Amitriptyline (Elavil®) versus Fluoxetine (Prozac®)

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

Amitriptyline advantages over Fluoxetine

  • Amitriptyline is effective for sleep problems associated with anxiety, depression, or chronic pain.

Fluoxetine advantages over Amitriptyline

  • Important benefit of fluoxetine is its significant relative safety in overdoses as compared to amitriptyline.
  • Good option for patients with poor medication compliance due to its long half-life.
  • Fluoxetine is licensed for treatment of major depressive disorder in children and adolescents 8 years and older.
  • No cardiac toxicity. Good safety profile for patients with cardiovascular problems.
  • Mild energizing effect is beneficial for patients experiencing hypersomnia, psychomotor retardation, apathy, or fatigue.
  • Long half-life protects from discontinuation syndrome.


Difference between Amitriptyline and Fluoxetine

Table 1. Comparison of Amitriptyline and Fluoxetine

Amitriptyline Fluoxetine
Brand names
Elavil® Prozac®
Drug class
Tricyclic antidepressant (TCA) Selective serotonin reuptake inhibitor (SSRI), Antidepressant
Dose formulations
• Tablets • Capsules
• Tablets
• Capsules, delayed-release
• Solution, oral
Legal status
• Rx only
• Not a controlled drug
FDA-approved indications
• Depression
  • Premenstrual dysphoric disorder (severe form of premenstrual syndrome)
• Obsessive-compulsive disorder
• Bulimia nervosa
• Panic disorder
"Off-label" uses
• Prevention of migraine
• Fibromyalgia2
• Insomnia
• Panic disorder
• Anxiety
• Neuropathic pain
• Chronic pain
• Premature ejaculation
• Social anxiety
• Anorexia nervosa
• Neurocardiogenic syncope
Mechanism of action
Equally inhibits serotonin and noradrenaline reuptake.
Also blocks histamine-H1 receptors, alpha-1 adrenergic receptors and muscarinic receptors.
Selectively inhibits reabsorption (reuptake) of serotonin in the brain.
• Is an antagonist at 5HT2C receptors1.
• 10-26 hours • 4-6 days (long-term use)
• 1-3 days (after a single dose)
Oral bioavailability
• 30–60% • 60–80%
Metabolism, Elimination
• Amitriptyline is extensively metabolized in the liver by hepatic enzymes CYP2C19 and CYP2D6 to its primary active metabolite, nortriptyline, and other metabolites.
• Eliminated mainly in urine (18% of the dose as unchanged drug), small amounts in feces.
• Fluoxetine is metabolized in the liver by hepatic enzyme CYP2D6 to norfluoxetine, its active metabolite.
• Eliminated in urine (18%), small amounts in feces.
• Concurrent use with a monoamine oxidase (MAO) inhibitors or within 14 days of stopping an MAOI
• Hypersensitivity to amitriptyline
• Acute recovery period after myocardial infarction
• Hypersensitivity to fluoxetine
Side effects
What gives amitriptyline a different unfavourable side effects profile is its ability to block histamine-H1, alpha-1 adrenergic and muscarinic receptor.

• Dry mouth
• Constipation
• Urinary retention
• Blurred vision
• Increased appetite
• Weight gain
• Tachycardia
• Palpitation
• Arrhythmias
• Sedation
• Nausea
• Vomiting
• Drowsiness
• Dizziness
• Excessive sweating

Unlike fluoxetine amitriptyline lacks activating side effects such as insomnia
and nervousness.
• Headache
• Nausea
• Insomnia
• Nervousness
• Anorexia
• Anxiety
• Weakness
• Diarrhea
• Somnolence
• Tremor
• Sexual dysfunction

Unlike amitriptyline fluoxetine does not cause sedation, most patients get insomnia (25%).
Drug interactions
• Additive effects with CNS depressants
• Monoamine oxidase inhibitors - concomitant use contraindicated
• Drugs that inhibit cytochrome P450 2D6 - concomitant use with amitriptyline may require lower doses for either the amitriptyline or the other drug.
• Cimetidine - increased level of tricyclic antidepressant
• Drugs metabolized by CYP2D6 - fluoxetine is a potent CYP2D6 inhibitor
• Drugs that affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, SNRIs, linezolid, lithium, tramadol.

Head-to-head comparative studies

Major depressive disorder
Both medications are effective in relieving the symptoms of depression 5. Recent memory can be improved significantly with the fluoxetine treatment 6.

Anxious depression
Fluoxetine and amitriptyline have comparable efficacy in the treatment of major depression with associated anxiety 3.

Fluoxetine and amitriptyline are similarly effective treatments for fibromyalgia, and they work better in combination than either medication alone 2.

Musculo-skeletal pain
In the study moderate or good pain relief was reported by 82% patients with amitriptyline, and by 77% patients with fluoxetine. Fluoxetine relieved low back pain and whiplash associated cervical pain as effectively as amitriptyline 4.

Migraine headache
Amitriptyline appears to be more effective than fluoxetine for migraine headache prophylaxis9.

Side effects
Adverse effects are more frequent and more severe with the amitriptyline 3. The most frequent side effects with fluoxetine are nausea, nervousness, sleep disturbances, and headaches. The most frequent side effects with amitriptyline are dry mouth, dizziness, and drowsiness 5, 6, 8. The incidence of weight gain is higher with amitriptyline 7.


Further reading


  • 1. Ni YG, Miledi R. Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac). Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2036-40. PubMed
  • 2. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. Fluoxetine and amitriptyline in fibromyalgia. Arthritis Rheum. 1996 Nov;39(11):1852-9. PubMed
  • 3. Versiani M, Ontiveros A, Mazzotti G, Ospina J, Da'vila J, Mata S, Pacheco A, Plewes J, Tamura R, Palacios M. Fluoxetine versus amitriptyline in major depression with associated anxiety. Int Clin Psychopharmacol. 1999 Nov;14(6):321-7. PubMed
  • 4. Schreiber S, Vinokur S, Shavelzon V, Pick CG, Zahavi E, Shir Y. Fluoxetine versus amitriptyline in musculo-skeletal pain. Isr J Psychiatry Relat Sci. 2001;38(2):88-94. PubMed
  • 5. Feighner JP. A comparative trial of fluoxetine and amitriptyline in patients with major depressive disorder. J Clin Psychiatry. 1985 Sep;46(9):369-72. PubMed
  • 6. Keegan D, Bowen RC, Blackshaw S, Saleh S, Dayal N, Remillard F, Shrikhande S, Cebrian Perez S, Boulton A. A comparison of fluoxetine and amitriptyline in major depression. Int Clin Psychopharmacol. 1991 Summer;6(2):117-24. PubMed
  • 7. Altamura AC, De Novellis F, Guercetti G, Invernizzi G, Percudani M, Montgomery SA. Fluoxetine compared with amitriptyline in elderly depression. Int J Clin Pharmacol Res. 1989;9(6):391-6. PubMed
  • 8. Young JP, Coleman A, Lader MH. A controlled comparison of fluoxetine and amitriptyline in depressed out-patients. Br J Psychiatry. 1987 Sep;151:337-40. PubMed
  • 9. Amelin AV, Skoromets AA, Korenko LA, Tumelevich BCh, Gonchar MA. A comparative efficiency of amitriptyline, fluoxetine and maprotiline in prevention of migraine in attack-free period. Zh Nevrol Psikhiatr Im S S Korsakova. 2000;100(8):20-3. PubMed

Published: October 20, 2017
Last updated: October 20, 2017


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