Antidepressants and sexual dysfunction☆

Effects of anxiety and depression on sex 

Anxiety disorders and depressive disorders represent one of the most commonly diagnosed and treated conditions by primary care physicians, as well as by psychiatrists. Bipolar disorder affects more than 2.2 million people, or 1.2% of American adults (3). Between 10 million and 14 million people in the United States suffer from depression in a given year, the majority being women (4). Community samples data show that 10%–25% of women and 4%–12% of men in the United States will have a major depressive episode at some point in their lives (5).

Anxiety may affect sexual performance in either a lack of ability to achieve erections (either partially or fully) or in an inability to reach orgasm for both men and women. One of the hallmark symptoms of major depression in both men and women is a diminished libido, or sexual dysfunction (seen in more than 70% of patients) (6). Treating depression effectively can often restore normal sexual desire. However, most of the current antidepressants also have significant side effects on normal sexual functioning.

Animal models and other studies have given us some information about drug sexual side effects. The pharmacologic treatments to counteract the sexual side effects of antidepressants follow from these biochemical effects, as shown in Table 2 (7). Almost all possible antidepressants currently being prescribed cause some degree of sexual dysfunction, as indicated in Table 3 (8).

Table 2. Biochemical Mechanisms of Sexual Dysfunction

	Drug	Sexual side effects
	Dopamine agonists	Enhance sexual functioning
	Dopamine antagonists	Impair sexual functioning
	SSRIs	Diminish sexual functioning
	Serotonin (5-HT) antagonists	Improve sexual functioning
	Alpha-2 receptor antagonists (eg., yohimbine)	Aids in arousal an orgasm by increasing norepinephrine
	Nitric oxide	Leads to engorgement of erectile tissue in men, increases blood flow to clitoris and vulva

Table 3. Sexual Side Effects of Specific Psychotropic Drugs

	Drug	Sexual side effects
	Tricyclic antidepressants (amitryptiline, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine, clomipramine)	High incidence of sexual side effects (clomipramine had highest frequency of incidence
	SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)	High incidence of sexual side effects
	MAOIs (isocarboxazid, phenelzine, tranylcypromine)	High incidence of sexual dysfunction
	MAOIs (nefazodone, mirtazapine)	Low incidence of sexual dysfunction

In one study examining patients taking antidepressant drugs (9), sexual dysfunction was assessed using the Changes in Sexual Functioning Questionnaire. Results indicated that Wellbutrin and Wellbutrin SR had the fewest sexual side effects in addition to nefazodone (22%–28%). The SSRIs, mirtazapine, and Effexor XR, were associated with much higher rates of sexual dysfunction (36%–43%). In a subpopulation who were not likely to have predisposing factors for sexual dysfunction, a prospective study showed the chance of developing a dysfunction to be 7%–30%, with SSRIs and Effexor being 4 to 6 times as likely to have sexual side effects as Wellbutrin.

In my practice, even these relatively high statistics seem to be an underestimate. In a situation where I carefully assess a patient's sexual functioning and make the patient aware of the potential side effects, well over 80% of my patients report some degree of sexual dysfunction that was not present prior to the initiation of treatment. For some, the sexual side effects (in addition to sedation and weight gain) feel so problematic that they request a change to other medication or leads to medication noncompliance.

This noncompliance is a particular problem for primary care physicians who routinely prescribe antidepressants to patients, as they often do not have the time to specifically ask about sexual (and other) side effects and they cannot follow their patients too frequently. Also, primary care physicians usually prescribe multiple refills and therefore may not be able to recognize when patients take their medication sporadically. This, in turn, leads to undertreatment of the psychiatric conditions (and thus a lack of remission of symptoms) and frequent recurrence of the underlying condition.

It is imperative that clinical trials determine which treatment alternatives may help patients suffering from sexual dysfunction.

Suggested remedies for sexual side effects of antidepressants 

There are several strategies which can be utilized for patients who suffer from sexual side effects from antidepressants. These include balancing the dose to a level that leads to the fewest side effects while maintaining efficacy, substituting another antidepressant, and using antidotes. Still another possibility is to wait for spontaneous remission of sexual dysfunction associated with the use of antidepressants.

Psychiatrists have attempted to use the lowest possible dose of medication or have suggested a “drug holiday.” Thus, patients could skip one or two doses before a time when they think they will be involved in a sexual encounter. There are potential benefits in the sense that the optimal medication regimen is still used. However, the problems can be complicated. First of all, the patient may not be in a position of being able to schedule a sexual encounter in order to know when to stop the medication temporarily. Furthermore, the effects of a long-acting antidepressant, such as fluoxetine, may not wear off.

On the other hand, a short acting drug such as paroxetine might cause withdrawal symptoms. So can venlafaxine, within 2 days of stopping the medication. Some common withdrawal symptoms include dizziness, imbalance, nausea, headache, imbalance, anxiety or agitation 10, 11. The other complication associated with skipping medication is that patients may become confused and get out of the habit of taking their medication and not resume taking it as previously prescribed. Thus, they might suffer a recurrence of their illness as a result of sporadic use of the medication.

Medications that have been tried to offset the sexual side effects of antidepressants have succeeded with varying efficacy (7), as shown in Table 4.

Table 4. Medications to Offset Sexual Side Effects of Antidepressants

	Agent	Mechanism	Initial dosage	Risks
	bupropion (Wellbutrin)	increases dopaminergic tone	75 mg qd 1–2 h PTSA (prior to sexual activity)	hypertension, increases seizure risk
	methylphenidate (Ritalin, Concerta)	increases dopaminergic tone	5–10 mg PTSA	overstimulation, potential abuse
	cyproheptadine (Periactin)	antagonizes 5HT receptors	4–12 mg qd or PTSA	sedation, dry mouth, may decrease antidepressant effect
	yohimbine (Yocon, Pro-comil)	increases norepinephrine outflow	5.4–10.8 mg qd or PTSA	increases anxiety, hypertension; not studied in women
	sildenafil (Viagra)	increases nitric oxide	50 mg PTSA	hypotension, other cardiovas-cular side effects
	bethanechol (Urecholine)	increases cholinergic tone	25–50 mg qd or PTSA	diarrhea, autonomic side effects, many medical contraindications

There have been some studies looking at the efficacy of some of these augmenting medications. A study by Michelson et al.(12) looked prospectively at premenopausal women with sexual dysfunction as a result of fluoxetine. They were either put on mirtazapine, yohimbine, olanzapine, or placebo for 6 weeks. Though each group improved, no drug was associated with more effect over placebo.

One of the most commonly utilized augmentation strategies used by physicians is the addition of bupropion either daily or prior to sexual activity. However, a recent study by Masand et al. (13) did not show any difference between Wellbutrin SR 150 mg/d and placebo in patients who took the medication for 3 weeks. This substantiates my clinical impression as well that bupropion does not make an appreciable difference in women's ability to get aroused or be orgasmic when they suffer from sexual side effects of the SSRIs. Another study looked at women's response to buspirone, amantadine or placebo when they experienced fluoxetine-related sexual dysfunction (14). The results also showed no benefit of either buspirone or amantadine.

One of the many limitations of these studies, however, is that depression in itself can affect the subtle relationships of women towards their families and partners. It is possible that some of the sexual dysfunction is a result of depression itself, thus making a pharmacological cure for the sexual problems impossible without attendant help in the psychosocial sphere.

Some physicians choose bupropion as a first-line antidepressant because of its relative lack of sexual side effects. However, bupropion does not work as well as the SSRIs for severe anxiety associated with depression, obsessional thoughts, hypochondriacal concerns, panic disorder, or social anxiety disorder. Alternatively, nefazodone was also tried by many because of its lack of sexual side effects. My experience is that unfortunately it is not a medication that works as consistently or as well as the SSRIs. Furthermore, reports of liver toxicity have taken it off the market in Europe and may do similarly in the future in the U.S.

Finally, and most interestingly, Nurnberg et al. (15) have studied the efficacy of sildenafil citrate in men with sexual dysfunction in a double-blind, placebo controlled study. The findings showed that sildenafil significantly improved all types of sexual function in men with SSRI-induced sexual side effects. Bartlik et al. (16) describes the belief that sildenafil has the potential of helping in all four phases of the sexual response cycle, although randomized, placebo-controlled trials of women are very much needed and have been appallingly absent.

In conclusion, the treatment of sexual dysfunction associated with antidepressant use has been extremely challenging, with minimal to moderate success. It is imperative that clinical trials determine which treatment alternatives may help patients suffering from sexual dysfunction. Only by addressing and being able to treat these difficult side effects can we, as physicians, ensure that our patients will remain compliant with the medications they need to treat their depression and associated psychiatric illnesses.