What classes of antidepressants are most suitable for patients with varying degrees of depression, including those with mild to moderate depression, severe depression, bipolar disorder, or significant medical comorbidities, and how should they be selected based on patient-specific needs and circumstances?

Antidepressant Selection by Clinical Context

Select second-generation antidepressants (SSRIs, SNRIs, bupropion, mirtazapine) as first-line therapy based on adverse effect profiles, cost, and patient preferences rather than efficacy differences, since no second-generation antidepressant demonstrates superior effectiveness over another. 1

First-Line Selection Framework

For Major Depressive Disorder (Moderate to Severe)

Start with SSRIs or SNRIs as they are considered first-line therapy due to superior tolerability compared to older agents. 1

• Efficacy is modest but real: SSRIs have a number needed to treat of 7-8 for remission in primary care populations, with greater benefit in severe versus mild depression 1
• No efficacy differences exist between second-generation antidepressants regardless of age, sex, or race 1

Specific Agent Selection Within Class

Choose specific agents based on side effect profiles and patient-specific factors:

When Sexual Dysfunction is a Concern

• Bupropion: Lower rates of sexual adverse events than fluoxetine or sertraline 1
• Avoid paroxetine: Higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline 1

For Older Adults (≥65 years)

• Preferred agents: Citalopram, escitalopram, sertraline, mirtazapine, or venlafaxine 1
• Start at 50% of adult starting dose and titrate slowly ("start low, go slow" approach) 1
• Avoid: Paroxetine (anticholinergic effects) and fluoxetine (agitation risk) 1

For Pregnancy and Breastfeeding

• High-quality evidence is lacking for antidepressant use in pregnancy 1
• For breastfeeding: Sertraline and paroxetine transfer to breast milk in lower concentrations than other antidepressants 1

For Comorbid Pain Disorders

• SNRIs provide additional benefits over SSRIs, though remission rates are only marginally superior (49% vs 42%) 1

For Bipolar Depression

Do NOT use conventional antidepressants (SSRIs, bupropion, SNRIs) as monotherapy in bipolar depression due to risk of mood destabilization. 2, 3

Preferred Approach for Bipolar Depression

• If antidepressants are used: Combine serotonin-reuptake inhibitors (SRIs) or bupropion with a mood stabilizer (lithium, anticonvulsants) or atypical antipsychotic 2
• Use moderate doses for limited duration with close clinical supervision 2
• Safer in bipolar II than bipolar I disorder 2
• Consider atypical antipsychotics (olanzapine, quetiapine) which possess antidepressant activity without destabilizing mood 3

For Mild Depression or Subsyndromal Depression

Antidepressants should NOT be used for initial treatment of adults with depressive symptoms in absence of current or prior moderate/severe depressive episode. 1

• Antidepressants show little difference from placebo in patients with less severe depression 1
• The drug-placebo difference increases with severity: virtually no difference in mild depression, small difference in moderate depression, medium difference in severe depression 1

Monitoring and Treatment Modification

Initial Monitoring

Assess patient status, therapeutic response, and adverse effects within 1-2 weeks of initiation. 1

• Monitor closely for suicidal thoughts/behaviors, especially in the first 1-2 months when risk is greatest 1, 4
• Watch for: Agitation, irritability, unusual behavior changes, anxiety, panic attacks, insomnia, hostility, impulsivity, akathisia, hypomania, or mania 4

Treatment Duration

Continue for 4-12 months for an initial episode of major depression. 1

• Patients with recurrent depression may benefit from prolonged treatment 1

When to Switch

Modify treatment if inadequate response after 6-8 weeks of therapy. 1

• Response rate to initial drug therapy may be as low as 50% 1
• No evidence supports preferring one agent over another as second-line therapy 1
• When switching: Direct crossover, moderate taper-overlap, or conservative approaches are all acceptable except when switching to/from MAOIs, which require adequate washout periods 5

Important Safety Considerations

Drug Interactions

• SSRIs increase risk for suicide attempts compared to placebo 1
• Fluoxetine inhibits CYP2D6: Use caution with TCAs, antipsychotics (phenothiazines), and antiarrhythmics; avoid thioridazine entirely 4
• Sertraline has less prominent CYP2D6 inhibition at lower doses but still requires caution with co-administered drugs metabolized by this pathway 6

Bleeding Risk

Caution with concurrent NSAIDs, aspirin, or warfarin as SSRIs/SNRIs interfere with serotonin-mediated platelet function and increase bleeding risk 6

Common Pitfalls to Avoid

• Do not use low-dose sedating antidepressants (trazodone, mirtazapine, doxepin, amitriptyline) as adequate treatment for major depression with comorbid insomnia; these require full antidepressant dosing 1
• Do not use antidepressants in children 6-12 years with depression in non-specialist settings 1
• For adolescents: Only fluoxetine (not TCAs or other SSRIs) may be considered in non-specialist settings, with close monitoring for suicidal ideation 1
• Avoid routine anticholinergic co-prescription with antipsychotics as there is no evidence supporting routine use for preventing extrapyramidal side effects 1