Needs Assessment: Despite available treatment strategies, numerous patients with depression remain symptomatic. There is an urgent need to expand available augmentation strategies for depression. The use of atypical antipsychotics represents one such strategy, but clinicians must be updated on the status of clinical evidence supporting this treatment strategy.

Learning Objectives:
• Describe the urgent need to expand our treatment armamentarium for treatment-resistant major depressive disorder (MDD).
• Understand the extent of the evidence supporting the use of the atypical antipsychotics for treatment-resistant MDD.
•  Understand limitations in knowledge regarding the use of the atypical antipsychotics for treatment-resistant MDD.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Faculty Disclosure Policy Statement:
It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by James C.-Y. Chou, MD, associate professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: October 6, 2008.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and Pfizer.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by November 1, 2010 to be eligible for credit. Release date: November 1, 2008. Termination date: November 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

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Primary Psychiatry. 2008;15(11):44-47

 

Dr. Papakostas is an assistant professor of psychiatry at Harvard Medical School and director of Treatment-Resistant Depression Studies at the Massachusetts General Hospital Depression Clinical and Research Program in Boston.

Disclosure relevant towards this article (as of October 1, 2008): Dr. Papakostas has served (over the past 12 months) or has agreed to serve (over the next 12 months) as a consultant for Eli Lilly Co. (makers of olanzapine). Dr. Papakostas has received (over the past 12 months) or is due to receive (over the next 12 months) honoraria from Bristol-Myers Squibb Company (makers of aripiprazole), Eli Lilly Co. (makers of olanzapine), and Pfizer Inc (makers of ziprasidone). Dr. Papakostas has received (over the past 12 months) research support or is due to receive research support (over the next 12 months) from Bristol-Myers Squibb Company (makers of aripiprazole), the National Institute of Mental Health, and Pfizer Inc. (makers of ziprasidone). Dr. Papakostas has served (over the past 12 months) on the speaker’s bureau for Bristol-Myers Squibb Company (makers of aripiprazole), and has agreed to do so throughout 2008.

This article includes discussion of the following unapproved medications for major depressive disorder: olanzapine, quetiapine, risperidone, and ziprasidone.

Please direct all correspondence to: George I. Papakostas, MD, Massachusetts General Hospital, Department of Psychiatry, Depression Clinical and Research Program, 15 Parkman St, WACC 812, Boston, MA 02114; Tel: 617-726-6697; Fax: 617-726-7541; E-mail: gpapakostas@partners.org.


Abstract

Given the relatively modest response and remission rates seen during monotherapy of major depressive disorder (MDD) with all contemporary, first-line antidepressants, there is an urgent need to develop treatments which are both safer and more effective than those currently available. Augmentation of standard antidepressants with atypical antipsychotics represents one such treatment development approach. The preclinical rationale for using atypical antipsychotics as adjunctive therapy in MDD lies in their affinity for a number of serotonergic structures, including the serotonin-1 and -2 receptor subtypes. As a result, numerous randomized, double-blind, placebo-controlled trials have recently been conducted focusing on evaluating whether or not this novel treatment strategy is truly efficacious. This article reviews such studies to inform the reader of the evidence supporting this treatment approach.

Introduction

Major depressive disorder (MDD) is a prevalent illness that can often be quite challenging to treat. Traditionally, antidepressants used as monotherapy have represented the most common (especially as first-line agents) approach to target the illness for >50 years. Over time, clinicians and researchers have come to realize that this approach, while relatively convenient and user friendly, is only effective for a subset of patients.1 As a result, during the course of the last 25 years we have seen a steady growth of studies focusing on testing the efficacy, safety, and tolerability of adjunctive therapies for MDD, either as first-line therapy or for treatment-resistant populations.1 While some studies have concluded that adjunctive therapy is, for the most part, not more effective than monotherapy, others have identified adjunctive treatment therapies that, when employed, have been shown to incrementally improve the outcome of patients with MDD. As a result, these treatments have been incorporated in the standard treatment armamentarium of clinicians nation wide.1 The results of the recently published sequenced treatment alternatives to relieve depression (STAR*D) trial suggest that many MDD patients remain symptomatic despite such adjunctive treatment therapies.2 Results of studies like STAR*D serve to remind clinicians and researchers alike of the urgent need to continue to develop new treatments for MDD. Atypical antipsychotics have recently received attention as potential novel adjunctive therapies for MDD, with numerous randomized, double-blind, placebo-controlled trials either published or presented at major scientific meetings. This article reviews such studies to inform the reader regarding the evidence in support of this treatment approach.

Atypical Antipsychotics: Neuropharmacology

The preclinical rationale for the use of the atypical antipsychotics for the treatment of MDD derives from their complex neuropharmacologic effects at various monoaminergic receptors and transporters.3 Specifically, all atypical antipsychotics appear to be serotonin (5-HT)2 receptor antagonists.4,5 Atypical antipsychotics also vary in terms of neuropharmacologic effects. Ziprasidone and aripiprazole possess affinity for the 5-HT1A receptor,4,5 while ziprasidone and risperidone possess affinity for the 5-HT1D receptor.4,5 Ziprasidone has also been shown to inhibit the reuptake of serotonin and norepinephrine,6 while aripiprazole has been shown to possess mixed agonist and antagonist effects at various dopamine receptors.7 These effects were thought to be suggestive of potential antidepressant activity.3

Atypical Antipsychotics: Clinical Studies

Not unlike many alternative augmentation strategies for treatment-resistant depression (TRD), until recently, there was a paucity of double-blind, placebo-controlled studies examining whether augmentation of standard antidepressants with atypical antipsychotics for TRD is, truly, an efficacious treatment strategy. Shelton and colleagues8 randomized 28 outpatients with fluoxetine-resistant MDD to continue treatment with fluoxetine monotherapy, undergo a switch to olanzapine monotherapy, or receive olanzapine augmentation for 8 weeks. Greater remission rates were reported for patients who received augmentation of fluoxetine with olanzapine than patients who received treatment with either fluoxetine or olanzapine monotherapy. However, two subsequent trials also focusing on the use of olanzapine failed to demonstrate the superiority of olanzapine plus fluoxetine versus fluoxetine monotherapy for patients with nortriptyline- or venlafaxine-resistant MDD.9,10 In 2006 alone, however, seven new double-blind, placebo-controlled trials focusing on the use of adjunctive olanzapine (included two trials),11 risperidone,12,13 or quetiapine14-16 were either presented at major scientific meetings or published. Six of these demonstrated greater efficacy for adjunctive treatment with an atypical antipsychotic than placebo in TRD (Thase and colleagues11 reported two separate but identical trials of olanzapine augmentation of fluoxetine, and found olanzapine augmentation to be effective in one but not the second study).

These results appear to be very promising for the use of this treatment strategy. In fact, a meta-analysis pooling data from these first 10 studies demonstrated greater remission rates for patients who received adjunctive atypical antipsychotics than placebo (Figure 1).17 However, tolerability appeared to be a considerable limitation of this treatment approach, with a greater than three-fold higher rate of premature discontinuation of treatment for patients who received atypical augmentation than those who received placebo (37% vs. 12%). While these discontinuation rates appear somewhat high, STAR*D2 found that discontinuation due to intolerance increased with each treatment failure. For example, at levels 3 and 4, dropout rates were 25.6% and 30.1%, respectively.18-20 Thus, the higher rates in the atypical trials may reflect inclusion of more resistant patients. Other more serious side effects, such as weight gain, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, glucose dysregulation, metabolic syndrome, hyperprolactinemia, neuroleptic malignant syndrome, and tardive dyskinesia have not been as well studied in the augmentation trials and would benefit from longer duration trials in any case. Further, there is a paucity of data from randomized, double-blind, placebo-controlled trials focusing on the risk of such adverse events during adjunctive therapy with atypical antipsychotics specifically for patients with MDD.

 

 

Placebo-controlled trials focusing on the use of olanzapine report significantly higher rates of somnolence,8,10 hypersomnia,11 peripheral edema,10,11 dry mouth,11 and tremor9 among patients treated with the combination of olanzapine and fluoxetine versus those treated with fluoxetine monotherapy. In addition, significantly greater weight-gain (mean difference in change in weight between treatment groups of 5.79 Kgr,8 4.7 Kgr,9 4.3 Kgr,10 and 4.5 Kgr,11) increases in cholesterol (mean difference in the degree of change in levels between treatment groups of 0.3 mmol/L9 or 0.4 mmol/L,10) triglyceride (mean difference in the degree of change in levels between the two treatment groups of 23.9 mg/dL,12) and prolactin levels (mean difference in the degree of change in levels between the two treatment groups of 0.31 mmol/L10) were reported among patients treated with the olanzapine plus fluoxetine versus those treated with fluoxetine monotherapy. There was no significant difference in the change over time in QTc interval duration,9-11 akathisia or dyskinesia scores,9,10 or mean serum glucose levels9-11 between the two treatment groups.

In contrast to studies focusing on the use of olanzapine, placebo-controlled trials focusing on the use of risperidone do not report on the majority of relevant safety and tolerability outcomes (ie change in cholesterol, triglyceride, prolactin, glucose levels, or QTc interval). Significantly greater weight gain (mean difference in change in weight between treatment groups of 2.5 lbs12 or 4.0 lbs13) was reported among patients treated with the risperidone plus antidepressants versus those treated with antidepressants alone. Finally, it is worth noting that, unlike studies employing the use of either olanzapine or risperidone, the three placebo-controlled trials focusing on the use of quetiapine14-16 were too small and underpowered to allow for an accurate assessment of the safety and tolerability of this treatment approach.

More recently, two separate but identical, double-blind, placebo-controlled trials investigating the use of adjunctive aripiprazole in MDD were published.21,22 These studies enrolled MDD patients resistant to 1–3 historic antidepressant trials, followed by an 8-week, open-label trial with either a selective serotonin reuptake inhibitor (SSRI; including fluoxetine, sertraline, paroxetine, or escitalopram, but not fluvoxamine) or the serotonin norepinephrine reuptake inhibitor venlafaxine. Non-responders to antidepressant monotherapy then randomized to have had either aripiprazole or placebo added to their antidepressant treatment regimen, for a total of 6 weeks. In both trials, a statistically significant difference in remission rates was observed (Figure 2),21,22 results that led to the approval by the Food and Drug Administration of aripiprazole as adjunctive therapy for TRD. This was the first ever approval for the use of any medication for TRD by the FDA. Significantly more patients treated with adjunctive aripiprazole than those treated with antidepressant monotherapy complained of akathisia,21,22 restlessness,22 insomnia,22 fatigue,22 tremor,22 and constipation.22 There was also significantly greater weight gain (mean difference in change in weight between treatment groups of 1.05 Kgr22 or 1.67 Kgr21), as well as greater increases in the scores of scales measuring the severity of extrapyramidal side-effects (Barnes Akathisia Scale; Simpson-Angus scale21,22) among patients treated with adjunctive aripiprazole than those treated with antidepressant monotherapy. There was no significant difference in the change in prolactin levels22 or QTc interval duration21 between these two treatment groups.

 

While studies conducted so far are in support of this treatment strategy, several questions remain. First, it is unclear whether all atypical antipsychotics are efficacious as adjunctive treatments in MDD and, if so, whether they are equally efficacious. For example, at the present time, evidence supporting the use of adjunctive ziprasidone in MDD derives exclusively from open-label,23 but not placebo-controlled, trials. However, a randomized, double-blind, placebo-controlled trial focusing on the use of ziprasidone as adjunctive treatment to the SSRIS escitalopram for escitalopram-resistant MDD is currently underway (NCT00633399).24

In addition, very little is known regarding the long-term efficacy of this therapeutic approach. Rapaport and colleagues25 examined patients with MDD who failed to experience sufficient symptom improvement following treatment with citalopram monotherapy, who then went on to receive adjunctive treatment with risperidone for a total of 4–6 weeks. Patients who experienced a significant improvement in depressive symptomatology following citalopram-risperidone treatment were then randomized, under double-blind conditions, to either continue to receive the combination of risperidone and citalopram or to continue with citalopram but to undergo a substitution of risperidone for placebo for a total of 24 weeks. Relapse rates between the two groups were not statistically significant (53.3% following continued treatment with risperidone and citalopram versus 54.6% following citalopram monotherapy). Of note, however, the unusually high rate of initial non-response to citalopram, 89%, followed by a high rate of remission with open label augmentation, 59%, suggest that the randomized population may have been enriched with placebo responders, resulting in the lack of “separation” in efficacy (differential relapse rates) between the two treatment groups (patients who continued on risperidone plus citalopram versus those who continued on risperidone plus placebo). Finally, much remains to be determined regarding the short- and long-term tolerability and safety of this treatment strategy in MDD populations, as well as how this treatment compares (both in terms of efficacy and tolerability) with other therapeutic strategies for TRD.

Conclusion

In light of the challenge which TRD poses to clinicians and patients, there is an urgent need to develop novel treatment strategies. From the evidence available to date, it appears that augmentation of antidepressants with atypical antipsychotics is effective in some cases of TRD, at least during the acute phase of treatment. However, the long-term efficacy, tolerability, and safety of this treatment has not yet been established. In particular, the risk of metabolic (weight gain and hyper- or dyslipidemia), endocrine (hyperprolactinemia), cardiac (QTc prolongation and arrhythmogenesis), and central nervous system (akathisia, parkinsonism, tardive dyskinesia, neuroleptic malignant syndrome) adverse events during treatment with these agents specifically in MDD populations needs to be better quantified. Further research in necessary to examine the efficacy, safety, and tolerability of augmentation of antidepressants with atypical antipsychotics for TRD. In addition, further research is also required examining how this treatment strategy compares, both in terms of efficacy as well as tolerability/safety, with other treatment strategies for TRD. PP

 

References

1.    Fava M, Rush AJ. Current status of augmentation and combination treatments for major depressive disorder: a literature review and a proposal for a novel approach to improve practice. Psychother Psychosom. 2006;75(3):139-153.
2.    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):1905-1917.
3.    Papakostas GI. Augmentation of standard antidepressants with atypical antipsychotic agents for treatment-resistant major depressive disorder. Essent Psychopharmacol. 2005;6(4):209-220.
4.    Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors, focus on newer generation compounds. Life Science. 2000;24;68(1):29-39.
5.    Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28(8):1400-1411.
6.    Schmidt AW, Lebel A, Howard HR Jr, Zom SH. Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol. 2001;425(3):197-201.
7.    Burris KD, Molski TF, Xu C, et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002;302(1):381-389.
8.    Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry. 2001;158(1):131-134.
9.    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):1289-1297.
10.    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):364-372.
11.    Thase ME, Corya SA, Osuntokun O, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. J Clin Psychiatry. 2007;68(2):224-236.
12.    Mahmoud RA, Pandina GJ, Turkoz I, Kosik-Gonzalez C, Canuso CM, Kujawa MJ, Gharabawi-Garibaldi GM. Risperidone for treatment-refractory major depressive disorder: a randomized trial. Ann Intern Med. 2007;147(9):593-602.
13.    Keitner GI, Garlow SJ, Ryan CE, et al. Risperidone augmentation for patients with difficult-to-treat major depression. Paper presented at: the 159th Annual Meeting of the American Psychiatric Association; May 20-25, 2006; Toronto, Canada.
14.    McIntyre A, Gendron A, McIntyre A. Quetiapine adjunct to selective serotonin reuptake inhibitors or venlafaxine in patients with major depression, comorbid anxiety, and residual depressive symptoms: a randomized, placebo-controlled pilot study. Depress Anxiety. 2007;24(7):487-494.
15.    Khullar A, Chokka P, Fullerton D, McKenna S, Blackman A. Quetiapine as treatment of non-psychotic unipolar depression with residual symptoms: double blind, randomized, placebo controlled study. Paper presented at: the 159th Annual Meeting of the American Psychiatric Association; May 20-25, 2006; Toronto, Canada.
16.    Mattingly GW, Ilivicky HJ, Canale JP, Anderson RH. Quetiapine augmentation for treatment-resistant depression. Paper presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-25, 2006; Toronto, Canada.
17.    Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68(6):826-831.
18.    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):1161-1172.
19.    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):1519-1530.
20.    McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531-1541.
21.    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;68(6):843-853.
22.    Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, Trivedi MH, Thase ME, Berman RM. 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;28(2):156-165.
23.    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. 2004b;65(2):217-221.
24.    ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed September 15, 2008.
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):2505-2513.

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