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Home , Amantadine, Moclobemide, Reboxetine

DRUG INFORMATION QUARTERLY Sexual adverse effects with new

Shameem Mir and David Taylor

Sexualdysfunction isa widely recognised adverse effect prescribed there have been reports of of many psychotropic agents. Older antidepressants prolonged erection (Murray & Hooberman, such as inhibitors and , 1993). involuntary sperm emission (Benazzi, particularly , 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 lowered libido as part of depressive illness itself. We (Charles et al, 1993, Waldinger et al, 1997), examined evidence relating to more recently introduced (Dorevitch & Davis, 1994), sertra- antidepressants: selective inhibitors, line (Doogan et al 1988) and (Bald . , , win & Johnson, 1995). and . We reviewed published trials and case In women, -induced sexual ad reports collated from searches of Mediine, Psychütand 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 . 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 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 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 (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 . Because of its lack of effect at 5HT2 receptors. Preskorn (1995) compared on , 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%), (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 . 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. Retrograde ejaculation Caused by prevention of complete closure of Internal urethral sphincter Priapismin men and clitoral priapism in e.g. women Hyperprolactinaemia Decreased libido in both men and e.g. typical antlpsychotics, women , 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 ) 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 underlying mechanism of sexual dysfunc treatment. tion. For example, if the adverse effect is thought to be caused by enhanced serotonergic neuro transmission, cyproheptadine may be the drug of References choice. Cyproheptadine is an with 5-HT2 antagonistic activity. Waldinger (1996) AIZENBERG. D., ZEMISHLANY,Z. & WEIZMAN, A. (1995) Cyproheptadine treatment of sexual dysfunction described an improvement in SSRI-induced induced by serotonin reuptake inhibitors. Clinical sexual dysfunction with cyproheptadine. Aizen- Neuropharmacology. 18. 320-324. berg et al (1995) also conclude that cyprohepta BALDWIN.D. & JOHNSON.N. (1995) Tolerability and safety of dine may be beneficial in those with SSRI- citalopram. Review of Contemporary Pharmacotherapy, 6. 315-325. induced decreased libido and anorgasmia, and BALÓN.R. (1996) Intermittent for fluoxetine- Lauerma (1996) reported the successful use of induced anorgasmia. Journal of Sex and Marital cyproheptadine in treating citalopram-induced Therapy, 22, 290-292. anorgasmia. Oddly, Nelson et al (1997) report the BENAZZI. F. (1995) Involuntary sperm emission with first case of using a 5-HT3 antagonist (granisi- fluoxetine. Canadian Journal of Psychiatry, 40. 431. tron) to treat fluoxetine-induced anorgasmia. BERK,M. & ACTON,M. (1997) Citalopram-associated clitoral priapism: a case series. International Clinical The use of to treat impotence is Psychopharmacology, 12, 121-122. widely recognised. Yohimbine is an a2-adreno- BERZEWSKI.H.. VANMOFFAERT.M. & CAGIANO.C. A. (1997) ceptor antagonist and an otj-adrenoceptor ago Efficacy and tolerability of reboxetine compared with nist. Jacobsen (1992) has shown yohimbine to in a double-blind study in patients suffering have some potential in the treatment of fluox from major depressive episodes. European etine-induced orgasmic and erectile difficulties. Neuropsychopharmacology, 7. S37-S47. CHARLES.F.. WEBER,C. & WEBER.S. S. (1993) Paroxetine: A Unlike the remedial pharmacological treat selective serotonin reuptake inhibiting antidepressant. ments discussed above, the Annals of Pharmacotherapy. 27. 1212-1220. of amantadine in treating antidepressant- DOOGAN.D. P. & CAILLARD,V. (1988) Sertraline: a new induced sexual dysfunction is not clear. antidepressant. Journal of Clinical Psychiatry. 49, 46- 51. Amantadine is a and Shrivas- DOREVITCH,A. & DAVIS,H. (1994) Fluvoxamine-associated tava et al (1995) describe its successful use in sexual dysfunction. Annais of Pharmacotherapy. 28. treating SSRI-induced ejaculatory difficulties. 872-874. Also, in one case amantadine has been used five DUBOVSKY,S. L. & THOMAS, M. (1995) Serotonergic to six hours before coitus to treat fluoxetine- mechanisms and current future psychiatric practice. Journal of Clinical Psychiatry. 56 (suppl.). 38-48. induced anorgasmia (Balón, 1996). GITLIN, M. J. (1994) Psychotropic medications and their effects on sexual dysfunction: Diagnosis, biology, and treatment approaches. Journal of Clinical Psychiatry, 55, 406-413. HAWLEY.C. & SMITH,V. (1994) Review of a paper entitled Therapeutic uses of sexual side-effects "Effects of antidepressants on sexual function". Medical The sexual adverse effects of some antidepres- Dialogue. 4. 1-4. sants are so well known that they are used to HERMAN.J. B.. BROTMAN,A. W., POLLACK,M. H.. et al (1990) Fluoxetine-induced sexual dysfunction. Journal of relieve some sexual problems. For example, Clinical Psychiatry. 51. 25-27. clomipramine and SSRIs can be used to treat HONG, S. L.. DONG. H. S.. CHAN-HYUNG.K.. et al (1996) An premature ejaculation and trazodone is used for open of fluoxetine in the treatment of erectile dysfunction. Readers are directed to the premature ejaculation. Journal of Clinical review of Waldinger (1996) for a full discussion. Psychopharmacology. 16. 379-382.

440 Mir & Taylor DRUG INFORMATION QUARTERLY

JACOBSEN. F. M. (1992) Fluoxetine-induced sexual PRESKORN,S. H. (1995) Comparison of the tolerability of dysfunction and an open trial of yohimbine. Journal of . fluoxetine, imipramine, nefazodone, Clinical Psychiatry, 53, 119-122. paroxetine, sertraline. and venlafaxine. Journal of LAUERMA,H. (1995) A case of moclobemide-induced Clinical Psychiatry, 56, 12-21. hyperorgasmia. International Clinical Psychopharma- REYNOLDS,R. D. (1997) Sertraline-induced anorgasmia cology. 10, 123-124. treated with intermittent nefazodone (letter). Journal of — (1996) Successful treatment of citalopram-induced Clinical Psychiatry, 58, 89. anorgasmia by cyproheptadine. Acta Psychiaírica ROTHSCHILD,A. J. (1995) Selective serotonin reuptake Scandinainca, 93. 69-70. inhibitor - induced sexual dysfunction: efficacy of a MENDELS,J., JOHNSTON,R, MATTES.J.. et al (1993) Efficacy drug holiday. American Journal of Psychiatry, 152. and safety of b.i.d. doses of venlafaxine in a dose 1514-1516. response study. Psychopharmacology Bulletin, 29, 169- SHRIVASTAVA,R. K., SHRIVASTAVA,S.. OVERWEG,N., et al 174. (1995) Amantadme in the treatment of sexual MICHAEL. A. & OWEN. A. (1997) Venlafaxine-induced dysfunction associated with selective serotonin increased libido and spontaneous erections. British reuptake inhibitors. Journal of Clinical Journal of Psychiatry, 170, 193. Psychopharmacology, 15, 83-84. MONTGOMERY,S. A. (1995) Safety of mirtazepine: a review. WALDINGER,M. D. (1996) Use of psychoactive agents in the International Clinical Psychopharmacology, 4. 37-45. treatment of sexual dysfunction. CNS Drugs. 6, 204- MORRIS, P. L. (1991) Fluoxetine and orgasmic sexual 216. experiences. International Journal of Psychiatry in —, HENGREVELD,M. W. & ZWINDERMAN,A. H. (1997) Medicine, 21, 379-382. Ejaculation-retarding properties of paroxetine In Mucci, M. (1997) Reboxetine: a review of antidepressant patients with primary premature ejaculation: a tolerability. Journal of Psychopharmacology, 11, 533- double-blind, randomized, dose response study. 537. British Journal of Urology, 79. 592-595. MURRAY,M. J. & HOOBERMAN.D. (1993) Fluoxetine and prolonged erection. American Journal of Psychiatry, 150. 167-168. NELSON,E. B.. KECK, Jr, P. E. & MCELROY,S. L. (1997) *Shameem Mir, Senior Clinical Pharmacist, David Resolution of fluoxetine-induced sexual dysfunction with the 5-HT3 antagonist granisitron. Journal of Taylor, Chief Pharmacist, Maudsley Hospital, Clinical Psychiatry, 58. 496-497. Hill, London SE5 8AZ PHILIPP,M., KOHNEN,R. & BENKERT,O. (1993) A comparison study of moclobemide and in major depression with special reference to effects on sexual dysfunction. International Clinical Psychopharmacology, 7. 149-153. 'Correspondence

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Sexual adverse effects with new antidepressants 441