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22 * * 3 1 2 3. 4 Drug Surveillance 1. 6-9 2 3 DSM-IV Anxious depression 4 Drug Surveillance GPRD A. (TCA) (SSRI) (SNRI) 20-77 -

SSRI 1999 SNRI 2000 5 56 80 SSRI 1 1999 2005 2 2005 92.4, 2010 1999 3 1 2 3. 4 Drug Surveillance B. Pubmed (APA) 2 NICE 3 US Preventive Services Task Force 4 level II-2 US Preventive Services Task Force Level I. 1 RCT > Level II-1. > Level II-2. > Level II-3. > Level III. C. 1 National Institute for Clinical Excellence (NICE) NICE 5, 6 HDRS>25-28 10 (2009) 7 25 2 2 6-9 2, 8, 9 8 1-2 - 78 -

10, 11 NICE 6-8 (Treatment Resistant Depression: TRD) 2 Sequenced Treatment Alternatives to Relieve Depression Study (STAR*D) 12, 13 2876 14 SSRI 28% 18-25 30% 2 / 12-25% 3 7-14% / 70% STAR*D SSRI 2 3, 14 Bollini 15 100mg 50 102-200mg 50 201mg/ 50% 1 SSRI SSRI 16 NICE 75-100mg/day, 125mg/day 140mg/day SSRI 50mg/day 20mg/day 50mg/day 50mg/day 60mg/day 30mg/day 150 mg/day SSRI STAR*D Licht 17 (100mg/ 200mg/ ) - 79 -

RCT 18 64 35 28 3 Angst 19 I II NOS I 12.8 47 67 3 (Anxious depression) (Non-anxious depression) Anxious depression STAR*D 20 NICE SSRI 1 2 833 8 21 4 Drug Surveillance The General Practice Research Database (GPRD: http://www.gprd.com ) 500 GPRD Jick 22 D. - 80 -

E. 1. 6-9 2 3 DSM-IV Anxious depression 4 Drug Surveillance GPRD F. 1. Nakagawa A, Grunebaum MF, Ellis SP, et al. Association of suicide and antidepressant prescription rates in Japan, 1999-2003. J Clin Psychiatry 2007 Jun;68(6):908-916. 2. APA. Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Washington, DC American Psychiatric Association; 2010. 3. NICE. Depression: the treatment and management of depression in adults, Clinical Guideline 90 London: National Institute for Clinical Excellence; 2009. 4. Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001 Apr;20(3 Suppl):21-35. 5. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008 Feb;5(2):e45. 6. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010 Jan 6;303(1):47-53. 7. Stone M, Laughren T, Jones ML, et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009;339:b2880. 8. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines. J Psychopharmacol 2008 Jun;22(4):343-396. 9. APA. Practice guideline for the treatment of - 81 -

patients with major depressive disorder. 2nd ed. Washington, DC: American Psychiatric Association; 2004. 10. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-xr after failure of SSRIs for depression. N Engl J Med 2006 Mar 23;354(12):1231-1242. 11. Szegedi A, Jansen WT, van Willigenburg AP, van der Meulen E, Stassen HH, Thase ME. Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry 2009 Mar;70(3):344-353. 12. Rush AJ, Warden D, Wisniewski SR, et al. STAR*D: revising conventional wisdom. CNS Drugs 2009 Aug 1;23(8):627-647. 13. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006 Mar 23;354(12):1243-1252. 14. Furukawa TA. Review: placebo is better than no treatment for subjective continuous outcomes and for treatment of pain. Evid Based Ment Health 2002 Feb;5(1):15. 15. Bollini P, Pampallona S, Tibaldi G, Kupelnick B, Munizza C. Effectiveness of antidepressants. Meta-analysis of dose-effect relationships in randomised clinical trials. Br J Psychiatry 1999 Apr;174:297-303. 16. Adli M, Baethge C, Heinz A, Langlitz N, Bauer M. Is dose escalation of antidepressants a rational strategy after a medium-dose treatment has failed? A systematic review. Eur Arch Psychiatry Clin Neurosci 2005 Dec;255(6):387-400. 17. Licht RW, Qvitzau S. Treatment strategies in patients with major depression not responding to first-line sertraline treatment. A randomised study of extended duration of treatment, dose increase or mianserin augmentation. Psychopharmacology (Berl) 2002 May;161(2):143-151. 18. Rothschild AJ, Williamson DJ, Tohen MF, et al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol 2004 Aug;24(4):365-373. 19. Angst J, Cui L, Swendsen J, et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry 2010 Oct;167(10):1194-1201. 20. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008 Mar;165(3):342-351. 21. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003 Nov;60(11):1079-1088. 22. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004 Jul 21;292(3):338-343. - 82 -