What is the appropriate dosage and treatment plan for an adult patient with a history of depression who is prescribed Nortryptilene (tricyclic antidepressant)?

Nortriptyline Dosing and Treatment Plan for Adult Depression

Initial Dosing Strategy

For adult outpatients with depression, start nortriptyline at 25 mg three to four times daily (total 75-100 mg/day), or alternatively give the entire daily dose once at bedtime, which offers equivalent efficacy with better adherence and no increase in side effects. 1, 2

Standard Dosing Algorithm

• Outpatients: Begin with 25 mg 3-4 times daily, increasing gradually as tolerated 1
• Alternative once-daily regimen: Administer the total daily dose at bedtime (75-150 mg), which provides equivalent therapeutic benefit with improved compliance 2
• Hospitalized patients: May initiate at higher doses (75-125 mg based on weight), with 81% reaching therapeutic plasma levels within one week and 45% symptom reduction observed 3
• Elderly patients (≥65 years): Start at 30-50 mg/day in divided doses, with mean effective doses around 50 mg/day (range 20-100 mg) 1, 4

Dose Titration

• Increase dosage gradually every 5-7 days by 25 mg increments until therapeutic response or side effects emerge 5
• Maximum recommended dose: 100 mg/day for most patients; doses above 100 mg/day carry increased risk of sudden cardiac death, particularly in those with cardiovascular disease 6
• Doses above 150 mg/day are not recommended under any circumstances 1

Therapeutic Plasma Monitoring

Target plasma concentration range is 50-150 ng/mL, with optimal responses typically occurring around 100 ng/mL. 1, 7

When to Monitor Plasma Levels

• When doses exceed 100 mg/day 1
• In elderly patients, who develop higher concentrations of the active metabolite 10-hydroxynortriptyline 6, 1
• If clinical response is inadequate despite adequate dosing 8
• When side effects emerge to distinguish between subtherapeutic and toxic levels 7

Critical Monitoring Caveat

• Plasma concentrations above 150 ng/mL are associated with decreased efficacy and increased adverse effects 8, 1
• In elderly patients, cardiotoxicity can occur even with nortriptyline levels in the "therapeutic range" due to elevated metabolite concentrations 1
• Clinical findings should predominate over plasma concentrations as primary determinants of dosage 1

Treatment Duration

• First episode of major depression: Continue treatment for at least 4 months after remission 5
• Recurrent depression: Prolonged maintenance treatment is beneficial 5
• Full therapeutic trial requires 4-8 weeks before declaring treatment failure 8
• Some patients show significant improvement within 1 week when adequate plasma levels are achieved 3, 9

Cardiovascular Monitoring Requirements

Obtain baseline ECG before initiating therapy, especially if doses will exceed 100 mg/day or in patients with any cardiac history. 8, 6

Specific Monitoring Parameters

• Measure blood pressure sitting and standing to detect orthostatic hypotension, particularly during the first 1-2 weeks 8, 10
• Monitor for QTc prolongation and cardiac conduction abnormalities 8
• Orthostatic hypotension is the most significant cardiovascular concern in younger patients, while arrhythmias are more problematic in elderly patients 3, 9

Common Adverse Effects and Management

The number needed to harm causing discontinuation ranges from 4 to 30 for tricyclic antidepressants, significantly higher than the 20-90 for SSRIs. 5

Anticholinergic Effects

• Dry mouth, constipation, urinary retention, blurred vision, and confusion are common 5, 6
• Nortriptyline causes fewer anticholinergic effects than tertiary amine TCAs (amitriptyline, imipramine), making it better tolerated, especially in elderly patients 8, 6
• If minor side effects develop, reduce the dosage rather than discontinuing 1

Serious Adverse Effects Requiring Discontinuation

• Discontinue promptly if serious adverse effects or allergic manifestations occur 1
• Orthostatic hypotension requiring intervention occurs in approximately 10% of patients but can usually be managed with fludrocortisone without discontinuation 3, 9

Critical Pitfalls to Avoid

• Do not abruptly discontinue: Taper over minimum 10-14 days with 25% dose reductions every 5-7 days; elderly patients require even slower tapers (10% reductions every 2-4 weeks) 10
• Do not use 1:1 dose conversion when switching between different TCAs, as they have different potencies 8
• Do not exceed 100 mg/day without compelling indication due to increased cardiac mortality risk 6
• Do not combine with other TCAs: Nortriptyline is the active metabolite of amitriptyline, making combination pharmacologically redundant and increasing toxicity risk 6

Special Population Considerations

Elderly Patients

• Nortriptyline is preferred over other TCAs in older adults due to fewer anticholinergic effects 5, 6
• Start at 30-50 mg/day with slower titration 1
• Monitor closely for falls risk due to orthostatic hypotension and sedation 10
• Therapeutic outcomes in elderly patients (≥65 years) are equivalent to or better than younger patients when properly dosed 7

Patients with Cardiovascular Disease

• Nortriptyline is contraindicated in recent MI, arrhythmias, or heart block 6
• Alternative treatments should be strongly considered in patients with cardiovascular disease 6

Efficacy Expectations

Antidepressants are most effective in patients with severe depression, with number needed to treat of 7-16 for TCAs. 5

• Approximately 80% of properly dosed patients achieve therapeutic response 7
• Early response (within 1 week) predicts ultimate treatment success when therapeutic plasma levels are achieved 3, 9
• TCAs show only modest superiority over placebo in primary care populations, but demonstrate clear benefit in severe depression 5