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Treatment-Resistant Depression -- Part III: Switching Antidepressants vs. Conventional Augmentation Strategies

 

 

 

George I. Papakostas, MD
Associate Professor of Psychiatry, Harvard Medical School; Director, Treatment-Resistant Depression Studies, Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital

 

First published in Psychiatry Weekly, April 27, 2009

This is the final installment of a three-part series covering treatment-resistant depression (TRD). Part I, by Dr. John O'Reardon, and Part II, by Dr. Michael Thase, cover the scope and clinical spectrum of TRD, and augmentation strategies, respectively.

 

CME Course Director

Dr. James C.-Y. Chou, MD. Associate Professor of Psychiatry at Mount Sinai School of Medicine

Accreditation Statement

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This activity has been planned and implemented in accordance with the Essential Areas and policies 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 1 AMA PRA Category 1 Credit™. 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.

Statement of Need

Although numerous clinical trials have demonstrated the clinical efficacy and safety of antidepressant drugs, their overall efficacy in MDD is, at best, modest. One meta-analysis, in particular, revealed that ~50% of patients with MDD receiving antidepressants experienced a clinical response (=50% reduction in symptoms). It is common for clinicians to resort to second-, third-, and sometimes fourth-line treatment strategies to reach full remission of a depressive episode.

Augmentation of antidepressants with an atypical antipsychotic is a common polypharmacy strategy in the treatment of MDD. Newer “atypicals” appear to be better tolerated than older “typical” antipsychotics. Some atypical antipsychotics possess affinity for the 5-HT1D receptor or the 5-HT1A receptor, both of which are of interest to treating depressive symptoms.

A series of clinical trials, conducted over the past decade, evaluated the efficacy of numerous atypical augmentation strategies for the treatment of MDD, finding, in general, that adjunctive use of atypicals is more effective than placebo at bringing about remission or response in patients with TRD. Tolerability, however, is still an area of question.

There is an urgent need to continue to expand the repertoire of treatments available for MDD, including TRD. The long-term efficacy and safety data for atypical augmentation strategies must still be established, and these strategies must be compared to other augmentation or switching strategies.

Target Audience

This activity will benefit psychiatrists, hospital staff physicians, and office-based “attending” physicians from the community.

Learning Objectives

  • Develop second-, third-, or fourth-line treatment strategies for patients with TRD (eg, who have not responded to an initial adequate antidepressant trial)
  • Appraise the data comparing treatment response rates of antidepressant monotherapy to augmentation strategies, noting which polypharmacy strategies have been approved for such an indication, and were shown to be safe and effective in clinical trials
  • List the relative advantages and disadvantages of polypharmacy—combination and augmentation—strategies for TRD treatment

Faculty Disclosure

For the past or future 12 months (date disclosed: 2/13/2009), George I. Papakostas, MD, has served as a consultant/advisor to Eli Lilly, GlaxoSmithKline, Otsuka, Pierre Fabre Medicament, and Shire; has served on the speaker board for Bristol-Myers Squibb; has received research support from Bristol-Myers Squibb, Pamlab, Pfizer, Precision Human Biolaboratories, and the National Institute of Mental Health; and has received honoraria from Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Jannsen-Cilag, Lundbeck, Otsuka, Pamlab, Pfizer, Pierre Fabre Medicament, and Servier. Dr. Papakostas discusses off-label investigational use of olanzapine, risperidone, ziprasidone, and quetiapine as adjunctive therapy for major depressive disorder.
James C.-Y. Chou, MD, has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Janssen, and Pfizer.
Sanjay J. Mathew, MD, has served as an advisor/consultant to AstraZeneca and Jazz.

Activity Review Information

The activity content has been peer-reviewed by Sanjay J. Mathew, MD, Assistant Professor of Psychiatry at Mount Sinai School of Medicine. Review Date: February 19, 2009.

Acknowledgement of Commercial Support

Funding for this activity has been provided by an educational grant from Eli Lilly and Company.

To Receive Credit for this Activity

Read this poster, reflect on the information presented, and then complete the CME posttest found in the accompanying brochure or online (mbl.cmeoutreach.com). To obtain credit you should score 70% or better. The estimated time to complete this activity is 1 hour.

Release Date: April 27, 2009

Termination Date: April 30, 2011

 

 

Introduction

Antidepressants have been available since the 1950s, when the monoamine oxidase inhibitors were first discovered. Since then, our armamentarium of antidepressants has progressively expanded with the discovery of the tricyclic antidepressants (TCAs) in the 1960s, the selective serotonin reuptake inhibitors (SSRIs) in the 1980s, and, subsequently, the serotonin norepinephrine reuptake inhibitors (SNRIs), and other agents possessing a diverse mechanism of action including buproprion, and mirtazapine.

Numerous clinical trials have repeatedly demonstrated the safety and efficacy of these antidepressants over time, but there has also been an accumulation of evidence suggesting that their overall efficacy in major depressive disorder (MDD) is, at best, modest. For example, a meta-analysis1 of all published, randomized, double-blind, placebo-controlled trials focusing on the use of antidepressants for the treatment of MDD revealed that ~50% of all patients treated with antidepressants experience a clinical response, conventionally defined as a 50% or greater reduction in depressive symptoms.

There also appears to be a limitation in the margin of efficacy of these agents, compared to placebo. More than one in three patients who received placebo in clinical trials1 experienced a clinical response, reducing the relative advantage of antidepressants versus placebo to approximately one in six patients, in terms of response rates (ie, the difference in response rates between the two groups).

Naturalistic studies2 have, however, demonstrated considerable response and remission rates with antidepressant treatment, although limitations are still apparent. In practice, patients usually become progressively better, but symptoms of depression often remain at treatment endpoint.

One naturalistic study2 examined treatment outcome following several successive therapies for patients with MDD enrolled in one of two academically-affiliated depression specialty clinics, finding that only ~50% of patients with depression had achieved a full remission of their depression at the time of survey. Therefore, although it is clear that pharmacologic and non-pharmacologic antidepressant treatments can be effective, clinicians may often need to resort to second-, third-, or fourth- line treatments to achieve full symptomatic remission. Polypharmacy strategies represent a popular treatment option for patients with antidepressant-resistant MDD.

Polypharmacy for Depression

Polypharmacy strategies for antidepressant-resistant MDD can include combination therapy (adding a second antidepressant to the treatment regimen), or augmentation therapy (adding a non-antidepressant drug to the treatment regimen). Combination strategies best studied in antidepressant-resistant MDD include the addition of the norepinephrine-dopamine reuptake inhibitor, bupropion; the serotonin-norepinephrine receptor antagonists (SNRAs), mirtazapine and mianserin; or the TCA, desipramine. Common augmentation strategies include the use of lithium, triiodothyronine (T3), buspirone, pindolol, omega-3 fatty acids, folic acid and methylfolate, and s-adenosylmethionine (Figure 1).

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There has been intense investigation over the past decade on the use of atypical antipsychotics as augmenting agents in MDD. By 2009, more controlled studies will have focused on the use of atypicals as augmentation of newer antidepressants (SSRIs and SNRIs) than for any other agent. There are several reasons for this. First, since antidepressant monotherapy is not always effective, there is a clinical need to further develop antidepressant augmentation strategies. Secondly, the atypical agents appear to be better tolerated—at least with respect to the emergence of extrapyramidal side effects (EPS)—than many of the older “typical” antipsychotic agents. Finally, the atypicals possess a robust neuropharmacologic profile, which is thought predictive of potential antidepressant efficacy.3

All atypical antipsychotics are varyingly effective at inhibiting the D2 receptor, which is a property they share with the typical antipsychotics. However, unlike the typical antipsychotics, the atypical antipsychotics appear to inhibit the 5-HT2A receptor, a mechanism shared by several antidepressants, including mirtazapine, agomelatine, nefazodone, and trazodone.4

Some atypical antipsychotics have additional pharmacologic properties of particular interest to MDD. For example, ziprasidone and risperidone possess affinity for the 5-HT1D receptor,5,6 a mechanism implicated in antidepressants,7 while ziprasidone and aripiprizole possess affinity for the 5-HT1A receptor.5,6 The presence of significant 5-HT1A receptor affinity is also relevant to the development of novel antidepressant therapies, since 5-HT1A agonists, such as buspirone and gepirone, have been found effective as monotherapy for MDD in several randomized trials.8-11

In addition, ziprasidone appears to be as potent as some of the TCAs at inhibiting the reuptake of serotonin and nonrepinephrine12—the mechanism of action of the SNRI antidepressants, including venlafaxine, duloxetine, desvenlafaxine, and milnacipran. Aripiprazole also appears to act as a dopamine receptor agonist/antagonist, a property also thought to be predictive of antidepressant activity in humans.13

Efficacy Trials

The first-ever study to examine the role of the atypical antipsychotics as augmentation in MDD was a case series compiled by Ostroff and Nelson,14 in which the authors described a series of patients with MDD whose symptoms did not improve with SSRI monotherapy, and who then had low-dose (0.5–1 mg) risperidone added to their antidepressant treatment regimen. Notably, all patients experienced resolution of their depressive symptoms within a week of combination treatment. These improvements were sustained until several months later.

This premier report14 prompted a number of randomized, double-blind trials all designed to further reveal whether the atypical antipsychotics could have a place in our treatment armamentarium for MDD.

These early studies, however, presented conflicting outcomes. A small pilot study showed that olanzapine augmentation of fluoxetine was more effective than fluoxetine monotherapy for patients with fluoxetine-resistant depression.15 However, two subsequent studies,16,17 both focusing on olanzapine, did not find any differences in efficacy between patients who were treated with olanzapine plus fluoxetine versus patients who were treated with fluoxetine monotherapy. In retrospect, it has been suggested that methodological limitations in these two latter studies may have contributed to their equivocal findings. Specifically, in those two trials, nortriptyline- or venlafaxine-resistant patients were switched to fluoxetine plus olanzapine versus fluoxetine monotherapy, as opposed to the more traditional design of adding olanzapine versus placebo to fluoxetine-resistant patients.15

Seven additional studies were conducted and published soon thereafter addressing the question of whether the atypical antipsychotics are effective as adjunctive therapy in MDD. Two trials focused on the use of olanzapine,18 two on risperidone,19,20 and three on the use of quetiapine.21-23 These trials employed the more traditional study design similar to the original controlled trial by Shelton and colleagues.15 All but one of these seven newer studies found that the use of the atypical antipsychotics was more effective than placebo at enhancing antidepressant effects of the SSRIs or venlafaxine.

A meta-analysis24 was conducted soon thereafter in attempt to reconcile the positive, and equivocal, findings of these 10 trials. Its results essentially demonstrated that adjunctive use of atypical antipsychotics was more effective than adjunctive use of a placebo pill at bringing about treatment response or remission for patients who had not experienced sufficient symptom improvement following an adequate trial of antidepressant monotherapy. Pooled response rates were 57% for patients taking an adjunctive atypical versus 35% for patients with an adjunctive placebo (Figure 2).

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At least four additional trials were since conducted. Two focused on the use of aripiprazole,25,26 both demonstrating a greater resolution of depressive symptoms for antidepressant-resistant patients treated with adjunctive aripiprazole than placebo. The results of these two aripiprazole-based studies led to the approval of aripiprazole as adjunctive therapy for antidepressant-resistant MDD by the US Food and Drug Administration (FDA). This was the first ever FDA approval for the use of any medication as augmentation for MDD (Figure 3).

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Two other studies27,28 focused on the use of quetiapine augmentation of antidepressants. These studies examined two separate doses of quetiapine (150 mg or 300 mg). One study28 found the 300 mg dose to be more effective than placebo, but not the 150 mg dose. The second study27 showed that both doses were more effective than placebo. Although quetiapine appears to be an effective adjunctive agent for MDD, minimally effective and optimal doses of quetiapine for this indication remain unclear.

Evaluating Efficacy Versus Tolerability

Adjunctive atypical antipsychotics are clearly an effective treatment strategy and remain the best-studied treatment strategies for antidepressant-resistant MDD, to date. Tolerability, however, is still an area of question. Antipsychotics, in general, have been implicated in several endocrinologic and metabolic disturbances, including hyperprolatinemia, weight gain, lipid dysregulation, and glucose dysregulation.29 Treatment with atypical antipsychotics can also result in the emergence of bothersome and uncomfortable EPS, including restlessness, akasthisia, and dystonic reactions,30 although to a lesser degree than the earlier typical antipsychotics.31 There is also the question of whether—and, if so, to what degree—atypical antipsychotics contribute to the emergence of rare but far more serious EPS-related adverse events, including tardive dyskinesia, and neuroleptic malignant syndrome, specifically in patients with MDD.

An additional disadvantage of using atypical antipsychotics in MDD is that, while they have been proven to be effective as augmenters for patients who have failed =2 treatments (most of the controlled trials cited in this article focus on patients who have not experienced sufficient symptom improvement to two or more consecutive antidepressant monotherapy trials), it is unknown whether atypical augmentation is an effective strategy for patients who have failed only one treatment trial. Finally, the long-term efficacy and tolerability of this treatment strategy has not been established (Figure 4).

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To date, there is only one published, placebo-controlled trial focusing on the long-term efficacy of atypical augmentation for MDD.32 In that study, patients with citalopram-resistant depression received open-label risperidone augmentation for 4-6 weeks. Citalopram-risperidone remitters then entered a 24-week, double-blind, treatment phase during which they were randomized to either continue therapy with the citalopram-risperidone combination, or undergo a placebo-substitution of risperidone and continue therapy with citalopram alone. This study did not demonstrate a difference in relapse rates between patients receiving adjunctive risperidone versus placebo, but the rather high rate of initial non-response to open-label citalopram (~89%), followed by a relatively high rate of remission following open label augmentation with risperidone (~59%), suggests that the population randomized to continued treatment with risperidone versus double-blind substitution of risperidone with placebo may have been enriched with “placebo” responders. This would have been responsible for the lack of difference in relapse rates between the two treatment groups (patients who continued on risperidone plus citalopram versus those who continued on risperidone plus placebo).

Conclusion

There is an urgent need to continue to expand the repertoire of treatments available for MDD, including antidepressant-resistant MDD. The weight of the evidence from randomized clinical trials on the use of atypical antipsychotics as adjunctive therapy for MDD suggests that this strategy can be quite effective for patients with antidepressant-resistant MDD. In fact, this line of investigation led to the approval of the first-ever pharmacologic agent indicated specifically for adjunctive therapy in MDD. The long-term efficacy, safety, and tolerability of this strategy have not yet been well established. In addition, the relative efficacy, safety, and tolerability of this versus other treatment strategies for antidepressant-resistant MDD have not been studied. Further studies are needed to better clarify the role of the atypical antipsychotics as antidepressants.

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References

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