Major depressive disorder medical therapy

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Major depressive disorder Microchapters


Major Depressive Disorder (Patient Information)


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Differentiating Major depressive disorder from other Diseases

Epidemiology and Demographics

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]


The mainstay of treatment for major depressive disorder is pharmacologic therapy with serotonergic agents.

Medical Therapy

Pharmacologic medical therapies for Major Depressive Disorder include: [1] [2]

Serotonin reuptake inhibitors

Serotonin-norepinephrine reuptake inhibitors

  • Serotonin-norepinephrine reuptake inhibitors (SNRIs) are also considered first-line medications for the treatment of MDD. SNRIs have a dual mechanism of action. They may be effective in treating concomitant pain conditions.
  • Adverse effects: Neuradrenergic symptoms (hypertension, dry mouth, constipation, insomnia, decreased appetite), serotonergic side effects ([[nausea, diarrhea, nervousness, insomnia, sexual dysfunction, withdrawal symptoms, and hyponatremia).
  • Duloxetine (Effective dose range 60-120 mg)
    • May be effective in treating neuropathic pain and other pain condition. Smoking decreases the plasma levels of duloxetine.
  • Venlafaxine (Effective dose range 75-350 mg)
    • Adverse effects: Compared to other serotonergic antidepressants, is associated with a slightly increased incidence of nausea and vomiting, higher risk of withdrawal symptoms, and hypertesnion.
  • Desvenlafaxine (Effective dose range 50-100 mg)
    • Benefit: may reduce neuropathic pain
  • Levomilnacipran (Effective dose range 40-120 mg)

Other antidepressants

Tricyclic antidepressants

Monoamine oxidase inhibitors

Treatment in primary care

Trails of medication[3]s and multifactorial interventions[4] show benefit.

A systematic review by the Cochrane Collaboration found benefit from medications in primary care[5].

Measurement-based care can be used in primary care[6].

Measurement-based care (STAR*D and VAST-D trials)

Treatment after SSRI (citalopram) failure
(STAR*D Studies)
Intervention Outcome
Medication Mean final dose Remision % Quit 2˚ ADRs (%)
Switch meds (NEJM 2006; PMID: 16554525[7])
Bupropion SR 283 mg 21% 27%
Sertraline (SSR) 136 mg 18% 21%
Venlafaxine ER (SNRI) 194 mg 25% 21%
Augment meds (NEJM 2006; PMID: 16554526[8])
Bupropion SR 268 mg 30% 13%
Buspirone 41 mg 30% 21%

When treated with monotherapy for depression, approximately 30% of patients have remission of symptoms while 50% have a response to medications.[9] For patients with inadequate response, either adding sustained-release bupropion ("bupropion was 200 mg per day during weeks 1 and 2, increasing to 300 mg per day by week 4 and to 400 mg per day (the final dose) during week 6") or buspirone (up to 60 mg per day) for augmentation as a second drug can cause remission in approximately 30% of patients (bupropion may be more effective than buspirone)[8], while switching medications can achieve remission in about 25% of patients[7]. Alternatively, "extended-release venlafaxine, the starting daily dose of 37.5 mg for 7 days was increased to 75 mg from day 8 to 14, to 150 mg from day 15 to 27, to 225 mg from day 28 to 41, to 300 mg from day 42 to 62, and to 375 mg from day 63 onward."[7]

In level 3 of the STAR*D trials, patients who had failed two trials of a second-generation antidepressant, tended to better with nortriptyline than mirtazapine.[10]

For patients failing anti-depressants, buproprion has been compared to aripiprazole in the VAST-D trial; while aripiprazole was "modestly' better, it had more adverse drug reactions[11].

Clinical Hints

When treating patients with major depressive disorder the following clinical hints should be taken into consideration: [12] [2]

  • Initiation of SSRIs may be associated with early transient anxiety, aggravating suicidal ideation. Reducing the dose or adding a benzodiazepine may be helpful in these patients.
  • In MDD patients with insomnia, benzodiazepines, zolpidem, trazodone, or mirtazapine are helpful. A systematic review in 2022 concluded that in the treatment of chronic insomnia, "eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce"[13]
  • In addition, when depressed patients begin to clinically improve, their physical energy also improves, enabling them to carry out suicidal acts that they did not have the power to perform before. This is known as paradoxical suicide.
  • Antidepressants may take as long as 6-8 weeks to take effect.
  • The goal of treatment is achieving complete remission of symptoms and return to normal functioning.
  • In patients who fail to respond to an SSRI, or experience intolerable side effects, another medication in this class may be tried. However, some physicians prefer to switch to another medication with a different mechanism of action.
  • Psychotherapy may be added in the treatment of patients with a partial response to pharmacotherapy alone.
  • In patients with the first episode of major depression, maintenance treatment for at least months may be helpful in preventing relapse. In patients with recurrent major depressive episodes, long-term treatment may be beneficial.
  • In patients experiencing intolerable sexual side effects with SSRIs, bupropion or mirtazapine may be considered.
  • Bupropion may be beneficial in patients with anergy and psychomotor retardation due to its stimulant-like effects.
  • Hospitalization may be considered in patients with significant suicidal ideation or intent without adequate family support or safe-guards at home. Patients who express intent to hurt others or those who are not able to care for themselves may also be hospitalized.
  • Pharmacogenomic testing to guide dosing may slightly improve remission (17% vs 16%)[14].


  1. Boland, Robert (2022). Kaplan & Sadock's synopsis of psychiatry. Philadelphia: Wolters Kluwer. ISBN 1975145569.
  2. 2.0 2.1 McCarron RM, Shapiro B, Rawles J, Luo J (2021). "Depression". Ann Intern Med. 174 (5): ITC65–ITC80. doi:10.7326/AITC202105180. PMID 33971098 Check |pmid= value (help).
  3. Williams JW, Barrett J, Oxman T, Frank E, Katon W, Sullivan M; et al. (2000). "Treatment of dysthymia and minor depression in primary care: A randomized controlled trial in older adults". JAMA. 284 (12): 1519–26. doi:10.1001/jama.284.12.1519. PMID 11000645.
  4. Dietrich AJ, Oxman TE, Williams JW, Schulberg HC, Bruce ML, Lee PW; et al. (2004). "Re-engineering systems for the treatment of depression in primary care: cluster randomised controlled trial". BMJ. 329 (7466): 602. doi:10.1136/bmj.38219.481250.55. PMC 516659. PMID 15345600.
  5. Arroll B, Elley CR, Fishman T, Goodyear-Smith FA, Kenealy T, Blashki G; et al. (2009). "Antidepressants versus placebo for depression in primary care". Cochrane Database Syst Rev (3): CD007954. doi:10.1002/14651858.CD007954. PMID 19588448.
  6. Gaynes BN, Rush AJ, Trivedi MH, Wisniewski SR, Balasubramani GK, McGrath PJ; et al. (2008). "Primary versus specialty care outcomes for depressed outpatients managed with measurement-based care: results from STAR*D". J Gen Intern Med. 23 (5): 551–60. doi:10.1007/s11606-008-0522-3. PMC 2324144. PMID 18247097.
  7. 7.0 7.1 7.2 Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME; et al. (2006). "Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression". N Engl J Med. 354 (12): 1231–42. doi:10.1056/NEJMoa052963. PMID 16554525. Review in: Evid Based Ment Health. 2006 Nov;9(4):100
  8. 8.0 8.1 Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D; et al. (2006). "Medication augmentation after the failure of SSRIs for depression". N Engl J Med. 354 (12): 1243–52. doi:10.1056/NEJMoa052964. PMID 16554526.
  9. Trivedi MH, Rush AJ, Wisniewski SR; et al. (2006). "Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice". The American journal of psychiatry. 163 (1): 28–40. doi:10.1176/appi.ajp.163.1.28. PMID 16390886.
  10. Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE, McGrath PJ; et al. (2006). "A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report". Am J Psychiatry. 163 (7): 1161–72. doi:10.1176/appi.ajp.163.7.1161. PMID 16816220. Review in: Evid Based Ment Health. 2007 Feb;10(1):16
  11. Mohamed S, Johnson GR, Chen P, Hicks PB, Davis LL, Yoon J; et al. (2017). "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. 318 (2): 132–145. doi:10.1001/jama.2017.8036. PMC 5817471. PMID 28697253.
  12. Boland, Robert (2022). Kaplan & Sadock's synopsis of psychiatry. Philadelphia: Wolters Kluwer. ISBN 1975145569.
  13. De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N; et al. (2022). "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis". Lancet. 400 (10347): 170–184. doi:10.1016/S0140-6736(22)00878-9. PMID 35843245 Check |pmid= value (help).
  14. Oslin DW, Lynch KG, Shih MC, Ingram EP, Wray LO, Chapman SR; et al. (2022). "Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial". JAMA. 328 (2): 151–161. doi:10.1001/jama.2022.9805. PMID 35819423 Check |pmid= value (help).

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