Jessica Warner, MD

Major depressive disorder (MDD) is a leading cause of disability in North America and in the world. For many patients with depression, full symptom remission remains elusive despite multiple trials of antidepressants. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, half of patients responded to an initial antidepressant trial, whereas a third of patients never achieved remission despite multiple adequate antidepressant trials.

As every clinician knows, these outcomes are in-adequate.

For patients who do not respond to initial pharmacological treatment, several options exist. For the purposes of this article, we focus on psychopharmacological and related interventions. However, we recommend that all of these interventions occur in the context of a comprehensive treatment program that includes medications, psychotherapy, and other interventions.

Standard approaches to pharmacology include the optimization of the current treatment regimen and within-class or between-class switching. Before concluding that an antidepressant has failed, clinicians should ensure that adherence, dose, and duration are sufficient. An antidepressant trial should last at least 6 weeks and be at the minimum established clinically effective dose; some argue that a dose as high as two-thirds the maximum recommended dose is appropriate.

Antidepressant augmentation is another approach. Augmentation using an antidepressant with established efficacy may also be referred to as combination therapy. This may be more effective than other options, but it carries the risks of polypharmacy, such as drug-drug interactions and increased adverse-effect burden.

In this article, we briefly review the current options for pharmacological augmentation in MDD and their associated literature. 

 presents a summary of current augmentation strategies.

Traditional augmentation agents: STAR*D results

 Augmentation with lithium is one of the oldest strategies, and it is believed to work through the enhancement of serotonergic neurotransmission. Findings from 10 placebo-controlled trials of lithium augmentation (at dosages from 600 to 1200 mg/d, with serum levels of 0.5 to 1 mEq/L) indicate that lithium augmentation was more effective than placebo.

 One caveat with the lithium data is that the vast majority of these studies used a TCA as the principal antidepressant agent. Other limitations included variable lithium doses and outcome measures.

The evidence that exists for lithium augmentation of SSRIs is more sobering. Studies by Fava and colleagues

 showed no benefit of this augmentation compared with simply increasing the dose of the primary antidepressant. Additional factors to review when considering lithium augmentation are adverse effects, potential toxicity, and need for serum monitoring. Notably, in STAR*D, when lithium augmentation was compared with thyroid hormone augmentation, the two approaches were equally efficacious, but lithium had a higher adverse-effect burden.

 Thyroid hormone augmentation, typically with triidothyronine (T

) but sometimes with thyroxine, is hypothesized to work by enhancing noradrenergic neurotransmission or correcting a brain bioenergetic deficiency. At a target dosage of 50 Î¼g/d, treatment tends to be well tolerated with few adverse effects. As with lithium, much of the data on T

 augmentation involves TCAs rather than SSRIs.

 and SSRIs often involve concurrent initiation of both agents. Results were mixed from the few available adequately powered studies: 2 were positive and 2 were negative.

 Results from several open-label trials of T

 is as effective as lithium but is better tolerated.

 augmentation usually include baseline measures with regular monitoring of thyroid hormone levels, in addition to a discussion of potential long-term risks associated with T

 supplementation (eg, cardiac and bone disease).

 Bupropion, a norepinephrine/dopamine reuptake inhibitor, is a popular choice as an augmenting agent, perhaps because of its lack of sexual adverse effects. In STAR*D, bupropion augmentation was compared with buspirone (a serotonin-1A receptor partial agonist) augmentation. There are no placebo-controlled data that support bupropion augmentation, and the results of placebo-controlled studies on buspirone augmentation have been negative.

 In STAR*D, these two agents were found to be equally efficacious, but bupropion had fewer adverse effects. Mean dosages were 267 mg/d of bupropion and 41 mg/d of buspirone.

 Mirtazapine, a tetracyclic antidepressant with a complex mechanism of action, including Î±2 and serotonin-2 antagonism, has some evidence as an augmenting agent.

 In STAR*D, mirtazapine was added to venlafaxine extended-release and compared with the MAOI tranylcypromine. Overall, efficacy was low at this stage of STAR*D, and there was no significant difference between the two, although mirtazapine was better-tolerated.

 Topiramate is an agonist at the Î²2 and Î²3 subunits of the Î³-aminobutyric acid receptor and may inhibit glutamate release by antagonizing kainate-type glutamate receptors. While there are limited data regarding its use in augmentation, one small placebo-controlled trial showed significant improvement in depression compared with placebo.

 Results of augmentation studies of lamotrigine, an inhibitor of presynaptic glutamate release, have been negative. These include 2 small placebo-controlled trials and a larger, more recent placebo-controlled trial.

Studies of stimulants for antidepressant augmentation have been negative, despite their initial euphorigenic effect. Two placebo-controlled trials of extended-release methylphenidate augmentation showed no improvement in depression symptoms.

 A study of lisdexamfetamine augmentation is currently under way. Results of studies of stimulant-related compounds have also been negative; modafinil augmentation did not differ from placebo in 2 large trials.

 Atomoxetine, a selective norepinephrine reuptake inhibitor used in ADHD, also showed no effect in a large placebo-controlled trial.

 There is little evidence that supports the use of this class of medication for augmentation. This is compounded by the high risk of stimulant abuse and diversion.

Pindolol is an antihypertensive medication that acts as a nonselective Î²-adrenergic receptor antagonist and serotonin-1A autoreceptor partial agonist, which is a known target of several antidepressant medications. Despite positive results found in open-label trials and a small placebo-controlled trial, results from larger placebo-controlled trials have been negative.

The use of sex hormones as augmentation agents in depression has also been studied, but results have been mixed and there is concern about long-term adverse effects. The results were positive in 1 study of men with low or low-normal testosterone levels, while the results from 2 small trials were negative.

 The results from an open-label trial of estrogen in women and a small trial of estrogen in perimenopausal women were positive, while another trial demonstrated benefit with testosterone but not progesterone or estrogen plus progesterone.

Atypical antipsychotics, which are believed to act by differing mechanisms depending on the specific agent (eg, serotonin-2A and Î±2 antagonism, serotonin-1A agonism, or monoamine reuptake inhibition), have the most evidence to support their use as augmentation agents. However, their effectiveness must be balanced with their high risk of adverse effects, including weight gain, metabolic syndrome, and extrapyramidal symptoms. There are few long-term efficacy and safety data for these agents, and there are no studies that directly compare them with other augmentation agents.

In a meta-analysis of controlled trials of atypical antipsychotic augmentation, Nelson and Papakostas

 found an odds ratio (OR) of 1.69 for response to atypical antipsychotics compared with placebo and an OR of 2.00 for remission; however, the OR for discontinuation because of adverse effects was 3.91.

Among atypical antipsychotics, aripiprazole and quetiapine have FDA approval for adjunctive use in depression treatment. For aripiprazole, 3 large, double-blind, placebo-controlled trials showed significantly improved response and remission rates compared with placebo, with an average dosage of 11 to 12 mg/d.

 In the first two trials, however, there was no improvement in patient-rated scales, only in clinician-rated scales. Later analyses showed a very high rate of medication-induced akathisia, which may or may not be a transient adverse effect.

The results from 2 large registration trials of quetiapine extended-release were positive.

 Pooled analysis showed a significant response in MADRS (Montgomery-Ãsberg Depression Rating Scale) scores compared with placebo.

 One trial that used the immediate-release formulation was negative.

 Significant adverse effects for quetiapine included sedation and weight gain.

The data for other atypical antipsychotics, such as olanzapine and risperidone, are mixed. Of the 5 placebo-controlled studies of the olanzapine-fluoxetine combination, 2 were positive and 3 were negative.

 The weight gain associated with olanzapine use was particularly concerning in these studies. For risperidone, there have been 2 placebo-controlled trials that showed advantage over placebo and 1 that had negative results.

 In addition, a long-term augmentation study showed no difference from placebo in time to relapse or relapse rate.

The results from open-label trials for ziprasidone have been inconclusive.

 To date, there have been no published studies of the newest atypical antipsychotics (paliperidone, iloperidone, asenapine, lurasidone) as augmentation agents, although such studies are ongoing, particularly for asenapine and lurasidone.

 Studies have shown lower rates of depression in persons with diets rich in Ï-3 fatty acids and lower plasma levels of Ï-3 fatty acids in patients with mood disorders compared with controls.

 In one small placebo-controlled trial, combination therapy with citalopram and a blend of 900 mg of eicosapentaenoic acid, 200 mg of docosahexaenoic acid, and 100 mg of other Ï-3 fatty acids was compared with citalopram plus placebo. The results showed a significant improvement in depressive symptoms in patients given citalopram plus the Ï-3 fatty acids.

Creatine is hypothesized to normalize abnormal brain bioenergetics in depression by increasing the cerebral reservoir of phosphocreatine and increasing production of adenosine triphosphate. It may also have neuroprotective antiapoptotic and antioxidant effects. In one placebo-controlled trial of creatine augmentation conducted in women with depression, creatine and escitalopram were started simultaneously. Patients who received creatine had higher remission rates and quicker treatment response than those who received placebo. It was generally well tolerated at a mean dosage of 5 g/d.

S-adenosyl methionine and l-methylfolate.

 Evidence suggests that low folate levels are associated with depression and poorer response to antidepressant treatment, perhaps related to monoamine deficiency. 

-methylfolate are involved in the synthesis of monoamines and are of increasing interest as augmentation agents for depression. A small study of SAMe augmentation in serotonin reuptake inhibitor nonresponders was promising; it showed higher response and remission rates and minimal adverse effects at a target dosage of 1600 mg/d.

-methylfolate are more compelling. Two recent randomized double-blind trials of 

-methylfolate augmentation in SSRI-resistant depression found significant improvement in response rate and change in depressive symptom scores at a dosage of 15 mg/d. Treatment was well tolerated and adverse effects did not differ from placebo.

A dopamine D2/dopamine D3 receptor agonist, pramipexole has been studied as a possible augmentation agent, on the basis of the theory that reduced dopamine neurotransmission might be involved in depression. Three small open-label studies of pramipexole have been promising, but the latter two included both patients with major depression and patients with bipolar depression.

 Results of one recent, modestly sized, controlled study of pramipexole augmentation for depression were negative.

 summarizes the data for the two most promising future augmentation options: glutamate and neuromodulation.

 Not surprisingly, given the high prevalence of treatment-resistant depression, the search for novel augmentation approaches remains an active area of research. Several classes of agents that target melatonin, acetylcholine, and glutamate receptors have had promising results in initial trials but require more evidence before clinical use is a realistic possibility.

The strongest data are for glutamatergic agents, particularly those that target glutamate neurotransmission via NMDA receptor antagonism. Ketamine and ketamine-based compounds are the most anticipated augmentation options. Intravenous ketamine has strong placebo-controlled data in acute antidepressant treatment, and research is actively ongoing to develop an oral ketamine-based compound for antidepressant augmentation.

 Results of a placebo-controlled trial of memantine monotherapy were negative.

 Riluzole, a glutamate release inhibitor that increases glutamate uptake into glial cells, has some evidence of efficacy in small open-label trials without any controlled data.

Drugs in development that target other aspects of the glutamate system include selective NR2B NMDA receptor antagonists, metabotropic glutamate receptor agonists and antagonists, and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid receptor–positive modulators.

 Noninvasive brain stimulation has been investigated for the treatment of mood disorders since the early 1990s. However, recently these efforts have accelerated with the FDA approval of devices for transcranial magnetic stimulation (TMS) for MDD. While neuromodulation options currently are not widely available, we anticipate that because of their strong safety and limited adverse-effect profile, these interventions may become a viable option in augmentation therapy for MDD.

Repetitive TMS (rTMS) uses induced current to modify activity in the dorsolateral prefrontal cortex and depression-related circuits. The data for its use in augmentation are promising. The results of one large open-label study of rTMS with concomitant use of antidepressants were positive.

 A sham-controlled trial found significant but transient improvement in depressive symptoms with rTMS compared with sham from the first week after the 2-week treatment period began until the 4-week follow-up, but not at the 5-week end point.

 Although there is a risk of seizure with rTMS, its incidence has been extremely low in clinical trials and subsequent use.

Transcranial direct current stimulation (tDCS), another novel noninvasive brain stimulation option, involves the use of a low current (typically 2 milliamps) passing through the dorsolateral prefrontal cortex. While results of several studies of tDCS monotherapy have been mixed, one study of tDCS augmentation of sertraline therapy was strongly positive, although mania was induced in a number of patients.

For the augmentation of SSRI treatment in MDD, the most robust evidence is available for atypical antipsychotics, particularly aripiprazole and quetiapine extended-release. However, the serious adverse effects of atypical antipsychotics make it prudent to consider other agents for first-line augmentation therapy; agents should be chosen on the basis of best practice and medical evidence. Supplements, while not traditionally considered augmentation options, have fewer adverse effects and have a growing evidence base supporting their use.

Other options include mirtazapine or referrals for neuromodulation. T

, bupropion, and buspirone are fair options, if one keeps in mind that placebo-controlled evidence of their efficacy with SSRIs is limited. The role of topiramate, lamotrigine, pindolol, pramipexole, and sex hormones is unclear, given the evidence at this time. Data indicate that stimulants do not have a role in augmentation. It makes sense to use lithium only after other agents have failed because of associated long-term risks. Newer options, such as ketamine-based compounds and tDCS, show promise for augmentation, but they would benefit from more rigorous trials before widespread clinical use.

Dr Warner is House Staff Officer in Psychiatry in the department of psychiatry and human behavior and Dr Philip is Assistant Professor of Psychiatry and Human Behavior, both at the Alpert Medical School of Brown University in Providence, RI. Dr Warner reports that she has no conflicts of interest concerning the subject matter of this article. Dr Philip reports that he has received research support from Neuronetics Inc and NeoSync Inc through contracts with Butler Hospital in Providence, RI.

Gaynes BN, Warden D, Trivedi MH, et al. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. 

 Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. 

 Fava M, Rosenbaum JF, McGrath PJ, et al. Lithium and tricyclic augmentation of fluoxetine treatment for resistant major depression: a double-blind, controlled study. 

Fava M, Alpert J, Nierenberg A, et al. Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. 

 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. 

Cooper-Kazaz R, Apter JT, Cohen R, et al. Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial. 

 Posternak M, Novak S, Stern R, et al. A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T

) used to accelerate and potentiate the antidepressant response.

 Appelhof BC, Brouwer JP, van Dyck R, et al. Triiodothyronine addition to paroxetine in the treatment of major depressive disorder. 

Joffe RT, Sokolov ST, Levitt AJ. Lithium and triiodothyronine augmentation of antidepressants.

 Iosifescu DV, Nierenberg AA, Mischoulon D, et al. An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder.

 augmentation of SSRI resistant depression. 

 Kelly TF, Lieberman DZ. Long term augmentation with T

 LandÃ©n M, BjÃ¶rling G, Agren H, FahlÃ©n T. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. 

Trivedi MH, Fava M, Wisniewski SR, et al; STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. 

 Carpenter LL, Jocic Z, Hall JM, et al. Mirtazapine augmentation in the treatment of refractory depression. 

 Carpenter LL, Yasmin S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. 

 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. 

Mowla A, Kardeh E. Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial. 

Prog Neuropsychopharmacol Biol Psychiatry. 

 Santos MA, Rocha FL, Hara C. Efficacy and safety of antidepressant augmentation with lamotrigine in patients with treatment-resistant depression: a randomized, placebo-controlled, double-blind study. 

 Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. 

 Barbee JG, Thompson TR, Jamhour NJ, et al. A double-blind placebo-controlled trial of lamotrigine as an antidepressant augmentation agent in treatment-refractory unipolar depression. 

 Patkar AA, Masand PS, Pae CU, et al. A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. 

 Ravindran AV, Kennedy SH, O’Donovan MC, et al. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial. 

 Dunlop BW, Crits-Christoph P, Evans DL, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: a double-blind, placebo-controlled study. 

 Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness.

 Michelson D, Adler LA, Amsterdam JD, et al. Addition of atomoxetine for depression incompletely responsive to sertraline: a randomized, double-blind, placebo-controlled study. 

 PÃ©rez V, Gilaberte I, Faries D, et al. Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment. 

 Sokolski KN, Conney JC, Brown BJ, DeMet EM. Once-daily high-dose pindolol for SSRI-refractory depression. 

 PÃ©rez V, Soler J, Puigdemont D, et al. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Grup de Recerca en Trastorns Afectius. 

 Perry EB, Berman RM, Sanacora G, et al. Pindolol augmentation in depressed patients resistant to selective serotonin reuptake inhibitors: a double-blind, randomized, controlled trial. 

Geretsegger C, Bitterlich W, Stelzig R, et al. Paroxetine with pindolol augmentation: a double-blind, randomized, placebo-controlled study in depressed in-patients. 

Pope HG Jr, Cohane GH, Kanayama G, et al. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. 

 Orengo CA, Fullerton L, Kunik ME. Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antidepressant therapy. 

Seidman SN, Rabkin JG. Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression.

 Rasgon NL, Altshuler LL, Fairbanks LA, et al. Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. 

Morgan ML, Cook IA, Rapkin AJ, Leuchter AF. Estrogen augmentation of antidepressants in perimenopausal depression: a pilot study. 

 Dias RS, Kerr-CorrÃªa F, Moreno RA, et al. Efficacy of hormone therapy with and without methyltestosterone augmentation of venlafaxine in the treatment of postmenopausal depression: a double-blind controlled pilot study. 

Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. 

 Gao K, Kemp DE, Fein E, et al. Number needed to treat to harm for discontinuation due to adverse events in the treatment of bipolar depression, major depressive disorder, and generalized anxiety disorder with atypical antipsychotics. 

 El-Khalili N, Joyce M, Atkinson S, et al. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. 

 Bauer M, Pretorius HW, Constant EL, et al. Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study. 

 Bauer M, El-Khalili N, Datto C, et al. A pooled analysis of two randomised, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder. 

 Philip NS, Carpenter LL, Tyrka AR, Price LH. Augmentation of antidepressants with atypical antipsychotics: a review of the current literature. 

 Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. 

 Gertsik L, Poland RE, Bresee C, Rapaport MH. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. 

 Lyoo IK, Yoon S, Kim TS, et al. A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. 

Papakostas GI, Mischoulon D, Shyu I, et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. 

 Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. 

Lattanzi L, Dell’Osso L, Cassano P, et al. Pramipexole in treatment-resistant depression: a 16-week naturalistic study. 

Articles

For many patients with depression, full symptom remission remains elusive despite multiple trials of antidepressants. This article focuses on psychopharmacological and related interventions.

Jessica Warner, MD

Articles

Augmentation Strategies in MDD Therapy