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Use of Atypical Antipsychotics for Treatment-Resistant Major Depressive Disorder George I. Papakostas, MD, and Richard C. Shelton, MD

Corresponding author George I. Papakostas, MD Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, WACC #812, Boston, MA 02114, USA. E-mail: [email protected] Current Psychiatry Reports 2008, 10:481–486 Current Medicine Group LLC ISSN 1523-3812 Copyright © 2008 by Current Medicine Group LLC

Despite the progressive increase in the number of pharmacologic agents with potential antidepressant activity, many patients suffering from major depressive disorder (MDD) continue to be symptomatic. Clearly, an urgent need exists to develop safer, better tolerated, and more effective treatments for MDD. Use of atypical antipsychotic agents as adjunctive treatment for treatment-resistant MDD (TRD) represents one such effort toward novel pharmacotherapy development. Atypical antipsychotic agents have been hypothesized to be beneficial in treating mood disorders, including TRD, as a result of their complex mechanisms of action. After an initial series of positive case reports, series, and small clinical trials, subsequent larger-scale projects have yielded conflicting results. However, more recently, larger-scale clinical trials have supported the effectiveness of at least some of these medications. This review summarizes the existing data regarding the effectiveness of these medications in treating TRD, including biochemical rationale and clinical data.

Introduction Despite the progressive increase in the number of available antidepressants, many patients suffering from depression continue to be symptomatic. For example, in the fi rst level of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only about 30% of patients had achieved remission of their depressive episode after up to 12 weeks of therapy with citalopram [1]. Moreover, it was recently reported that as many as half of all patients enrolled in two academic-based depression specialty clin-

ics did not achieve remission despite receiving a series of adequate trials of antidepressant therapies [2]. To complicate matters further, residual symptoms among remitters are common and associated with poorer psychosocial functioning [3] and increased relapse rates [4]. Yet little consensus exists among psychiatrists regarding optimizing treatment for patients with incomplete response. Generally, management of treatment-resistant major depressive disorder (TRD) can involve pharmacologic and nonpharmacologic interventions, such as the use of cognitive-behavioral psychotherapy [5••], electroconvulsive therapy [6], vagus nerve stimulation [7], and transcranial magnetic stimulation [8]. Pharmacologic interventions can involve increasing the dose of an antidepressant [9], switching to a second antidepressant [10–13], or using adjunctive pharmacotherapeutic strategies. When a second antidepressant is added to an existing antidepressant, this is termed combination pharmacotherapy. When a nonantidepressant agent is added, this is termed augmentation treatment. Combination strategies can involve adding bupropion [14], mirtazapine [13,15], and tricyclic antidepressants [9,16] to an antidepressant treatment regimen. Augmentation strategies can involve adding lithium [9,17,18], triiodothyronine [18], buspirone [14], pindolol [19], omega-3 fatty acids [20], dopaminergic agents [21,22], folates, or S-adenosyl methionine [23,24] to an antidepressant treatment regimen. Nevertheless, as described previously, despite the broad armamentarium available to clinicians for managing TRD, many patients remain symptomatic despite several adequate pharmacologic and nonpharmacologic trials. Clearly, there is an urgent need to develop safer, better tolerated, and more effective treatments for major depressive disorder. Using atypical antipsychotic agents as adjunctive treatment for TRD represents one such effort toward novel pharmacotherapy development.

Mechanisms of Action Atypical antipsychotics are a heterogeneous group, each with a distinct and complex set of receptor affi nities involving dopaminergic and serotoninergic receptors and

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various effects on noradrenergic, histaminergic, and cholinergic systems. As a result, the receptor-binding profi le of the atypical neuroleptics differs substantially from that of other typical agents. This difference may provide clinical advantages to the atypical antipsychotic agents in therapeutic areas other than in schizophrenia. Specifically, similar to the typical antipsychotic agents, atypical antipsychotics act as dopamine-2 (D2)–receptor antagonists [25]. However, unlike typical antipsychotic agents, atypical antipsychotics, including olanzapine; quetiapine; risperidone; ziprasidone [25]; and, to a much lesser extent, aripiprazole [26], act as serotonin-2 (5-HT2)–receptor antagonists. Ziprasidone [25] and aripiprazole [26] also act as serotonin-1A (5-HT1A)–receptor agonists, whereas ziprasidone and risperidone [25] act as serotonin-1D (5-HT1D) agonists. Antagonism of 5-HT1D, a presynaptic autoreceptor inhibiting serotonin release, indicates potential efficacy in major depression [27], whereas selective 5-HT1A–receptor partial agonists, such as gepirone [28], have shown antidepressant effects in clinical trials. Similarly, 5-HT2 –receptor antagonists, such as trazodone [29] and nefazodone [30], also have shown antidepressant effects. Aripiprazole and ziprasidone have other unique neurochemical properties that distinguish them from the other atypicals. Aripiprazole is a potent dopamine D2-receptor partial agonist, blocking D2 receptors under hyperdopaminergic conditions while acting as a D2 agonist under hypodopaminergic conditions [31–35]. Ziprasidone has been shown to inhibit the neuronal uptake of 5-HT and norepinephrine in a way comparable to the antidepressant imipramine [36].

Clinical Effects of Atypical Antipsychotics in Treatment-Resistant Depression The neurochemical effects described previously led to the testing, initially, of atypical antipsychotics for cognitive and mood symptoms associated with schizophrenia. This subsequently led to the evaluation of atypicals for mood symptoms in TRD and bipolar depression. This section reviews the data supporting effects of these drugs individually and focuses primarily on controlled clinical trials.

Olanzapine The fi rst controlled test of the effects of an atypical in TRD was a small study with olanzapine that compared the effects of olanzapine alone (ie, olanzapine + placebo), olanzapine plus fluoxetine, and fluoxetine alone in treating TRD [37]. All participants had previously failed adequate trials of a selective serotonin reuptake inhibitor (SSRI) and a non-SSRI antidepressant, as well as a prospective treatment period with fluoxetine alone (up to 60 mg/d). Nonresponders (n = 28) to this run-in treatment then were randomly assigned to one of the three condi-

tions in a double-blind fashion. The average maximum doses in the double-blind period were as follows: 12.5 mg/d for olanzapine alone; 52 mg/d for fluoxetine alone; and 13.5 and 52 mg/d, respectively, for the olanzapine and fluoxetine combination. The continuation of fluoxetine for this period yielded essentially no further improvement. Olanzapine administered alone achieved a modest benefit over fluoxetine, whereas the olanzapine plus fluoxetine combination resulted in robust and significantly greater improvement in depressive symptoms than either monotherapy. Remission, defi ned as a 17-item Hamilton Depression Rating Scale (HAM-D) score of 7 or less, was achieved in 60% of patients receiving the combination, 25% receiving olanzapine alone, and 20% receiving fluoxetine alone. Two large-scale clinical trials testing the effects of the olanzapine plus fluoxetine combination were undertaken next. In the fi rst, 500 patients were prospectively treated with nortriptyline; responders were excluded, leading into the double-blind phase [38]. Patients then were randomly assigned to one of four treatment groups for 8 weeks: olanzapine plus placebo, fluoxetine plus placebo, a combination of olanzapine plus fluoxetine, or a continuation of nortriptyline. Olanzapine was dosed in groups at 6 to 12 mg/d and fluoxetine at 25 to 50 mg/d. The combination of olanzapine and fluoxetine produced a rapid effect relative to the other groups. However, the groups did not differ at end point. Several design and execution factors may have affected these results. Patients had failed only one adequate trial of an SSRI before entry. The doses of olanzapine and fluoxetine were lower than in the previous study (mean maximal dose of olanzapine, 8.5 mg/d; mean maximal dose for fluoxetine, 36.5 mg/d). Furthermore, the use of nortriptyline may have been problematic. Although the mean dose in the initial phase was respectable (104.6 mg/d), many patients achieve their maximum dose relatively late in phase 1. Given the delay until maximum response to antidepressant treatment, the response to the dose achieved before phase 2 may have been experienced after the start of this period. A second study [39] using venlafaxine as a comparator suffered from many of the same design problems and is not reviewed in detail here. Despite these discouraging results, two subsequent large-scale trials undertaken [40] were of similar design to the original study by Shelton et al. [37]. In each, patients with a single drug failure were treated prospectively with fluoxetine. Those who did not respond were randomly assigned to continuation fluoxetine (+ placebo), olanzapine (+ placebo), or the olanzapine and fluoxetine combination. In one (n = 638), combined olanzapine/fluoxetine produced no greater effect than either monotherapy. However, the fluoxetine monotherapy condition produced a robust effect by study’s end, indicating another failed trial. However, the second project (n = 675) confi rmed the more robust effect of combined olanzapine/fluoxetine in treatment-resistant unipolar major depression compared

Atypical Antipsychotics for Treatment-Resistant Major Depressive Disorder Papakostas and Shelton

with olanzapine or fluoxetine monotherapy. The pooled analysis of both studies also showed a significantly superior effect of the combination. Meanwhile, a successful trial of the combination was tested in bipolar I depression (non–treatment-resistant), leading to US Food and Drug Administration (FDA) approval for this indication [41].

Risperidone The fi rst published report of the effectiveness of an atypical antipsychotic in TRD was with risperidone [42]. In this case series, eight patients who failed to respond to an adequate trial of an SSRI were given risperidone in an open fashion, and all experienced a rapid and robust effect. However, there were no controlled clinical trial data with risperidone in TRD until recently. In one study [43], 489 patients with one to three prior documented failures were treated prospectively with citalopram, 20 to 60 mg/d. Those who experienced greater than 50% improvement were excluded. The remainder (n = 390) were given 4 to 6 weeks of open-label risperidone, 0.25 to 2.0 mg/d, in combination with citalopram. Patients with 17-item HAM-D scores of 7 or less or a Clinical Global Impression Severity Scale score of 2 or less (ie, “much improved” or “very much improved”) were randomized to risperidone or placebo augmentation (n = 243 remitters, 241 randomized). The primary end point, time to relapse, did not differ between groups. The median time to relapse was 102 days for risperidone plus citalopram and 85 days for placebo plus citalopram. Relapse rates were 53.3% with the combination and 54.6% with continuation of citalopram alone. These data indicate that continuation of risperidone plus citalopram was no more effective for preventing relapse than citalopram alone. In a second controlled trial [44], 463 depressed patients were treated with an optimized trial of an antidepressant. The 274 patients who did not respond were randomized to receive risperidone, 1 to 2 mg/d, or placebo combined with the initial antidepressant for 6 weeks. Mean HAM-D scores dropped from 24.2 to 15.2 in the risperidone group and from 24.6 to 17.5 in the placebo group, a statistically significant difference. In a third controlled trial, Keitner et al. [45] studied 97 outpatients who met the DSM-IV criteria for a unipolar, nonpsychotic major depressive episode and failed to respond or only partially responded to at least a 5-week trial of an adequate dose of antidepressant monotherapy. Patients were randomized to receive adjunctive risperidone or placebo for a total of 4 weeks of treatment. The odds of remitting were significantly better for patients treated with adjunctive risperidone than placebo (52% vs 24%, respectively).

Quetiapine Quetiapine has received FDA approval for treating bipolar depression as monotherapy. However, there are now

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three controlled trials in unipolar TRD. One study (n = 40) evaluated the effects of quetiapine for SSRI/(SNRI) partial response [46]. In this 8-week, double-blind, placebo-controlled study, patients were randomized (2:1 ratio) to receive quetiapine, 200 to 400 mg/d, or placebo along with their previous SSRI/serotonin–norepinephrine reuptake inhibitor (SNRI). Twenty-one of 26 quetiapinetreated patients (80.8%) completed the study, compared with 11 of 14 (78.6%) in the placebo group. At the end of 8 weeks, the quetiapine group had significantly lower 17-item HAM-D scores than the placebo group (8.3 vs 14.7) plus higher response (67% vs 27%) and remission rates (43% vs 15%). In a separate study, McIntyre et al. [47] studied 58 patients who did not experience sufficient symptom improvement after adequate treatment with an SSRI or venlafaxine. Patients were randomized in double-blind fashion to receive adjunctive treatment with quetiapine or placebo for 8 weeks. Eighteen of 29 quetiapine-treated and 16 of 29 placebo-treated patients completed the study. A greater resolution of depressive symptoms was reported among patients treated with adjunctive quetiapine than placebo (mean difference in the reduction in HAM-D scores during treatment was 5.7 points in favor of quetiapine, P < 0.01). Finally, in a third trial, Khullar et al. [48] studied 15 outpatients with TRD (to SSRIs or SNRIs) who underwent augmentation with quetiapine or placebo for 8 weeks. Quetiapine was more effective in reducing depressive symptoms than placebo, as 37% of patients remitted after adjunctive treatment with quetiapine, whereas none remitted after treatment with placebo. Additional largerscale studies of quetiapine therapy for TRD recently have been completed by the manufacturer, although results are not yet available in the published literature.

Ziprasidone An initial open trial supported the effects of ziprasidone in TRD. In this study, 20 patients who had an incomplete response to a trial of an SSRI were treated with ziprasidone in an open fashion [49]. Thirteen (65%) completed the trial; of this group, eight (61.5%) were responders, as defi ned by a 50% improvement in 17-item HAM-D score. Of all the patients randomized, 10 were responders (50%), and 5 remitted (25%). In a second randomized, open trial, adult outpatients who had not responded to a prior trial with an antidepressant were treated prospectively with sertraline, 100 to 200 mg/d, for 6 weeks [50]. Those who failed to achieve a 30% or greater change in Montgomery-Asberg Depression Rating Scale score were randomly assigned to continuation with sertraline; sertraline plus ziprasidone, 80 mg/d (mean dose, 78 mg/d); or sertraline plus ziprasidone, 160 mg/d (mean dose, 129.9 mg/d) for 8 weeks. The mean change from baseline was greater in the two ziprasidone

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aripiprazole, 1.7% for placebo; P > 0.05). The results of a separate study of identical design also demonstrated greater remission rates for adjunctive aripiprazole than placebo-treated patients [53••]. The results of these two trials led to FDA approval of a new indication for aripiprazole as adjunctive treatment to antidepressants for antidepressant-resistant major depressive disorder (Fig. 1). This was the fi rst approval for an adjunctive treatment in major depressive disorder and the fi rst FDA approval for the use of any medication for TRD.

Conclusions

Figure 1. Aripiprazole augmentation for antidepressant-resistant major depressive disorder: results of two identical randomized, double-blind, phase 3 trials (P < 0.05, aripiprazole augmentation vs antidepressant monotherapy for both trials).

augmentation groups (80 mg/d: -5.98 points; 160 mg/d: -8.27 points) than in the sertraline monotherapy group (-4.45 points), although this did not achieve statistical significance. Respective response rates were 19%, 32%, and 10%, and remission rates were 5%, 21%, and 5%. Although these results suggest possible benefit, they did not conclusively support ziprasidone augmentation.

Aripiprazole Until recently, aripiprazole had received relatively little attention in this area. In one open-label trial, 12 patients who had failed to respond sufficiently to an adequate trial of an SSRI were treated with adjunctive aripiprazole in an open fashion for 8 weeks [51]. Nine patients (75%) patients completed the trial; five (55.6%) achieved response (mean change in HAM-D score > 50%), whereas seven of the total group (58.3%) responded. More recently, results of two positive, double-blind, placebo-controlled trials investigating the use of adjunctive aripiprazole in major depressive disorder were published. In the fi rst such study, Berman and colleagues [52••] focused on the use of aripiprazole augmentation for patients resistant to up to three “retrospective” (historical) antidepressant trials. To “confi rm” treatment resistance, those patients underwent an 8-week, openlabel trial with an SSRI (fluoxetine, sertraline, paroxetine, or escitalopram) or an SNRI (venlafaxine). The patients who made insufficient symptom improvement had aripiprazole or placebo added to their SSRI or SNRI regimen under double-blind conditions for a total of 6 weeks. A statistically significant difference in remission rates was also observed, with 26% remission for aripiprazole, compared with 15.7% remission for placebo (P < 0.05). This study also reported relatively low rates of discontinuation due to intolerance in the two treatment groups (2% for

TRD is a common clinical occurrence, and its management poses a formidable clinical challenge for clinicians and patients alike. Despite several pharmacologic and nonpharmacologic treatment options for TRD, many patients remain symptomatic. Thus, there is an urgent need to develop novel treatments for TRD. From the evidence available to date, it appears that augmenting antidepressants with atypical antipsychotics (specifically aripiprazole, olanzapine, quetiapine, and risperidone) can be effective in some patients, at least during the acute phase of treatment. However, the long-term efficacy, tolerability, and safety of this treatment are not yet understood. In particular, the risk of metabolic (weight gain and hyperlipidemia 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 in major depressive disorder needs to be better quantified. Further research also is required into how this compares with other augmentation strategies and other strategies for addressing TRD.

Acknowledgments This work was supported in part by National Institute of Mental Health grant K24 MH01741 (to Dr. Shelton).

Disclosures Dr. Papakostas has received research support from Bristol-Myers Squibb, Forest Pharmaceuticals, the National Institute of Mental Health, Pamlab, Pfi zer, and Precision Human BioLaboratories; has served as a consultant for Bristol-Myers Squibb, Eli Lilly and Company, Evotec, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Pamlab, Pfi zer, Pierre Fabre Medicament, Shire Pharmaceuticals, and Wyeth; has received honoraria from Bristol-Myers Squibb, Eli Lilly and Company, Evotec, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, H. Lundbeck A/S, Pamlab, Pfi zer, Pierre Fabre Medicament, Shire Pharmaceuticals, Titan Pharmaceuticals, and Wyeth; and has served on the speakers’ bureau for Bristol-Myers Squibb and Pfi zer.

Atypical Antipsychotics for Treatment-Resistant Major Depressive Disorder Papakostas and Shelton

Dr. Shelton has received grant/research support from Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceutica, Pfi zer, Sanofi-Aventis, Wyeth-Ayerst Laboratories, AstraZeneca Pharmaceuticals, and Abbott Laboratories; has served as a paid consultant for Pfi zer, Janssen Pharmaceutica, and Sierra Neuropharmaceuticals; and has served on the speakers’ bureau for Bristol-Myers Squibb, Eli Lilly and Company, Janssen Pharmaceutica, Pfi zer, GlaxoSmithKline, Wyeth-Ayerst Laboratories, and Abbott Laboratories.

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