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Placebo Effects on Pharmacotherapy Outcomes in Major Depression

Placebo Effects on Pharmacotherapy Outcomes in Major Depression

If clinical trials data are any indication, the potential impact of placebo treatment on depression outcomes may be potent. Placebo response rates in clinical trials for depression average approximately 30%, with a top range beyond 50%—and the trend is upward.1 Granted, estimates of the magnitude of the placebo response are open to debate2,3 because placebo response rates do not account for statistical regression to the mean or spontaneous remission (an important consideration given the natural waxing and waning of symptoms in depression). In fact, there are no data to support the conclusion that the placebo response is not spontaneous remission. However, converging evidence suggests that placebo effects can exert a significant impact on both clinical symptoms and functional brain changes in depressive illness.


The placebo response or placebo effect is increasingly being conceptualized as the effect of the environmental and psychosocial context surrounding treatment.4,5 Focus has shifted from physical features of the placebo (eg, the dummy sugar pill or sham treatment) toward the larger therapeutic setting,6 including the "meaning" that this setting holds for the individual.7 The beliefs and expectations of the patient and physician/clinician, as well as the nature of the patient-physician relationship, are of primary importance in the treatment context.

If one considers the placebo response to include classic conditioning effects that can occur in pharmacotherapy,8 then the patient's previous exposure to pharmacological agents also becomes an important factor. Following exposure to an active agent, the cues associated with drug administration (eg, a look-alike placebo pill or saline placebo injection) can come to elicit physiological responses.

Placebo research uses pill placebos or other sham interventions that do not have specific efficacy for the condition being treated, with the understanding that placebo administration serves as a proxy for the effects of the treatment setting. That is, a subject showing a response to placebo is thought to be responding to all the trappings of treatment and the meaning that it holds for him or her.

Studies designed to examine the so-called placebo response in pain conditions often do not use placebo at all. The open-hidden paradigm9 has offered a particularly productive approach to examining the effects of the treatment context. Numerous reports of clinical and experimental pain studies have demonstrated the greater efficacy of analgesics during open administration (in full view and with full knowledge of the patient or subject) compared with hidden administration, ie, usually delivered via a computer-driven infusion pump without the patient's awareness and without a physician present.

The difference in effectiveness between open and hidden administration of active drug is attributed to placebo mechanisms. The presence of a physician, and the patient's expectations of relief achieved with open administration, provide a context that enhances or augments the effect of medication. Although the open-hidden paradigm is relevant to acute pain conditions, this type of within-subjects approach is not applicable to placebo research in depression because treatments for depression require ongoing administration to achieve clinical results.

Placebo research in depression typically is conducted in conjunction with clinical efficacy studies that include a placebo control. Thus the primary study is usually designed to address the efficacy of one or more medications/ interventions, rather than to target placebo effects. Because of ethical concerns, studies in depression do not typically use a "no treatment" or "no treatment context" condition against which to compare the effects of placebo. Nonetheless, substantial placebo response rates in antidepressant trials of medication, psychotherapy, and somatic interventions for depression suggest that the treatment context itself does indeed influence the expression of depressive symptoms.1,10,11

One NIH-funded study currently in progress (A. F. Leuchter, personal communication, July 2007) is specifically designed to assess contributions of various aspects of the treatment setting to the placebo response in depression. This study assigns patients to 1 of 3 treatment conditions: interpersonal clinical interaction, in which patients interact with clinical research personnel on a fixed schedule; placebo treatment, in which patients have the same clinical interaction and placebo pills are added; and medication treatment, in which patients have the same clinical interaction and medication is added instead of placebo. By varying aspects of the treatment context, this study will provide information regarding the relative contributions of interpersonal interactions, expectations associated with taking a placebo pill, and medication effects, to the clinical outcomes in depression.


Neuroimaging studies provide evidence that the placebo effect in depression has demonstrable physiological underpinnings. Depressed individuals who respond during placebo treatment show brain functional changes that are not observed in nonresponders. Several reports have examined brain functional changes during placebo administration in double-blind trials of antidepressant medication. In a study of depressed males, fluorodeoxyglucose positron emission tomography (FDG-PET) scans were obtained at pretreatment baseline, and again after 1 and 6 weeks of treatment with fluoxetine or placebo.12 Both medication- and placebo-responders showed metabolic changes at week 6 (end of trial), including increases in activity in the prefrontal, parietal, and posterior cingulate regions, and decreases in the subgenual cingulate cortex. Additional changes were seen in the fluoxetine group in the subcortical and limbic regions, including increases in the pons and decreases in the striatum, hippocampus, and anterior insula.

Another functional imaging study used quantitative electroencephalography cordance to assess serial brain functional changes in patients with depression who were randomized to 8 weeks of treatment with antidepressant medication (fluoxetine or venlafaxine) or placebo.13 Electroencephalographic recordings were obtained at baseline, 48 hours after start of treatment, and at weekly intervals throughout randomized treatment. Analysis of predefined scalp regions revealed significant and unique baseline to end-of-trial increases in prefrontal cordance in placebo responders. In contrast, medication group responders showed early (week 2) decreases in prefrontal cordance, whereas nonresponder groups did not show significant changes from baseline prefrontal cordance at any point in the trial.

Although differences in imaging techniques and study designs do not allow for direct comparisons across these studies, both reports found significant frontal brain changes that distinguished between placebo responders and nonresponders. At minimum, this indicates that the placebo response in depression does not merely reflect a response bias wherein placebo responders simply report symptoms differently; placebo responders do in fact show underlying physiological changes that are not observed in nonresponders.

It appears that "pill placebo response" in depression has both shared and distinct neurophysiological features compared with medication response. However, as with all imaging studies in depression, it is difficult to isolate which functional brain changes reflect improvement in symptoms and which are related to treatment mechanisms. There is marked heterogeneity in findings regarding functional brain changes associated with remission of symptoms of depression even without considering placebo treatment conditions.

One framework that finds traction in the literature is the notion of "bottom-up" versus "top-down" neurophysiological effects of different treatment modalities. Pharmacotherapy interventions generally initiate a bottom-up cascade primarily targeting the brain stem, limbic, and subcortical regions with longer-term effects occurring in cortical areas. Conversely, psychotherapeutic interventions that directly address maladaptive cognitions and emotions are thought to work "top-down," first affecting changes in frontal cortical mechanisms.

FDG-PET imaging studies of cognitive-behavioral therapy14 or interpersonal psychotherapy15 provide an interesting basis of comparison with the pill placebo study findings. Results of cognitive-behavioral therapy and interpersonal psychotherapy studies show clinical response associated with substantive bilateral prefrontal decreases in metabolism.14,15 This is in contrast to the FDG-PET imaging of the placebo response in a placebo-controlled trial of fluoxetine that found prefrontal increases in both medication and placebo responders.12

With respect to FDG-PET studies to date, the functional neurophysiology of the pill placebo response appears to more closely resemble medication response than psychotherapy response. Further research is needed to delineate the neurophysiology of placebo mechanisms from those of specific interventions for major depressive disorder (MDD).


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