Noah S. Philip, 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.

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Articles

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

Noah S. Philip, MD

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Augmentation Strategies in MDD Therapy