What are the guidelines for selecting and switching between different classes of antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), Tricyclic Antidepressants (TCAs), and Monoamine Oxidase Inhibitors (MAOIs)?

Antidepressant Selection Guide

First-Line Treatment: SSRIs

For treatment-naive patients with major depressive disorder, start with an SSRI as they demonstrate equivalent efficacy to other antidepressants but with superior safety and tolerability profiles. 1

SSRI Selection Algorithm

Choose based on these specific clinical features:

• Fluoxetine: Select when patient presents with fatigue, hypersomnia, or psychomotor retardation (most activating SSRI with least sedation) 2

  • Avoid in patients with significant anxiety, agitation, insomnia, or seizure disorders 2
  • Avoid in older adults due to higher adverse effect rates 1, 2

• Sertraline, Citalopram, or Escitalopram: Preferred for older adults (age >65) 1

  • Citalopram/escitalopram have lowest drug-drug interaction potential among SSRIs 1
  • Citalopram contraindicated if doses exceed 40 mg/day due to QT prolongation risk 1

• Paroxetine: Generally avoid as second-line due to higher suicidal thinking risk compared to other SSRIs and problematic discontinuation syndrome 1

  • Also avoid in older adults 1

• Fluvoxamine: Avoid when polypharmacy is present due to extensive CYP450 interactions (affects CYP1A2, 2C19, 2C9, 3A4, 2D6) 1

SSRI Dosing and Duration

• Acute treatment: Continue for 8-12 weeks to assess efficacy, though improvement may be evident by 2-4 weeks 1, 3
• Maintenance after first episode: Minimum 4-12 months after remission 1
• Recurrent depression: Consider prolonged or indefinite treatment 1, 3

Second-Line Treatment: SNRIs

Switch to an SNRI (venlafaxine or duloxetine) when SSRIs fail or when treating severe depression with prominent physical symptoms. 1

• SNRIs show slightly higher response rates than SSRIs (NNT 4.94 vs 4.70) but with increased nausea/vomiting 1
• Duloxetine and venlafaxine have higher discontinuation rates due to adverse effects compared to SSRIs 1
• SNRIs may be more effective for severe depression and physical symptoms than SSRIs 4
• Venlafaxine demonstrates superior remission rates versus SSRIs in pooled analyses 1

Third-Line Treatment: TCAs

Reserve TCAs for treatment-resistant depression after SSRI and SNRI failure, or when dual-action mechanism is specifically needed. 1, 5

• Clomipramine and amitriptyline (dual reuptake inhibitors) show superior efficacy to SSRIs in severe depression and hospitalized patients 1
• TCAs have significantly worse tolerability: NNH 4-30 versus 20-90 for SSRIs 1
• Major safety concerns: anticholinergic effects, orthostatic hypotension, sedation, cognitive impairment, and high lethality in overdose 6, 7
• Avoid in elderly, patients with cardiac disease, and those at suicide risk 8

Fourth-Line Treatment: MAOIs

Consider MAOIs only for highly treatment-resistant depression after multiple failed trials, particularly in atypical depression. 1, 5

• Phenelzine superior to imipramine specifically in patients with atypical symptoms 1
• Require strict dietary restrictions (tyramine-free diet) and extensive drug interaction monitoring 1
• Absolute contraindication: Cannot combine with any serotonergic drug (SSRIs, SNRIs, TCAs, tramadol, dextromethorphan, etc.) due to fatal serotonin syndrome risk 1, 3

Switching Between Antidepressants

MAOI Washout Requirements (Critical Safety Issue)

• Switching TO MAOI: Minimum 14 days after stopping SSRI/SNRI/TCA 3, 9
• Switching FROM MAOI: Minimum 14 days before starting any serotonergic agent 3
• Exception for fluoxetine: Requires 5-6 weeks washout due to long half-life 9

Within-Class Switching

• SSRI to different SSRI: Can switch directly or with brief taper, no mandatory washout 1
• SSRI to SNRI: Can switch directly with cross-taper 1

Discontinuation Protocol

• Always taper gradually rather than abrupt cessation to minimize discontinuation syndrome (dizziness, paresthesias, anxiety, nausea) 3, 9
• Paroxetine, fluvoxamine, and sertraline have highest discontinuation syndrome risk 1

Special Populations

Adolescents with Depression

• Fluoxetine is the only FDA-approved and most evidence-supported SSRI for adolescent depression 1
• Combination therapy (fluoxetine + CBT) superior to either alone 1
• Avoid duloxetine, venlafaxine, and paroxetine due to poor tolerability in youth 1
• TCAs and MAOIs not recommended due to lack of efficacy and safety concerns 1

Anxiety Disorders

• Social anxiety disorder: SSRIs or SNRIs first-line (NNT 4.70 and 4.94 respectively) 1
• OCD: SSRIs first-line; clomipramine more efficacious but worse tolerability 1
  • Higher SSRI doses required for OCD than depression 1
• Panic disorder: SSRIs first-line, continue 6+ months after response 3

Comorbid Conditions

• Diabetic neuropathy: Duloxetine 60 mg daily 9
• Chronic pain/fibromyalgia: Duloxetine or SNRIs preferred 9
• Cardiac disease: Avoid TCAs; use SSRIs (sertraline has best cardiac safety data) 1
• Hepatic impairment: Avoid duloxetine; reduce SSRI doses 3, 9
• Severe renal impairment (GFR <30): Avoid duloxetine; adjust SSRI doses 3, 9

Critical Drug Interactions

• Linezolid or IV methylene blue: Stop SSRI/SNRI immediately if urgent treatment needed; monitor 2 weeks (SSRI) or 5 days (duloxetine) before restarting 3, 9
• Pimozide: Contraindicated with sertraline due to QT prolongation 3
• Anticoagulants/NSAIDs: Increased bleeding risk with SSRIs; monitor closely 1
• CYP2D6 substrates (TCAs, flecainide, propafenone): Reduce doses when combined with SSRIs 3