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

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.

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