MEASURE Resource Module 2005

1
MEASURE Resource Module 2005

• Section 2
• An Update on Clinical Trialsin Bipolar Disorder

2
Objective

• To discuss the standards of care as well as
  current research on pharmacotherapeutic
  strategies for treating bipolar depression

3
Modern History of Bipolar Disorder
1921 Distinguished manic-depression from
schizophrenia 1949 Lithium antimanic effects
reported 1962 Bipolar terminology
introduced 1970s Lithium approved by FDA for
acute mania and maintenance therapy 1978
First inclusion of bipolar disorder in
DSM 1980s Traditional carelithium,
neuroleptics, ECT 1990s Lamotrigine,
depakote, and carbamazepine as mood
stabilizers (?? class effect) 2000 Role
of atypical antipsychotics/monotherapy of 2nd
generation antipsychotics (?? class effect)
DSM Diagnostic and Statistical Manual of Mental
Disorders ECT electroconvulsive therapy
4
Few Therapies With Bipolar Disorder Indications
2005 Physicians Desk Reference. Available at
http//www.pdr.net. Accessed July 25, 2005.
5
Lithium Efficacyin Bipolar Depression

• Lithium gt placebo in early placebo-controlled
  studies, but
• All crossover designs
• Lithium stopped abruptly in placebo groups,
  resulting in worse outcomes
• Mixed samples of bipolar and unipolar depressed
  patients
• In randomized studies, lithium minimally better
  than placebo and inferior to tricyclic
  antidepressants (TCAs)

Fieve RR, et al. Am J Psychiatry.
1968125487-491 Goodwin FK, et al. Arch Gen
Psychiatry. 196921486-496 Stokes PE, et al.
Lancet. 197111319-1325 Goodwin FK, et al. Am J
Psychiatry. 197212944-47 Mendels J, et al.
Arch Gen Psychiatry. 197226154-157 Noyes R Jr,
et al. Compr Psychiatry. 197415187-193 Baron
M, et al. Arch Gen Psychiatry. 1975321107-1111
Watanabe S, et al. Arch Gen Psychiatry.
197532659-668 Mendels J, et al. Lancet.
19761966 Donnelly EF, et al. J Consult Clin
Psychol. 197644233-237 Worrall EP, et al. Br J
Psychiatry. 1979135255-262.
6
Bipolar Depression Lithium With Antidepressants
(N 117)
70
Li PBO
60
Li PAR
50
Li IMI
Percent Reduction of HAMD Score
40
30
20
10
0
Li ? 0.8 mEq/L
Efficacy Overall

• Greater relapse prevention in mania vs depression
• Switch rate 0 paroxetine 3 placebo 7
  imipramine
• Mean Li level 0.78 mEq/L

Li lithium, IMI imipramine, PAR paroxetine,
PBO placebo
Nemeroff CB, et al. Am J Psychiatry.
2001158906-912.
7
Theories Why Lithium May Reduce Suicide Rates
Due to therapeutic monitoring increased
interaction with health care providers (more
socialization)
General mood-stabilizing effect
Effects on limbic dopamine activity
Specific anti-suicide effect theorized
Lithium
Decreased impulsive and aggressive features
Effects on limbic serotonin related activity
Note 13-fold reduction rate in suicide on lithium
vs no lithium treatment This is a long-term
benefit
Baldessarini RJ, et al. Ann NY Acad Sci.
200193224-38. Ernst CL, Goldberg JF. Harv Rev
Psychiatry. 20041214-41.
8
Time to Relapse of Any Mood Episode in Patients
Receiving Valproate, Lithium, or Placebo
1
Valproate
Lithium
0.8
Placebo
0.6
Survival
0.4
0.2
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Weeks
No significant difference in time to relapse was
found in bipolar I patients receiving maintenance
therapy with valproate, lithium, or placebo.
Bowden CL, et al. Arch Gen Psychiatry.
200057481-489.
9
Prophylaxis With Divalproex, Lithium, or
Placebo Additional Analyses
Double-blind1-year outcome
(n 372)
Recovery
Divalproex(n 187)
(n 571)
Open treatment 12 weeks
Acute episode within 3 months
Lithium(n 91)
Placebo(n 94)
McElroy SL, et al. Poster presented at IPS, 2003.
10
Divalproex Maintenance Period 59 Greater Than
Lithium
Mean number of days in the maintenance periodfor
subjects who were treated with the same
medicationin the open phase and maintenance phase
250
206.9
200
59
130.3
150
Mean Number of Days
100
50
0
Lithium
Divalproex
P 0.019
McElroy SL, et al. Poster presented at IPS, 2003.
11
Adding a Second Mood Stabilizer vs Adding an
Antidepressant
25
Hamilton Rating Scale for Depression
Two mood stabilizers Mood stabilizer
and paroxetine
(16)
20
Young Mania Rating Scale Two mood
stabilizers Mood stabilizer and
paroxetine
(11)
(15)
15
(11)
(12)
Score
(11)
(11)
(11)
10
(11)
(11)
(11)
n 27
(10)
(10)
(10)
5
0
Baseline
1
2
3
4
5
6
Duration of Treatment (weeks)
Parenthetical numbers indicate numbers of the
remaining 27 subjects, but the data points
include imputed (last observation carried
forward) data on dropouts. Medications used are
valproate lithium Young LT, et al. Am J
Psychiatry. 2000157124-126.
12
Lamotrigine in Bipolar Depression
Placebo
Lamotrigine 50 mg
Lamotrigine 200 mg
60
54
51
51
48
45
50

41
37
40
29
26
Responders ()
30
20
10
0
HAM-D-17
MADRS
CGI-I
Response defined as 50 reduction on the
17-item HAM-D or MADRS scale or a rating of very
much improved or much improved on the CGI-I scale
P lt 0.05 vs. placebo P lt 0.1 vs. placebo
Calabrese JR, et al. J Clin Psychiatry.
19996079-88.
13
Lamotrigine in Bipolar Depression (cont.)
Week
0
0.5
1
2
3
4
5
6
7
0
-2
P lt .05 vs placebo
-4
-6
-8
MADRS Change From Baseline

-10

-12



-14



Placebo (N 65)
-16
Lamotrigine 50 mg/d (N 64)

-18
Lamotrigine 200 mg/d (N 63)
-20
Dose gt 50 mg/d in lamotrigine 200 mg/d group only
after week 3
Calabrese JR, et al. J Clin Psychiatry.
200263(suppl 3)5-9.
14
Adverse Events From Lamotrigine Maintenance Trials

P lt 0.05 Li vs PBO P lt 0.05 Li vs LTG
Goodwin GM, et al. J Clin Psychiatry.
200465432-441.
15
Treatment Guidelines
16
First-line Treatments for Bipolar Depression
2002 APA Treatment Guidelines

• Lithium or lamotrigine are first-line treatments
  for bipolar depression
• Antidepressant monotherapy is not recommended
  (Category I)
• Lithium plus an SSRI is not considered a
  first-line treatment
• New controlled studies have recentlyemerged

American Psychiatric Association. Practice
Guidelines for the Treatment of Patients with
Bipolar Disorder. 2nd ed. Washington, DC 2002.
Category I Recommended with substantial
clinical confidence. Category II Moderate
confidence.
17
2004 Expert Consensus GuidelinesTreatment Acute
Bipolar Depression

• Lamotrigine monotherapy rated first line for
  every presentation except psychotic depression
• Lamotrigine or lithium rated first line as
  initial medication for severe nonpsychotic
  depression, depression with antidepressant-induced
  mania, and rapid cycling
• New controlled studies have recently emerged

Keck PE Jr, et al. Postgrad Med Special Report.
2004 (December)1-120.
18
2004 Expert Consensus GuidelinesTreatment Acute
Bipolar Depression (cont.)

• Antidepressants plus lithium rated first line for
  severe nonpsychotic depression despite the
  controversy
• Atypical antipsychotic and an antidepressant
  rated first line for psychotic bipolar
  depression, but second line for severe
  nonpsychotic depression

Keck PE Jr, et al. Postgrad Med Special Report.
2004 (December)1-120.
19
Treatment Guidelines

• Guidelines help avoid non-evidence-based
  treatment decision
• As new studies emerge, guidelines can become
  outdated

Fountoulakis KN, et al. J Affect Disord.
2005861-10.
20
Guidelines for Acute Mania
AP antipsychotic Cbz carbamazepine ECT
electroconvulsive therapy Li lithium Olz
olanzapine Quet quetiapine Risp
risperidone Vp valproate.
Fountoulakis KN, et al. J Affect Disord.
2005861-10. Keck PE Jr, et al. Postgrad Med
Special Report. 20041-120.
21
Guidelines for Acute Bipolar Depression
AD antidepressant Cbz carbamazepine ECT
electroconvulsive therapy La lamotrigine Li
lithium Olz olanzapine Quet quetiapine
Risp risperidone Vp valproate.
Fountoulakis KN, et al. J Affect Disord.
2005861-10. Keck PE Jr, et al. Postgrad Med
Special Report. 20041-120.
22
Guidelines for Bipolar Maintenance
Arip aripiprazole Cbz carbamazepine ECT
electroconvulsive therapy La lamotrigine Li
lithium OCBz oxcarbamazepine Olz
olanzapine Quet quetiapine Risp
risperidone Vp valproate Zipr ziprasidone.
Fountoulakis KN, et al. J Affect Disord.
2005861-10. Keck PE Jr, et al. Postgrad Med
Special Report. 20041-120.
23
Proportion of Use of Each Classof Medications
for Bipolar Patients
Bipolar I
Bipolar II
70
60
50
40
Percent
30
20
10
0
Benzo-diazepine
Adequate Mood Stabilizer
Stimulant
Antipsychotic
Antidepressant

• STEP Study

Simon NM, et al. J Clin Psychopharmacol.
200424512-520.
24
Monotherapy for Bipolar Disorder Adverse Events
Atypical Antipsychotics

• Olanzapine
• Weight gain, somnolence, diabetes, hyperlipidemia
• Risperidone
• EPS, ? prolactin, weight gain
• Quetiapine
• Somnolence, hypotension, weight gain
• Ziprasidone
• Akathisia, ? QTc
• Aripiprazole
• Akathisia, insomnia, nausea

Dose related EPS. Adverse effects with
moderate/high frequencies listed. Bold face
indicates marked significance. EPS
extrapyramidal syndrome Akathisia is noted in
all atypical antipsychotics Adapted from
Nasrallah HA, et al. Ann Clin Psychiatry.
200113215-227. Adapted from Halbreich UM, et
al. Psychoneuroendocrinology. 20032853-67.
25
Monotherapy for Bipolar Disorder Adverse Events
(cont.)
Mood Stabilizers

• Lithium
• Polyuria, tremor, weight gain, hypothyroidism
• Valproate
• Weight gain, somnolence, gastrointestinal, memory
  impairment
• Lamotrigine
• Rash, drug interactions
• Carbamazepine
• Enzyme induction, rash, leukopenia

Common benign and rare serious. Adverse effects
with moderate/high frequencies listed. Bold face
indicates marked significance. Adapted from
Nasrallah HA, et al. Ann Clin Psychiatry.
200113215-227. Adapted from Halbreich UM, et
al. Psychoneuroendocrinology. 20032853-67.
26
Pharmacotherapyof Bipolar Depression
27
Inadequate Response to Initial Strategy for
Bipolar Depression

• Optimize dose and duration of trial although the
  benefit of optimization has never been studied
• Given a partial response in nonpsychotic bipolar
  depression, experts recommended adding (not
  switching) medication
• If initial treatment was a mood stabilizer or
  atypical antipsychotic, add lamotrigine or an
  antidepressant

Keck PE Jr, et al. Postgrad Med Special Report.
2004 (December)1-120.
28
Medications With at Least One Randomized,
Controlled Trial for Bipolar Depression
Risk of serious side effects associated with
rapid titration. Doses used for maintenance
treatment may be lower. Adapted from Goldberg
JF, et al. Bipolar Disord. 2003.
29
Medications With at Least One Randomized,
Controlled Trial for Bipolar Depression (cont.)
Adapted from Calabrese JR, et al. Am J
Psychiatry. 20051621351-1360 Adapted from
Tohen MF Jr, et al. Arch Gen Psychiatry.
2003601079-1088. Erratum in Arch Gen
Psychiatry. 20046176. US Food and Drug
Administration. Available at http//www.fda.gov/c
der/foi/appletter/2004/20825s009ltr.pdf.
Accessed December 1, 2004.
30
Mood Stabilizers Acrossthe Bipolar Spectrum
1 or more randomized, controlled trials
Ghaemi SN, et al. Bipolar Disord.
20035421-433.Goodwin GM, et al. J
Psychopharmacol. 200317149-173.Baldessarini
RJ, et al. Bipolar Disord. 20035169-179.
31
Atypical Antipsychotics Acrossthe Bipolar
Spectrum
1 or more randomized, controlled trials
Ghaemi SN, et al. Bipolar Disord.
20035421-433.Goodwin GM, et al. J
Psychopharmacol. 200317149-173.Baldessarini
RJ, et al. Bipolar Disord. 20035169-179.
32
Bipolar DepressionOlanzapine-Fluoxetine
Combination (OFC)
Placebo (n 355)
-2
Olanzapine (n 351)
-4
Olanzapine-fluoxetine combination (n 82)
-6
-8
Visitwise Improvement From Baseline in MADRS
(LOCF)

-10

-12



-14



-16


-18





-20
0
1
2
3
4
5
6
7
8
Week

P lt .05 vs placebo

P lt .05 vs olanzapine
Tohen MF Jr, et al. Arch Gen Psychiatry.
2003601079-1088. Erratum in Arch Gen
Psychiatry. 20046176.
33
Bipolar DepressionOFC MADRS Item Analyses
Source

Apparent sadness
Review

Reported sadness

Inner tension


Reduced sleep


Olanzapine fluoxetine
Reduced appetite

Olanzapine
Reviewer Memo
Placebo
Concentration difficulties

Lassitude

Inability to feel

Pessimistic thoughts
Suicidal thoughts
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
P lt .05 Olanzapine vs placebo P lt .05 OFC
vs placebo P lt .05 OFC vs Olanzapine Tohen MF
Jr, et al. Arch Gen Psychiatry.
2003601079-1088. Erratum in Arch Gen
Psychiatry. 20046176.
Mean Change From Baseline MADRS Items (LSM)
Slide Modified
Memo
34
Bipolar Depression Mood Stabilizer Plus
Risperidone and/or Paroxetine
Risperidone (n 10)
24
Paroxetine (n 10)
22
Risperidone paroxetine (n 10)
20
Paroxetine
18
P ns
16
Risperidone paroxetine
14
HAM-D Score
12
Risperidone
10
8
6
4
2
0
2
0
1
3
4
5
6
7
8
9
10
11
12
Week
Shelton R, Stahl S. J Clin Psychiatry.
2004651715-1719.
35
Time to Relapse Into Mania or DepressionWith
Olanzapine vs Placebo
Tohen M, et al. Olanzapine versus placebo for
relapse prevention in bipolar disorder,
(Abstract) Presented at 156th Annual Meeting of
the American Psychiatric Association. San
Francisco, CA, 2003
36
Bipolar DepressionQuetiapine Monotherapy
Study Week
1
2
4
3
6
5
7
8
0
Placebo (n 169)
Quetiapine 300 mg (n 172)
-5
Quetiapine 600 mg (n 170)

Mean Change From Baselinein MADRS Total Score

-10








-15






P lt 0.001 vs placebo (ITT, LOCF)
-20
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
37
Bipolar Depression QuetiapineMADRS Item
Analyses

Apparent Sadness


Reported Sadness


Inner Tension


Reduced Sleep

Reduced Appetite

Quetiapine 600 mg (n 170) Quetiapine 300 mg (n
172) Placebo (n 169)
Conc. Difficulties


Lassitude

Inability to Feel


Pessimistic Thoughts


Suicidal Thoughts

0
10
20
30
40
50
60
70
80
Mean Change in Score
P lt 0.05 P lt 0.01 P lt 0.001 vs placebo ITT,
LOCF
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
38
Common Adverse Events (gt 10 patients and 2x
placebo rate)
Dropouts due to sedation or somnolence 10.9
mostly within 7 days.
Calabrese JR, et al. Am J Psychiatry.
20051621351-1360.
39
Observed Magnitudeof Antidepressant Effect
1.2
BP I
1.0
QUET 600
QUET 300
0.8
BP II
LTG 200
0.6
OFC
Effect Size
0.4
LTG 50
OLA
0.2
0
OFC
OLA
LTG 50
QUET 300
QUET 600
LTG 200
QUET 600
QUET 300
Effect size (ES) improvement over
placebo/pooled SD. small lt 0.4 moderate
0.40.79 large gt 0.79. Combined ES for
quetiapine 0.66/0.80
Calabrese JR. Issues in treating bipolar
depression. Paper presented at APA 2005 Annual
Meeting May 22, 2005 Atlanta, Georgia.
40
Safety and Tolerability
41
Metabolic Syndrome and Serious Mental Illness

• Recent reports by the FDA, ADA, APA, AACE, and
  NAASO have raised concerns regarding obesity,
  diabetes, and dyslipidemia as adverse effects of
  atypical antipsychotic agents1
• In addition, the metabolic syndrome appears to be
  more common in patients with schizophrenia and
  bipolar disorder
• Monitoring is now recommended1,2

AACE American Association of Clinical
Endocrinologists NAASO North American
Association for the Study of Obesity. 1 American
Diabetes Association. Diabetes Care. 200427596.
2 Buse JB. J Clin Psychiatry. 200263(suppl
4)37-41.
42
Incidence of Selected Serious Adverse Effects
With Boxed Warnings in Prescribing
Information SJS Stevens-Johnson Syndrome TEN
Toxic Epidermal Necrolysis. 1. Physicians Desk
Reference. 59th ed. Montvale, NJ Medical
Economics Co 2005. 2. Pellock JM. Epilepsia.
198728(suppl 3)S64-S70. 3. Leppik I.
Contemporary Diagnosis and Management of the
Patient With Epilepsy. Newtown, PA Handbooks in
Health Care 2001130.
43
Antipsychotic Safetyand Tolerability Concerns

• Second-generation
• Weight gain
• Sedation
• Diabetes
• Cardiac
• Akathisia
• Hyperprolactinemia
• NMS
• Cerebrovascular

Warning in prescribing information
44
Fixed-Effect Model of Clinical Response in
Randomized, Controlled Trials of Antidepressants
Versus Placebofor the Treatment of Bipolar
Depression
Favors placebo Favors antidepressant
0.1 0.2 0.5 1.0 2.0
5.0 10.0
aSignificance test for heterogeneity (?2 10.51,
df 3, P 0.01 I2 71.4). Significance test
for overall effect (z 5.60, P lt
0.00001). Gijsman HJ, et al. Am J Psychiatry.
20041611537-1547.
45
Bipolar DepressionDivalproex Monotherapy
Week
Subjects Responding
1
2
3
4
5
6
7
8
50
0

-2
40
Placebo (n 22)
-4
30
Percentage of Patients
-6
Mean ? From Baseline HAM-D
20
-8

10
DVP (n 22)

-10
0
-12
DVP
Placebo
P 0.051 vs placebo P 0.052 vs placebo
P lt 0.035 vs placebo
Sachs GS, et al. Presented at American College
of Neuropsychopharmacology Annual Meeting May
2001 Honolulu, HI. Davis LL, et al. Expert Rev
Neurother. 20044349-362.
46
Carbamazepine Extended-release Capsules Improve
Depressive Symptoms in Patients With Mixed
Episodes
MIXED
Moderate
Placebo n 67
Change -2.25
Mild
Change -4.77
Carbamazepine extended-release capsules n 80
MANIC
Placebo n 146
Change -0.70
Non-depressed
Change -1.72
Carbamazepine extended-release capsules n 134
P lt .05 compared to placebo following ANCOVA
with baseline score as covariate. Data on file,
Shire Pharmaceuticals. Wayne, PA.
47
Do the SSRIs Destabilizethe Course of Bipolar
Disorder?
SSRI PBO vs DVP SSRI P lt 0.05 DVP vs PBO
P lt 0.05
Gyulai L, et al. Neuropsychopharmacology.
2003281374-1382.
48
Why Do Antidepressants Appear More Effective Than
They Are?

• Negative studies go unpublished, which inflates
  reported effect sizes
• Old studies took credit for switching
• Antidepressants work acutely, but have been
  ineffective in randomized clinical trials
• May be effective for short term but not long term

Ghaemi SN, et al. J Clin Psychiatry.
200162565-569. Kraemer HC, et al. Int
Psychogeriatr. 19981043-51. Calabrese JR, et
al. Eur Neuropsychopharmacol. 19999S109-S112.
49
Bipolar Depression and Antidepressants General
Guidelines and Risks

• Always use mood stabilizer in bipolar I patients,
  even while depressed
• Promptly wean the antidepressant if evidence of
  hypomania or mania emerges
• Antidepressants may trigger mania (mood
  destabilization) or accelerate mood cycle
• Up to 33 of patients with bipolar disorder may
  be susceptible to antidepressant-induced manias
• Possibly less efficacious in BP than UP
  depression
• Few standard antidepressants have been studied in
  bipolar depression

Dantzler A, Osser DN. Psychiatr Ann.
199929270-284. Frances AJ, et al. J Clin
Psychiatry. 199859(suppl 4)73-79. Goldberg JF,
Ernst CL. J Clin Psychiatry. 200263985-991. Gold
berg JF, Truman CJ. Bipolar Disord.
20035407-420. Möller HJ, et al. J Affect
Disord. 200167141-146.
50
The Consequences of Inappropriate Treatment of
Bipolar Depression

• Misdiagnosis can result in inappropriate
  treatment, aggravated course and future treatment
  resistance
• Naturalistic study of 32 patients with bipolar
  disorder in a psychiatric clinic, all of whom had
  been misdiagnosed and (mis)treated as unipolar
  depressives
• 55 developed a manic/hypomanic episode on
  antidepressants
• 23 developed new or accelerated rapid cycling

Rapid cycling occurs when a person experiences
four or more mood swings or episodes in a
twelve-month period. An episode can consist of
depression, mania, hypomania or even be a mixed
state. Rapid cycling in children can be ultra
rapid in contrast to adults.
Ghaemi SN, et al. J Clin Psychiatry.
200061804-808.
51
Summary

• Evidence-based treatment for bipolar depression
  includes lithium, lamotrigine, and
  antidepressants
• Quetiapine and OFC are emerging as viable
  alternatives for bipolar depression
• Monotherapy standard antidepressants may cause
  problems in terms of mood destabilization in
  bipolar depression
• Using antidepressants in bipolar depression is
  better than nothing, but not better than using
  lithium or a mood stabilizer
• Some novel antipsychotics may have a role in
  treating bipolar depression as monotherapy while
  stabilizing mania
• Goal is to stabilize depression without causing
  mania and minimizing side effects