Evidence-Based Reviews

Antidepressants: The spectrum beyond depression

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

References

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2. Raskin J, Pritchett YL, Wang F, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med 2005;6(5):346-56.

3. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 2004;110:697-706.

4. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992;326:1250-6.

5. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol 2005;96:399-409.

6. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 2001;57:1583-8.

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.

8. Salerno SM, Browning R, Jackson JL. The effect of antidepressant treatment on chronic back pain. Arch Intern Med 2002;162:19-24.

9. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA 2004;292:2388-95.

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11. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004;50:2974-84.

12. Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 2005;119:5-15.

13. Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction: The CAPS. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators. Am J Cardiol 1988;61(8):501-9.

14. Di Girolamo E, Di Iorio C, Sabatini P, et al. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999;33:1227-30.

15. Jackson JL, O’Malley PG, Tomkins G, et al. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med 2000;108:65-72.

16. Tabas G, Beaves M, Wang J, et al. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. Am J Gastroenterol 2004;99(5):914-20.

17. Vahedi H, Merat S, Rashidioon A, et al. The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study. Aliment Pharmacol Ther 2005;22:381-5.

18. Tack J, Broekaert D, Fischler B, et al. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 2006;55:1095-103.

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28. Pryor JL, Althof SE, Steidle C, et al. Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials. Lancet 2006;368:929-37.

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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.

Clinical Point

Duloxetine is thought to improve stress urinary incontinence by increasing urethral sphincter tone and force of contraction

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

A ‘beneficial’ adverse effect: SSRIs for premature ejaculation

Delayed ejaculation is among the sexual side effects commonly associated with antidepressant medication. In a 6-week trial,²⁷ 3 selective serotonin reuptake inhibitors (SSRIs)— paroxetine, fluoxetine, and sertraline— were shown to improve intravaginal ejaculatory latency time (IELT) in men with lifelong rapid ejaculation. Compared with baseline, the greatest delay in ejaculation was seen with paroxetine, 20 mg/d, followed by fluoxetine, 20 mg/d, and then sertraline, 50 mg/d, whereas delay with fluvoxamine, 100 mg/d, did not differ significantly from placebo.

Dapoxetine is a non-antidepressant SSRI under investigation for on-demand treatment of moderate-to-severe premature ejaculation.²⁸ In two 12-week, randomized, double-blind, placebo-controlled trials, 870 men took placebo, 874 took 30-mg dapoxetine, and 870 took 60-mg dapoxetine 1 to 3 hours before sexual activity. Efficacy was determined by IELT measured at home by stopwatch.

Both dapoxetine doses improved IELT significantly more than placebo (P

Nausea, diarrhea, headache, and dizziness occurred in ≤20% of patients and were more common with the 60-mg than 30-mg dapoxetine dose.

Source: References 27,28

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.