What is the recommended dosage and treatment protocol for Nortriptyline (tricyclic antidepressant) in patients with major depressive disorder?

Nortriptyline Dosing for Major Depressive Disorder

Start nortriptyline at 25 mg three to four times daily (or 10 mg at bedtime in elderly patients), titrate gradually every 5-7 days based on clinical response, and maintain plasma levels between 50-150 ng/mL for optimal therapeutic effect. 1, 2

Initial Dosing Strategy

Standard Adult Dosing

• Begin with 25 mg three to four times daily (total 75-100 mg/day) 1
• Alternative regimen: Give total daily dose once daily after initial titration 1
• Increase dosage gradually using increments of the initial dose every 5-7 days until therapeutic benefits or significant side effects appear 2

Elderly Patients (Special Population)

• Start at 10 mg at bedtime, with maximum of 40 mg per day given in divided doses 2
• Alternative elderly dosing: 30-50 mg/day in divided doses 1
• Lower doses are critical for elderly patients due to higher risk of cardiotoxicity and anticholinergic effects 2

Therapeutic Plasma Level Monitoring

Target plasma concentration: 50-150 ng/mL 2, 1, 3

• This therapeutic "window" is well-established—levels below 50 ng/mL are associated with poor response, while levels above 150 ng/mL correlate with increased adverse effects without additional benefit 2, 3
• When doses exceed 100 mg daily, plasma level monitoring should be performed and maintained in the optimal range 1
• Patients with plasma levels between 50-139 ng/mL show significantly better therapeutic response compared to those with levels of 140-260 ng/mL 3

Important Caveat on Plasma Monitoring

• Elderly patients may have higher concentrations of the active metabolite 10-hydroxynortriptyline, which can cause cardiotoxicity even when nortriptyline levels appear therapeutic 1
• Clinical findings should predominate over plasma concentrations as primary determinants of dosage changes 1

Maximum Dosing

• Do not exceed 150 mg per day 1
• Doses above 150 mg daily are not recommended due to increased adverse effects without improved efficacy 1

Treatment Timeline and Response Assessment

Acute Phase (4-8 weeks)

• A full therapeutic trial requires at least 4-8 weeks 2
• Assess patient status, therapeutic response, and adverse effects beginning within 1-2 weeks of initiation 2
• If no adequate response within 6-8 weeks, modify treatment 2

Continuation Phase (4-9 months)

• Continue treatment for 4-9 months after satisfactory response in first-episode depression 2
• After 9 months, consider dosage reduction to reassess the need for continued medication 2

Maintenance Phase

• For patients with 2 or more depressive episodes, longer duration therapy (years to lifelong) may be beneficial 2

Clinical Characteristics and Patient Selection

Nortriptyline is particularly useful for:

• Patients with agitated depression and insomnia (due to sedating properties) 2
• Treatment-resistant depression—approximately 40% of patients who failed other antidepressants respond to nortriptyline 4

Tolerance profile:

• Similar to desipramine but more sedating 2
• Lower risk for cardiotoxic, hypotensive, and anticholinergic effects compared to other tricyclics 2
• May cause tachycardia 2

Discontinuation Protocol

Taper over 10-14 days to limit withdrawal symptoms 2

Critical Safety Considerations

• Monitor for orthostatic hypotension, especially in elderly patients 5
• ECG monitoring is prudent, particularly at higher doses or in elderly patients 1
• Patients with depression and psychosis require concomitant antipsychotic medication 2
• Close monitoring for suicidal ideation is essential, particularly in the first 1-2 months of treatment 2

Context: Modern Treatment Landscape

While second-generation antidepressants (SSRIs, SNRIs) are now first-line due to lower toxicity in overdose and similar efficacy 2, nortriptyline remains a valuable option for treatment-resistant depression 4. The American College of Physicians guidelines note that first-generation antidepressants like tricyclics are "very rarely used" in current practice 2, but nortriptyline's well-defined therapeutic window and efficacy in SSRI non-responders justify its continued use as a second- or third-line agent 4.