Antidepressant-Induced Sexual Dysfunction: Five Management Strategies

Abstract: Selective serotonin reuptake inhibitors and other second-generation antidepressants have become common therapeutic options for the management of depression. Although these agents are effective and generally well tolerated, they frequently cause sexual adverse effects that can impact patients' quality of life, thus ultimately leading to nonadherence to therapy in many cases. Counsel patients about these possible adverse effects, and assess their sexual function at baseline and during therapy to monitor for these effects. Management strategies include watchful waiting, dosage reduction, drug holidays, switching antidepressants, and use of add-on medications.

Key words: sexual dysfunction, antidepressants, serotonin reuptake inhibitors

The American College of Physicians recommends that second-generation antidepressants (including selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], and atypical agents) replace the classic antidepressants (tricyclic antidepressants and monoamine oxidase inhibitors) as the standard of care for pharmacological treatment of major depressive disorder (MDD) because of their reduced toxicity and adverse-effect profiles.¹ The second-generation antidepressants are equally efficacious in the treatment of MDD¹; thus, the challenge is to select the best agent for the patient. A complete evaluation should include potential adverse effects and consequent impact on quality of life.

Sexual dysfunction is an adverse effect of antidepressants that occurs in about 20% to 45% of treated patients, depending on the antidepressant used.² Dysfunction presents as alterations in one or more sexual phases, and antidepressants can affect all phases of sexual function.³ Common dysfunctions include reduced libido, erectile or vaginal dysfunction, delayed orgasm, and anorgasmia.³ Further complicating the problem is that the sexual phases can have varying degrees of dysfunction.

The onset and duration of sexual dysfunction may vary between patients as a result of their medical and sexual history; thus, tracking any changes in sexual function after the initiation of treatment is crucial. If antidepressant therapy is not well tolerated because of sexual adverse effects, nonadherence may result, potentially leading to relapse or recurrence of depressive symptoms.²

In this article, we present 5 strategies that can be used to manage antidepressant-induced sexual dysfunction.

ROLE OF NEUROTRANSMITTERS IN SEXUAL FUNCTION

Numerous neurotransmitter systems are critical for normal sexual function, including the serotonin, dopamine, acetylcholine, and norepinephrine receptors^4,5:

Because antidepressants target these neurotransmitter systems, they can alter sexual functioning. Although sexual dysfunction has been attributed to a number of antidepressant classes, the SSRIs, which are highly serotonergic, appear to be most likely to cause sexual dysfunction.² Indeed, about 30% to 60% of patients who receive SSRI therapy experience these adverse effects.² In contrast, bupropion, nefazodone, and mirtazapine are associated with much lower rates of sexual dysfunction,⁶ presumably because of 5-HT₂ receptor antagonism (nefazodone and mirtazapine) or absence of serotonin reuptake inhibition (bupropion).

COUNSELING AND ASSESSMENT

Antidepressant-induced sexual dysfunction can have a dramatic effect on relationships, life satisfaction, and self-esteem; therefore, weigh the risk of sexual dysfunction when selecting an antidepressant for a specific patient. Counseling patients about antidepressant-induced sexual dysfunction is critical; it should include general information about the approximate likelihood of dysfunction, signs of dysfunction, what to do should it occur (ie, discuss with the clinician, do not discontinue medication), and management strategies. Being honest and forthright with patients about this issue will help build a therapeutic alliance and encourage full compliance with therapy.

One of the clinical challenges in managing sexual dysfunction is determining its exact cause and, in fact, it can be multifactorial in some patients. Depression itself often causes detrimental sexual effects,⁷ and many other factors can contribute to sexual dysfunction (Table 1). In our clinical experience, women are more likely to attribute sexual dysfunction to psychosocial factors than to antidepressant therapy; however, they appear to be as vulnerable as men to sexual adverse effects caused by antidepressants.⁸

Monitor patients' sexual functioning before and during therapy to determine the impact of antidepressant therapy. Take a thorough history to assess how important sexual activity is to the patient and to establish the baseline (nondepressed) level of sexual functioning. We suggest that patients be asked directly about their sexual history, since questionnaires have not produced accurate results regarding sexual dysfunction.⁹ Recommended questions to ask before and during therapy are presented in Table 2. It is important to determine whether the antidepressant is truly the underlying cause of the sexual dysfunction before attempting the management strategies described below.

MANAGEMENT STRATEGIES

There are 5 basic strategies for managing antidepressant-induced sexual dysfunction (Table 3). The selection of a strategy is based on various patient-specific factors, including the importance of sexual activity in the patient's life, the degree of sexual dysfunction, the severity of depression, the response of the patient to the prescribed antidepressant, the expected duration of antidepressant therapy, and the willingness of the patient to switch medications or to take additional medications.

Watchful waiting. This strategy involves continuing therapy at the same dosage to determine whether tolerance will develop. It should be the first management strategy to consider during the initial months of antidepressant therapy, when the patient is responding very well to antidepressant therapy, or when the patient is likely to be treated only for a short term, such as in first-episode depression. However, in general, this option is only occasionally effective.²

Dosage reduction. Downward titration of the antidepressant dosage sometimes diminishes sexual adverse effects.^2,6 However, this option must be used only when the patient's depressive symptoms have responded well to the antidepressant and it is possible that a positive clinical response would continue at a lower dose. Obviously, the risk of reducing the dose of the antidepressant is potential loss of effectiveness.

Drug holiday. Patients may be allowed to skip 1 or more doses of their antidepressant in the hope of decreasing medication levels enough to reduce adverse effects without affecting antidepressant activity. The danger is that blood antidepressant levels could reach subtherapeutic levels, potentially leading to the relapse or recurrence of depression. Moreover, this approach might give the patient the impression that skipping doses is acceptable, thus leading to nonadherence. This approach is far more likely to work when the patient is taking an antidepressant with a shorter half-life (eg, paroxetine) than one with a longer half-life (eg, fluoxetine).¹⁰

Switching antidepressants. Another approach is to simply switch to an antidepressant that is associated with a lower incidence of adverse sexual effects. Since an estimated 50% of patients do not achieve remission with initial antidepressant therapy,¹¹ switching is especially attractive when the offending drug has not been optimally effective.

The substitution of one SSRI for another SSRI will probably not alleviate sexual dysfunction.¹² However, switching to an antidepressant whose mechanism of action differs from the enhancement of the serotonergic system may be an effective strategy. For example, a switch from a moderate/high-dose SSRI to a low/moderate-dose SNRI could minimize sexual dysfunction while still adequately treating the depression.

Mirtazapine, nefazodone, and bupropion are each in alternative classes of antidepressants that are associated with fewer adverse sexual effects and have been shown to improve many phases of sexual function in both men and women who were originally treated with SSRIs.⁶ However, these medications have adverse effects of their own:

After the antidepressant is switched, monitor the patient for relapse or recurrence of depressive symptoms. Although the new antidepressant may reduce sexual adverse effects, it may prove to be less effective or even ineffective in the amelioration of depressive symptoms for the patient.

Add-on therapy. Various medications may be added to ongoing antidepressant therapy to help manage sexual dysfunction; these medications and their dosing information are presented in Table 4. We would like to note that none of these medications are FDA-approved for the specific indication of treatment of antidepressant- induced sexual dysfunction. Add-on therapy is a particularly attractive option when patients are responding well to antidepressant therapy and they do not want to risk any loss of effectiveness. However, patients must be willing to accept the consequences of an additional medication, such as adverse effects, drug interactions, and cost.

Targeting dopaminergic neurotransmission has proved beneficial in treating SSRI-induced sexual dysfunction.³ The dopamine receptor agonist, ropinirole, which is typically used to treat Parkinson disease and restless legs syndrome, and amantadine, an agent with a complex mechanism of action that enhances dopamine activity, have been shown to improve sexual function.^3,16 Bupropion, an agent that elevates both norepinephrine and dopamine levels in the brain, alleviates sexual dysfunction caused by SSRIs when given on a fixed-dose schedule or when taken as needed.³ However, adverse effects such as anxiety and tremor can occur when bupropion is coadministered with SSRIs, especially fluoxetine.⁹

Modulation of serotonin neurotransmission is another option for the treatment of antidepressant-induced sexual dysfunction. Buspirone, a partial agonist of 5-HT_1A receptors that is typically used as an antianxiety agent, has been shown to improve sexual function in SSRI-treated patients.¹⁷ Since activation of the 5-HT_2A receptor reduces sexual responses,⁴ inhibition of its function can be used as a therapeutic option. Mirtazapine and nefazodone, which are both antidepressants that antagonize 5-HT_2A receptors, can alleviate SSRI-induced sexual dysfunction.^3,18 Cyproheptadine is another 5-HT₂ antagonist that can reduce SSRI-induced sexual adverse effects, and it is effective with both routine and as-needed dosing.^3,18 However, sedation and fatigue associated with the use of cyproheptadine may limit its tolerability. In addition, because it has the potential to block the beneficial effects of SSRIs, it should be used cautiously for this indication.⁹

Yohimbine, an α₂-adrenergic antagonist that causes elevated norepinephrine levels in the brain, can also be used as concomitant therapy. It has been reported to alleviate SSRIinduced sexual dysfunction.³ Common adverse effects include nausea, anxiety, and insomnia³; other notable effects include elevated blood pressure and heart rate.

Phosphodiesterase type 5 (PDE5) inhibitors (ie, sildenafil, tadalafil, and vardenafil) have demonstrated benefit in both men^19-21 and women²² with antidepressant-induced sexual dysfunction. However, the use of PDE5 inhibitors should be closely monitored in patients at risk for cardiovascular diseases and should be avoided in patients who take organic nitrates (nitroglycerin or isosorbide dinitrate) for cardiac disorders.

Scheduling of add-on therapy should be addressed with the patient. Some patients may respond to asneeded dosing of certain medications (see Table 4), while others will require routine dosing. Routine dosing is more likely to result in additional adverse effects; however, as-needed administration can spoil spontaneity and could "ruin the moment."²³ When used as add-on therapy, routine dosing of mirtazapine, nefazodone, or bupropion might provide additional antidepressant benefits as well as help alleviate sexual dysfunction.

References:

REFERENCES:

1.

Qaseem A, Snow V, Denberg TD, et al; Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians.

Ann Intern Med

. 2008;149: 725-733.

2.

Gregorian RS, Golden KA, Bahce A, et al. Antidepressant- induced sexual dysfunction.

Ann Pharmacother

. 2002;36:1577-1589.

3.

Woodrum ST, Brown CS. Management of SSRI-induced sexual dysfunction.

Ann Pharmacother

. 1998;32:1209-1215.

4.

Kennedy SH, Rizvi S. Sexual dysfunction, depression, and the impact of antidepressants.

J Clin Psychopharmacol

. 2009;29:157-164.

5.

Stevenson RW. Sexual medicine: why psychiatrists must talk to their patients about sex.

Can J Psychiatry

. 2004;49:673-677.

6.

Hirschfeld RM. Management of sexual side effects of antidepressant therapy.

J Clin Psychiatry

. 1999;60(suppl 14):27-35.

7.

Baldwin DS. Depression and sexual dysfunction.

Br Med Bull

. 2001;57:81-99.

8.

Segraves RT. Female sexual disorders: psychiatric aspects.

Can J Psychiatry

. 2002;47:419-425.

9.

Rothschild AJ. Sexual side effects of antidepressants.

J Clin Psychiatry

. 2000;61(suppl 11):28-36.

10.

Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday.

Am J Psychiatry

. 1995;152:1514-1516.

11.

Rosenzweig-Lipson S, Beyer CE, Hughes ZA, et al. Differentiating antidepressants of the future: efficacy and safety.

Pharmacol Ther

. 2007;113: 134-153.

12.

Clayton AH, Montejo AL. Major depressive disorder, antidepressants, and sexual dysfunction.

J Clin Psychiatry

. 2006;67(suppl 6):33-37.

13.

Cates M. Selecting antidepressant therapy for patients with major depression.

Am J Pharm Educ

. 2001;65:190-194.

14.

DeSanty KP, Amabile CM. Antidepressantinduced liver injury.

Ann Pharmacother

. 2007;41: 1201-1211.

15.

Feighner JP. Mechanism of action of antidepressant medications.

J Clin Psychiatry

. 1999;60(suppl 4): 4-13.

16.

Worthington JJ 3rd, Simon NM, Korbly NB, et al; Anxiety Disorders Research Program. Ropinirole for antidepressant-induced sexual dysfunction.

Int Clin Psychopharmacol

. 2002;17:307-310.

17.

Landén M, Eriksson E, Agren H, Fahlén T. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors.

J Clin Psychopharmacol

. 1999; 19:268-271.

18.

Stimmel GL, Gutierrez MA. Sexual dysfunction and psychotropic medications.

CNS Spectr

. 2006; 11(8, suppl 9):24-30.

19.

Nurnberg HG, Hensley PL, Gelenberg AJ, et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial.

JAMA

. 2003;289:56-64.

20.

Segraves RT, Lee J, Stevenson R, et al. Tadalafil for treatment of erectile dysfunction in men on antidepressants.

J Clin Psychopharmacol

. 2007;27:62-66.

21.

Berigan T. Antidepressant-induced sexual dysfunction treated with vardenafil.

Can J Psychiatry

. 2004;49:643.

22.

Nurnberg HG, Hensley PL, Heiman JR, et al. Sildenafil treatment of women with antidepressantassociated sexual dysfunction: a randomized controlled trial.

JAMA

. 2008;300:395-404.

23.

Fava M, Rankin M. Sexual functioning and SSRIs.

J Clin Psychiatry

. 2002;63(suppl 5):13-16; discussion 23-25.

The authors report that they have no relevant financial relationships to disclose.