David Baxter PhD
Late Founder
An Update on the Sexual Side Effects of Medication
Anita H. Clayton, MD, interviewed by Norman Sussman, MD on December 4, 2007
Primary Psychiatry. 2008;15(3):43-46
Dr. Clayton is David C. Wilson professor of psychiatry and professor of clinical obstetrics and gynecology at the University of Virginia in Charlottesville. She is distinguished fellow of the American Psychiatric Association and certified by the American Board of Psychiatry and Neurology. Dr. Clayton is consulting editor for the Journal of Sex & Marital Therapy and received the Columnist of the Year award in 2005 for her bi-monthly column in Primary Psychiatry, ?Considerations in Women?s Mental Health.? In 2007, her book, Satisfaction: Women, Sex and the Quest for Intimacy, was published for the general public.
Why were the sexual side effects of selective serotonin reuptake inhibitors (SSRIs) initially overlooked?
The initial clinical focus was on the improved tolerability and safety of SSRIs compared to tricyclic antidepressants (TCAs). The TCAs first appeared approximately 20 years ago, followed by fluoxetine entering the market in 1998. Their side effects included constipation, blurred vision, urinary retention, and cardiac effects. In addition, newer agents appeared to be safer than TCAs, particularly with respect to overdose risk. Since a systemic study of adverse events was not conducted and published at that time, the prevalence rate of sexual dysfunction was determined by spontaneous reports in registration trials. These reports dramatically underestimate the occurrence rates of sexual dysfunction. In addition, depression is associated with sexual dysfunction, possibly making it difficult to separate illness effects from antidepressant side effects.
Are today?s clinicians both better at recognizing and more comfortable with addressing the issue of sexual dysfunction?
Yes. In the past, patients did not easily mention issues of adverse sexual events, and physicians hardly ever asked about them. Patients would easily disclose problems such as nausea without trepidation, but they would not necessarily discuss their problems concerning sexual function. Clinicians were not even aware of this potential problem and it went unrecognized. However, today?s clinicians recognize that sexual dysfunction is a problem and are becoming more comfortable with the concept. They routinely ask their patients about it, and are more willing to help those who have a problem in this area stay on their medication.
What are the side effects of these drugs?
SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) like venlafaxine appear to affect all phases of the sexual response cycle. Approximately 40% of patients on antidepressant monotherapy reported global sexual dysfunction.1 There are some differences in the degree and form of sexual dysfunction with respect to gender. For example, desire and orgasm are more significantly affected in men, but arousal is more diminished in women on antidepressants.2 In addition, drugs such as bupropion, mirtazapine, nefazodone, and reboxetine, the latter of which is prescribed in Europe, work by other mechanisms and so have different effects. Clinicians should talk to patients about both a variety of sexual problems in all phases of the sexual response cycle and the timing of onset. In addition, clinicians should let patients know that these problems may persist for an extended period of time.
In a recently published study,3 interactive voice response technology was used to measure sexual function in normal healthy men without depression. It consisted of the Changes in Sexual Functioning Questionnaire (CSFQ), which was administered at very close time periods (ie, within 1?2 days of the previous administration). The study made sure to only involve normal, mentally healthy men in order to measure the drug effects without the results being confounded by the presence of depression. The study found that the SSRI paroxetine was associated with significantly greater orgasmic dysfunction than placebo by day 4. Problems with arousal developed by day 6, and difficulties and adverse events with desire and satisfaction appeared by day 14. In addition, the study suggests that medication therapy involving drugs with relatively short half-lives may worsen global sexual dysfunction within 2 weeks. This pattern of onset suggests that sexual dysfunction progressively worsens over time. It starts once a steady state of the drug is achieved and all phases may be subsequently affected. Thus, time to steady state appears to reflect the time to onset in susceptible patients.
Are the side effects generally dose related?
Yes. In our study examining the prevalence of sexual dysfunction in patients taking antidepressant therapy, sexual dysfunction is seen in a greater percentage of depressed patients on doses of antidepressants in the upper half of the normal dose range than those taking doses in the lower half of the normal range.1 However, there were a couple of exceptions in which the effects varied. Fluoxetine showed no difference in sexual dysfunction regardless of the dose, while bupropion and mirtazapine had fewer negative sexual side effects at higher doses.
Do the side effects diminish as a patient continues to use the medication?
Approximately 5% to 10% of people who initially develop sexual dysfunction associated with antidepressants develop tolerance to the side effects 4?6 months after the initiation of drug therapy. However, this means that 90% to 95% of people do not see the adverse events diminish over time. In addition, as people get older they tend to have more problems with sexual functioning. Therefore, aging may contribute to sexual dysfunction as well as the effects of chronic antidepressant therapy.
Is there an increasing or decreasing risk of experiencing certain sexual side effects among the drugs within their respective classes?
No. I think sexual dysfunction is a class effect associated with serotonin reuptake inhibition. However, norepinephrine reuptake inhibition in a clinically meaningful ratio of < 10:1 could possibly mitigate this effect. This might explain the results of a clinical trial which found duloxetine to have significantly fewer sexual side effects than the SSRI escitalopram in a long-term study of approximately 8 months.4 In another study, the effects on sexual functioning were similar for escitalopram, as measured by the Changes in Sexual Functioning Questionnaire in both studies. In addition, other studies have demonstrated nominal differences between the SSRIs and the SNRIs available in 2001.1
Was the dose that was used to compare duloxetine to escitalopram greater or less than duloxetine?s recommended dose of ≤60 mg?
During the acute phase of treatment, duloxetine 60 mg and escitalopram 10 mg were used for 8 weeks Significant differences between escitalopram and placebo were found. However, sexual dysfunction with duloxetine did not differ from either placebo or escitalopram during the 8-week acute treatment phase. After the acute phase of treatment, a significant number of patients were increased to higher doses of duloxetine (120 mg/day) and escitalopram (20 mg/day). During the long-term phase, there were statistically significant differences between the two active treatment groups, and sexual dysfunction, once it occurred, persisted in 95% of the patients. It is possible that the sexual dysfunction may be an effect of depression. However, both groups showed fairly equivalent response rates in terms of antidepressant efficacy, thus suggesting a negative effect on sexual functioning with the SSRI escitalopram compared to the SNRI duloxetine. Studies of the SNRI venlafaxine demonstrated effects similar to those of the SSRIs, with doses in the upper half of the normal range for venlafaxine associated with greater sexual dysfunction than doses in the lower half of the normal dose range.1 In a study comparing venlafaxine to bupropion,5 the percentage of patients experiencing sexual dysfunction, as measured with the same patient-rated scale (CSFQ), on venlafaxine was similar to the SSRIs and significantly greater than bupropion.
What serotonergic drug is the least likely to induce sexual dysfunction?
A clinician might try duloxetine or the selegiline transdermal system. However, I think it is rather difficult to address that with ultimate certainty because there are other factors to consider such as the primary diagnosis, other adverse effects, comorbid medical/psychiatric conditions, and concomitant medications.
Which forms of sexual dysfunction are associated with TCAs?
TCAs and the monoamine oxidase inhibitors also cause sexual dysfunction, but may affect the phases of the sexual response cycle in different ways. For example, men who take TCAs tend to experience more problems with arousal than do men who take SSRIs. The MAOI patch known as the selegiline transdermal system seems to cause fewer sexual side effects than oral MAOIs. A recent study discusses the selegiline transdermal system and its effects on sexual functioning as comparable to placebo using a patient-rated scale.6
Are there treatments available in the market that have been proven to mitigate anorgasmia or the loss of sexual desire?
Yes, but the effects are not robust or were secondary outcome measures, and so potentially underpowered. One study7 was originally designed to look at buspirone as an adjunctive treatment in SSRI partial-responders with major depressive disorder. In another study examining effects on SSRI-induced sexual dysfunction,8 buproprion in antidepressant doses was superior to placebo even when the dose of the SSRI was maintained at the baseline level, and it is difficult to overcome SSRI-associated sexual side effects when the dose is maintained. Other potential treatments examined in placebo-controlled studies include testosterone and sildenafil in men. However, systematic placebo-controlled data examining potential antidotes are lacking. This is the reason why drugs in development need to be studied in terms of their potential effects on sexual functioning; these effects can be predicted to some degree based on the mechanism of action.
In the clinical world, what percentage of people discontinue their antidepressants because of either sexual or other side effects?
Ashton and colleagues9 conducted a study in patients taking psychotropic medications that examined both medication discontinuation, which is completely stopping treatment, and non-compliance, which is not taking the drug the way it is prescribed. Approximately 60% of patients taking an antidepressant acknowledged the discontinuation of their treatment with lack of efficacy as their primary reason. Medication non-compliance resulted from weight gain and fatigue. However, sexual side effects were the most frequently cited reason for medication discontinuation. Approximately 20% of patients reported anorgasmia, and a similar percentage of patients reported a loss of interest in sex. In addition, both the inability to have an erection and problems reaching orgasm were extremely difficult for patients to live with. Although many patients in clinical practice are non-compliant with their dosing regimen and decide to discontinue antidepressant therapy due to negative sexual side effects, patients are often reluctant to tell their physicians that the reason why they stopped treatment was due to sexual side effects.
Does the treatment have other unusual side effects?
Very different drugs that clinicians do not commonly prescribe often lead to unusual side effects. For example, patients report spontaneous orgasms in association with some medications, e.g., trazodone. In addition, SSRIs can change sensation, including increased pain sensation or hyperalgesia, and diminished genital sensation. These are often issues reported by older people. They complain of diminished orgasms, diminished sensation, or delayed reaction to sexual stimulation, all of which may also be related to effects of aging on the serotonin system.
What is the developmental impact of TCAs on adolescents and young adults who already experience decreased desire, lowered libido, and weakened sexual functioning?
There have been neither studies nor case reports published about this subject, and I think it should be more carefully examined and studied. The effect of antidepressants on adolescent development is a heavy concern and a potentially long-term, lifelong, iatrogenically induced problem. During their teenage years, adolescents establish who they are as sexual beings. If these drugs inhibit sexual functioning, they can make it difficult for young adults to sexually identify themselves. Although parents do not really want to give their children medication, parents often view sexual side effects in a positive light as they lead to inhibition of sexual impulses. However, while this may have short-term benefits such as abstinence, in the long-run, it could become a real problem in the adolescent?s personal and sexual development. The repercussions of the long-term effects on sexuality should be more carefully studied in adolescents.
References
Disclosure: Dr. Clayton is a consultant to or on the advisory boards of Boehringer-Ingelheim, Concert Pharmaceuticals, Eli Lilly, Fabre-Kramer Pharmaceuticals, GlaxoSmithKline, Novartis, PGx Health, sanofi-aventis, and Wyeth; receives grant support from Biosante, Boehringer-Ingelheim, Eli Lilly, Novartis, sanofi-aventis, and Wyeth; and receives honoraria from Eli Lilly, Palatin Technologies, Pfizer, and Wyeth.
Anita H. Clayton, MD, interviewed by Norman Sussman, MD on December 4, 2007
Primary Psychiatry. 2008;15(3):43-46
Dr. Clayton is David C. Wilson professor of psychiatry and professor of clinical obstetrics and gynecology at the University of Virginia in Charlottesville. She is distinguished fellow of the American Psychiatric Association and certified by the American Board of Psychiatry and Neurology. Dr. Clayton is consulting editor for the Journal of Sex & Marital Therapy and received the Columnist of the Year award in 2005 for her bi-monthly column in Primary Psychiatry, ?Considerations in Women?s Mental Health.? In 2007, her book, Satisfaction: Women, Sex and the Quest for Intimacy, was published for the general public.
Why were the sexual side effects of selective serotonin reuptake inhibitors (SSRIs) initially overlooked?
The initial clinical focus was on the improved tolerability and safety of SSRIs compared to tricyclic antidepressants (TCAs). The TCAs first appeared approximately 20 years ago, followed by fluoxetine entering the market in 1998. Their side effects included constipation, blurred vision, urinary retention, and cardiac effects. In addition, newer agents appeared to be safer than TCAs, particularly with respect to overdose risk. Since a systemic study of adverse events was not conducted and published at that time, the prevalence rate of sexual dysfunction was determined by spontaneous reports in registration trials. These reports dramatically underestimate the occurrence rates of sexual dysfunction. In addition, depression is associated with sexual dysfunction, possibly making it difficult to separate illness effects from antidepressant side effects.
Are today?s clinicians both better at recognizing and more comfortable with addressing the issue of sexual dysfunction?
Yes. In the past, patients did not easily mention issues of adverse sexual events, and physicians hardly ever asked about them. Patients would easily disclose problems such as nausea without trepidation, but they would not necessarily discuss their problems concerning sexual function. Clinicians were not even aware of this potential problem and it went unrecognized. However, today?s clinicians recognize that sexual dysfunction is a problem and are becoming more comfortable with the concept. They routinely ask their patients about it, and are more willing to help those who have a problem in this area stay on their medication.
What are the side effects of these drugs?
SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) like venlafaxine appear to affect all phases of the sexual response cycle. Approximately 40% of patients on antidepressant monotherapy reported global sexual dysfunction.1 There are some differences in the degree and form of sexual dysfunction with respect to gender. For example, desire and orgasm are more significantly affected in men, but arousal is more diminished in women on antidepressants.2 In addition, drugs such as bupropion, mirtazapine, nefazodone, and reboxetine, the latter of which is prescribed in Europe, work by other mechanisms and so have different effects. Clinicians should talk to patients about both a variety of sexual problems in all phases of the sexual response cycle and the timing of onset. In addition, clinicians should let patients know that these problems may persist for an extended period of time.
In a recently published study,3 interactive voice response technology was used to measure sexual function in normal healthy men without depression. It consisted of the Changes in Sexual Functioning Questionnaire (CSFQ), which was administered at very close time periods (ie, within 1?2 days of the previous administration). The study made sure to only involve normal, mentally healthy men in order to measure the drug effects without the results being confounded by the presence of depression. The study found that the SSRI paroxetine was associated with significantly greater orgasmic dysfunction than placebo by day 4. Problems with arousal developed by day 6, and difficulties and adverse events with desire and satisfaction appeared by day 14. In addition, the study suggests that medication therapy involving drugs with relatively short half-lives may worsen global sexual dysfunction within 2 weeks. This pattern of onset suggests that sexual dysfunction progressively worsens over time. It starts once a steady state of the drug is achieved and all phases may be subsequently affected. Thus, time to steady state appears to reflect the time to onset in susceptible patients.
Are the side effects generally dose related?
Yes. In our study examining the prevalence of sexual dysfunction in patients taking antidepressant therapy, sexual dysfunction is seen in a greater percentage of depressed patients on doses of antidepressants in the upper half of the normal dose range than those taking doses in the lower half of the normal range.1 However, there were a couple of exceptions in which the effects varied. Fluoxetine showed no difference in sexual dysfunction regardless of the dose, while bupropion and mirtazapine had fewer negative sexual side effects at higher doses.
Do the side effects diminish as a patient continues to use the medication?
Approximately 5% to 10% of people who initially develop sexual dysfunction associated with antidepressants develop tolerance to the side effects 4?6 months after the initiation of drug therapy. However, this means that 90% to 95% of people do not see the adverse events diminish over time. In addition, as people get older they tend to have more problems with sexual functioning. Therefore, aging may contribute to sexual dysfunction as well as the effects of chronic antidepressant therapy.
Is there an increasing or decreasing risk of experiencing certain sexual side effects among the drugs within their respective classes?
No. I think sexual dysfunction is a class effect associated with serotonin reuptake inhibition. However, norepinephrine reuptake inhibition in a clinically meaningful ratio of < 10:1 could possibly mitigate this effect. This might explain the results of a clinical trial which found duloxetine to have significantly fewer sexual side effects than the SSRI escitalopram in a long-term study of approximately 8 months.4 In another study, the effects on sexual functioning were similar for escitalopram, as measured by the Changes in Sexual Functioning Questionnaire in both studies. In addition, other studies have demonstrated nominal differences between the SSRIs and the SNRIs available in 2001.1
Was the dose that was used to compare duloxetine to escitalopram greater or less than duloxetine?s recommended dose of ≤60 mg?
During the acute phase of treatment, duloxetine 60 mg and escitalopram 10 mg were used for 8 weeks Significant differences between escitalopram and placebo were found. However, sexual dysfunction with duloxetine did not differ from either placebo or escitalopram during the 8-week acute treatment phase. After the acute phase of treatment, a significant number of patients were increased to higher doses of duloxetine (120 mg/day) and escitalopram (20 mg/day). During the long-term phase, there were statistically significant differences between the two active treatment groups, and sexual dysfunction, once it occurred, persisted in 95% of the patients. It is possible that the sexual dysfunction may be an effect of depression. However, both groups showed fairly equivalent response rates in terms of antidepressant efficacy, thus suggesting a negative effect on sexual functioning with the SSRI escitalopram compared to the SNRI duloxetine. Studies of the SNRI venlafaxine demonstrated effects similar to those of the SSRIs, with doses in the upper half of the normal range for venlafaxine associated with greater sexual dysfunction than doses in the lower half of the normal dose range.1 In a study comparing venlafaxine to bupropion,5 the percentage of patients experiencing sexual dysfunction, as measured with the same patient-rated scale (CSFQ), on venlafaxine was similar to the SSRIs and significantly greater than bupropion.
What serotonergic drug is the least likely to induce sexual dysfunction?
A clinician might try duloxetine or the selegiline transdermal system. However, I think it is rather difficult to address that with ultimate certainty because there are other factors to consider such as the primary diagnosis, other adverse effects, comorbid medical/psychiatric conditions, and concomitant medications.
Which forms of sexual dysfunction are associated with TCAs?
TCAs and the monoamine oxidase inhibitors also cause sexual dysfunction, but may affect the phases of the sexual response cycle in different ways. For example, men who take TCAs tend to experience more problems with arousal than do men who take SSRIs. The MAOI patch known as the selegiline transdermal system seems to cause fewer sexual side effects than oral MAOIs. A recent study discusses the selegiline transdermal system and its effects on sexual functioning as comparable to placebo using a patient-rated scale.6
Are there treatments available in the market that have been proven to mitigate anorgasmia or the loss of sexual desire?
Yes, but the effects are not robust or were secondary outcome measures, and so potentially underpowered. One study7 was originally designed to look at buspirone as an adjunctive treatment in SSRI partial-responders with major depressive disorder. In another study examining effects on SSRI-induced sexual dysfunction,8 buproprion in antidepressant doses was superior to placebo even when the dose of the SSRI was maintained at the baseline level, and it is difficult to overcome SSRI-associated sexual side effects when the dose is maintained. Other potential treatments examined in placebo-controlled studies include testosterone and sildenafil in men. However, systematic placebo-controlled data examining potential antidotes are lacking. This is the reason why drugs in development need to be studied in terms of their potential effects on sexual functioning; these effects can be predicted to some degree based on the mechanism of action.
In the clinical world, what percentage of people discontinue their antidepressants because of either sexual or other side effects?
Ashton and colleagues9 conducted a study in patients taking psychotropic medications that examined both medication discontinuation, which is completely stopping treatment, and non-compliance, which is not taking the drug the way it is prescribed. Approximately 60% of patients taking an antidepressant acknowledged the discontinuation of their treatment with lack of efficacy as their primary reason. Medication non-compliance resulted from weight gain and fatigue. However, sexual side effects were the most frequently cited reason for medication discontinuation. Approximately 20% of patients reported anorgasmia, and a similar percentage of patients reported a loss of interest in sex. In addition, both the inability to have an erection and problems reaching orgasm were extremely difficult for patients to live with. Although many patients in clinical practice are non-compliant with their dosing regimen and decide to discontinue antidepressant therapy due to negative sexual side effects, patients are often reluctant to tell their physicians that the reason why they stopped treatment was due to sexual side effects.
Does the treatment have other unusual side effects?
Very different drugs that clinicians do not commonly prescribe often lead to unusual side effects. For example, patients report spontaneous orgasms in association with some medications, e.g., trazodone. In addition, SSRIs can change sensation, including increased pain sensation or hyperalgesia, and diminished genital sensation. These are often issues reported by older people. They complain of diminished orgasms, diminished sensation, or delayed reaction to sexual stimulation, all of which may also be related to effects of aging on the serotonin system.
What is the developmental impact of TCAs on adolescents and young adults who already experience decreased desire, lowered libido, and weakened sexual functioning?
There have been neither studies nor case reports published about this subject, and I think it should be more carefully examined and studied. The effect of antidepressants on adolescent development is a heavy concern and a potentially long-term, lifelong, iatrogenically induced problem. During their teenage years, adolescents establish who they are as sexual beings. If these drugs inhibit sexual functioning, they can make it difficult for young adults to sexually identify themselves. Although parents do not really want to give their children medication, parents often view sexual side effects in a positive light as they lead to inhibition of sexual impulses. However, while this may have short-term benefits such as abstinence, in the long-run, it could become a real problem in the adolescent?s personal and sexual development. The repercussions of the long-term effects on sexuality should be more carefully studied in adolescents.
References
- Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357-366.
- Clayton A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord. 2006;91(1):27-32.
- Dunn J, Arakawa R, Greist JH, Clayton AH. Assessing the onset of antidepressant induced sexual dysfunction using interactive voice response technology. J Clin Psychiatry. 2007;68(4):525-532.
- Clayton A, Kornstein S, Prakash A, Mallinckrodt C, Wohlreich M. Changes in sexual functioning associated with duloxetine, escitalopram, and placebo in the treatment of patients with major depressive disorder. J Sex Med. 2007;4(4 Pt 1):917-929.
- Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA. A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability. J Clin Psychopharmacol. 2006;26(5):482-488.
- Clayton AH, Campbell BJ, Favit A, et al. Symptoms of sexual dysfunction in patients treated for major depressive disorder: a meta-analysis comparing selegiline transdermal system and placebo using a patient-rated scale. J Clin Psychiatry. 2007;68(12);1860-1866.
- Landen M, Eriksson E, Agren H, Fahlen T. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1999;19(3):268-271.
- Clayton AH, Warnock JK, Kornstein SG, Pinkerton R, Sheldon-Keller A, McGarvey EL. A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor ? induced sexual dysfunction. J Clin Psychiatry. 2004;65(1):62-67.
- Ashton AK, Jamerson BD, Weinstein WL, et al. Antidepressant-related adverse effects impacting treatment compliance: results of a patient survey. Curr Ther Res Clin Exp. 2005;66:96-106.
Disclosure: Dr. Clayton is a consultant to or on the advisory boards of Boehringer-Ingelheim, Concert Pharmaceuticals, Eli Lilly, Fabre-Kramer Pharmaceuticals, GlaxoSmithKline, Novartis, PGx Health, sanofi-aventis, and Wyeth; receives grant support from Biosante, Boehringer-Ingelheim, Eli Lilly, Novartis, sanofi-aventis, and Wyeth; and receives honoraria from Eli Lilly, Palatin Technologies, Pfizer, and Wyeth.
