Treatment of Acute Mania:

1
Treatment of Acute Mania

• Evidence of Efficacy

2
APA Bipolar 2002 Treatment Guidelines

• Pharmacologic management
• Severe manic or mixed episodes lithium or
  valproate plus antipsychotic
• Less ill patients monotherapy with lithium, or
  valproate, or an antipsychotic, such as
  olanzapine may be sufficient
• Atypical antipsychotics are preferred over
  typical antipsychotics because of their more
  benign side effect profile
• When first-line medication treatment at optimal
  doses fails to control symptoms, recommended
  treatment options include addition of another
  first-line medication

American Psychiatric Association. Practice
Guideline for the Treatment of Patients with
Bipolar Disorder. 2nd ed. Washington, DC 2002.
3
APA Bipolar 2002 Treatment Guidelines

• Pharmacologic management (cont.)
• Alternative treatment options include adding an
  antipsychotic if not already prescribed or
  changing from one antipsychotic to another
• Manic or mixed episodes with psychotic features
  usually require treatment with an antipsychotic
  medication
• Clozapine may be particularly effective with
  refractory cases

American Psychiatric Association. Practice
Guideline for the Treatment of Patients with
Bipolar Disorder. 2nd ed. Washington, DC 2002.
4
Treatment of Acute Mania
Lithium
5
Variable Lithium Response Rate
Based on Bipolar Subtype
Rapid Cycling(30)
Dysphoric Manic
Substance Abuse (current and/ or history)
(-) Family History
gt 3 Episodes
DMI Pattern
Poor Response
M
D
Nonrapid Cycling (70)
Euphoric Manic
No Substance Abuse
() Family History
Few Lifetime Episodes
MDI Pattern
Adequate Response
M
D
Frye MA et al. Curr Psychiatry. 20032(suppl)
10-13.
6
Treatment of Acute ManiaCarbamazepine
7
Carbamazepine Monotherapy Effective inAcute
Mania 4 Randomized Comparative Trials
76
80
71
67
70
63
60
56
50
Percentage Responders
40
33
33
30
20
10
n 26
n 32
n 18
n 19
n 19
n 28
n 26
CBZ
CBZ
Li
CBZ
CPZ
CBZ
CPZ
Post, 1987
Small, 1991
Okuma, 1979
Grossi, 1984
Duration of studies ranged from 11 to 56 days.
CBZ carbamazepine, Li lithium, CPZ
chlorpromazine Post RM et al. Psychiatry Res.
19872171-83 Small JG et al. Arch Gen
Psychiatry. 199148915-921 Okuma T et al.
Psychopharmacology. 197966211-217 Grossi E et
al. In Anticonvulsants in Affective Disorders.
1984177-187.
8
Treatment of Acute Mania
Valproate
9
Valproate Monotherapy Effective in Acute Mania
5 Randomized Controlled Trials
90
92
80
80
75
P lt 0.01
70
63
60

53
48
50
Percentage Responders
40
30
25
20
10
10
n 17
n 68
n 5
n 73
n 8
n 14
n 13
n 19
VPA
VPA
VPA
PBO
VPA
PBO
VPA
Li
Emrich
Brennan
Pope
Bowden
Freeman
Emrich HM et al. Adv Biochem Psychopharmacol.
198126287-296 Brennan MJ et al.
Anticonvulsants in Affective Disorders.
Amsterdam Excerpta Medica 198456-65 Pope HG
Jr. et al. Arch Gen Psychiatry. 19914862-68
Freeman TW et al. Am J Psychiatry.
1992149108-111 Bowden CL et al. JAMA.
1994271918-924.
10
Treatment of Acute Mania

• Clozapine

11
Clozapine in Bipolar Disorder
100
Clozapine
80
60
Percent of Patients With 30 Improvement
Treatment as Usual
40
20
0
12
11
10
9
8
7
6
5
4
3
2
1
0
Months
Suppes T et al. Am J Psychiatry.
19991561164-1169.
12
Treatment of Acute Mania
Olanzapine
13
Olanzapine in Bipolar Disorder
70
Olanzapine
Divalproex
60
62
50
Number of Days
40
30
20
10
14
0
Median Time to Symptomatic Mania Remission
Tohen M et al. Am J Psychiatry.
20031601263-1271.
14
Efficacy of Olanzapine Monotherapy Improvements
in Mania Ratings Across Studies
vs Placebo1
vs Placebo2
vs Valproate4
vs Valproate3
3 wks
4 wks
3 wks
3 wks
0
-2
n 66
-4
Olanzapine
-4.88
-6
n 56
Placebo
Mean Change in MRS Score
-8
n 123
-8.13
n 70
-10
-10.39
Valproate
-10.26

n 125
-12
n 63
n 54
-14
-13.36

n 57
-14.8
-14.78

-16
-17.2
P NS
-18
P .019
P lt .001
P .028
The Zajecka study used the SADS-C derived for
mania ratings other studies used the YMRS.
Results shown are from a three-week period where
all patients were inpatients
1. Tohen M et al. Am J Psychiatry.
1999156702-709. 2. Tohen M et al. Arch Gen
Psychiatry. 200057841-849. 3. Tohen M et al. Am
J Psychiatry. 20021591011-1017. 4. Zajecka JM
et al. J Clin Psychiatry. 2002631148-1155.
15
Treatment of Acute Mania
Risperidone
16
Risperidone vs Placebo in Acute Mania Mean
Reduction in YMRS Score
Baseline
Day 3
Week 1
Week 2
Week 3
Endpoint
0
LOCF analysis P lt 0.001 risperidone vs placebo
-2
Placebo (n 125 BL YMRS 29.2)
-4
-6
Mean Change in Total YMRS Score

-8
Risperidone (n 134 BL YMRS 29.1 ) Median
dose 4.1 mg/day
-10




-12
BL Baseline Hirschfeld RO et al. Presented at
ACNP Annual Meeting. San Juan, Puerto Rico.
December 2002.
17
Add-on to Mood Stabilizer Response Placebo vs
Haloperidol vs Risperidone
70
58
57
60
50
38
40
Percent of Patients
30
20
10
0
RIS Mood Stabilizer
Placebo Mood Stabilizer
HAL Mood Stabilizer
Response defined as ? 50 decrease in YMRS from
baseline. Mood stabilizer lithium or divalproex.
Sachs GS et al. Am J Psychiatry.
20021591146-1154.
18
Treatment of Acute Mania
Quetiapine
19
Quetiapine vs Haloperidol vs Placebo Mean
Reduction in YMRS Score in Acute Mania
0
-5

-10
YMRS Mean Change From Baseline

-15

-20

-25
7
4
21
0
14
28
42
56
70
84
Time (days)
Quetiapine vs placebo, P 0.010, Haloperidol
vs placebo, P lt0.001 Quetiapine vs placebo, P
lt0.001 ITT, LOCF analysis results of a 12-week,
multicenter, double-blind, randomized,
parallel-group, placebo-controlled trial.
Jones M, Huizar K. Presented at the Fifth
International Conference on Bipolar Disorder.
Pittsburgh, PA June 12-14, 2003.
20
Quetiapine vs Lithium vs Placebo Mean Reduction
in YMRS Score in Acute Mania
0
-5
-10

YMRS Mean Change From Baseline
-15


-20

-25
4
7
21
0
14
28
42
56
70
84
Day
Quetiapine vs placebo, P lt0.001 Lithium vs
placebo, P lt0.001
Jones M, Huizar K. Presented at the Fifth
International Conference on Bipolar Disorder.
Pittsburgh, PA June 12-14, 2003.
21
Quetiapine vs Placebo Mean Reduction in YMRS
Score in Acute Mania
0

-5
Placebo

-10
YMRS Mean Change From Baseline
Quetiapine


-15




-20

-25
4
21
7
0
14
28
42
56
70
84
Days
P lt 0.001 P 0.021
Jones M, Huizar K. Presented at the Fifth
International Conference on Bipolar Disorder.
Pittsburgh, PA June 12-14, 2003.
22
Quetiapine vs Placebo in Combination With Mood
Stabilizer Change in Total YMRS
0
Placebo Li/DVP
Quetiapine Li/DVP
-5
-10
Change From Baseline YMRS
-9.93
-13.76
-15
P 0.021
-20
4
7
10
14
21
Day
Sachs GS et al. Presented at the 3rd European
Stanley Foundation Conference on Bipolar
Disorder. Freiberg, Germany September 12-14,
2002.
23
Treatment of Acute Mania
Ziprasidone
24
Ziprasidone vs Placebo Mean Reduction in YMRS
Score

0
-2
-4
-6

-8
-10


-12

YMRS Mean Change From Baseline
-14

-16
P lt.001 P lt.001 vs placebo
-18
Placebo (n 66)
-20
Ziprasidone (n 131) 160 mg/day
-22
-24
-26
21
7
14
0
Study Day
Keck PE Jr. et al. Am J Psychiatry.
2003160741-748.
25
Treatment of Acute Mania
Aripiprazole
26
Aripiprazole vs Placeboin Acute Mania Mean
Change in YMRS
0
-2
-4

-6




-8
-10
Placebo (n 122 mean baseline 29.7)
Mean Change From Baseline (SD)
-12
-14
Aripiprazole (n 123 mean baseline 28.2)
-16
-18
-20
-22
-24
-26
Day 4
Week 1
Day 10
Week 2
Week 3
P lt0.01 vs placebo, LOCF analysis. Keck PE Jr.
et al. Am J Psychiatry. 20031601651-1658.
27
Aripiprazole vs Haloperidol in Acute Mania
Efficacy (YMRS)
0
Average Daily Dose At end of week 12
Aripiprazole 21.6 mg/d Haloperidol 11.1
mg/d
-5
-10
Aripiprazole
(n 173)
Change in YMRS (LOCF)
-15
Haloperidol
(n 164)
-20
Average Daily Dose At end of week 3
Aripiprazole 22.6 mg/d Haloperidol 11.7 mg/d
-25
(Day 4)
1
2
3
4
6
8
10
12
Treatment Duration (wk)
Baseline YMRS scores aripiprazole 31.07,
haloperidol 31.39. Bourin M et al. Presented
at American Psychiatric Association 156th Annual
Meeting. San Francisco, CA May 17-22, 2003.
28
Treatment of Acute ManiaTopiramate and
Gabapentin

• Topiramate and gabapentin have not shown
  differentiation from placebo in the treatment of
  acute mania

Johnson Johnson press release, September 2,
2002. Pande AC. Bipolar Disord. 20022(3 pt
2)249-255.
29
Bipolar DepressionLithium
30
Double Blind Lithium Plus Placebo, Paroxetine,
or Imipramine
70
Li PBO
60
Li PAR
50
Li IMI
Percent Reduction of HAMD Score
40
30
20
10
0
Efficacy Overall
Li ? 0.8 mEq/L
Li lithium, IMI imipramine, PAR paroxetine,
PBO placebo
Nemeroff CB et al. Am J Psychiatry.
2001158906-912.
31
Bipolar DepressionDivalproex
32
Divalproex Monotherapy for Bipolar Depression
Subjects Responding
Week
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 ACNP Annual
Meeting. Honolulu, HI May 2001.
33
Bipolar DepressionCarbamazepine
34
Carbamazepine Possibly Effective in Acute
Bipolar Depression

• At least 8 small, open studies and 4 small,
  controlled studies have evaluated CBZ in acute
  bipolar depression
• Overall response rate (from 249 combined bipolar
  and unipolar patients) of 551
• Largest published trial2
• 27 patients with bipolar depression
• 3-week, open-label CBZ
• Mean Hamilton score decreased 23.7 10.9 (P lt
  0.0001)
• 17 (63) patients entered remission

1. Post RM et al. Psychopharmacology.
1996128115-129. 2. Dilsaver SC et al. Biol
Psychiatry. 199640935-937.
35
Bipolar DepressionLamotrigine
36
Lamotrigine Efficacy in Bipolar I Depression
Week
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.
37
Bipolar DepressionTopiramate
38
Topiramate vs Bupropion in Bipolar Depression
25
Topiramate 50-300 mg/day (n 18)
20
Bupropion SR 100-400 mg/day (n 18)
15
HAM-D Score
10
5
0
1
2
3
4
5
6
7
8
Weeks
P not significant
McIntyre RS et al. Bipolar Disord. 20024207-213.
39
Bipolar DepressionRisperidone
40
Risperidone ? Paroxetine vs Paroxetine Combined
With Mood Stabilizer in Bipolar Depression
24
22
20
Paroxetine
18
16
14
Risperidone paroxetine
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
Stahl S et al. Presented at ACNP Annual Meeting.
Honolulu, HI. May 2001.
41
Bipolar DepressionOlanzapine
42
Rapid Improvement of Bipolar DepressionOlanzapin
e-Fluoxetine Combination (OFC), Olanzapine
(OLZ), and Placebo (PBO)
Source
Review
0

-2
P lt 0.05 vs placebo
Olanzapine (n 351)

P lt 0.05 vs olanzapine
-4
Placebo (n 355)
OFC (n 82)
-6
Visitwise Improvement From Baseline in MADRS
(LOCF)
-8

Reviewer Memo
-10


-12


-14



-16


-18





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

• OFC separates statistically from PBO at weeks 1,
  3, 4, 6, and 8 postbaseline
• OFC separates statistically from OLZ at weeks 4,
  6, and 8 postbaseline
• OLZ separates statistically from PBO at every
  week (1, 2, 3, 4, 6, and 8) postbaseline

Tohen M et al. Presented at 155th APA Annual
Meeting. Philadelphia, PA. May 18-23, 2002.
Memo
43
Bipolar MaintenanceLithium
44
Double-Blind, Controlled Long-Term Trials With
Lithium
Li lithium IMI imipramine
Ghaemi SN et al. J Clin Psychiatry.
200162565-569.
45
Lithium vs Placebo in Maintenance
1.2
1
0.8
0.6
Probability of Remaining Well
0.4
Lithium
0.2
Placebo
0
0
10
20
30
40
50
60
Follow-Up (wks)
Keck PE Jr et al. Biol Psychiatry.
200047756-761.
46
Bipolar Maintenance
Divalproex
47
Improvement in Manic Symptoms and Number of
Lifetime Affective Episodes in Acute Mania at
Treatment Baseline
Divalproex Placebo Lithium
9 8 7 6 5 4 3 2 1 0
Improvement in Manic Symptoms
0
10
15
20
5
Total Affective Episodes

• Swann AC et al. Arch Gen Psychiatry.
  19975437-42.

48
Bipolar MaintenanceOlanzapine
49
Relapse Into Mania or Depression Scale-Based
Outcomes in 1-Year Olanzapine-Lithium Comparison
50
P .055
Olanzapine (n 217)
Lithium (n 214)
38.8
40
P lt .001

30.0
28.0
30
P .895
Percent of Patients

20
16.1
15.4
14.3
10
0
Overall Relapse
Depressive Relapse
Manic Relapse
Relapse defined by YMRS ?15 and/or HAM-D
?15. Tohen M et al. Presented at Stanley
Bipolar Meeting. Freiberg, Germany. September
11-14, 2002.
50
Prevention of Relapse Into Depression or Mania
Olanzapine (OLZ) With Concomitant Lithium (Li) or
Valproate (VAL) vs Lithium or Valproate Alone
100
OLZ cotherapy (n 30)
Li or VAL monotherapy (n 38)
80
P .023
60
Percent Probability ofRemaining in Remission
40
20


0
0
100
200
300
400
500
Time to Recurrence Into Mania or Depression
(days)
Time to recurrence into either pole following
symptomatic remission of mania (YMRS ? 12) and
depression (HAM-D21 ? 8), was significantly
longer for the olanzapine cotherapy group
compared to the monotherapy group (estimated 25th
percentile 124 vs 15 days, respectively).
Tohen MF et al. Presented at 155th APA Annual
Meeting. Philadelphia, PA. May 18-23, 2002.
51
Bipolar Maintenance
Lamotrigine
52
Lamotrigine vs Lithium vs Placebo Time to
Intervention for a Mood Episode
1
Li vs PBO, P 0.029 LTG vs PBO, P 0.029 LTG
vs Li, P 0.915
0.9
0.8
0.7
Median 24 weeks
0.6
Median 29 weeks
Survival Estimate
0.5
Li (n 46)
0.4
LTG (n 59)
0.3
PBO (n 70)
0.2
0.1
0
60
70
0
10
20
30
40
50
Week
LTG lamotrigine 100 to 400 mg daily Li
lithium 0.8-1.1 mEq/L PBO placebo
Bowden CL et al. Arch Gen Psychiatry.
200360392-400.
53
Bipolar Maintenance
Carbamazepine
54
Randomized, Open, 2½-Year Maintenance
Study of
Lithium vs Carbamazepine Recurrent/Concomitant
Medication
1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Li gt CBZ, P .01
Survival
Lithium (Li) Carbamazepine (CBZ)
0
4
8
12
16
20
24
28
32
Survival Time (months)
Greil W et al. J Affect Disord. 199743151-161.