Most theoretical accounts of the placebo response (pure classic conditioning accounts notwithstanding) rely on the concept of patient expectations. The patient must have some expectation of getting better, or of experiencing relief of symptoms, in order to recruit the placebo response. This poses an interesting paradox or circularity for depression because one of the hallmark symptoms of depressive illness is a sense of hopelessness. To the extent that the treatment environment can help elicit positive expectations and a sense of hope, this in itself may make inroads in altering the course of depression, at least briefly.
Numerous studies have documented the importance of expectation-related factors for treatment outcomes in MDD. Negative expectations have been found to portend poorer outcomes. For example, higher "dysfunctional attitudes" before treatment were negatively associated with response to tricyclic antidepressants, fluoxetine(Drug information on fluoxetine), or placebo in patients with mixed depression.16,17 In a more recent study, baseline hopelessness (Beck Hopelessness Scale) was demonstrated to predict poorer response to fluoxetine in a clinical trial sample of 312 patients.18
The converse has been demonstrated for positive expectations. A study of 63 depressed inpatients receiving naturalistic treatment for depressive illness revealed that both the psychiatrist's optimism regarding the patient's treatment regimen and the degree to which patients believed that their treatment was right for them predicted severity of symptoms at discharge.19
In a study of reboxetine(Drug information on reboxetine), higher baseline expectations of treatment outcomes were associated with better 8-week outcomes.20 As part of the NIMH Treatment of Depression Collaborative Research Program, a study of 162 patients with MDD revealed that pretreatment expectations of improvement were a significant predictor of patient response to pharmacotherapy.21Imaging "expectations" in depression treatment
Is there a neurobiology of hopefulness or patient expectations in depression? It is interesting to consider that some brain functional changes that occur early in the course of treatment might reflect expectation-related processes that are associated with later clinical response. Because symptoms do not typically resolve in the first week of treatment, brain changes observed within this timeframe are less likely to be influenced by clinical improvement.
In an intriguing post hoc analysis of the FDG-PET study of pill placebo response in depression,4,12 investigators examined metabolic changes occurring in the first week of treatment for those patients who later were classified as medication or placebo responders or nonresponders. Both responder groups (but not nonresponders) were found to have metabolic increases in the ventral striatal and orbital frontal regions at week 1; moreover, this change pattern dissipated by week 6 when clinical response was established. Because of the brain regions involved and time course of this change pattern, the investigators speculated that such early metabolic changes might have reflected subject expectations of clinical benefit before the actualization of clinical response.4
Other studies using quantitative electroencephalography cordance have examined brain functional changes during an initial week of placebo treatment (a placebo lead-in phase) before randomized treatment with antidepressant medication or placebo, and similarly, researchers have speculated that these brain changes were related to patient expectations. Of importance, the placebo lead-in phase of the trial included all of the same contextual features as the medication treatment phase (eg, relationships with physicians and other health care staff, clinical assessments and monitoring, pill taking)—except for the active drug. Neurophysiological changes at this point could not have been influenced by medication and were not likely to be influenced by change in clinical status, because most patients did not show significant improvement during a 1-week placebo lead-in; those who did were discontinued from the study.
In a report of depressed patients randomized to 8 weeks of treatment with medication (fluoxetine or venlafaxine) or placebo, bilateral decreases in prefrontal cordance during placebo lead-in predicted 19% of the final clinical outcome in the medication-treated group.22 The authors suggested that the initial neurophysiological response to the treatment setting might have captured patient expectations that had a subsequent impact on medication outcome.
Another study examined brain functional changes during placebo lead-in in healthy never-depressed persons randomly assigned to 4 weeks of treatment with venlafaxine or placebo.23 Although clinical benefits were not expected in nondepressed persons, medication adverse effects were anticipated. In that study, decreases in left prefrontal cordance during placebo lead-in were associated with later adverse-effect burden in the medication group, suggesting that expectations during initial placebo treatment might have influenced the experience of medication adverse effects.
The preponderance of data suggests that expectations and subsequent outcomes can be predicted by the initial changes in brain physiology early in treatment. Further research is required to directly assess whether early brain functional changes reflect differences in patient expectationsSustaining positive expectations
It is worth noting that the role of expectation in MDD has by and large been examined in relation to acute treatment outcomes. The potential for longer-term placebo effects in depression is less clear. Although placebo response rates in clinical trials can be quite high, maintenance studies examining longer-term outcomes of placebo treatment have found placebo to be substantially less effective than active medication as a prophylactic against relapse.24-27 Some of the loss of placebo effects over time may be due to decreased expectations. Positive expectations may be difficult to sustain because of the nature of depression, an illness that is characterized by hopelessness as well as disruptions in cognitive processing and frontal function.
A recent study in patients with Alzheimer disease showed that reduced cognitive status and reduced prefrontal connectivity were associated with decrements in the placebo component of response to analgesic, indicating that the loss of expectation-related mechanisms can decrease the effectiveness of pharmacological treatment. From a different but consistent perspective, a study of baseline predictors of the placebo outcomes in depression identified a frontocentral electroencephalographic marker, as well as higher neurocognitive processing speed, as significant positive predictors of placebo response.28CONCLUSION
There is strong evidence that the treatment context, including patient and physician expectations, can have an important impact on clinical outcomes in depression, and that placebo effects in depression have demonstrable neurophysiological underpinnings. Placebo-related mechanisms may interact synergistically with specific interventions for MDD to achieve enhanced outcomes. Positive expectations and related placebo mechanisms are shown to enhance the effectiveness of medications and other specific interventions; symbiotically, medications and other specific interventions may support a neurophysiological substrate for fostering and maintaining positive expectations and related placebo mechanisms.