The Emperor s New Drugs: Medication and Placebo in the Treatment of Depression

Transcription

1 The Emperor s New Drugs: Medication and Placebo in the Treatment of Depression Irving Kirsch, PhD Associate Director, Program in Placebo Studies Harvard Medical School Professor Emeritus of Psychology Plymouth University, University of Connecticut, and University of Hull I have no affiliations, sponsorships, honoraria, monetary support or conflict of interest from any commercial source.

2 26 th February 2008

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7 February 19, 2012

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9 How it happened Meta-analysis of published antidepressant trials (Kirsch & Sapirstein, 1998)

10 I don t really have a problem.

11 Meta-analysis of the placebo effect in depression (Kirsch & Sapirstein, 1998) SMD 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 0 25% 50% 25% Drug Placebo No Treatment

12 Listening to Prozac but Hearing Placebo (1998) The Critics: Your analysis is flawed It derives from a miniscule group of unrepresentative, inconsistently and erroneously selected articles (Klein, 1998)

13 Freedom of Information Act FDA Data Fluoxetine Paroxetine Sertraline Venlafaxine Nefazodone Citalopram

14 FDA data The basis for drug approval Includes all adequate and well-controlled studies 40% not published 76% 12% Not significant Significant Published Not published Melander (2003)

15 Drug-Placebo Differences (Kirsch et al., 2002, 2008) Drug Placebo HAM-D (range: 0-53) ,13 8, points (d = 0.32) 82% 2 0 NICE Criteria for Clinical Significance: 3 points (d = 0.50)

16 Statistical vs. Clinical Significance Statistical Significance Is an effect real or just chance? Clinical Significance How big is the effect? A study on 500,000 people finds that smiling increases life expectancy by 10 seconds

17 The Critics in 2002: The patients weren t depressed enough

18 HAM-D Improvement Drug-Placebo Differences 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 0,07 Clinical Significance (NICE) 2,36 Moderate Severe Very Severe Severity of Depression (Kirsch et al., 2008)

19 HAM-D Improvement Drug-Placebo Differences 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 0,07 Clinical Significance (NICE) 2,36 Moderate Severe Very Severe Severity of Depression (Kirsch et al., 2008) 4.28

20 The critics in 2008: The patients were too depressed! (Editorial, Nature Reviews Drug Discovery, 2008)

21 HAM-D Improvement Drug-Placebo Differences 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 0,07 Clinical Significance (NICE) 1,86 Moderate Severe Very Severe Severity of Depression (Kirsch et al., 2008) 4.28

22 SMD Independent Replication (Fournier et al., 2010) 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0,00-0,10 Clinical Significance (NICE) 0,30 0,19 0,14-0,05 Mild Moderate Severe Very Severe Severity of Depression 0.76

23 The Critics: The NICE criteria are arbitrary as arbitrary as criteria for: Statistical significance: p <.05 What would a non-arbitrary criterion be?

24 HAM-D and CGI-Improvement (Leucht et al., 2013; Moncrieff & Kirsch, 2015) Mean Improvement Raw data 43 trials N = HAM-D Very much worse Much worse Minimally worse No change Minimally improved Much improved Very much improved Clinical Global Impression

25 HAM-D Improvement Drug-Placebo Differences ,07 CGI-I: Minimally Improved CGI-I: No Change 1,86 Moderate Severe Very Severe Severity of Depression (Kirsch et al., 2008) 4.28

26 The critics last resort: "Antidepressants work...everybody knows they work (Nutt, 2008) Millions of content patients can t be that wrong (Werner, 2008)

27 History of Medicine Treatments that have worked for millions: Bloodletting Lizard s blood Crocodile dung Pig's teeth Putrid meat Fly specks Frog s sperm Powdered stone Human sweat Worms Spiders Furs Feathers Honigfeld 1964

28 Everyone gets the same results Drug-Placebo Differences (HAM-D) Kirsch et al. (2002, 2008) Fountoulakis and Möller (2010) Fournier et al (2010) Gibbons et al. (2012) FDA (2011) FDA (2015) CGI-I: Minimally Improved 1,80 CGI-I: No Change 2,18 1,94 2,56 2,50 Patient level data - 23,295 patients - 92 trials 1,80

29 We all agree The difference in improvement between drug and placebo is rather small. (Tom Laughren, MD Director, FDA Division of Psychiatry Products)

30 Response Rates It doesn t matter which antidepressant you take 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 62% 65% 59% 62% SSRI NDRI Tricyclic Benzodiazepine

31 SSRI Selective Serotonin Reuptake Inhibitor SSRE Tianeptine Selective Serotonin Reuptake Enhancer

32 Response Rates Head to Head Comparisons 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 62% 65% 59% 62% 63% SSRI NDRI Tricyclic Benzodiazepine SSRE

33 What do you call pills, the effects of which are independent of their chemical composition?

34 How Should Depression be Treated? Prescribe Antidepressants as Active Placebos?

35 Benefits vs Risks Side Effects Sexual dysfunction (75% on SSRIs) Weight gain (25%) Insomnia (20%) Diarrhea (15%) Nausea (15%) Anorexia Bleeding Forgetfulness Seizures

36 Antidepressant Discontinuation Syndrome

37 Health Risks Children & Young Adults Suicidal behaviour Violent crime Elderly Stroke Death from all causes Pregnant women Miscarriage Babies born with birth defects, persistent pulmonary hypertension, autism, neonatal abstinence syndrome (30%) Everyone Diabetes Relapse

38 Continuation and Discontinuation Trials (Andrews et al., 2010, 1912; Williams et al., 2009) 60% 50% 40% 49% 30% 20% 10% 0% 23% 21% Drug-Placebo Drug-Drug Placebo-Placebo

39 Continuation and Discontinuation Trials (Andrews et al., 2010, 1912; Williams et al., 2009) 60% 50% 40% 30% 49% Increased relapse 20% 10% 0% Drug-Placebo 21% Placebo-Placebo

40 NIMH Collaborative Research Program 18 month follow-up 60% 50% 50% Relapse 40% 30% 36% 33% 33% 20% 10% 0% CBT Interpersonal psychotherapy Placebo Imipramine Treatment

41 Exercise (Babyak et al., 2000) 80% 70% 60% 50% 40% 30% 20% 66% SSRI Exercise SSRI+Exercise 60% 69% 38% Adding an SSRI quadrupled the risk of relapse 31% 10% 0% Remission 4 months 8% Relapse 10 months

42 Is exercise a placebo? Antidepressants Sexual dysfunction Insomnia Weight gain Diarrhea Nausea Anorexia Bleeding Forgetfulness Seizures Side Effects Exercise Enhanced libido Better sleep Decreased body fat Improved muscle tone Longer life Increased strength and endurance Improved cholesterol levels

43 Should we prescribe placebos? But if I know it s a placebo, will it still work?

44 Take this placebo twice a day. If it doesn t work, I ll give you a stronger one.

45 Should we prescribe open placebos for depression? Mr. Hastings wants to know if he can pay you with fake money?

46 Symptom Reduction (Blind Ratings) Treatments for Depression (Khan, Faucett, Lichtenberg, Kirsch, & Brown, 2012) 60% 50% 40% 46% 38% 36% 47% 52% 47% 52% 30% 20% 10% 13% 0%

47 Advantages of psychotherapy over ADM Better long-term effectiveness Safer Preferred Meta-analysis of 34 patient choice studies (McHugh et al., 2013) 75% prefer psychotherapy

48 We can t prescribe placebos yet But I wish we could

49 Placebo Approved by FDA 13 December 2016 After decades of testing in tandem with SSRIs, placebo gained approval for prescription use from a regulatory agency. The FDA has approved placebo in doses ranging from 1 to 40,000 mg. Eleven major drug companies have developed placebo tablets.

50 Investigational New Drug approval for placebo

51 Prevaricain A genuine placebo medication Tested: in more clinical trials than any other treatment. Powerful: the standard by which all other medications are judged. Effective: used in the treatment of thousands of ailments. Safe: it can be given to infants, the elderly, and pregnant women. Warning: no serious side effects or health risks. If it s a placebo, you can believe in it!

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