Practical ExperiencePractical Experience•Approach to treatment•Evidence of Efficacy and Effectiveness•Pharmacology•Adverse Effects•Activation, Agitation, Akathisia

Gary Sachs, MDAssociate Professor of Psychiatry, Harvard Medical School

Director, Bipolar Clinic and Research ProgramMassachusetts General Hospital

Depression is the most common overt expression of Bipolar Disorders

Depression is the most common overt expression of Bipolar Disorders

Judd et al NIMH CDS, 2001

BPI

BP II

% weeksDepression

31%

52%

BPIBPII

% weeksManic Spectrum

10%

1.4%

37:1

Pathways for

SystematicTreatment

Measurement

Iterative approach Critical decision point

Intervention Intervention

Menu of reasonable choices

Option AOption AOption BOption BOption COption C

€€€€€€€€$$$$$$$$££££££££

++++++++++

++++++

NegotiateEducateEducate

Evidence Evidence A-FA-F

Individual factorsIndividual factors

Sequential Care: Most Benign

Urgent Care:Most Effective

Selection of Initial Intervention

MonotherapyStart LowGo Slow

Combination TherapyAggressive titration

to effective dose range

Usuallydriven by

Patient Preference

Usually

driven by

Clinician’s responsibility

Individual factorsIndividual factors

• Course •Polarity Predominance•Number / Frequency of prior episodes•Rapid Cycling

• Index Episode•Mixed Episodes•Psychosis

• Residual Symptoms• Female Gender• Comorbid Psychiatric Illness

•Substance misuse•Anxiety Disorders•ADHD

• Biomarkers (?)• Prior Treatment Response

• Acute• Prophylaxis

• Adverse Effect Tolerance• General Medical

Disorder/Risk factors•Cardiac: Obesity, Hypertension•Endocrine: Thyroid, Diabetes•Hemopoetic/Immune Function

• Therapeutic Priority- Urgent Care Strategy- Sequential Strategy

• Concordance

Sachs, Acta Psychatr Scand 2004

Genomics: Chronic Illness

Wellcome Trust Data

Sufficient to support valid causal inference

Quality of evidence made simple

A. Double blind placebo controlled trial with adequate sample*

B. Double blind comparison studies with adequate sample*

C. Open comparison trials with adequate sample*

D. Uncontrolled observation or controlled study with ambiguous result

E. No published evidence (+/- class effect)

F. Available evidence negative

* statistical power > 0.8 to detect meaningful differences at p< 0.05

Quality of Evidence for Widely Used PsychotropicsProphylaxisProphylaxis Acute Acute Mania /Mixed Mania /Mixed AcuteAcute Bipolar Depression Bipolar Depression Rapid CyclingRapid Cycling

LithiumLithium A+A+ A+A+ BB C-C-

DivalproexDivalproex A-A- A+A+ DD DD

CarbamazepineCarbamazepine DD A+A+ DD DD

LamotrigineLamotrigine A+A+ FF AA AA

GabapentinGabapentin E-E- FF DD DD

TopiramateTopiramate E-E- DD DD DD

OxcarbazepineOxcarbazepine E-E- DD E-E- DD

AripiprazoleAripiprazole AA A+A+ DD DD

ClozapineClozapine DD DD EE DD

HaloperidolHaloperidol DD AA E-E- E-E-

OlanzapineOlanzapine AA A+A+ AA DD

RisperidoneRisperidone E+E+ A+A+ DD DD

QuetiapineQuetiapine E+E+ A+A+ AA DD

ZiprasidoneZiprasidone E+E+ A+A+ E-E- E-E-

Omega 3Omega 3 DD E-E- FF FF

Acute Mania: Placebo controlled trialswith adequate* sample size

Positive• Lithium• Valproate• Carbamazepine

• Olanzapine• Ziprasidone• Aripiprazole• Risperidone• Haloperidol• Quetiapine

Negative/Failed• Lamotrigine• Gabapentin• Topiramate• Oxcarbazepine

*power to detect a difference > 0.8

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 sizePositivePositivePositivePositive

Li+ ParoxetineLi+ ParoxetineLi+ ImipramineLi+ ImipramineMS+ ParoxetineMS+ ParoxetineMS+ BupropionMS+ Bupropion

*power to detect a difference > 0.8

LamotrigineLamotrigine

OlanzapineOlanzapine

QuetiapineQuetiapine

Negative or FailedNegative or Failed

Olanzapine + FluoxetineOlanzapine + Fluoxetine

ImipramineImipramine

MS+ CBTMS+ CBTMS+ FFTMS+ FFTMS+ IPSRTMS+ IPSRT

Maintenance and continuation phase:Adequate Controlled Clinical trials

Positive

• Lithium*

• Valproate*

• Lamotrigine*

• Olanzapine*

• Aripirazole*

Negative/failed

• Imipramine

• Clonazepam

• Lithium

• Valproate*

* Some but not all outcomes

How well does How well does it work?it work?

20

What Is the Most Meaningful to Guide Clinical Practice?

Efficacy Outcomes– Response– Remission– Recovery– Roughening

• Adverse effects– Safety– Tolerability

Effectiveness Outcomes

– Durable Recovery

– Days well– Longest well interval

– Mean Duration of use

– 50% Improvement without treatment emergent switch

– Response X completion

Predictors– Treatment

outcome– Adherence– Self harm– Resilience– Death– Genes

•Adverse effectsTolerability

Safety

•Function

Big Picturevs

Detail

A Simple Metric for Effect Size Number Needed to Treat (NNT)= 1/(Active Response Rate - Placebo

Response Rate )

2.7

4.04.5

4.8 4.85.3

5.9

6.7NNT Acute Mania

Study Response Rate

Tohen 19991 Olanzapine (OLZ)=49%Placebo=24%

Tohen 20002 OLZ=65%Placebo=43%

Khanna 20053 Risperidone (RIS)=73%Placebo=36%

Hirschfeld 20044

RIS=43%Placebo=24%

Vieta 20055 Quetiapine (QTP)=48%Placebo=31%

Keck 20036 Ziprasidone (ZIP)=50%Placebo=35%

Keck 20037 Aripiprazole (ARI)=40%Placebo=19%

Sachs 20068 ARI=53%Placebo=32%

1. Tohen M et al. Am J Psychiatry. 1999;156:702-709; 2. Tohen M et al. Arch Gen Psychiatry. 2000;57:841-849; 3. Khanna S et al. Br J Psychiatry. 2005;187:229-234; 4. Hirschfeld RM et al. Am J Psychiatry. 2004;161:1057-1065; 5. Vieta E et al. Curr Med Res Opin. 2005;21:923-934; 6. Keck PE Jr et al. Am J Psychiatry. 2003;160:741-748; 7. Keck PE Jr et al. Am J Psychiatry. 2003;160:1651-1658; 8. Sachs G et al. J Psychopharmacol. 2006;epub Feb 14.

RIS3

OLZ1 OLZ2

ARI7

RIS4

QTP5

ZIP6ARI8

Same protocol different resultDosing Matters

-25

-20

-15

-10

-5

0Bas

elin

e

Day 3

Wee

k 1

Wee

k 2

Wee

k 3

Endpoint

RIS-USA-239

-25

-20

-15

-10

-5

0

Ch

an

ge

in

to

tal

YM

RS

sc

ore

RIS-IND-2

*

** **

**

** * * *

LOCF analysis. *P<.01; †P<.001 risperidone vs placebo.

Khanna S et al. 2005:187:229-34 Br J Psychiatry.

LOCF analysis. *P<.001 risperidone vs placebo.

Hirschfeld RM et al. 2004;161:1057-1065. Am J Psychiatry.

Risperidone Monotherapy for Acute Mania

25

162 166

197

97 99

127

59%47%

67%53% 54% 57%

Median treatment duration (d)

Recovered/recovering (%)

Lithium(n=49)

Valproate(n=38)

Lamotrigine(n=89)

AtypicalAntipsychotics

(n=216)

Antidepressants(n=264)

Anxiolytics(n=93)

MGH=Massachusetts General Hospital.Sachs G et al. APA, 2006; Toronto Canada

Real-World Pharmaco-EpidemiologyNew Treatment Starts at MGH Bipolar

Clinic

N=466 with at least 4 visits/year

26

Risperidonen=49

Quetiapinen=77

Aripiprazolen=46

MGH=Massachusetts General Hospital.Sachs G et al. Presented at: APA 2006 Toronto, Canada

MGH Bipolar Clinic Atypical Antipsychotics with least 20 new

starts

Olanzapinen=36

43%

65%

84.5

51%

65%

112

43%

59%

111

33%

64%

75

No significant differences

112111

Median Duration (days) % Recovering ≤ 3 months % Recovered ≤ 12 months

27

Paroxetinen=43

Venlafaxinen=21

Trazodonen=20

MGH=Massachusetts General Hospital.Sachs G et al. Presented at: APA 2006 Toronto, Canada

MGH Bipolar Clinic Antidepressants with least 20 new starts111

Bupropionn=52

75%

55%

145

43%

63%

100

56%

72%

103

54%

75%

109100

Citalopramn=20

119

62%

48%

No significant differences

112111

Median Duration (days) % Recovering ≤ 3 months % Recovered ≤ 12 months

Unintended Polypharmacy of MonotherapyUnintended Polypharmacy of MonotherapyUnintended Polypharmacy of MonotherapyUnintended Polypharmacy of Monotherapy

Many drugs act as fixed ratio combination agents

Pharmacology2007

Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. Caddo, OK: Professional Communications, Inc; 1996. http://www.preskorn.com.

Pharmacologic Determinants of Pharmacologic Determinants of ClinicalClinical ResponseResponsePharmacologic Determinants of Pharmacologic Determinants of ClinicalClinical ResponseResponse

Site of ActionSite of Action

Affinity for Affinity for receptorreceptor

Intrinsic Intrinsic activity at activity at sitesite

Drug Drug Concentration Concentration at Site of Actionat Site of Action

AbsorptionAbsorptionDistributionDistributionMetabolismMetabolismEliminationElimination

(ADME)(ADME)

IndividualIndividualBiologyBiology

GeneticsGeneticsAgeAgeDiseaseDiseaseEnvironmentEnvironment

(GADE)(GADE)

Relative Binding Affinity (RBA):

The affinity of a drug for a secondary site(s) target in relationship to most

potent binding site

Kd for secondary receptors

Kd for primary receptor

Preskorn SH. J Psych Pract. 2004

RBA =

Preskorn S J Psychiat Practice 9:376-384, 2005

Drug Concentration, Receptor Occupancy, and Selectivity

0.1 100 1,00010

1

0.01

25%

50%

75%

100%

% B

ou

nd

Concentration (nM)

3 fold 10 fold 100 fold= 1Target

Nonselective

Selective

Highly Selective

Range of Therapeutic

Action

In vitro Affinity Profiles: Known receptor affinities relative to most potent binding activity

Haloperidol profile relative to its most potent binding

1 10 100 1,000 10,000

5HT1A M-1 5HT2A H1 D2 5HT2C

Alpha1

1 10 100 1,000 10,000

5HT1A M-1

5HT2A H1

D2 5HT2C Alpha1

1 10 100 1,000 10,000

5HT1A M-1 5HT2A H1 D2

5HT2C

Alpha1

Aripiprazole profile relative to its most potent binding

Clozapine profile relative to its most potent binding

Arnt and Sharfeldt 1998; Daniel 1999; Bymaster et al 1996; Seegers et al 1995. Adapted from Preskorn 2006

In vitro Affinity Profiles: Known receptor affinities relative to most potent binding activity

1 10 100 1,000 10,000

5HT1A M-1 5HT2A H1 D2 5HT2CAlpha1

1 10 100 1,000 10,000

Alpha1 5HT1A 5HT2C 5HT2A H1 M-1 D2

1 10 100 1,000 10,000

M-1 H1 Alpha1D2 5HT1A 5HT2C 5HT2A

Ziprasidone profile relative to its most potent binding

Risperidone profile relative to its most potent binding

Quetiapine profile relative to its most potent binding

Olanzapine profile relative to its most potent binding

1 10 100 1,000 10,000

Alpha1D2 H1

5HT2C 5HT1A M-1 5HT2A

Arnt and Sharfeldt 1998; Daniel 1999; Bymaster et al 1996; Seegers et al 1995. Adapted from Preskorn 2006

The principles of Sequential and Urgent care dosing

The principles of Sequential and Urgent care dosing

SequentialCare

Urgent Care

Risperidone: DosingRisperidone: Dosing

Day 1-71-2 mgqd-bid

2-4 mgqd-bid

Day 3-28

UsualEffectiveRange

1- 4 mg

2-4mg/q

1-2 wks

1-2mg/q

2-4wks

Day 1-7

Day 8-14

Day 15-21

0.5 - 3 mg

0.5-2mgqd-bid

1-2 mgqd

2-3 mgqd

3-4 mgqd Day 22-28

SequentialCare

Urgent Care

Aripiprazole: DosingAripiprazole: Dosing

Day 1-715-30 mgqd

Day 3-28

UsualEffectiveRange

15-30 mg

15mg/q

1-2 wks

152-4wks

Day 1-7

Day 8-28

15 - 30 mg

5-10 mgqd

15-30 mgqd

15-30 mgqd

SequentialCare

Urgent Care

Olanzapine: DosingOlanzapine: Dosing

Day 1-710-20 mgqd

15-30 mgqd

Day 3-28

UsualEffectiveRange

10-30 mg

5-10mg/q

1-2 wks

2 .5 -10mg/q

2-4wks

Day 1-7

Day 8-21

5 - 20 mg

5-10mgqd

10-20 mgqd

20-30 mgqd

Day 22-28

Somnolence as an Adverse Event

Physicians’ Desk Reference ® 57th ed., Montvale, NJ: Medical Economics; 2003.

6

14 14

33

50

Olanzapine Quetiapine Ziprasidone Aripiprazole Risperidone

Number needed to observe=1/(active drug rate - placebo rate)

Number of Cases Needed to cause an extra case of Significant Somnolence

Abilify® [package insert]. Princeton NJ: Bristol-Myers Squibb and Rockville, Md: Otsuka America Pharmaceutical; 2005; Geodon® [package insert]. New York, NY: Pfizer; 2004; Risperdal® [package insert]. Titiusville, NJ: Janssen Pharmaceutica Products, LP; 2003; Seroquel® [package insert]. Wilmington DE: AstraZenaca; 2004; Zyrexa® [package insert]. Indianapolis, Ind: Eli Lilly and Company; 2004.

Clinically Significant Weight Gain (7%)In

cid

ence

(%

)

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

Place

bo

Aripip

razo

le

Place

bo

Zipra

sidone

Place

bo

Risper

idone

Place

bo

Quetia

pine

Place

bo

Olanza

pine

Atypical Antipsychotics vs PlaceboNNT 2025 12 6 4

Effects on Insulin Resistance

*Significant difference vs typicals, adjusted for weight and age (P<.05); Based on homeostatic model assessment, assessing insulin resistance and beta-cell function.

Adapted with permission. Newcomer JW et al. Arch Gen Psychiatry.Vol 59. pp337-345. Copyright © 2002. American Medical Association. All rights reserved.

HO

MA

In

suli

n R

esis

tan

ce,

Me

an

**

0

1

2

3

4

5

6

Control Typical Olanzapine ClozapineRisperidone

Treatment of Acute Mania:Divalproex, Lithium, vs Placebo

30

14

Bowden et al, JAMA 1994

Placebo

Divalproex

LithiumMan

ia R

ati

ng

Sca

le

14 217

Days

48%

9%

43%

54%

23% 23%27%

29%

44%

Lithium Divalproex Placebo

Marked Improvement >0 <10 WORSE

Acute Antimanic Efficacy vs Worsening• Adapted from Bowden et al

Antimanic Response to AripiprazoleWith High Versus Low Agitation

YMRS Total: Mean Change Baseline to Endpoint High or Low Agitation

• Including baseline YMRS score as a covariate and least-square means, aripiprazole-treated patients showed significant improvements at endpoint compared with placebo-treated patients in both high and low agitation groups

*P ≤ 0.0005, unadjusted means.

** *

* * *

Mean CGI-BP Scores: Acutely Manic Patients With High or Low Agitation

• Including baseline CGI-BP Severity score as a covariate and least-square means, aripiprazole-treated patients showed significant improvements at endpoint compared with placebo-treated patients in both high and low agitation groups

*P ≤ 0.05, unadjusted means.

* * * **

PEC Scores: Mean Change Baseline to Endpoint

• Including baseline PEC score as a covariate and least-square means, aripiprazole-treated patients showed significant improvements at endpoint compared with placebo-treated patients in both high and low agitation groups

Make the Guidelines your own!Customized Self guidance, not imperative directive

• Every clinical user can• Define decision points• Weigh options• Discipline assessment and intervention

• Utility requires– Concision – Critical Awareness of the evidence

• Subject to revision • New data becomes available • New Interventions become available

– Integration of Measurement into management

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