What is the recommended dosing for Selective Serotonin Reuptake Inhibitors (SSRIs)?

SSRI Dosing Recommendations

Start SSRIs at low doses and titrate slowly over 3-4 week intervals to avoid exceeding the optimal dose, as clinical improvement occurs by week 6 with maximal benefit by week 12 or later. 1

General Dosing Principles

Titration Strategy

• Use slow up-titration with small increments (5-10mg increases) to prevent dose-related adverse effects, particularly behavioral activation and agitation. 1, 2
• The logarithmic response model shows statistically significant improvement within 2 weeks, but clinically meaningful improvement requires 6 weeks, with maximal response at 12+ weeks. 1
• Begin with a subtherapeutic "test dose" in patients prone to anxiety or agitation, as SSRIs can paradoxically worsen these symptoms initially. 2

Frequency of Administration

• Most SSRIs permit once-daily dosing due to long elimination half-lives, particularly fluoxetine (1-3 days for parent drug, 4-16 days for active metabolite norfluoxetine). 1, 2
• Sertraline at low doses and fluvoxamine at any dose require twice-daily dosing in children and adolescents. 1
• Fluoxetine should be dosed in the morning due to its activating properties and risk of insomnia. 2
• Sertraline can be administered at any time of day (morning or evening). 3

Medication-Specific Dosing

Sertraline

• Start at 50mg daily, which is the optimal therapeutic dose for most patients balancing efficacy and tolerability. 4
• Therapeutic range: 50-200mg/day across all approved indications. 3
• Increase in 50mg increments at no less than weekly intervals if inadequate response after 2-4 weeks. 3, 4
• Dose adjustments can occur at 1-2 week intervals due to shorter half-life compared to fluoxetine. 3

Fluoxetine

• Start at 10mg every other morning or 10mg daily for adults. 2
• Increase at 3-4 week intervals (not 1-2 weeks) using smallest available increments (5-10mg) due to very long half-life. 2
• Side effects may not manifest for several weeks due to prolonged half-life, requiring extended monitoring periods. 2

General SSRI Class

• No specific dose titration required for most SSRIs, as initial doses are often therapeutically effective. 5
• Higher doses are associated with more adverse effects without clear evidence of superior efficacy. 2
• SSRIs demonstrate a flat dose-response curve, meaning dose escalation beyond initial therapeutic doses rarely improves outcomes. 6

Critical Safety Monitoring

Suicidality Risk

• All SSRIs carry a boxed warning for suicidal thinking and behavior through age 24 years. 1
• Absolute risk: 1% with antidepressants vs 0.2% with placebo (NNH=143 vs NNT=3 for response). 1
• Monitor closely during the first months of treatment and following all dosage adjustments. 1

Behavioral Activation/Agitation

• More common in younger children than adolescents and in anxiety disorders versus depression. 1
• Occurs early in treatment, with dose increases, or with concomitant CYP inhibitors. 1
• If increased anxiety occurs after dose escalation, immediately reduce back to the previous tolerated dose. 2
• Typically improves quickly after dose reduction, unlike mania which persists and requires active intervention. 1

Other Serious Adverse Effects

• Serotonin syndrome can develop within 24-48 hours when combining serotonergic medications. 1
• Sexual dysfunction (erectile dysfunction, delayed ejaculation, anorgasmia) occurs in adolescents. 1
• Abnormal bleeding risk, especially with concurrent NSAIDs or aspirin. 1
• Use cautiously in patients with seizure history. 1

Common Pitfalls to Avoid

• Do not increase doses at 1-2 week intervals for fluoxetine—its long half-life requires 3-4 week intervals to assess true response. 2
• Avoid assuming higher doses are more effective; SSRIs have flat dose-response curves. 6
• Do not overlook CYP2D6 poor metabolizers who may have 3.9-11.5 fold higher fluoxetine levels at standard doses, leading to toxicity. 2
• Consider adding CBT to current tolerated SSRI dose rather than escalating medication, as combination therapy shows superior outcomes to medication alone. 2

Assessment and Monitoring

• Use standardized symptom rating scales to systematically assess treatment response. 2, 3
• Monitor weekly during dose adjustments. 2
• Ensure parental oversight of medication regimens in children and adolescents. 3
• Avoid abrupt discontinuation, particularly with sertraline, due to discontinuation syndrome risk. 3