CNS Drugs

, Volume 23, Issue 5, pp 369–377 | Cite as

Utility of Atypical Antipsychotics in the Treatment of Resistant Unipolar Depression

  • Charles DeBattista
  • Jessica Hawkins
Review Article


Many patients fail to achieve an adequate response to antidepressant medication. Growing evidence suggests that atypical antipsychotics may augment antidepressant effects, resulting in a greater potential for response. Atypical antipsychotics possess pharmacological actions that are associated with antidepressant properties, including serotonin 5-HT2 receptor antagonist and 5-HT1A and dopamine receptor partial agonist activity. In fact, the term ‘atypical antipsychotic’ is an unfortunate remnant of the early indication of these drugs in the treatment of schizophrenia. Soon after their introduction, the usefulness of atypical antipsychotics in bipolar disorder was firmly established and their use in the treatment of mood disorders has far outpaced their use in schizophrenia and other psychotic disorders. Aripiprazole has become the first agent to receive US FDA approval for the adjunctive treatment of unipolar depression. Most recently, Symbyax, a fluoxetine/olanzapine combination, received FDA approval for the acute treatment of treatment-resistant depression. This is the first medication to be FDA approved for this indication. In the present article, the usefulness of antipsychotics in the treatment of resistant unipolar depression is reviewed.


Fluoxetine Risperidone Olanzapine Quetiapine Selective Serotonin Reuptake Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used to assist in the preparation of this review. Dr DeBattista receives grant support from AstraZeneca, Lilly, Wyeth, GlaxoSmithKline, Pfizer, Cephalon, Novartis, Neuronetics, Cyberonics, Medtronics and CNS Response, and is on the speaker’s bureau for Lilly, Wyeth, Cephalon, GlaxoSmithKline, Pfizer, Cyberonics and Bristol Myers Squibb. In addition, Dr DeBattista is a stock holder of Corcept Therapeutics. Jessica Hawkins has no conflicts of interest to declare that are directly relevant to the content of this review.


  1. 1.
    Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry 2007; 52(1): 46–54PubMedGoogle Scholar
  2. 2.
    Thase ME. Therapeutic alternatives for difficult-to-treat depression: a narrative review of the state of the evidence. CNS Spectr 2004; 9(11): 808–16, 818-21PubMedGoogle Scholar
  3. 3.
    Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163(11): 1905–17PubMedCrossRefGoogle Scholar
  4. 4.
    Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 2006; 163(9): 1519–30; quiz 1665PubMedCrossRefGoogle Scholar
  5. 5.
    Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006; 163(7): 1161–72PubMedCrossRefGoogle Scholar
  6. 6.
    DeBattista C. Augmentation and combination strategies for depression. J Psychopharmacol 2006; 20(3 Suppl.): 11–8PubMedCrossRefGoogle Scholar
  7. 7.
    Jarema M. Atypical antipsychotics in the treatment of mood disorders. Curr Opin Psychiatry 2007; 20(1): 23–9PubMedGoogle Scholar
  8. 8.
    Blier P, Szabo ST. Potential mechanisms of action of atypical antipsychotic medications in treatment-resistant depression and anxiety. J Clin Psychiatry 2005; 66 Suppl. 8: 30–40Google Scholar
  9. 9.
    Möller HJ. Antidepressive effects of traditional and second generation antipsychotics: a review of the clinical data. Eur Arch Psychiatry Clin Neurosci 2005 Apr; 255(2): 83–93PubMedCrossRefGoogle Scholar
  10. 10.
    Candy M, Jones L, Williams R, et al. Psychostimulants for depression. Cochrane Database Syst Rev 2008 Apr 16; (2): CD006722Google Scholar
  11. 11.
    Satel SL, Nelson JC. Stimulants in the treatment of depression: a critical overview. J Clin Psychiatry 1989 Jul; 50(7): 241–9PubMedGoogle Scholar
  12. 12.
    Zhang W, Perry KW, Wong DT, et al. Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 2000; 23(3): 250–62PubMedCrossRefGoogle Scholar
  13. 13.
    Ballas C, Yang C, O’Reardon J, et al. Ziprasidone: a novel psychotropic with unique properties. Expert Rev Neurother 2004; 4(2): 179–86PubMedCrossRefGoogle Scholar
  14. 14.
    Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001; 158(1): 131–4PubMedCrossRefGoogle Scholar
  15. 15.
    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): 1289–97PubMedCrossRefGoogle Scholar
  16. 16.
    Corya SA, Williamson D, Sanger TM, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety 2006; 23(6): 364–72PubMedCrossRefGoogle Scholar
  17. 17.
    Thase ME, Corya SA, Osuntokun O, et al. A randomized, double-blind, comparision of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. J Clin Psychiatry 2007 Feb; 68(2): 224–36PubMedCrossRefGoogle Scholar
  18. 18.
    Barbee JG, Conrad EJ, Jamhour NJ. Aripiprazole augmentation in treatment-resistant depression. Ann Clin Psychiatry 2004; 16(4): 189–94PubMedCrossRefGoogle Scholar
  19. 19.
    Ketter TA, Wang PW, Chandler RA, et al. Adjunctive aripiprazole in treatment-resistant bipolar depression. Ann Clin Psychiatry 2006; 18(3): 169–72PubMedCrossRefGoogle Scholar
  20. 20.
    Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2007 Jun; 68(6): 843–53PubMedCrossRefGoogle Scholar
  21. 21.
    Baune BT, Caliskan S, Todder D. Effects of adjunctive antidepressant therapy with quetiapine on clinical outcome, quality of sleep and daytime motor activity in patients with treatment-resistant depression. Hum Psychopharmacol 2007; 22(1): 1–9PubMedCrossRefGoogle Scholar
  22. 22.
    Sagud M, Mihaljević-Peles A, Mück-Seler D, et al. Quetiapine augmentation in treatment-resistant depression: a naturalistic study. Psychopharmacology (Berl) 2006; 187(4): 511–4CrossRefGoogle Scholar
  23. 23.
    Mattingly GLH, Canale J, Anderson R. Quetiapine combination for treatment resistant depression. 159th Meeting of the American Psychiatric Association; 2006 May 20—25; Toronto (ON)Google Scholar
  24. 24.
    Doree JP, Des Rosiers J, Lew V, et al. Quetiapine augmentation of treatment-resistant depression: a comparison with lithium. Curr Med Res Opin 2007; 23(2): 333–41PubMedCrossRefGoogle Scholar
  25. 25.
    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; 31(11): 2505–13PubMedCrossRefGoogle Scholar
  26. 26.
    Papakostas GI, Petersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry 2004; 65(2): 217–21PubMedCrossRefGoogle Scholar
  27. 27.
    Dunner DL, Amsterdam JD, Shelton RC, et al. Efficacy and tolerability of adjunctive ziprasidone in treatment resistant depression: a randomized, open label, pilot study. J Clin Psychiatry 2007; 68(7): 1071–7PubMedCrossRefGoogle Scholar
  28. 28.
    Corya SA, Andersen SW, Detke HC, et al. Long-term antidepressant efficacy and safety of olanzapine/fluoxetine combination: a 76-week open-label study. J Clin Psychiatry 2003; 64(11): 1349–56PubMedCrossRefGoogle Scholar
  29. 29.
    Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol 2008 Apr; 20(2): 156–65CrossRefGoogle Scholar
  30. 30.
    Dremencov E, El Mansari M, Blier P. Noradrenergic augmentation of escitalopram response by risperidone: electrophysiologic studies in the rat brain. Biol Psychiatry 2007; 61(5): 671–8PubMedCrossRefGoogle Scholar
  31. 31.
    Barbee JG, Conrad EJ, Jambour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry 2004 Jul; 65(7): 975–81PubMedCrossRefGoogle Scholar
  32. 32.
    Alexopoulos GS, Canuso CM, Gharabawi GM, et al. Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression. Am J Geriatr Psychiatry 2008 Jan; 16(1): 21–30PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral SciencesStanford University School of MedicineStanfordUSA

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