Irving Kirsch

Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Background Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials. Methods and Findings We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug–placebo difference scores. Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups. Conclusions Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome

Objective To investigate whether placebo effects can experimentally be separated into the response to three components—assessment and observation, a therapeutic ritual (placebo treatment), and a supportive patient-practitioner relationship—and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome. To assess the relative magnitude of these components. Design A six week single blind three arm randomised controlled trial. Setting Academic medical centre. Participants 262 adults (76% women), mean (SD) age 39 (14), diagnosed by Rome II criteria for and with a score of ≥150 on the symptom severity scale. Interventions For three weeks either waiting list (observation), placebo acupuncture alone (“limited”), or placebo acupuncture with a patient-practitioner relationship augmented by warmth, attention, and confidence (“augmented”). At three weeks, half of the patients were randomly assigned to continue in their originally assigned group for an additional three weeks. Main outcome measures Global improvement scale (range 1-7), adequate relief of symptoms, symptom severity score, and quality of life. Results At three weeks, scores on the global improvement scale were 3.8 (SD 1.0) v 4.3 (SD 1.4) v 5.0 (SD 1.3) for waiting list versus “limited” versus “augmented,” respectively (P<0.001 for trend). The proportion of patients reporting adequate relief showed a similar pattern: 28% on waiting list, 44% in limited group, and 62% in augmented group (P<0.001 for trend). The same trend in response existed in symptom severity score (30 (63) v 42 (67) v 82 (89), P<0.001) and quality of life (3.6 (8.1) v 4.1 (9.4) v 9.3 (14.0), P<0.001). All pairwise comparisons between augmented and limited patient-practitioner relationship were significant: global improvement scale (P<0.001), adequate relief of symptoms (P<0.001), symptom severity score (P=0.007), quality of life (P=0.01).Results were similar at six week follow-up. Conclusion Factors contributing to the placebo effect can be progressively combined in a manner resembling a graded dose escalation of component parts. Non-specific effects can produce statistically and clinically significant outcomes and the patient-practitioner relationship is the most robust component. Trial registration Clinical Trials NCT00065403.

Response expectancy as a determinant of experience and behavior.

Response expectancies, defined as ex- pectancies of the occurrence of nonvolitional responses, have generally been ignored in theories of learning. Research on placebos, hypnosis, and fear reduction indicates that response expectancies generate corre- sponding subjective experiences. In many cases, the genuineness of these self-reported effects has been substantiated by corresponding changes in behavior and physiological function. The means by which re- sponse expectancies affect experience, physiology, and behavior are hypothesized to vary as a function of re- sponse mode. The generation of changes in subjective experience by corresponding response expectancies is hypothesized to be a basic psychological mechanism. Physiological effects are accounted for by the mind- body identity assumption that is common to all non- dualist philosophies of psychology. The effects of re- sponse expectancies on volitional behavior are due to the reinforcing properties of many nonvolitional re- sponses. Classical conditioning appears to be one method by which response expectancies are acquired, but response expectancy effects that are inconsistent with a conditioning hypothesis are also documented.

How expectancies shape experience.

Expectations and the Social Cognitive Perspective - Basic Principles, Processes and Variables, James E. Maddux Expectancy Operation - Cognitive/Neural Models and Architecture, Mark S. Goldman Mood-Related Expectancy, Emotional Experience and Coping Behaviour, Salvatore J. Catanzaro and Jack Mearns Expectancies and Memory - Inferring the Past From What We Know Must Have Been, Edward R. Hirt et al Expectancy and Fear, Nancy Schoenberger Expectation and Desire in Pain and Pain Reduction, Donald Price and James J. Barrell Response Expectancy and Sexual Dysfunction, Eileen M. Palace Expectancy and Asthma, Samantha C. Sodergren and Michael E. Hyland Expectancy and Behavioural Effects of Social Used Drugs, M. Vogel-Sprott and M. Filmore Expectancy Meditation of Biopsychosocial Risk for Alcohol Use and Alcoholism, Mark S. Goldman et al Expectancies for Tobacco Smoking, Thomas H. Brandon et al Listening to Prozac But Hearing Placebo - a Meta-Analysis of Antidepressant Medication, Irving Kirsch and Guy Sapirstein Is the Placebo Effect Dependent on Time? a Meta-Analysis, Harald Walach and Catharina Maidof Expectations of Sickness and Symptoms - Concept and Evidence of the Nocebo Phenomenon, Robert A. Hahn Expectancies - the Ignored Common Factor in Psychotherapy, Joel Weinberger and Andrews Eig Hypnosis and Response Expectancies.

An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm

Placebo analgesia was produced by conditioning trials wherein heat induced experimental pain was surreptitiously reduced in order to test psychological factors of expectancy and desire for pain reduction as possible mediators of placebo analgesia. The magnitudes of placebo effects were assessed after these conditioning trials and during trials wherein stimulus intensities were reestablished to original baseline levels. In addition, analyses were made of the influence of these psychological factors on concurrently assessed pain and remembered pain intensities. Statistically reliable placebo effects on sensory and affective measures of pain were graded according to the extent of surreptitious lowering of stimulus strength during the manipulation trials, consistent with conditioning. However, all of these effects were strongly associated with expectancy but not desire for relief. These results show that although conditioning may be sufficient for placebo analgesia, it is likely to be mediated by expectancy. The results further demonstrated that placebo effects based on remembered pain were 3 to 4 times greater than those based on concurrently assessed placebo effects, primarily because baseline pain was remembered as being much more intense than it actually was. However, similar to concurrent placebo effects, remembered placebo effects were strongly associated with expected pain levels that occurred just after conditioning. Taken together, these results suggest that magnitudes of placebo effect are dependent on multiple factors, including conditioning, expectancy, and whether analgesia is assessed concurrently or retrospectively.

Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome

Background Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS). Methods Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47±18 with IBS diagnosed by Rome III criteria and with a score ≥150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as “placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes” or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL). Findings Open-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2±1.0 vs. 4.0±1.1, p<.001) and at 21-day endpoint (5.0±1.5 vs. 3.9±1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08). Conclusion Placebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent. Trial Registration ClinicalTrials.gov NCT01010191

Sham device v inert pill: randomised controlled trial of two placebo treatments

Abstract Objective To investigate whether a sham device (a validated sham acupuncture needle) has a greater placebo effect than an inert pill in patients with persistent arm pain. Design A single blind randomised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls. Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study. Setting Academic medical centre. Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale. Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks. Main outcomemeasures Arm pain measured on a 10 point pain scale. Secondary outcomes were symptoms measured by the Levine symptom severity scale, function measured by Pranskys upper extremity function scale, and grip strength. Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups, but changes were not different between the groups (−0.14, 95% confidence interval −0.52 to 0.25, P = 0.49). Changes in severity scores for arm symptoms and grip strength were similar between groups, but arm function improved more in the placebo pill group (2.0, 0.06 to 3.92, P = 0.04). Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group (−0.33 (−0.40 to −0.26) v −0.15 (−0.21 to −0.09), P = 0.0001) and on the symptom severity scale (−0.07 (−0.09 to −0.05) v −0.05 (−0.06 to −0.03), P = 0.02). Differences were not significant, however, on the function scale or for grip strength. Reported adverse effects were different in the two groups. Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in. Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals.

Classical conditioning and the placebo effect

Abstract Stimulus substitution models posit that placebo responses are due to pairings of conditional and unconditional stimuli. Expectancy theory maintains that conditioning trials produce placebo response expectancies, rather than placebo responses, and that the expectancies elicit the responses. We tested these opposing models by providing some participants with information intended to impede the formation of placebo expectancies during conditioning trials and by assessing placebo expectancies. Although conditioning trials significantly enhanced placebo responding, this effect was eliminated by adding expectancies to the regression equation, indicating that the effect of pairing trials on placebo response was mediated completely by expectancy. Verbal information reversed the effect of conditioning trials on both placebo expectancies and placebo responses, and the magnitude of the placebo effect increased significantly over 10 extinction trials. These data disconfirm a stimulus substitution explanation and provide strong support for an expectancy interpretation of the conditioned placebo enhancement produced by these methods.

Brain Activity Associated with Expectancy-Enhanced Placebo Analgesia as Measured by Functional Magnetic Resonance Imaging

In this study, a well established expectancy manipulation model was combined with a novel placebo intervention, a validated sham acupuncture needle, to investigate the brain network involved in placebo analgesia. Sixteen subjects completed the experiment. We found that after placebo acupuncture treatment, subjective pain rating reduction (pre minus post) on the placebo-treated side was significantly greater than on the control side. When we calculated the contrast that subtracts the functional magnetic resonance imaging (fMRI) signal difference between post-treatment and pretreatment during pain application on placebo side from the same difference on control side [e.g., placebo (post – pre) – control (post – pre)], significant differences were observed in the bilateral rostral anterior cingulate cortex (rACC), lateral prefrontal cortex, right anterior insula, supramarginal gyrus, and left inferior parietal lobule. The simple regression (correlation) analysis between each subjects fMRI signal difference of post-treatment and pretreatment difference on placebo and control side and the corresponding subjective pain rating difference showed that significant negative correlation was observed in the bilateral lateral/orbital prefrontal cortex, rACC, cerebellum, right fusiform, parahippocampus, and pons. These results are different from a previous study that found decreased activity in pain-sensitive regions such as the thalamus, insula, and ACC when comparing the response to noxious stimuli applied to control and placebo cream-treated areas of the skin. Our results suggest that placebo analgesia may be configured through multiple brain pathways and mechanisms.

Hypnosis as an Adjunct to Cognitive-Behavioral Psychotherapy: A Meta-Analysis.

: A meta-analysis was performed on 18 studies in which a cognitive-behavioral therapy was compared with the same therapy supplemented by hypnosis. The results indicated that the addition of hypnosis substantially enhanced treatment outcome, so that the average client receiving cognitive-behavioral hypnotherapy showed greater improvement than at least 70% of clients receiving nonhypnotic treatment. Effects seemed particularly pronounced for treatments of obesity, especially at long-term follow-up, indicating that unlike those in nonhypnotic treatment, clients to whom hypnotic inductions had been administered continued to lose weight after treatment ended. These results were particularly striking because of the few procedural differences between the hypnotic and nonhypnotic treatments.