Unipolar depression in adults: Treatment with antidepressant combinations
- John A Rush, MD
John A Rush, MD
- Professor Emeritus
- National University of Singapore, Duke-NUS
Antidepressant combinations are generally used for unipolar major depression (major depressive disorder) that is resistant to treatment with antidepressant monotherapy. Add-on pharmacotherapy is often necessary because initial treatment with a single antidepressant leads to remission in only 30 to 50 percent of patients [1-3]. Options for adjunctive pharmacotherapy include a second antidepressant, as well as second-generation antipsychotics, lithium, and triiodothyronine. Adjunctive psychotherapy is also an option.
Combining two antidepressants for treatment resistant depression is common . As an example, retrospective studies of patients treated for depression with a single antidepressant (insurance claims database n >134,000; registry database n >240,000) found that a second antidepressant was added in approximately 10 percent of patients [5,6].
This topic reviews the indications and efficacy of combining antidepressants for patients with unipolar, nonpsychotic major depression. Choosing a drug regimen for major depression and using a second antidepressant as a hypnotic are discussed separately. (See "Unipolar depression in adults: Treatment of resistant depression" and "Unipolar major depression in adults: Choosing initial treatment" and "Treatment of insomnia", section on 'Antidepressants'.)
Indications for antidepressant combinations include:
●Unipolar major depression that does not respond to multiple courses of treatment with antidepressant monotherapy as well as an antidepressant plus adjunctive pharmacotherapy (eg, antidepressant plus a second-generation antipsychotic, lithium, or triiodothyronine). (See "Unipolar depression in adults: Treatment of resistant depression", section on 'Choosing a drug'.)
- Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163:28.
- Thase ME, Haight BR, Richard N, et al. Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry 2005; 66:974.
- Thase ME, Nierenberg AA, Vrijland P, et al. Remission with mirtazapine and selective serotonin reuptake inhibitors: a meta-analysis of individual patient data from 15 controlled trials of acute phase treatment of major depression. Int Clin Psychopharmacol 2010; 25:189.
- Gersing KR, Sheehan JJ, Burchett B, et al. Use of augmentation agents for treating depression: analysis of a psychiatric electronic medical record data set. Psychiatr Serv 2014; 65:1062.
- Milea D, Guelfucci F, Bent-Ennakhil N, et al. Antidepressant monotherapy: A claims database analysis of treatment changes and treatment duration. Clin Ther 2010; 32:2057.
- Valenstein M, McCarthy JF, Austin KL, et al. What happened to lithium? Antidepressant augmentation in clinical settings. Am J Psychiatry 2006; 163:1219.
- Preskorn SH. Treatment options for the patient who does not respond well to initial antidepressant therapy. J Psychiatr Pract 2009; 15:202.
- Preskorn SH, Lacey RL. Polypharmacy: when is it rational? J Psychiatr Pract 2007; 13:97.
- Young JP, Lader MH, Hughes WC. Controlled trial of trimipramine, monoamine oxidase inhibitors, and combined treatment in depressed outpatients. Br Med J 1979; 2:1315.
- Paslakis G, Gilles M, Deuschle M. Clinically relevant pharmacokinetic interaction between venlafaxine and bupropion: a case series. J Clin Psychopharmacol 2010; 30:473.
- Lopes Rocha F, Fuzikawa C, Riera R, et al. Antidepressant combination for major depression in incomplete responders--a systematic review. J Affect Disord 2013; 144:1.
- Licht RW, Qvitzau S. Treatment strategies in patients with major depression not responding to first-line sertraline treatment. A randomised study of extended duration of treatment, dose increase or mianserin augmentation. Psychopharmacology (Berl) 2002; 161:143.
- Fornaro M, Martino M, Mattei C, et al. Duloxetine-bupropion combination for treatment-resistant atypical depression: a double-blind, randomized, placebo-controlled trial. Eur Neuropsychopharmacol 2014; 24:1269.
- Zhou X, Ravindran AV, Qin B, et al. Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: systematic review and network meta-analysis. J Clin Psychiatry 2015; 76:e487.
- Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354:1243.
- McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry 2006; 163:1531.
- Gulrez G, Badyal DK, Deswal RS, Sharma A. Bupropion as an augmenting agent in patients of depression with partial response. Basic Clin Pharmacol Toxicol 2012; 110:227.
- Rocha FL, Fuzikawa C, Riera R, Hara C. Combination of antidepressants in the treatment of major depressive disorder: a systematic review and meta-analysis. J Clin Psychopharmacol 2012; 32:278.
- Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry 2011; 168:689.
- Stewart JW, McGrath PJ, Blondeau C, et al. Combination antidepressant therapy for major depressive disorder: speed and probability of remission. J Psychiatr Res 2014; 52:7.
- Blier P, Gobbi G, Turcotte JE, et al. Mirtazapine and paroxetine in major depression: a comparison of monotherapy versus their combination from treatment initiation. Eur Neuropsychopharmacol 2009; 19:457.
- Blier P, Ward HE, Tremblay P, et al. Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study. Am J Psychiatry 2010; 167:281.
- Coryell W. The search for improved antidepressant strategies: is bigger better? Am J Psychiatry 2011; 168:664.
- Parker G, Fink M, Shorter E, et al. Issues for DSM-5: whither melancholia? The case for its classification as a distinct mood disorder. Am J Psychiatry 2010; 167:745.