Upgrading Your Brain Made Easy

1
UpgradingYour BrainMade Easy
2

• New Treatment Options for Patients with Bipolar
  Disorders Terence A. Ketter, M.D.

3
Disclosure Information Research Support /
Consultant / Speaker

• Abbott Laboratories, Inc.
• AstraZeneca Pharmaceuticals LP
• Bristol-Myers Squibb Company
• Cephalon Inc.
• Corcept Therapeutics
• Elan Pharmaceuticals, Inc.
• Eli Lilly and Company
• Forest Laboratories, Inc.
• GlaxoSmithKline
• Janssen Pharmaceutica Products, LP
• Jazz Pharmaceuticals, Inc.
• Merck Co., Inc.
• Novartis Pharmaceuticals Corporation
• Pfizer Inc.
• Shire Pharmaceuticals Group plc.
• Solvay Pharmaceuticals, Inc.
• UCB Pharmaceuticals
• Wyeth Pharmaceuticals

4
(No Transcript)
5
Overview

• Mood Stabilizers
• A - Lithium, divalproex, carbamazepine
• B - Lamotrigine
• New Anticonvulsants
• Oxcarbazepine
• Gabapentin, topiramate, tiagabine
• Levetiracetam, zonisamide
• New Antipsychotics
• Clozapine
• Risperidone, olanzapine, quetiapine
• Ziprasidone, aripiprazole

6
Agents Approved for Bipolar I Disorder in the U.S.

• Acute Mania
• Year Drug
• 1970 Lithium
• 1973 Chlorpromazine
• 1994 Divalproex
• 2000 Olanzapine
• Risperidone
• 2004 Quetiapine
• Ziprasidone
• 2004 Aripiprazole
• 2004 Carbamazepine

• Maintenance
• Year Drug
• 1974 Lithium
• 2003 Lamotrigine
• Olanzapine
• 2005 Aripiprazole

• Acute Depression
• Year Drug
• Olanzapine-   fluoxetine   combination
• 2006 Quetiapine

Adjunctive as well as monotherapy
Ketter TA (ed). Advances in the Treatment of
Bipolar Disorders. Am Psychiatric Press, Inc.
20052.
7
Overview of 20 Acute Mania Studies Response Rates
5 Combination Therapy Studies
15 Monotherapy Studies
62
65
60
55
50
Plt0.0001
50
42
45
40
Plt0.0001
35
29
Percent responders ( 50 mania rating decrease)
30
25
20
15
10
5
N 413
N 521
N 1265
N 2338
0
Li/DVPX/CBZ/Atypical Monotherapy
Atypical Li/DVPX Combination
Li/DVPX Monotherapy
Placebo
Ketter TA (ed). Advances in the Treatment of
Bipolar Disorders. Am Psychiatric Press, Inc.
200512.
8
Summary of 15 Acute Mania Monotherapy Studies
Response Rates
Atypical Antipsychotics
Mood Stabilizers
Placebo
60
50
40
Percent responders ( 50 mania rating decrease)
30
20
707 mg/d N 223
4.9 mg/d N 273
575 mg/d N 208
121 mg/d N 268
28 mg/d N 260
16 mg/d N 304
1694 mg/d N 255
1950 mg/d N 134
10
N 1265
0
Carbamazepine
Risperidone
Quetiapine
Ziprasidone
Aripiprazole
Olanzapine
Divalproex
Lithium
Placebo
Ketter TA (ed). Advances in the Treatment of
Bipolar Disorders. Am Psychiatric Press, Inc.
200513.
9
Summary of 4 Acute Bipolar Depression Studies
Response Rates
Active-Placebo Response Rate Difference
Placebo Response Rate
6
0

5
0

4
0

Response Rate ( 50 decrease in depression
rating)
3
0

36
29
25
29
35
35
25
36
2
0

1
0

22
25
24
19
11
4
8
22
0

Q
T
P
Q
T
P
L
T
G
O
F
C
L
T
G
L
i

P
a
x
L
i

I
M
I
O
l
z
6
0
0
m
g
3
0
0
m
g
2
0
0
m
g
5
0
m
g
Sachs GS. In Ketter TA (ed). Advances in the
Treatment of Bipolar Disorders. Am Psychiatric
Press, Inc. 2005.
10
3-Week Double-Blind Divalproex vs Placebo
Monotherapy in Acute Mania
Response Rates


53

49
48
Percent Responders ( 50 YMRS/SADS-C MRS
decrease)
25
11
2000 mg/d 93 ug/mL N 69
1950 mg/d 1.2 mEq/L N 36
2400 mg/d N 17
N 74
N 19
p lt 0.05 p 0.01 vs placebo
Divalproex
Placebo
Divalproex
Lithium
Placebo
Pope HG, et al. Arch Gen Psychiatry
19914862-8. Bowden CL, et al. JAMA
1994271918-24.
Later studies found loading 20-30 mg/kg was well
tolerated.
Excluded mixed patients.
11
Acute Antimanic Effect Size Increases with Serum
Valproate Concentration in Controlled Studies
N 374
Allen MH et al., Am J Psychiatry 2006163272-5.
12
3-Week Double-Blind Divalproex ER vs Placebo
Monotherapy in Acute Mania
Response Rates

48
Percent Responders ( 50 SADS-C MRS decrease)
34
day ug/mL
5 97
21 96
3057 mg/d 96 ug/mL N 187
N 177
Divalproex
Placebo
DVPX started at 25 mg/kg/d (rounded up to nearest
500 mg), increased 500 mg on day 3.
p lt 0.05 vs placebo
Bowden CL, et al. APA Ann Mtg, Toronto, May
20-25, 2006.
13
3-Week Double-Blind Divalproex ER vs Placebo
Monotherapy in Acute Mania
Change in Mania Ratings
Day 1
Day 5
Day 10
Day 15
Day 21
-2
-4
-6
Placebo (n 177)
Change in SADS-C MRS
-8

-10

-12


Divalproex ER 3065 mg/d, 95.9 ug/mL (n 187)
-14
Baseline MRS 26.6 for both Placebo and Divalproex
ER
p lt 0.05, p lt 0.01, p lt 0.001 vs placebo
Bowden CL, et al. APA Ann Mtg, Toronto, May
20-25, 2006.
14
Divalproex ER Dosing Regimen

• Initiated at 25mg/kg/day, rounded up to nearest
  500mg
• Additional 500mg/day beginning on Day 3
• Dosage adjustments on Days 7, 12 and 17
• At investigators discretion based on clinical
  effect, adverse events, and serum valproate
  levels
• Investigator titrated to target of 85-125 mcg/mL
• Limited rescue lorazepam allowed during first 10
  days

Bowden CL, et al. APA Ann Mtg, Toronto, May
20-25, 2006.
15
Divalproex ER Mean Doses Levels
Time Dose (mg/d) (mg/kg/d) Level (ug/mL)
Day 5 2,874 33.2 96.5
Final 3,065 35.4 95.9

• Target serum valproate level 85 125 ug/mL

Bowden CL, et al. APA Ann Mtg, Toronto, May
20-25, 2006.
16
Adverse Effect Discontinuations and Serum
Valproate Levels
Group Valproate level (ug/mL)
No adverse effect discontinuation 93.9
Adverse effect discontinuation 114.1
GI adverse effect discontinuation 123.2
Bowden CL, et al. APA Ann Mtg, Toronto, May
20-25, 2006.
17
VPA Antipsychotic Superior to Antipsychotic
Monotherapy
Clinical Global Impression Very much
improved Much improved
67
P lt 0.002
40
36
18
day ug/mL
3 60
7 76
18 80
21 80
31
32
Placebo Antipsychotic
Valproate Antipsychotic
20 mg/kg/day Muller-Oerlinghausen et al., J
Clin Psychopharmacol 20 195-203, 2000
18
3-Week Double-Blind ERC-Carbamazepine vs Placebo
Monotherapy in Acute Mania
Response Rates
60
61
55
50
42
45
Plt0.0001
40
35
Percent responders ( 50 YMRS decrease)
29
Plt0.01
30
22
25
20
15
10
756 mg/d 8.9 ug/mL N 94
643 mg/d N 120
5
N 98
N 115
0
Extended-Release Carbamazepine
Placebo
Extended-Release Carbamazepine
Placebo
Weisler RH, et al. J Clin Psychiatry
200566323-30.
Weisler RH, et al. J Clin Psychiatry
200465478-84.
Titration necessary, watch for drug interactions.
19
Controlled Carbamazepine and Oxcarbazepine Acute
Mania Studies
Carbamazepine
Oxcarbazepine
CBZ - 1 Weisler, et al. 2004 2 Weisler, et al.
2005 3 Okuma, et al. 1979 4 Grossi, et al.
1984 5 Lerer, et al. 1987 6 Small, et al.
1991 7 Klein, et al. 1984 8 Müller Stoll
1984 9 Gonclaves Stoll 1985 10 Desai, et al.
1987 11 Möller, et al. 1989 12 Okuma, et al.
1989 13 Stoll, et al. 1986 14 Brown, et al.
1989 15 Lenzi, et al. 1986 16 Luznat, et al.
1988 17 Okuma, et al. 1990. OXC - 18 Emrich, et
al. 1990 19 Müller Stoll 1984.
20
7-Week Double-Blind Oxcarbazepine vs Placebo
Monotherapy in Acute Pediatric Mania
Response Rates
All (7-18 yrs)
Children (7-12 yrs)
Adolescents (13-18 yrs)
60
55
50
40
43
42
45
41
P NS
40
P NS
35
Percent responders ( 50 YMRS decrease)
26
30
P lt 0.04
25
17
20
15
10
1515 mg/d N 59
1200 mg/d N 37
2040 mg/d N 22
5
N 56
N 36
N 20
0
Oxcarbazepine
Placebo
Oxcarbazepine
Placebo
Oxcarbazepine
Placebo
Wagner KD, et al. Am J Psychiatry
20061631179-86.
21
Weight Gain During Maintenance Treatment
25

20
15
Percentage of Patients with Weight Gain
10
5
0
Divalproex
Lithium
Placebo
p 0.004 vs PBO
Bowden CL, et al. Arch Gen Psychiatry
200057481-9.
22
Bipolar Disorder Symptoms areChronic and
Predominantly Depressive
of Weeks
Asymptomatic
Depressed
146 bipolar I patientsfollowed 12.8 years
86 bipolar II patientsfollowed 13.4 years
Manic/hypomanic
Cycling / mixed
Judd et al. Arch Gen Psychiatry. 200259530-7.
Judd et al. Arch Gen Psychiatry. 200360261-9.
23
Polarity of Index Episode Predicts Polarity of
Relapse Relapses on Placebo
Index Episode Relapse Into Depression Relapse Into Mania
Recently Depressed 39 16
2.41
Recently Manicor Hypomanic 30 41
1.41
Bowden et al. Arch Gen Psychiatry.
200360392-400 Calabrese et al. J Clin
Psychiatry. 2003641013-1024 Calabrese et al. J
Clin Psychiatry. 200263(suppl 10)18-22.
24
Controlled Trials in Acute Bipolar Depression
Better than Placebo Imipramine1-2 Bupropion3-4
Fluoxetine5 Lamotrigine6 OlanzapineFluoxetine gt
Olanzapine7 Pramipexole8-9 Quetiapine10 Modafinil2
2
Better than Imipramine Tranylcypromine12-13 Fluoxe
tine5
Similar to Tricyclic Maprotiline
Imipramine14 Moclobemide Imipramine15-16 Moclobe
mide Tricyclic17 s Bupropion Desipramine18 s
Paroxetine Imipramine11
Similar to Placebo Imipramine11 Paroxetine11
Similar to One Another s Paroxetine
Venlafaxine19 Bupropion Topiramate20 Paroxetine
(Li/VPA) LiVPA21
gt PBO if Li lt 0.8 mEq/L s Less switch
1Fieve, 1968 2Worrall 1979 3Fabre 1983
4Merideth 1983 5Cohn 1989 6Calabrese 1999
7Tohen 2003 8Goldberg 2004 9Zarate 2004
10Calabrese 2004 11Nemeroff 2001 12Himmelhoch
1991 13Thase 1992 14Kessell 1975 15Baumhackl
1989 16Silverstone 2001 17Angst 1992 18Sachs
1994 19Vieta 2002 20McIntyre 2002 21Young
2000 22Frye 2006.
25
Are Antidepressants a Good Ideain Bipolar
Depression?
Ketter TA, et al. Bipolar Disord 200523(Suppl
2)23.
26
8-Week Randomized Double-Blind Divalproex
Monotherapy in Acute Bipolar Depression
0
-2
-4
Mean HAM-D Change From Baseline (LOCF)
Placebo (N 12)
-6
-8
P 0.0002
-10
Divalproex 82 ug/mL (N 13)
-12
0
1
2
3
4
5
6
7
8
Week
Baseline HAM-D Placebo, 19.9 Divalproex 22.0.
Last observation carried forward. Davis LL, et
al. J Affective Disord 200585259-66.
27
Oligomenorrhea and Hyperandrogenismawith
Valproate
230 Women Age 18-45
10.5 (9/86)
12
10
8
Percentage with Oligomenorrhea and
Hyperandrogenism
6

4
1.4 (2/144)
2
0
Valproate
No Valproateb
aHirsutism, acne, male-pattern alopecia, elevated
androgens bOther anticonvulsants (lamotrigine,
topiramate, gabapentin, carbamazepine,
oxcarbazepine) and lithium
p lt0.002
Joffe H, et al. Biol Psychiatry
200659(11)1078-86.
28
Unfortunately, theres no cure - theres not
even a race for a cure.
29
AEDs Marketed in the U.S.
Year Drug 1981 Clorazepate 1993 Felbamate
1993 Gabapentin 1994 Lamotrigine 1996 Fosphenytoi
n 1997 Topiramate 1997 Tiagabine 2000 Oxcarbazepi
ne 2000 Levetiracetam 2000 Zonisamide 2005 Pregab
alin
Year Drug 1912 Phenobarbital 1935 Mephobar
bital 1938 Phenytoin 1946 Trimethadione 1947 Mephe
nytoin 1951 Phenacemide 1953 Phensuximide 1954 Pr
imidone 1957 Methsuximide 1957 Ethotoin 1960 Etho
suximide 1968 Diazepam 1974 Carbamazepine 1975 Clo
nazepam 1978 Valproate
30
Placebo Controlled Gabapentin Trials

• Diagnosis N Dose Finding
• Bipolar Disorder - Ineffective as Primary
  Treatment
• Mania (add-on) 1 117 600-3600 GBP
  lt PBO
• Rx Resistant RCBP 2 31 4000 GBP PBO
• Comorbid Disorders - Effective for Comorbidities
  (Non-bipolar pts)
• Social Phobia 3 69 900-3600 GBP gt PBO
• Panic Disorder 4 103 600-3600 GBP gt
  PBO
• Post-herpetic Neuralgia 5 229 1200-3600
  GBP gt PBO
• Neuropathic Pain 6 305 900-2400 GBP gt
  PBO
• Chronic Daily Headache 7 95 2400 GBP gt PBO

1 Pande AC, et al. Bipolar Disord 20002249-552
Frye MA, et al. J Clin Psychopharmacol
200020607-14 3 Pande AC, et al. J Clin
Psychopharmacol 199919341-8 4 Pande AC, et al.
J Clin Psychopharmacol 200020467-71 5
Rowbotham M, et al. JAMA 19992801837-42
Serpell MG. Pain 200299557-66 Spira PJ, Beran
RG. Neurology 2003611753-9.
31
"Read the instructions very, very, very, very
carefully."
32
Gradual Lamotrigine Titration Crucial to Reduce
Risk of Rash

• Double lamotrigine dose with carbamazepine
• Halve lamotrigine dose with valproate

1 Guberman et al. Epilepsia. 1999 2 Physicians
Desk Reference. 2003.
33
If you remember, I did mention possible
side-effects.
34
Slower Titration and Dermatology Precautions to
Decrease Drug-Induced Rash

• Slower titration
• 25 mg/d x 2 wks, 50 mg/d x 2 wks, then increase
  25 mg weekly
• 80 longer to 200 mg/d (9 vs 5 wks)
• Dermatology Precautions
• Do not start drug within 2 weeks of
• Rash, viral infection, vaccination
• During first 3 months of therapy, avoid
• New medicines, foods
• New cosmetics, conditioners, deodorants,
  detergents, fabric softeners
• Sunburn, poison ivy/oak
• Observational evidence of potential benefit
  (N100)
• No serious rash Rash discontinuation in 3
  (3/100)
• Rash rates
• All patients 5 (5/100)
• Dermatology/dosing adherent patients 3.1 (3/97)

Ketter TA, et al. J Clin Psychiatry
200566642-5.
35
Weight Loss with Lamotrigine in Obese Bipolar
Disorder Patients
p lt 0.02 vs PBO, p lt 0.0001 vs Li
Ginsberg L, et al. 156th Annual Meeting of
American Psychiatric Association San Francisco,
Calif May 17-22, 2003.
36
7-Week Randomized Double-Blind Lamotrigine
Monotherapy in Acute Bipolar I Depression
Last Observation Carried Forward
Observed Cases
0
0
-5
-5
Placebo (n 65)
MADRS Change From Baseline
Placebo
LTG 50 mg/d (n 64)
-10
-10



LTG 50 mg/d


Switch Rates




-15
-15

PBO 5
LTG 50 3
LTG 200 8
LTG 200 mg/d (n 63)





LTG 200 mg/d
-20
-20
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
Week
Week
Plt0.1 Plt0.05.
Calabrese et al. J Clin Psychiatry. 19996079-88.
37
16-Week Randomized Open Adjunctive Therapy of
Treatment Resistant Bipolar Depression a
23.8 5.8-41.8
17.4 2.4-32.4
4.6 0-14.6
138 mg/d
9429 mg/d
1.5 mg/d
Nierenberg AA, et al. Am J Psychiatry
2006163210-6.
a 54 BPI, 46 BPII.
38
Lamotrigine and LithiumEffective in Bipolar I
Prophylaxis
Time to Intervention for Any Episode (pooled
recently manic/dep pts)
Goodwin et al. J Clin Psychiatry 200465432-41.
39
Lamotrigine Effective inBipolar I Depression
Prophylaxis
Time to Intervention for Depression (pooled
recently manic/dep pts)
1
LTG v. PBO, p 0.009 Li v. PBO, p 0.120 LTG v.
Li, p 0.325
0.9
0.8
0.7
0.6
Survival Estimate
0.5
0.4
0.3
0.2
0.1
0
0
10
20
30
40
50
60
70
Week
Some patients considered intervention-free for
depression could have had intervention for mania.
Goodwin et al. J Clin Psychiatry 200465432-41.
40
Lamotrigine and Lithium Effective inBipolar I
Mania Prophylaxis
Time to Intervention for Mania (pooled recently
manic/dep pts)
Some patients considered intervention-free for
mania could have had intervention for depression.
Goodwin et al. J Clin Psychiatry 200465432-41.
41
6-Week Lamotrigine Versus Gabapentin Versus
Placebo in Treatment Resistant Mood Disorders
Crossover trial with 74 Rapid-Cycling BP, 6
Non- Rapid-Cycling BP, 20 UP
52 (16/31)
60

50
40
26 (8/31)
Percent Clinical Global Impression Response
23 (7/31)
30
20
10
275 mg/d
4000 mg/d
0
Lamotrigine
Gabapentin
Placebo
p lt 0.05 versus GBP and PBO.
Frye MA, et al. J Clin Psychopharmacol
200020607-14.
42
Lamotrigine Effective in Rapid Cycling BPII

46

41
39
31
26
18
p lt 0.05.
Calabrese JR, et al. J Clin Psychiatry
200061841-50.
43
Lamotrigine Ineffective in Acute Mania

Response Rates
62
Low Dose (3 weeks)
Add-on (6 weeks)
55
47
46
44
42
Percent Responders ( 50 MRS decrease)
50 mg/d N 85
0.8-1.3 mEq/L N 36
200 mg/d N 74
0.8-1.3 mEq/L N 77
N 95
N 77
Lamotrigine
Placebo
Lithium
Lamotrigine
Placebo
Lithium
Similar percentages of patients had MRS increases
with LTG, LI, and PBO. Bowden C, et al. 39th Ann
ACNP Meeting. San Juan, Puerto Rico, Dec 10-14,
2000.
p lt 0.05 vs PBO.
44
Lamotrigine Stabilizes Mood From Below Baseline?
Types of Mood Stabilizers

• A - work From Above baseline to help
• Manic, hypomanic, mixed episodes
• Subsyndromal manic, hypomanic, mixed symptoms
• B - work From Below baseline to help
• Major depressive episode
• Subsyndromal depressive symptoms

Ketter TA, Calabrese JR. J Clin Psychiatry 2002
63(2)146-151.
45
Being on a diet does not give you the right to
go berserk in a donut shop."
46
Placebo Controlled Topiramate Trials

• Diagnosis N Dose Finding
• Bipolar Disorder - Ineffective as Monotherapy in
  Adult Mania
• Mania (Adult - 4 studies)1 1,301
  200-600 TPM PBO
• Mania (Adolescent)2 56 278 TPM PBO
• Comorbid Disorders - Effective for Comorbidities
  (Non-bipolar pts)
• Obesity3 376 64-384 TPM gt PBO
• ObeseBinge Eat4 61 212 TPM gt PBO
• Bulimia5 69 100 TPM gt PBO
• Etoh Dependence6 150 200 TPM gt PBO
• Migraine7 468 50-200 TPM gt
  PBO

1 Kushner S, et al. Bipolar Disord 2006815-27
2 DelBello M, et al. J Am Acad Child Adolesc
Psychiatry 200544539-47 3 Bray GA, et al. Obes
Res 2003 11722-33 4 McElroy SL, et al. Am J
Psychiatry 2003160255-61 5 Hoopes SP, et al. J
Clin Psychiatry 2003641335-41 6 Johnson BA, et
al. Lancet 20033611677-85 7 Brandes JL, et al.
JAMA 2004291965-73.
47
Weight Loss with Zonisamide in Obesity
Obese (No psychiatric disorder)
Obese Euthymic Medicated Bipolar
p lt 0.001

Gadde KM, et al. JAMA. 20032891820-5.
Yang YS, et al. 156th APA Ann Mtg San Francisco
May 17-22, 2003.
48
Emerging Diverse Roles of Anticonvulsants in
Patients with Bipolar Disorders

• Primary Therapies for Bipolar Disorders
• Divalproex - Mania, maintenance, rapid
  cycling
• Carbamazepine - Mania, maintenance, rapid
  cycling
• Lamotrigine - Maintenance, depression, rapid
  cycling
• Oxcarbazepine - Mania?
• Adjuncts for Comorbid Conditions
• Benzodiazepines - Anxiety, insomnia, agitation
• Gabapentin - Anxiety, insomnia, pain
• Topiramate - Obesity, eating disorders, migraine,
  alcoholism
• Zonisamide - Obesity, eating disorders

Ketter TA (ed). Advances in the Treatment of
Bipolar Disorders. Am Psychiatric Press, Inc.
20056.
49
New Anticonvulsants Not (Yet) Proven Effective in
Mania

• Oxcarbazepine - B, underpowered active-comparator
  monotherapy studies1
• Gabapentin - F, negative placebo-controlled
  add-on study2
• Lamotrigine - F, negative placebo-
  lithium-controlled add-on studies3
• Topiramate - F, negative placebo-
  lithium-controlled adult monotherapy
  studies4
• Tiagabine - D, negative open add-on study5
• Levetiracetam - D, no controlled study
• Zonisamide - D, no controlled study

1 Emrich HM. Int Clin Psychopharmacol
19905(Suppl 1)83-8 2 Pande AC, et al. Bipolar
Disord 20002249-55 3 Bowden C, et al. 39th
Ann ACNP Mtg. San Juan, Puerto Rico, Dec 2000 4
Powers P, et al. 157th APA Ann Mtg, New York, May
2004 5 Grunze H, et al. J Clin Psychiatry
199960759-62.
Adapted from Ketter TA (ed). Advances in the
Treatment of Bipolar Disorders. Am Psychiatric
Press, Inc. 200537.
50
Im going to prescribe something that works like
aspirin, but costs much, much more.
51
12-Month Randomized Adjunctive Clozapine
inBipolar Schizoaffective Dsiorder Patients
26 bipolar, 12 schizoaffective disorder, bipolar
type patients
Clozapine 355 mg/d (n19)
100
80
p lt.05
Percent of patients with 30 improvement
60
40
Treatment as usual (n19)
20
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Months
Suppes T, et al. Am J Psychiatry 19991561164-9.
Mean clozapine doses - in bipolar 234 mg/d, in
schizoaffective 623 mg/d.
52
3-Week Double-Blind Risperidone vs Placebo
Monotherapy in Acute Maniaa
Young Mania Rating Scale Response Rates
60


48

50
47
43
40
33
Percent Response ( 50 YMRS decrease)
30
24
20
10
4.1 mg/d N 127
4.2 mg/d N 153
8.0 mg/d N 144
N 119
N 138
0
Risperidone
Placebo
Risperidone
Placebo
Haloperidol
Smulevich AB, et al. Eur Neuropsychopharmacol
20051575-84.
Hirschfeld RM, et al. Am J Psychiatry
20041611057-65.
Watch for extrapyramidal symptoms at higher doses.
aExcluded mixed episodes p lt 0.01 vs placebo.
53
3-Week Double-Blind Adjunctive Risperidone vs
Placebo (Monotherapy) in Acute Mania
Young Mania Rating Scale Response Rates
59
58
57
60
p lt 0.05
50
p lt 0.06
42
38
Percent Responders ( 50 YMRS decrease)
40
30
20
3.8 mg/d
4.0 mg/d
6.2 mg/d
10
N 55
N 62
N 52
N 51
N 53
0
Risperidone Li/VPA
Placebo Li/VPA
Haloperidol Li/VPA
Risperidone Li/VPA
Placebo Li/VPA
Yatham LN, et al. Br J Psychiatry 2003182141-7.
Sachs G, et al. Am J Psychiatry
20021591146-54.

Excluded 14 RSPCBZ, 12 PBOCBZ pts.
Carbamazepine decreased plasma risperidone
concentrations by 40 percent.
54
3- and 4-Week Double-Blind Olanzapine vs Placebo
Monotherapy in Acute Mania
Young Mania Rating Scale Response Rates
70
65
60
49
p lt 0.05
50
43
Percent Response ( 50 YMRS decrease)
40
p lt 0.01
30
24
20
15 mg/d N 69
16 mg/d N 55
10
N 70
N 60
0
Olanzapine
Placebo
Olanzapine
Placebo
Tohen M, et al. Am J Psychiatry 1999156702-9.
Tohen M, et al. Arch Gen Psychiatry
200057841-9.
Often started clinically at 20 mg/day.
55
Olanzapine vs Divalproex Acute Mania Studies
Response Rates
62
p 0.31
54
53
p 0.06
42
Percent Responders ( 50 Young/SADS-C MRS
decrease)
day ug/mL
3 78
6 97
10 101
1401 mg/d 84 ug/mL N 126
1956 mg/d 85 ug/mL N 60
day ug/mL
5 77
7 82
17 mg/d N 125
15 mg/d N 55
Olanzapine
Divalproex
Olanzapine
Divalproex
Zajecka J, et al. J Clin Psychiatry
2002631148-55.
Tohen M, et al. Am J Psychiatry 20021591011-7.
Olanzapine slightly more effective, divalproex
slightly better tolerated.
56
6-Week Double-Blind Adjunctive Olanzapine vs
Placebo (Monotherapy) in Acute Mania
Young Mania Rating Scale Response Rates

68
45
Percent Responders ( 50 YMRS decrease)
10.4 mg/d N 220
N 114
Placebo Li 0.82 mEq/L /VPA 75 ug/mL
Olanzapine Li 0.76 mEq/L / VPA 64 ug/mL


Tohen M, et al. Arch Gen Psychiatry 20025962-9.
p lt 0.05, p 0.001 vs placebo.
Low therapeutic mood stabilizer plasma
concentrations in combination therapy.
57
Double-Blind Olanzapine vs Lithium Maintenance
Monotherapy
Olanzapine Compared to Lithium After Manic/Mixed
Episodes
Equivalent Depression Prevention
Equivalent Episode Prevention
Superior Mania Prevention
50
38.8
40
p.055
30.0
28.0
30
Percentage of Patients
plt.001
p.895
20
16.1
15.4
14.3
10
0
Overall Relapse
Relapse Into Depression
Relapse Into Mania
Stabilized on OLZLi before randomization.
Relapse criteria - YMRS or HAMD-21 gt 15. Tohen
MF, et al. Am J Psychiatry 20051621281-90.
58
Double-Blind Olanzapine Monotherapy vs Placebo
Maintenance
Olanzapine Compared to Placebo After Manic/Mixed
Episodes
Superior Depression Prevention
Superior Episode Prevention
Superior Mania Prevention
100
80.1
80
plt.001
60
Percentage of Patients
46.7
47.8
p.015
41.2
34.7
40
plt.001
16.4
20
0
Overall Relapse
Relapse Into Depression
Relapse Into Mania
Stabilized on OLZ before randomization. Relapse
criteria - hospitalized or YMRS or HAMD-21 gt
15. Tohen MF, et al. Am J Psychiatry
2006163247-56.
59
8-Week Randomized Double-Blind Olanzapine
Fluoxetine in Acute Bipolar I Depression
0
Switch Rates
PBO 7
OLZ 6
OFC 6

-5


Mean Change in MADRS Scores
-10



PBO (N 355)
OLZ 9.7 mg (N 351)
-15
OLZ 7.4 mg FLX 39.3 mg (N 82)



-20
0
1
2
3
4
6
8
Week
Baseline MADRS 31.3 PBO, 32.6 OLZ, 30.8
OLZFLX. P lt 0.05 vs OLN, OLNFLX. P lt 0.05
vs OLN.
Tohen M, et al. Arch Gen Psychiatry
2003601079-88.
60
7-Week Randomized Double-Blind Olanzapine
Fluoxetine vs Lamotrigine in Acute Bipolar I
Depression
Week
Switch Rates
LTG 5
OFC 4
Weight Change (kg)
LTG -0.3
OFC 3.1
Mean Change in MADRS Scores

LTG 106 mg (N 205)

OLZ 10.7 mg FLX 38.3 mg (N 205)



Baseline MADRS 30.9 OFC, 31.4 LTG. P lt 0.05,
P lt 0.001 OFC vs LTG. Trade-off 3 lbs/MADRS
point.
Brown EB, et al. J Clin Psychiatry
2006661025-33.
61
7-Week Randomized Double-Blind Olanzapine
Fluoxetine vs Lamotrigine in Acute Bipolar I
Depression
Responders
7 Weight Gain
P lt 0.08, P lt 0.001 OFC vs LTG. Trade-off
9 response vs 23 weight gain.
Brown EB, et al. J Clin Psychiatry
2006661025-33.
62
12-Week Double-Blind Quetiapine vs Placebo
Monotherapy in Acute Mania (Pooled Data)a
Young Mania Rating Scale Response Rates
60
48
50
40
p lt 0.0006
31
Percent Responders ( 50 YMRS decrease)
30
20
576 mg/dr N 208
10
N 195
0
Quetiapine
Placebo
Vieta E, et al. Curr Med Res Opin. 200521923-34.
Important to use adequate dosage - started at 100
mg/day and increased by 100 mg/day.
aExcluded mixed episodes, rapid cycling bMean
final dose in responders
63
3-Week Double-Blind Adjunctive Quetiapine vs
Placebo (Monotherapy) in Acute Mania (Pooled
Data)a
Young Mania Rating Scale Response Rates

56
60
50
41
40
Percent Responders ( 50 YMRS decrease)
30
20
10
492 mg/db N 185
N 185
0
Placebo Li 0.73 mEq/L / VPA 74 ug/mL
Quetiapine Li 0.76 mEq/L / VPA 70 ug/mL
aExcluded mixed episodes, rapid cycling bMean
final dose in responders p 0.01 vs placebo.
Yatham LN, et al. J Clin Psychopharmacol
200424599-606.
Low therapeutic mood stabilizer plasma
concentrations in combination therapy.
64
8-Week Randomized Double-Blind Quetiapine
Monotherapy in Acute Bipolar Depression
Study Week
0
1
2
4
3
6
5
7
8
0
-5
Change From Baseline (LS Means)
Placebo (N 169)

-10



Quetiapine 300 mg (N 172)


Switch Rates




-15
PBO 4
QTP 300 4
QTP 600 2






Quetiapine 600 mg (N 170)
-20
Baseline MADRS 30.3 PBO, 30.4 QTP 300, 30.6 QTP
600. Plt0.001 (quetiapine vs placebo)
ITT, LOCF
Calabrese JR, et al. Am J Psychiatry
20051621351-60.
65
8-Week Randomized Double-Blind Quetiapine
Monotherapy in Acute Bipolar Depression
Switch Rates
PBO 7
QTP 300 2
QTP 600 4
Baseline MADRS 29.6 PBO, 31.1 QTP 300, 29.9 QTP
600. Plt0.01, Plt0.001 (quetiapine vs placebo).
ITT, LOCF
Thase ME, et al. J Clin Psychopharmacol
200626600-9.
66
8-Week Randomized Double-Blind Quetiapine
Monotherapy in Acute Bipolar Depression
Response Rates
Thase ME, et al. J Clin Psychopharmacol
200626600-9.
Calabrese JR, et al. Am J Psychiatry
20051621351-60.
p lt 0.05, plt 0.01, p lt 0.001 vs placebo.
67
BOLDER I and II MADRS Total Score Bipolar I vs.
II Disorder
Bipolar Disorder II(N321)
Bipolar Disorder I (N657)
0
-4
MADRS LS Mean Change From Baseline
-8
Improvement
-12
-16
Quetiapine 300
Quetiapine 600


Placebo
-20


plt0.01 plt0.001 vs. placebo (N at baseline)
ITT intent to treat AstraZeneca (data on
file) Thase ME (2006), Presented at the 159th
Annual Meeting of the APA. Toronto, Canada May
20-25 Calabrese JE et al. (2005), Am J
Psychiatry 162(7)1351-1360
68
3-Week Double-Blind Ziprasidone vs Placebo
Monotherapy in Acute Mania
SADS-C Mania Rating Scale Response Rates
Potkin SG, et al. J Clin Psychopharmacol
200525301-10.
Keck PE, et al. Am J Psychiatry 2003160741-8.
Important to use adequate dosage - day one 80
mg/day, day two 160 mg/day - with food.
Schedule for Affective Disorders and
Schizophrenia-Change
69
Adjunctive Pramipexolein Acute Bipolar Depression
Response Rates
67 (8/12)
60 (6/10)
70
60
50
45
Plt0.02
40
35
Percent responders ( 50 HDRS/MADRS decrease)
Plt0.04
30
20 (2/10)
25
20
9 (1/11)
15
10
1.7 mg/d
1.7 mg/d
5
0
Pramipexole
Placebo
Pramipexole
Placebo
Zarate CA, et al. Biol Psychiatry 2004 5654-60.
Goldberg JF, et al. Am J Psychiatry 2004
161564-6
70
6-week Randomized Double-Blind Adjunctive
Modafinil in Acute Bipolar Depression
Response Rates

44
Percent Responders ( 50 IDS decrease)
22
177 mg/d N 41
N 44
Modafinil
Placebo
p lt 0.05 vs placebo TEAS Modafinil 4.9,
Placebo 11.4
Frye M, et al. APA, Toronto, 2006.
71
3-Week Double-Blind Aripiprazole vs Placebo
Monotherapy in Acute Mania
Young Mania Rating Scale Response Rates
60
53
50
45
40
Plt0.01
40
35
32
Percent responders ( 50 YMRS decrease)
Plt0.01
30
25
19
20
15
10
28 mg/d N 123
28 mg/d N 135
5
N 120
N 129
0
Aripiprazole
Placebo
Aripiprazole
Placebo
Sach GS, et al. J Psychopharmacol 2006.
Keck PE, Jr, et al. Am J Psychiatry
20031601651-8.
Starting with 15 mg/day briefly prior to
increasing to 30 mg/day can decrease nausea.
72
26-Week Double-Blind Aripiprazole vs Placebo
Continuation/Maintenance Monotherapy
Aripiprazole Compared to Placebo After
Manic/Mixed Episodes
Equivalent Depression Prevention
Superior Episode Prevention
Equivalent Mixed Prevention
Superior Mania Prevention
50
43
40
p.013
30
25
Percent of Patients
23
20
p.009
13
12
8
10
6
5
0
Relapse into Mania
Relapse into Mixed
Relapse into Depression
Overall Relapse
Stabilized on ARI before randomization. Keck PE,
et al. J Clin Psychiatry 200667626-37.
73
Broad Efficacy Spectra of Atypical Antipsychotics
Agent Mixed Psychotic Rapid Cycling
Olanzapine1,2
Risperidone3,4 ?
Quetiapine5,p ? ?
Ziprasidone6,p ?
Aripiprazole7,p
1Tohen M, et al. Am J Psychiatry 1999156702-9
2Tohen M, et al. Arch Gen Psychiatry
200057841-9 3Sachs G et al. Am J Psychiatry.
20021591146-1154 4Hirschfeld RM, et al. Am J
Psychiatry 20041611057-65 5Yatham LN, et al. J
Clin Psychopharmacol 200424599-606 6Potkin SG,
et al. 157th APA Ann Mtg, New York, May 1-6,
2004 7Jody D, et al. 157th APA Ann Mtg. New
York, NY, May 1-6, 2004. p pooled data.
74
Rapid Onset of Action of Atypical Antipsychotics
Separated From Placebo by Week 1
Olanzapine 1
Risperidone2
Quetiapine3,p
Ziprasidone4,5
Aripiprazole6,7
1Tohen M, et al. Arch Gen Psychiatry
200057841-9 2Hirschfeld RM, et al. Am J
Psychiatry 20041611057-65 3Calabrese JR, et
al. In Review 4Keck P, et al. Am J Psychiatry.
2003160741-8 5Segal S, et al. 156th APA Ann
Mtg. San Francisco, CA, May 17-22, 2003 6Keck
PE, et al. Am J Psychiatry. 20031601651-8
7Sachs GS, et al. 157th APA Ann Mtg. New York,
NY, May 1-6, 2004. p pooled data.
75
Mood StabilizerSafety and Tolerability Concerns
Divalproex Gastrointestinal Weight
gain Tremor Hepatic Coagulation Hair
Loss Pancreatitis Teratogen PCOS
Carbamazepine Gastrointestinal Rash Neurotoxicity
Hepatic Thyroid Hematologic Cardiac Teratogen Hypo
natremia
Lithium Gastrointestinal Weight
gain Neurotoxicity Renal Thyroid Hair
Loss Cardiac Teratogen Acne, Psoriasis
Adapted from Ketter TA (ed). Advances in the
Treatment of Bipolar Disorders. Am Psychiatric
Press, Inc. 200511-55.
76
Antipsychotic Safety and Tolerability Concerns

• Second-Generation
• Weight gain
• Sedation
• Hyperglycemia, Diabetes
• Cardiac
• Akathisia
• Hyperprolactinemia
• Cerebrovascular
• Tardive dyskinesia
• Neuroleptic malignant
• Cardiac/pneumonia in elderly

• First-Generation
• Depression
• Akathisia
• Acute dystonia
• Tardive dyskinesia
• Weight gain
• Sedation
• Cardiac
• Hyperprolactinemia
• Neuroleptic malignant
• Cardiac/pneumonia in elderly?

Warnings - In prescribing information ?Under
consideration boxed
Adapted from Ketter TA (ed). Advances in the
Treatment of Bipolar Disorders. Am Psychiatric
Press, Inc. 200511-55.
77
Obesity Associated with Earlier Relapse in
Bipolar Disorder
Any Relapse
Depressive Relapse
p lt 0.007
p lt 0.02
Fagiolini A et al. Am J Psychiatry.
2003160112-7.
78
Second Generation Antipsychotics and Metabolic
Abnormalities

• Drug Weight Diabetes Lipids
• Clozapine
• Olanzapine
• Risperidone D D
• Quetiapine D D
• Aripiprazole - -
• Ziprasidone - -

increase effect - no effect D
discrepant. Newer drugs with limited long-term
data.
Am Diabetes Assoc, Am Psychiatric Assoc, Am Assoc
Clin Endocrinologists, N Am Assoc for Study of
Obesity Diabetes Care 200427596601.
79
Emerging Uses of Atypical Antipsychotics in
Bipolar Disorders

• Primary Therapies for Bipolar Disorder
• Olanzapine - Mania, maintenance, depression
  (combined w fluoxetine)
• Risperidone - Mania
• Quetiapine - Mania, depression
• Ziprasidone - Mania
• Aripiprazole - Mania, maintenance
• Adjuncts for Bipolar Disorder
• Olanzapine - Mania
• Risperidone - Mania
• Quetiapine - Mania
• Clozapine - Treatment resistant

Ketter TA (ed). Advances in the Treatment of
Bipolar Disorders. Am Psychiatric Press, Inc.
20056.
80
Conclusions

• Many new agents in development
• Diverse mechanistic, efficacy, and adverse effect
  profiles
• New Anticonvulsants
• Not as a class effective in acute mania
• Variable efficacy in bipolar disorders and
  comorbid conditions
• Newer Antipsychotics
• As a class effective in acute mania
• Emerging efficacy in acute depression and
  maintenance