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TRICYCLIC ANTIDEPRESSANTS (TCAs) - Complete Master Guide

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1. INTRODUCTION & HISTORY

• Treatment-resistant depression
• Neuropathic pain
• Migraine prophylaxis
• Nocturnal enuresis
• OCD (clomipramine)
• Anxiety disorders

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2. CLASSIFICATION

TERTIARY AMINES (TCA parent drugs)

SECONDARY AMINES (metabolites of tertiary amines)

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3. MECHANISM OF ACTION (MOA)

Primary MOA:

• Block SERT (serotonin transporter) - increases synaptic serotonin
• Block NET (norepinephrine transporter) - increases synaptic norepinephrine
• This is the basis of the monoamine hypothesis of depression

Secondary Receptor Actions (cause side effects):

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4. PHARMACOKINETICS

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5. INDIVIDUAL TCA DRUG PROFILES

AMITRIPTYLINE (Elavil)

• "The most sedating TCA"
• Tertiary amine; metabolized to nortriptyline
• Uses: Depression, migraine prophylaxis, neuropathic pain, fibromyalgia, insomnia (low dose)
• Dose: Depression: 75-150 mg/day (max 300 mg); Migraine/pain: 10-25 mg at night; start at 25 mg and titrate
• Special note: Most commonly used TCA for pain - most evidence
• Side effects prominent: Most anticholinergic, most sedating, significant weight gain, significant orthostatic hypotension
• Formulation: Tablets (10mg, 25mg, 50mg, 75mg, 100mg, 150mg)

IMIPRAMINE (Tofranil)

• "The original TCA, gold standard for enuresis"
• Tertiary amine; metabolized to desipramine
• Uses: Depression, nocturnal enuresis (in children >6 years - only TCA FDA-approved for this), panic disorder, ADHD
• Dose: Depression: 75-200 mg/day; Enuresis: 25-75 mg at bedtime in children
• Metabolized: CYP2C19 and CYP1A2 (tertiary); desipramine product is CYP2D6
• Formulation: Tablets, capsules (Tofranil-PM)

NORTRIPTYLINE (Pamelor)

• "The safest TCA for elderly, has a therapeutic window"
• Secondary amine (metabolite of amitriptyline)
• Unique feature: Has a curvilinear (therapeutic window) dose-response - levels BELOW 50 ng/mL OR ABOVE 150 ng/mL both cause worsening. This is a classic exam question!
• Uses: Depression, neuropathic pain, smoking cessation (off-label), migraine prophylaxis
• Dose: 25-75 mg/day (lower doses than amitriptyline)
• Advantages: Least orthostatic hypotension among TCAs, better tolerated
• Preferred in: Elderly, patients with postural hypotension, cardiac patients (relatively)

DESIPRAMINE (Norpramin)

• "Least anticholinergic TCA, most norepinephrine selective"
• Secondary amine (metabolite of imipramine)
• Uses: Depression, ADHD, cocaine dependence (off-label), bulimia nervosa
• Dose: 25-200 mg/day
• Metabolism: CYP2D6 (no major alternative pathway - highly susceptible to drug interactions)
• Advantage: Best tolerated; preferred when anticholinergic effects must be minimized
• Disadvantage: Most susceptible to CYP2D6 drug interactions (fluoxetine can raise levels 3-4 fold!)

CLOMIPRAMINE (Anafranil)

• "The serotonin TCA - gold standard for OCD"
• Tertiary amine; most potent SERT inhibitor among TCAs
• FDA-approved uses: OCD (first drug ever approved for OCD, 1989)
• Also used: Cataplexy (in narcolepsy), panic disorder, body dysmorphic disorder
• Dose: OCD: 25 mg/day, titrate to 100-250 mg/day (max 250 mg/day)
• Special concern: Most associated with QT prolongation and QTc dispersion → ventricular arrhythmia risk
• Unique risk: Highest seizure risk of all TCAs
• Formulation: Capsules (25mg, 50mg, 75mg)

DOXEPIN (Sinequan, Silenor)

• "Most potent H1 antihistamine - great for sleep and itch"
• Tertiary amine
• Uses: Depression/anxiety (higher doses 75-150 mg), insomnia (low dose 3-6 mg, brand Silenor), pruritus/urticaria
• Topical: 5% cream (Zonalon) for pruritic dermatoses - potent H1+H2 antagonist
• Unique: Approved for insomnia at very low doses (3-6 mg) - "Silenor" - a completely different indication/dose range than its antidepressant use
• Metabolized: CYP2D6 substrate
• Formulation: Capsules (10-150mg), oral concentrate, topical cream, 3mg/6mg sleep tablets

AMOXAPINE (Asendin)

• "The TCA with antipsychotic properties"
• Secondary amine; active metabolite of loxapine (antipsychotic)
• Unique: Also blocks D2 dopamine receptors
• Risk: Tardive dyskinesia, EPS, NMS - unique among TCAs
• Uses: Depression with anxiety/agitation, psychotic depression
• Dose: 50-300 mg/day
• Viva trap: "Which TCA can cause tardive dyskinesia?" Answer: Amoxapine.

PROTRIPTYLINE (Vivactil)

• "The stimulating TCA - activating, no sedation"
• Secondary amine; norepinephrine-selective
• Uses: Depression, sleep apnea (off-label - reduces REM sleep)
• Dose: 15-40 mg/day (given in morning, not at night - causes insomnia)
• Side effects: Insomnia, palpitations - not good for anxious or agitated patients

TRIMIPRAMINE (Surmontil)

• "The sedating TCA with minimal reuptake inhibition"
• Tertiary amine
• Unusual: Weak reuptake inhibitor but potent sedative (mechanism not well understood; possibly H1 + alpha blockade dominant)
• Uses: Depression, insomnia
• Dose: 25-150 mg/day at bedtime

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6. INDICATIONS (FDA-Approved and Off-Label)

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7. SIDE EFFECTS (Full Profile)

ANTICHOLINERGIC (muscarinic blockade):

• Dry mouth
• Constipation
• Urinary retention (especially males with BPH)
• Blurred vision (cycloplegia)
• Tachycardia
• Confusion/cognitive impairment (especially elderly)
• Worst with: Amitriptyline, imipramine, doxepin
• Least with: Desipramine, nortriptyline

CARDIOVASCULAR:

• Orthostatic hypotension (alpha-1 blockade) - most common serious side effect
• QTc prolongation (K+ channel blockade) - risk of torsades de pointes
• QRS widening (Na+ channel blockade) - at toxic doses
• T-wave changes on ECG
• Sinus tachycardia (anticholinergic)
• AV block (rare at therapeutic doses)
• Sudden death in patients with pre-existing cardiac disease

CNS:

• Sedation (especially tertiary amines)
• Tremor (fine)
• Seizures (lower seizure threshold - especially clomipramine)
• Confusion, delirium (especially elderly)
• Nightmares
• Mania (can precipitate mania in bipolar disorder)

METABOLIC:

• Weight gain (H1 blockade)
• Increased appetite

SEXUAL:

• Decreased libido
• Anorgasmia
• Ejaculatory dysfunction

OTHER:

• Sweating (cholinergic rebound)
• Photosensitivity
• Hepatotoxicity (rare)
• Bone marrow suppression (very rare)

• Anticholinergic
• Blood pressure (orthostatic hypotension)
• Cardiac (QTc, QRS widening)
• Drowsiness (sedation), Danger in overdose
• Endocrine/metabolic (weight gain)

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8. DOSING & FORMULATIONS

• Start LOW (25 mg) and titrate SLOWLY over 1-2 weeks
• For pain/sleep: much lower doses (10-25 mg at night) are effective
• Give at bedtime to exploit sedation as an advantage
• Full antidepressant effect takes 3-6 weeks

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9. THERAPEUTIC DRUG MONITORING (TDM)

• Inadequate clinical response at therapeutic dose
• Suspected toxicity
• Drug interaction concerns
• Elderly or renally/hepatically impaired patients
• Children and adolescents
• CYP2D6 poor metabolizers (genetic polymorphism)

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10. TOXICITY & OVERDOSE

Why TCAs are dangerous in overdose:

Mechanisms of toxicity (4 mechanisms):

1. Anticholinergic: Dry, hot, flushed skin, urinary retention, tachycardia, ileus, confusion
2. Sodium channel blockade: QRS widening, ventricular arrhythmias (most lethal!)
3. Alpha-1 blockade: Hypotension, cardiovascular collapse
4. GABA antagonism: Seizures

Timeline of TCA overdose:

• 0-2 hours: Anticholinergic symptoms dominant (tachycardia, agitation, confusion, dry mouth)
• 2-6 hours: Cardiac toxicity begins (QRS widening, arrhythmias, hypotension)
• After 6 hours: If no toxicity by 6 hours, serious toxicity is unlikely

ECG Changes in TCA Toxicity (MUST KNOW):

• Sinus tachycardia (early - anticholinergic)
• QRS > 100 ms - predicts seizures
• QRS > 160 ms - predicts ventricular dysrhythmias
• Tall R wave in aVR (terminal 40ms axis shift to right) - classic sign
• QT prolongation

Treatment of TCA Overdose:

• Activated charcoal within 1 hour, ONLY if patient is awake and airway intact (not if comatose/seizing - aspiration risk)
• NO gastric lavage (no role)

• Sodium bicarbonate is the CORNERSTONE of treatment
  • Indication: QRS > 100 ms, ventricular arrhythmias
  • Dose: 1-2 mEq/kg IV bolus, repeat every 5-10 min until QRS narrows
  • Then infusion to maintain pH 7.50-7.55
  • Mechanism: Alkalinization reduces TCA binding to Na+ channels; sodium load also directly reverses Na+ channel blockade
  • Make infusion with D5W, NOT normal saline (avoid hypernatremia)
• 3% hypertonic saline if refractory ventricular arrhythmias despite max alkalinization (pH > 7.55)
• Direct vasopressors (norepinephrine, epinephrine) for hypotension refractory to fluids
• Avoid Class IA and IC antiarrhythmics (quinidine, procainamide, flecainide) - additive Na+ channel blockade!
• Avoid physostigmine - risk of asystole especially with bradycardia/AV block (controversial, but exam answer is to avoid)

• IV benzodiazepines (lorazepam 1-4 mg or diazepam 5-10 mg)
• Phenobarbital for refractory seizures (15-20 mg/kg IV)
• Avoid phenytoin - also blocks Na+ channels, no proven benefit, may worsen cardiac toxicity

• If seizures refractory and not controlled, rapidly paralyze + intubate to prevent metabolic acidosis (acidosis worsens Na+ channel block - vicious cycle!)

• Observe for minimum 6 hours - if no toxicity by 6 hours, unlikely to develop serious toxicity
• Patients with any cardiac changes: ICU admission

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11. DRUG INTERACTIONS

Pharmacodynamic:

Pharmacokinetic:

• Desipramine: metabolized by CYP2D6 only - most susceptible to interactions
• Tertiary amines: metabolized by CYP1A2, CYP2C19, CYP3A4 (multiple pathways = less susceptible)
• SSRIs (fluoxetine, paroxetine) are potent CYP2D6 inhibitors - dangerous combination with desipramine!

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12. CONTRAINDICATIONS

Absolute:

• Recent MI (within 3-6 months)
• Bundle branch block or significant conduction defects
• Concurrent MAOI use (within 14 days)
• Known hypersensitivity
• Angle-closure glaucoma (anticholinergic can precipitate acute attack)
• Urinary retention (worsened by anticholinergic effects)

Relative:

• Bipolar disorder (can precipitate mania)
• Seizure disorder (lowers seizure threshold)
• Cardiac arrhythmias
• Severe hepatic disease
• Concurrent alcohol use disorder
• Severe BPH
• Hyperthyroidism (increased risk of arrhythmias)
• Long QT syndrome

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13. SPECIAL POPULATIONS

ELDERLY:

• High risk - TCAs are on the Beers Criteria (potentially inappropriate in elderly)
• Reasons: Anticholinergic effects → confusion/delirium, falls from orthostatic hypotension, cognitive impairment, urinary retention
• If TCA must be used: Prefer nortriptyline or desipramine (least orthostatic hypotension, least anticholinergic)
• Start with VERY low doses (10-25 mg)
• Viva tip: "Which TCAs are most appropriate for elderly?" → Nortriptyline or desipramine

PREGNANCY:

• Category C/D depending on drug
• Associated with: neonatal withdrawal syndrome (jitteriness, irritability, feeding difficulties, tachycardia, hyperthermia, respiratory distress)
• Neonates born to TCA-taking mothers can have serious, potentially life-threatening withdrawal - this is a key exam point!
• Generally avoid in first trimester
• If needed: weigh risk/benefit; taper before delivery
• Clomipramine: avoid (more cardiac malformation reports)

CHILDREN:

• TCAs generally not first-line in children
• Imipramine: FDA approved for enuresis >6 years (only pediatric indication)
• Sudden cardiac death cases reported with desipramine in children - requires careful ECG monitoring
• Clomipramine for OCD: approved ≥10 years
• Antidepressants in children: FDA black box warning - increased risk of suicidal ideation in children/adolescents

HEPATIC IMPAIRMENT:

• Reduce dose; monitor levels closely
• Avoid in severe hepatic failure (extensive hepatic metabolism)

RENAL IMPAIRMENT:

• Moderate dose reduction needed
• Active metabolites may accumulate
• Dialysis NOT useful in overdose (large volume of distribution)

CARDIAC DISEASE:

• Use with extreme caution
• Get baseline ECG; check QTc
• Nortriptyline is least risky among TCAs for cardiac patients
• Avoid if: recent MI, significant conduction defects, QTc > 450ms

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14. MONITORING GUIDELINES

1. ECG (baseline) - especially in patients >40 years or with cardiac history
2. Blood pressure (baseline)
3. Liver function tests
4. Blood glucose/lipids (baseline)
5. Pregnancy test if applicable

1. ECG at therapeutic dose - look for QTc prolongation, QRS changes
2. TCA serum levels (1 week after starting or changing dose)
3. Blood pressure monitoring (especially orthostatic readings)
4. Cognitive function (especially elderly)
5. Weight

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15. DISCONTINUATION

TCA Discontinuation Syndrome:

• Onset: Within 2-3 days of stopping
• Symptoms: Nausea, GI upset, anxiety, irritability, headache, malaise, insomnia, sweating, flu-like symptoms
• Less common than SSRI withdrawal: No "electric shock" sensations, less disequilibrium
• Non-life-threatening in adults (unlike benzodiazepine withdrawal)
• EXCEPTION: Neonates born to TCA-treated mothers - can be life-threatening (cardiac arrhythmias, respiratory distress)

How to discontinue:

1. Taper by 10-25% per month
2. Slower taper if on drug >1 year
3. If withdrawal symptoms occur: restart and taper more slowly
4. For planned pregnancy: taper before delivery to minimize neonatal withdrawal

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16. GUIDELINES / JICE / IPS

• TCAs (amitriptyline, nortriptyline, imipramine) = FIRST-LINE treatment for peripheral neuropathic pain
• Strong recommendation based on high-quality evidence
• NNT (number needed to treat) ~3-4 for 50% pain relief

• TCAs not recommended as first-line (SSRIs/SNRIs preferred)
• TCAs appropriate for: treatment-resistant depression, psychotic depression (with antipsychotic), certain pain conditions

• SSRIs are first choice; TCAs acceptable for treatment-resistant depression
• Low-dose amitriptyline/nortriptyline recommended for chronic pain and migraine prophylaxis

• Amitriptyline: Level A evidence for migraine prophylaxis
• Nortriptyline: Level C (less evidence but better tolerated)

• Clomipramine + behavioral therapy: established first-line treatment
• Note: SSRIs often tried first due to better tolerability; clomipramine used if SSRIs fail

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17. RECENT ADVANCES & NEW TRIALS

1. Tianeptine - an atypical TCA with paradoxical MOA: it enhances serotonin reuptake (opposite of other TCAs) and acts on mu-opioid receptors. Used in Europe for depression; associated with addiction/abuse (2025 systematic review - PMID 42177839). Banned in some regions due to misuse.
2. TCA in functional dyspepsia - amitriptyline shown effective in a controlled trial (Harrison's 22E): "amitriptyline produced symptom reductions in functional dyspepsia" - neuromodulatory mechanism involving blunting of visceral pain processing.
3. Low-dose doxepin (Silenor) - FDA approved for insomnia at 3-6 mg doses; mechanism is highly selective H1 blockade at these doses with minimal anticholinergic effects.
4. ECMO for TCA overdose - ECMO (extracorporeal membrane oxygenation) emerging as rescue therapy for refractory TCA-induced cardiovascular collapse unresponsive to bicarbonate therapy (2025 review - PMID 40263908).
5. Nortriptyline for smoking cessation - head-to-head with bupropion showing comparable efficacy in several recent systematic reviews.
6. TCA + SSRI combination - nortriptyline/desipramine sometimes added to SSRI for treatment-resistant depression (augmentation strategy); CYP2D6 interaction monitoring essential.

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18. VIVA TIPS & TRICKY QUESTIONS

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QUICK MEMORY SUMMARY TABLE

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