Sexual Adverse Effects with New Antidepressants

DRUG INFORMATION QUARTERLY Sexual adverse effects with new antidepressants Shameem Mir and David Taylor Sexualdysfunction isa widely recognised adverse effect prescribed fluoxetine there have been reports of of many psychotropic agents. Older antidepressants prolonged erection (Murray & Hooberman, such as monoamine oxidase inhibitors and tricyclics, 1993). involuntary sperm emission (Benazzi, particularly clomipramine, are known to engender 1995) and delayed ejaculation (Hong et al, sexual adverse effects. In depression, this problem is 1996). Ejaculatory abnormalities (failure or exacerbated by the occurrence of impotence and delay) have also been reported with paroxetine lowered libido as part of depressive illness itself. We (Charles et al, 1993, Waldinger et al, 1997), examined evidence relating to more recently introduced fluvoxamine (Dorevitch & Davis, 1994), sertra- antidepressants: selective serotonin reuptake inhibitors, line (Doogan et al 1988) and citalopram (Bald moclobemide. venlafaxine, nefazodone, mirtazapine win & Johnson, 1995). and reboxetine. We reviewed published trials and case In women, antidepressant-induced sexual ad reports collated from searches of Mediine, PsychÃ¼tand verse effects seem more varied. Morris (1991) Micromedex from 1985 to December 1997, and con reported spontaneous orgasm with fluoxetine, tacted manufacturers of new antidepressants and whereas Herman et al (1990) described delayed requested information from them. orgasm and anorgasmia. Fluvoxamine has been linked with an increase in libido and multiple The true incidence of antidepressant-induced orgasms (Dorevitch & Davis, 1994). Citalopram sexual dysfunction is difficult to establish. For appears to be the only SSRI reported to cause instance, people may be understandably reluc clitoral priapism (Berk & Acton, 1997). tant to voluntarily report such information. Clinical studies of the SSRIs report the in Direct questioning regarding sexual side-effects cidence and nature of sexual adverse effects. may then produce a higher estimate of the level However, incidence figures for the same drug of sexual dysfunction than by allowing indi vary considerably (perhaps because different viduals simply to volunteer the information. Also, methods of evaluation were used) and there are psychogenic factors such as anxiety and depres few direct comparisons between drugs. Never sion are known to contribute to impairment of theless, given that the SSRIs by definition have sexual function. Furthermore, few prospective the same mode of action, differences in the controlled studies of sexual dysfunction have incidence or nature of sexual dysfunction are been performed, and so the literature available likely to be small, if indeed they exist. mainly reports single cases. Moclobemide Selective serotonin reuptake Moclobemide is a reversible inhibitor of mono inhibitors amine oxldase-A (RIMA). Philipp et al (1993) There are a number of case reports associating describe how moclobemide led to an increase in SSRIs with sexual dysfunction. Indeed there are libido in 18% of patients compared with 6.3% on more than with other new antidepressants. doxeprin. They also described a case of moclo- However, this probably reflects more widespread bemide-induced sexual hyperarousal in one use rather than a greater propensity to cause woman. Lauerma (1995) reported a similar case such effects. Nevertheless, it is accepted that all of hyperorgasmia and sexual hyperactivity In a SSRIs cause a variety of sexual adverse effects female patient taking moclobemide. Despite (Gitlin. 1994). The most commonly reported relatively widespread use. particularly in Eur effects are reduced libido, ejaculatory delay, ope, we could find no other case reports linking erectile failure and anorgasmia (Hawley & Smith. moclobemide with sexual dysfunction. This and 1994). clinical experience suggests the incidence of Fluoxetine seems to be the most widely sexual side-effects caused by moclobemide to reported of the SSRIs to cause sexual impair be very low. Of particular note is that delayed ment (it is. however, the most prescribed). In men orgasm or anorgasmia seem not to occur. 438 Psychiatric Bulletin (1998). 22. 438-441 DRUG INFORMATION QUARTERLY Venlafaxine with sexual dysfunction. However, it is difficult Venlafaxlne inhibits the reuptake of both nora- to establish whether or not nefazodone is completely free from sexual side-effects as it drenaline and serotonin. The manufacturers of venlafaxine have received reports of anorgasmia, has only been introduced to the market recently increase or decrease in libido, ejaculation dis and therefore has not been widely used. orders, impotence and priapism; most of which could be causally linked to venlafaxine. In their efficacy and safety study, Mendels et al (1993) Mirtazapine found the difference in incidence of sexual side- Mirtazapine increases noradrenergic and seroto- effects between placebo and the highest dose of nergic neurotransmission via a2-auto-receptor venlafaxine (200 mg a day) to be statistically blockade. The increased serotonergic neuro significant. This may suggest a dose-related transmission is mediated only through post- effect, further supported by Michael & Owen synaptic 5-HT1A receptors. This is because (1997), who described increased libido and mirtazapine blocks 5-HT2 and 5-HT3 receptors. spontaneous erections in a man taking the Thus, as with nefazodone one might expect a low maximum daily dose of venlafaxine. The number incidence of sexual dysfunction. Indeed, clinical of reports of sexual side-effects with venlafaxine trials show mirtazapine to cause sexual dysfunc is fairly high considering the drug's recent tion no more frequently than placebo and at introduction to the market. lower frequency than amitriptyline (Montgomery, 1995). We could find no reports of sexual dysfunction related to the use of mirtazapine. Nefazodone Nefazodone is a relatively recently marketed antidepressant. It appears to lack sexual side- Reboxetine effects (Dubovsky & Thomas, 1995); this is Reboxetine acts as a specific noradrenaline thought to be because of its antagonist activity reuptake inhibitor. Because of its lack of effect at 5HT2 receptors. Preskorn (1995) compared on cholinergic, adrenergic and serotonergic information from different databases and found systems (see Table 1) a low incidence of sexual that sexual dysfunction with nefazodone was dysfunction might be expected. This seems to be less common than with other antidepressants. borne out in clinical trials (Berzewski et al, For example, the placebo adjusted incidence for 1997). especially at doses of 8mg a day or less abnormal ejaculation/orgasm with nefazodone (Mucci, 1997). was 0.6% compared with paroxetine (12.9%), sertraline (13.3%) and venlafaxine (12%). Indeed, Mechanism of sexual side-effects intermittent nefazodone has been used in one case to treat sertraline-induced anorgasmia in a It can be assumed that certain drugs can be man (Reynolds, 1997), although caution is associated with specific types of sexual side- required with such a combination of drugs effects. Observing which sexual side-effects are because of the potential of serotonin syndrome. caused by a particular drug or class of drugs (not We could find no reports associating nefazodone only antidepressants), and relating them to its Table 1. Suggested mechanisms of drug-induced sexual dysfunction Pharmacological effect Adverse effect Comments Cholinergic blockade May decrease or inhibit sexual function Data inconclusive a,-adrenergic blockade Inhibition of ejaculation Orgasm achieved but without ejaculation, e.g. sertindole Retrograde ejaculation Caused by prevention of complete closure of Internal urethral sphincter Priapismin men and clitoral priapism in e.g. trazodone women Hyperprolactinaemia Decreased libido in both men and e.g. typical antlpsychotics, women risperidone, amoxapine Impotence and azoospermia in men Inhibition of serotonin reuptake Spontaneous orgasm in women e.g. SSRIs,venlafaxine, clomipramlne (Indirect stimulation of 5-HT2 Impotence and delayed ejaculation receptors) In men Anorgasmia in both genders Sexual adverse effects with new antidepressants 439 DRUG INFORMATION QUARTERLY pharmacology, allows one to suggest mechan Comment isms of sexual dysfunction (see Table 1). The true incidence and type of sexual dysfunc tion caused by antidepressants is difficult to establish. Furthermore, the incidence figures quoted for the same drug may vary considerably Treatment of drug-induced sexual and there are few direct comparisons. Of the dysfunction newer antidepressants, nefazodone and moclo- Drug-induced sexual dysfunction can be man bemide appear to cause few sexual side-effects. aged in several ways. Wherever possible, the first The SSRIs and venlafaxine are more widely step should be a dose reduction. If this falls or is associated with sexual dysfunction. Such ad not feasible, the use of another drug with a lower verse effects, however, can have therapeutic propensity to cause sexual dysfunction would be uses. The treatment options available for anti- the next step. Before remedial drug therapy (for depressant-induced sexual dysfunction are a example cyproheptadine) is considered, a drug dose reduction, changing to a different anti- holiday (Rothschild, 1995) may be an appro depressant, a drug holiday or remedial therapy. priate option. In clinical practice a dose reduction or change of The choice of remedial drug therapy depends drug therapy are the most common forms of on the

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