Major depression is another useful model to examine neurobiological mechanisms of the placebo effect, because placebo responses are common in antidepressant trials of many interventions, including medication, psychotherapy, and somatic treatments (DeRubeis et al., 1999
, 2005; Kirsch and Sapirstein, 1998; Enserink, 1999; Khan et al., 2000; Quitkin and Klein, 2000; Quitkin et al., 2000; Walsh et al., 2002; Koerselman et al., 2004). As in clinical trials for other medical conditions, the effectiveness of a new antidepressant is determined by comparing an active treatment with a controlled comparison condition. Because there are a number of proven treatments for major depression, it has been suggested that placebo-controlled studies are no longer appropriate for testing potential new treatments. However, evidence of significant and increasing rates of placebo response in published antidepressant trials has justified their continued use (Khan et al., 2000; Andrews, 2001; Walsh et al., 2002). Complicating the picture of determining the efficacy of a new treatment in light of significant placebo effects is the additional confound of improvement in depressive symptoms attributable to the natural history of the disorder. Together, these synergistic effects have been interpreted by some as evidence that the active intervention actually contributes a relatively small percentage to the observed efficacy rates of published antidepressant drug trials (Kirsch and Sapirstein, 1998). Such observations of significant short-term placebo response rates are in contrast to continuation studies that demonstrate a significant advantage of maintenance medication over continued placebo treatment in preventing relapse and recurrence (Frank et al., 1990; Montgomery, 1996; Stewart et al., 1998, McGrath et al., 2000). These findings lay critical foundation for the design of experiments targeting placebo effect mechanisms, because the clinical data suggest that such effects are not sustained long term.
As outlined previously, the study of the placebo effect is the study of the psychosocial context specific to a particular trial situation that includes the expectation of clinical improvement and conditioning (Colloca and Benedetti, 2005; Finniss and Benedetti, 2005). Clinical practice works to maximize and reinforce the effects of expectation and conditioning but in the setting of a known effective treatment. Research trials, conversely, are focused on detecting significant clinical effects that can be unambiguously attributed to the active treatment under investigation and therefore work to reduce these phenomena. Thus, a standard 6-8 week double-blind, placebo-controlled clinical study would appear to provide a unique opportunity to examine synergistic mechanisms mediating depression remission, including those specific to the active treatment as well as those involved in expectation and conditioning, i.e., placebo effects. From this perspective, one might presume that the identification of pure placebo-mediated response changes would reveal a "final common pathway" for depression remission because the placebo group would be unaffected by nonspecific drug, cognitive, or lesion effects evoked by the medication, psychotherapy, or surgical procedure under investigation. As will be illustrated below, this presumption is likely incorrect, because mechanisms mediating different antidepressant treatments are themselves diverse. Instead, placebo effects seen with different treatments are more likely to track closely with the active treatment to which they are experimentally paired. To test such a hypothesis, studies of well-validated, efficacious treatments are needed to define these purported intervention-specific and response-specific effects.
Before examining neurobiological changes associated with placebo effects using either established or novel treatments, it is also important to consider the unavoidable confounds inherent in clinical studies of depressed patients. Given the current availability of a number of approved, effective treatments for depression, new trials of novel interventions rarely recruit treatmentnaive or first-episode patients and, as such, are potentially influenced by the knowledge (expectation) of the anticipated clinical endpoint (i.e., recovery or remission) as well as past conditioning and learning as to the usual time course of change in symptoms with similar treatments (i.e., other medications). Studies of first-episode, never-before-treated patients provides the most theoretically ideal design to study these conditioning and expectation effects because these patients have no experience with either clinical recovery or the trajectory of symptom improvement. Unlike single-dose trials of an intervention such as the intravenous analgesia or intraoperative DBS studies described previously, it is generally considered unethical to include a negative expectation control condition during a multi-week depression trial. Furthermore, antidepressants do not work acutely, requiring on average a minimum of 3 weeks to see clinical effects. The mandates of informed consent actually require disclosure of the possible time course of likely change in target symptoms as well as the nature and scope of all potential side effects (Barsky et al., 2002), further prohibiting such a control group. The role of personality and dispositional factors such as optimism (or the antithesis) are now also being reconsidered as important contributors (Geers et al., 2005). Taking these various factors into account, repeated poor response to previous treatments might actually be predicted to result in lower placebo response to a novel intervention because of negative expectation and conditioning (Gunstad and Suhr, 2001). This hypothesis, however, would appear to be contradicted by findings of consistently low placebo rates with somatic treatments such as electroconconvulsive therapy (ECT), although the typical patient has generally already failed multiple previous interventions (Pagnin et al., 2004). Such observations, nonetheless, suggest a more complex interaction between mechanisms mediating expectation and conditioning effects for a given antidepressant treatment and the heterogeneity of the depressed patient population under study. These factors necessitate caution in both the design and interpretation of studies examining explicit placebo effects in what is often a heterogeneous group of depressed subjects.
With these variables in mind, PET measures of regional glucose metabolism [using the fluorodeoxyglucose (FDG) method] and regional CBF have proven to be sensitive indices of brain function in both the untreated depressed state and after various treatments. Changes in cortical (prefrontal and parietal), limbic-paralimbic (cingulate, amygdala, and insula), and subcortical (caudate/pallidum, thalamus, and brainstem) regions have been described after such diverse treatments as medication, psychotherapy, sleep deprivation, ECT, repetitive transcranial magnetic stimulation ablative surgery, and DBS (for review, see Mayberg, 2003). Although normalization of frontal abnormalities is the best-replicated finding, other regional effects are commonly reported with variable patterns with different treatments. These modality-specific effects are consistent with the hypothesis that different interventions modulate specific regional targets, resulting in a variety of complementary, adaptive chemical and molecular changes sufficient to reestablish a euthymic, remitted state (Hyman and Nestler, 1996; Vaidya and Duman, 2001). The functional neural architecture of these observed change patterns provides a foundation to examine putative brain mechanisms mediating placebo effects under comparable treatment conditions. If expectation and conditioning are the principle mediators of such effects (Colloca and Benedetti, 2005; Finniss and Benedetti, 2005), one would predict comparable patterns between active and sham-treated responders in a given experiment, if pathways mediating expectation and conditioned learning are not otherwise impaired (for review, see Schultz, 2002).
To first test this hypothesis, cerebral glucose metabolism was measured using FDG PET in a group of depressed men participating in an inpatient, randomized, placebo-controlled study of the approved antidepressant fluoxetine (Mayberg et al., 2000, 2002). Scans were acquired at three time points: before treatment (baseline) and again after 1 and 6 weeks of treatment. Brain changes associated with clinical response (6 weeks of treatment relative to baseline) were first assessed separately for the active drug and placebo groups; change patterns were then compared. Anatomically concordant metabolic changes were seen with both active fluoxetine and placebo response: increases in prefrontal (at BA 9/46), parietal (BA 40), and posterior cingulate (BA31), and decreases in subgenual cingulate (BA 25) (Fig. 6, rows 1, 2). The magnitude of regional fluoxetine changes was generally greater than placebo. Unique to fluoxetine were additional increases in pons and decreases in caudate, insula, and hippocampus, regions with known efferent connections to both subgenual cingulate and prefrontal cortex, in which changes were seen in both groups. There were no regional changes unique to placebo at 6 weeks. Unfortunately, there were inadequate numbers of placebo nonresponders completing the 6 week trial to evaluate placebo nonresponse patterns.
Although not tested by an extended continuation study, it was speculated from these findings that the hippocampal, brainstem, striatal, and insula changes seen uniquely in drug-treated responders might be important to clinical response long term. In support of this argument, failed response to active fluoxetine was associated with persistent hippocampal increases and posterior cingulate decreases, the pattern seen in all active drug-treated subjects after 1 week of treatment, regardless of eventual outcome (Mayberg et al., 2000). The reversal of the week 1 pattern at 6 weeks in responders suggested a process of neural adaptation in specific brain regions over time with chronic treatment. The presence of an inverse pattern in responders and nonresponders further suggests that failure to induce these adaptive changes may underlie treatment nonresponse. These responder-nonresponder differences are also consistent with the time course and location of changes identified in animal studies of selective serotonin reuptake inhibitors antidepressants that emphasize early brainstem and hippocampal changes and late cortical effects (Duman et al., 1999; Freo et al., 2000; Blier, 2001; Vaidya and Duman, 2001).
Without a comparable study contrasting sham treatment to a different active treatment modality such as cognitive or psychotherapy, one could easily conclude from this study that the subgenual cingulate and prefrontal changes shared by both active and sham medication reflect a final common pathway for depression remission. At the time these data were first analyzed, there were not yet published studies demonstrating consistent psychotherapy-specific or cognitive therapy-specific patterns (with or without a sham condition) to negate such a conclusion. Another problem was that the 6 week scan findings provided no real clues as to which regions were most likely linked to either expectation or conditioning, the putative mechanisms of placebo effects. Two subsequent studies addressed these open issues.
First, the issue of nonspecific but known therapeutic effects of the inpatient environment were considered. If the common subgenual and prefrontal changes seen in the fluoxetine-placebo study were in fact attributable to nonspecific psychological effects, one would expect similar and likely more robust changes with a more formal course of a specific psychological intervention. Contrary to this hypothesis, recent studies of clinical response to either cognitive behavioral therapy (CBT) (Goldapple et al., 2004) or interpersonal psychotherapy (IPT) (Brody et al., 2001; Martin et al., 2001) demonstrate very different regional brain change patterns from those seen with placebo (Mayberg et al., 2002). Both CBT and IPT are associated with prominent prefrontal decreases with other regional effects specific to each psychotherapy strategy. With clinical response to cognitive behavioral therapy, additional changes were seen in regions not targeted by medication, including the orbital frontal and medial frontal cortex and dorsal anterior cingulate (Fig. 6, bottom).
The change patterns seen with these specific psychotherapies provide preliminary evidence refuting the hypothesis that placebo response is mediated by changes in a common antidepressant response pathway. These findings additionally suggest that placebo response is also not the result of uncontrolled, nonspecific psychological treatment effects. Brain changes with placebo response, in fact, most closely match the active drug-response pattern to which it was experimentally yoked (conditioned), similar to that seen in acute placebo-controlled experiments discussed elsewhere in this review (i.e., striatal dopamine changes with both dopamine agonist and sham medication for Parkinson's disease; cingulate and brainstem blood flow changes with acute opiate and placebo opiate analgesia) (de la Fuente-Fernandez et al., 2001; Petrovic et al., 2002). Obviously, a placebo-controlled CBT trial will be necessary to fully definitely test the hypothesis that placebo-response changes mirror the specific intervention to which they are paired, meaning that placebo-CBT would be anticipated to overlap true CBT changes, not those seen with placebo medication. A wait-list control group will also be needed to address effects potentially attributable to spontaneous remission with either treatment.
Last, and not yet addressed by the previous analyses, is the specific contribution of expectation. Although the 6 week placebo-controlled fluoxetine study was not designed to examine such effects explicitly, the availability of a scan early in the course of treatment before clinical response combined with the known and expected delay in clinical symptom changes with this class of medication has allowed for some exploratory analyses. Pertinent to interpreting the results is converging evidence from animal models and human imaging studies implicating the ventral striatum and orbital frontal cortex in the expectation and delivery of reward during various conditioned learning paradigms (Ikemoto and Panksepp, 1999; Schultz et al., 2000; Schultz, 2002; Knutson and Cooper, 2005, among many). Although beyond the scope of this symposium, studies further demonstrate that dopamine-mediated striatal activity, when paired with specific sensory stimuli, can enhance corticocortical connections and facilitate neural plasticity, in keeping with the behavioral salience of the stimuli (Bao et al., 2001).
Extrapolating liberally from these many preclinical experiments, metabolic changes occurring at 1 week of fluoxetine (or sham) treatment relative to baseline were assessed as a function of eventual 6 week response outcome, during what one might consider a period of ongoing expectation for clinical benefit (i.e., delivery of reward). Because none of the patients showed any signs of clinical improvement at this 1 week time point, differences between eventual drug responders, placebo responders, and drug nonresponders were interpreted as an index of the expectation component of the later antidepressant response. It was postulated that such reward expectation effects would be most robust in those patients who went on to do well compared with those patients that failed to improve (i.e., successful conditioned expectation). It was further speculated that this "expectation" pattern would involve different regions than those defining the time course of active medication effects (hippocampal and brainstem increases, posterior cingulate decreases). As illustrated in Figure 7, there were in fact unique ventral striatal and orbital frontal changes in both placebo and drug responders at 1 week of treatment. Such changes were not seen in the eventual drug nonresponders. Furthermore, this change pattern was not seen at 6 weeks when the antidepressant response was well established, consistent with differential patterns of activity with expectation and delivery of reward in animal models (Schultz et al., 2000; Knutson and Cooper, 2005). Additional multivariate analyses, examining the interaction of these ventral striatal changes with the rest of the brain over time, further identified an ongoing correlation between ventral striatal activity and lateral prefrontal and subgenual cingulate changes at both the early and late time points, which was predictive of clinical outcome with both active drug and placebo (data not shown). Such functional connectivity analyses are consistent with preclinical models of striatal-mediated cortical plasticity, although the role of dopamine in the depression study is unknown (Bao et al., 2001). Although future studies will require more explicit evaluations of patients' expectations during a specific clinical trial, these retrospective analyses demonstrate proof-of-principle that such studies can provide important clues as to the mechanisms mediating placebo effects in trials of diverse antidepressant treatments.
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