Sandbox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2] Aiden Nguyen[3]
Overview
The mainstay of therapy for major depressive disorder (MDD) in adults is either evidence-based psychotherapy (particularly cognitive behavioral therapy) or a second-generation antidepressant (SGA), selected according to severity, comorbidity, adverse-effect profile, prior response, drug interactions, cost, and patient preference. Treatment is stratified by baseline severity and proceeds through an acute phase (achieve remission), a continuation phase (sustain remission), and a maintenance phase (prevent recurrence), with the goal of full remission and functional recovery rather than response alone. Among SGAs, no single agent is reliably superior in efficacy, so agent choice rests mainly on tolerability, target symptoms, and preference. Patients with inadequate response are managed by confirming an adequate trial and then switching, augmenting, or combining treatments; treatment-resistant depression may be managed with esketamine or off-label ketamine. Electroconvulsive therapy and repetitive transcranial magnetic stimulation are addressed in the procedural-therapy microchapter.
Medical Therapy
Pharmacologic medical therapies for major depressive disorder include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, serotonin modulators (vortioxetine, vilazodone, trazodone), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and glutamatergic agents (esketamine, ketamine).[1][2] Empiric selection depends on symptom profile, comorbidity, and prior treatment response.
Treatment Phases and Goals
- Acute phase (typically 6–12 weeks): the goal is remission.[3]
- Continuation phase: the goal is to sustain remission and prevent relapse.
- Maintenance phase: the goal is to prevent recurrence in patients at higher risk.
- The treatment goal is full remission with functional recovery, not response alone.
Severity-Stratified Initial Treatment
| Severity (PHQ-9) | ACP 2023 | VA/DoD 2022 | Other guidance |
|---|---|---|---|
| Mild (<10) | CBT monotherapy suggested (conditional; low-certainty)[3] | Either psychotherapy or pharmacotherapy as monotherapy, by patient preference[4] | CANMAT lists supervised exercise (first-line) and light therapy for seasonal presentations[2] |
| Moderate (10–14) | Monotherapy with CBT or an SGA | Monotherapy by preference | Combination may be superior to either alone[5] |
| Moderately severe to severe (≥15) | Monotherapy with CBT or an SGA recommended (strong; moderate-certainty); CBT + SGA suggested as an alternative (conditional; low-certainty)[3] | Combination pharmacotherapy plus evidence-based psychotherapy suggested for severe, persistent (>2 y), or recurrent (≥2 episodes) MDD[4] | — |
First-Line Pharmacotherapy
First-line pharmacotherapy consists of SGAs, which the VA/DoD 2022 guideline lists as interchangeable first choices with no rank order: an SSRI, an SNRI, bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine.[4] In the network meta-analysis of 21 antidepressants (522 trials, 116,477 participants), all agents outperformed placebo (odds ratios 1.37–2.13); agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were among the more efficacious, while agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were best tolerated.[6] Because differences among agents are modest and do not reliably predict individual response, escitalopram and sertraline are frequently favored for their efficacy–acceptability balance.[5] The VA/DoD guideline suggests against esketamine, ketamine, MAOIs, nefazodone, and TCAs as initial pharmacotherapy.[4]
| Agent / class | Usual daily dose | Key clinical considerations |
|---|---|---|
| Escitalopram (SSRI) | 10–20 mg | GI upset, sexual dysfunction, sleep disturbance; hyponatremia in older adults |
| Sertraline (SSRI) | 50–200 mg | As above; favorable efficacy–acceptability balance |
| Fluoxetine (SSRI) | 20–80 mg | Long half-life minimizes discontinuation symptoms |
| Paroxetine (SSRI) | 20–50 mg | Highest discontinuation-symptom and anticholinergic burden among SSRIs |
| Citalopram (SSRI) | 20–40 mg | Dose-dependent QTc prolongation; max 20 mg/day if age >60 y, hepatic impairment, or CYP2C19 inhibitor |
| SNRIs (venlafaxine, desvenlafaxine, duloxetine, levomilnacipran) | Per labeling | Useful with comorbid chronic pain; venlafaxine causes dose-dependent BP elevation and notable discontinuation symptoms |
| Bupropion | Per labeling | Weight-neutral, minimal sexual dysfunction; useful for fatigue/hypersomnia; lowers seizure threshold (avoid in seizure/eating disorders) |
| Mirtazapine | Per labeling | Promotes sleep and appetite; low sexual dysfunction; weight gain and sedation |
| Vortioxetine, vilazodone | Per labeling | Lower sexual dysfunction; vortioxetine causes dose-related nausea |
| TCAs (second-line) | Per labeling | Cardiotoxic; dangerous in overdose (low therapeutic index) |
| MAOIs (third-line) | Per labeling | Tyramine dietary restriction; hypertensive-crisis and serotonin syndrome risk; contraindicated with other serotonergic agents |
Safety and Monitoring
- Antidepressants carry a boxed warning for increased suicidal thoughts and behavior in patients up to age 24 years; monitor closely early in treatment and after dose changes, and dispense limited quantities to patients at suicide risk (particularly TCAs).[7]
- Confirm the diagnosis and screen for bipolarity and comorbid conditions before starting or changing therapy.[8]
- Use measurement-based care (serial PHQ-9 at 2–4 week intervals) to guide dose adjustment; allow 4–8 weeks at a therapeutic dose before judging efficacy.[5]
Inadequate Response: Switching, Augmentation, Combination
About 30% of patients remit and roughly 50% respond to an adequate first trial, with declining odds at each subsequent step.[9] Before changing therapy, confirm adequate dose and duration (4–8 weeks at therapeutic dose), adherence, and diagnosis.[8] Options are:[8][10]
- Switch to another agent (within or across class).
- Augment with an atypical antipsychotic (aripiprazole, brexpiprazole, quetiapine), lithium, or liothyronine (T3).
- Combine two antidepressants with complementary mechanisms (e.g., add bupropion or mirtazapine).
No strategy is clearly dominant. In STAR*D, both switching and augmentation were reasonable options; in VAST-D, aripiprazole augmentation was modestly superior to switching to bupropion but caused more adverse effects.[11][12] Aripiprazole and brexpiprazole are FDA-approved adjuncts for MDD; lumateperone was approved as adjunctive therapy in November 2025.[8]
Treatment-Resistant Depression
Treatment-resistant depression (TRD) is commonly defined as failure of at least two adequate antidepressant trials.[13]
- Esketamine (intranasal): FDA-approved with an oral antidepressant for TRD (and as monotherapy since January 2025), and for MDD with acute suicidal ideation/behavior. In ESCAPE-TRD, esketamine plus an SSRI/SNRI was superior to quetiapine XR plus an SSRI/SNRI (week-8 remission 27.1% vs 17.6%; week-32 remission 55% vs 37%).[13] Available only through a REMS program with in-office administration and ≥2 hours of post-dose monitoring.[4]
- IV racemic ketamine (0.5 mg/kg): rapid antidepressant and anti-suicidal effect within 24 hours, but benefit largely dissipates within 1–2 weeks without repeat dosing; long-term data are limited; used off-label (not FDA-approved for depression).[8][14]
- The VA/DoD 2022 guideline reverses its 2016 stance and now suggests ketamine or esketamine for patients who have failed several adequate trials, reserving them as later-line therapy.[15]
Duration of Therapy and Relapse Prevention
- Continuing the same antidepressant at the effective dose after remission reduces relapse compared with discontinuation.[16]
- Continue for at least 6 months after a first episode; for patients with ≥2 prior episodes, residual symptoms, or severe/high-risk episodes, continue 12–24 months and consider indefinite therapy.[4][17]
- Maintain the acute-phase therapeutic dose during continuation and maintenance rather than reducing to a lower dose. Detailed maintenance content is covered in secondary prevention.
Pharmacogenomic Testing
In the PRIME Care RCT (n=1944 US veterans), pharmacogenomic-guided care increased interaction-free prescribing (59.3% vs 25.7%) and modestly improved remission across 24 weeks (odds ratio 1.28; 95% CI 1.05–1.57), but the difference was not significant at week 24 (risk difference 1.5%; P=0.45).[9] The VA/DoD guideline found insufficient evidence to recommend for or against routine testing.[4] Testing may be considered as an adjunct after prior intolerance or nonresponse, not as a standalone determinant of therapy.
Treatment Algorithm
| Confirm MDD diagnosis • Screen for bipolarity, comorbidity, and suicide risk • Assess severity (PHQ-9) • Establish measurement-based care | |||||||||||||||||||||||||||||
| Mild (PHQ-9 <10) Preferred: psychotherapy (CBT); consider exercise/light therapy | Moderate (PHQ-9 10–14) SGA or psychotherapy monotherapy; combination may be superior | Severe (PHQ-9 ≥15) Combined SGA + psychotherapy | |||||||||||||||||||||||||||
| Start first-line SGA (choose by adverse-effect profile, target symptoms, comorbidity, interactions, preference; escitalopram or sertraline are strong defaults) Reassess at 4–8 weeks at therapeutic dose | |||||||||||||||||||||||||||||
| Remission Continue effective dose: ≥6 mo (first episode); 12–24 mo or indefinite (recurrent/high-risk) | Inadequate response Confirm dose, duration, adherence, diagnosis | ||||||||||||||||||||||||||||
| Switch, augment, or combine • Switch agent (within/across class) • Augment: aripiprazole, brexpiprazole, quetiapine, lithium, or T3 • Combine: add bupropion or mirtazapine | |||||||||||||||||||||||||||||
| Treatment-resistant depression (≥2 failed adequate trials) • Intranasal esketamine + oral antidepressant (REMS, ≥2-h monitoring) • IV ketamine (off-label) • Refer for ECT or rTMS | |||||||||||||||||||||||||||||
References
- ↑ Park LT, Zarate CA. Depression in the Primary Care Setting. N Engl J Med. 2019.
- ↑ 2.0 2.1 Coles S, Wise D. Management of Major Depressive Disorder in Adults: Guidelines From CANMAT. Am Fam Physician. 2025.
- ↑ 3.0 3.1 3.2 Qaseem A, Owens DK, Etxeandia-Ikobaltzeta I, et al. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major Depressive Disorder: A Living Clinical Guideline From the American College of Physicians. Ann Intern Med. 2023.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Department of Veterans Affairs / Department of Defense. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder, Version 4.0. 2022.
- ↑ 5.0 5.1 5.2 Simon GE, Moise N, Mohr DC. Management of Depression in Adults: A Review. JAMA. 2024.
- ↑ Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366.
- ↑ US Food and Drug Administration. Antidepressant class labeling: boxed warning for suicidality.
- ↑ 8.0 8.1 8.2 8.3 8.4 Gaddey HL, Mason B, Naik A. Depression: Managing Resistance and Partial Response to Treatment. Am Fam Physician. 2024.
- ↑ 9.0 9.1 Oslin DW, Lynch KG, Shih MC, et al. 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. 2022;328(2):151-161.
- ↑ Ruberto VL, Jha MK, Murrough JW. Pharmacological Treatments for Patients With Treatment-Resistant Depression. Pharmaceuticals. 2020.
- ↑ Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression; and Trivedi MH, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006.
- ↑ Mohamed S, Johnson GR, Chen P, et al. Effect of antidepressant switching vs augmentation on remission among patients with MDD unresponsive to antidepressant treatment: the VAST-D randomized clinical trial. JAMA. 2017.
- ↑ 13.0 13.1 McIntyre RS, Alsuwaidan M, Baune BT, et al. Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World Psychiatry. 2023.
- ↑ Dean RL, Hurducas C, Hawton K, et al. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021.
- ↑ McQuaid JR, Buelt A, Capaldi V, et al. The Management of Major Depressive Disorder: Synopsis of the 2022 VA/DoD Clinical Practice Guideline. Ann Intern Med. 2022.
- ↑ Kato M, Hori H, Inoue T, et al. Discontinuation of antidepressants after remission with antidepressant medication in major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry. 2021.
- ↑ Malhi GS, Bell E, Singh AB, et al. The 2020 RANZCP clinical practice guidelines for mood disorders. Bipolar Disord. 2020.