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), as this is the recommended initial dose 4:

• The starting dose can often be the therapeutic dose for SSRIs, unlike TCAs which require titration 3
• Dose increases may be considered after several weeks if insufficient clinical improvement is observed 4
• Maximum fluoxetine dose should not exceed 80 mg/day 4
• Use a "start low, go slow" approach in older adults, with lower starting doses 1, 2

Monitoring Timeline

Assess patient status within 1-2 weeks of treatment initiation to monitor for adverse effects and suicidal ideation 1:

• Close monitoring for suicidal thoughts is critical in the first 1-2 weeks after starting therapy 1
• Reassess at 4 and 8 weeks using standardized validated instruments to evaluate symptom relief and adverse events 3
• If no improvement after 6-8 weeks despite good adherence, modify the treatment regimen (change medication, add psychotherapy, or augment with another agent) 3, 1
• Full therapeutic effect may be delayed until 4-5 weeks of treatment or longer 4

Treatment Duration

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

• After remission, maintain treatment for 4-9 months minimum 1
• Patients with recurrent depression require prolonged treatment of at least one year to prevent recurrence 3, 1

Common Adverse Effects to Anticipate

Approximately 63% of patients will experience at least one adverse effect during SSRI treatment 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
• SSRIs have lower lethal potential in overdose compared to TCAs, making them safer for patients at suicide risk 2

Alternative to Medication: Psychotherapy

Cognitive behavioral therapy (CBT), behavioral activation, interpersonal therapy, and problem-solving therapy are equally valid first-line options with medium-sized effects over usual care 5:

• Combined psychotherapy plus antidepressant medication is superior to either alone, particularly for severe or chronic depression 5
• A network meta-analysis showed combined treatment produced greater symptom improvement than psychotherapy alone (SMD 0.30) or medication alone (SMD 0.33) 5

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
• Do not discontinue treatment prematurely; many patients stop before achieving full benefit 1
• Allow at least 5 weeks washout when switching from fluoxetine to an MAOI due to its long half-life 4
• At least 14 days must elapse between discontinuing an MAOI and starting an SSRI 4