Evidence-Based Reviews

Antidepressants: The spectrum beyond depression

Current Psychiatry. 2007 October;6(10):35-42

Referring to certain groups of drugs as antidepressants does them a great disservice; their potential uses range far beyond mood disorders.

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References

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7. Tomkins GE, Jackson JL, O’Malley PG, et al. Treatment of chronic headache with antidepressants: a meta-analysis. Am J Med 2001;111:54-63.

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A molecule is a molecule is a molecule—until it becomes identified with a purpose. Consider, for example, (-)-trans-4R-(4’-fluorophenyl)-3S-[(3’,4’-methylenedioxyphenoxy) methyl] piperidine. You probably know this molecule as paroxetine—an antidepressant, of course, but it is more than that. If you examine paroxetine’s FDA-approved indications, it also has anti-panic, anti-social anxiety, anti-obsessive-compulsive disorder, anti-posttraumatic stress disorder, and anti-premenstrual dysphoric disorder effects.

“Antidepressants” have achieved fame as antidepressants; one could say these molecules’ search for meaning has been fulfilled. Yet even within psychiatry, their many other uses (Table) can create semantic misunderstandings. Beyond psychiatry, consider the nondepressed patient with neurocardiogenic syncope who wonders why he’s being treated with an antidepressant.

Rather than calling antidepressants “panaceas,” the better choice is to educate patients about the drugs’ wide spectrum of activity. Let’s look broadly across the so-called antidepressants and examine their varied uses in psychiatry and other medical specialties.

Table

FDA-approved psychiatric indications for serotonin uptake inhibitors*

SSRIs
Citalopram	X
Escitalopram	X				X
Fluoxetine	X	X				X	X	X
Fluvoxamine						X
Paroxetine	X	X	X	X	X	X	X
Sertraline	X	X	X	X		X	X
SNRIs
Duloxetine	X				X
Venlafaxine	X	X	X		X
SSRIs: selective serotonin reuptake inhibitors; SNRIs: serotonin-norepinephrine reuptake inhibitors; MDD: major depressive disorder; PD: panic disorder; SAD: social anxiety disorder; PTSD: posttraumatic stress disorder; GAD: generalized anxiety disorder; OCD: obsessive-compulsive disorder; PMDD: premenstrual dysphoric disorder; BUL: bulimia
* The absence of an X does not necessarily imply that a drug is ineffective for a given indication but, more likely, that definitive studies are lacking.

Pain syndromes

Peripheral neuropathy. The only antidepressant with an FDA-approved pain indication is duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI). Its approval for diabetic peripheral neuropathic pain (DPNP) was based on two 12-week, randomized, double-blind, placebo-controlled studies using fixed doses of 60 mg once or twice daily.^1,2 Another SNRI—venlafaxine XR, 150 to 225 mg/d, but not 75 mg/d—also was found to be more effective than placebo for this indication in a 6-week, double-blind study (Box 1).³

Using antidepressants to treat pain syndromes is neither new nor restricted to SNRIs, however. In combined double-blind, cross-over studies of patients with DPNP, Max et al⁴ found:

moderate or greater pain relief in 74% and 61% of subjects, respectively, from the tricyclics amitriptyline, mean 105 mg/d, and desipramine, mean 111 mg/d—with pain reduced by equal amounts in depressed and nondepressed patients
no statistically significant difference in pain relief between the selective serotonin reuptake inhibitor (SSRI) fluoxetine, 40 mg/d, and placebo.

Sindrup et al⁵ concluded in a 2005 review that antidepressants relieve DPNP according to this hierarchy:

tricyclics: 1 in every 2 to 3 patients
SNRIs: 1 in every 4 to 5 patients
SSRIs: 1 in every 7 patients.

Bupropion SR—a norepinephrine dopamine reuptake inhibitor—also may be more effective than placebo in relieving neuropathic pain, as shown in a small (N=41) 6-week, double-blind study.⁶

Clinical Point

Patients with chronic low back pain (averaging 10 years) seem to benefit from antidepressants, as do patients with chronic migraine

Chronic headache. A meta-analysis⁷ of randomized, placebo-controlled studies found antidepressants more effective than placebo for chronic migraine and tension headache prophylaxis. Although a subgroup meta-analysis found similar effects for tricyclics and SSRIs, the authors characterized the tricyclics’ results as well established and the SSRIs’ as “less certain.”

The results of this meta-analysis might not accurately reflect bona fide antidepressants, however. Some of the 38 studies (25 of migraine, 12 of tension headache, 1 of both) included treatment with serotonin antagonists—most commonly pizotifen, which is not available in the United States and does not appear to be an antidepressant.

Back pain. Patients with chronic low back pain (average 10 years) seem to benefit from antidepressants, according to a meta-analysis of 9 randomized, controlled trials by Salerno et al.⁸ The effect on pain in the total 504 patients was “small but significant,” and improvement in function was “small but nonsignificant.” Individual sample sizes also were small, however, and only 2 studies excluded depressed patients.

Fibromyalgia, with chronic generalized musculoskeletal pain and tenderness, has been a focus of antidepressant drug therapy. Goldenberg et al⁹ concluded from an ambitious literature review (505 articles) that evidence of efficacy was strong for amitripty-line and modest for SSRIs and SNRIs.

Clinical Point

Benefits for patients with pain syndromes without depression are well established for tricyclics and SNRIs, whereas SSRIs are less effective

On the other hand, Littlejohn and Guymer¹⁰ concluded in a clinical review that trials of SSRIs “have been somewhat disappointing,” that tricyclics are, at best, “only moderately effective,” and that more balanced dual uptake inhibitors such as duloxetine and the investigational agent milnacipran “are showing more promise.” Two placebo-controlled studies by Arnold et al^11,12 of women with fibromyalgia showed benefit from duloxetine that appeared independent from its effect on depression and anxiety.