What are tricyclic antidepressants?

What Are Tricyclic Antidepressants?

Tricyclic antidepressants (TCAs) are a class of first-generation antidepressants that were originally developed for treating depression but are now primarily used for chronic pain conditions, particularly neuropathic pain, due to their dual norepinephrine and serotonin reuptake inhibition. 1

Chemical Structure and Mechanism

• TCAs are named for their three-ring chemical structure and work by blocking the reuptake of both norepinephrine and serotonin at presynaptic nerve terminals 2
• This dual mechanism distinguishes them from selective serotonin reuptake inhibitors (SSRIs), which only affect serotonin 1

Common TCA Medications

Secondary amine TCAs (preferred):

• Nortriptyline - preferred over other TCAs due to fewer anticholinergic side effects 2, 3
• Desipramine - another secondary amine with better tolerability 2

Tertiary amine TCAs:

• Amitriptyline - most studied TCA with established efficacy but more side effects 2
• Imipramine - older TCA with similar efficacy profile 4
• Doxepin - comparable effectiveness to amitriptyline 5
• Clomipramine - associated with higher rates of side effects 5

Primary Clinical Uses Today

Neuropathic pain (first-line indication):

• TCAs are recommended as first-line treatment for neuropathic pain including diabetic neuropathy and postherpetic neuralgia 2
• Nortriptyline is preferred over amitriptyline for neuropathic pain due to equivalent efficacy with superior tolerability 3
• Number needed to treat ranges from 7 to 16 for pain relief 2

Migraine prevention:

• Amitriptyline has consistent evidence supporting efficacy at dosages of 30-150 mg/day for migraine prevention 2
• Amitriptyline is superior to propranolol for patients with mixed migraine and tension-type headache 2

Fibromyalgia:

• Amitriptyline is commonly used and recommended for fibromyalgia symptoms, though evidence for effectiveness is limited 2

Other chronic pain conditions:

• TCAs serve as first-line or augmenting drugs for headache, gastrointestinal syndromes, pelvic pain, and insomnia 6

Depression Treatment (Historical Context)

• TCAs were the original antidepressants but have been largely superseded by second-generation antidepressants (SSRIs/SNRIs) for depression treatment 1
• TCAs show only minimal superiority to active placebos in older depression studies 2
• When used for depression, the number needed to treat is 7-16 2
• TCAs maintain efficacy for treatment-resistant depression, with approximately 40% response rate after failed antidepressant trials 3

Dosing Strategy

For neuropathic pain:

• Start at 10-25 mg at bedtime and titrate gradually every 3-7 days 3
• Target dose range: 25-100 mg daily 3
• Maximum recommended dose: 150 mg/day 3
• Therapeutic drug monitoring is recommended when approaching maximum doses 3

For depression:

• Higher doses (equivalent to 150 mg amitriptyline) are required compared to pain indications 5
• Full therapeutic trial requires 4-8 weeks 3

Significant Adverse Effects

Anticholinergic effects (most common):

• Dry mouth, orthostatic hypotension, constipation, urinary retention 2
• These effects can be reduced by starting with low bedtime doses and using secondary amines (nortriptyline, desipramine) 2

Cardiovascular toxicity:

• TCAs are highly lethal in overdose and should never be prescribed to suicidal patients 7
• Can cause prolonged PR and QT intervals, bundle branch block patterns, and various arrhythmias 8
• First-degree atrioventricular block and orthostatic hypotension occur commonly 9
• Baseline ECG is required before initiating therapy, particularly in patients with cardiac history 3

Other common side effects:

• Fatigue, depression, nausea, dizziness, insomnia 2
• Weight gain, drowsiness 2

Special Population Considerations

Older adults (≥65 years):

• TCAs are potentially inappropriate due to anticholinergic effects 2
• Preferred antidepressants for older patients include citalopram, escitalopram, sertraline, mirtazapine, and venlafaxine instead 2

Cardiac patients:

• TCAs can be used safely in cardiac transplant recipients with appropriate monitoring 3
• Contraindicated in patients with recent MI, arrhythmias, heart block, or prolonged QTc syndrome 3

Pediatric patients:

• TCAs lack efficacy in children for depression, unlike their effectiveness in adults 2
• This suggests depression in children may differ neurochemically from adult depression 2

Critical Monitoring Parameters

• Obtain baseline ECG before initiating therapy 3
• Monitor for orthostatic hypotension, especially during the first 1-2 weeks 3
• Assess therapeutic response within 1-2 weeks, though full trial requires 4-8 weeks 3
• Monitor serum levels when approaching maximum doses to ensure therapeutic window 3

Treatment Duration

• Continue treatment for 4-9 months after satisfactory response for first-episode major depression 3
• Patients with 2 or more episodes may benefit from longer duration therapy 3

Why TCAs Are No Longer First-Line for Depression

• Second-generation antidepressants (SSRIs, SNRIs) have similar efficacy but lower toxicity in overdose 1
• TCAs have significantly more dangerous side effect profiles, particularly cardiovascular and anticholinergic effects 2, 8
• The high lethality of TCAs in overdose makes them unsuitable for patients with suicidal ideation 7