Using Adjunctive Treatments When First-Line Antidepressants Fail

Michael E. Thase, MD

Departments of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia Veterans Affairs Medical Center, and the University of Pittsburgh Medical Center, Philadelphia and Pittsburgh

Broadly defined as an inadequate response to a course of adequate antidepressant therapy, treatment-resistant depression is a common clinical challenge.1 In fact, about two-thirds of patients do not achieve remission after initial treatment with a first-line antidepressant, and only about half experience response.2 Treatment resistance can be seen as occurring in stages, with the likelihood of responding to antidepressant treatment decreasing as the number of unsuccessful trials increases. Stage 1 resistance—ie, nonresponse to the first antidepressant trial—represents the mildest or least complicated form of treatment resistance.3

Major strategies to improve treatment outcomes of patients with Stage 1 resistance include switching to another antidepressant or augmenting the initial treatment with an adjunctive medication (generally a nonantidepressant). Switching antidepressants has a lower risk of drug interactions than augmentation and may be preferable for patients who are experiencing little or no symptom relief or intolerable side effects from the initial therapy. For partial responders, adjunctive strategies preserve the benefits of the initial antidepressant, potentially achieving faster therapeutic benefits than switching, and can be easier to implement, with no need for cross-titration or washout of the first medication. Adjunctive medications also have the potential of enhancing the antidepressant’s effect through complementary mechanisms of action and can target the patient’s specific residual symptoms, such as insomnia or anxiety (AV 1AV 1). Common adjunctive agents are lithium, thyroid hormone, anxiolytic medications, and atypical antipsychotics.

First-Choice Adjunctive Treatment Strategies

Lithium. The oldest and most extensively studied of the adjunctive agents is the mood stabilizer lithium, although lithium augmentation is infrequently used today. A meta-analysis4 of randomized, placebo-controlled studies confirmed that the mean response rate among patients receiving adjunctive lithium was significantly higher than for those receiving placebo (41% vs 14%, P < .001). However, most of the studies examined lithium added to TCAs; additional studies with SSRIs and SNRIs are needed. Disadvantages of lithium use include an up-titration period, with up to 6 weeks needed for response, and the need for blood drug level monitoring.

Thyroid hormone. A meta-analysis5 of studies of thyroid hormone (T3) augmentation of TCAs in treatment-resistant depression found evidence of increased response and decreased severity compared with control subjects. The STAR*D6 trial compared remission rates for patients with treatment-resistant depression who were randomly assigned to lithium or T3 augmentation and found a trend in favor of T3 (25%) over lithium (16%), although the difference was not significant. Thyroid hormone augmentation was easier to implement and had a smaller side effect burden.

Thyroid hormone augmentation should be considered for treatment-resistant patients with low thyroid function, including those patients with an elevated TSH level but without clinical hypothyroidism. In a study7 of acceleration of SSRI response—not augmentation following nonresponse—patients with an inherited genetic abnormality that lowered their ability to convert T4 into T3 had the greatest response to T3 augmentation. Whether T3 augmentation benefits depressed patients with normal TSH levels and normal thyroid function is not definitively proven.

Buspirone or benzodiazepines. The STAR*D study8 found that patients with anxious depression were less likely to achieve remission than patients without prominent anxiety. Benzodiazepines are anxiolytic agents that can be used to augment antidepressants to treat anxious depression, but some patients may develop dependence on them. Buspirone is a non–habit-forming anxiolytic that can address symptoms of anxiety in some patients receiving an antidepressant for depression. Overall, patients in STAR*D who received the SSRI citalopram plus buspirone had about the same probability of responding or remitting as patients receiving combined antidepressant therapy with citalopram and bupropion (AV 2AV 2).9 Among patients with anxious depression, more reached remission with bupropion than with buspirone augmentation, but logistic regression analyses did not indicate that one treatment worked better for anxiety than the other.8

Atypical antipsychotics. Several atypical antipsychotics have evidence supporting their use as augmentation of antidepressants in refractory depression. While a marked increase in the use of atypical antipsychotics has occurred in the past decade, their long-term efficacy and risk:benefit ratio as adjunctive therapies in patients with major depressive disorder have not yet been adequately assessed.

A meta-analysis10 of trials that examined quetiapine, risperidone, and olanzapine augmentation of mainly SSRIs for treatment-resistant depression found that the pooled remission rate was about 25% higher for patients receiving adjunctive medication than for those receiving placebo (AV 3AV 3). However, although the overall discontinuation rate did not differ between the 2 groups, the pooled discontinuation rate due to adverse events for those receiving atypical antipsychotics was more than 3 times greater than for those receiving placebo.

The olanzapine-fluoxetine combination is approved by the FDA for treatment-resistant depression, but patients should be monitored closely for weight gain and metabolic side effects. For example, the mean weight gain in an 8-week study11 for patients receiving the combination treatment was about 5 kg, versus 0.4 kg for patients receiving fluoxetine alone.

Another atypical antipsychotic approved by the FDA as an adjunctive treatment to antidepressants in patients with inadequate response is quetiapine XR. A recent pooled analysis12 of 2 placebo-controlled trials that studied treatment regimens of 150 mg/d and 300 mg/d found that both doses provided significantly increased remission rates over adjunctive placebo by week 6 (P < .01 for all). Dry mouth and somnolence were the most common adverse effects, occurring in about one-fourth to one-third of patients, depending on dose.

Aripiprazole has also received approval from the FDA as an adjunct to antidepressants to treat resistant depression. Two randomized, double-blind, placebo-controlled studies13,14 found that remission and response rates were significantly greater with adjunctive aripiprazole (P < .05 for all) than with placebo. Mean medication dosages averaged about 11 mg/d, and a rapid onset of benefit (≤ 2 weeks) was reported. Weight gain is not as great with aripiprazole as it is with olanzapine, but about 1 in 3 patients experience either akathisia or restlessness with aripiprazole.

Two positive placebo-controlled studies10 of adjunctive therapy with risperidone have been published, although this therapy has not received an FDA indication. In addition, an open-label pilot study15 of adjunctive ziprasidone demonstrated greater efficacy in treatment-resistant depression than continued SSRI monotherapy, but larger-scale placebo-controlled studies have yet to be published. At this time, no controlled data exist for the several other newer atypical antipsychotic agents as adjunctive therapies for treatment-resistant depression.


Several effective augmentation strategies are available for treatment-resistant depression. Some augmenting agents may not only enhance the effect of the initial antidepressant but also target specific symptoms, such as insomnia or anxiety, or treat adverse effects from the initial medication. Clinicians should be aware of the differing adverse effect profiles of adjunctive medications when choosing an augmenting strategy for their patients with treatment-resistant depression.

For Clinical Use

  • Use augmentation strategies for patients who have achieved partial response to a well-tolerated antidepressant, but weigh the adverse effect profiles associated with various augmenting agents
  • Carefully monitor blood drug levels of patients receiving lithium augmentation
  • Use T3 augmentation for patients who have low thyroid function or who have high TSH levels
  • Consider adjunctive buspirone for patients with prominent anxiety
  • Be aware of atypical antipsychotics with an FDA-approved indication for adjunctive treatment of refractory depression

Drug Names

aripiprazole (Abilify), buspirone (BuSpar and others), bupropion (Wellbutrin, Aplenzin, and others), citalopram (Celexa and others), fluoxetine (Prozac and others), lithium (Lithobid and others), olanzapine (Zyprexa), olanzapine-fluoxetine (Symbyax), quetiapine (Seroquel), risperidone (Risperdal and others), ziprasidone (Geodon)


FDA = US Food and Drug Administration, HDRS-17 = 17 Item Hamilton Depression rating Scale, QIDS-SR-16 = 16 Item Quick Inventory of Depressive Symptomatology–Self Report, SNRI = serotonin norepinephrine reuptake inhibitor, SR = sustained release, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, T3 = triiodothyronine, T4 = thyroxine, TCA = tricyclic antidepressant, TSH = thyroid-stimulating hormone, XR = extended release

Take the online posttest.


  1. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649–659.
  2. Rush AJ, Trivedi JH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–1917.
  3. Thase ME, Rush AJ. When at first you don't succeed: sequential strategies for antidepressant nonresponders. J Clin Psychiatry. 1997;58(suppl 13):23–29.
  4. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68(6):935–940.
  5. Aronson R, Offman HJ, Joffe RT, et al. Triiodothyronine augmentation in the treatment of refractory depression: a meta-analysis. Arch Gen Psychiatry. 1996;53(9):842–848.
  6. 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. Am J Psychiatry. 2006;163(9):1519–1530.
  7. Cooper-Kazaz R, van der Deure WM, Medici M, et al. Preliminary evidence that a functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine. J Affect Disord. 2009;116(1–2):113–116.
  8. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342–351.
  9. Trivedi MH, Fava M, Wisniewski SR, et al for the STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243–1252.
  10. Papakostas GI, Shelton RC, Smith J, et al. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68(6):826–831.
  11. Thase ME, Corya SA, Osuntokun O, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. J Clin Psychiatry. 2007;68(2):224–236.
  12. Bauer M, El-Khalili N, Datto C, et al. A pooled analysis of two randomized, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder. J Affect Disord. 2010;127(1–3):19–30.
  13. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68(6):843–853.
  14. Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28(2):156–165.
  15. Dunner DL, Amsterdam JD, Shelton RC, et al. Efficacy and tolerability of adjunctive ziprasidone in treatment-resistant depression: a randomized, open-label, pilot study. J Clin Psychiatry. 2007;68(7):1071–1077.