1. Antidepressant use in Bipolar Disorder: The ISBD Task Force Consensus Report Eduard Vieta

3. ISBD Task-Force Expert Panel 1. Hagop Akiskal 2. Lori Altshuler 3. Jay D. Amsterdam 4. Jean-Michel Azorin 5. Ross J. Baldessarini 6. Michael Bauer 7. Michael Berk 8. Boris Birmaher 9. David J. Bond 10. Charles L. Bowden 11. Joseph R. Calabrese 12. Frederick Cassidy 13. Francesc Colom 14. Rif S. El-Mallakh 15. Robert L. Findling 16. Kostantinos N. Fountoulakis 17. Mark A. Frye 18. S. Nassir Ghaemi 19. Paolo Girardi 20. Joseph F. Goldberg 21. Guy M. Goodwin 22. Ana Gonzalez-Pinto 23. Heinz Grunze 24. Robert M.A. Hirschfeld 25. Kyooseob Ha 26. Diego Hidalgo Mazzei 27. Siegfried Kasper 28. Shigenobu Kanba 29. Flávio Kapczinski 30. Tadafumi Kato 31. Terence A. Ketter 32. Giorgio D. Kotzalidis 33. Athanasios Koukopoulos 34. Beny Lafer 35. Rasmus W. Licht 36. Carlos Lopez-Jaramillo 37. Glenda M MacQueen 38. Gin S. Malhi 39. Anabel Martinez-Aran 40. Lorenzo Mazzarini 41. Susan L. McElroy 42. Philip B. Mitchell 43. Andrew A. Nierenberg 44. Willem A. Nolen 45. Aysegul Ozerdem 46. Gordon Parker 47. Roy H. Perlis 48. Giulio Perugi 49. Robert R. Post 50. Zoltan Rihmer 51. Janusz Rybakowski 52. Gary S. Sachs 53. Alessandro Serretti 54. Daniel Souery 55. Michael E. Thase 56. Mauricio Tohen 57. Leonardo Tondo 58. Juan Undurraga 59. Marc Valentí 60. Gustavo Vazquez 61. Aysegul Yildiz 62. Allan H. Young 63. Lakshmi N. Yatham 64. Eric A. Youngstrom 65. Carlos A. Zarate Chair: Eduard Vieta Coordinator: Isabella Pacchiarotti Task Force members were selected by citations on the topic over the past 3 years and geographical balance: 76% agreed to participate

4. Volume of interactions during the process 1 st draft sent to authors 2 nd draft and 1 st round survey 2 nd round survey 3 rd draft sent to authors Sent to journal Draft revised and sent to journal

5. Is there a rational for starting ADs in BD? Is there a rational for maintaining ADs during the long-term? Is there a rational for maintaining ADs during the long-term? When ADs should be introduced? When ADs should be introduced? How ADs should be introduced? How ADs should be introduced? Which type of bipolar patients might benefit from the use of ADs? Which type of bipolar patients might benefit from the use of ADs? In which type of bipolar patients the use of ADs should be avoided? In which type of bipolar patients the use of ADs should be avoided? The need for a consensus

6. Consensus method 1st Step: to assemble a group of experts of ADs in BD 2nd Step: The ISBD Task-Force discussed and integrated the procedures through a face-to-face meeting (ISBD Congress, Istanbul, March, 2012) 3rd Step: The Task-Force drawed-up an updated systematic review through personal and group e-mail correspondence 4th Step:The Task-Force provided a final guide of the use of ADs in BD 4th Step: The Task-Force provided a final guide of the use of ADs in BD 65 authors agreed to participate Delphi method Consensus Method

7. Methods 1. 2. 3. Search strategy Systematic review Delphi survey PubMed search limited to human studies and strictly to ADs drugs Efficacy studies Safety studies Average quality (Jadad): 0-2 = poor (not included) 3-5 = acceptable or good (included) Levels of evidence (NHRMC): A = Excellent B = Good C = Satisfactory D = Poor 1st round: items from literature search 2nd round: items rated 3rd round: items re-rated Endorsed items: rated by ≥ 80% as essential or important Re-rated items: rated as essential or important by 65%–79% Rejected items: items with lower consensus levels Methods

8. Flow-diagram of study design and results Search results: limit to human studies ADs and bipolar disorder/ mania, depression, mixed state, safety, switch, suicide, side effects: 1,359 Not included: 1,187; 110, incongruent with aims; 379, low level of evidence/quality; 299, unfocused; 399, methodological flaws and doubles Included: 173 Observational: 33 Other open: 7 - n>100 - relevant outcomes RCT:97 - n ≥10/group - Statistically reliable findings Reviews/Meta-analyses: 6/30 Overlap between typologies of studies included in the review: 0%

9. Antidepressant monotherapy 3D Adjunctive antidepressants: short-term efficacy in acute depression 4B Predictors of initial response to adjunctive Ads 3D Adjunctive antidepressants: maintenance studies 3.5C Predictors of long-term responsiveness to adjunctive AD- treatment 3D Antidepressant use in mania and mixed states 3D Antidepressants and affective switch (mania/hypomania/mixed) 4C Are newly emerging, or increasing irritability and agitation during AD-treatment a form of mood switching? 3.5D Antidepressants and cycle acceleration 3.5D Antidepressants and suicidality 3D Results: evidence and quality TopicAveragequalityEvidencelevel

10. Recommendations

11. 1. Acute treatment 1. Adjunctive ADs may be used for an acute bipolar I or II depressive episode when there is a history of previous positive response to ADs. 2. Adjunctive ADs should be avoided for an acute bipolar I or II depressive episode with two or more concomitant core manic symptoms, in presence of psychomotor agitation or rapid cycling. Other 13.12 86.88 Essential/ Important Other 11.47 88.53 Essential/ Important

12. 2. Maintenance treatment 3. Maintenance treatment with adjunctive antidepressants may be considered if a patient relapses into a depressive episode after stopping AD therapy. Other 15.00 85.00 Essential/ Important *Re-rated

13. 4. Switch to (hypo)mania or mixed states and rapid cycling 6. Bipolar patients starting ADs should be closely monitored for signs of hypomania or mania and increased psychomotor agitation in which case ADs should be discontinued. 7. The use of ADs should be discouraged if there is history of past mania, hypomania or mixed episodes emerging during AD treatment. Other 6.56 93.44 Essential/ Important Other 16.39 83.61 Essential/ Important 8. AD use should be avoided in bipolar patients with a high mood instability (i.e., high number of episodes) or with a history of rapid cycling. Other 14.75 85.25 Essential/ Important

14. 3. AD monotherapy 4. AD mono-therapy should be avoided in bipolar I disorder. 5. AD mono-therapy should be avoided in bipolar I and II depression with two or more concomitant core manic symptoms. Other 8.20 91.80 Essential/ Important Other 14.76 85.24 Essential/ Important

15. 5. Use in mixed states 9. ADs should be avoided during manic and depressive episodes with mixed features. 10. ADs should be avoided in bipolar patients with predominantly mixed states. Other 4.92 95.08 Essential/ Important Other 19.68 80.32 Essential/ Important 11. Previously prescribed ADs should be discontinued in patients experiencing current mixed states. Other 16.39 83.61 Essential/ Important

16. 6. Drug class 12. Adjunctive treatment with SNRIs and TCAs should be considered only after other ADs have been tried, and should be closely monitored due to increased risk of switch or mood destabilization. Other 16.39 83.61 Essential/ Important

17. Rejected items 1. The use of adjunctive ADs may be considered for an acute bipolar depressive episode only after treatment with mood stabilizers or atypical antipsychotics with evidence of efficacy for bipolar depression has been tried without clinical benefits. 75.00% Essential/ Important *Re-rated 2. If a patient responds to an AD for an acute depressive episode, continuing ADs in the long-term might be reasonable in bipolar I or II subjects, with the exception of rapid cyclers and highly unstable bipolar patients. 62.29% Essential/ Important 3. If a patient responds to an AD for an acute depressive episode, it should be continued to full clinical remission of the index episode and then gradually removed. 60.65% Essential/ Important

18. Rejected items 4. AD mono-therapy should be avoided during a first depressive episode in patients with no history of mania or hypomania but with two or more indicators of latent “bipolarity” 70.00% Essential/ Important *Re-rated 5. AD mono-therapy should be avoided in bipolar II disorder. 42.62% Essential/ Important 6. AD mono-therapy may be considered in a subgroup of bipolar II patients who have infrequent hypomanic episodes but long protracted depressive episodes. 54.09% Essential/ Important 44.27% Essential/ Important *Re-rated 7. The use of ADs should be avoided during a current depressive episode that is preceded by a recent manic/hypomanic (rather than euthymic) phase of the illness or in patients with manic predominant polarity.

19. Rejected items 8. Among the different ADs, the SSRIs (especially fluoxetine), bupropion, and MAOIs should be preferred over other ADs as adjunctive treatment to mood stabilizers and/or atypical antipsychotics in bipolar I depression. 76.67% Essential/ Important *Re-rated 9. In bipolar II disorder, SSRI monotherapy may be considered in a subgroup of patients who have infrequent hypomanic episodes but long protracted depressive episodes. 60.66% Essential/ Important 10. TCA and SNRI monotherapy should be avoided in bipolar I and II disorder. 71.66% Essential/ Important 62.29% Essential/ Important 11. Adjunctive ADs may be used as a second line treatment choice after failure of mood stabilizers and/or atypical antipsychotics in bipolar patients with comorbid anxiety disorders. *Re-rated

20. ISBD Task-Force Expert Panel