upgrading your brain made easy new treatment options for patients with bipolar disorders terence a....

UpgradingUpgradingYour BrainYour Brain

Made Made EasyEasy

New Treatment Options for

Patients with Bipolar Disorders

Terence A. Ketter, M.D.

Disclosure InformationDisclosure Information Research Support / Consultant / SpeakerResearch Support / Consultant / Speaker

Abbott Laboratories, Inc.AstraZeneca Pharmaceuticals LPBristol-Myers Squibb Company

Cephalon Inc.Corcept Therapeutics

Elan Pharmaceuticals, Inc.Eli Lilly and Company

Forest Laboratories, Inc.GlaxoSmithKline

Janssen Pharmaceutica Products, LPJazz Pharmaceuticals, Inc.

Merck & Co., Inc.Novartis Pharmaceuticals Corporation

Pfizer Inc.Shire Pharmaceuticals Group plc.

Solvay Pharmaceuticals, Inc.UCB Pharmaceuticals

Wyeth Pharmaceuticals

OverviewOverview

Mood Stabilizers– A - Lithium, divalproex, carbamazepine– B - Lamotrigine

New Anticonvulsants– Oxcarbazepine – Gabapentin, topiramate, tiagabine– Levetiracetam, zonisamide

New Antipsychotics – Clozapine– Risperidone, olanzapine, quetiapine– Ziprasidone, aripiprazole

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

Acute Mania

Year Drug

1970 Lithium

1973 Chlorpromazine

1994 Divalproex

2000 Olanzapine*

2003 Risperidone*

2004 Quetiapine*

2004 Ziprasidone

2004 Aripiprazole

2004 Carbamazepine

Maintenance

Year Drug

1974 Lithium

2003 Lamotrigine

2004 Olanzapine

2005 Aripiprazole

Acute Depression

Year Drug

2003 Olanzapine- fluoxetine combination

2006 Quetiapine

*Adjunctive as well as monotherapy

Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:2.

Overview of 20 Acute Mania StudiesOverview of 20 Acute Mania Studies Response Rates

5 CombinationTherapy Studies

15 MonotherapyStudies

Per

cen

t re

spo

nd

ers

(≥ 5

0% m

ania

rat

ing

dec

reas

e)

P<0.0001

05

10152025303540455055 P<0.000150%

Li/DVPX/CBZ/AtypicalMonotherapy

N = 2338

Atypical + Li/DVPXCombination

62%

N = 521

Li/DVPXMonotherapy

42%

N = 413

29%

Placebo

N = 1265

6065


Summary of 15 Acute Mania Monotherapy StudiesSummary of 15 Acute Mania Monotherapy Studies Response Rates

Atypical AntipsychoticsMood Stabilizers

0

10

20

30

40

50

60

Carbamazepine

707mg/d

N = 223

Risperidone

4.9mg/d

N = 273

Quetiapine

575mg/d

N = 208

Ziprasidone

121mg/d

N = 268

Aripiprazole

28mg/d

N = 260

Placebo

N = 1265

Olanzapine

16mg/d

N = 304

Divalproex

1694mg/d

N = 255

Lithium

1950mg/d

N = 134

Per

cen

t re

spo

nd

ers

(≥ 5

0% m

ania

rat

ing

dec

reas

e)

Placebo


22

36

25

29

24

25

19

29

11

35

4

35

8

25

0%

10%

20%

30%

40%

50%

60%

Q T P600mg

Q T P300mg

LTG200mg

OFC L TG50mg

Li Pax L i IM I Olz

Active-Placebo Response Rate Difference

Res

po

nse

Rat

e(≥

50%

dec

reas

e in

dep

ress

ion

rat

ing

)

Summary of 4 Acute Bipolar Depression StudiesSummary of 4 Acute Bipolar Depression Studies Response Rates

Placebo Response Rate

Sachs GS. In Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005.

22

36

Response Rates

Pope HG, et al. Arch Gen Psychiatry 1991;48:62-8. Bowden CL, et al. JAMA 1994;271:918-24.

Per

cen

t R

esp

on

der

s(≥

50%

YM

RS

/SA

DS

-C M

RS

dec

reas

e)

25%

49%

11%

*p < 0.05**p ≤ 0.01vs placebo

53%

48%

Divalproex Placebo Divalproex Lithium Placebo0

10

20

30

40

50

60

2000mg/d

93ug/mLN = 69

1950mg/d1.2

mEq/LN = 36 N = 74

2400mg/d

N = 17 N = 19

*****

3-Week Double-Blind Divalproexvs Placebo Monotherapy in Acute Mania

Excluded mixed patients. Later studies found loading 20-30 mg/kg was well tolerated.

Acute Antimanic Effect Size Increases with Serum Valproate Concentration in Controlled Studies

Allen MH et al., Am J Psychiatry 2006;163;272-5.

N = 374

Response Rates

Per

cen

t R

esp

on

der

s(≥

50%

SA

DS

-C M

RS

dec

reas

e)

*p < 0.05 vs placebo

Divalproex Placebo0

10

20

30

40

50

60

34%

48%

3057 mg/d96 ug/mLN = 187 N = 177

*

3-Week Double-Blind Divalproex ERvs Placebo Monotherapy in Acute Mania

Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.

day ug/mL

5 97

21 96

DVPX started at 25 mg/kg/d (rounded up to nearest 500 mg), increased 500 mg on day 3.

Baseline MRS 26.6 for both Placebo and Divalproex ER

Placebo (n = 177)

Divalproex ER 3065 mg/d, 95.9 ug/mL (n = 187)-14

-12

-10

-8

-6

-4

-2

Day 1 Day 5 Day 10 Day 15 Day 21

*

*

*** **

Change in Mania Ratings

Ch

ang

e in

SA

DS

-C M

RS

*p < 0.05, **p < 0.01, ***p < 0.001 vs placebo

3-Week Double-Blind Divalproex ERvs Placebo Monotherapy in Acute Mania


Divalproex ER Dosing RegimenDivalproex 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 investigator’s 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


Divalproex ER Divalproex ER Mean Doses & LevelsMean Doses & Levels

Target serum valproate level 85 – 125 ug/mL

TimeDose

(mg/d) (mg/kg/d)Level

(ug/mL)

Day 5 2,874 33.2 96.5

Final 3,065 35.4 95.9


Adverse Effect Discontinuations Adverse Effect Discontinuations and Serum Valproate Levelsand Serum Valproate Levels

GroupValproate level

(ug/mL)

No adverse effect discontinuation 93.9

Adverse effect discontinuation 114.1

GI adverse effect discontinuation 123.2


VPA + Antipsychotic Superior to Antipsychotic Monotherapy

* 20 mg/kg/dayMuller-Oerlinghausen et al., J Clin Psychopharmacol 20; 195-203, 2000

Placebo + Antipsychotic

Valproate* + Antipsychotic

Clinical Global ImpressionVery much improvedMuch improved

40%

67%

32% 31%

18%

36%P < 0.002

day ug/mL

3 60

7 76

18 80

21 80

Response RatesP

erce

nt

resp

on

der

s(≥

50%

YM

RS

dec

reas

e)

22%

42%

P<0.01

Extended-ReleaseCarbamazepine

Placebo Extended-ReleaseCarbamazepine

Placebo0

5

10

15

20

25

30

35

40

45

50

61%

29%

55

P<0.0001

756 mg/d8.9 ug/mL

N = 94

643mg/d

N = 120

Weisler RH, et al. J Clin Psychiatry 2005;66:323-30.Weisler RH, et al. J Clin Psychiatry 2004;65:478-84.

N = 98 N = 115

3-Week Double-Blind ERC-Carbamazepine vs Placebo Monotherapy in Acute Mania

60

Titration necessary, watch for drug interactions.

Design N Finding N Finding

Monotherapy vs PBO 443 CBZ > PBO 1-2 - -

Monotherapy vs NL/Li 173 CBZ = NL/Li 3-6 90 OXC = NL/Li 18

Adjunct vs PBO 231 CBZ ≥ PBO 7-12 - -

Adjunct vs NL/Li 216 CBZ ≥ NL/Li 13-17 20 OXC = NL 19

Total N 1063 110

Controlled Carbamazepine and Controlled Carbamazepine and Oxcarbazepine Acute Mania StudiesOxcarbazepine Acute Mania Studies

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.

Carbamazepine Oxcarbazepine

7-Week Double-Blind Oxcarbazepine vs Placebo Monotherapy in Acute Pediatric Mania

Wagner KD, et al. Am J Psychiatry 2006:163:1179-86.

Response Rates

Per

cen

t re

spo

nd

ers

(≥ 5

0% Y

MR

S d

ecre

ase)

26%

42%

P = NS

Oxcarbazepine Placebo Oxcarbazepine Placebo0

5

10

15

20

25

30

35

40

45

50

41%

17%

55

1515mg/d

N = 59

1200mg/d

N = 37N = 56 N = 36

60

Oxcarbazepine Placebo

43% 40%

2040mg/d

N = 22 N = 20

All(7-18 yrs)

Children(7-12 yrs)

Adolescents(13-18 yrs)

P < 0.04

P = NS

Weight Gain During Maintenance TreatmentWeight Gain During Maintenance Treatment

Divalproex Lithium Placebo0

5

10

15

20

25

Per

cen

tag

e o

f P

atie

nts

wit

h W

eig

ht

Gai

n

Bowden CL, et al. Arch Gen Psychiatry 2000;57:481-9.Bowden CL, et al. Arch Gen Psychiatry 2000;57:481-9.** p = 0.004 vs PBO** p = 0.004 vs PBO

****

Bipolar Disorder Symptoms areBipolar Disorder Symptoms areChronic and Predominantly DepressiveChronic and Predominantly Depressive

53%32%

9%6%

AsymptomaticDepressedManic/hypomanicCycling / mixed

% of Weeks

146 bipolar I patients146 bipolar I patientsfollowed 12.8 yearsfollowed 12.8 years

86 bipolar II patients86 bipolar II patientsfollowed 13.4 yearsfollowed 13.4 years

46%50%

1% 2%

Judd et al. Arch Gen Psychiatry. 2002;59:530-7.Judd et al. Arch Gen Psychiatry. 2002;59:530-7. Judd et al. Arch Gen Psychiatry. 2003;60:261-9.Judd et al. Arch Gen Psychiatry. 2003;60:261-9.

Polarity of Index Episode Predicts Polarity of Polarity of Index Episode Predicts Polarity of Relapse: Relapses on PlaceboRelapse: Relapses on Placebo

Index EpisodeRelapse Into Depression Relapse Into Mania

Recently Depressed 39% 16%

2.4:1

Recently Manicor Hypomanic

30% 41%

1.4:1

Bowden et al. Arch Gen Psychiatry. 2003;60:392-400; Calabrese et al. J Clin Psychiatry. 2003;64:1013-1024; Calabrese et al. J Clin Psychiatry. 2002;63(suppl 10):18-22.

Controlled Trials in Acute Bipolar DepressionControlled Trials in Acute Bipolar Depression

Better than PlaceboImipramine1-2

Bupropion3-4 Fluoxetine5

Lamotrigine6

Olanzapine+Fluoxetine > Olanzapine7

Pramipexole8-9

Quetiapine10

Modafinil22

Similar to Placebo* Imipramine11

* Paroxetine11

Better than ImipramineTranylcypromine12-13

Fluoxetine5

Similar to TricyclicMaprotiline = Imipramine14

Moclobemide = Imipramine15-16

Moclobemide = Tricyclic17

s Bupropion = Desipramine18

s Paroxetine = Imipramine11

* > PBO if [Li] < 0.8 mEq/Ls Less switch

Similar to One Anothers Paroxetine = Venlafaxine19

Bupropion = Topiramate20

Paroxetine+(Li/VPA) = Li+VPA21

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.

Course and Subtype Depressive

Burden

Switch

Risk

Antidepressant

Risk:Benefit Ratio

Rapid Cycling Bipolar I Higher Higher Less Favorable

Non-Rapid Cycling Bipolar I Lower Higher Less Favorable

Rapid Cycling Bipolar II Higher Higher Intermediate

Non-Rapid Cycling Bipolar II Higher Lower More Favorable

Are Antidepressants a Good IdeaAre Antidepressants a Good Ideain Bipolar Depression?in Bipolar Depression?

Ketter TA, et al. Bipolar Disord 2005;23(Suppl 2):23.

Baseline HAM-D: Placebo, 19.9; Divalproex 22.0. Last observation carried forward.Davis LL, et al. J Affective Disord 2005;85:259-66.

Baseline HAM-D: Placebo, 19.9; Divalproex 22.0. Last observation carried forward.Davis LL, et al. J Affective Disord 2005;85:259-66.

Mea

n H

AM

-D C

hang

e F

rom

Bas

elin

e (L

OC

F)

Mea

n H

AM

-D C

hang

e F

rom

Bas

elin

e (L

OC

F)

Week0 1 2 3 4 5 6 7 8

-12

-10

-8

-6

-4

-2

0

Placebo (N = 12)

Divalproex 82 ug/mL (N = 13)

P = 0.0002

8-Week Randomized Double-Blind Divalproex 8-Week Randomized Double-Blind Divalproex Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression

Oligomenorrhea and HyperandrogenismOligomenorrhea and Hyperandrogenismaa

with Valproatewith Valproate

**p <0.002 Joffe H, et al. Biol Psychiatry 2006;59(11):1078-86.

Valproate

Per

cen

tag

e w

ith

Oli

go

men

orr

hea

and

Hyp

eran

dro

gen

ism

0

2

4

6

8

10

12

No Valproateb

10.5%(9/86)

1.4%(2/144)

**

230 Women Age 18-45

aHirsutism, acne, male-pattern alopecia, elevated androgens bOther anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium

“Unfortunately, there’s no cure -there’s not even a race for a cure.”

AEDs Marketed in the U.S.AEDs Marketed in the U.S.Year Drug

1981 Clorazepate

1993 Felbamate1993 Gabapentin1994 Lamotrigine1996 Fosphenytoin1997 Topiramate1997 Tiagabine

2000 Oxcarbazepine2000 Levetiracetam2000 Zonisamide

2005 Pregabalin

Year Drug

1912 Phenobarbital1935 Mephobarbital1938 Phenytoin1946 Trimethadione1947 Mephenytoin

1951 Phenacemide1953 Phensuximide1954 Primidone1957 Methsuximide1957 Ethotoin

1960 Ethosuximide1968 Diazepam

1974 Carbamazepine1975 Clonazepam1978 Valproate

Placebo Controlled Gabapentin Trials

Diagnosis N Dose FindingBipolar Disorder - Ineffective as Primary Treatment

Mania (add-on) 1 117 600-3600 GBP <= PBO

Rx Resistant RCBP 2 31 4000 GBP = PBO

Comorbid Disorders - Effective for Comorbidities (Non-bipolar pts)

Social Phobia 3 69 900-3600 GBP > PBO

Panic Disorder 4 103 600-3600 GBP > PBO

Post-herpetic Neuralgia 5 229 1200-3600 GBP > PBO

Neuropathic Pain 6 305 900-2400 GBP > PBO

Chronic Daily Headache 7 95 2400 GBP > PBO

1 Pande AC, et al. Bipolar Disord 2000;2:249-55;2 Frye MA, et al. J Clin Psychopharmacol 2000;20:607-14; 3 Pande AC, et al. J Clin Psychopharmacol 1999;19:341-8; 4 Pande AC, et al. J Clin Psychopharmacol 2000;20:467-71; 5

Rowbotham M, et al. JAMA 1999;280:1837-42; Serpell MG. Pain 2002;99:557-66; Spira PJ, Beran RG. Neurology 2003;61:1753-9.

"Read the instructions very, very, very, very carefully."

Gradual Lamotrigine Titration Crucial to Gradual Lamotrigine Titration Crucial to Reduce Risk of RashReduce Risk of Rash

1 Guberman et al. Epilepsia. 1999; 2 Physicians’ Desk Reference. 2003.1 Guberman et al. Epilepsia. 1999; 2 Physicians’ Desk Reference. 2003.

Double lamotrigine dose with carbamazepine Halve lamotrigine dose with valproate

Double lamotrigine dose with carbamazepine Halve lamotrigine dose with valproate

Lamotrigine Titration in Adults1,2Lamotrigine Titration in Adults1,2

Week Daily Dose

1 25 mg

2 25 mg

3 50 mg

4 50 mg

Week 5 Add 50-100 mg/wkonward as clinically indicated

Maintenance 100-400 mg

Week Daily Dose

1 25 mg

2 25 mg

3 50 mg

4 50 mg

Week 5 Add 50-100 mg/wkonward as clinically indicated

Maintenance 100-400 mg

“If you remember,I did mention possible side-effects.”

Ketter TA, et al. J Clin Psychiatry 2005;66:642-5. Ketter TA, et al. J Clin Psychiatry 2005;66:642-5.

Slower Titration and Dermatology Precautions Slower Titration and Dermatology Precautions to Decrease Drug-Induced Rashto 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 (N=100) – No serious rash; Rash discontinuation in 3% (3/100)– Rash rates

All patients 5% (5/100) Dermatology/dosing adherent patients 3.1% (3/97)

Ginsberg L, et al. 156th Annual Meeting of American Psychiatric Association; San Francisco, Calif; May 17-22, 2003. Ginsberg L, et al. 156th Annual Meeting of American Psychiatric Association; San Francisco, Calif; May 17-22, 2003.

Weight Loss with Lamotrigine in Weight Loss with Lamotrigine in Obese Bipolar Disorder PatientsObese Bipolar Disorder Patients

-10-8-6-4-202468

10

0 10 20 30 40 50Week

We

igh

t C

han

ge

(lb

)

Placebo(n=48)

Lamotrigine(n=51)

Lithium(n=43)

*

* p < 0.02 vs PBO, p < 0.0001 vs Li* p < 0.02 vs PBO, p < 0.0001 vs Li

Calabrese et al. J Clin Psychiatry. 1999;60:79-88.Calabrese et al. J Clin Psychiatry. 1999;60:79-88.

Last Observation Carried Forward Observed Cases

MA

DR

SM

AD

RS

Ch

an

ge

Fro

m B

ase

line

Ch

an

ge

Fro

m B

ase

line

PBO 5%

LTG 50 3%

LTG 200 8%

7-Week Randomized Double-Blind Lamotrigine 7-Week Randomized Double-Blind Lamotrigine Monotherapy in Acute Bipolar I DepressionMonotherapy in Acute Bipolar I Depression

LTG 50 mg/d (n = 64)LTG 50 mg/d (n = 64)

LTG 200 mg/d (n = 63)LTG 200 mg/d (n = 63)

Placebo (n = 65)Placebo (n = 65)

WeekWeek

0

-5

-10

-15

-20

0 1 2 3 4 5 6 7

±±

±±**

******

WeekWeek

0

-5

-10

-15

-20

0 1 2 3 4 5 6 7

††

**** ** **

**** **

**

LTG 50 mg/dLTG 50 mg/d

LTG 200 mg/dLTG 200 mg/d

PlaceboPlacebo

Switch RatesSwitch Rates

±± P<0.1; P<0.1; †† * P<0.05. * P<0.05.

16-Week Randomized Open Adjunctive Therapy of 16-Week Randomized Open Adjunctive Therapy of Treatment Resistant Bipolar DepressionTreatment Resistant Bipolar Depression a a

Nierenberg AA, et al. Am J Psychiatry 2006;163;210-6.

138mg/d

9429mg/d

1.5mg/d

23.8%[5.8-41.8]

17.4%[2.4-32.4]

4.6%[0-14.6]

a 54% BPI, 46% BPII.

Goodwin et al. J Clin Psychiatry 2004;65:432-41.

Lamotrigine and LithiumLamotrigine and LithiumEffective in Bipolar I Prophylaxis Effective in Bipolar I Prophylaxis

Time to Intervention for Any Episode (pooled recently manic/dep pts)Time to Intervention for Any Episode (pooled recently manic/dep pts)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20 30 40 50 60 70Week

Su

rviv

al E

sti

ma

te

Placebo (n=188)

Lamotrigine 245 mg/d (n=223)

Lithium 0.7 mEq/L (n=164)

LTG v. PBO, p < 0.001Li v. PBO, p < 0.001LTG v. Li, p = 0.629

LTG Li PBO0

10

20

30

40

50

22%

42%37%

18 Months

Some patients considered intervention-free for depression could have had intervention for mania.


Lamotrigine Effective inLamotrigine Effective inBipolar I Depression Prophylaxis Bipolar I Depression Prophylaxis

Time to Intervention for Depression (pooled recently manic/dep pts)Time to Intervention for Depression (pooled recently manic/dep pts)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70Week

Su

rviv

al E

sti

ma

te

LTG v. PBO, p = 0.009Li v. PBO, p = 0.120LTG v. Li, p = 0.325

LTG Li PBO0

10

20

30

40

50

60

41%

53%57%

18 Months

Placebo (n=188)



Some patients considered intervention-free for mania could have had intervention for depression.


Lamotrigine and Lithium Effective inLamotrigine and Lithium Effective inBipolar I Mania Prophylaxis Bipolar I Mania Prophylaxis

Time to Intervention for Mania (pooled recently manic/dep pts)Time to Intervention for Mania (pooled recently manic/dep pts)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70Week

Su

rviv

al E

sti

ma

te

LTG v. PBO, p = 0.034Li v. PBO, p < 0.001LTG v. Li, p = 0.030

Placebo (n=188)



LTG Li PBO0

20

40

60

80

53%

80%

65%

18 Months

6-Week Lamotrigine Versus Gabapentin Versus Placebo in Treatment Resistant Mood Disorders

Lamotrigine Gabapentin Placebo

0

10

20

30

40

50

60

Per

cen

t C

lin

ical

Glo

bal

Imp

ress

ion

Res

po

nse

52%(16/31)

26%(8/31) 23%

(7/31)

*

* p < 0.05 versus GBP and PBO.

Frye MA, et al. J Clin Psychopharmacol 2000;20:607-14.

275 mg/d 4000 mg/d

Crossover trial with 74% Rapid-Cycling BP, 6% Non- Rapid-Cycling BP, 20% UP

Lamotrigine Effective in Rapid Cycling BPII

41%

46%

18%

*

* p < 0.05.Calabrese JR, et al. J Clin Psychiatry 2000;61:841-50.

0

10

20

30

40

50

All BPI BPII

PBOLTG

31%

39%

26%

*

Lamotrigine Ineffective in Acute Mania

44%42%

46%

*

* p < 0.05 vs PBO.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.

Per

cen

t R

esp

on

der

s(≥

50%

MR

S d

ecre

ase)

Lamotrigine Placebo Lithium Lamotrigine Placebo Lithium0

10

20

30

40

50

60

70

55%

62%

47%

Response RatesLow Dose(3 weeks)

Add-on(6 weeks)

50mg/d

N = 85 N = 95

0.8-1.3mEq/LN = 36

200mg/d

N = 74 N = 77

0.8-1.3mEq/LN = 77

Lamotrigine Stabilizes Mood From Below Baseline?Lamotrigine Stabilizes Mood From Below Baseline?

Ketter TA, Calabrese JR. J Clin Psychiatry 2002; 63(2):146-151.

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

Types of Mood Stabilizers

”Being on a diet does not give you the right to go berserk in a donut shop."

Placebo Controlled Topiramate Trials

Diagnosis N Dose FindingBipolar 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 > PBO

Obese+Binge Eat4 61 212 TPM > PBO

Bulimia5 69 100 TPM > PBO

Etoh Dependence6 150 200 TPM > PBO

Migraine7 468 50-200 TPM > PBO1 Kushner S, et al. Bipolar Disord 2006;8:15-27; 2 DelBello M, et al. J Am Acad Child Adolesc Psychiatry 2005;44:539-47; 3 Bray GA, et al. Obes Res 2003; 11:722-33; 4 McElroy SL, et al. Am J Psychiatry 2003;160:255-61; 5 Hoopes SP, et al. J Clin Psychiatry 2003;64:1335-41; 6 Johnson BA, et al. Lancet 2003;361:1677-85; 7 Brandes JL, et al. JAMA 2004;291:965-73.

Weight Loss with Zonisamide in Obesity

Gadde KM, et al. JAMA. 2003;289:1820-5.Gadde KM, et al. JAMA. 2003;289:1820-5.

Obese (No psychiatric disorder) Obese Euthymic Medicated Bipolar

*

Week

0 1 2 3 4 6 10 14 18 22 26

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Mean Duration9.0 ± 6.7 wks

Weight (lbs)

Baseline 221.2 ± 27.0

LOCF 211.3 ± 19.4

Change -9.9 ± 13.7

Rate of Change

-1.3 ± 2.0 lb/wk

Wei

gh

t C

han

ge

(lb

s)

*

*

*

*

±

± p < 0.10, * p < 0.05 vs Baseline

Yang YS, et al. 156th APA Ann Mtg; San Francisco; May 17-22, 2003. Yang YS, et al. 156th APA Ann Mtg; San Francisco; May 17-22, 2003.

p < 0.001

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 disordersKetter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:6.

Emerging Diverse Roles of Anticonvulsants in Patients with Bipolar Disorders

New Anticonvulsants Not (Yet) ProvenEffective 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 study1 Emrich HM. Int Clin Psychopharmacol 1990;5(Suppl 1):83-8; 2 Pande AC, et al. Bipolar Disord 2000;2:249-55; 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 1999;60:759-62.

Adapted from: Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:37.

“I’m going to prescribe something that works like aspirin, but costs much, much more.”

Suppes T, et al. Am J Psychiatry 1999;156:1164-9.

12-Month Randomized Adjunctive Clozapine in12-Month Randomized Adjunctive Clozapine inBipolar & Schizoaffective Dsiorder PatientsBipolar & Schizoaffective Dsiorder Patients

26 bipolar, 12 schizoaffective disorder, bipolar type patients

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Clozapine 355 mg/d (n=19)

Treatment as usual (n=19)

Months

Pe

rce

nt

of

pa

tien

ts w

ith

30%

imp

rove

men

t

p <.05

Mean clozapine doses - in bipolar 234 mg/d, in schizoaffective 623 mg/d.

Smulevich AB, et al. Eur Neuropsychopharmacol 2005;15:75-84.Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057-65.

Young Mania Rating Scale Response Rates

3-Week Double-Blind Risperidonevs Placebo Monotherapy in Acute Maniaa

Risperidone Placebo0

10

20

30

40

50

60

Per

cen

t R

esp

on

se(≥

50%

YM

RS

dec

reas

e)

43%

24%

**

4.1mg/d

N = 127

Risperidone

48%

4.2mg/d

N = 153N = 119

Placebo

33%

N = 138

47%

8.0mg/d

N = 144

Haloperidol

aExcluded mixed episodes; **p < 0.01 vs placebo.

** **

Watch for extrapyramidal symptoms at higher doses.

Yatham LN, et al. Br J Psychiatry 2003;182:141-7.

Per

cen

t R

esp

on

der

s(≥

50%

YM

RS

dec

reas

e)

38%42%

59%57%

p < 0.05

p < 0.06

Risperidone+ Li/VPA

Placebo+ Li/VPA

Haloperidol+ Li/VPA

Risperidone+ Li/VPA

Placebo+ Li/VPA

0

10

20

30

40

50

6058%

Sachs G, et al. Am J Psychiatry 2002;159:1146-54.

3.8mg/d

4.0mg/d

6.2mg/d

N = 52 N = 51 N = 55* N = 62*N = 53

*Excluded 14 RSP+CBZ, 12 PBO+CBZ pts.


3-Week Double-Blind Adjunctive Risperidonevs Placebo (Monotherapy) in Acute Mania

Carbamazepine decreased plasma risperidone concentrations by 40 percent.

Olanzapine Placebo Olanzapine Placebo0

10

20

30

40

50

60

70

Per

cen

t R

esp

on

se(≥

50%

YM

RS

dec

reas

e)

49%

43%

65%

24%


p < 0.05

p < 0.01

Tohen M, et al. Am J Psychiatry 1999;156:702-9. Tohen M, et al. Arch Gen Psychiatry 2000;57:841-9.

15mg/d

N = 69

16mg/d

N = 55N = 70 N = 60

3- and 4-Week Double-Blind Olanzapinevs Placebo Monotherapy in Acute Mania

Often started clinically at 20 mg/day.

Response Rates

Olanzapine vs Divalproex Acute Mania Studies

Zajecka J, et al. J Clin Psychiatry 2002;63:1148-55.

Per

cen

t R

esp

on

der

s(≥

50%

Yo

un

g/S

AD

S-C

MR

S d

ecre

ase)

p = 0.06

Olanzapine Divalproex Olanzapine Divalproex0

10

20

30

40

50

60

70

54% 53%

62%

42%

p = 0.31

Tohen M, et al. Am J Psychiatry 2002;159:1011-7.

17mg/d

N = 125

15mg/d

N = 55

1401mg/d

84ug/mLN = 126

1956mg/d

85ug/mLN = 60

day ug/mL

3 78

6 97

10 101

day ug/mL

5 77

7 82

Olanzapine slightly more effective, divalproex slightly better tolerated.


Tohen M, et al. Arch Gen Psychiatry 2002;59:62-9.

Per

cen

t R

esp

on

der

s(≥

50%

YM

RS

dec

reas

e)

Olanzapine + Li 0.76 mEq/L / VPA 64 ug/mL Placebo + Li 0.82 mEq/L /VPA 75 ug/mL

6-Week Double-Blind Adjunctive Olanzapinevs Placebo (Monotherapy) in Acute Mania

68%

45%

*p < 0.05, ***p = 0.001 vs placebo.

0

10

20

30

40

50

60

70

10.4 mg/dN = 220 N = 114

****

***

Low therapeutic mood stabilizer plasma concentrations in combination therapy.

Pe

rce

nta

ge

of

Pa

tie

nts

Stabilized on OLZ+Li before randomization. Relapse criteria - YMRS or HAMD-21 >= 15. Tohen MF, et al. Am J Psychiatry 2005;162:1281-90.

0

10

20

30

40

50

14.3%

28.0%

p=.055

p=.895p<.001

Overall Relapse Relapse Into Depression Relapse Into Mania

15.4%16.1%

38.8%

30.0%

Olanzapine 11.9 mg/d (n=217)

Lithium 1103 mg/d (0.77 mEq/L) (n=214)

Double-Blind Olanzapine vs Lithium Double-Blind Olanzapine vs Lithium Maintenance MonotherapyMaintenance Monotherapy

EquivalentDepressionPrevention


Olanzapine Compared to Lithium After Manic/Mixed EpisodesOlanzapine Compared to Lithium After Manic/Mixed Episodes

EquivalentEpisode

Prevention

EquivalentEpisode

Prevention

SuperiorMania

Prevention

SuperiorMania

Prevention

Olanzapine 12.5 mg/d (n=225)

Placebo (n=136)

0

20

40

60

80

100

Overall Relapse Relapse Into Depression Relapse Into Mania

Pe

rce

nta

ge

of

Pa

tie

nts

p<.001

p=.015

p<.001

16.4%

41.2%47.8%

34.7%

80.1%

46.7%

Stabilized on OLZ before randomization. Relapse criteria - hospitalized or YMRS or HAMD-21 >= 15. Tohen MF, et al. Am J Psychiatry 2006;163:247-56.

Double-Blind Olanzapine Monotherapy vs Double-Blind Olanzapine Monotherapy vs Placebo MaintenancePlacebo Maintenance

Olanzapine Compared to Placebo After Manic/Mixed EpisodesOlanzapine Compared to Placebo After Manic/Mixed Episodes

SuperiorDepressionPrevention

SuperiorDepressionPrevention

SuperiorEpisode

Prevention

SuperiorEpisode

Prevention

SuperiorMania

Prevention

SuperiorMania

Prevention

OLZ 9.7 mg(N = 351)

PBO (N = 355)

OLZ 7.4 mg+ FLX 39.3 mg(N = 82)

Week

0 1 2 3 4 6 8

Me

an

Ch

an

ge

in M

AD

RS

Sc

ore

s

-20

-15

-10

-5

0

*

*

**

**

†† †

Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88.Baseline MADRS 31.3 PBO, 32.6 OLZ, 30.8 OLZ+FLX.

* P < 0.05 vs OLN, OLN+FLX. † P < 0.05 vs OLN.

8-Week Randomized Double-Blind Olanzapine ± 8-Week Randomized Double-Blind Olanzapine ± Fluoxetine in Acute Bipolar I DepressionFluoxetine in Acute Bipolar I Depression

PBO 7%

OLZ 6%

OFC 6%

Switch Rates

LTG 106 mg(N = 205)

OLZ 10.7 mg+ FLX 38.3 mg(N = 205)

Week

Me

an

Ch

an

ge

in M

AD

RS

Sc

ore

s

Brown EB, et al. J Clin Psychiatry 2006;66:1025-33.

Baseline MADRS 30.9 OFC, 31.4 LTG. *P < 0.05, ***P < 0.001 OFC vs LTG. Trade-off: 3 lbs/MADRS point.

7-Week Randomized Double-Blind Olanzapine + 7-Week Randomized Double-Blind Olanzapine + Fluoxetine vs Lamotrigine in Acute Bipolar I DepressionFluoxetine vs Lamotrigine in Acute Bipolar I Depression

LTG 5%

OFC 4%

Switch Rates0 1 2 3 4 6 8

-20

-15

-10

-5

0

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

-25

5

* * *

*

*

LTG -0.3***

OFC +3.1

Weight Change (kg)

Responders ≥ 7% Weight Gain

7-Week Randomized Double-Blind Olanzapine + 7-Week Randomized Double-Blind Olanzapine + Fluoxetine vs Lamotrigine in Acute Bipolar I DepressionFluoxetine vs Lamotrigine in Acute Bipolar I Depression

OFC LTG OFC LTG0

10

20

30

40

50

60

69%

60%

Per

cen

tag

e o

f P

atie

nts

23%

0%

±

***

70

Brown EB, et al. J Clin Psychiatry 2006;66:1025-33.

± P < 0.08, *** P < 0.001 OFC vs LTG. Trade-off: 9% response vs 23% weight gain.

Young Mania Rating Scale Response RatesP

erc

en

t R

esp

on

der

s(≥

50

% Y

MR

S d

ecr

eas

e)48%

31%

p < 0.0006

Quetiapine Placebo0

10

20

30

40

50

60

576mg/dr

N = 208

12-Week Double-Blind Quetiapine vs Placebo Monotherapy in Acute Mania (Pooled Data)a

Vieta E, et al. Curr Med Res Opin. 2005;21:923-34.

N = 195

aExcluded mixed episodes, rapid cycling; bMean final dose in respondersImportant to use adequate dosage - started at 100 mg/day and increased by 100 mg/day.


Yatham LN, et al. J Clin Psychopharmacol 2004;24:599-606.

3-Week Double-Blind Adjunctive Quetiapine vs Placebo (Monotherapy) in Acute Mania (Pooled Data)a

Per

cen

t R

esp

on

der

s(≥

50%

YM

RS

dec

reas

e)

Quetiapine + Li 0.76 mEq/L / VPA 70 ug/mL Placebo + Li 0.73 mEq/L / VPA 74 ug/mL

56%

41%

0

10

20

30

40

50

60

492 mg/db

N = 185 N = 185

**

aExcluded mixed episodes, rapid cycling; bMean final dose in responders; **p = 0.01 vs placebo.

Low therapeutic mood stabilizer plasma concentrations in combination therapy.

-20

-15

-10

-5

0

Quetiapine 600 mg (N = 170)

Quetiapine 300 mg (N = 172)

Placebo (N = 169)

†

†

†

†

† †† †

†

†

† †

† † † †

0 1 2 43 65 7 8

Study Week

ITT, LOCF

Ch

ang

e F

rom

Bas

elin

e(L

S M

ean

s)

Baseline MADRS 30.3 PBO, 30.4 QTP 300, 30.6 QTP 600.

†P<0.001 (quetiapine vs placebo)

8-Week Randomized Double-Blind Quetiapine 8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression

Calabrese JR, et al. Am J Psychiatry 2005;162:1351-60.

PBO 4%

QTP 300 4%

QTP 600 2%

Switch Rates

ITT, LOCFBaseline MADRS 29.6 PBO, 31.1 QTP 300, 29.9 QTP 600.

*P<0.01, †P<0.001 (quetiapine vs placebo).


Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9.

Mo

ntg

om

ery-

Asb

erg

Dep

ress

ion

Rat

ing

Sca

leIm

plr

ove

men

t

PBO 7%

QTP 300 2%

QTP 600 4%

Switch Rates


Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9.

BOLDER I BOLDER II

Per

cen

tag

e o

f P

atie

nts

Res

po

nd

ing

(≥ 5

0% M

AD

RS

Dec

reas

e)

PBO QTP300

QTP600

PBO0

10

20

30

40

50

60 58% 58%

36%40%

37%

24%

***

***

QTP300

QTP600

***

Response Rates

Calabrese JR, et al. Am J Psychiatry 2005;162:1351-60.

*p < 0.05, **p< 0.01, *** p < 0.001 vs placebo.

Bipolar Disorder I(N=657)

Bipolar Disorder II(N=321)

†

‡

MA

DR

S L

S M

ean

C

han

ge

Fro

m B

asel

ine

Imp

rove

men

t

†p<0.01; ‡p<0.001 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

BOLDER I and II: MADRS Total Score BOLDER I and II: MADRS Total Score Bipolar I vs. II DisorderBipolar I vs. II Disorder

‡

†

Quetiapine 300Quetiapine 600Placebo-20

-16

-12

-8

-4

0

Potkin SG, et al. J Clin Psychopharmacol 2005;25:301-10. Keck PE, et al. Am J Psychiatry 2003;160:741-8.

Per

cen

t re

spo

nd

ers

(≥ 5

0% S

AD

S-C

MR

S d

ecre

ase)

35%

50%

P<0.01

Ziprasidone Placebo Ziprasidone Placebo0

5

10

15

20

25

30

35

40

45

50 46%

29%

60

P<0.05

136mg/d

N = 131

127mg/d

N = 137N = 66 N = 65

3-Week Double-Blind Ziprasidonevs Placebo Monotherapy in Acute Mania

SADS-C* Mania Rating Scale Response Rates

*Schedule for Affective Disorders and Schizophrenia-ChangeImportant to use adequate dosage - day one 80 mg/day, day two 160 mg/day - with food.

Adjunctive PramipexoleAdjunctive Pramipexolein Acute Bipolar Depressionin Acute Bipolar Depression

Response RatesP

erce

nt

resp

on

der

s(≥

50%

HD

RS

/MA

DR

S d

ecre

ase)

20%(2/10)

67%(8/12)

P<0.04

Pramipexole Placebo Pramipexole Placebo0

5

10

15

20

25

30

35

40

45

50

60%(6/10)

9%(1/11)

60

P<0.02

1.7mg/d

1.7mg/d

Zarate CA, et al.Biol Psychiatry 2004; 56:54-60.

Goldberg JF, et al.Am J Psychiatry 2004; 161:564-6

70

Response Rates

Per

cen

t R

esp

on

der

s(≥

50%

ID

S d

ecre

ase)

*p < 0.05 vs placebo TEAS Modafinil 4.9%, Placebo 11.4%

Modafinil Placebo0

10

20

30

40

50

60

22%

44%

177 mg/dN = 41 N = 44

*

Frye M, et al. APA, Toronto, 2006.

6-week Randomized Double-Blind Adjunctive 6-week Randomized Double-Blind Adjunctive Modafinil in Acute Bipolar DepressionModafinil in Acute Bipolar Depression

Sach GS, et al. J Psychopharmacol 2006.Keck PE, Jr, et al. Am J Psychiatry 2003;160:1651-8.

Per

cen

t re

spo

nd

ers

(≥ 5

0% Y

MR

S d

ecre

ase)

19%

40%

P<0.01

Aripiprazole Placebo Aripiprazole Placebo0

5

10

15

20

25

30

35

40

45

5053%

32%

60

P<0.01

28mg/d

N = 123

28mg/d

N = 135N = 120 N = 129

3-Week Double-Blind Aripiprazolevs Placebo Monotherapy in Acute Mania


Starting with 15 mg/day briefly prior to increasing to 30 mg/day can decrease nausea.

0

10

20

30

13%12%

6%5%Pe

rce

nt

of

Pa

tien

ts

43%

25% 23%

8%

Relapse intoMania

40

50

Relapse intoMixed

Relapse intoDepression

OverallRelapse

Aripiprazole 24.3 mg/d (n=77)

Placebo (n=83)

p=.013

p=.009



SuperiorEpisode

Prevention

SuperiorEpisode

Prevention

EquivalentMixed

Prevention

EquivalentMixed

Prevention

SuperiorMania

Prevention

SuperiorMania

Prevention

Stabilized on ARI before randomization.Keck PE, et al. J Clin Psychiatry 2006;67:626-37.

26-Week Double-Blind Aripiprazole vs Placebo 26-Week Double-Blind Aripiprazole vs Placebo Continuation/Maintenance MonotherapyContinuation/Maintenance Monotherapy

Aripiprazole Compared to Placebo After Manic/Mixed EpisodesAripiprazole Compared to Placebo After Manic/Mixed Episodes

Broad Efficacy Spectra of Atypical AntipsychoticsBroad Efficacy Spectra of Atypical Antipsychotics

1Tohen M, et al. Am J Psychiatry 1999;156:702-9; 2Tohen M, et al. Arch Gen Psychiatry 2000;57:841-9; 3Sachs G et al. Am J Psychiatry. 2002;159:1146-1154; 4Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057-65; 5Yatham LN, et al. J Clin Psychopharmacol 2004;24:599-606; 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.

Agent Mixed Psychotic Rapid Cycling

Olanzapine1,2 + + +

Risperidone3,4 + + ?

Quetiapine5,p ? + ?

Ziprasidone6,p + + ?

Aripiprazole7,p + + +

Rapid Onset of Action of Atypical AntipsychoticsRapid Onset of Action of Atypical Antipsychotics

1Tohen M, et al. Arch Gen Psychiatry 2000;57:841-9; 2Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057-65; 3Calabrese JR, et al. In Review; 4Keck P, et al. Am J Psychiatry. 2003;160:741-8; 5Segal S, et al. 156th APA Ann Mtg. San Francisco, CA, May 17-22, 2003; 6Keck PE, et al. Am J Psychiatry. 2003;160:1651-8; 7Sachs GS, et al. 157th APA Ann Mtg. New York, NY, May 1-6, 2004. p = pooled data.

Separated From Placebo by Week 1

Olanzapine 1

Risperidone2

Quetiapine3,p

Ziprasidone4,5

Aripiprazole6,7

Mood StabilizerMood StabilizerSafety and Tolerability Safety and Tolerability

ConcernsConcernsDivalproexDivalproex

GastrointestinalGastrointestinal

Weight gainWeight gain

TremorTremor

HepaticHepatic

CoagulationCoagulation

Hair LossHair Loss

PancreatitisPancreatitis

TeratogenTeratogen

PCOSPCOS

CarbamazepineCarbamazepine

GastrointestinalGastrointestinal

RashRash

NeurotoxicityNeurotoxicity

HepaticHepatic

ThyroidThyroid

HematologicHematologic

CardiacCardiac

TeratogenTeratogen

HyponatremiaHyponatremia= boxed warning in prescribing information

LithiumGastrointestinal

Weight gainNeurotoxicity

RenalThyroid

Hair LossCardiac

TeratogenAcne, Psoriasis

Adapted from: Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:11-55.

Second-GenerationSecond-GenerationWeight gainWeight gain

SedationSedation

Hyperglycemia, Diabetes*Hyperglycemia, Diabetes*

CardiacCardiac

± Akathisia± Akathisia

± Hyperprolactinemia± Hyperprolactinemia

± Cerebrovascular*± Cerebrovascular*

± Tardive dyskinesia*± Tardive dyskinesia*

± Neuroleptic malignant*± Neuroleptic malignant*

Cardiac/pneumonia in elderly*Cardiac/pneumonia in elderly*

Antipsychotic Antipsychotic Safety and Tolerability Safety and Tolerability

ConcernsConcerns

Warnings - *In prescribing information; ?Under consideration; boxed

First-GenerationDepressionAkathisia

Acute dystoniaTardive dyskinesia*

Weight gainSedationCardiac

Hyperprolactinemia

± Neuroleptic malignant*± Neuroleptic malignant*

± Cardiac/pneumonia in elderly± Cardiac/pneumonia in elderly?

Adapted from: Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:11-55.

Obesity Associated with Earlier Relapse Obesity Associated with Earlier Relapse in Bipolar Disorderin Bipolar Disorder

Fagiolini A et al. Am J Psychiatry. 2003;160:112-7.

Any RelapseAny Relapse Depressive RelapseDepressive Relapse

p < 0.02p < 0.02

p < 0.007p < 0.007

Second Generation Antipsychotics and Metabolic Abnormalities

Drug Weight Diabetes Lipids

Clozapine +++ + +

Olanzapine +++ + +

Risperidone ++ D D

Quetiapine ++ D D

Aripiprazole* ± - -

Ziprasidone* ± - -

Am Diabetes Assoc, Am Psychiatric Assoc, Am Assoc Clin Endocrinologists, N Am Assoc for Study of Obesity: Diabetes Care 2004;27:596:601.

+ = increase effect; - = no effect; D = discrepant. * Newer drugs with limited long-term data.

Emerging Uses of Atypical Antipsychoticsin 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 resistantKetter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:6.

ConclusionsConclusions

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

upgrading your brain made easy new treatment options for patients with bipolar disorders terence a....

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