Antidepressants
The class of antidepressants with the most proven efficacy are the tricyclic antidepressants , of which amitriptyline has the most data to support its use.30 Three placebo controlled trials found amitriptyline significantly better than placebo at reducing headache frequency. It was found to be similar to propranolol.31 Anticholinergic side effects were frequently reported with tricyclic antidepressants including dry mouth, constipation, and urinary retention.13 Nortriptyline is similar to amitriptyline but is associated with fewer side effects.3 Protriptyline is another tricyclic antidepressants that is used for the treatment of headache, but unlike amitriptyline and nortriptyline, which can be sedating, protriptyline tends to have an activating effect. Serotonin norepinephrine reuptake inhibitors have also demonstrated some efficacy in the treatment of headaches. In a class I study, the Serotonin norepinephrine reuptake inhibitors venlafaxine extended-release 150 mg significantly reduced the number of headache days per month.25 The most common side effects were vomiting and drowsiness. Selective serotonin reuptake inhibitors like fluoxetine in clinical practice tend to be less effective than tricyclic antidepressants, and have less evidence to support their use.