Best Initial Treatment for Depression
For treatment-naive patients with moderate to severe major depressive disorder, initiate a second-generation antidepressant (SSRI or SNRI) at standard dosing, selecting the specific agent based on the patient's symptom profile, adverse effect tolerance, and cost considerations. 1, 2
First-Line Pharmacotherapy Selection
Second-generation antidepressants demonstrate equivalent efficacy to each other and to cognitive behavioral therapy for achieving response and remission in major depressive disorder. 1 All SSRIs and SNRIs have a number needed to treat of 7-8 for achieving remission, with no clinically significant differences in effectiveness among agents. 1, 2
Symptom-Targeted Selection Strategy
For cognitive symptoms (difficulty concentrating, indecisiveness, mental fog):
- First choice: Bupropion due to dopaminergic and noradrenergic effects with lower cognitive side effects 2
- Second choice: SNRIs (venlafaxine or duloxetine) for noradrenergic enhancement of attention 2
For general depressive symptoms without specific cognitive complaints:
- Any SSRI is appropriate (fluoxetine, sertraline, citalopram, escitalopram) 1, 2
- Selection should prioritize adverse effect profile and cost 1
For older adults (≥60 years):
- Preferred agents: Citalopram, sertraline, venlafaxine, or bupropion 1, 2
- Avoid paroxetine and fluoxetine due to higher anticholinergic effects and less favorable profiles 2
Initial Dosing Recommendations
Fluoxetine: Start 20 mg daily in the morning; this dose is sufficient for most patients. 3 May increase after several weeks if insufficient response, maximum 80 mg/day. 3
Sertraline: Start 50 mg daily, which is the optimal dose considering both efficacy and tolerability. 4 May increase in 50 mg increments weekly if needed, maximum 200 mg/day. 4
Venlafaxine: Start 75 mg/day in divided doses with food. 5 May increase to 150 mg/day based on tolerability, with further increases up to 225 mg/day (or 375 mg/day for severely depressed patients) at intervals of no less than 4 days. 5
Critical Monitoring Requirements
Initiate close monitoring within 1-2 weeks of starting treatment for: 1
- Suicidal thoughts and behaviors (highest risk in first 1-2 months) 1
- Emergence of agitation, irritability, or unusual behavioral changes 1
- Adverse effects that may prompt discontinuation 1
Expected Timeline and Response Assessment
Full therapeutic effect may be delayed until 4 weeks of treatment or longer. 3 Assess response at 6-8 weeks; if inadequate response, modify treatment by switching agents or augmenting therapy. 1 Approximately 38% of patients will not achieve treatment response and 54% will not achieve remission during initial 6-12 weeks of treatment. 1
Treatment Duration
Continue treatment for 4-9 months after achieving remission for a first episode. 1, 2 For patients with two or more prior episodes, extend treatment to at least one year or longer to prevent recurrence. 1, 2
Common Adverse Effects to Anticipate
Approximately 63% of patients experience at least one adverse effect. 2 Most common include nausea/vomiting (leading cause of discontinuation), diarrhea, dizziness, headache, insomnia, and sexual dysfunction. 1, 2
Sexual dysfunction considerations:
- Bupropion has the lowest rates of sexual adverse events 1, 2
- Paroxetine has the highest rates among SSRIs 1, 2
Critical Pitfalls to Avoid
Do not prescribe antidepressants for mild depression or subsyndromal symptoms without a current moderate-to-severe depressive episode, as the benefit over placebo is minimal in mild cases. 1, 2
Do not use tricyclic antidepressants as first-line agents due to higher adverse effect burden, overdose risk, and lack of superiority over second-generation antidepressants. 1, 2
Do not assume all SSRIs are identical: Paroxetine specifically has higher anticholinergic effects and sexual dysfunction rates compared to other SSRIs. 1, 2
When discontinuing, taper gradually rather than stopping abruptly to minimize withdrawal symptoms. 5