Augmentation and Combination Strategies for Complicated Depression

Maurizio Fava, MD

Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston

Approximately half of patients with depression who receive an adequate course of first-line antidepressant monotherapy will experience no response or only partial response to treatment.1 To improve a patient’s response and work toward remission, clinicians may try switching to a different antidepressant, or they may add an additional medication to the patient’s regimen. For partial responders, adding another medication may be preferable to switching because the benefit from the first antidepressant can be preserved. When adding medications, clinicians can try to complement or enhance antidepressant treatment by augmenting with an agent not considered a standard antidepressant, or they may choose to use combination therapy, which combines the original antidepressant with another FDA-approved antidepressant, usually of a different class.

Augmentation Strategies

A variety of agents have been studied as potential augmenting agents, including lithium, thyroid hormones, buspirone, pindolol, methylphenidate, modafinil, atypical antipsychotics, folic acid, SAMe, and omega-3 fatty acids. A meta-analysis2 showed that lithium augmentation of antidepressants significantly increased the rate of treatment responders compared with placebo augmentation (41.2% vs 14.4%, P < .001). However, most of the studies included in the meta-analysis used TCAs, and lithium may be less effective when added to SSRIs than to TCAs.3,4 Lithium also has a risk for toxicity (requiring blood monitoring) and adverse side effects.3

Augmentation of TCAs with the thyroid hormone T3 has been shown to improve the treatment response rate in patients with refractory depression by 23%.5 The efficacy of T3 augmentation of SSRIs has been supported by open-label studies and 1 randomized controlled trial, but more research is needed.6 The use of T3 is associated with fewer adverse side effects than lithium.6,7

Buspirone and pindolol have also been tried, with some success, in studies of antidepressant augmentation.3 A randomized, controlled trial8 augmenting citalopram with buspirone for patients with refractory depression resulted in remission rates of about 30%. Pindolol may also aid response in patients with SSRI-refractory depression, but most double-blind studies are negative and 1 large daily dose instead of 3 small daily doses may provide better efficacy.9

Stimulants have long been used to augment antidepressants.3 A randomized, double-blind, placebo-controlled trial10 of extended-release methylphenidate augmentation in 60 patients found that, although response was numerically higher in the augmentation group (40%) versus the placebo group (23%), no statistically significant benefit was shown in the efficacy measures between the 2 groups. Larger trials are needed. However, a pooled analysis11 from 2 large, multicenter, placebo-controlled trials of partial responders to SSRI therapy with fatigue and excessive sleepiness found that patients treated with modafinil showed significantly greater improvement in overall clinical condition, wakefulness, and depressive symptoms at endpoint than patients administered placebo (AV 1AV 1).


A review12 of antidepressant augmentation with atypical antipsychotics found that olanzapine, risperidone, and aripiprazole (typically prescribed in lower doses than when used for monotherapy) have demonstrated efficacy for treatment-resistant depression. Aripiprazole has received an FDA indication for this purpose. The published evidence in support of the efficacy of quetiapine augmentation is based only on small, somewhat underpowered studies, and 1 open-label trial of ziprasidone showed some efficacy; additional trials of quetiapine and ziprasidone are clearly needed.13

Folate and SAMe may be useful adjunctive therapies in treatment-resistant depression. A randomized, double-blind study14 in which 127 patients received fluoxetine plus either folic acid or placebo found a significantly greater improvement in the group receiving folate (P < .005; AV 2AV 2). The enhanced antidepressant response was seen only in women, possibly because the dose of folate was not sufficient to lower the men’s plasma homocysteine. It has been argued that MTHF, the active form of folate, may be a relatively more suitable form of folate augmentation, particularly among depressed patients with inherited forms of MTHF reductase deficiencies, commonly observed in depressed populations.15 An open study16 of 30 patients with antidepressant-resistant depression receiving augmentation with SAMe for 6 weeks reported a response rate of 50% and a remission rate of 43%.

A study17 of omega-3 fatty acid augmentation for 20 patients experiencing breakthrough depression while on maintenance treatment with an antidepressant reported significant benefits versus placebo augmentation (P < .001). A meta-analysis18 of placebo-controlled trials of omega-3 fatty acid also found some evidence of efficacy in depression; however, the analysis also found publication bias and heterogeneity among the trials.

Combination Strategies

Combination strategies typically involve combining antidepressant agents that affect different neurotransmitter systems.3 For example, a double-blind, randomized study19 combining the TCA desipramine (which has norepinephrine reuptake inhibition) with the SSRI fluoxetine (which has serotonin reuptake inhibition) in 39 patients showed that remission rates were significantly higher with the combination than with either drug alone (P = .001). However, high-dose fluoxetine may be as effective as, or more effective than, fluoxetine plus desipramine.20 Additionally, the combination of TCAs and SSRIs requires monitoring of TCA blood levels due to the potential of cardiac toxicity.

Adding a newer agent with norepinephrine reuptake inhibition, such as reboxetine or atomoxetine, to an SSRI has also been tried. Although no controlled trials have been reported for the combination of reboxetine with an SSRI, open trials have suggested efficacy.3 However, a placebo-controlled trial21 of atomoxetine added to an SSRI failed to demonstrate efficacy.

Bupropion, which inhibits the reuptake of dopamine and norepinephrine, was the most popular combination agent in a psychiatrist survey22 of “next-step” strategies for patients with treatment-resistant depression. STAR*D, a large, randomized, controlled study,8 compared augmentation of an SSRI with either bupropion or buspirone for patients with treatment-resistant depression and found a remission rate of about 30% for bupropion (AV 3AV 3). Remission was similar in both groups, but bupropion was better tolerated.

Another dual-action antidepressant is mirtazapine, which increases both serotonergic and noradrenergic activity. A small (N = 26) double-blind, placebo-controlled study23 showed a response rate of 64% with mirtazapine augmentation of an antidepressant versus 20% for placebo augmentation, with remission rates of about 45% for the patients receiving mirtazapine versus about 13% for the placebo group. A study24 of very treatment-resistant patients that compared tranylcypromine monotherapy with venlafaxine plus mirtazapine found that the 2 treatments offered similar rates of remission, albeit rather low; however, the combination treatment was easier to use and better tolerated than tranylcypromine.


Many safe and relatively effective augmentation and combination strategies are available to the clinician for treating patients with refractory depression. However, additional controlled studies are needed to compare the efficacy of these treatment options, provide indicators that might guide treatment selection for individual patients, and answer questions regarding the duration of combination or augmentation strategies for achieving and maintaining remission in patients with treatment-resistant depression.

Drug Names

aripiprazole (Abilify), atomoxetine (Strattera), bupropion (Wellbutrin, Aplenzin, and others), buspirone (BuSpar and others), citalopram (Celexa and others), desipramine (Norpramin and others), fluoxetine (Prozac and others), lithium (Eskalith, Lithobid, and others), methylphenidate (Ritalin, Concerta, and others), mirtazapine (Remeron and others), modafinil (Provigil), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal and others), tranylcypromine (Parnate and others), venlafaxine (Effexor and others), ziprasidone (Geodon)


ESS = Epworth Sleepiness Scale, FDA = US Food and Drug Administration, HAM-D = Hamilton Rating Scale for Depression, MTHF = methyltetrahydrofolate, QIDS-SR-16 = 16-item Quick Inventory of Depressive Symptomatology–Self-Report, SAMe = S-adenosyl-L-methionine, SR = sustained release, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, T3 = triiodothyronine, TCA = tricyclic antidepressant

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