Combining and Augmenting Antidepressants

Full update December 2021

Less than one-third of patients achieve remission with the first antidepressant tried.41 The chart below provides practical considerations for combining or augmenting antidepressants. (For information on alternative strategies [e.g., switching], see footnote a.) Combining or augmenting antidepressants may help patients who have a partial response (>25% improvement) to a single antidepressant.1 Combining or augmenting instead of switching avoids the risk of antidepressant withdrawal symptoms and loss of benefit from the first antidepressant.14 Choose an agent based on target symptoms, side effects, and cost.1,2 Look for early improvement after two to four weeks.1 The optimal duration of combination treatment is unclear, but most patients stay on combination therapy for months.43 Consult product labeling regarding switching to/from or combining medications with MAOIs. Keep in mind, many of the combinations below can increase the risk of serotonin syndrome.

Combining Antidepressants

Combining two antidepressants is a common strategy, but is not supported by high-level evidence.1,12 The rationale is that targeting different receptors will have a synergistic effect.12 Combinations of an SSRI or venlafaxine with bupropion or mirtazapine have the best evidence of efficacy.1,2,5,10 Less evidence for tricyclics as add-ons.1

Combination

Comments

Bupropion added to SSRI or SNRI

Bupropion plus an SSRI is the most common antidepressant combination.10,43

Consider adding bupropion for patients with fatigue, low energy, or SSRI/SNRI sexual side effects.5,10

Bupropion is associated with seizures and increased blood pressure.2

Bupropion may cause agitation or insomnia and is less effective for depression than SSRIs for patients with high levels of anxiety.2,10

Bupropion can inhibit metabolism of some SSRIs or SNRIs through CYP2D6 inhibition.2

Most studies of the combination have used the bupropion SR formulation.17,32,41

Total bupropion dose is 150 to 400 mg/day.1,17,41 A total daily dose of 300 mg may be needed to ameliorate SSRI-associated sexual dysfunction.32

Mirtazapine added to SSRI or SNRI

A second-line option, per Canadian guidelines.1

The addition of mirtazapine to an SSRI or SNRI in patients with depression despite at least six weeks’ treatment with an SSRI or SNRI alone showed no benefit over the addition of placebo.46 Adverse effects were more common in mirtazapine-treated patients [Evidence level A-1].46

In an open-label study (n=112), the addition of mirtazapine in patients who did not respond to venlafaxine was not as effective as switching to imipramine.47

Mirtazapine may ameliorate SSRI/SNRI sexual side effects, but studies are limited.11 Mirtazapine may also offset the activating effects of SSRIs or SNRIs.10

Sedating: consider for patients with insomnia(give at bedtime).1,2,10

Consider to improve appetite or reduce nausea.2,6 Weight gain may be especially problematic if used with paroxetine.34

Serotonin syndrome reported with mirtazapine/venlafaxine combo.28 

Hypomania reported with SSRI (sertraline) combo.33 

Bleeding reported when mirtazapine used with SSRI (escitalopram) plus SNRI (venlafaxine).36

Trazodone added to SSRI or SNRI

A third-line add-on, per Canadian guidelines.1

Sedating: consider for patients with insomnia.1,2

Warn men about the risk of priapism.2

Consider max daily trazodone dose of 100 mg with antidepressants that can inhibit its metabolism via CYP2D6 and/or CYP3A4.2,12,14

Risk of serotonin syndrome, particularly with additional CYP2D6 inhibitors or serotonergic drugs.29,30

Tricyclic added to SSRI or SNRI

Use low tricyclic dose (e.g., 25 to 75 mg daily) with antidepressants that can inhibit their metabolism (i.e., most antidepressants to some extent).12 Monitor tricyclic blood levels to prevent cardiac toxicity.5,12

Theoretical risk of serotonin syndrome when combined with an SSRI or SNRI.13

Sedating: consider for patients with insomnia(give tricyclic as single dose at bedtime).2

Consider for patients with comorbidity that may benefit (e.g., neuropathic pain, migraine, tension headaches).2

May not be a good combination in the elderly due to tricyclic anticholinergic effects.13

SSRI plus SNRI

Rationale: provide additional serotonergic activity, plus adrenergic activity (i.e., hit additional receptors).

Case reports only, mostly with venlafaxine.

Any benefit may be due to an increase in the total SSRI effect; venlafaxine is more like an SSRI at low doses.2

Risk of serotonin syndrome and increased blood pressure; may be due to SSRI-induced CYP2D6 inhibition of venlafaxine metabolism (e.g., by fluoxetine).12,35 Paroxetine/duloxetine combo poses same drug interaction concern.37

Bleeding reported with SSRI (escitalopram)/SNRI (venlafaxine)/mirtazapine combination.36

SSRI plus SSRI

Rationale: agents differ slightly in potency and neurotransmitter effects (i.e., hit additional receptors).12 Example, sertraline has some dopaminergic activity, and paroxetine and fluoxetine have some noradrenergic activity.12

Case reports only.

Success combining fluvoxamine (Luvox) or fluoxetine with citalopram might result from increased levels of the more potent S-citalopram due to a drug interaction, rather than a combined antidepressant effect.12,35

Risk of drug interactions.12 Risk of increased serotonergic side effects or serotonin syndrome.12,13

Augmenting Agents (Antidepressant Add-Ons)

For additional considerations in choosing an antidepressant, see our chart, Choosing and Switching Antidepressants.

Add-On

Comments

Agents with the Most Evidence

Atypical Antipsychotics

A first-line option, per Canadian guidelines.1

Aripiprazole more effective than bupropion as an add-on [Evidence level B-1].41

Aripiprazole, brexpiprazole (U.S.), and quetiapine have labeled indications for major depression. Symbyax (fluoxetine/olanzapine) is FDA-approved for treatment-resistant depression. Risperidone and ziprasidone have also been studied.1

  • Not all studies have shown benefit.3,48

Consider for patients with sexual dysfunction or insomnia.15,16

Lower doses than those used for schizophrenia may be effective.2,15,16

Monitoring for metabolic side effects (e.g., weight gain, hyperglycemia, dyslipidemia) is outlined in the product labeling, and in expert recommendations. Also see our chart, Lab Monitoring for Common Medications.

See our chart, Comparison of Atypical Antipsychotics (U.S.)(Canada) for dosing, CYP450 drug interactions, and comparative safety (metabolic side effects, QT prolongation, sedation). Antipsychotics also carry risks of movement disorders, hyperprolactinemia, and neuroleptic malignant syndrome.2

Lithium

A second-line option, per Canadian guidelines.1 Only a small number of patients have been studied.43

May reduce risk of suicide long-term, perhaps by decreasing aggression, impulsivity, and relapse.2,26

Consider targeting a serum level of 0.5 to 1.2 mEq/L.13

Response should be noticeable in one to two weeks.13

Most data from studies wherein lithium was added to a tricyclic, but seems to boost SSRIs and mirtazapine too.1,4,31,43

Drawbacks: lab monitoring, weight gain, and adverse thyroid and renal effects.4,12

Liothyronine (T3) (Cytomel)

A second-line option, per Canadian guidelines.1

Most data from studies wherein T3 was added to a tricyclic.43

Efficacy similar to lithium as an SSRI add-on, but better tolerated than lithium (STAR*D trial).7,8

A dose of 25 mcg, increased if needed to 50 mcg after about a week, is a typical dose in euthyroid patients.2

Response should be noticeable in one to two weeks.13

Potential adverse effects include nervousness and insomnia.12

Ensure hypothyroid patients are optimally treated.2

Add-Ons with Less Evidence

Buspirone (Buspar)

In STAR*D, remission and response rates were similar to add-on bupropion-SR, but bupropion-SR improved symptom scores more and was better tolerated.17

Consider for patients with anxiety2or SSRI sexual side effects [Evidence level B-1].9

Risk of serotonin syndrome when combined with a serotonergic antidepressant.27

Stimulants

General considerations:

  • There is limited data supporting stimulant and stimulant alternatives (e.g., modafinil) for depression.38,39,44
  • Modafinil is a second-line option, and other stimulants are third-line, per Canadian guidelines.1
  • U.S. guidelines suggest considering stimulants and modafinil for augmentation.2
  • Some studies show no benefit when adding modafinil or other stimulants.1,38,39,42 Other studies demonstrate benefit with methylphenidate and modafinil within a few days to two weeks of initiation, much sooner than when traditional antidepressant therapies are initiated without a stimulant.38,39
  • Duration of therapy with stimulants is not well established.38,39 Study durations with methylphenidate have ranged from eight to 16 weeks.44

Methylphenidate

  • Studies suggest that geriatric patients may benefit from the addition of immediate-release methylphenidate to an SSRI (citalopram was studied) to modestly improve antidepressant response [Evidence level B-2].44
  • Augmenting with methylphenidate may improve depression-related apathy or fatigue (regardless of impact on depression).20
  • Consider starting with a dose of 2.5 mg twice daily, titrating about every two to three days based on response and side effects, and aiming for 5 mg to 10 mg twice daily.40,44,45 Suggest scheduling the second dose of the day at or before 3 PM, to minimize nighttime wakefulness.40
  • Consider tapering off methylphenidate, once the antidepressant has had time to take full effect, in about eight to 16 weeks.40,44
  • Avoid methylphenidate in patients with a history of substance abuse,40 anxiety, arrhythmias, recent MI, etc.2,40 Recommend monitoring heart rate and blood pressure with methylphenidate, especially in patients with coronary artery disease, hypertension, or heart failure.2

Modafinil

  • Consider adding modafinil 100 to 400 mg once daily for patients with residual fatigue, sleepiness, or antidepressant-associated sedation, especially those with severe depression.2,10,19
  • Modafinil side effects include nausea, jitteriness, and life-threatening dermatologic reactions.2,19
  • Be aware that modafinil can reduce efficacy of oral contraceptives via CYP3A4 induction.2

Anticonvulsants

Lamotrigine has the most evidence, but data are limited.18

Valproic acid and carbamazepine have also been used.2

Consider for patients who also need them for a comorbid condition (e.g., migraine prevention).

Folate

A small study suggests NNT = 6 for response to L-methylfolate 15 mg (similar to lithium or atypical antipsychotics), but remission not different from placebo.5

Good tolerability.5

Current evidence does not support efficacy of folic acid as an add-on for most patients [Evidence level B-1].22,23

Consider folic acid supplementation for patients with low folate [Evidence level B-3]24,25 and women of reproductive age.Discourage supplementation with >400 mcg due to evidence of cancer risk.21

Light therapy

See our FAQ, Seasonal Affective Disorder.

SAM-e (S-adenosyl-L-methionine)

Well-tolerated.5

U.S. guidelines say it can be considered in patients who prefer a “natural” treatment.2

A dose of 400 to 800 mg twice daily is effective as an SSRI add-on.5

More effective than placebo (NNT = 6 for response; NNT = 7 for remission) [Evidence level B-1].5

  1. Switching is a common strategy if there is no response (<25% improvement) four to eight weeks after dose optimization, or the patient cannot tolerate an adequate dose.1,2 Our chart, Choosing and Switching Antidepressants, provides practical considerations for selecting among, and switching antidepressants. Also consider adding psychotherapy (cognitive behavioral therapy [CBT], interpersonal psychotherapy, etc). Psychotherapy is safe and has good evidence of efficacy; adding CBT is as effective as adding bupropion.2

Abbreviations: MAOI - monoamine oxidase inhibitor; SSRI - selective serotonin reuptake inhibitor; SNRI - serotonin norepinephrine reuptake inhibitor

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.]

References

  1. Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: Section 3. Pharmacological treatments. Can J Psychiatry 2016;61:540-60.
  2. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (3rd Edition). October 2010. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. (Accessed November 5, 2021).
  3. Ruberto VL, Jha MK, Murrough JW. Pharmacological treatments for patients with treatment-resistant depression. Pharmaceuticals 2020;13:116.
  4. Connolly KR, Thase ME. If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs 2011;71:43-64.
  5. 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. Am J Psychiatry 2010;167:942-8.
  6. Alam A, Voronovich Z, Carley JA. A review of therapeutic uses of mirtazapine in psychiatric and medical conditions. Prim Care Companion CNS Disord 2013;15:PCC.13r01525.
  7. Sussman N. Translating science into service: lessons learned from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Prim Care Companion J Clin Psychiatry 2007;9:331-7.
  8. 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;163:1519-30.
  9. Landen M, Eriksson E, Agren H, Fahlen T. Effect of buspirone on sexual dysfunction in depressed patients with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1999;19:268-71.
  10. DeBattista C, Lembke A. Update on augmentation of antidepressant response in resistant depression. Curr Psychiatry Rep 2005;7:435-40.
  11. Atmaca M, Korkmaz S, Topuz M, Mermi O. Mirtazapine augmentation for selective serotonin reuptake inhibitor-induced sexual dysfunction: a retrospective investigation. Psychiatry Investig 2011;8:55-7.
  12. Fava M. Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 2001;62(Suppl 18):4-11.
  13. Angelini MC. Depressive disorders. In: Zeind CS, Carvalho MG, editors. Applied Therapeutics: the Clinical Use of Drugs. 11th ed. Philadelphia, PA: Wolters Kluwer Health, 2018: 1813-33.
  14. Keller MB. Issues in treatment-resistant depressionJ Clin Psychiatry 2005;66(Suppl 8):5-12.
  15. Nemeroff CB. Use of atypical antipsychotics in refractory depression and anxiety. J Clin Psychiatry 2005;66(Suppl 8):13-21.
  16. 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;68:843-53.
  17. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354:1243-52.
  18. Goh KK, Chen CH, Chiu YH, Lu ML. Lamotrigine augmentation in treatment-resistant unipolar depression: a comprehensive meta-analysis of efficacy and safety. J Psychopharmacol 2019;33:700-13 [abstract].
  19. 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. J Clin Psychiatry 2005;66:85-93.
  20. 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. J Clin Psychiatry 2008;69:87-94.
  21. TRC Healthcare. Folic acid. [Natural Medicines website]. November 5, 2020. Available at: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1017. (Accessed November 5, 2021).
  22. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord 2000;60:121-30.
  23. Bedson E, Bell D, Carr D, et al. Folate augmentation of treatment-evaluation for depression (FolATED): a randomised trial and economic evaluation. Health Technol Assess 2014;18:1-159.
  24. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry 2004;65:1090-5.
  25. Papakostas GI, Petersen T, Lebowitz BD, et al. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive disorder and the timing of improvement with fluoxetine. Int J Neuropsychopharmacol 2005;8:523-8.
  26. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ 2013;346:f3646.
  27. Manos GH. Possible serotonin syndrome associated with buspirone added to fluoxetine. Ann Pharmacother 2000;34:871-4.
  28. Decoutere L, DeWinter S, Vander Weyden L, et al. A venlafaxine and mirtazapine-induced serotonin syndrome confirmed by de- and re-challenge. Int J Clin Pharm2012;34:686-8.
  29. McCue RE, Joseph M. Venlafaxine- and trazodone-induced serotonin syndrome. Am J Psychiatry 2001;158:2088-9.
  30. Ripple MG, Pestaner JP, Levine BS, Smialek JE. Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol 2000;21:370-4.
  31. Nelson JC, Baumann P, Delucchi K, et al. A systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression. J Affect Disord 2014;168:269-75.
  32. Zisook S, Rush AJ, Haight BR, et al. Use of bupropion in combination with serotonin reuptake inhibitors. Biol Psychiatry 2006;59:203-10.
  33. Soutullo CA, McElroy SL, Keck PE Jr. Hypomania associated with mirtazapine augmentation of sertraline. J Clin Psychiatry 1998;59:320.
  34. 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;19:457-65.
  35. Rojo JE, Ros S, Aguera L, et al. Combined antidepressants: clinical experience. Acta Psychiatr Scand Suppl 2005;428:25-31, 36.
  36. Benazzi F. Hemorrhages during escitalopram-venlafaxine-mirtazapine combination treatment of depression. Can J Psychiatry 2005;50:184.
  37. Skinner MH, Kuan HY, Pan A, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 2003;73:170-7.
  38. Orr K, Taylor D. Psychostimulants in the treatment of depression: a review of the evidence. CNS Drugs 2007;21:239-57.
  39. Corp SA, Gitlin MJ, Altshuler LL. A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder. J Clin Psychiatry 2014;75:1010-8.
  40. Lavretsky H, Reinlieb M, St Cyr N, et al. Citalopram, methylphenidate, or their combination in geriatric depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2015;172:561-9.
  41. Mohamed S, Johnson GR, Chen P, et al. Effect of antidepressant switching vs augmentation on remission among patients with major depressive disorder unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA 2017;318:132-45.
  42. Richards C, Iosifescu DV, Mago R, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of lisdexamfetamine dimesylate augmentation for major depressive disorder in adults with inadequate response to antidepressant therapy. J Psychopharmacol 2017;31:1190-1203.
  43. Cowen PJ. Backing into the future: pharmacological approaches to the management of resistant depression. Psychol Med 2017;47:2569-77.
  44. Smith KR, Khalon CH, Brown JN, Britt RB. Methylphenidate use in geriatric depression: a systematic review. Int J Geriatr Psychiatry 2021;36:1304-12.
  45. Mintzer J, Lanctot KL, Scherer RW, et al. Effect of methylphenidate on apathy in patients with Alzheimer disease: the ADMET 2 randomized clinical trial. JAMA Neurol 2021;78:1324-32.
  46. Kessler DS, MacNeill SJ, Tallon D, et al. Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: Phase III randomised placebo controlled trial (MIR). BMJ 2018;363:k4218.
  47. Navarro V, Boulahfa I, Obach A, et al. Switching to imipramine versus add-on mirtazapine in venlafaxine-resistant major depression: a 10-week randomized open study. J Clin Psychopharmacol 2019;39:63-6 [abstract].
  48. Hobart M, Skuban A, Zhang P, et al. Efficacy and safety of flexibly dosed brexpiprazole for the adjunctive treatment of major depressive disorder: a randomized, active-referenced, placebo-controlled study. Curr Med Res Opin 2018;34:633-42.

Cite this document as follows: Clinical Resource, Combining and Augmenting Antidepressants. Pharmacist’s Letter/Prescriber’s Letter. December 2021[371209]


Related Articles