What are the first-line medications for a patient with major depressive disorder (MDD) without significant medical comorbidities or contraindications?

First-Line Medications for Major Depressive Disorder

Second-generation antidepressants (SSRIs and SNRIs) are the first-line pharmacologic treatment for patients with moderate to severe major depressive disorder, with all agents demonstrating equivalent efficacy for general depressive symptoms. 1

Preferred SSRI Selection

For most patients without specific symptom profiles, select from sertraline, escitalopram, or citalopram as your initial SSRI. 2, 1 These three agents have the most favorable balance of efficacy, tolerability, and safety profiles. 2

• Sertraline demonstrates a trend toward superior effectiveness compared to other SSRIs and has favorable acceptability/tolerability compared to older agents like amitriptyline and imipramine. 3
• All SSRIs have a number needed to treat of 7-8 for achieving remission, indicating moderate but clinically meaningful efficacy. 1

SSRIs to Avoid

Avoid paroxetine and fluoxetine as first-line agents, particularly in elderly patients. 2, 1

• Paroxetine has notably higher rates of sexual dysfunction and anticholinergic effects compared to other SSRIs. 2, 1
• Fluoxetine has a long half-life (2-7 days for parent compound, 4-15 days for active metabolite) that increases risk of drug accumulation and requires prolonged washout periods before switching to other antidepressants. 2, 4

Symptom-Targeted Selection

When patients present with specific symptom clusters, tailor medication selection accordingly:

For Cognitive Symptoms (Concentration, Indecisiveness, Mental Fog)

Choose bupropion as the first-line agent for prominent cognitive symptoms. 1

• Bupropion's dopaminergic and noradrenergic effects specifically target cognitive dysfunction with lower rates of cognitive side effects. 1
• SNRIs (venlafaxine or duloxetine) serve as second-choice options, as their noradrenergic component improves attention and concentration better than SSRIs. 1

For Elderly Patients

Start with sertraline, escitalopram, or citalopram at low initial doses with gradual titration. 2

• Alternative options include venlafaxine, mirtazapine, and bupropion. 2, 1
• These agents balance efficacy with lower risk of falls, hyponatremia, and drug interactions in older adults. 2

Critical Monitoring Requirements

Initiate monitoring within 1-2 weeks of treatment initiation, focusing on:

• Suicidal thoughts and behaviors (particularly in adolescents and young adults). 2, 1
• Falls risk in elderly patients. 2
• Hyponatremia (especially in older adults). 2
• Drug interactions, particularly with TCAs where SSRIs inhibit TCA metabolism. 1
• Gastrointestinal symptoms (nausea, diarrhea—sertraline has higher rates of diarrhea). 2, 3

Regularly assess both mood and cognitive symptoms using standardized measures. 1

Treatment Duration

Continue treatment for at least 4-9 months after achieving remission for a first depressive episode. 2, 1

• For recurrent depression, extend treatment to at least one year to prevent recurrence. 2
• The decision to continue or discontinue should be revisited periodically with active patient involvement. 5

Common Adverse Effects

Approximately 63% of patients experience at least one adverse effect with second-generation antidepressants. 1

Most common adverse effects include:

• Nausea and vomiting, diarrhea, dizziness, dry mouth, fatigue, headache, and sexual dysfunction. 1
• Bupropion has significantly lower rates of sexual adverse events compared to SSRIs. 1
• Monitor for emergence of side effects that could worsen function, particularly sedation and anticholinergic effects. 1

Critical Pitfalls to Avoid

Do not prescribe antidepressants for mild depression or subsyndromal depressive symptoms without a current moderate-to-severe episode. 1 Antidepressants are most effective in patients with severe depression, with the drug-placebo difference increasing with initial severity. 1

Do not use tricyclic antidepressants as first-line agents due to higher adverse effect burden, overdose risk, and lack of superiority over SGAs. 6, 1

Do not assume all SSRIs have identical profiles—individual agents differ significantly in side effect profiles, drug interactions, and pharmacokinetics despite similar efficacy. 1, 3

Alternative First-Line Considerations

The American College of Physicians guideline demonstrates that SGAs show equivalent efficacy to cognitive behavioral therapy (CBT) for response and remission rates in moderate-quality evidence. 6 Consider offering either pharmacotherapy or psychotherapy as first-line treatment, or combination therapy for patients with work-functioning impairment. 6