Placebo Effect a Major Factor in Antidepressant Response
Activation of the mu-opioid receptor (MOR) system by placebo contributes to the formation of placebo responses in the setting of major depressive disorder and is behind much of a patient's response to drug treatment, new research indicates.

"Placebo response rates in depression are as high as 50%, which is pretty close to the response rates we see with antidepressant therapy, so it's important to understand placebo responses because they account for an important proportion of the actual response to antidepressant treatment," Marta Peciña, MD, PhD, University of Michigan, in Ann Arbor, told Medscape Medical News.

"Basically, we've shown that the mu-opioid system — our own endogenous opioids — are associated with the formation of the placebo response [in depression] and that this occurs in regions of the brain that are involved in emotional regulation and the biology of depression."

The study was published online September 30 in JAMA Psychiatry.

Symptom Reduction

The study included 35 patients who had been diagosed as having major depressive disorder and who were not receiving antidepressant therapy at the time of study enrollment.

Patients were assigned to a 2-week, single-blind, randomized controlled trial in which they received placebo. This was followed by a 10-week, open-label, active-treatment phase.

During the first phase of the trial, patients were randomly assigned to receive for 1 week either "active" oral placebo treatment (but were told the placebo was a fast-acting antidepressant drug) or "real" placebo (in which patients were told the pill they were taking was an inactive control).

After each week during this placebo phase, patients underwent a positron emission tomographic (PET) scan.

To induce activation of the endogenous opioid system and determine acute placebo effects, the PET session following the first week of "active" oral placebo included IV administration of active placebo.

The IV placebo treatment was only given during the scanning session that followed "active" placebo.

Patients' impression of severity (PIDS) ratings were acquired every 4 minutes during the two PET scans in the presence and absence of IV placebo.

Depression was assessed using the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) at baseline and after each placebo treatment.

Following the crossover placebo phases of the trial, patients were invited to participate in a 10-week, open-label treatment trial, which in most cases involved receiving citalopram (multiple brands) at a starting dose of 20 mg a day, which was increased to 40 mg a day in most patients.

Oral placebo-induced improvement in depression, as reflected by changes in QIDS-SR16 score, significantly correlated with changes in PIDS scores after IV placebo administration (P = .04).

Conversely, placebo-induced changes in QIDS-SR16 and PIDS scores did not correlate with QIDS-SR16 scores at either baseline or with initial expectations of recovery rated prior to the placebo treatment (P > .05).

Women showed greater reductions in depressive symptoms after receiving oral placebo compared with men (P = .02) but not after receiving IV placebo.

Patients who received the active oral placebo first reported significantly greater oral placebo–induced reductions in depressive symptoms than those who received the active oral placebo second (P = .04).

First Objective Evidence

Investigators also found that improvement in the QIDS-SR16 score after administration of the "active" oral placebo was positively associated with placebo-induced opioid release in multiple areas of the brain involved in the biology of depression in comparison with effects after the inactive placebo was given.

Reductions in the PIDS score during PET scanning after IV administration of placebo were associated with greater placebo MOR-system activation in several key areas of the brain as well.

The investigators also examined the relationship between IV placebo activation of endogenous opioid neurotransmission and improvement in depression after 10 weeks of active antidepressant treatment.

Here too the authors observed that reductions in the QIDS-SR16 score after the 10-week open-label treatment trial were significantly associated with placebo-induced MOR-system activation in the same regions of the brain associated with placebo antidepressant effects.

Objectively measured, placebo-induced opioid release in several key areas of the brain accounted for 43% of the variance in response to open-label treatment with an antidepressant.

"This means that 43% of the overall response that we observed at the end of active antidepressant treatment was explained by opioid-releasing placebo administration," said Dr Peciña.

"This is the first objective evidence we have that the brain's own opioid system is involved in response to both antidepressants and placebo and that variation in this response is associated with variation in symptom relief," she said in a statement.

"And we can envision that by enhancing placebo effects, we might be able to develop faster-acting or better antidepressants."

Commenting on the study in a statement, senior researcher Jon-Kar Zubieta, MD, PhD, now chair, Department of Psychiatry, University of Utah, in Salt Lake City, noted that the placebo effect in this study came from participants not only believing that they were receiving a "real" drug but also from simply being in a treatment environment.

"These results suggest that some people are more responsive to the intention to treat their depression and that they may do better if psychotherapies or cognitive therapies that enhance the clinician-patient relationship are incorporated into their care as well as antidepressant medications," he said.

Brain Changes

In an accompanying editorial, Maurizio Fava, MD, Massachusetts General Hospital, Boston, noted that the identification of a biological response to placebo exposure in patients with major depressive disorder is consistent with the view that placebo treatment can induce robust neurobiological changes in the brain.

In one of his own studies (Transl Psychiatry. 2013;e282. Doi:10.1038/tp.2013.43), Dr Fava and colleagues found that they could classify treated patients in a clinical trial of depression on the basis of each patient's propensity to respond to a given type of treatment.

The so-called D (drug)–negative, P (placebo)–negative population consists of patients who are not responsive to either active treatment or placebo, Dr Fava noted.

"In depression trials in nonresistant populations, the D-negative, P-negative group typically represents 50% of the population, based on nonresponse rates frequently observed with active treatments," he writes.

A meta-analysis of 182 antidepressant trials (Eur Neuropsychopharmacol. 2009;19:34-40) showed that the average placebo response rate with two active treatments and placebo was about 40%.

"When the placebo response rate (and therefore the D-positive, P-positive group) is 40% in a given population and the D-negative, P-negative group is 50%, this means that only 10% of patients belong to the D-positive, P-negative group, which comprises patients who respond to active treatment but not to placebo," Dr Fava observed.

"Therefore, it is quite possible that most of the patients who responded to open-label antidepressant therapy in the Peciña et al study actually belonged to the D-positive, P-positive group," he added.

"In such case, the fact that placebo-induced endogenous opioid release...was associated with a better open-label antidepressant treatment response may be simply accounted for by the fact that the placebo response in the lead-in phase was the same type of response observed following open-label antidepressant therapy."

Dr Peciña reports no relevant financial relatinships. Dr Fava has relevant financial relationships with a wide range of pharmaceutical companies, all which have been disclosed in a conflict of interest statement published with his editorial.

JAMA Psychiatry. Published online September 30, 2015. Abstract, Editorial