Despite the clinician's goal of treating the depressed patient to the point of remission, this state is generally achieved in only 15% to 30% of patients.1 Another 10% to 30% of patients respond poorly to antidepressant treatment, while 30% to 40% have a remitting and relapsing course.1 Patients without a major depressive disorder are likely to be treated successfully by primary care physicians and/or other mental health professionals, which leaves psychiatrists to treat patients who have forms of depression that are less responsive to treatment.
Initially, patients may have high expectations of treatment outcome, only to discover that many forms of depression are not readily responsive to even adequate dosages of an antidepressant. Such patients have been described as having difficult-to-treat depression.2 Other patients with treatment-resistant forms of depression are defined as having depressions that do not respond to various numbers of treatment trials.3
As psychiatrists, how do we help patients who continue to experience significant depressive symptoms, despite the use of evidence-based first-line treatment? Options that are currently available for the treatment of depressive disorders include monotherapy with an antidepressant medication; psychosocial treatment (individual, family, or group therapy); combined pharmacotherapy and psychosocial treatment; substitution of one antidepressant for another; augmentation of an antidepressant with other agents such as lithium, thyroid hormone, or atypical antipsychotic agents; a combination of antidepressants; electroconvulsive therapy; repetitive transcranial magnetic stimulation; and vagus nerve stimulation.
One of the most common options that clinicians recommend is augmentation. In a large-scale study (N = 244,859), 22% of patients with depression were found to have received an augmenting agent; a second antidepressant (11%) or a second-generation antipsychotic (7%) were the most common agents added to treatment.4
Most literature on treatment-resistant or difficult-to-treat depression presents findings from clinical trials of various agents that typically have a small number of patients, are open-label studies, and lack control subjects. DeBattista5 noted, "The most common augmentation strategies in depression are those with the least controlled evidence."
Mental health professionals seem as ready as patients to seek easy solutions to difficult problems. Although a variety of alternative pharmacological treatment trials have yielded benefits for some patients, the STAR*D studies have highlighted the limitations of such sequential trials. Sequential and augmentation trials have yielded 15% to 30% remission rates.6,7
Given this evidence, it is important for patients to have realistic expectations about the nature of their depressive illness and for clinicians to help them find ways to cope with depression, even while they continue to test responsiveness to new treatments. Excessively focusing on symptom resolution may paradoxically worsen a patient's psychosocial functioning and quality of life. Disease management approaches that focus on learning how to deal with one's illness in the face of symptom persistence have been used successfully with a number of medical conditions, including chronic fatigue syndrome, diabetes, arthritis, chronic pain, and asthma.1 Evidence-based treatment can be best pursued within the context of a broadly based model for coping with chronic illness.
What evidence exists for the efficacy of atypical antipsychotic augmentation? When is atypical antipsychotic augmentation appropriate, and which agents should be used and for how long? Possible answers to these questions are addressed below.
1. Keitner GI, Ryan CE, Solomon DA. Realistic expectations and a disease management model for depressed patients with persistent symptoms. J Clin Psychiatry. 2006;67:1412-1421.
2. Rush AJ, Thase ME, Dube S. Research issues in study of difficult-to-treat depression. Biol Psychiatry. 2003; 53:743-753.
3. Thase ME, Rush AJ. When at first you don't succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58(suppl 13):23-29.
4. Valenstein M, McCarthy JF, Austin KL, et al. What happened to lithium? Antidepressant augmentation in clinical settings. Am J Psychiatry. 2006;163:1219-1225.
5. DeBattista C. Augmentation and combination strategies for depression. Psychopharmacology. 2006;20 (suppl 3):11-18.
6. Trivedi MH, Rush AJ, Wisniewski SB, et al. Evaluation of outcome with citalopram for depression using measurements-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.
7. 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;163:1519-1530.
8. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry. 1999;60:256-259.
9. Shelton R, Tollefson GB, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry. 2001;158:131-134.
10. Hirose S, Ashby CR Jr. An open pilot study combining risperidone and a selective serotonin reuptake inhibitor as initial antidepressant therapy. J Clin Psychiatry. 2002;63:733-736.
11. 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;65:217-221.
12. Barbee JG, Conrad EJ, Jamhour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry. 2004;65:975-981.
13. Parker G, Brotchie H, Parker K. Is combination olanzapine and antidepressant medication associated with a more rapid response trajectory than antidepressant alone? Am J Psychiatry. 2005;162:796-798.
14. Papakostas GI, Petersen TJ, Kinrys G, et al. Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depression disorder. J Clin Psychiatry. 2005;66:1326-1330.
15. Simon J, Nemeroff CB. Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J Clin Psychiatry. 2005;66:1216-1220.
16. Shelton R, Addington S, Thakker V. Risperidone vs bupropion combined with SSRIs in treatment resistant unipolar major depression. Presented at: 44th Annual Meeting of the American College of Neuropsychopharmacology; 2005; Waikoloa, Hawaii.
17. 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;31:2514.
18. Dunner DA, Amsterdam JD, Shelton RC, et al. Adjunctive ziprasidone in treatment-resistant depression: a pilot study. Poster presented at: American Psychiatric Association Annual Meeting; May 17-22, 2003; San Francisco.
19. Keitner GI, Garlow S, Ryan CE, et al. Risperidone augmentation for patients with difficult-to-treat major depression. Presented at: American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto.
20. Thase ME, Corya SA, Olawale O, et al. Olanzapine/ fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. Presented at: American Psychiatric Association Annual Meeting; May 23, 2006; Toronto.
21. Mattingly G, Ilivicky H, Canale J, Anderson R. Quetiapine augmentation for treatment-resistant depression. Presented at: American Psychiatric Association Annual Meeting; May 22, 2006; Toronto.
22. Khullar A, Chokka P, Fullerton D, et al. Quetiapine as treatment of non-psychotic unipolar depression with residual symptoms: double-blind, randomized, placebo controlled study. Presented at: American Psychiatric Association Annual Meeting; May 22, 2006; Toronto.
23. Ravindran L, Lam R, Chaput Y, et al. A. Impact of low vs high dose olanzapine or risperidone on outcome and side effects in non-psychotic treatment-resistant depression. Presented at: the New Clinical Drug Evaluation Unit; June 12-15, 2006; Boca Raton, Fla.