2. Upgrading Your Brain Made Easy

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

4. 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

6. 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

7. 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 combi nation 2006 Quetiapine *Adjunctive as well as monotherapy Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:2.

8. Overview of 20 Acute Mania Studies Overview of 20 Acute Mania Studies Response Rates 5 Combination Therapy Studies 15 Monotherapy Studies Percent responders (≥ 50% mania rating decrease) P<0.0001 0 5 10 15 20 25 30 35 40 45 50 55 P<0.0001 50% Li/DVPX/CBZ/Atypical Monotherapy N = 2338 Atypical + Li/DVPX Combination 62% N = 521 Li/DVPX Monotherapy 42% N = 413 29% Placebo N = 1265 60 65 Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:12.

9. Summary of 15 Acute Mania Monotherapy Studies Summary of 15 Acute Mania Monotherapy Studies Response Rates Atypical AntipsychoticsMood Stabilizers 0 10 20 30 40 50 60 Carbamazepine 707 mg/d N = 223 Risperidone 4.9 mg/d N = 273 Quetiapine 575 mg/d N = 208 Ziprasidone 121 mg/d N = 268 Aripiprazole 28 mg/d N = 260 Placebo N = 1265 Olanzapine 16 mg/d N = 304 Divalproex 1694 mg/d N = 255 Lithium 1950 mg/d N = 134 Percent responders (≥ 50% mania rating decrease) Placebo Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005:13.

10. 22 36 25 29 24 25 19 29 11 35 4 8 25 0% 10% 20% 30% 40% 50% 60% QTP 600mg QTP 300mg LTG 200mg OFC LTG 50mg Li Pax Li IMIOlz Active-Placebo Response Rate Difference Response Rate (≥ 50% decrease in depression rating) Summary of 4 Acute Bipolar Depression Studies Summary 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

11. Response Rates Pope HG, et al. Arch Gen Psychiatry 1991;48:62-8. Bowden CL, et al. JAMA 1994;271:918-24. Percent Responders (≥ 50% YMRS/SADS-C MRS decrease) 25% 49% 11% *p < 0.05 **p ≤ 0.01 vs placebo 53% 48% DivalproexPlaceboDivalproexLithiumPlacebo 0 10 20 30 40 50 60 2000 mg/d 93 ug/mL N = 69 1950 mg/d 1.2 mEq/L N = 36 N = 74 2400 mg/d N = 17 N = 19 * ** 3-Week Double-Blind Divalproex vs Placebo Monotherapy in Acute Mania Excluded mixed patients. Later studies found loading 20-30 mg/kg was well tolerated.

12. 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

13. Response Rates Percent Responders (≥ 50% SADS-C MRS decrease) *p < 0.05 vs placebo Divalproex Placebo 0 10 20 30 40 50 60 34% 48% 3057 mg/d 96 ug/mL N = 187 N = 177 * 3-Week Double-Blind Divalproex ER vs Placebo Monotherapy in Acute Mania Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006. dayug/mL 597 2196 DVPX started at 25 mg/kg/d (rounded up to nearest 500 mg), increased 500 mg on day 3.

14. 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 1Day 5Day 10Day 15Day 21 * * *** ** Change in Mania Ratings Change in SADS-C MRS *p < 0.05, **p < 0.01, ***p < 0.001 vs placebo 3-Week Double-Blind Divalproex ER vs Placebo Monotherapy in Acute Mania Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.

15. 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 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.

16. Divalproex ER Mean Doses & Levels  Target serum valproate level 85 – 125 ug/mL Time Dose (mg/d) (mg/kg/d) Level (ug/mL) Day 52,874 33.296.5 Final3,065 35.495.9 Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.

17. Adverse Effect Discontinuations and Serum Valproate Levels Group Valproate level (ug/mL) No adverse effect discontinuation93.9 Adverse effect discontinuation114.1 GI adverse effect discontinuation123.2 Bowden CL, et al. APA Ann Mtg, Toronto, May 20-25, 2006.

18. VPA + Antipsychotic Superior to Antipsychotic Monotherapy * 20 mg/kg/day Muller-Oerlinghausen et al., J Clin Psychopharmacol 20; 195-203, 2000 Placebo + Antipsychotic Valproate* + Antipsychotic Clinical Global Impression Very much improved Much improved 40% 67% 32% 31% 18% 36% P < 0.002 dayug/mL 360 776 1880 2180

19. Response Rates Percent responders (≥ 50% YMRS decrease) 22% 42% P<0.01 Extended-Release Carbamazepine PlaceboExtended-Release Carbamazepine Placebo 0 5 10 15 20 25 30 35 40 45 50 61% 29% 55 P<0.0001 756 mg/d 8.9 ug/mL N = 94 643 mg/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 = 98N = 115 3-Week Double-Blind ERC-Carbamazepine vs Placebo Monotherapy in Acute Mania 60 Titration necessary, watch for drug interactions.

20. Controlled Carbamazepine and Oxcarbazepine 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

21. 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 Percent responders (≥ 50% YMRS decrease) 26% 42% P = NS OxcarbazepinePlaceboOxcarbazepinePlacebo 0 5 10 15 20 25 30 35 40 45 50 41% 17% 55 1515 mg/d N = 59 1200 mg/d N = 37 N = 56N = 36 60 OxcarbazepinePlacebo 43% 40% 2040 mg/d N = 22 N = 20 All (7-18 yrs) Children (7-12 yrs) Adolescents (13-18 yrs) P < 0.04 P = NS

22. Weight Gain During Maintenance Treatment DivalproexLithiumPlacebo 0 5 10 15 20 25 Percentage of Patients with Weight Gain Bowden CL, et al. Arch Gen Psychiatry 2000;57:481-9. ** p = 0.004 vs PBO **

23. Bipolar Disorder Symptoms are Chronic and Predominantly Depressive 53% 32% 9% 6% Asymptomatic Depressed Manic/hypomanic Cycling / mixed % of Weeks 146 bipolar I patients followed 12.8 years 86 bipolar II patients followed 13.4 years 46% 50% 1% 2% Judd et al. Arch Gen Psychiatry. 2002;59:530-7. Judd et al. Arch Gen Psychiatry. 2003;60:261-9.

24. Polarity of Index Episode Predicts Polarity of Relapse: Relapses on Placebo Index Episode Relapse Into DepressionRelapse Into Mania Recently Depressed39%16% 2.4:1 Recently Manic or 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.

25. Controlled Trials in Acute Bipolar Depression Better than Placebo Imipramine 1-2 Bupropion 3-4 Fluoxetine 5 Lamotrigine 6 Olanzapine+Fluoxetine > Olanzapine 7 Pramipexole 8-9 Quetiapine 10 Modafinil 22 Similar to Placebo * Imipramine 11 * Paroxetine 11 Better than Imipramine Tranylcypromine 12-13 Fluoxetine 5 Similar to Tricyclic Maprotiline = Imipramine 14 Moclobemide = Imipramine 15-16 Moclobemide = Tricyclic 17 s Bupropion = Desipramine 18 s Paroxetine = Imipramine 11 * > PBO if [Li] < 0.8 mEq/L s Less switch Similar to One Another s Paroxetine = Venlafaxine 19 Bupropion = Topiramate 20 Paroxetine+(Li/VPA) = Li+VPA 21 1 Fieve, 1968; 2 Worrall 1979; 3 Fabre 1983; 4 Merideth 1983; 5 Cohn 1989; 6 Calabrese 1999; 7 Tohen 2003; 8 Goldberg 2004; 9 Zarate 2004; 10 Calabrese 2004; 11 Nemeroff 2001; 12 Himmelhoch 1991; 13 Thase 1992; 14 Kessell 1975; 15 Baumhackl 1989; 16 Silverstone 2001; 17 Angst 1992; 18 Sachs 1994; 19 Vieta 2002; 20 McIntyre 2002; 21 Young 2000; 22 Frye 2006.

26. Are Antidepressants a Good Idea in Bipolar Depression? Ketter TA, et al. Bipolar Disord 2005;23(Suppl 2):23.

27. 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. Mean HAM-D Change From Baseline (LOCF) Mean HAM-D Change From Baseline (LOCF) Week 012345678 -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 Monotherapy in Acute Bipolar Depression

28. Oligomenorrhea and Hyperandrogenism a with Valproate **p <0.002Joffe H, et al. Biol Psychiatry 2006;59(11):1078-86. Valproate Percentage with Oligomenorrhea and Hyperandrogenism 0 2 4 6 8 10 12 No Valproate b 10.5% (9/86) 1.4% (2/144) ** 230 Women Age 18-45 a Hirsutism, acne, male-pattern alopecia, elevated androgens b Other anticonvulsants (lamotrigine, topiramate, gabapentin, carbamazepine, oxcarbazepine) and lithium

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

30. AEDs Marketed in the U.S. Year Drug 1981Clorazepate 1993Felbamate 1993Gabapentin 1994Lamotrigine 1996Fosphenytoin 1997Topiramate 1997Tiagabine 2000Oxcarbazepine 2000Levetiracetam 2000Zonisamide 2005Pregabalin Year Drug 1912Phenobarbital 1935Mephobarbital 1938Phenytoin 1946Trimethadione 1947Mephenytoin 1951Phenacemide 1953Phensuximide 1954Primidone 1957Methsuximide 1957Ethotoin 1960Ethosuximide 1968Diazepam 1974Carbamazepine 1975Clonazepam 1978Valproate

31. Placebo Controlled Gabapentin Trials Diagnosis NDose Finding Bipolar 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 952400 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.

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

33. Gradual Lamotrigine Titration Crucial to Reduce Risk of Rash 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 Adults 1,2 WeekDaily Dose 125 mg 225 mg 350 mg 450 mg Week 5Add 50-100 mg/wk onwardas clinically indicated Maintenance100-400 mg WeekDaily Dose 125 mg 225 mg 350 mg 450 mg Week 5Add 50-100 mg/wk onwardas clinically indicated Maintenance100-400 mg

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

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

36. Ginsberg L, et al. 156th Annual Meeting of American Psychiatric Association; San Francisco, Calif; May 17-22, 2003. Weight Loss with Lamotrigine in Obese Bipolar Disorder Patients -10 -8 -6 -4 -2 0 2 4 6 8 10 0 20304050 Week Weight Change (lb) Placebo (n=48) Lamotrigine (n=51) Lithium (n=43) * * p < 0.02 vs PBO, p < 0.0001 vs Li

37. Calabrese et al. J Clin Psychiatry. 1999;60:79-88. Last Observation Carried ForwardObserved Cases MADRS Change From Baseline PBO5% LTG 503% LTG 2008% 7-Week Randomized Double-Blind Lamotrigine Monotherapy in Acute Bipolar I Depression LTG 50 mg/d (n = 64) LTG 200 mg/d (n = 63) Placebo (n = 65) Week 0 -5 -10 -15 -20 01234567 ± ± * * * * Week 0 -5 -10 -15 -20 01234567 † * * * * * * * * LTG 50 mg/d LTG 200 mg/d Placebo Switch Rates ± P<0.1; † * P<0.05.

38. 16-Week Randomized Open Adjunctive Therapy of Treatment Resistant Bipolar Depression a Nierenberg AA, et al. Am J Psychiatry 2006;163;210-6. 138 mg/d 9429 mg/d 1.5 mg/d 23.8% [5.8-41.8] 17.4% [2.4-32.4] 4.6% [0-14.6] a 54% BPI, 46% BPII.

39. Goodwin et al. J Clin Psychiatry 2004;65:432-41. Lamotrigine and Lithium Effective in Bipolar I Prophylaxis 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 010203040506070 Week Survival Estimate Placebo (n=188) Lamotrigine 245 mg/d (n=223) Lithium 0.7 mEq/L (n=164) LTG v. PBO, p < 0.001 Li v. PBO, p < 0.001 LTG v. Li, p = 0.629 LTGLiPBO 0 10 20 30 40 50 22% 42% 37% 18 Months

40. 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 in Bipolar I Depression Prophylaxis 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 010203040506070 Week Survival Estimate LTG v. PBO, p = 0.009 Li v. PBO, p = 0.120 LTG v. Li, p = 0.325 LTGLiPBO 0 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)

41. 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 in Bipolar I Mania Prophylaxis 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 010203040506070 Week Survival Estimate LTG v. PBO, p = 0.034 Li v. PBO, p < 0.001 LTG v. Li, p = 0.030 Placebo (n=188) Lamotrigine 245 mg/d (n=223) Lithium 0.7 mEq/L (n=164) LTGLiPBO 0 20 40 60 80 53% 80% 65% 18 Months

42. 6-Week Lamotrigine Versus Gabapentin Versus Placebo in Treatment Resistant Mood Disorders LamotrigineGabapentinPlacebo 0 10 20 30 40 50 60 Percent Clinical Global Impression Response 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/d4000 mg/d Crossover trial with 74% Rapid-Cycling BP, 6% Non- Rapid-Cycling BP, 20% UP

43. Lamotrigine Effective in Rapid Cycling BPII 41% 46% 18% * * p < 0.05. Calabrese JR, et al. J Clin Psychiatry 2000;61:841-50. 31% 39% 26% *

44. 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. Percent Responders (≥ 50% MRS decrease) LamotriginePlaceboLithiumLamotriginePlaceboLithium 0 10 20 30 40 50 60 70 55% 62% 47% Response Rates Low Dose (3 weeks) Add-on (6 weeks) 50 mg/d N = 85 N = 95 0.8-1.3 mEq/L N = 36 200 mg/d N = 74 N = 77 0.8-1.3 mEq/L N = 77

45. 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

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

47. 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) Obesity 3 37664-384 TPM > PBO Obese+Binge Eat 4 61 212 TPM > PBO Bulimia 5 69 100 TPM > PBO Etoh Dependence 6 150 200 TPM > PBO Migraine 7 468 50-200 TPM > PBO 1 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.

48. Weight Loss with Zonisamide in Obesity Gadde KM, et al. JAMA. 2003;289:1820-5. Obese (No psychiatric disorder)Obese Euthymic Medicated Bipolar * Yang YS, et al. 156th APA Ann Mtg; San Francisco; May 17-22, 2003. p < 0.001

49. 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. 2005:6. Emerging Diverse Roles of Anticonvulsants in Patients with Bipolar Disorders

50. New Anticonvulsants Not (Yet) Proven Effective in Mania  Oxcarbazepine - B, underpowered active-comparator monotherapy studies 1  Gabapentin - F, negative placebo-controlled add-on study 2  Lamotrigine - F, negative placebo- & lithium-controlled add-on studies 3  Topiramate - F, negative placebo- & lithium-controlled adult monotherapy studies 4  Tiagabine - D, negative open add-on study 5  Levetiracetam - D, no controlled study  Zonisamide - D, no controlled study 1 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.

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

52. Suppes T, et al. Am J Psychiatry 1999;156:1164-9. 12-Month Randomized Adjunctive Clozapine in Bipolar & Schizoaffective Dsiorder Patients 26 bipolar, 12 schizoaffective disorder, bipolar type patients 0 20 40 60 80 100 0123456789101112 Clozapine 355 mg/d (n=19) Treatment as usual (n=19) Months Percent of patients with 30% improvement p <.05 Mean clozapine doses - in bipolar 234 mg/d, in schizoaffective 623 mg/d.

53. 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 Risperidone vs Placebo Monotherapy in Acute Mania a RisperidonePlacebo 0 10 20 30 40 50 60 Percent Response (≥ 50% YMRS decrease) 43% 24% ** 4.1 mg/d N = 127 Risperidone 48% 4.2 mg/d N = 153 N = 119 Placebo 33% N = 138 47% 8.0 mg/d N = 144 Haloperidol a Excluded mixed episodes; **p < 0.01 vs placebo. ** Watch for extrapyramidal symptoms at higher doses.

54. Yatham LN, et al. Br J Psychiatry 2003;182:141-7. Percent Responders (≥ 50% YMRS decrease) 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 60 58% Sachs G, et al. Am J Psychiatry 2002;159:1146-54. 3.8 mg/d 4.0 mg/d 6.2 mg/d N = 52N = 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 Risperidone vs Placebo (Monotherapy) in Acute Mania Carbamazepine decreased plasma risperidone concentrations by 40 percent.

55. OlanzapinePlaceboOlanzapinePlacebo 0 10 20 30 40 50 60 70 Percent Response (≥ 50% YMRS decrease) 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. 15 mg/d N = 69 16 mg/d N = 55 N = 70N = 60 3- and 4-Week Double-Blind Olanzapine vs Placebo Monotherapy in Acute Mania Often started clinically at 20 mg/day.

56. Response Rates Olanzapine vs Divalproex Acute Mania Studies Zajecka J, et al. J Clin Psychiatry 2002;63:1148-55. Percent Responders (≥ 50% Young/SADS-C MRS decrease) p = 0.06 OlanzapineDivalproexOlanzapineDivalproex 0 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. 17 mg/d N = 125 15 mg/d N = 55 1401 mg/d 84 ug/mL N = 126 1956 mg/d 85 ug/mL N = 60 dayug/mL 378 697 10101 dayug/mL 577 782 Olanzapine slightly more effective, divalproex slightly better tolerated.

57. Young Mania Rating Scale Response Rates Tohen M, et al. Arch Gen Psychiatry 2002;59:62-9. Percent Responders (≥ 50% YMRS decrease) 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 Olanzapine vs 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/d N = 220 N = 114 **** Low therapeutic mood stabilizer plasma concentrations in combination therapy.

58. Percentage of Patients 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=.895 p<.001 Overall RelapseRelapse Into DepressionRelapse 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 Maintenance Monotherapy Equivalent Depression Prevention Equivalent Depression Prevention Olanzapine Compared to Lithium After Manic/Mixed Episodes Equivalent Episode Prevention Equivalent Episode Prevention Superior Mania Prevention Superior Mania Prevention

59. Olanzapine 12.5 mg/d (n=225) Placebo (n=136) 0 20 40 60 80 100 Overall RelapseRelapse Into DepressionRelapse Into Mania Percentage of Patients 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 Placebo Maintenance Olanzapine Compared to Placebo After Manic/Mixed Episodes Superior Depression Prevention Superior Depression Prevention Superior Episode Prevention Superior Episode Prevention Superior Mania Prevention Superior Mania Prevention

60. OLZ 9.7 mg (N = 351) PBO (N = 355) OLZ 7.4 mg + FLX 39.3 mg (N = 82) Week 0123468 Mean Change in MADRS Scores -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 ± Fluoxetine in Acute Bipolar I Depression PBO7% OLZ6% OFC6% Switch Rates

61. LTG 106 mg (N = 205) OLZ 10.7 mg + FLX 38.3 mg (N = 205) Week Mean Change in MADRS Scores 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 + Fluoxetine vs Lamotrigine in Acute Bipolar I Depression LTG5% OFC4% Switch Rates 0123468 -20 -15 -10 -5 0 -25 5 * * * * * LTG-0.3*** OFC+3.1 Weight Change (kg)

62. Responders≥ 7% Weight Gain 7-Week Randomized Double-Blind Olanzapine + Fluoxetine vs Lamotrigine in Acute Bipolar I Depression OFCLTGOFC LTG 0 10 20 30 40 50 60 69% 60% Percentage of Patients 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.

63. Young Mania Rating Scale Response Rates Percent Responders (≥ 50% YMRS decrease) 48% 31% p < 0.0006 Quetiapine Placebo 0 10 20 30 40 50 60 576 mg/d r 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 a Excluded mixed episodes, rapid cycling; b Mean final dose in responders Important to use adequate dosage - started at 100 mg/day and increased by 100 mg/day.

64. 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 Percent Responders (≥ 50% YMRS decrease) 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/d b N = 185 ** a Excluded mixed episodes, rapid cycling; b Mean final dose in responders; **p = 0.01 vs placebo. Low therapeutic mood stabilizer plasma concentrations in combination therapy.

65. -20 -15 -10 -5 0 Quetiapine 600 mg (N = 170) Quetiapine 300 mg (N = 172) Placebo (N = 169) † † † † † † † † † † † † † † † † 012436578 Study Week ITT, LOCF Change From Baseline (LS Means) 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 Monotherapy in Acute Bipolar Depression Calabrese JR, et al. Am J Psychiatry 2005;162:1351-60. PBO4% QTP 3004% QTP 6002% Switch Rates

66. ITT, LOCF Baseline 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 Monotherapy in Acute Bipolar Depression Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9. Montgomery-Asberg Depression Rating Scale Implrovement PBO7% QTP 3002% QTP 6004% Switch Rates

67. 8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar Depression Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9. BOLDER IBOLDER II Percentage of Patients Responding (≥ 50% MADRS Decrease) PBOQTP 300 QTP 600 PBO 0 10 20 30 40 50 60 58% 36% 40% 37% 24% * ** *** QTP 300 QTP 600 *** Response Rates Calabrese JR, et al. Am J Psychiatry 2005;162:1351-60. *p < 0.05, **p< 0.01, *** p < 0.001 vs placebo.

68. Bipolar Disorder I (N=657) Bipolar Disorder II (N=321) † ‡ MADRS LS Mean Change From Baseline Improvement † 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 Bipolar I vs. II Disorder ‡ † Quetiapine 300 Quetiapine 600 Placebo -20 -16 -12 -8 -4 0

69. Potkin SG, et al. J Clin Psychopharmacol 2005;25:301-10. Keck PE, et al. Am J Psychiatry 2003;160:741-8. Percent responders (≥ 50% SADS-C MRS decrease) 35% 50% P<0.01 ZiprasidonePlaceboZiprasidonePlacebo 0 5 10 15 20 25 30 35 40 45 50 46% 29% 60 P<0.05 136 mg/d N = 131 127 mg/d N = 137 N = 66N = 65 3-Week Double-Blind Ziprasidone vs Placebo Monotherapy in Acute Mania SADS-C* Mania Rating Scale Response Rates *Schedule for Affective Disorders and Schizophrenia-Change Important to use adequate dosage - day one 80 mg/day, day two 160 mg/day - with food.

70. Adjunctive Pramipexole in Acute Bipolar Depression Response Rates Percent responders (≥ 50% HDRS/MADRS decrease) 20% (2/10) 67% (8/12) P<0.04 PramipexolePlaceboPramipexolePlacebo 0 5 10 15 20 25 30 35 40 45 50 60% (6/10) 9% (1/11) 60 P<0.02 1.7 mg/d 1.7 mg/d Zarate CA, et al. Biol Psychiatry 2004; 56:54-60. Goldberg JF, et al. Am J Psychiatry 2004; 161:564-6 70

71. Response Rates Percent Responders (≥ 50% IDS decrease) *p < 0.05 vs placebo TEAS Modafinil 4.9%, Placebo 11.4% Modafinil Placebo 0 10 20 30 40 50 60 22% 44% 177 mg/d N = 41 N = 44 * Frye M, et al. APA, Toronto, 2006. 6-week Randomized Double-Blind Adjunctive Modafinil in Acute Bipolar Depression

72. Sach GS, et al. J Psychopharmacol 2006. Keck PE, Jr, et al. Am J Psychiatry 2003;160:1651-8. Percent responders (≥ 50% YMRS decrease) 19% 40% P<0.01 AripiprazolePlaceboAripiprazolePlacebo 0 5 10 15 20 25 30 35 40 45 50 53% 32% 60 P<0.01 28 mg/d N = 123 28 mg/d N = 135 N = 120N = 129 3-Week Double-Blind Aripiprazole vs 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.

73. 0 10 20 30 13% 12% 6% 5% Percent of Patients 43% 25% 23% 8% Relapse into Mania 40 50 Relapse into Mixed Relapse into Depression Overall Relapse Aripiprazole 24.3 mg/d (n=77) Placebo (n=83) p=.013 p=.009 Equivalent Depression Prevention Equivalent Depression Prevention Superior Episode Prevention Superior Episode Prevention Equivalent Mixed Prevention Equivalent Mixed Prevention Superior Mania Prevention Superior Mania Prevention Stabilized on ARI before randomization. Keck PE, et al. J Clin Psychiatry 2006;67:626-37. 26-Week Double-Blind Aripiprazole vs Placebo Continuation/Maintenance Monotherapy Aripiprazole Compared to Placebo After Manic/Mixed Episodes

74. Broad Efficacy Spectra of Atypical Antipsychotics 1 Tohen M, et al. Am J Psychiatry 1999;156:702-9; 2 Tohen M, et al. Arch Gen Psychiatry 2000;57:841-9; 3 Sachs G et al. Am J Psychiatry. 2002;159:1146-1154; 4 Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057-65; 5 Yatham LN, et al. J Clin Psychopharmacol 2004;24:599-606; 6 Potkin SG, et al. 157th APA Ann Mtg, New York, May 1-6, 2004; 7 Jody D, et al. 157th APA Ann Mtg. New York, NY, May 1-6, 2004. p = pooled data. AgentMixedPsychoticRapid Cycling Olanzapine 1,2 +++ Risperidone 3,4 ++? Quetiapine 5,p ?+? Ziprasidone 6,p ++? Aripiprazole 7,p +++

75. Rapid Onset of Action of Atypical Antipsychotics 1 Tohen M, et al. Arch Gen Psychiatry 2000;57:841-9; 2 Hirschfeld RM, et al. Am J Psychiatry 2004;161:1057-65; 3 Calabrese JR, et al. In Review; 4 Keck P, et al. Am J Psychiatry. 2003;160:741-8; 5 Segal S, et al. 156th APA Ann Mtg. San Francisco, CA, May 17-22, 2003; 6 Keck PE, et al. Am J Psychiatry. 2003;160:1651-8; 7 Sachs 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 Risperidone 2 Quetiapine 3,p Ziprasidone 4,5 Aripiprazole 6,7

76. Mood Stabilizer Safety and Tolerability Concerns DivalproexGastrointestinal Weight gain TremorHepaticCoagulation Hair Loss PancreatitisTeratogenPCOSCarbamazepineGastrointestinalRashNeurotoxicityHepaticThyroidHematologicCardiacTeratogenHyponatremia = boxed warning in prescribing information 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. 2005:11-55.

77. Second-Generation Weight gain Sedation Hyperglycemia, Diabetes* Cardiac ± Akathisia ± Hyperprolactinemia ± Cerebrovascular* ± Tardive dyskinesia* ± Neuroleptic malignant* Cardiac/pneumonia in elderly* Antipsychotic Safety and Tolerability Concerns Warnings - *In prescribing information; ? Under consideration; boxed First-Generation Depression Akathisia Acute dystonia Tardive dyskinesia* Weight gain Sedation Cardiac Hyperprolactinemia ± 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.

78. Obesity Associated with Earlier Relapse in Bipolar Disorder Fagiolini A et al. Am J Psychiatry. 2003;160:112-7. Any Relapse Depressive Relapse p < 0.02 p < 0.007

79. Second Generation Antipsychotics and Metabolic Abnormalities DrugWeight DiabetesLipids 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.

80. 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. 2005:6.

81. 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