vienna practical experience 2007
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Practical ReviewTRANSCRIPT
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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