ISCTM~ECNP Joint Conference ▪29 August 2015 ▪Amsterdam The Netherlands

Placebo response in MDD/Bipolar studies

Eduard Vieta

University of Barcelona

Interest Name of organisation

Grant Almirall, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, the European 7th

Framework Program, GlaxoSmithKline, Janssen-Cilag, NARSAD, Novartis,

Otsuka, Pfizer, Richter, Sanofi-Aventis, Seny Foundation, Servier, the Spanish

Ministry of Health (CIBERSAM), the Spanish Ministry of Science and Education,

the Stanley Medical Research Institute, and Teva

Advisory boards Almirall, Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly, Esteve, Forest,

GlaxoSmithKline, Janssen, Lundbeck, MSD, Novartis, Otsuka, Pfizer, Richter,

Roche, Sanofi-Aventis, Servier, Shire, Sumitomo Dainippon, Sunovion, Takeda,

and UBC

Other involvement Consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Ferrer, Forest

Research Institute, GlaxoSmithKline, Janssen, Jazz, Lundbeck, MSD, Novartis,

Otsuka, Pierre-Fabre, Pfizer, Sanofi-Aventis, Servier, Solvay, Sunovion, and UBC

Potential conflicts of interest

Placebo Response Rates in Monotherapy Trials of Acute Bipolar Depression

Mean placebo response = 43%

3

1. Calabrese JR, et al. J Clin Psychiatry. 1999;60(2):79-88. 2. Calabrese JR, et al. Bipolar Disord. 2008;10(2):323-333. 3. Tohen M, et al. Br J Psychiatry. 2012;201(5):376-382.

4. Tohen M, et al. Arch Gen Psychiatry. 2003;60(11):1079-1088. 5. Young AH, et al. J Clin Psychiatry. 2010;71(2):150-162. 6. McElroy SL, et al. J Clin Psychiatry.

2010;71(2):163-174. 7. Thase ME, et al. J Clin Psychopharmacol. 2006;26(6):600-609. 8. Calabrese JR, et al. Am J Psychiatry. 2005;162(7):1351-1360. 9. Suppes T, et al. J

Affect Disord. 2010;121(1-2):106-115. 10. Thase ME, et al. J Clin Psychopharmacol. 2008;28(1):13-20. 11. Lombardo I, et al. J Clin Psychopharmacol. 2012;32(4):47-48. 12.

Loebel A, et al. Am J Psychiatry. 2014;171(2):160-168.

1,2

Negative

3,4

Positive

5-9

Positive

10

Negative

11 12

Negative Positive

Pla

ce

bo

Re

sp

on

se

(%

)

100

Placebo Response Rates in Adjunctive Therapy Trials of Acute Bipolar Depression

Mean placebo response = 37%

4

OFC, olanzapine-fluoxetine combination.

1. Nemeroff CB, et al. Am J Psychiatry. 2001;158(6):906-912. 2. Tohen M, et al. Arch Gen Psychiatry. 2003;60(11):1079-1088. 3. SYMBYAX [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013. 4. Sachs GS, et al. N Engl J Med. 2007;356(17):1711-1722. 5. Frye M, et al. Am J Psychiatry. 2007;164(8):1242-1249. 6. Ketter T, et al. Poster presented at: 25th Annual US Psychiatric and Mental Health Congress; November 8-11, 2012; San Diego, CA. 7. van der Loos ML, et al. J Clin Psychiatry. 2009;70(2):223-231. 8. Loebel A, et al. Am J Psychiatry. 2014;171(2):169-177. 9. Yatham LN, et al. Unpublished data.

1 2,3

4 5,6

7 8 9

Negative Positive Negative Positive Positive Positive Negative

Pla

ce

bo

Re

sp

on

se

(%

)

100

Efficacy of drug versus placebo as a function of placebo response rates in bipolar depression trials

0

10

20

30

40

50

60

Pbo R<30% (n=557) Pbo R>30% (n=6877)

Drug

Placebo

Iovieno et al, IJNP in press

Response rates (%)

6

Placebo Active Treatment

Increased Placebo response over time in Depression Trials

Rief et al, JAD 2009

Reasons for Placebo response in Bipolar Disorder Trials

1. Less severe populations

2. Continued care in trial

3. Collaborative patients

4. “Professional” patients

5. Subjective outcome measures

6. Spontaneous remission

7. Diagnostic uncertainity

8. Benzos and hypnotics allowed

9. Rater drift and “noise”

10.Baseline inflation

11.Regression to the mean

12.Trial design and expectations

Vieta & Carne, Psychotherapy Psychosom 2005

What leads the increase in placebo response over time?

1. Less severe populations

2. Continued care in trial

3. Collaborative patients

4. “Professional” patients

5. Subjective outcome measures

6. Spontaneous remission

7. Diagnostic uncertainity

8. Benzos and hypnotics allowed

9. Rater drift and “noise”

10.Baseline inflation

11.Regression to the mean

12.Trial design and expectations

Vieta, 2015

Increased ethical standards

Financial incentives

Both of the above

Financial incentives

Lack of biomarkers

Trial design

Emphasis on paperwork over inner quality

Feasibility

Cost issues: multisite studies

Financial incentives

Financial incentives and cost issues

High patient & investigator motivation

Variable Reason

Kappa

0,21

0,28

0,31

0,36

0,46

0,46

0,48

0,5

0,56

0,56

0,59

0,61

0,67

0,78

0.50

0.40

0.40

0.20

-0,004

-0,1 0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8

Mixed anxiety-depressive disorder

Generalised anxiety disorder

Antisocial personality disorder

Major depressive disorder

Obsessive–compulsive personality disorder

Mild traumatic brain injury

Bipolar II disorder

Alcohol use disorder

Attenuated psychotic symptoms syndrome

Schizophrenia

Mild neurocognitive disorder

Schizoaffective disorder

Borderline personality disorder

Binge eating disorder

Bipolar I disorder

Hoarding disorder

Complex somatic symptom disorder revised

Posttraumatic stress disorder

Major neurocognitive disorder

Adult diagnosis

Kappa:

Very good agreement

Good agreement

Questionable agreement

Unacceptable agreement

Freedman et al, Am J Psychiatry 2013

A critical problem: phenotype reliability (DSM-5)

MADRS response rates across six lamotrigine multicentre acute bipolar depression studies

0

10

20

30

40

50

60

Calabrese

et al 1999

SCAA2010 SCA40910 SCA30924 SCA100223 LamLit

Study

Placebo Lamotrigine

p=0.42p=0.36

p=0.89p=0.005 p=0.21 p=0.03

Calabrese et al 1999; Calabrese et al 2008; aVan der Loos et al, 2009

a

Patients

(%)

2003-2005

BP I

2000-2002

BP I

1997-1998

BP I & II

1996-1997

BP I

2003-2005

BP II

2003–2006

BP I & II

MADRS response = 50% improvement over baseline

Pooled Relative Risk of Response: 1.22 CI 1.06-1.41. p=0.005. Geddes et al 2007

Adjunctive trial

When are clinical trials most likely to succeed?

True YMRS Score

GeneralPopulation

Manic population

6 20 40

CD A B

Treatment seeking population

Enrolled RCTpopulation

0

True MADRS Score

Depressed population

Sachs, 2001

13 Bridge et al, Am J Psychiatry 2009

Placebo response and number of study sites

Placebo-controlled trials in Pediatric depression

Zarate et al, BioI Psychiatry 2012

Placebo response mimicks drug response: timing

40 50 60 70 80 90

100

5

0

5-

10-

15-

20-

25-

30-

35-

40-

45-

body weight (kg)

HA

MD

17-

score

change a

t th

e e

nd p

oin

t

Fig. 1. Scatter plot of the association between the baseline body weight and the 17-item Hamilton Depression Rating Scale (HAMD-17) reduction at the end point

Lin CH et al, JAD 2014

Body mass affects treatment response in depression

Thase M et al, submitted

Thase M et al, submitted

Thase M et al, submitted

Antoni BenabarreC. Mar Bonnín

Francesc ColomMercè Comes

Marina GarrigaJosé M. Goikolea

Íria GrandeDiego Hidalgo-Mazzei

Esther JiménezAnabel Martínez-Arán

Andrea MurruIsabella Pacchiarotti

Rosa PalausDina Popovic

Maria ReinaresJose Sánchez-Moreno

Brisa SoléCarla TorrentImma TorresMarc ValentíCristina VaroEduard Vieta