What is the recommended first-line treatment for depression?

First-Line Treatment for Depression

Second-generation antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are the recommended first-line pharmacological treatment for major depressive disorder, with selection based on adverse effect profiles, cost, and patient preferences. 1, 2

Why SSRIs Are First-Line

• SSRIs are modestly superior to placebo for treating major depressive disorder in primary care populations, with a number needed to treat of 7-8 3, 1, 2
• All second-generation antidepressants show equivalent efficacy for treatment-naïve patients, meaning no single SSRI or other second-generation antidepressant is more effective than another 3, 1
• The benefit over placebo is most pronounced in patients with severe depression, making them particularly valuable for this population 3, 1
• SSRIs have a superior safety profile compared to older tricyclic antidepressants (TCAs), with lower toxicity in overdose and better tolerability 1, 2

Specific SSRI Selection

For most adults, start with citalopram, escitalopram, or sertraline as these are well-tolerated first-line options 1, 2:

• Citalopram, escitalopram, and sertraline are preferred for older adults due to more favorable adverse effect profiles 3, 1, 2
• Avoid paroxetine and fluoxetine in older adults due to higher rates of adverse effects 3, 1, 2
• For breastfeeding mothers, sertraline and paroxetine transfer to breast milk in lower concentrations than other antidepressants 1, 2
• Consider bupropion if sexual dysfunction is a concern, as it has lower rates compared to SSRIs 1

Starting Dose and Titration

Begin with fluoxetine 20 mg/day in the morning (if fluoxetine is chosen), which is the recommended initial dose for adults 4:

• This starting dose can serve as the therapeutic dose without need for immediate titration 4
• Dose increases may be considered after several weeks if insufficient clinical improvement is observed 4
• Maximum dose should not exceed 80 mg/day 4
• Use a "start low, go slow" approach in older adults, with preferred starting doses at the lower end of the range 1, 2

Monitoring Timeline

Assess patient status within 1-2 weeks of treatment initiation and continue regular monitoring 1:

• Monitor closely for suicidal thoughts and behaviors in the first 1-2 weeks, as SSRIs are associated with increased risk for suicide attempts compared to placebo 1
• Reassess at 4 and 8 weeks to evaluate symptom relief, adverse effects, and patient satisfaction 3
• If no adequate response by 6-8 weeks, modify treatment by switching medications, adding another agent, or augmenting with psychotherapy 3, 1
• Response is defined as a 50% reduction in symptom severity using standardized assessment tools 1

Treatment Duration

Continue treatment for at least 4 months after achieving remission for a first episode 3, 1:

• After remission, maintain treatment for at least 4-9 months 1
• For recurrent depression, extend treatment to at least one year to prevent recurrence 3, 1
• The full therapeutic effect may be delayed until 4 weeks of treatment or longer 4

Common Adverse Effects to Anticipate

Approximately 63% of patients will experience at least one adverse effect 3, 2:

• Nausea and vomiting are the most common reasons for discontinuation 3, 2
• Other common effects include sexual dysfunction, sweating, tremor, weight gain, diarrhea, dizziness, dry mouth, fatigue, and headache 3
• The number needed to harm causing discontinuation ranges from 20-90 for SSRIs 3

When to Consider Psychotherapy Instead or in Addition

For moderate to severe depression, consider combining psychotherapy with medication rather than medication alone 3, 5:

• Combined treatment shows greater symptom improvement than psychotherapy alone (SMD 0.30) or medication alone (SMD 0.33) 5
• Cognitive behavioral therapy (CBT), behavioral activation, interpersonal therapy, and problem-solving therapy all show medium-sized effects over usual care (SMD ranging from 0.50 to 0.73) 5
• Psychotherapy and SSRIs show no difference in response or remission rates when compared head-to-head, making either acceptable as monotherapy for less severe cases 3

Critical Pitfalls to Avoid

• Never use SSRIs as monotherapy in bipolar disorder, as they can trigger manic episodes; always combine with a mood stabilizer if antidepressant is needed 2
• Allow at least 5 weeks after stopping fluoxetine before starting an MAOI due to its long half-life 4
• Do not combine SSRIs with other serotonergic medications without caution, as this increases risk of serotonin syndrome 3