It has become more and more painful for us to prescribe SSRIs and SNRIs over the last few years. The reason? Sexual dysfunction.

Depending on the strictness of criteria used for defining it, antidepressant-induced sexual dysfunction rates range from about 40% to 60%. Generally, Wellbutrin and Serzone are much less likely to cause problems, while the experience with Remeron is mixed. Compare these numbers with the PDR, which reports SSRI sexual dysfunction rates in the range of <1% to a “high” of 14%. The moral? You can design a study to achieve the numbers you want.

Recognized authorities can do no better than guess at why SSRIs cause this nasty side effect. The most widely accepted theory is that stimulation of the serotonin 2 receptor is the culprit, based primarily upon the fact that drugs that block this receptor (eg., Serzone, Periactin) can improve sexual functioning. Another theory is that SSRIs lower libido indirectly, by decreasing levels of dopamine.

So now lets talk nostrums.

Viagra
Curiously enough, erections occur because of muscle relaxation, rather than contraction. Penile smooth muscle relaxation allows blood to flow into the erectile bodies, which in turn compresses penile veins, keeping blood trapped in the penis. Arousal in women works similarly, in that clitoral smooth muscle relaxes, allowing artery inflow and clitoral tumescence.

How do these muscles get signaled to relax? The process starts with sexual stimulation, which leads to the release of nitric oxide (NO) into the penile blood stream. NO leads to the synthesis of cGMP, a second messenger, which is the chemical that directly causes smooth muscle relaxation. An enzyme called phosphodiesterase-5 (PDE-5) then works on cGMP to break it down. Viagra (sildenafil) is classified as a “PDE-5 inhibitor”, causing cGMP levels to remain high, thus prolonging smooth muscle relaxation and erection. So Viagra cannot initiate erection; but, once initiated, it prolongs it.

Placebo-controlled trials have shown robust efficacy in men, and specifically in antidepressant-associated sexual dysfunction (1). But does Viagra work for women? Unclear. A few letters and case series have reported benefits, but controlled trials have not. It certainly causes the clitoris to stay swollen and engorged longer, but women have not reported increased sexual satisfaction as compared to placebo (2).

To prescribe Viagra, start at 50 mg QD as needed for sexual activity. It is absorbed within 30 minutes to an hour, and lasts roughly 6 hours. But absorption is impeded if taken up to an hour after a meal. Common side effects are headache, flushing, and fatigue. Warn your patients that it may take 3 or 4 trials to get the hang of the drug. Otherwise, they may return after having taken it once, not having attained an erection, and feeling discouraged because this was another experience of sexual failure.

Lilly will soon launch Cialis, a longer half-life version of Viagra

Incidentally, Lilly/ICOS is getting ready to launch an improved version of Viagra, called Tadalafil (brand name Cialis). This is also a PDE-5 inhibitor, but has a much longer half-life of 17.5 hours, meaning that it will remain effective for about 36 hours after ingestion, substantially improving the degree of sexual spontaneity possible among users.

ArginMax
The buzz in the treatment of sexual dysfunction is about ArginMax, an overthe- counter mixture of L-Arginine, (the amino acid precursor of nitric oxide), Ginkgo Biloba (which probably improves sexual functioning on its own), Korean Ginseng, and a smattering of vitamins and minerals.

Only one controlled study has been published in a peer-reviewed journal, but it was impressive: a double-blind, randomized placebo controlled trial of 77 women with sexual dysfunction showed a 73% improvement in the ArginMax group vs. 37% improvement in the placebo group (3). The ArginMax website reports an unpublished study by the same University of Hawaii group showing efficacy in 48 males with erectile dysfunction recruited through a urology clinic: 75% of the men taking ArginMax reported overall satisfaction vs. 21% in the placebo group.

The usual dose of ArginMax is 3 capsules twice daily, with a response expected in 2 to 4 weeks. The cost is about $30/month, much cheaper than Viagra, which goes for $8-10/tablet. ArginMax appears to be without side effects, and there are no drug-drug interactions of note. But does it work outside of Hawaii? That is the question.

Drug Holiday
While this technique is usually discouraged by experts because of the risks of depressive relapse and discontinuation side effects, most patients who try it report that it works pretty well. As long as you don’t do this with Paxil or Effexor, withdrawal is generally not a problem, and relapse to depression is rare as well. The usual technique is to have your patient take no dose Friday and Saturday, and to resume at the usual dose on Sunday.

Drug Switch
Switch to either Wellbutrin, Serzone, or St. John’s Wort (TCR 1:1,2003), all of which rarely cause sexual side effects. Unfortunately, many of us are now reluctant to use Serzone at all, because of a recently reported risk of hepatotoxicity 20-fold greater than other newer antidepressants (about 3 cases/10,000 patientyears).

Add Wellbutrin
Adding Wellbutrin to an SSRI or SNRI probably works to enhance sexual functioning. All of the open-label studies reviewed by TCR reported good efficacy in improving sexual response in both men and women; unfortunately, the one double-blind study to be published thus far showed no separation between Wellbutrin and placebo (4). This trial only lasted 3 weeks and limited the dose of Wellbutrin SR to 150 mg QD. The open label studies were more flexible, allowed higher dosing, and allowed treatment to last longer. Go down a list Each of the following has been reported effective in cases series but placebo-controlled trials are either absent or negative: Buspar 30-60 mg QD; Periactin 8 mg 30 minutes before sex; Amantadine 100 mg QD; Serzone 50-100 mg QHS; Ritalin 5-10 mg prn. They are all basically worth trying when nothing else works.

TCR VERDICT: Viagra for Men; ArginMax for Women?