Evidence-Based Reviews

Treatment-resistant depression: Are atypical antipsychotics effective and safe enough?

Current Psychiatry. 2006 October;5(10):31-44

References

1. Shelton RC. The use of antidepressants in novel combination therapies. J Clin Psychiatry 2003;64(suppl 2):14-8.

2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006;163(1):28-40.

3. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354(12):1243-52.

4. 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;354(12):1231-42.

5. Simon GE, Heiligenstein J, Revicki D, et al. Long-term outcomes of initial antidepressant drug choice in a “real world” randomized trial. Arch Fam Med 1999;8(4):319-25.

6. Nierenberg AA, Petersen TJ, Alpert JE. Prevention of relapse and recurrence in depression: the role of long-term pharmacotherapy and psychotherapy. J Clin Psychiatry 2003;64(suppl 15):13-17.

7. Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000;342(20):1462-70.

8. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997;349(9064):1498-1504.

9. Bennett MR. Monoaminergic synapses and schizophrenia: 45 years of neuroleptics. J Psychopharmacol 1998;12(3):289-304.

10. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21(2 suppl):106S-115S.

11. Meltzer HY, Bastani B, Ramirez L, Matsubara S. Clozapine: new research on efficacy and mechanism of action. Eur Arch Psychiatry Neurol Sci 1989;238(5-6):332-9.

12. Hirschfeld RM, Weisler RH, Raines SR, Macfadden W. for the BOLDER Study Group. Quetiapine in the treatment of anxiety in patients with bipolar I or II depression: a secondary analysis from a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2006;67(3):355-62.

13. 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;60(11):1079-88.

14. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158(1):131-4.

15. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 1999;60(4):256-9.

16. Shelton RC. The combination of olanzapine and fluoxetine in mood disorders. Expert Opin Pharmacother 2003;4(7):1175-83.

17. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 2005;66(10):1289-97.

18. Thase ME, Corya SA, Olawale O, et al. Olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. Presented at: Society of Biological Psychiatry annual meeting; May 18-20, 2006; Toronto, Ontario.

19. Nemeroff CB. Use of atypical antipsychotics in refractory depression and anxiety. J Clin Psychiatry 2005;66(suppl 8):13-21.

20. Dunner DL, Amsterdam JD, Shelton RC, et al. Adjunctive ziprasidone in treatment-resistant depression: a randomized, double-blind, 8-week pilot study. Presented at: American College of Neuropsychopharmacology annual meeting; December 12-16, 2004; San Juan, PR.

21. Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology 2006 (in press; advance online publication June 7, 2006; doi:10.1038/sj.npp.1301113).

22. Gharabawi G, Canuso C, Pandina G, et al. A double-blind placebocontrolled study of adjunctive risperidone for treatment-resistant major depressive disorder. Int J Neuropsychopharmacol 2006;9(suppl 1):S236.-

23. Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry 2004;65(12):1715-9.

24. Shelton RC. A comparison of risperidone and bupropion augmentation of serotonin reuptake inhibitors in treatment-resistant unipolar major depression. Presented at: Society of Biological Psychiatry annual meeting; May 18-20, 2006; Toronto, Ontario.

25. Simon JS, Nemeroff CB. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J Clin Psychiatry 2005;66(10):1216-20.

26. Papakostas GI, Petersen TJ, Kinrys G, et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 2005;66(10):1326-30.

27. Barbee JG, Conrad EJ, Jamhour NJ. Aripiprazole augmentation in treatment-resistant depression. Ann Clin Psychiatry 2004;16:189-94.

28. Adson DE, Kushner MG, Eiben KM, Schulz SC. Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors. Depress Anxiety 2004;19:121-6.

29. Yargic LI, Corapcioglu A, Kocabasoglu N, et al. A prospective randomized single-blind, multicenter trial comparing the efficacy and safety of paroxetine with and without quetiapine therapy in depression associated with anxiety. Int J Psychiatry Clin Pract 2004;8(4):205-11.

30. McIntyre A, Gendron A, McIntyre A. Quetiapine augmentation of SSRIs/SNRIs in major depression with anxiety. Poster presented at: American Psychiatric Association annual meeting; May 2006; Toronto, Ontario.

31. Mattingly G, Ilivicky H, Canale J, Anderson R. Quetiapine combination for treatment-resistant depression. Poster presented at: American Psychiatric Association annual meeting; May 2006; Toronto, Ontario.

32. Keck PE, Jr, McElroy SL, Strakowski SM, Soutullo CA. Antipsychotics in the treatment of mood disorders and risk of tardive dyskinesia. J Clin Psychiatry 2000;61(suppl 4):33-8.

33. Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: mechanisms, clinical features and management. Drugs 2004;64(20):2291-314.

34. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997;42(4):233-46.

35. Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63(9):763-71.

36. Tollefson GD, Kuntz AJ. Review of recent clinical studies with olanzapine. Br J Psychiatry Suppl 1990;(37):30-5.

37. Goff DC, Posever T, Herz L, et al. An exploratory haloperidolcontrolled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. J Clin Psychopharmacol 1998;18(4):296-304.

SGAs probably belong ahead of electroconvulsive therapy or vagal nerve stimulation. But should they come before augmentation with lithium or thyroid hormone? Or, for that matter, trials of tricyclics or monoamine oxidase inhibitors?

Unfortunately, the available evidence provides little guidance. For a list of therapeutic algorithms developed for treatment-resistant depression, see Related resources.

Table 2

Recommended dosing of SGAs to augment antidepressant therapy

Medication	Therapeutic range (mg/d)
Aripiprazole	5 to 30
Olanzapine	5 to 20
Quetiapine	100 to 400
Risperidone	2 to 4
Ziprasidone	80 to 160

Related resources

Algorithms for treatment-resistant depression

Trivedi MH, Kern JK, Grannemann BD, et al. A computerized clinical decision support system as a means of implementing depression guidelines. Psychiatr Serv 2004;55(8);879-85.
Rush AJ, Crismon ML, Kashner TM, et al. Texas Medication Algorithm Project, phase 3 (TMAP-3): rationale and study design. J Clin Psychiatry 2003;64(4);357-69.
Trivedi M. Algorithms in clinical psychiatry: a stepped approach toward the path to recovery. Psychopharmacol Bull 2002;36(suppl 2);142-9.
Trivedi MH, Kleiber BA. Algorithm for the treatment of chronic depression. J Clin Psychiatry 2001;62(suppl 6);22-9.
Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60(3);142-56.

Drug brand names

Aripiprazole • Abilify
Bupropion • Wellbutrin
Buspirone • BuSpar
Citalopram • Celexa
Clozapine • Clozaril
Desipramine • Norpramin
Duloxetine • Cymbalta
Imipramine • Tofranil
Lithium • various
Nortriptyline • Pamelor
Olanzapine • Zyprexa
Olanzapine/fluoxetine • Symbyax
Phenelzine • Nardil
Pindolol • Visken
Quetiapine • Seroquel
Risperidone • Risperdal
Selegiline (patch) • EMSAM
Sertraline • Zoloft
Tranylcypromine • Parnate
Venlafaxine • Effexor
Ziprasidone • Geodon

Disclosure

Dr. Shelton receives grant/research support from Eli Lilly and Co., GlaxoSmithKline, Pfizer, Janssen Pharmaceutica, sanofi-aventis, Wyeth Pharmaceuticals, AstraZeneca Pharmaceuticals, and Abbott Laboratories. He is a consultant to Pfizer and Janssen Pharmaceutica and a speaker for Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, Pfizer, GlaxoSmithKline, Solvay Pharmaceuticals, Wyeth Pharmaceuticals, and Abbott Laboratories.