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George I. Papakostas, MD, and Carlos A. Zarate, Jr., MD
Needs Assessment: The contemporary literature largely focuses on a handful of traditional augmentation strategies for treatment-resistant depression (TRD), including bupropion, buspirone, lithium, triiodothyronine, and mirtazapine. Thus, there is a need to update clinicians on potential novel augmentation strategies for TRD. This article summarizes findings on such novel augmentation strategies.

Learning Objectives:
• Describe the urgent need to expand our treatment armamentarium for treatment-resistant depression (TRD).
• Identify several potential new leads of augmentation strategies for TRD.
• Understand the extend of the evidence supporting each of these treatments.

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 Eric Hollander, MD, chair 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: December 13, 2006.

Dr. Hollander reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Sussman is a consultant to and on the advisory boards of GlaxoSmithKline and Wyeth; and has received honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Wyeth.

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 quiz. To obtain credits, you should score 70% or better. Release date: January 2007. Termination date: January 2009. The estimated time to complete all three articles and the quiz is 3 hours.

Primary Psychiatry. 2007;14(1):59-65

Dr. Papakostas is assistant professor of psychiatry at Harvard Medical School in Boston, Massachusetts and Dr. Zarate is chief of the Mood Disorders Research Unit and associate clinical director at the Laboratory of Molecular Pathophysiology at the National Institutes of Health Mark O. Hatfield Clinical Research Center in Bethesda, Maryland.

Disclosure: Dr. Papakostas is a consultant to the Aphios Corporation, Bristol-Myers Squibb, Evotec Ltd, GlaxoSmithKline, Inflabloc, Jazz, PAMLAB LLC, and Pfizer; has received research support from Bristol-Myers Squibb, the National Institute of Mental Health, PAMLAB LLC, and Pfizer; and has received honoraria from Evotec Ltd, GlaxoSmithKline, Inflabloc, Jazz, PAMLAB LLC, Pfizer, and Titan. Dr. Zarate receives research support from the National Alliance for Research in Schizophrenia and Depression and the National Institute of Mental Health.

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:


Despite the progressive increase in the number of available antidepressants, many patients suffering from depression continue to be symptomatic. For example, it has been recently reported that as many as 50% of all patients enrolled in two academic-based depression specialty clinics did not achieve remission despite receiving numerous adequate antidepressant treatment trials. To complicate matters further, residual symptoms among remitters are common and associated with poorer psychosocial functioning and increased relapse rates. In light of the challenge which treatment-resistant depression (TRD) poses to clinicians and patients alike, there is an urgent need to develop novel treatment strategies for TRD which are both safer and more effective than those currently employed. This article focuses on several novel augmentation strategies for TRD.


Despite the progressive increase in the number of available antidepressants, many patients suffering from depression continue to be symptomatic.1 For example, in the first level of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only approximately 30% of patients achieved remission of their depression following up to 12 weeks of therapy with citalopram.2 Moreover, it has been recently reported that as many as 50% of all patients enrolled in two academic-based depression specialty clinics did not achieve remission despite receiving a series of adequate trials of antidepressant therapies.3 To complicate matters further, residual symptoms among remitters are common, and associated with poorer psychosocial functioning4 and increased relapse rates.5 Yet, there is little consensus among psychiatrist regarding optimizing treatment for patients with incomplete response.

For patients who continue to experience depressive symptoms despite an optimal antidepressant trial, two general treatment strategies exist. The first strategy involves switching from one antidepressant to another. The second strategy, termed augmentation, involves adding an antidepressant or non-antidepressant agent to the treatment regimen. Despite the prevalence and consequences of treatment-resistant depression (TRD) and decades of clinical trials focusing on exploring effective and safe treatments for TRD, no gold-standard treatment or treatment consensus among experts has emerged, a fact largely owing to the serious lack of positive double-blind, placebo controlled studies. In fact, the majority of double-blind augmentation studies conducted focusing on a handful of compounds have yielded discouraging results. Such adjunctive compounds have included (but are not limited to) lithium,6 triiodothyronine,7 pindolol,8 and the tricyclic antidepressants (TCAs).6 In addition, small placebo-controlled studies which do identify promising compounds for use as adjunctive treatment in TRD often go unreplicated.9,10 Even less is known regarding the relative efficacy of the various possible switching strategies (ie, from a selective serotonin reuptake inhibitor [SSRI] to either an SSRI, a serotonin norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, or vice-versa). As a result, more often than not, clinicians’ decisions regarding the treatment of TRD is guided by anecdotal reports, case series, uncontrolled trials or, at best, small and unreplicated double-blind studies. Fortunately, the publication of the results of the STAR*D trial in 2006 has greatly improved our understanding of the relative efficacy and tolerability of many traditional augmentation and switch strategies for TRD. Perhaps one of the most interesting findings of STAR*D are the relatively low remission rates achieved with most contemporary pharmacotherapeutic strategies for major depressive disorder (MDD; remission rates, regardless of the definition, ranged from 33% to as low as 6.9%). Such findings highlight the urgent need to identify and develop novel treatments for MDD and TRD, identifying novel treatments for TRD as a necessary next step in order to help further refine the standard of care for depression. This article focuses on several novel augmentation strategies for TRD.

Monoamine-Based Strategies

Atypical Antipsychotics

Atypical antipsychotics are heterogeneous, each with a distinct and complex set of receptor affinities involving dopaminergic and serotonergic receptors as wells as various effects on noradrenergic, histaminergic, and cholinergic systems.11 As a result, the receptor-binding profile of the atypical neuroleptics differs substantially from that of other typical agents. This difference may provide clinical advantages to the atypical antipsychotics in therapeutic areas other than schizophrenia.

Although the results of several open-label trials suggested a potential role of the atypical antipsychotics in TRD,11-13 there has been a paucity of double-blind, placebo-controlled studies confirming whether this treatment strategy is truly effective. Prior to 2006, for instance, only three double-blind, placebo-controlled trials focusing on the use of adjunctive atypical antipsychotics for TRD14-16 had either been published or presented at a major psychiatric meeting (Table).14-22 In the first such study, Shelton and colleagues14 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 symptom resolution was reported for the combination than either monotherapy groups. However, two subsequent, larger studies15,16 also focusing on the use of adjunctive olanzapine in TRD failed to confirm the findings of Shelton and colleagues.14 In 2006 alone, however, seven new double-blind, placebo-controlled trials focusing on the use of adjunctive olanzapine,17 risperidone,18,19 or quetiapine20-22 were presented at two major scientific meetings in 2006. Five out of seven studies revealed greater efficacy for adjunctive treatment with an atypical antipsychotic agent than placebo for TRD (Table).

These results appear to be very promising for the use of this treatment strategy. In fact, a meta-analysis pooling data from all 10 clinical trials (n=1,500) revealed greater response and remission rates for patients who received adjunctive atypical antipsychotic agents than placebo.23 However, although it appears that the sum of the evidence supports a potential role of the atypical antipsychotics as adjuncts in TRD, the evidence is far from definitive. Specifically, three important limitations remain. First, the extent to which the pooled findings apply to each of the five individual atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) remains undetermined, and there appears to be significant variability in the evidence stemming from each of these five agents. For example, none of the studies pooled involved the use of either ziprasidone or aripiprazole. A second limitation is that all 10 clinical trials were funded by the makers of each individual atypical antipsychotic, while none of the studies were funded by independent sources (ie, government sources or private not-for-profit organizations, etc). This may have introduced bias in the meta-analysis.24 Finally, double-blind, randomized studies comparing the safety, tolerability, and efficacy of augmenting with atypical antipsychotics versus other augmentation or switching strategies for TRD have yet to be published. This limitation is particularly important, given the potential adverse events that have been associated with the atypical antipsychotics, including the risk of extrapyramidal symptoms (eg, neuroleptic malignant syndrome and tardive dyskinesia), metabolic abnormalities (eg, glucose dysregulation, dyslipidemia, weight-gain), endocrine abnormalities (eg, hyperprolactinemia), and cardiac conduction abnormalities (eg, QT prolongation). Therefore, in light of the challenge TRD poses to clinicians and patients alike, independently-funded studies establishing the efficacy, safety, and tolerability of each individual antipsychotic in TRD are warranted. If as safe and effective as an antidepressant adjunct, the atypical antipsychotics would represent an attractive option for many of these patients who have had unsatisfactory initial response to standard treatment. If not found to be either safe or effective, this would also be highly informative given the significant proportion of TRD patients who, despite the relative paucity of data from studies of rigorous design, are prescribed atypical antipsychotics off-label.

Dopaminergic Agents

The psychostimulants dextroamphetamine, pemoline, and methylphenidate have been traditionally regarded as presynaptic releasers of dopamine and as blockers of dopamine reuptake.25 Several case series and open-label trials support the use of augmentation of TCAs,26 SSRIs,27,28 and monoamine oxidase inhibitors26,29 with psychostimulants for the treatment of MDD. However, controlled, prospective studies of psychostimulants for depression are limited. Masand and colleagues30 recently presented the results of a double-blind, placebo-controlled trial of methylphenidate augmentation of antidepressants for TRD. There was no difference in efficacy between the two treatment groups. The disadvantages of the use of psychostimulants in depression include weight loss, irritability, agitation, nausea, and their abuse potential.

Bromocriptine and pergolide are Food and Drug Administration-approved for the treatment of Parkinson’s disease. Open-label trials suggest the utility of adjunct (to TCAs) treatment with the dopamine agonist pergolide31,32 and bromocriptine for depression. Pramipexole and ropinirole are selective dopamine (D)2– and D3– receptor agonists25 FDA-approved for the treatment of Parkinson’s disease. An open-label study suggesting adjunct (to SSRIs and TCAs) pramipexole to be effective in the treatment of unipolar and bipolar depression33 was soon followed by two double-blind, placebo-controlled studies of adjunctive pramipexole for bipolar depression.34,35 A double-blind, placebo-controlled trial focusing on the use of pramipexole as an adjunct for TRD is currently underway at Massachusetts General Hospital. Side-effects associated with the use of dopamine-receptor agonists for depression include nausea, insomnia, weight loss, and headaches.

Strategies Focusing on Other Neurotransmitter Systems


Modafinil has a complex mechanism of action and is theorized to work by influencing the function of several neurotransmitter systems, including histamine, γ-aminobutyric acid (GABA), and glutamate.36 Small, open-label trials37,38 suggest the potential utility of modafinil augmentation for the treatment of depression and fatigue in MDD outpatients who experienced insufficient improvement, residual fatigue, and hypersomnia following treatment with various antidepressants. To date, two double-blind, placebo-controlled studies have been published focusing on the use of modafinil for TRD. DeBattista and colleagues39 studied 136 MDD outpatients with incomplete response to a number of antidepressants as well as residual fatigue and/or hypersomnia randomized to receive modafinil augmentation (100–400 mg) versus placebo for a total of 6 weeks. Overall, there was no difference between the two groups at endpoint in terms of the change in depressive symptoms, global improvement, hypersomnia, or fatigue. However, significantly greater improvement in hypersomnia and fatigue early on (weeks 1–2) in modafinil-treated patients compared to those receiving placebo was reported. Fava and colleagues40 studied 311 MDD outpatients with an incomplete response to an SSRI, residual fatigue, and hypersomnia randomized to receive modafinil augmentation (200 mg) versus placebo for 8 weeks. Overall, there was no difference between the two groups at endpoint in terms of the change in depressive symptoms, hypersomnia, or fatigue. However, greater global improvement was reported at endpoint for modafinil patients than those receiving placebo. The disadvantage of this treatment strategy is the lack of data supporting its efficacy in patients with TRD who do not present with symptoms of sleepiness and fatigue.

Opioidergic Agents

Only a small case report41 and a small open-label trial42 have been published focusing on the use of adjunct opiates for the treatment of refractory depression, the latter study reporting a 0% response rate. For the opiate antagonist naltrexone there is only a case report for its use as an adjunctive agent for TRD.43 There is also a small (n=12) open-label trial of tramadol augmentation of SSRIs in SSRI-resistant MDD reporting a 50% response rate following 3 weeks of treatment.44 Tramadol, structurally similar to venlafaxine,45 is a μ-opioid receptor agonist with relatively weak serotonin and norepinephrine reuptake inhibitor properties.46 In addition to the paucity of data, the use of opioid-receptor agonists for TRD is severely limited by their abuse potential.

GABA-ergic Agents

Similarly, there is a small open-label trial47 but no controlled trials of benzodiazepine augmentation for TRD. However, Fava and colleagues40 recently reported greater remission rates during GABA-agonist eszopiclone augmentation of fluoxetine for MDD compared to placebo. Whether augmentation with eszopiclone or other GABA-receptor agonists is an effective strategy for TRD has yet to be determined. Limitations of this strategy include sedation, fatigue, concentration and memory impairment, and the risk of dependence/abuse.

Glutamatergic Agents

Lamotrigine is an inhibitor of glutamate release while riluzole is a glutamate-modulating agent. A double-blind, placebo-controlled study of lamotrigine (25–100 mg/day) augmentation in 23 patients with TRD (MDD and bipolar depression) did not reveal greater improvement in depression severity for lamotrigine. However, global clinical improvement was significantly greater for lamotrigine than placebo.48 An open-label trial of riluzole as monotherapy for TRD was soon followed by open-label trials examining the use of riluzole as an adjunct to antidepressants in treatment-resistant unipolar depression49,50 and lithium in treatment-resistant bipolar depression.51 Double-blind studies on the use of riluzole as an augmentation for TRD have yet to be published.

Only case series and small open-label trials report on the use of adjunctive amantadine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist in mixed MDD and depressed bipolar populations with TRD.52-54 A double-blind, placebo-controlled trial of memantine, a non-competitive NMDA receptor antagonist, did not support its use as monotherapy in non-treatment–resistant MDD.55 However, more recently, Zarate and colleagues56 demonstrated a greater resolution of depressive symptoms at approximately 2 hours lasting 1 week after a single intravenous infusion of the NMDA-receptor antagonist ketamine than placebo in TRD. The main limitation of this treatment strategy involves the potential for uncomfortable cognitive side effects (eg, mild hallucinations, temporary disorientation, concentration difficulties). However, in light of this pivotal work, studies examining whether such effects can be reproduced with the use of more tolerable NMDA-receptor antagonists such as amantadine and/or memantine, and whether such effects can be sustained for longer periods of time, are urgently warranted. Finally, a small (n=22), double-blind, placebo-controlled, cross-over trial involving the use of the antibiotic d-cycloserine, an agonist at the glycine site of the NMDA receptor, as an augmentation for TRD, did not reveal statistically significant therapeutic advantages over placebo-adjuvant treatment.57

Neuroendocrine-Based Strategies


Studies have also explored the potential utility of adjunct testosterone in TRD.58,59 In a double-blind study, 22 hypogonadal men with TRD received either adjunct testosterone (10 g/day of 1% testosterone gel) or placebo for 8 weeks.10 A greater reduction in depressive symptoms was reported in the testosterone group compared to placebo. However, a subsequent, smaller (n=12) double-blind, placebo-controlled study of testosterone gel (1%) augmentation for TRD did not show greater efficacy for testosterone than placebo.60 Potential disadvantages involving the use of androgens for depression include irritability, insomnia, agitation, and the risk of prostate enlargement.


To date, two double-blind, placebo-controlled trials of estrogen augmentation for women with TRD have been published. The first study focuses on the use of estrogen for pre- and post-menopausal women with TRD (TCA-resistant).61 This study did not reveal any difference in efficacy between estrogen and placebo. However, a second study revealed greater resolution of depressive symptoms among perimenopausal women with TRD randomized to receive treatment with adjunctive estrogen when compared to placebo.62 Larger trials are needed to either confirm or refute these findings.59 Disadvantages include the risk of deep vein thrombosis and breast cancer (with long-term use).

Steroids and Steroid Synthesis Inhibitors

Only open-label trials support the role of either steroids63,64 or steroid synthesis inhibitors in TRD.53 However, a double-blind, placebo-controlled trial of metyrapone augmentation of antidepressants demonstrated a greater resolution of depressive symptoms among MDD patients who received adjunctive metyrapone than placebo, although a more rapid response was observed among fluoxetine- and nefazodone-treated patients who received adjunctive metyrapone and placebo.65 However, whether this finding can be replicated in patients with TRD has yet to be determined. Disadvantages of using metyrapone include the risk of adrenal insufficiency and intolerability (nausea, vomiting, hypotension).

Strategies with Miscellaneous Mechanisms of Action

Folates and S-Adenosyl Methionine

Hypofolatemia has been linked to depression and an increased risk of depressive relapse, and has consistently been found to confer an increased risk of poorer response to pharmacotherapy in MDD,66-69 including the specific clinical scenario of augmentation of SSRIs for TRD.12,70 However, only one study explores whether the addition of folate to the psychopharmacologic regimen of SSRI-resistant MDD patients can improve outcome. Among subjects with SSRI refractory depression, Alpert and colleagues71 reported that folinic acid, a form of folate that enters the central nervous system as biologically active methyltetrahydrofolate, was associated with improved response in a proportion of subjects when added to the SSRI in an open trial.

S-adenosyl methionine (SAMe) is one of the metabolic end products of folate.70 The results of an open-trial report a 50% response rate when SAMe (1600 mg/day) was added to the SSRI regimen of SSRI nonresponders.72 Controlled trials for adjunctive folates or oral SAMe in TRD have yet to be published. Two such placebo-controlled trials are currently underway at Massachusetts General Hospital. The major disadvantage of using SAMe or many of the folate formulations for MDD is cost, as they are not routinely covered by health insurance.

Omega-3 Fatty Acids

To date, two double-blind studies have been published regarding omega-3 fatty acids for treatment of TRD. Peet and Horrobin73 reported greater improvement in depressive symptoms among TRD patients who received augmentation with 1 g/day of ethyl-ecosapentanoic acid (ethyl-EPA) versus placebo. However, no difference in outcome between placebo-treated patients and patients treated with 2 or 4 g/day of ethyl-EPA was reported in that study. Finally, Su and colleagues74 reported greater improvements in depressive symptoms of TRD patients following 8 weeks of adjunctive treatment with omega-3 fatty acids (440 mg EPA plus 220 mg docosahexanoic acid) compared to placebo. These preliminary findings await confirmation from larger, more definitive studies. The major disadvantage of using omega-3 fatty acids for MDD is cost, as they are not routinely covered by health insurance.

Other Agents

A small (n=14) double-blind, placebo-controlled study reported greater efficacy for zinc than placebo augmentation of standard antidepressant therapy in MDD.75 Similarly, a small (n=40) double-blind, placebo-controlled study also reported greater efficacy for augmentation of the selective norepinephrine reuptake inhibitor reboxetine with the cycloxygenase-2 inhibitor celecoxib than placebo in MDD.76 More recently, the use of the antimuscarinic agent scopolamine was also evaluated in TRD. In a study which enrolled patients with either unipolar or bipolar TRD, intravenous scopolamine was more effective than placebo in resolving depressive symptoms.77 These three trials have yet to be replicated on a larger scale. Finally, there is only anecdotal evidence to support the use of chromium augmentation of antidepressants for TRD.78


In light of the challenge TRD poses to clinicians and patients, there is an urgent need to develop novel treatment strategies for TRD which are both safer and more effective than those currently employed. Open-label as well as randomized, controlled studies published to date help identify a number of potential candidates of a variety of mechanisms of action for development as adjunctive pharmacotherapies for TRD. Adequately powered, double-blind, placebo-controlled trials are needed to help explore the relative efficacy, safety, and tolerability of these potential new treatments for TRD. PP


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