Critical Issues for Bipolar Disorder Gary S. Sachs, M.D. Harvard Medical School Massachusetts General Hospital October 25, 2005 Psychopharmocological Drugs

Critical Issues for Bipolar Disorder

Gary S. Sachs, M.D.Harvard Medical School

Massachusetts General Hospital

October 25, 2005

Psychopharmocological Drugs Advisory Committee

Treatments for Chronic Mental Illness:Principles

1. Approval standards should reflect the interest of patients

2. Research design should be informed by clinical epidemiology

3. The best design methodology is that which optimizes validity and feasibility

Bipolar Disorder: Bipolar Disorder: Untreated vs TreatedUntreated vs TreatedStandardized Mortality RatiosStandardized Mortality Ratios

Bipolar Disorder: Bipolar Disorder: Untreated vs TreatedUntreated vs TreatedStandardized Mortality RatiosStandardized Mortality Ratios

Neoplasm Cardio-vascular

Cerebro-vascular

Accidents Suicide Other All Causes

UntreatedTreated

29.2*

6.4

1.4*0.6

2.2*1.7 1.6†

1.3 1.62.0 2.0*1.3

2.2*1.3

* p< 0.001 † p< 0.05

Zurich Cohort, n=4061959-1997

Adapted from

Angst, 2000

Should approval for an acute indication include a requirement for demonstration of

long-term efficacy?

• The Public Health interest is not served by establishing this requirement

• A policy intended to protect patients against acutely efficacious treatments without proven long-term benefit would benefit few, while depriving many of potentially helpful treatments

Is there a need to protect patients from treatments only proven to have short-term efficacy?

• Patients remain on ineffective medications briefly

• Effective medications are frequently discontinued over relatively short time periods

• Most patients using medications long-term are those who responded acutely and either perceive continued benefit or have suffered recurrence when attempting to taper.

Based on Altshuler et al. AJP.

2003

Discontinues afteracute response

Lack of efficacy

Continues long-termtreatment

Few get long-term treatment in the real world

Lithium Use and Discontinuation in a Health Maintenance Organization

Length of first continuous period of Lithium use (n=1594)Days

Lithium under used- only 8% used Li for 90% of days enrolled- median continuous use = 76 days

Adapted from: Johnson, Am J Psychi 1996100%

50%

20%

10%

30%

40%

60%

70%

80%

90%

0 500 1000 1500 2000

Principles of Current Clinical Practice• Bipolar disorder is a life long condition in which acute

episodes are separated by period of variable remission

• The episodic nature of bipolar disorder provides the organizing principle of treatment– Episodes are the target of acute and prophylactic treatment– Multiphase Treatment model

• Acute, Continuation, Maintenance/Discontinuation• Maintenance phase treatment reflects prior acute phase experience

Multiphase Treatment StrategyMultiphase Treatment Strategy

RecoveringRecovering RecoveredRecovered

Natural Course

Eu

thym

icD

epressed

Start Tx

AcuteMaintenance / DiscontinuationContinuationContinuation

Treated Course

Measurement

Basic Treatment paradigm is iterativeCritical

decision point

Intervention Intervention

Menu of reasonable choices

Option AOption AOption BOption BOption COption C

€€€€€€€€$$$$$$$$££££££££

++++++++++

++++++

Evidence Evidence A-FA-F

Individual factorsIndividual factors

Benefit: Adverse Effect + Cost

Each treatment trial is evaluated for

Iterative Process: Individual Response Directs Treatment Iterative Process: Individual Response Directs Treatment

Benefit

adverse effects

+ expense

None Fair Good Excellent

NoneMildModerate

Severe

+ +?

?? ? ?

? ?

? ?

Acuteepisode

Recovery

Maintenance Therapies in Bipolar Disorder Study Design

4 wks average •HRSD <7 &• Bech-Rafaelsen <7

Patient and family attend psychoeducational workshop

Weekly Acute treatment

RecoveryICM + protocol

pharmacotherapy

IPSRT + protocol pharmacotherapy


ICM + protocol pharmacotherapy



Preventative tx bi-weekly x 12 weeksthen monthly x 2 years

Relationship of TreatmentAssignment to Time to Recurrence

(n = 82)

Weeks to Recurrence in Preventative Phase0 10 20 30 40 50

Su

rviv

al D

istr

ibu

tio

n F

un

cti

on

0.0

0.2

0.4

0.6

0.8

1.0

ICM/ICMIPSRT/IPSRTICM/IPSRTIPSRT/ICM

* p = .03

*

Frank et al., Journal of Abnormal Psychology, in press

How well do our current treatments work?• Acute Bipolar depression

– No single agent has FDA approval for treatment of BP depression– STEP-BD and Altshuler/StanleyFBN data indicates need for

more efficacious treatments.

• Acute mania (8 approved agents)– The data from 3-4 week double blind trials indicates that on

average participants receiving active treatment finish the study with symptom severity scale scores above the severity score required for study entry.

• Prophylaxis (4 approved agents)– None consistently efficacious for all relevant outcome variables– None shown effective for subjects remaining well longer than 6

months

Acute Bipolar Depression:Acute Bipolar Depression:Placebo controlled therapy TrialsPlacebo controlled therapy Trials

with adequate* sample sizewith adequate* sample size

Acute Bipolar Depression:Acute Bipolar Depression:Placebo controlled therapy TrialsPlacebo controlled therapy Trials

with adequate* sample sizewith adequate* sample size

PositivePositivePositivePositive

Li+ ParoxetineLi+ ParoxetineLi+ ImipramineLi+ Imipramine

*power to detect a difference > 0.8

combinationcombination

LamotrigineLamotrigine

OlanzapineOlanzapine

QuetiapineQuetiapine

NegativeNegativeoror

FailedFailed

Olanzapine + Fluox.Olanzapine + Fluox.

monotherapymonotherapy

ImipramineImipramine

Placebo-Controlled Bipolar Depression Studieswith Adequate Samples

0 1 2 3 4 5 6 7

Week

PBO n=65LTG 50mg/day n=64LTG 200mg/day n=63

**

****

**

*

-20

-15

-10

-5

0

0 1 2 3 4 5 6 7 8Week

Chan

ge fr

om B

aseli

ne

PBO n=355OLZ n=351OFC n=82

*

**

**

*

*

****

*

Tohen et al.Calabrese et al.

*p<0.05 vs. PBO

OFC-olanzapine fluoxetine combination. Montgomery Asberg Depression Rating Scale.Calabrese et al. J Clin Psychiatry. 1999. Tohen et al. APA. 2002.

Calabrese et al

Calabrese et al APA 2004;

-20

-15

-10

-5

0

0 1 2 3 4 5 6 7 8

Seroquel 600mg/daySeroquel 300mg/dayPlacebo

*

*

*

* * * * *

*

**

* * * * *

MA

DR

SM

AD

RS

Ch

ang

e F

rom

Bas

elin

eC

han

ge

Fro

m B

asel

ine

16

A rough metric of clinical effectiveness: CE= Response Rate x Completion Rate

Study Response rate Completion rate CE NNT

OlZ = 39.0%OFC = 56.1%Placebo = 30.4%

QTP 300 = 58.2%QTP 600 = 57.6%Placebo = 36.1%

Calabrese1999

Calabrese 2005

Tohen 2003

48.4%64.0%38.5%

66.9%54.4%59.1%

18.9%35.9%11.7%

38.9%31.3%21.3%

5.710.0

13.94.1

65.0%71.0%71.0%

LTG 50 = 41%LTG 200 = 51%Placebo = 29%

26.7%36.2%20.6%

16.46.4

Real World Pharmaco-epidemologyNew treatment starts at MGH Bipolar Clinic

162

59%

166

47%

197

67%

97

53%

99

54%

127

57%

Lithium (n=49)

Valproate (n=38)

Lamotrigine(n=89)

AtypicalAntipsychotics

(n=216)

Antidepressants(n=264)

Anxiolytics(n=93)

Median tx duration (in days) % Recovered/Recovering

Majority use < 6 months

N =466 with at least 4 visits in year

Clinical intent to treat Bipolar Depression

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.000 88 1616 2424 3232 4040 4848

Number of Weeks Until RelapseNumber of Weeks Until Relapse

Medication continuation groupMedication continuation groupMedication discontinuation groupMedication discontinuation group

Altshuler et al. AJP. 2003

N=1,078

84

15% remitted15% remitted

Acute Phase Maintenance PhaseResults from Stanley Foundation Bipolar Network

What is the benefit of standard antidepressants?Enriched sample of 84 Remitters = 15% of total84 Remitters = 15% of total

Adapted from Altshuler et al. AJP. 2003.

~ 25% relapse < 4 months ~ 25% relapse < 4 months onon or or offoff antidepressant antidepressant

~ 41% relapse 12 months ~ 41% relapse 12 months onon antidepressant antidepressant

~ 71% relapse < 4 months ~ 71% relapse < 4 months offoff antidepressant antidepressant

15%

11%

9%

4%

Ever 4 months 12 months usingAntidepressant

% Remaining Well> 1 year

Discontinued usingAntidepressant <6 months

12m -AD

STEP-BD Naturalistic data also indicatesgreat need for better acute treatments

0 40 80 120 160 200 240 280 320 360Days Well

15

10

5

0

Per

cent

Days well after reaching “Recovered”

Status(8 Wks Well)

MajorityMajorityhave remissionhave remission

< 6 months< 6 months

Acute Phase Maintenance Phase

2000 BP Subjects

377 Intent to treat Acute depression

Outcome at 90 Days% recovered

With AD = 21.5%No Ad = 27.2%

Median 96.5

Psychiatric patients need more acute treatments

• The proportion of patients achieving an acute benefit is modest

• There is a compelling need for more acutely efficacious medications

• Raising the bar to require long-term efficacy is not yet practical

• Limiting patient choice to only new treatments with proven long-term efficacy will leave potential responders untreated or seeking options unavailable here

Less than 10% will benefitLess than 10% will benefitLess than 10% will benefitLess than 10% will benefit• The proportion meeting criteria for response or remission in most The proportion meeting criteria for response or remission in most

pivotal trial overstates the benefit of acute treatmentpivotal trial overstates the benefit of acute treatment• The proportion depressed meeting DSM-IV criteria for recovered is The proportion depressed meeting DSM-IV criteria for recovered is

modest (<20%)modest (<20%)• Among those achieving recovery, > 50% experience a recurrence Among those achieving recovery, > 50% experience a recurrence

within 3 monthswithin 3 months

• The vast majority will be negatively impactedThe vast majority will be negatively impacted by virtue of not having access to acutely beneficial treatmentsby virtue of not having access to acutely beneficial treatments

Is the Public Health interest well served by requiring demonstration of long term

efficacy at time of registration?

• No compelling benefit – The proportion of patients achieving an acute benefit is modest

– There is no surplus of acutely efficacious medications

– Patients usually stop ineffective medications quickly

– Even effective medications are discontinued over relatively short time periods

• New obstacles to approval of treatments with acute efficacy will harm patients

Critical Design Issues in Conducting Long-Term Trials in

Bipolar Disorder

Gary S. Sachs, M.D.Harvard Medical School

Massachusetts General Hospital

October 25, 2005

Psychopharmocological Drugs Advisory Committee

Relapse Study Design – Stabilization PeriodRelapse Study Design – Stabilization Period

Design Should Reflect Validity & Feasibility

• DSM-IV defines recovery from a mood episode as 8 weeks well• New proposal calls for 6 months for all chronic conditions• EU guidelines are condition dependent: 2 – 6 months• Data suggests one duration does not fit all conditions• The design should reflect clinical epidemiology of each condition• Successful studies use enriched designs• Study designed to enrich with atypical patients can be misleading

Stabilization Period – EU Guidelines

Flexibility Depending on Condition

Disorder Stabilization Period Major Depressive Disorder 8 – 12 weeks

Schizophrenia > 6 weeks

Manic Episode

Bipolar Depression

9 weeks

12 – 26 weeks

Generalized Anxiety Disorder 8 – 26 weeks

Panic Disorder 8 – 12 weeks

Obsessive Compulsive Disorder > 26 weeks

Social Anxiety Disorder 8 – 12 weeks

STEP – BD Data Time to Relapse and Roughening after Recovery

RougheningRoughening

Full EpisodeFull Episode

00 5050 100100 150150 200200 250250 300300 350350 400400Time to Event/CensoringTime to Event/Censoring

1.001.00

0.750.75

0.500.50

0.250.25

0.000.00

Su

rviv

al D

istr

ibu

tion

Fu

nct

ion

Su

rviv

al D

istr

ibu

tion

Fu

nct

ion Steady gradual slope

( 8 weeks stable remission)( 8 weeks stable remission)

(Days).

Placebo vs Olanzapine in Combination with Lithium or Valproate

% R

emai

ning

in R

emis

sion

0 100 200 300 400 500

0

20

40

60

80

100

p=.023

Time to Recurrence Into Mania or Depression

OLZ plus Li or VPA, (n=30)Li or VPA, (n=38)

Immediate steep slope

Randomized after symptomatic Randomized after symptomatic remission of mania (YMRS remission of mania (YMRS 12) and depression Ham-D 12) and depression Ham-D 8 8

Tohen et al. Poster presented at XXIII Congress of CINP; 2002; Montreal, QuebecTohen et al. Poster presented at XXIII Congress of CINP; 2002; Montreal, Quebec..

Time to Recurrence (Days)Time to Recurrence (Days)00 100100 200200 300300 400400 500500

Lithium or valproate, n=48Lithium or valproate, n=48

Olanzapine plus lithium or valproate, n=46Olanzapine plus lithium or valproate, n=46

Time to recurrence of mania after symptomatic Time to recurrence of mania after symptomatic remission of mania (YMRS remission of mania (YMRS 12)12)

P=0.005

Pro

bab

ility

of R

em

ain

ing

Pro

bab

ility

of R

em

ain

ing

in R

em

issi

on

(%)

in R

em

issi

on

(%)

0%

20%

40%

60%

80%

100%

Placebo vs Olanzapine in Combination with Lithium or Valproate


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70Week

Su

rviv

al E

stim

ate

PBO (n=119)

LTG200/400 (n=165)

Li (n=120)

2nd Lamotrigine Maintenance Study*

LTG v. PBO, p = 0.029Li v. PBO, p = 0.029LTG v. Li, p = 0.915

Randomized subjects well on monotherapy 1 week Randomized subjects well on monotherapy 1 week


Relapse* Following Open, Prospective Non-Random Antidepressant Discontinuation vs. Continuation

53 BPI 24 BPII53 BPI 24 BPII1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.000 88 1616 2424 3232 4040 4848



* Relapse = CGI-S 4Altshuler et al. AJP. 2003

Steady gradual slope

Enriched Sample of 84 Remitters Enriched Sample of 84 Remitters 6 weeks CGI-S 6 weeks CGI-S 2 2

Aripiprazole Maintenance of Stability in Bipolar Mania

Aripiprazole

Placebo

Required 6 Weeks Well for RandomizationRequired 6 Weeks Well for Randomization

0.4

0.6

0.7

0.8

0.9

1.0

0.5

0 14 25 42 55 70 84 95 112 125 140 154 168 182 195 210

Relative risk = 0.523 (0.30, 0.913). Data on file, Otsuka America Pharmaceutical, Inc.

Days

Pro

por

tion

of

Pat

ien

ts W

ith

out

Rel

apse

Log-rank P value 0.020

Steady gradual slope

Successful studies use enriched designs

Total Entering

Study

Acute Phase“Responders”

=

ProportionRandomized

Lithium

65%

49% 49%

28%

15%

Valproate LTG-P Olanzapine Aripip M SFBN

Primary outcome NSPrimary outcome NSPrimary outcome positivePrimary outcome positive

Enrichment MostMostLeastLeast

Inherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design Problem• Conservative Assumptions – Great Obstacles to FeasibilityConservative Assumptions – Great Obstacles to Feasibility

•Eligibility Criteria for Randomization = “Responder”True Responder /All meeting response criteria = 50%

Assumes Response for Active = 50% Placebo = 25%

•“Enriched Sample” is a composite of 50% True Responders50% Pseudo Responders

In the Double blind Phase: Pseudo Responder Relapse Rates

Placebo = Active

Inherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemStudy Powered for relapse rate Study Powered for relapse rate

Placebo = 60% vs Active 40%Placebo = 60% vs Active 40%

“Enriched Sample” N=200 50% True Responders 50% Pseudo Responders

Placebo Cell n=100 50% True Responders50% Pseudo Responders

“Active Cell n=100

Subjects Subjects relapsingrelapsing

50 Pseudo Responders

50 TrueResponders

3030 1010 6060

Positive result requires active agent sustains effectiveness in at least 80%

Inherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemInherent Maintenance Design ProblemLonger stabilization phase: Longer stabilization phase:

Study Powered for relapse rate Study Powered for relapse rate Placebo = 40% vs Active 20%Placebo = 40% vs Active 20%

“Enriched Sample” N=200 50% True Responders 50% Pseudo Responders

Placebo Cell n=100 50% True Responders50% Pseudo Responders

“Active Cell n=100

Subjects Subjects relapsingrelapsing

50 Pseudo Responders

50 TrueResponders

2020 00 4040

Positive result requires active agent sustains effectiveness in 100%

0 40 80 120 160 200 240 280 320 360Days Well

15

10

5

0

Per

cent

Days well after reaching “Recovered” Status

(8 Wks Well)

produces a sample unrepresentative of patients seeking treatment

Use of a 6 month stabilization

MajorityMajorityhave remissionhave remission

< 6 months< 6 months

Summary Statistics

Number of Obs 281N Missing 19N 262

Median 96.5Mean 116.57Std Deviation 83.21Mode 63Maximum 365Minimum 3.5

Narrows the separation

Limiting randomization to subjects 6 months willalter study results

Antidepressant Discontinuation vs. ContinuationConditional on 6 months well



1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.000 88 1616 2424 3232 4040 4848

Relationship of TreatmentAssignment to Time to Recurrence

(n = 82)

Weeks to Recurrence in Preventative Phase0 10 20 30 40 50

Su

rviv

al D

istr

ibu

tio

n F

un

cti

on

0.0

0.2

0.4

0.6

0.8

1.0

ICM/ICMIPSRT/IPSRTICM/IPSRTIPSRT/ICM

Frank et al., Journal of Abnormal Psychology

Consequence of 6 Month StabilizationConditional on

remaining well for 6 monthsOriginal curves after 6 months

Trial Design: Summary of IssuesValidity• One size does not fit all conditions• Data shows what got you well keeps you well• 8 wks well is adequate to achieve stabilization• 6 month stabilization produces sample

unrepresentative of patients seeking treatment• 6 month stabilization will make it difficult to

detect a true difference between a NME and placebo

Trial Design: Summary of Issues

Feasibility• 6 month stabilization will require a larger sample• Larger samples will increase enrollment phase 8-

24 month heightening rater drift and sample variability

• An increase in enrollment times will delay or prevent patient access to innovative new treatments

• This proposal is not in the best interest of patients

Documents

Critical Issues for Bipolar Disorder Gary S. Sachs, M.D. Harvard Medical School Massachusetts General Hospital October 25, 2005 Psychopharmocological Drugs