Antidepressants

Antidepressants: Quick Look

UsePrevent migraine or reduce the severity of attacks
EffectivenessProbable efficacy for amitriptyline, venlafaxine1
Migraine-specific?No
Prescription?Yes
Side effectsAmitriptyline: Frequent and numerous side effects2
Venlafaxine: Occasional, especially nausea and vomiting2
Taken how?Tablet
Drugs in this class
Brand Name(s)Generic Name
Amitid*, Amitril*, Elavil*, Endep*amitriptyline
Aventyl, Pamelornortriptyline
Effexor*venlafaxine
Cymbalta, Irenkaduloxetine
Prozac, Rapiflux, Selfemra, Sarafemfluoxetine
Brand Name(s)Generic Name
Amitid*, Amitril*, Elavil*, Endep*amitriptyline
Aventyl, Pamelornortriptyline
Effexor*venlafaxine
Cymbalta, Irenkaduloxetine
Prozac, Rapiflux, Selfemra, Sarafemfluoxetine

*Brand name product has been discontinued, but the drug is still available in generic form.

National guidelines classify two antidepressants as “probably effective” for preventing migraine:1,3

  • Amitriptyline, a tricyclic antidepressant
  • Venlafaxine, a serotonin-norepinephrine reuptake inhibitor

There are many other antidepressants. Some are used to prevent migraine but have not been formally studied for this purpose. These include:

  • Nortriptyline, a tricyclic antidepressant
  • Duloxetine, a serotonin-norepinephrine reuptake inhibitor
  • Fluoxetine, a selective serotonin reuptake inhibitor

These antidepressants target serotonin, norepinephrine, or both. Serotonin and norepinephrine play a role in mood. They also have a role in pain. This may be the reason that antidepressants may reduce the frequency or severity of migraine.

There are medications that work better than antidepressants for migraine prevention. However, antidepressants could be a good option if you have migraine and depression, anxiety, or insomnia.3

Our 10th annual Migraine In America survey is now open. Take the survey to help us paint a clear picture that while an attack might be over, the disease never really ends.

Tricyclic antidepressants

Amitriptyline

Amitriptyline is the best studied antidepressant for migraine prevention.3 It has a long history of use for migraine. National guidelines once recommended it as a first-line choice,2 but no longer.1 Today, there are more effective options with fewer side effects.

Amitriptyline is taken by mouth once a day. Your health care provider will start you on a low dose and increase it slowly. Typically, a lower dose is needed to treat migraine than depression. Amitriptyline will make you sleepy, so it should be taken at bedtime. Do not drive until you know how this drug affects you.

Side effects are common. Possible side effects of amitriptyline are:3

  • Blurry vision
  • Constipation
  • Dry mouth
  • Palpitations and increased heart rate
  • Incomplete bladder emptying (urinary retention)
  • Weight gain

Amitriptyline has a black box warning—the FDA’s strongest warning—about increased risk of suicidal thoughts.4 All antidepressants have this warning.

Other serious side effects include change in the heart rhythm and low blood pressure when moving from a sitting to a standing position. Amitriptyline should not be used by patients with seizure disorders. If you have heart disease, your doctor will probably tell you not to take it. There are other risks and side effects of amitriptyline. Read the Medication Guide and talk to your health care provider.

Nortriptyline

If amitriptyline works for you but causes intolerable side effects, nortriptyline may be an alternative.5 Nortriptyline is a byproduct of amitriptyline breakdown.5 It causes fewer side effects than amitriptyline. Very few studies have been done of nortriptyline for migraine.5

Serotonin-norepinephrine reuptake inhibitors

Venlafaxine

There have only been a few formal studies of venlafaxine for migraine.3 It was effective in those studies. One randomized controlled trial showed that daily treatment with 150 mg venlafaxine reduced the number of migraine days compared with placebo.6 In a head-to-head comparison, venlafaxine worked as well as amitriptyline.7 Both drugs reduced the number, duration, and severity of migraine attacks.

Venlafaxine is taken by mouth. Your health care provider will start you on a low dose and increase it slowly. If you need to stop taking venlafaxine, you must taper it slowly.

Nausea and vomiting are common side effects of venlafaxine.3 Other possible side effects include:5

  • Constipation
  • Loss of appetite
  • Dizziness
  • Dry mouth
  • Heat intolerance
  • Excessive sweating
  • Fatigue or insomnia
  • Sexual dysfunction

Venlafaxine has a black box warning—the FDA’s strongest warning—about increased risk of suicidal thoughts.8 All antidepressants have this warning. There are other risks and side effects of venlafaxine. Read the Medication Guide and talk to your health care provider.

Duloxetine

National guidelines do not recommend for or against duloxetine.1 There have not been enough studies.

Of the people who have been studied, most had migraine plus depression or other comorbid conditions.5 Duloxetine reduced headache frequency in people with chronic migraine, medication overuse, and depression.9 In another small study, treatment with duloxetine improved depression, pain, and quality of life.10

Selective serotonin reuptake inhibitor

Fluoxetine

National guidelines once classified fluoxetine as a second-tier choice for migraine prevention.2 Newer guidelines do not recommend for or against it.1 The few existing studies have had mixed results.

These are not all the possible side effects of antidepressants. Patients should talk to their doctor about what to expect with treatment with antidepressants. Some of these symptoms can be more serious in older people, so it’s important to check with your doctor and monitor your health carefully if you are taking antidepressants.

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Written by: Sarah O'Brien | Reviewed June 2021