Can you prescribe citalopram (Celexa) and amitriptyline (Elavil) for an adult patient with depression?

Can You Prescribe Citalopram and Amitriptyline Together for Depression?

Yes, you can prescribe citalopram and amitriptyline together for depression, but this combination requires careful monitoring for serotonin syndrome and QT prolongation, and should generally be reserved for treatment-resistant cases after exhausting standard switching and augmentation strategies. 1

Evidence Supporting Combination Use

• Citalopram does not significantly increase tricyclic antidepressant plasma levels, unlike other SSRIs such as fluoxetine and fluvoxamine, making it a safer choice if combining with amitriptyline is necessary 2
• In a case series of five patients, adding citalopram 40-60 mg/day to amitriptyline 75 mg/day resulted in clinical improvement without adverse effects or changes in amitriptyline/nortriptyline plasma levels 2
• Both medications have demonstrated efficacy as monotherapy for major depressive disorder, with amitriptyline showing significant superiority over placebo (OR 2.67,95% CI 2.21 to 3.23) 3

Critical Safety Concerns and Monitoring Requirements

Serotonin Syndrome Risk

• The FDA explicitly warns that combining SSRIs like citalopram with tricyclic antidepressants increases the risk of potentially life-threatening serotonin syndrome 1
• Monitor for mental status changes (agitation, hallucinations, confusion), autonomic instability (tachycardia, labile blood pressure, hyperthermia), neuromuscular symptoms (tremor, rigidity, myoclonus), and gastrointestinal symptoms (nausea, vomiting, diarrhea) 1
• If serotonin syndrome develops, discontinue both medications immediately and initiate supportive treatment 1

QT Prolongation Risk

• Citalopram prolongs the QT interval in a dose-dependent manner and should not be used with other drugs that prolong QTc, including tricyclic antidepressants like amitriptyline 1
• Obtain baseline ECG before initiating combination therapy, particularly in patients over 60 years, those with cardiac disease, or those taking other QT-prolonging medications 1
• Check baseline serum potassium and magnesium levels, as electrolyte disturbances increase arrhythmia risk; correct abnormalities before starting treatment 1
• Discontinue citalopram if QTc measurements exceed 500 ms 1
• Limit citalopram to maximum 20 mg/day in patients over 60 years, those with hepatic impairment, CYP2C19 poor metabolizers, or those taking CYP2C19 inhibitors 1

Recommended Clinical Algorithm

First-Line Approach

• Start with monotherapy using either citalopram or another second-generation antidepressant, as recommended by the American College of Physicians 4
• Reserve combination therapy for patients who have failed adequate trials of monotherapy 4

If Monotherapy Fails

• Switch to a different antidepressant class rather than combining two agents, as switching strategies show equivalent efficacy (25% remission rate) with lower risk profiles 5
• The American College of Physicians found no significant differences in efficacy when switching between bupropion, sertraline, or venlafaxine after citalopram failure 4

Augmentation Strategy (If Switching Fails)

• Augment with bupropion rather than amitriptyline, as this provides superior efficacy with lower discontinuation rates due to adverse events compared to buspirone augmentation 4, 6
• Add cognitive behavioral therapy alongside any pharmacologic strategy, as combination therapy provides superior outcomes 5, 6

When Combination May Be Considered

• Only after exhausting switching strategies and non-serotonergic augmentation options 5
• In treatment-resistant depression where the patient has failed multiple adequate trials 4
• When the patient has partial response to citalopram but requires additional noradrenergic effects from amitriptyline 7

Practical Implementation

Dosing Considerations

• If combining, use lower doses of both agents initially (citalopram 20 mg/day, amitriptyline 25-50 mg/day) 2
• Citalopram 40-60 mg/day combined with amitriptyline 75 mg/day has been used successfully in case reports, but requires intensive monitoring 2
• Never exceed citalopram 40 mg/day in combination therapy due to QT prolongation risk 1

Monitoring Protocol

• Baseline: ECG, electrolytes (potassium, magnesium), liver function tests 1
• Weekly monitoring for first month: vital signs, serotonin syndrome symptoms, cardiac symptoms (palpitations, dizziness, syncope) 1
• Monitor intensively for suicidal ideation during initiation and dose changes, as all antidepressants carry black box warnings for increased suicidal thinking 6, 1
• Repeat ECG at steady state (approximately 1 week) and with any dose adjustments 1

Common Pitfalls to Avoid

• Do not combine two serotonergic antidepressants as first-line treatment—exhaust switching strategies first 5
• Avoid this combination in patients over 60 years unless citalopram is limited to 20 mg/day maximum 1
• Do not use in patients with pre-existing cardiac conduction abnormalities, congenital long QT syndrome, or those taking other QT-prolonging medications 1
• Tricyclic antidepressants like amitriptyline are not recommended as first-line or even second-line treatment due to their high anticholinergic burden and cardiovascular risks 8

Comparative Efficacy Evidence

• A direct comparison trial found citalopram as efficacious as amitriptyline for endogenous depression, but with significantly fewer side effects when used as monotherapy 7
• Amitriptyline causes more anticholinergic effects, sedation, cardiovascular effects, and weight gain compared to citalopram 3
• The combination may be theoretically beneficial by targeting both serotonergic (citalopram) and noradrenergic (amitriptyline) systems, but this has not been validated in controlled trials 9, 7