Outline. Understanding Placebo Response in Psychiatry: The Good, The Bad, and The Ugly. Definitions

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1 Outline Understanding Placebo Response in Psychiatry: The Good, The Bad, and The Ugly Michael E. Thase, MD Professor of Psychiatry Perelman School of Medicine University of Pennsylvania and Philadelphia VAMC Philadelphia, Pennsylvania Why we care about placebo response: the good the bad, and some really ugly implications Future directions for research Practical recommendations for practice Definitions Placebo: Substance that has no inherent power to produce a pharmacologic effect (Origin: from Greek, meaning to please); the term sham is used for the equivalent of a placebo for a device or procedure Placebo response: Change in symptoms among participants randomized to placebo Nocebo: A placebo with a negative effect or side effect The Good: A Placebo Response is a Fundamental Component of Helping Relationships Stewart-Williams S, et al. Psychol Bull. 2004;130(2): A Model of Placebo Response in Antidepressant Clinical Trials Placebo: The Major Reason People Get Better in Modern Antidepressant Trials Placebo Effects Drug (25.16%) Natural History (23.87%) Placebo (50.97%) Rutherford BR, et al. Am J Psychiatry. 2013;170(7): Kirsch I, et al. Prevention & Treatment. 1998;1:1-16.

2 Placebo Accounted for 70+% of Benefit of Bupropion and SSRIs in Standard RCTs Remission Rate (%) HAM-D < PBO < SSRI = BUP PBO (N = 524) SSRI* (N = 758) BUP (N = 748) *Pooled data from 9 trials; SSRI: sertraline (N = 358), fluoxetine (N = 348), paroxetine (N = 52). BUP = bupropion; HAM-D = Hamilton Rating Scale for Depression; PBO = placebo; RCT = randomized controlled trial; SSRI = selective serotonin reuptake inhibitor. Thase ME, et al. J Clin Psychiatry. 2005;66(8): Placebo Amplifies the Natural History (Spontaneous Remission) Acute depressive episodes often spontaneously remit 30% untreated depressed patients recover in 10 weeks and up to 60% by 6 months Wait-list controls: 10 studies (N = 340), improve 4 HAM-D points on average, 10% response rate Placebo response rates higher among more acute and less severe patients Placebo response lower among older depressed patients with elevated urinary free cortisol levels Thase ME. Curr Psychiatry Rep. 2011;13(6): Rutherford BR, et al. J Psychiatr Res. 2012;46(6): A Placebo is So Much More Than a Pill Therapeutic Contact Moderates Placebo Response in RCTs Patients prescribed a medication receive a pill/capsule PLUS: A coherent narrative about their illness and a timehonored/tested approach to relief This can restore morale/hope and create an expectation for symptom relief Prescription is accompanied by regular visits with a health care professional who is empathic and offers helpful advice and Regularly monitors progress and makes changes In clinical trials, the more visits and the longer the visits, the higher the likelihood of a placebo response Response Rate Difference Adults Medication vs. placebo difference Treatment visit interaction NS 3 less visits Mean visits 3 more visits Rutherford BR, et al. Curr Rev Psychiatry. 2010;6(1):1-10. Rutherford BR, et al. J Clin Psychiatry. 2013;74(7): Is a Placebo Still Useful If You Know It s a Placebo? Kaptchuk TJ, et al. PLoS One. 2010;5(12):e15591.

3 Open-Label Administration of Placebo in Irritable Bowel Syndrome N = 80 No Treatment Control N = 43 N = 37 Open-Label Placebo N = 39 N = 31 No Treatment Control Completers Kaptchuk TJ, et al. PLoS One. 2010;5(12):e Open-Label Placebo Completers Kaptchuk TJ, et al. PLoS One. 2010;5(12):e Several Surveys Suggest That Physicians Want to Utilize Placebos A Model of Placebo Response in Antidepressant Clinical Trials Placebo Effects Associated Press. Half of US doctors often prescribe placebos. October 23, Accessed August 11, Tilburt JC, et al. BMJ. 2008;337:a1938. Rutherford BR, et al. Am J Psychiatry. 2013;170(7): Placebos Mitigate the Impact of Pain via Impact on Opiate Circuitry The Good: Placebo Responses Can be Helpful via Classical Conditioning Zubieta JK, et al. J Neurosci. 2005;25(34):

4 Nocebo: The Bad The Bad: Placebo Responses are Not Always Beneficial Placebos are notorious for eliciting the same side effects as the matched drug (just less frequent and less severe) Under some circumstances, the very idea of taking a placebo can cause outcomes to worsen Recent work in pain studies suggests that a nocebo effect is associated with a failure to elicit the expected effect on opiate receptors Bridge JA, et al. Am J Psychiatry. 2009;166(1): Relapses Resulting from a Switch from Open-Label to Double-Blind Therapy Doubt about the Treatment Adversely Affected Drug and Placebo Equally r = -0.46, same for drug and placebo Rutherford BR, et al. J Clin Psychiatry. 2014;75(10): Rutherford BR, et al. J Clin Psychiatry. 2014;75(10): Nocebo Effect Mediated by Failure to Engage Endogenous Opiate System Placebo: The Ugly High placebo response rather than low medication response causes failed trials Compared to other drugs, developing CNS agents are less successful (8.1% CNS drug candidates reach marketplace vs 15% for all drugs), take longer (CNS drugs spend > 2 years longer in human testing compared to other drugs), and are more expensive ($800 million per new agent approved) Scott DJ, et al. Arch Gen Psychiatry. 2008;65(2): CNS = central nervous system. Bridge JA, et al. Am J Psychiatry. 2009;166(1):42-49.

5 The Ugly: Companies Bailing Out AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Sanofi-Aventis, and Novartis have essentially stopped psychiatric medication Research & Development High Placebo Responses Have Reduced Public Trust and Confidence in Our Therapeutics Psychopharmacology in crisis Vanishing clinical psychopharmacology Cressey D. Psychopharmacology in crisis. Nature. June 14, Accessed August 11, Van Gerven J, et al. Br J Clin Pharmacol. 2011;72(1):1-5. The Placebo Response Epidemic : The Really, Really Ugly Mean Placebo Response 30% TCA = tricyclic antidepressant. Walsh BT, et al. JAMA. 2002;287(14): Effect Sizes of Placebo and Drug Placebo Differences over Time Temporal Trends with Increasing Placebo Response Seen across Indications in Psychiatry Dunlop BW, et al. Neuropsychopharmacology. 2012;37(13):

6 Temporal Increase in Placebo Response Rates in RCTs of Schizophrenia The Bad: Some Evidence Suggests True Drug Effects Only for the Most Severely Symptomatic Patients Rutherford BR, et al. JAMA Psychiatry. 2014;71(12): Mean Drug Placebo Differences as a Function of Initial Severity Meta-analysis: Pretreatment Severity and Response to ADMs and PBO Plotted values are sized according to sample sizes (n); the green line represents the NICE clinical significance criterion. The solid blue regression line represents the trend across all 35 trials; the dashed red line excludes outlier. Kirsch I, et al. Prevention & Treatment. 2002;5(1). ADM = antidepressant medication; HDRS = Hamilton Rating Scale for Depression. Fournier JC, et al. JAMA. 2010;303(1): Why are These Observations So Controversial? The percentage of persons treated with ADMs in the United States increased from 5.8% to 10.1% between 1996 to 2005; 11% to 13% of US adults now take ADMs Increasing use of ADMs corresponded to decreasing rates of counseling and psychotherapy ADMs are about twice as likely to be prescribed by primary care providers than psychiatrists; patients give primary care treatment lower marks for consumer satisfaction Small Effects in Grouped Data Obscure Larger Effects in Subsets of Patients Study of escitalopram data set using studies permitting 20 mg/day dose Latent class analysis applied to placebo and escitalopram arms of the trials Outcomes in both sub-samples were consistent with 2 classes of response A small overall effect corresponded to large and clinically meaningful differences in the proportions who benefit and don t benefit from therapy Olfson M, et al. Arch Gen Psychiatry. 2009;66(8): Thase ME. Curr Psychiatry Rep. 2011;13(6): Thase ME, et al. Br J Psychiatry. 2011;199(6):

7 Latent Class Analysis of Severe Depression: Placebo Group Latent Class Analysis: Escitalopram Group Thase ME, et al. Br J Psychiatry. 2011;199(6): Thase ME, et al. Br J Psychiatry. 2011;199(6): Design Alternatives to Reduce Placebo Response Limit number of study arms: simple 2-arm placebocontrolled studies have the lowest expectations of benefit and the greatest chances of success Longer double-blind placebo lead-in Variable length, double-blind placebo lead-in Sequential parallel group design Concealed focus on subset of participants with higher severity scores Psychotherapy lead-in Psychotherapy Lead-in: Rationale Provides an accepted intervention for the first x weeks (4, 6, 8, 12?) to address concerns about duration of placebo exposure Addition of placebo to psychotherapy does not appreciably increase response rate Outcome of 12- to 16-week courses of focused psychotherapy can be predicted with 80+% accuracy after 6 to 8 weeks Reduces attrition and improves satisfaction with care Non-inferiority Designs: Pros and Cons Pros: More acceptable to real patients, fewer ethical concerns, better comparative data on novel compounds Cons: Require extremely large samples (> 3 that of a placebo-controlled design), absence of placebo raises expectations of benefit, interpretability problems Interpretive Issues with Non-inferiority Trials The inherent bias in a non-inferiority trial favors conclusion of non-inferiority Inclusion criteria, dosing, small Ns, reliability of assessment, nonadherence, early attrition, and unblinding all can contribute to biased non-inferiority trials Interpretation problematic if active comparator inconsistently separates from placebo

8 Sequential Parallel Comparison Design Phase 1 R D Randomize 1 2 NR Phase D D P D P R R P NR NR Randomize R NR Summary Placebo response is a fundamental part of the therapeutic process A placebo response includes spontaneous remission, regression to the mean, nonspecific benefit from clinical support, and for some indications classical conditioning It is not ethical to use placebos as part of standard (nonresearch) care Nevertheless, contributions of expectancy and therapeutic contact can be capitalized upon to improve outcomes in everyday patient care You can improve outcomes in practice by delivering more of the characteristics that amplify placebo response D = Drug; P = Placebo; R = Responder; NR = Non-Responders.