Antidepressants: The spectrum beyond depression
Referring to certain groups of drugs as antidepressants does them a great disservice; their potential uses range far beyond mood disorders.
Overall, antidepressants are generally understood to have analgesic effects in the absence of depression. Benefits for patients with pain syndromes are well established for tricyclics (especially amitriptyline) and recently with SNRIs, whereas SSRIs are less effective.
Serotonin and norepinephrine are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord. Serotonin-norepinephrine reuptake inhibitors (SNRIs) have been shown to reduce the severity of diabetic peripheral neuropathic pain (DPNP) in randomized controlled trials.
Duloxetine. In 2 double-blind studies,1,2 nondepressed patients with DPNP received duloxetine, 60 mg once daily; duloxetine, 60 mg bid; or placebo for 12 weeks. They rated the severity of neuropathic pain every 24 hours on an 11-point Likert scale, and weekly mean scores were the primary outcome measure. Average pain scores improved more in both duloxetine groups vs placebo. Duloxetine treatment did not interfere with diabetic control, and both dosages were well tolerated.
The FDA approved an added indication for duloxetine in the management of DPNP.
Venlafaxine. In a double-blind study,3 244 adult outpatients with moderately severe DPNP received venlafaxine ER, 75 or 150 to 225 mg/d, or placebo for 6 weeks. Daily scores on the Visual Analog Pain Intensity (VAS-PI) and Pain Relief (VAS-PR) scales were primary efficacy measures.
Patients receiving the higher venlafaxine dosage—but not 75 mg/d—showed statistically significant less-intensive pain vs placebo. VAS-PI scores were 27% lower than at enrollment with placebo, 32% lower with venlafaxine, 75 mg/d, and 50% lower with venlafaxine, 150 to 225 mg/d (P
Nausea and somnolence were the most common side effects; clinically important ECG changes occurred in 7 patients treated with venlafaxine, 150 to 225 mg/d.
Smoking cessation
Bupropion SR is FDA-approved to aid smoking cessation, and this effect is independent of the drug’s antidepressant activity. Bupropion may act as a nicotine receptor antagonist as well as a norepinephrine dopamine reuptake inhibitor.
Other antidepressants have been studied for smoking cessation, with nortriptyline showing benefit in 2 large placebo-controlled trials. Studies with doxepin, fluoxetine, and moclobemide found little or no benefit for this indication.
Cardiovascular uses
Angina. Monoamine oxidase inhibitor (MAOI) antidepressants were used to treat angina pectoris in the late 1950s and early 1960s. This practice stopped after evidence showed that whereas angina pain may have improved with MAOIs, stress-induced ischemia on ECG did not.
Antiarrhythmia. Tricyclics had a brief fling in cardiovascular therapeutics when their quinidine-like class I antiarrhythmic activity was recognized. Imipramine was one of several drugs included in the Cardiac Arrhythmia Pilot Study in the 1980s that involved 502 postmyocardial infarction patients with ventricular arrhythmias. Imipramine was the least effective of the 4 drugs studied and the least well tolerated.13
variety of medications. Options include the vasopressor midodrine, fludrocortisone, beta blockers, and SSRIs— none
FDA-approved for this indication. Paroxetine, 20 mg/d, was considerably more effective than placebo in preventing
recurrent syncope in 68 patients who had been unresponsive
to or intolerant of traditional medications. During a mean 25 months of treatment, 82% of patients remained syncope-free on paroxetine vs 47% on placebo.14
Selective serotonin reuptake inhibitors (SSRIs) often are used to treat irritable bowel syndrome (IBS), though evidence of their effectiveness is scarce. SSRIs can improve IBS patients’ quality of life, but effects on abdominal pain and bloating are less clear.
Paroxetine. In a randomized, double-blind trial,16 gastroenterologists tested a highfiber diet plus paroxetine in nondepressed patients with IBS. Ninety-eight patients ages 18 to 65 who experienced IBS symptoms on low- or average-fiber diets were first put on high-fiber diets and assessed for well-being and abdominal pain and bloating. Of these, 81 symptomatic patients continued highfiber diets with added paroxetine, 10 to 40 mg/d (n=38) or placebo (n=43).
With paroxetine, patients’ overall well-being improved more than with placebo, but abdominal pain and bloating and social functioning did not.
Fluoxetine. In a double-blind, randomized trial,17 44 patients with pain and constipation-predominant IBS received fluoxetine, 20 mg/d, or placebo for 12 weeks. These patients met Rome II criteria for IBS—abdominal discomfort/pain for ≥12 weeks in past year that met 2 of 3 criteria:
- relieved by defecation
- onset associated with change in stool frequency
- onset associated with change in stool appearance.
Patients receiving fluoxetine had less abdominal discomfort, less bloating, more frequent bowel movements, and decreased consistency of stool vs placebo 4 weeks after treatment stopped. Mean number of symptoms per patient decreased from 4.6 to 0.7 in the fluoxetine group vs 4.5 to 2.9 in controls (P
Citalopram. IBS symptom severity was the primary outcome in a crossover trial comparing citalopram (20 mg for 3 weeks and 40 mg for 3 weeks) with placebo in 23 nondepressed patients.18 Abdominal pain and bloating, impact of symptoms on daily life, and overall well-being improved significantly more with citalopram than with placebo after 3 and 6 weeks.
Symptom improvements were not related to changes in depression, anxiety, or colonic sensorimotor function.
