Atypical Antipsychotic Augmentation in the Treatment of Depression

March 1, 2007

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. 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.

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.

Published studies
Ostroff and Nelson8 added 0.5 to 1 mg/d of risperidone to the treatment regimens of 8 patients with depression who had "incomplete" responses to 16 weeks of treatment with fluoxetine or paroxetine. In this open-label trial, all of the patients' depressive symptoms remitted in less than 1 week.

In a more substantial 8-week, double-blind trial, Shelton and colleagues9 randomly assigned 28 patients with nonpsychotic treatment-resistant depression to olanzapine plus placebo (n = 8), fluoxetine plus placebo (n = 10), or olanzapine plus fluoxetine (n = 10). The symptoms of patients taking a combination of olanzapine and fluoxetine improved significantly more than the symptoms of those receiving either monotherapy.

In the 2 studies cited above, patients had poor responses to treatment with antidepressants before atypical antipsychotic augmentation was initiated. Hirose and Ashby10 conducted an open- label study of 36 patients with depression who were administered a combination of fluvoxamine and risperidone as first-line treatment for 6 weeks. Of the 30 patients who completed the study, 93% had a positive response to the combined treatment (as signified by the percentage of reductions in the Hamilton rating scale for depression).

In another open-label study of 20 patients with depression who failed to respond to an adequate trial of an SSRI, Papakostas and colleagues11 augmented antidepressant treatment with ziprasidone. Thirteen patients completed the study (suggesting a high discontinuation rate). At completion, 25% of the patients remitted and 50% responded to the augmentation.

In a retrospective chart review, olanzapine, risperidone, quetiapine, and ziprasidone were given in a fee-for- service setting as augmenting agents to patients with treatment-resistant depression (N = 49).12 Barbee and associates12 found an overall response rate of 65%, based on clinical global impression scale ratings. There was no difference in response rates between the different atypical agents.

The question of whether patients' responses to atypical antipsychotic augmentation are greater in those who have been pretreated with antidepressants than in those in whom antidepressants and atypical antipsychotics are started together continues to be a focus of investigation. Twenty patients with major depression were treated with antidepressants for 2 weeks and showed minimal or no improvement. The patients were then randomly assigned to augmentation with placebo or olanzapine for an additional 4 weeks.

Improvement rates between the 2 groups (45% and 43%, respectively) were no different, although of the 12 primary responders, 8 were in the olanzapine group and 4 were in the placebo augmentation groups. Four patients did not improve with placebo augmentation and showed a "distinct and rapid" effect with subsequent olanzapine augmentation.13 This study suggests-as may be the case with lithium augmentation-that pretreatment with an antidepressant may be needed in order for the patient to benefit from augmentation with an atypical antipsychotic.

Another small open-label study (N = 12) reported on the effects of aripiprazole augmentation of SSRIs for patients with treatment-resistant depressive disorders.14 In this 8-week trial, 9 patients completed the study; 5 were classified as "responders." For those who did respond, the improvement was reported as "robust and rapid" by the end of the first week of treatment.

Similarly, in a small open-label study, 15 depressed patients responded poorly to 8 weeks of antidepressant therapy.15 In these patients, treatment was augmented for another 4 weeks with aripiprazole. Remission rates were 40% by the first week and 60% by the second week of treatment. Response rates were faster and higher in patients receiving 10 mg/d of aripiprazole; however, more patients in that group discontinued treatment because of adverse effects than in the group who received 2.5 mg/d.

Shelton and associates16 conducted a large (N = 500), multisite (71 sites) study of patients with treatment-resistant depression. All patients were treated with nortriptyline for 7 weeks. Those patients who had less than 30% improvement were randomly assigned to 8 weeks of double-blind treatment with olanzapine plus fluoxetine (n = 146), olanzapine plus placebo (n = 144), or fluoxetine plus placebo (n = 142) or were kept on nortriptyline plus placebo (n = 68). In contrast to the small open-label studies described earlier, overall response rates were low; this was similar in all groups (20% to 30%) by week 8. Patients in the olanzapine-plus-fluoxetine group showed quicker response (by weeks 1 through 3) than did those in the monotherapy groups; however, all groups had comparable response rates by week 8.

Another large (N = 386), multicenter study assessed the usefulness of risperidone continuation-phase augmentation for treatment-resistant depression. In a 4- to 6-week open-label phase trial, 63% of patients improved with risperidone augmentation; 241 of these patients then entered a 24-week, double-blind, placebo-controlled continuation-phase trial.17 The mean number of days to relapse was 102 in the risperidone augmentation group and 85 in the placebo augmentation group, which was a nonsignificant difference.

Unpublished studies
Several additional studies have been presented at national meetings but not yet published. Dunner and colleagues18 randomized patients with treatment- resistant depression to an 8-week trial of sertraline monotherapy (n = 20) or sertraline plus ziprasidone (n = 40). Patients with a history of non-SSRI treatment resistance (but not those who were poorly responsive to SSRIs) showed significantly greater improvement with combination treatment than with monotherapy.

Keitner and associates19 presented the results of a large (N = 97) randomized, double-blind, placebo-controlled study of risperidone augmentation for patients with difficult-to-treat depression. Although both study groups improved significantly over a 4-week trial, patients receiving risperidone augmentation had significantly greater odds for remitting (odds ratio, 3.33) and responded faster than those augmented with placebo. The augmented risperidone group also reported having significantly better quality of life and more satisfaction with their medication.19

Patients with depression (N = 605) who were not responsive to SSRI treatment were enrolled in 2 parallel 8-week, double-blind studies comparing a combination of olanzapine plus fluoxetine, olanzapine alone, and fluoxetine alone.20 Response rates were 40%, 30%, and 26%, respectively. Pooled results from the 2 studies demonstrated significantly greater symptomatic improvement in the combination group. Patients taking olanzapine had greater weight gain and an increase in cholesterol level.

Treatment was augmented with quetiapine in an 8-week, double-blind, placebo-controlled trial of patients with treatment-resistant depression.21 Significantly more patients who received treatment with the quetiapine augmentation responded to treatment (67%) or achieved remission (43%) than did those whose treatment was augmented with placebo (27% and 15%, respectively). A smaller (N = 15) randomized, double-blind, placebo-controlled study with quetiapine augmentation also found significantly greater improvement in the quetiapine group than in the placebo-augmented group.22

In the only study comparing the efficacy and tolerability of atypical antipsychotics, Ravindran and associates23 conducted a 6-week randomized, double-blind study of low and high doses of risperidone or olanzapine in 43 patients who had difficult-to-treat depression. Both low-dose groups (risperidone 0.5 to 1 mg/d and olanzapine 2.5 to 5 mg/d) did better than the high-dose groups (risperidone 2 to 3 mg/d and olanzapine 10 to 15 mg/d) but were comparable to each other. Interestingly, there was no reported difference in adverse effects between the low- and high-dose groups, while patients in the olanzapine group reported more adverse effects than did those in the risperidone groups.

Clinical implications
What can we conclude from these studies about when and how to use atypical antipsychotics for patients with depression? Overall, it appears that some patients respond well to augmentation with atypical antipsychotics. To date, no study has been able to identify predictors of which patients are more likely to benefit from such augmentation. One study has suggested that patients whose symptoms failed to improve on non- SSRIs are likely to have better responses than those whose symptoms failed to improve on SSRIs,18 but most studies have noted symptom improvement in SSRI nonresponders as well.

The most clinically useful and reasonably consistent finding is that treatment augmentation with an atypical antipsychotic is associated with a faster response than continuing the primary antidepressant alone. A majority of the studies suggest that a significant ben-efit to augmentation is evident with- in 1 to 2 weeks after initiating the treatment.8,9,11,12,15,17,19

Recommended treatment
The data suggest that atypical augmentation may be most useful when a rapid response is desirable. Such situations may arise when patients become particularly discouraged by lack of response, when safety considerations are paramount, and when psychosocial functioning is excessively compromised. The literature also suggests that pretreatment with antidepressants may lead to a better outcome than starting combination therapy from the outset.13 However, this may not be the case for all patients.10

Which antipsychotic should psychiatrists prescribe? Two studies comparing one antipsychotic to another as an augmentative agent in patients with depression did not find any differences in effectiveness between the two.12,23 Given the comparable efficacies, the choice of antipsychotic should be made according to the agent's adverse-effect profile, patient preference and his or her past history with a particular drug, and cost. In general, the studies cited have found the atypicals to be well tolerated in patients with poorly responsive depressions. The most problematic adverse effect reported was weight gain with olanzapine, ranging from 3 to 6 kg over a 4- to 8-week treatment period. Examples of potential antipsychotics and effective dosages are provided in the Table.

Table Suggested dosages of antipsychotics*
 Antipsychotic agents Effective dosage
Aripiprazole 0.25 - 25 mg/d
Olanzapine 5 - 20 mg/d
Quetiapine 150 - 400 mg/d
Risperidone 0.25 - 3 mg/d
Ziprasidone 40 - 160 mg/d

How long should augmentation last?
Only one study to date has looked at the effectiveness of a continuation of treatment with atypical antipsychotic augmentation over a 24-week period.17 The study did not find significant benefits for delaying relapse with risperidone augmentation. Most of the studies have ranged from 4 to 6 weeks and have reported measurable benefits within 1 to 2 weeks. Based on these findings, it seems reasonable to use atypical antipsychotics for a 2- to 4-week treatment trial. Past this point, the financial cost and side- effect burden may not be justifiable. To date, augmentation with atypical antipsychotics for short periods in patients who relapse has not been studied.

Atypical augmentation of antidepressants for patients with difficult-to-treat and/or treatment-resistant forms of depression appears to be a reasonable treatment option, particularly when a faster response is desirable. Most research evidence points to the use of low dosages of an antipsychotic agent for a 2- to 4-week trial period. As with antidepressants, the choice of the antipsychotic agent should depend on the patient's history of previous response to medication, the adverse-effect profile, patient preference, and additional cost.

It is important to highlight the reality that even atypical augmentation leads to a 15% to 40% remission rate, leaving a significant number of patients with continuing and bothersome depressive symptoms. Pharmacological treatment continues to have its limitations. In addition to pharmacological therapy, patients need to learn to cope with their illness in a way that improves their social and vocational functioning, as well as their quality of life, despite persistent symptoms.


References1. 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.