cortex, rostral anterior cingulate cortex (rACC), and dopaminergic reward pathways in the striatum. Pathological decreases in PFC and striatal function, increases in limbic activity, and disordered connectivity between these regions have all been observed in MDD, and the rostral and dorsal ACC have been repeatedly linked to antidepressant treatment response. Therefore, studying placebo effects offers a window into the functioning of the neural circuits that are disturbed in MDD and improve with effective treatment. The goals of this study are to determine whether expectancy affects the outcome of antidepressant pharmacotherapy and to investigate the neural mechanisms of expectancy effects. These will be accomplished by conducting a clinical trial randomizing adult outpatients with MDD to 8 weeks of treatment in high vs. low expectancy conditions. The high expectancy condition will be open administration of citalopram, while the low expectancy condition will be placebo-controlled administration of citalopram. The neural mechanisms of expectancy will be determined using functional Magnetic Resonance Imaging (fMRI) paradigms to investigate treatment activation differences in brain regions associated with placebo effects and MDD.

Blinded treatment with either citalopram 20mg or placebo, increased to citalopram 40mg or placebo at week 4 if depression has not remitted.

The patient is rated by a clinician among 24 dimensions with a score on a 3 or 5 point scale. A score of 0-9 is considered to be normal. Score between 10-18 is considered as mild depression, Scores between 19-26 indicate moderate, scores between 27-34 indicate severe, and score between 35-75 indicate very severe depression.

Inclusion Criteria: Men and women aged 24-75 years Diagnosed with Diagnostic and Statistical Manual of Mental Disorders (DSM) IV Major Depressive Disorder, nonpsychotic 24-item Hamilton Rating Scale for Depression (HRSD) score ≥ 16 Willing to and capable of providing informed consent and complying with study procedures Subjects are right-handed Using appropriate contraceptive method if woman of child-bearing age Exclusion Criteria: Current comorbid Axis I DSM IV disorder other than Nicotine Dependence, Adjustment Disorder, Panic Disorder, Generalized Anxiety Disorder, or Social Phobia Diagnosis of substance abuse or dependence (excluding Nicotine Dependence) within the past 12 months History of psychosis or psychotic disorder, mania or bipolar disorder Subject is considered to be at significant risk of suicide based on current mental status and recent history History of allergic or adverse reaction to citalopram, or nonresponse to adequate trial of citalopram (at least 4 weeks at dose of 40mg) or escitalopram (at least 4 weeks at dose of 20mg) Subject is considered based on history to be unlikely to respond to the single agent citalopram (i.e., subjects with treatment resistant depression) Current treatment with psychotherapy Clinical Global Impression (CGI)-Severity score of 7 at baseline Clinical Interview Current or recent (within the past 4 weeks) treatment with any of the following: antidepressants, antipsychotics, mood stabilizers, isoniazid, glucocorticoids, opiates, centrally active antihypertensive drugs (e.g. clonidine, reserpine) Subject has metal in body or prior history working with metal fragments (e.g., as a machinist), tattoos, or unable to tolerate the scanning procedures (i.e., severe obesity, claustrophobia) Acute, severe, or unstable medical illness

Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013 Jul;170(7):723-33. doi: 10.1176/appi.ajp.2012.12040474.

Zilcha-Mano S, Wang Z, Peterson BS, Wall MM, Chen Y, Wager TD, Brown PJ, Roose SP, Rutherford BR. Neural mechanisms of expectancy-based placebo effects in antidepressant clinical trials. J Psychiatr Res. 2019 Sep;116:19-25. doi: 10.1016/j.jpsychires.2019.05.023. Epub 2019 May 26.