2. Terence A. Ketter, M.D. Acute and Maintenance Treatment of Bipolar Depression Terence A. Ketter, M.D.

3. Teaching Points Mood stabilizers are foundational agents and should be considered first line treatments, with the strongest evidence supporting the use of lithium and lamotrigine. Emerging data suggest atypical antipsychotics provide benefit in acute bipolar depression, with the strongest evidence supporting the use of quetiapine monotherapy and the olanzapine plus fluoxetine combination. The utility of adjunctive antidepressants in bipolar depression is controversial, as these agents can yield switching into mania or hypomania in some patients.

4. Pre-Lecture Exam Question 1 1.The most pervasive symptoms in bipolar disorder are those of: (choose one) A.Mania, hypomania B.Hypomania C.Depression D.Mixed States E.None of the above

5. Question 2 Which of the treatments below is the LEAST appropriate strategy in bipolar depression: (choose one) A. Mood stabilizer without antidepressant B. Mood stabilizer with antidepressant C. Atypical antipsychotic with antidepressant D. Antidepressant with neither mood stabilizer nor atypical antipsychotic

6. Question 3 Which antidepressant option carries the greatest risk of hypomania/mania: (choose one) A. Tricyclic antidepressants (TCAs) B. Selective serotonin reuptake inhibitors (SSRIs) C. Mirtazepine D. Bupropion

7. Question 4 Which of the following treatments do NOT have controlled data suggesting utility in bipolar depression: (choose one) A. Lithium B. Lamotrigine C. Olanzapine plus fluoxetine combination D. Quetiapine E. Citalopram F. Pramipexole

8. Question 5 Which of the following statements best describes the role of maintenance adjunctive antidepressants in patients with bipolar disorder: (choose one) A. Long-term adjunctive antidepressants are always beneficial. B. Long-term adjunctive antidepressants are never beneficial. C. Long-term adjunctive antidepressants are beneficial in most patients. D. Long-term adjunctive antidepressants may be beneficial in some patients.

9. Overview  Treatment options –Mood stabilizers –Atypical antipsychotics –Adjunctive antidepressants –Alternative treatments  Treatment of acute bipolar depression  Prevention of bipolar depression

10. Bipolar disorders symptoms are chronic and predominantly depressive Judd et al 2002 53% 32% 9% 6% Asymptomatic Depressed Hypomanic Cycling / mixed % of Weeks 146 Bipolar I Patients followed 12.8 yrs 86 Bipolar II Patients followed 13.4 yrs 46% 50% 1%2% Judd et al 2003

11. Treatment Options in Bipolar Depression Alternative Treatments Pramipexole Gabapentin Omega-3 fatty acids Phototherapy Psychotherapy Sleep deprivation Thyroid hormones Mood Stabilizers Lithium Lamotrigine Carbamazepine Divalproex ECT Atypical Antipsychotics Quetiapine Olanzapine Jefferson JW, Greist JH. Textbook of Psychiatry, Washington, DC, American Psychiatric Press, 1994; Post RM, et al. Neuropsychopharmacology 1998; Worthington JJ III, Pollack MH. Am J Psychiatry 1996; Amsterdam J. J Clin Psychopharmacol 1998; Barbini B, et al. Psychiatry Res 1998; Wirz-Justice A, et al. Biol Psychiatry 1999; Stoll AL, et al. Arch Gen Psychiatry 1999; Bowden CL. J Clin Psychiatry 1998; Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88; Calabrese JR, et al. J Clin Psychiatry 1999;60:79-88; Goldberg JF, et al. Am J Psychiatry 2004;161:564-6. Adjunctive Antidepressants Fluoxetine + Olanzapine Bupropion SSRIs Venlafaxine Nefazodone Mirtazapine MAOIs TCAs

12. Acute Treatment of Bipolar Depression

13. Mendels J. Am J Psychiatry 1976;133:373-8 1 Watanabe S, et al. Arch Gen Psychiatry 1975;32:659-668 2 Lithium in Acute Bipolar Depression  Li > placebo in 5/7 studies (N=158) 1 –Pooled data  19% little or no antidepressant effect  81% significant antidepressant effect  Li versus TCA studies 1,2 –Some included unipolars –TCA  Li in 3 studies (N=98) 1,2

14. 28 Reports* (16,800 Patients) *19 of 28 reports (16,000 patients) recorded only actual suicides. Tondo, et al. 1997. Lithium and Suicide Risk in Major Affective Disorder No. of Annual risk reports of suicide With lithium 22 0.26 ± 0.4 Without lithium 10 1.68 ± 1.5 } } 7 to 8-fold difference pp<0.0001

15. Suicide and Suicide Attempts with Randomized Lithium or Carbamazepine Suicide Total Suicidal Attempts Behavior Lithium 0 0 0 Carbamazepine 5 4 9 Thies-Flechtner et al. Pharmacopsychiatry 1994;29:103-7. 30-month prospective study in 285 recently hospitalized patients (175 bipolar, 110 schizoaffective)

16. Mood Stabilizer Choice and Suicide Events in Bipolar Disorder Patients in Two Large HMOs Events per 1,000 pt-years Goodwin et al. JAMA 2003;290:1467-73 a Treatment-resistant patients; *Sig. Diff from Lithium alone (p<.05)

17. Risk ratios of events relative to patients on lithium (Adjusted for age, sex, year of treatment, comedications, comorbidity) Mood Stabilizer Choice and Suicide Events in Bipolar Disorder Patients in Two Large HMOs Goodwin et al. JAMA 2003;290:1467-73 a Treatment-resistant patients; Sig. Diff from Lithium alone (*p<.001; **p<.004)

18. ± p < 0.1 vs PBO, LOCF -12 -10 -8 -6 -4 -2 0 01234568 Placebo (N=22) Divalproex 62 ug/mL (N=21) ± ± Week Mean Change from Baseline Baseline - PBO 20.5, DVPX 22.6 Sachs G, et al. 40th Ann ACNP Mtg, December 9-13, 2001, Waikaloa, HI. 8-Week Randomized Double-Blind Divalproex Monotherapy in Acute Bipolar Depression

19. 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. 8-Week Randomized Double-Blind Divalproex Monotherapy in Acute Bipolar Depression 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

20. 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

21. 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.

22. 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. Lamotrigine19% Inositol13% Risperidone13% Switch Rates

23. 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 Fluoxetine monotherapy arm excluded due to risk of mania induction.

24. * P < 0.05 vs OLN, OLN+FLX. † P < 0.05 vs OLN. ITT-LOCF Responders Remitters OFCOLNPBOOFCOLNPBO 0 10 20 30 40 50 60 54% 37% 29% Percentage of Patients 47% 31% 23% * † * † Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88. PBO7% OLZ6% OFC6% Switch Rates 8-Week Randomized Double-Blind Olanzapine ± Fluoxetine in Acute Bipolar I Depression

25. LTG 106 mg (N = 205) OLZ 10.7 mg + FLX 38.3 mg (N = 205) 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 Lamotrigine vs Olanzapine + Fluoxetine in Acute Bipolar I Depression LTG5% OFC4% Switch Rates LTG-0.3*** OFC+3.1 Weight Change (kg) Week Mean Change in MADRS Scores 0123467 -20 -15 -10 -5 0 -25 5 * * * * *

26. Responders≥ 7% Weight Gain OFCLTGOFCLTG 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. LTG5% OFC4% Switch Rates 7-Week Randomized Double-Blind Lamotrigine vs Olanzapine + Fluoxetine in Acute Bipolar I Depression

27. -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

28. 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

29. 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. PBO4% QTP 3004% QTP 6002% PBO7% QTP 3002% QTP 6004% Switch Rates

30. 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

31. Magnitudes of Effects in Controlled Trials in Acute Bipolar I Depression 1 Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-1088; 2 Calabrese JR, et al. 157th APA Annual Meeting, May 1-6, 2004, New York, NY. Abstract NR756. Page 284; 3 Calabrese JR, et al. J Clin Psychiatry 1999;60:79-88. Effect Size 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 OLZ 10 mg OLZ 7.5 mg + FLX 40 mg QTP 300 mg QTP 600 mg LTG 50 mg LTG 200 mg Response Rate (%) a 0 10 20 30 40 50 60 70 OLZ 10 mg OLZ 7.5 mg + FLX 40 mg QTP 300 mg QTP 600 mg LTG 50 mg LTG 200 mg 2 Calabrese 2004. 3 Calabrese 1999. 1 Tohen 2003. 2 Calabrese 2004. 3 Calabrese 1999. 1 Tohen 2003. Effect Size (ES) = (improvement over PBO) / (pooled SD)(small 1.0). a >50% MADRS decrease

32. 6-week Randomized Double-Blind 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 21 BPII on Li (N=12, 0.8 mEq/L), DVPX (N=9, 73 ug/mL) 15 BPI, 7 BPII on Li (N=6, 0.7 mEq/L), DVPX (N = 9, 81 ug/mL), LTG (N=6), GBP (N=3), CBZ (N=2)

33. 6-week Randomized Double-Blind Adjunctive Pramipexole in Acute Bipolar Depression Switch Rates Percent with Hypomania o r Mania 0% (0/10) 8% (1/12 mania) PramipexolePlaceboPramipexolePlacebo 0 5 10 15 20 25 30 35 40 45 50 10% (1/10 hypomania) 18% (2/11 hypomania) 60 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 21 BPII on Li (N=12, 0.8 mEq/L), DVPX (N=9, 73 ug/mL) 15 BPI, 7 BPII on Li (N=6, 0.7 mEq/L), DVPX (N = 9, 81 ug/mL), LTG (N=6), GBP (N=3), CBZ (N=2)

34. Response Rates Percent Responders (≥ 50% IDS decrease) *p < 0.05 vs placebo. Modafinil Placebo 0 10 20 30 40 50 60 22% 44% 177 mg/d N = 41 N = 44 * 6-week Randomized Double-Blind Adjunctive Modafinil in Acute Bipolar Depression Frye M, et al. Am J Psychiatry 2007;164:1242-9. Placebo11.4% Modafinil4.9% Switch Rates

35. Response in Randomized Controlled Trials of Antidepressants vs. Placebo in Bipolar Depression Gijsman et al, American Journal of Psychiatry. 2004;161:1537-1547.

36. Paroxetine, Imipramine, Placebo Added to Lithium in Bipolar Depression Nemeroff CB, et al. Am J Psychiatry. 2001;158:906-912. *p < 0.05 Li + PXT 33 mg/d (n=35)Li + IMI 167 mg/d (n=39)Li + PBO (n=43) 0 10 20 30 40 50 60 All Subjects % Responders Lithium < 0.8 * * Li + PBO2% Li + PXT0% Li + IMI8% Switch Rates

37. Young, et al. Am J Psychiatry 2000;157:124-6. Adjunctive Paroxetine vs Second Mood Stabilizer in Bipolar Depression Similar Efficacy* Treatment Duration (wks) 50% Response Rates 64% Hamilton Depression Scale (17 item) Double-Blind Adjunctive 2nd Mood Stabilizer Paroxetine Baseline123456 0 5 10 15 20 25 *Last Observation Carried Forward Analysis Better Tolerability 2nd Mood Stabilizer Dropout Rate (%) 38% (6/16) 0% (0/11) 40 20 0 Paroxetine p < 0.05

38. Recovery Rates Percentage of Patients 0 5 10 15 20 25 68% BPI, 32% BPII Bupropion - 300 mg/d (median, N = 86) Paroxetine - 30 mg/d (median, N = 93) 26-Week Double-Blind Adjunctive Antidepressant vs Placebo in Acute Bipolar Depression 30 Adding antidepressant no better or worse than adding placebo to mood stabilizer(s). P=0.40 NNT = 26 Mood Stabilizer + Antidepressant Mood Stabilizer + Placebo 27.3% (51/187) 23.5% (42/179) P=0.84 NNH = 167 Mood Stabilizer + Antidepressant Mood Stabilizer + Placebo 10.7% (20/187) 10.1% (18/179) Switch Rates Sachs GS, et al. N Engl J Med 2007;356:1711-22.

39. Miklowitz DJ, et al. Arch Gen Psychiatry 2007;64:419-27. 52-Week Adjunctive Intensive Psychosocial Intervention vs Collaborative Care in Acute Bipolar Depression Up to 30 sessions 3 sessions N = 163 N = 130 p = 0.01 IntensiveCollaborative Median time to 50% recovery (days)169 [138-230]279 [-] Median time to 25% recovery (days)98 [88-112]125 [105-168] Recovered at 1 year (%)64.451.5

40. Miklowitz DJ, et al. Arch Gen Psychiatry 2007;64:419-27. 52-Week Adjunctive Intensive Psychosocial Intervention vs Collaborative Care in Acute Bipolar Depression Up to 30 sessions 3 sessions N = 163 N = 130 p < 0.05

41. Miklowitz DJ, et al. Arch Gen Psychiatry 2007;64:419-27. 52-Week Adjunctive Intensive Psychosocial Intervention vs Collaborative Care in Acute Bipolar Depression Up to 30 sessions 3 sessions N = 163 N = 130 Odds of Being Well in Any Month Intensive 1.58 x Collaborative p = 0.003

42. Lewis JL, Winokur G. Arch Gen Psychiatry 1982 1 ; Prien RF, et al. Arch Gen Psychiatry 1984. Do Antidepressants Induce Mania?  41% Natural switch rate depression to mania (on no antidepressants) 1  Switch rate on medications 2 –53% Imipramine –28% Lithium plus imipramine –26% Lithium

43. Switch Rate From Index Depression Into Mania Angst J. Psychopathology 1985. Switch Rate (%) 1920193019401950196019701980 Spontaneous (N=200) ECT (N=100) Nano- leptics (N=100) Tricyclics (N=509) 0 6 8 4 2 10 Year By Era and Prevailing Treatment

44. Peet M. Br J Psychiatry. 1994;164:549-550. Increased Mania Switch Rates with Tricyclics % With Manic Switch 0 2 4 6 8 10 12 PBOSertraline / ParoxetineTCAs 11.2% (14/125) 3.7% (9/242) 4.2% (2/48) ** ** p < 0.01 vs PBO

45. Switch Rates With Tricyclic vs. Other Antidepressants Gijsman et al, American Journal of Psychiatry. 2004; 161: 1537-1547

46. Manic Switch Rates in Randomized Controlled Trials of Antidepressants vs. Placebo Gijsman et al, American Journal of Psychiatry. 2004;161:1537-1547

47. P = NS. Bupropion SertralineVenlafaxine 49% 53% 51% Percentage of Patients with Either ≥ 50% IDS Decrease or ≥ 2 point CGI Improvement 10-Week Randomized Adjunctive Antidepressants in Acute Bipolar Depression a a 73% Bipolar I, 26% Bipolar II, 1% Bipolar NOS; 82% double-blind, 12% open. Post RM, et al. Br J Psychiatry 2006;189:124-31. 286 mg/d N = 51 192 mg/d N = 58 195 mg/d N = 65 Response Rates 0 10 20 30 40 50 60

48. 0 10 20 30 40 P = 0.05. YMRS >13 BUPSERTVEN 4% 7% 15% Percentage of Patients P < 0.01. CGI-M Increase ≥ 2 BUPSERTVEN 10% 9% 29% P = 0.03. YMRS >13 or CGI-M ≥ 3 BUPSERTVEN 14% 16% 31% N = 51 N = 58 N = 65 Switch Rates 10-Week Randomized Adjunctive Antidepressants in Acute Bipolar Depression a a 73% Bipolar I, 26% Bipolar II, 1% Bipolar NOS; 82% double-blind, 12% open. Post RM, et al. Br J Psychiatry 2006;189:124-31.

49. Angst J. Psychopathology 1985 1 ; Prien RF, et al. Arch Gen Psychiatry 1973 2 ; Wehr TA, Goodwin FK. Psychopharmacol Bull 1987 3 Do Antidepressants Induce Rapid Cycling?  Increased rapid cycling since TCAs introduced 1  Mania rates over 2 years 2 –67% Imipramine –33% Placebo –18% Lithium  Antidepressants induce reversible rapid cycling in double-blind placebo-controlled studies. 3

50. Tricyclics Shorten Cycle Length Wehr TA, Goodwin FK. Am J Psychiatry 1987. Tricyclic Treatment Status Cycle Length (days) 300 250 200 150 100 50 0 10 Bipolar Disorder Patients Off On TCAs

51. Acute Bipolar I Depression Algorithm  Optimize current mood stabilizer (if applicable) before initiating additional treatment for depression  Patients on Li - optimize (serum Li level ≥ 0.8 mEq/L) to determine whether adjunctive intervention necessary  Patients with recent and/or severe history of mania - receive or add an effective antimanic agent  Stage 1  Adjunctive LTG if depression persists after mood stabilizer optimization Number of iterations at each level and adjunctive treatment(s) to be determined by clinician judgment Suppes T, et al. J Clin Psychiatry 2005;66:870-86.

52. Acute Bipolar I Depression Algorithm  Stage 2: If Stage 1 ineffective or not tolerated*  QTP monotherapy or OFC  Although onset of action faster than LTG, overall efficacy and long-term tolerability evidence favors LTG (at Stage 1)  Stage 3: If Stages 1 and 2 ineffective or not tolerated*  Combination of two agents already introduced in algorithm  Li, LTG, QTP, and OFC combination  OFC a two-drug combination, so adding another agent yields three-drug combination Number of iterations at each level and adjunctive treatment(s) to be determined by clinician judgment Suppes T, et al. J Clin Psychiatry 2005;66:870-86.

53. Acute Bipolar I Depression Algorithm  Stage 4: If Stages 1, 2, and 3 ineffective or not tolerated*  ECT and combination therapy ( Li, LTG, QTP, OFC combination, VPA or CBZ in combined with SSRI, bupropion, or venlafaxine)  Minority opinion that Stage 4 should precede Stages 2 and 3  Stage 5: If Stages 1, 2, 3, and 4 ineffective or not tolerated*  MAO-I, other atypical antipsychotics not included, pramipexole, new combinations of drugs included in the algorithm, inositol, stimulants, and thyroid supplementation Number of iterations at each level and adjunctive treatment(s) to be determined by clinician judgment Suppes T, et al. J Clin Psychiatry 2005;66:870-86.

54. Maintenance Treatment of Bipolar Depression

55. Lithium (n=251) Placebo (n=263) 0 20 40 60 80 100 Overall RelapseRelapse Into DepressionRelapse Into Mania or Hypomania Percentage of Patients 23% 56% 37% 21% 81% 34% Goodwin FK, Jamison KR: Manic-Depressive Illness, Oxford University Press, New York 1990:688-9. Summary of Double-Blind Lithium Monotherapy vs Placebo Maintenance Trials in 1970s Lithium Compared to Placebo, Primarily After Manic/Mixed Episodes Superior Depression Prevention Superior Depression Prevention Superior Episode Prevention Superior Episode Prevention Superior Mania Prevention Superior Mania Prevention

56. Lithium Prevention of Any Relapse in Bipolar Disorder Geddes JR et al. Am J Psychiatry 2004;161:217-222. Areas of blue boxes reflect weights of studies in meta-analysis. b Lower confidence interval extends beyond graph (0.08).

57. Lithium Prevention of Depressive Relapse in Bipolar Disorder Geddes JR et al. Am J Psychiatry 2004;161:217-222. Areas of blue boxes reflect weights of studies in meta-analysis. b Lower confidence interval extends beyond graph (0.10).

58. Lithium Prevention of Manic Relapse in Bipolar Disorder Geddes JR et al. Am J Psychiatry 2004;161:217-222. Areas of blue boxes reflect weights of studies in meta-analysis.

59. DVP = divalproexPBO = placebo Gyulai et al. Neuropsychopharmacol 2003;28:1374-82. LI = lithium SSRI = selective serotonin reuptake inhibitor 0% 5% 10% 15% 20% DVP (n=187)PBO (n=94) Percentage of Patients Discontinuing Due to Depression P = 0.017 Overall Patients Receiving SSRI Rescue 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 50% DVP + SSRI (n=41) PBO + SSRI (n=20) P = 0.03 Percentage of Patients Discontinuing Due to Depression 12-Month Double-Blind Divalproex, Lithium Monotherapy vs Placebo Maintenance Fewer Dropouts Due to Depression with Divalproex vs Placebo After Manic/Mixed Episodes

60. Goodwin GM, 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 Patients stabilized on lamotrigine prior to randomization.

61. Some patients considered intervention-free for depression could have had intervention for mania. Goodwin GM, 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) Patients stabilized on lamotrigine prior to randomization.

62. Some patients considered intervention-free for mania could have had intervention for depression. Goodwin GM, 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 Patients stabilized on lamotrigine prior to randomization.

63. Incidence of Mania/Hypomania/Mixed Episodes Reported as Adverse Events Combined Analysis 0 5 10 15 20 25 Lamotrigine (n=227) Lithium (n=166) Placebo (n=190) Percent of patients In all bipolar controlled trials, adverse events of mania were reported as 5% lamotrigine, 3% lithium, and 4% placebo. Goodwin GM, et al. J Clin Psychiatry 2004;65:432-41. Patients stabilized on lamotrigine prior to randomization. 5% 4% 7%

64. 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. 12-Month 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

65. 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) 12-Month 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

66. 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. 157th APA Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR746. 26-Week Double-Blind Aripiprazole vs Placebo Continuation/Maintenance Monotherapy Aripiprazole Compared to Placebo After Manic/Mixed Episodes

67. Antidepressants After Depression Resolution Sachs G, 2000. Personal communication. Disorder / Episode Pattern Begin TaperComments Unipolar 6–12 monthsMaintenance if ≥ 3 episodes Bipolar Monophasic 6–12 weeksRepeat if relapse Biphasic - MDE Maintenance if repeated relapses Bipolar Biphasic - DME 6–12 days Start taper after Polyphasic first euthymic visit Hx rapid cycling Hx iatrogenic mania

68. Controlled Maintenance Studies of Antidepressants for Bipolar Depression StudyN, DurationEfficacySwitch Prien et al ’73N=44, 24 moLi > IMI = PBO Wehr & Goodwin ‘79 N=5, 27 moLi = Li + DMILi + DMI >> Li Quitkin et al ‘81N=75, 19 moLi = Li + IMILi + IMI > Li Kane et al ‘82N=22, 11 moLi > PBO = IMI Prien et al ‘84N=117, 30 moLi = Li + IMI> IMIIMI > Li + IMI = Li Sachs et al ‘94N=15, 12 moLi + BUP= Li + DMI Li + DMI > Li + BUP Kane et al Arch Gen Psychiatry 1982;39:1065-9; Prien et al Arch Gen Psychiatry 1984;41:1096-1104; Prien et al Arch Gen Psychiatry 1973;29:420-5; Quitkin et al Arch Gen Psychiatry 1981;38:902-7; Sachs et al J Clin Psychiatry 1994;55:391-3; Wehr & Goodwin Arch Gen Psychiatry 1979;36:555-9.

69. Bipolar Versus Unipolar Maintenance Treatment Dissociation Adapted from Prien et al Arch Gen Psychiatry 1984;41:1096:1104. Li 0.8 mEq/L; IMI 125 mg/d Bipolar Unipolar IMI+LI LiIMI PBO Cumulative Probability of Remaining Well 0 10 20 30 40 50 60 70 80 90 3691215182123252730 Months 100 Cumulative Probability of Remaining Well

70. Antidepressant Continuation Beneficial in Some (15%?) Patients Prospective 1-year follow-up Remission of MDE with AD added to mood stabilizer Tolerated AD ≥ 2 months Continuation: AD > 6 months Discontinuation: AD < 6 months n = 41 (36% relapsed) n = 43 (70% relapsed) Altshuler et al. Am J Psychiatry. 2003;160:1252-62.

71. Treatment of Bipolar Depression  Acute treatment –Lithium, lamotrigine –Olanzapine plus fluoxetine, quetiapine –Adjunctive antidepressants –Alternative treatments  Maintenance treatment –Lithium, lamotrigine –Divalproex –Adjunctive antidepressants (controversial) –Alternative treatments  New treatment options emerging

72. Post-Lecture Exam Question 1 1.The most pervasive symptoms in bipolar disorder are those of: (choose one) A.Mania, hypomania B.Hypomania C.Depression D.Mixed States E.None of the above

73. Question 2 Which of the treatments below is the LEAST appropriate strategy in bipolar depression: (choose one) A. Mood stabilizer without antidepressant B. Mood stabilizer with antidepressant C. Atypical antipsychotic with antidepressant D. Antidepressant with neither mood stabilizer nor atypical antipsychotic

74. Question 3 Which antidepressant option carries the greatest risk of hypomania/mania: (choose one) A. Tricyclic antidepressants (TCAs) B. Selective serotonin reuptake inhibitors (SSRIs) C. Mirtazepine D. Bupropion

75. Question 4 Which of the following treatments do NOT have controlled data suggesting utility in bipolar depression: (choose one) A. Lithium B. Lamotrigine C. Olanzapine plus fluoxetine combination D. Quetiapine E. Citalopram F. Pramipexole

76. Question 5 Which of the following statements best describes the role of maintenance adjunctive antidepressants in patients with bipolar disorder: (choose one) A. Long-term adjunctive antidepressants are always beneficial. B. Long-term adjunctive antidepressants are never beneficial. C. Long-term adjunctive antidepressants are beneficial in most patients. D. Long-term adjunctive antidepressants may be beneficial in some patients.

77. Answers to Pre & Post Competency Exam 1. C 2. D 3. A 4. E 5. D