Sunday, November 2, 2008

Management of Sexual Dysfunction Associated with Antidepressants: Drug Holidays


o · Drug holidays in which the antidepressant is discontinued 2 to 3 days prior to sexual activity is more successful with drugs that have a short half-life.

o · Clinicians should ask specifically about sexual desire, sexual enjoyment, erectile problems, erections unrelated to sexual activity, capacity to reach orgasm, changes in capacity to reach
orgasm, and painful orgasm.

o · Antidepressants also have been used to treat some sexual dysfunctions, such as premature ejaculation.

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) have been used in psychiatry and other disciplines for almost 4 decades. Antidepressants were originally reserved for serious cases of depression. Selective serotonin reuptake inhibitors (SSRIs) were introduced into clinical psychiatry about 10 years ago. The use of SSRIs, along with advances in clinical
psychopharmacology research and the decrease in payments for psychotherapy by third-party payers, have to some extent revolutionized the field of clinical psychopharmacology. Since
these times, psychiatrists and primary care doctors have started to treat disorders that were once considered the domain of psychotherapy, such as dysthymia and some anxiety disorders, with antidepressants.

We have been treating patients mostly in the outpatient setting. The results of well-designed, long-term studies have helped to define the duration of treatment of an episode of depression.1,2

We now continue antidepressant treatment for about 6 months following remission, using the dosage that was effective in the acute phase. Clinical psychopharmacologists have also become more aware of various side effects, reasons for noncompliance, and quality-of -life issues during treatment with antidepressants. One such side effect is sexual dysfunction. Changes in sexual
functioning can occur with various mental disorders, such as depression, and can also result from antidepressant therapy (see Table 1).

The effects of psychotropic medication on sexual functioning have been the subject of various excellent reviews.3-6 Drugs used for treating depression have been implicated in sexual dysfunction with increasing frequency, and changes in sexual functioning havebeen reported with almost all the antidepressants (see Table 2). Estimates of the incidence of treatment-emergent sexualdysfunction with antidepressants vary from 1.9% (Physicians Desk Reference, for fluoxetine) to over 90% (see Table 3). This vast range is probably at least partially a reflection of the lack ofattention to sexual side effects in previous studies and the lack of thorough and uniform methodology in current studies focused on sexual dysfunction caused by antidepressant therapy. The majorityof studies have been nonsystematic. For example, some described sexual dysfunctions that were reported spontaneously, some described sexual dysfunction after patients were asked about it in a systematic way, and some studies used questionnaires.

Frequently, changes in sexual desire were not elicited. Serial questioning about sexual dysfunction during the course of pharmacotherapy has also not been used. Our understanding of the biology of normal sexual functioning and of mechanismsof action of antidepressant-induced sexual dysfunction is rather poor. Various neurotransmitter systems (adrenergic, dopaminergic, serotonergic, muscarinic) seem to be involved in the biology of normal sexual response and activity, centrally and peripherally.3,5 None of these systems should be solely implicated, and interactions on central and peripheral levels are likely. Some other neurotransmitters, such as acetylcholine, probably play a mediating role as well.5

Interestingly, a correlation between sexual dysfunction and the anticholinergic effects of antidepressants was not observed in one study.11 Sexual hormones and other substances (eg, vasoactive intestinal peptide) probably have at least a modulating role.

Administration of drugs influencing various neurotransmitter systems, such as antidepressants, could affect sexual functioning in different ways. Various sexual dysfunctions are the most frequently observed effects, but occasional improvement of sexual functioning with antidepressants14 or unusual sexual experiences15 have been reported. Antidepressants also have been used to treat some sexual dysfunctions, such as premature ejaculation.16 Obviously, antidepressants can cause various changes in sexual functioning (see Table 4).

Sexual dysfunction has been a frequently mentioned cause of noncompliance with antidepressant therapy, but this issue has not been systematically studied. Rabkin et al17 reported four cases of discontinuation of monoamine oxidase inhibitors (MAOIs), but only one case was solely due to sexual dysfunction, without any other major side effects. Other reports of noncompliance because of sexual dysfunction are anecdotal. Nevertheless, antidepressant-induced changes in sexual functioning pose a difficult and interesting clinical problem, in part because of the possibility of noncompliance.

Diagnosis of Sexual Dysfunction

The first two steps in the management of sexual dysfunction are (1) recognition or identification of the dysfunction, and (2) patient education. A baseline assessment of sexual functioning is absolutely necessary. Without this there is nothing with which to compare recent sexual functioning, and the clinician is unable to determine accurately if the dysfunction is a new or an old phenomenon.

As shown in Table 1, various factors can contribute to sexual dysfunction; therefore, sexual dysfunction should not always be attributed to medication. It may be a component of depressive
symptomatology (decreased libido); it may be due to concomitant medical illness (impaired erectile capacity may be the first symptom of diabetes mellitus); it may represent primary sexual dysfunction (sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders); or it may be a side effect of medication. Ruling out all other causes before

attributing the dysfunction to medication seems to be a prudent, but not always practiced, approach. Given the multiple possible sources of sexual dysfunction, caution should be used when determining etiology.

Skilled clinicians should ask very specific questions. General questions such as "How is your sex life?" are not enough because they often lead to nonspecific answers such as "All right," "OK,"

"No problem." These answers will not provide adequate baseline information for the assessment of possible future dysfunction.

Clinicians should ask specifically about sexual desire, sexual enjoyment, erectile problems, erections unrelated to sexual activity, capacity to reach orgasm, changes in capacity to reach orgasm, and painful orgasm. It is known that asking about sexual dysfunction elicits twice the incidence found when no questions are asked. A good psychosexual history should be a part of every initial evaluation.

Identification of antidepressant-induced sexual dysfunction can be a diagnostic challenge. Is the problem a true sexual dysfunction or has the patient mislabeled it? What type of dysfunction is involved? Is it a single dysfunction or a combination of dysfunctions? If a combination, which dysfunction is primary? Is the problem generalized or situational? Is it the result of a combination of medications? What is the patient's reaction to the dysfunction? Were comorbid conditions, substance abuse, and relationship problems considered?

Occasionally, other diagnostic procedures, such as physiologic tests of erectile capacity (nocturnal penile tumescence, visual stimulation method), tests of penile vascular competence,neurologic evaluation, and hormonal assessment, must be used.

Patient education about possible sexual dysfunction can be problematic. A good physician-patient relationship plays a significant role. Some clinicians advocate either no discussion of possible sexual dysfunction or a discussion with little emphasis on dysfunctions and their severity, because they do not want to discourage patients. However, some patients may be informed about this topic because of increased attention by the media or because of aggressive marketing strategies used by the pharmaceutical companies. Oc-casionally, pharmacists may discuss various side effects of antidepressants, including sexual dysfunction, with patients, or other patients share their experiences. At least some discussion of these problems is better than no discussion. Clinicians should also mention that various management options for antidepressant-induced sexual dysfunctions are available.


Once the diagnosis of sexual dysfunction induced by an antidepressant is established, the clinician should carefully consider management options (see Table 5) and discuss them with the patient.

Waiting for Spontaneous Remission of Sexual Dysfunction

This might be considered a questionable approach. As with many other side effects of antidepressants, spontaneous remission or decrease in severity to a tolerable level is possible. Cases of spontaneous remission have been reported for some antidepressants, such as sertraline and phenelzine.18 However, spontaneous remission may occur only after several weeks or months, which may be too long for the patient to wait. This approach requires a very good physician-patient relationship. Also, it has not been reported to be effective for tricyclic antidepressant-induced anorgasmia.5

Reduction to the Minimal Effective Dosage

This approach may occasionally help, but it is also risky. Balancing between the minimal effective dose and a subtherapeutic dose can be precarious. The dose at which the dysfunction appears is frequently the lowest that alleviates depression. Some authors 19 have suggested that there is a relationship between sexual dysfunction and the dosage of fluoxetine. They observed an improvement of sexual dysfunction and no recurrence of depression when they decreased the dosage of fluoxetine to 20 mg every other day, and in some cases to 20 mg a week. Sexual dysfunction associated with venlafaxine also showed a dose relation in one study.20 Despite the potential double-blind nature of dose reduction, it has been frequently recommended in erectile dysfunction.

Drug Holidays

A variant of dose reduction, the drug holiday approach requiresthat the antidepressant be discontinued 2 to 3 days prior to sexual activity. The success of this approach depends oncareful planning and a comfortable physician-patient relationship. It is probably more successful with drugs that have a short half-life, such as paroxetine and sertaline, and may be difficult with long half-life drugs, such as fluoxetine. Again, worsening of depressive symptomatology may complicate this practical alternative for management of sexual dysfunction associated with antidepressants.

Switching to Another Antidepressant

Several reports in the literature have described successful substitution of desipramine for imipramine or clomipramine, imipramine for amoxapine, and nortriptyline for imipramine or doxepin. This approach may take a long time and its success may be hindered by relapse of the depressive disorder.

Several studies report no sexual dysfunction with bupropion. In one study,21 24 of 28 patients who reported sexual dysfunction on various antidepressants reported resolution of their sexual dysfunctions when switched to bupropion. Another study reported significant improvement of fluoxetine-associated sexual dysfunction in patients who were switched to bupropion.22

However, caution is needed because one unpublished report has noted sexual dysfunctions in patients treated with the sustained-release form of bupropion.23 With nefazodone, the newest antidepressant available in the United States, there have been no reports of sexual dysfunction to date, and in some clinical trials, the incidence of sexual dysfunctions was found to be equivalent for nefazodone and placebo.

Using Secondary Pharmacologic Agents

Numerous pharmacologic agents have been successfully used in the "treatment" of sexual dysfunctions induced by antidepressants. These include bethanechol (30 mg, 1 to 2 hours before coitus),24 cyproheptadine (4 to 12 mg, 1 to 2 hours before coitus; caution patient that severe sedation or depression may occur),25, 26 yohimbine (5.4 mg tid or prn 2- to 4 hours before coitus; caution patient that yohimbine may induce anxiety),9,27 neostigmine (7.5 to 15 mg, 30 min before coitus), amantadine (100 mg one or twice daily up to 600 mg),28 bupropion (75 mg/day with fluoxetine),29 buspirone (30 mg/day or more with various SSRIs),30 dextroamphetamine (10 to 25 mg/day), and pemoline (18.75 mg/day).31 Other reportedly used agents include methylphenidate, trazodone, and bromocriptine.

Vacuum Erectile Devices

Use of vacuum erectile devices and injection of agents into the corpus cavernosum are specialized procedures that are best handled by urologists.

Matching Therapy to Type of Sexual Dysfunction

There are various treatment strategies for different types of drug-induced sexual dysfunction. In the case of decreased libido, drug holidays, the addition of neostigmine, or the substitutionof another drug such as bupropion or nefazodone may be effective.

For erectile problems, dose reduction, drug holidays, coadministration of bethanechol, or substitution of another drug may be tried. Orgasmic dysfunction may be resolved by waiting for spontaneous remission, or by drug holidays, coadministration of another drug, or substitution of another drug.

Two important additional points are the following:

1. Only tentative conclusions about the efficacy of the above treatments can be drawn because most of the literature in this area consists of case reports or series of cases.6

2. Priapism (abnormal, persistent, usually painful erection unrelated to sexual arousal) constitutes a urologic emergency. Priapism has been reported with trazodone and various other psychotropic drugs.

Positive Effects of Antidepressants on Sexual Function

Antidepressants do not necessarily adversely affect sexual functioning. A few cases of "improved" sexual functioning have been reported. Smith and Levitte reported a return of sexual potency in three elderly men treated with fluoxetine.14 Others32 described an elderly male who developed "orgasmic sensations" on fluoxetine. Orgasms associated with yawning in patients treated with clomipramine and fluoxetine have also been reported.

Trazodone has been used to treat impotence. Lal and colleagues33 described the case of a psychiatrist who successfully treated his own impotence with trazodone, 250 to 350 mg prior to coitus once a week for 4 years. Montorsi and colleagues34 reported that the combination of yohimbine (15 mg/day) and trazodone (50 mg/day) is a safe and effective first-line treatment for psychogenic impotence.

As already noted, one side effect of antidepressants ­p; delayed or inhibited ejaculation ­p; has been used for treatment of primary premature ejaculation. Some case reports have described improvement of premature ejaculation with selective serotonin reuptake inhibitors, such as sertraline35 and fluoxetine.36 Controlled studies have reported greater clinical improvement of premature ejaculation with clomipramine compared with placebo37 (25 or 50 mg/day; the higher dose produced a longer time toejaculation), and paroxetine compared with placebo.16


The effects of antidepressants on human sexuality are complex. The etiologic mechanisms of sexual dysfunctions are unclear and intricate. The diagnosis and management of sexual dysfunction induced by these agents is a challenging clinical issue requiring a good physician-patient relationship, keen and skillful observation, and a certain degree of creativity and patience.

Most effects of antidepressants on human sexuality are adverse, but some effects are beneficial ­p; for example, antidepressants can be used for the treatment of premature ejaculation.



Anorgasmia ­p; Inability to achieve orgasm, absence of orgasm. Drug holidays ­p; Regular periods during which the patient is not given medication.

Impaired erectile capacity ­p; Persistent or recurrent inability to attain or to maintain an adequate erection, until completion of the sexual activity.

Libido ­p; Sexual desire, drive, interest.

Priapism ­p; Persistent penile erection accompanied by severepain.

Primary sexual dysfunction ­p; Disturbance in sexual desire and in the psychophysiological changes that characterize the sexual response cycle causing marked distress. The term primarily refers to etiology.



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