Expectancy of Improvement Affects Efficacy of SSRIs for Anxiety in Patients With SAD

Escitalopram is an antidepressant medication used as a drug to help treat depression, obsessive-compulsive disorder, social anxiety disorder and other mental illnesses.
In this randomized clinical trial of participants with social anxiety disorder, investigators examined how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment.

Expectancy effects on dopamine signaling are largely responsible for anxiety reduction through selective serotonin reuptake inhibitors (SSRIs) in patients with social anxiety disorder (SAD), researchers found in a study published in Translational Psychiatry.

Researchers randomly assigned sex- and age-matched patients (17 men and 10 women aged 31.1±10.3 years) with SAD to either overt (n=14) or covert (n=13) treatment with escitalopram 20 mg daily for 9 weeks (following 1 week of 10 mg) after assessing them with positron emission tomography (PET). Patients who had recently ended or were undergoing psychiatric treatment were excluded from the study.

Patients received different descriptions of the efficacy of the drug. Researchers told the patients in the overt group that they would receive escitalopram, which was demonstrated to be effective for SAD. They told the individuals in the covert group that they would receive a non-effective neurokinin-1-receptor antagonist, an active placebo with side effects that mimicked those of escitalopram but without any expectation of improvement in symptoms.

They found that patients in the overt group experienced reduced availability of dopamine (DAT) nondisplaceable binding potentials (BPND) while the covert group experienced increases in BPND.

Serotonin (SERT) occupancy levels were inversely associated with DAT BPND in the overt group and increased DAT BPND in the group that received covert treatment.

Logistic regression analysis of transporter changes and group indicated that including SERTxDAT interaction to the models with main effects of SERT and DAT significantly raised R2 variance (interaction/main effects: putamen = 0.28/0.02; left pallidum = 0.19/0.03, right thalamus = 0.41/0.11), apart from in the right pallidum (0.27/0.27).

Clinical analysis after 9 weeks found that the overt group experienced more improvement (Mdiff ± SD = 47.07±19.23, Cohen’s d = 2.33) compared with the covert (Mdiff = 21.46±17.25, Cohen’s d = 0.93) group, as determined through self-report of symptoms on the Liebowitz Social Anxiety Scale (LSAS-SR). More individuals in the overt group (57%) than in the covert group (15%) responded to treatment (Fisher’s exact test: OR = 0.15, P =.046).

Limitations of the study included only 2 of the 4 arms in the balanced placebo design being used and no measurement of subjective expectancies during treatment.

“[T]he anti-anxiety properties of SSRIs appear to be largely dependent on expectancy effects on dopamine signaling while SERT blockade is not sufficient for symptom remission,” the investigators said. “This provides new insights on the key therapeutic mechanisms of SSRIs, incorporating psychological effects on dopamine neurotransmission.”


Hjorth OR, Frick A, Gingnell M, et al. Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial. Translational Psychiatry. Published online November 3, 2021. doi: 10.1038/s41398-021-01682-3