Upgradin Upgradin g g Your Your Brain Brain Made Made Easy Easy
Jan 11, 2016
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
Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:12.
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
Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:13.
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
Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.
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
Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.
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
Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.
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
Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.
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.
Goodwin et al. J Clin Psychiatry 2004;65:432-41.
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)
Lamotrigine 245 mg/d (n=223)
Lithium 0.7 mEq/L (n=164)
Some patients considered intervention-free for mania could have had intervention for depression.
Goodwin et al. J Clin Psychiatry 2004;65:432-41.
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)
Lamotrigine 245 mg/d (n=223)
Lithium 0.7 mEq/L (n=164)
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.
Young Mania Rating Scale Response Rates
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%
Young Mania Rating Scale Response Rates
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.
Young Mania Rating Scale Response Rates
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
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.
Young Mania Rating Scale Response Rates
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).
8-Week Randomized Double-Blind Quetiapine 8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression
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
8-Week Randomized Double-Blind Quetiapine 8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression
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
Young Mania Rating Scale Response Rates
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
EquivalentDepressionPrevention
EquivalentDepressionPrevention
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