Antidepressants: The spectrum beyond depression

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

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.

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.

 

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.

Box 1

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

Syncope. Neurocardiogenic (vasovagal) syncope—a common cause of fainting— can be treated when necessary with a
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

Box 2

 

Gastrointestinal

Peptic ulcer disease was shown in the 1980s to respond to tricyclic antidepressants. At the time, both anticholinergic and antihistaminic effects were thought to be responsible, but the later observation that trimipramine inhibited Campylobacter pylori in vitro suggested an additional explanation. Today, tricyclics are only of historic interest as treatments for peptic ulcer.

Irritable bowel syndrome (IBS) patients have responded favorably to antidepressants, although it is often difficult to know if the benefit is independent of improved coexisting anxiety or depression. A meta-analysis of 12 randomized, placebo-controlled trials—mostly with tricyclics—found an odds ratio for improvement of 4.2 and a number needed to treat of 3.2.¹⁵

More recently, a few placebo-controlled studies have shown SSRIs to be beneficial for IBS,^16-18 although not all symptoms improved and some IBS subtypes might be more responsive than others (Box 2). In an editorial, Talley¹⁹ concluded that antidepressant therapy of IBS was “at best only a ‘band-aid’ approach to management.”

Genitourinary

Nocturnal enuresis. In the 1960s, imipramine was shown—in some but not all placebo-controlled studies—to be beneficial for nocturnal enuresis in children and adults. Although imipramine is not FDA-approved for this indication, it is thought to work by relaxing bladder muscle and contracting bladder neck smooth muscle. Imipramine appears to have a vasopressin-independent antidiuretic effect in enuretic patients with nocturnal polyuria.

Stress urinary incontinence. Placebo-controlled studies have shown duloxetine to be an effective treatment for stress urinary incontinence in women. A Cochrane Database Review of 9 randomized studies in adults (N=3,327) concluded that duloxetine significantly improved patients’ quality of life, although how long the benefits would last was unclear.²⁰

Duloxetine is thought to improve stress urinary incontinence by increasing urethral sphincter tone and the force of sphincter contraction. This indication is not FDA- approved for duloxetine but is approved in the European Union.

Oncology

At one time antidepressants were suggested to promote tumors, based on observations that amitriptyline, fluoxetine, and several antihistamines promoted tumor growth in rodents.²¹ In 1995, a few case reports associated these 2 antidepressants with atypical cutaneous lymphoid infiltrates.²² A review by Sternback in 2003²³ concluded that a link between antidepressants and cancer was questionable but acknowledged the need for very long-term studies.

Recently, a nested case-control study found an association between high-dose SSRI use for ≤5 years and reduced risk of colorectal cancer, whereas no association was found with tricyclic use.²⁴ A study of this design does not establish a causal relationship, how-ever, and one can only speculate whether SSRIs might have direct cytotoxic or anti-promoter effects.

At present, it seems reasonable to continue to treat depressed cancer patients with antidepressants without concern that cancer will worsen or hope that it will improve as a result.

Immunology

The pathogenesis of depression may be linked to pro-inflammatory cytokines—proteins such as tumor necrosis factor-alpha (TNF-α) and certain interleukins that mediate immune function. Bupropion markedly lowered pro-inflammatory cytokine levels in a mouse inflammation model, prompting the authors to suggest that this anti-inflammatory effect be explored in humans.²⁵

Case reports have suggested benefit from bupropion in Crohn’s disease, recurrent aphthous ulcerations, psoriasis, atopic dermatitis, and Blau syndrome (a rare autosomal-dominant trait characterized by granulomatous arthritis, iritis, and skin rash). Whether this antidepressant has much anti-inflammatory potential remains to be determined, however.

Box 3

Infectious disease

Pathogenic protozoa—such as Trypanosoma cruzi (Chagas disease), Leishmania donovani (Kala-azar), Leishmania major (Oriental sore), and Giardia lamblia (Giardiasis)—infect millions of humans worldwide. Clomipramine has been shown in vitro and in mice to inhibit or kill these protozoa, but these potential benefits have not been extended to humans.

 

Sertraline, on the other hand, might exert antifungal activity. Three patients with recurrent vulvovaginal candidiasis had no episodes while being treated with sertraline for premenstrual dysphoric disorder but relapsed when the drug was discontinued.²⁶ Although sertraline demonstrated antifungal activity in vitro against several Candida species, this SSRI seems unlikely to gain prominence as an antifungal agent.

Sexual function

Premature ejaculation. SSRIs are well-known causes of delayed or absent orgasm, but a perceived liability can become an asset in treating premature ejaculation. By measuring intravaginal ejaculation latency time under double-blind, placebo-controlled conditions, Waldinger et al²⁷ showed pronounced delay in ejaculation with sertraline, fluoxetine, and paroxetine in men with long-standing rapid ejaculation. Dapoxetine—a short-acting non-antidepressant SSRI—is being studied as a treatment for this condition (Box 3).²⁸

Spermicidal effect. SSRIs—including fluoxetine— have demonstrated in vitro spermicidal and antitrichomonas activity²⁹ but are unlikely to be developed as microbicidal contraceptives.

Related Resources

• Gorman JM, Kent JM. SSRIs and SMRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry 1999;60(suppl 4):33-8.
  
• About.com: Mental Health. Antidepressants for more than depression. http://mentalhealth.about.com/cs/psychopharmacology/a/antimore.htm.
  

Drug brand names

• Amitriptyline • Elavil, Endep
  
• Bupropion • Wellbutrin, Zyban
  
• Citalopram • Celexa
  
• Clomipramine • Anafranil
  
• Desipramine • Norpramin, Pertofrane
  
• Doxepin • Adapin, Sinequan
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fludrocortisone • Florinef
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Imipramine • Tofranil
  
• Midodrine • ProAmitine
  
• Nortriptyline • Pamelor, Aventyl
  
• Paroxetine • Paxil
  
• Phenelzine • Nardil
  
• Sertraline • Zoloft
  
• Trimipramine • Surmontil
  
• Venlafaxine • Effexor
  

Disclosure

Dr. Jefferson receives research support from Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Company, Novartis, Pfizer, Roche, Solvay, UCB Pharma, and Wyeth. He is a consultant to GlaxoSmithKline, Schwarz Pharma, Shire, and Organon and a speaker for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Eli Lilly and Company, Pfizer, Schwarz Pharma, Shire, and Wyeth. He holds stock in Bristol-Myers Squibb, GlaxoSmithKline, and SciClone.

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

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.

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.

 

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.

Box 1

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

Syncope. Neurocardiogenic (vasovagal) syncope—a common cause of fainting— can be treated when necessary with a
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

Box 2

 

Gastrointestinal

Peptic ulcer disease was shown in the 1980s to respond to tricyclic antidepressants. At the time, both anticholinergic and antihistaminic effects were thought to be responsible, but the later observation that trimipramine inhibited Campylobacter pylori in vitro suggested an additional explanation. Today, tricyclics are only of historic interest as treatments for peptic ulcer.

Irritable bowel syndrome (IBS) patients have responded favorably to antidepressants, although it is often difficult to know if the benefit is independent of improved coexisting anxiety or depression. A meta-analysis of 12 randomized, placebo-controlled trials—mostly with tricyclics—found an odds ratio for improvement of 4.2 and a number needed to treat of 3.2.¹⁵

More recently, a few placebo-controlled studies have shown SSRIs to be beneficial for IBS,^16-18 although not all symptoms improved and some IBS subtypes might be more responsive than others (Box 2). In an editorial, Talley¹⁹ concluded that antidepressant therapy of IBS was “at best only a ‘band-aid’ approach to management.”

Genitourinary

Nocturnal enuresis. In the 1960s, imipramine was shown—in some but not all placebo-controlled studies—to be beneficial for nocturnal enuresis in children and adults. Although imipramine is not FDA-approved for this indication, it is thought to work by relaxing bladder muscle and contracting bladder neck smooth muscle. Imipramine appears to have a vasopressin-independent antidiuretic effect in enuretic patients with nocturnal polyuria.

Stress urinary incontinence. Placebo-controlled studies have shown duloxetine to be an effective treatment for stress urinary incontinence in women. A Cochrane Database Review of 9 randomized studies in adults (N=3,327) concluded that duloxetine significantly improved patients’ quality of life, although how long the benefits would last was unclear.²⁰

Duloxetine is thought to improve stress urinary incontinence by increasing urethral sphincter tone and the force of sphincter contraction. This indication is not FDA- approved for duloxetine but is approved in the European Union.

Oncology

At one time antidepressants were suggested to promote tumors, based on observations that amitriptyline, fluoxetine, and several antihistamines promoted tumor growth in rodents.²¹ In 1995, a few case reports associated these 2 antidepressants with atypical cutaneous lymphoid infiltrates.²² A review by Sternback in 2003²³ concluded that a link between antidepressants and cancer was questionable but acknowledged the need for very long-term studies.

Recently, a nested case-control study found an association between high-dose SSRI use for ≤5 years and reduced risk of colorectal cancer, whereas no association was found with tricyclic use.²⁴ A study of this design does not establish a causal relationship, how-ever, and one can only speculate whether SSRIs might have direct cytotoxic or anti-promoter effects.

At present, it seems reasonable to continue to treat depressed cancer patients with antidepressants without concern that cancer will worsen or hope that it will improve as a result.

Immunology

The pathogenesis of depression may be linked to pro-inflammatory cytokines—proteins such as tumor necrosis factor-alpha (TNF-α) and certain interleukins that mediate immune function. Bupropion markedly lowered pro-inflammatory cytokine levels in a mouse inflammation model, prompting the authors to suggest that this anti-inflammatory effect be explored in humans.²⁵

Case reports have suggested benefit from bupropion in Crohn’s disease, recurrent aphthous ulcerations, psoriasis, atopic dermatitis, and Blau syndrome (a rare autosomal-dominant trait characterized by granulomatous arthritis, iritis, and skin rash). Whether this antidepressant has much anti-inflammatory potential remains to be determined, however.

Box 3

Infectious disease

Pathogenic protozoa—such as Trypanosoma cruzi (Chagas disease), Leishmania donovani (Kala-azar), Leishmania major (Oriental sore), and Giardia lamblia (Giardiasis)—infect millions of humans worldwide. Clomipramine has been shown in vitro and in mice to inhibit or kill these protozoa, but these potential benefits have not been extended to humans.

 

Sertraline, on the other hand, might exert antifungal activity. Three patients with recurrent vulvovaginal candidiasis had no episodes while being treated with sertraline for premenstrual dysphoric disorder but relapsed when the drug was discontinued.²⁶ Although sertraline demonstrated antifungal activity in vitro against several Candida species, this SSRI seems unlikely to gain prominence as an antifungal agent.

Sexual function

Premature ejaculation. SSRIs are well-known causes of delayed or absent orgasm, but a perceived liability can become an asset in treating premature ejaculation. By measuring intravaginal ejaculation latency time under double-blind, placebo-controlled conditions, Waldinger et al²⁷ showed pronounced delay in ejaculation with sertraline, fluoxetine, and paroxetine in men with long-standing rapid ejaculation. Dapoxetine—a short-acting non-antidepressant SSRI—is being studied as a treatment for this condition (Box 3).²⁸

Spermicidal effect. SSRIs—including fluoxetine— have demonstrated in vitro spermicidal and antitrichomonas activity²⁹ but are unlikely to be developed as microbicidal contraceptives.

Related Resources

• Gorman JM, Kent JM. SSRIs and SMRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry 1999;60(suppl 4):33-8.
  
• About.com: Mental Health. Antidepressants for more than depression. http://mentalhealth.about.com/cs/psychopharmacology/a/antimore.htm.
  

Drug brand names

• Amitriptyline • Elavil, Endep
  
• Bupropion • Wellbutrin, Zyban
  
• Citalopram • Celexa
  
• Clomipramine • Anafranil
  
• Desipramine • Norpramin, Pertofrane
  
• Doxepin • Adapin, Sinequan
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fludrocortisone • Florinef
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Imipramine • Tofranil
  
• Midodrine • ProAmitine
  
• Nortriptyline • Pamelor, Aventyl
  
• Paroxetine • Paxil
  
• Phenelzine • Nardil
  
• Sertraline • Zoloft
  
• Trimipramine • Surmontil
  
• Venlafaxine • Effexor
  

Disclosure

Dr. Jefferson receives research support from Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Company, Novartis, Pfizer, Roche, Solvay, UCB Pharma, and Wyeth. He is a consultant to GlaxoSmithKline, Schwarz Pharma, Shire, and Organon and a speaker for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Eli Lilly and Company, Pfizer, Schwarz Pharma, Shire, and Wyeth. He holds stock in Bristol-Myers Squibb, GlaxoSmithKline, and SciClone.

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

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.

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.

 

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.

Box 1

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

Syncope. Neurocardiogenic (vasovagal) syncope—a common cause of fainting— can be treated when necessary with a
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

Box 2

 

Gastrointestinal

Peptic ulcer disease was shown in the 1980s to respond to tricyclic antidepressants. At the time, both anticholinergic and antihistaminic effects were thought to be responsible, but the later observation that trimipramine inhibited Campylobacter pylori in vitro suggested an additional explanation. Today, tricyclics are only of historic interest as treatments for peptic ulcer.

Irritable bowel syndrome (IBS) patients have responded favorably to antidepressants, although it is often difficult to know if the benefit is independent of improved coexisting anxiety or depression. A meta-analysis of 12 randomized, placebo-controlled trials—mostly with tricyclics—found an odds ratio for improvement of 4.2 and a number needed to treat of 3.2.¹⁵

More recently, a few placebo-controlled studies have shown SSRIs to be beneficial for IBS,^16-18 although not all symptoms improved and some IBS subtypes might be more responsive than others (Box 2). In an editorial, Talley¹⁹ concluded that antidepressant therapy of IBS was “at best only a ‘band-aid’ approach to management.”

Genitourinary

Nocturnal enuresis. In the 1960s, imipramine was shown—in some but not all placebo-controlled studies—to be beneficial for nocturnal enuresis in children and adults. Although imipramine is not FDA-approved for this indication, it is thought to work by relaxing bladder muscle and contracting bladder neck smooth muscle. Imipramine appears to have a vasopressin-independent antidiuretic effect in enuretic patients with nocturnal polyuria.

Stress urinary incontinence. Placebo-controlled studies have shown duloxetine to be an effective treatment for stress urinary incontinence in women. A Cochrane Database Review of 9 randomized studies in adults (N=3,327) concluded that duloxetine significantly improved patients’ quality of life, although how long the benefits would last was unclear.²⁰

Duloxetine is thought to improve stress urinary incontinence by increasing urethral sphincter tone and the force of sphincter contraction. This indication is not FDA- approved for duloxetine but is approved in the European Union.

Oncology

At one time antidepressants were suggested to promote tumors, based on observations that amitriptyline, fluoxetine, and several antihistamines promoted tumor growth in rodents.²¹ In 1995, a few case reports associated these 2 antidepressants with atypical cutaneous lymphoid infiltrates.²² A review by Sternback in 2003²³ concluded that a link between antidepressants and cancer was questionable but acknowledged the need for very long-term studies.

Recently, a nested case-control study found an association between high-dose SSRI use for ≤5 years and reduced risk of colorectal cancer, whereas no association was found with tricyclic use.²⁴ A study of this design does not establish a causal relationship, how-ever, and one can only speculate whether SSRIs might have direct cytotoxic or anti-promoter effects.

At present, it seems reasonable to continue to treat depressed cancer patients with antidepressants without concern that cancer will worsen or hope that it will improve as a result.

Immunology

The pathogenesis of depression may be linked to pro-inflammatory cytokines—proteins such as tumor necrosis factor-alpha (TNF-α) and certain interleukins that mediate immune function. Bupropion markedly lowered pro-inflammatory cytokine levels in a mouse inflammation model, prompting the authors to suggest that this anti-inflammatory effect be explored in humans.²⁵

Case reports have suggested benefit from bupropion in Crohn’s disease, recurrent aphthous ulcerations, psoriasis, atopic dermatitis, and Blau syndrome (a rare autosomal-dominant trait characterized by granulomatous arthritis, iritis, and skin rash). Whether this antidepressant has much anti-inflammatory potential remains to be determined, however.

Box 3

Infectious disease

Pathogenic protozoa—such as Trypanosoma cruzi (Chagas disease), Leishmania donovani (Kala-azar), Leishmania major (Oriental sore), and Giardia lamblia (Giardiasis)—infect millions of humans worldwide. Clomipramine has been shown in vitro and in mice to inhibit or kill these protozoa, but these potential benefits have not been extended to humans.

 

Sertraline, on the other hand, might exert antifungal activity. Three patients with recurrent vulvovaginal candidiasis had no episodes while being treated with sertraline for premenstrual dysphoric disorder but relapsed when the drug was discontinued.²⁶ Although sertraline demonstrated antifungal activity in vitro against several Candida species, this SSRI seems unlikely to gain prominence as an antifungal agent.

Sexual function

Premature ejaculation. SSRIs are well-known causes of delayed or absent orgasm, but a perceived liability can become an asset in treating premature ejaculation. By measuring intravaginal ejaculation latency time under double-blind, placebo-controlled conditions, Waldinger et al²⁷ showed pronounced delay in ejaculation with sertraline, fluoxetine, and paroxetine in men with long-standing rapid ejaculation. Dapoxetine—a short-acting non-antidepressant SSRI—is being studied as a treatment for this condition (Box 3).²⁸

Spermicidal effect. SSRIs—including fluoxetine— have demonstrated in vitro spermicidal and antitrichomonas activity²⁹ but are unlikely to be developed as microbicidal contraceptives.

Related Resources

• Gorman JM, Kent JM. SSRIs and SMRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry 1999;60(suppl 4):33-8.
  
• About.com: Mental Health. Antidepressants for more than depression. http://mentalhealth.about.com/cs/psychopharmacology/a/antimore.htm.
  

Drug brand names

• Amitriptyline • Elavil, Endep
  
• Bupropion • Wellbutrin, Zyban
  
• Citalopram • Celexa
  
• Clomipramine • Anafranil
  
• Desipramine • Norpramin, Pertofrane
  
• Doxepin • Adapin, Sinequan
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fludrocortisone • Florinef
  
• Fluoxetine • Prozac
  
• Fluvoxamine • Luvox
  
• Imipramine • Tofranil
  
• Midodrine • ProAmitine
  
• Nortriptyline • Pamelor, Aventyl
  
• Paroxetine • Paxil
  
• Phenelzine • Nardil
  
• Sertraline • Zoloft
  
• Trimipramine • Surmontil
  
• Venlafaxine • Effexor
  

Disclosure

Dr. Jefferson receives research support from Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Company, Novartis, Pfizer, Roche, Solvay, UCB Pharma, and Wyeth. He is a consultant to GlaxoSmithKline, Schwarz Pharma, Shire, and Organon and a speaker for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, Eli Lilly and Company, Pfizer, Schwarz Pharma, Shire, and Wyeth. He holds stock in Bristol-Myers Squibb, GlaxoSmithKline, and SciClone.