management of antidepressant induced sexual dysfunction

Management of Antidepressant-induced Sexual DysfunctionLiterature Review

Prepared and Presented by:

Badr Saleh AlaseeriPsychiatry R2King Abdulaziz Medical CityNational Guard Health AffairsJeddah

Reviewed by:

Dr. Tarek SherifConsultant PsychiatristKing Abdulaziz Medical CityNational Guard Health AffairsJeddah

Content

Overview Epidemiology How Antidepressants affect sexuality? What leads to the other depression or sexual dysfunction? Management

Overview

How common are antidepressants used?

264 million prescriptions filled for antidepressants in the USA in 2011, accounting for $11 billion and making antidepressants the most commonly used group of medications at that year .Lindsley 2012.

Overview

What is meant by sexual dysfunction?

Sexual dysfunction could affect any of thefollowing phases of the sexual responsecycle: Desire decreased libido Arousal/ erection erectile dysfunction Orgasm anorgasmia Ejaculation Delayed ejaculation

Overview

Consequences of antidepressants-induced sexual dysfunction:

Early discontinuation of antidepressant. Relapse of depression. Poor quality of life.

Gregorian et al 2002; Rosenberg et al 2003; Clayton and Balon 2009, in Reichenpfader et al 2014.

Epidemiology

Taylor D., Paton C., Kapur S., (2015). The Maudsley Prescribing Guidelines in Psychiatry.

Epidemiology

Taylor D., Paton C., Kapur S., (2015). The Maudsley Prescribing Guidelines in Psychiatry.

Epidemiology

Serretti and Chiesa (2009)

Epidemiology

Citalopram* was found to cause:54%: Decreased libido.36%: Difficulty achieving orgasm.37% of men: Erectile dysfunction.*In 14-week prospective study that involved 1473 patients taking citalopram by Perlis RH et al (2009).

SSRIs and SNRIs were associated with sexual dysfunction in 50%*.

* In a cross-sectional survey that included 740 patients by Williams VS et al (2010).

Epidemiology

A systematic review and meta analysis (Reichenpfader et al 2014) concluded that: Bupropion has a statistically significantly lower

risk of sexual dysfunction than some other antidepressants,

escitalopram and paroxetine show a statistically significant higher risk of sexual dysfunction than some other antidepressants.

Epidemiology

Clayton et al* (2015) found that desvenlafaxine did not affect sexual functioning more than placebo.

No head-to-head comparisons were conducted to compare desvenlafaxine to other antidepressants regarding effects on sexual functioning.

*Some authors have affiliation with Pfizer.

Epidemiology

Genetic Polymorphism may be involved.Perlis RH et al (2009).

Men have more dysfunction in desire and orgasm.

Women have more arousal dysfunction.Clayton et al (2006)

Epidemiology

Men showed more incidence of sexual dysfunction than women, but women's sexual dysfunction was more intense than men's.

Incidence of antidepressant-indeuced sexual dysfunction was higher when asked directly (58%) than when reported spontaneously (14%).

Montejo-González et al 1997

Overview

“Both men and women who are taking antidepressants should be asked whether sexual side effects are occurring with these medications [level I*].”

American Psychiatric Association (APA). Practice guideline for the treatment of patients with major depressive disorder. 3rd ed. Arlington (VA): American Psychiatric Association (APA); 2010 Oct.

*Levels of evidence: [I] Recommended with substantial clinical confidence. [II] Recommended with moderate clinical confidence. [III] May be recommended on the basis of individual circumstances.

What leads to the other?

Depression itself can cause sexual dysfunction in 50% of patients.

Angst J. (1998) and Kennedy SH et al (1999).

Treatment with SSRI helps improving sexual satisfaction in those with depression and sexual dysfunction.

Baldwin DS and Foong T (2013).

What leads to the other?

A systematic review and meta-analysis by Atlantis and Sullivan (2012) concluded the presence of biderctional association between depression and sexual dysfunction, and that the presence of one necessitate the screening of the another.

Atlantis and Sullivan (2012).

Amongst those presenting with sexual dysfunction, some will see an improvement, some no change and some a worsening when taking on antidepressant.

Werneke U et al (2006)

Mechanisms by which antidepressants cause sexual dysfunctionDesire: The mesolimbic system has an essential role in

sexuality, mediated by dopaminergic neurotransmission

Segraves (1989), Bitran et al (1988) and Baldessarini and Marsh (1990) in Serretti and Chiesa (2009)

Serotonin reuptake blockade reduce dopamine activity in that area through 5-HT₂ receptors

Baldessarini (1990) and Meltzer (1979) in Serrtti and Chiesa (2009)

Mechanisms by which antidepressants cause sexual dysfunction Arousal dysfunction could be a result of:

Low dopamine in the mesolimbic system. Inhibition of peripheral spinal reflexes of the

sympathetic and parasympathetic systems which mediate erection and clitoral engorgement and this is influenced by several neurotransmitters including serotonin.

Segraves (1989), Bitran et al (1988) and Pollack (1992) in Serretti and Chiesa (2009).

Possible role of low nitric oxide, that was shown to be reduced by paroxetine in a study.

Finkel et al (1996).

Mechanisms by which antidepressants cause sexual dysfunction Orgasm dysfunction could be related to low

dopamine and noradrenaline levels caused by 5-HT₂ activation.

Pollack et al (1992), Zajecka et al (1991) and Crenshaw (1996) in Serretti and Chiesa (2009)

Those changes seems to alter the sympathetic and parasympathetic systems, that are essential for orgasm and ejaculation.

Bitran et al (1988) and Pollack et al (1992) in Serretti and Chiesa (2009)

Agents that exert antagonism at 5-HT₂ (e.g., mirtazapine and nefazodone) do not appear to cause sexual dysfunction. (57).

Mechanisms by which antidepressants cause sexual dysfunction Agents that exert antagonism at 5-HT₂ (e.g.,

mirtazapine and nefazodone) do not appear to cause sexual dysfunction.

Zajecka et al (1991) in Serretti and Chiesa (2009)

Management

Management

FIRST:Determine the factors contributed to the dysfunction and manage them.

Management

Shafer L (2016)

Management

Shafer L (2016)

Management

Shafer L (2016)

Management

Shafer L (2016)

Management

Shafer L (2016)

Management: Strategies

Options to treat Antidepressant-induced sexual dysfunction: Wait for spontaneous resolution. Drug holiday. Decrease the dose. Switch to another antidepressants. Augmentation with (add) another agent.

Management: Strategies

Wait for Spontaneous resolution19-30% of patients with antidepressant-induced

sexual dysfunction have moderate to total regain of their sexual functions after 6 months of using antidepressants.

Serretti and Chiesa (2009) and Montejo-González et al (1997).

Management: Strategies

Drug holiday Rothschild (1995) concluded that holding the

antidepressant during the weekend for those on paroxetine or sertraline (but not fluoxetine) significantly improved sexual functioning without significant worsening of depressive symptoms.

Maudsley prescribing guidelines in psychiatry doesn’t prefer this strategy as it may carry a risk for relapse of depression or experiencing antidepressant discontinuation symptoms.

Management

Decrease the dose Antidepressant-induced sexual dysfunction

appears to be dose-related. Zajecka (2001)

In a prospective observational study, 77% had moderate to complete improvement in sexual functioning when antidepressant dose was reduced by 50%.

Montejo-González et al (1997).

Management

Switch to another antidepressant:BupropionAgomelatineMirtazapineNefazodoneMoclobemideSelegiline

Management: Switch

Bupropion: Incidence of sexual dysfunction among those treated by

bupropion is less than other antidepressants and was comparable to placebo.

Thase ME et al (2005) and Clayton AH (2006).

Walker et al (1993): 39 patients who had sexual dysfunction while on fluoxetine were

switched to bupropion and were followed for 8 weeks 94%: Orgasm dysfunction completely or partially resolved. 81%: Libido improved “much” or “very much”. 81%: Overall sexual functioning was “much” or “very much”

more satisfying.

Management: Switch

Mirtazapine: In a systematic review, it was found to cause less

sexual dysfunction than SSRIs (OR: 0.31, 95% CI:[0.13, 0.74])

Watanabe et al (2011) 54% of patients with SSRI-induced sexual

dysfunction regained their normal sexual functioning after switching to mirtazapine, with no worsening of depressive symptoms.

Gelenberg et al (2000)

Management: Switch

Agomelatine:Causes less sexual dysfunction than

escitalopram in healthy individuals.Montejo et al (2015)Causes less sexual dysfunction than paroxetine

(OR 0.14. 95% CI: [ 0.04, 0.47 ])Guaiana G et al (2013)

Management: Switch

Agomelatine:44.9% of patients having sexual dysfunction

due to SSRIs or SNRIs had resolved their sexual dysfunction after switching to agomelatine. 18.4% still had moderate-severe sexual dysfunction. Others stopped agomelatine due to inefficacy or tolerability issues.

Montejo et al (2014)Bear in mind the risk of liver injury (4.6% for

agomelatine vs 2.1% for placebo).Freiesleben and Furczyk (2015).

Management: Switch

Nefazodone:Ferguson et al (2001):

105 Patients with sexual dysfunction induced by treatment with sertraline stopped it for 2 weeks.

At the end of 2 weeks, those whose sexual functioning returned back to normal were enrolled in the study.

Participants were divided into 2 groups, the first restart sertraline 100 mg/day, and the other was put on nefazodone 400 mg/day.

76% of sertraline group had re-emergence sexual dysfunction.

26% of nefazodone had sexual dysfunction.

Management: Switch

Selegiline (Stryjer R et al 2009) and trazaodone(Clayton AH et al 2007) were found to have a similar incidence of sexual dysfunction to placebo.

Moclobemide No significant difference with placebo in

incidence of sexual dysfunction.Serretti A and Chiesa A (2009)

Management

Augmentation:BupropionPhosphodiesterase-5 inhibitorsOthers

Management: Augmentation

Bupropion:A systematic review and meta-analysis (Taylor

MJ et al 2013) favoured bupropion as an augmenting agent over placebo

(SMD: 1.60, 95% CI 1.40 to 1.81)‘The most promising approach studied so far’

in treating women with antidepressant-induced sexual dysfunction.

(Taylor et al 2013)

Management: Augmentation

Phosphodiesterase-5 inhibitors:Sildenafil:

Metal-analysis (Taylor MJ et al 2013) found that sildenafil (50 to 100 mg on demand) was associated with greater improvement of antidepressant-induced erectile dysfunction than placebo.

(MD 1.04, 95%CI 0.65 to 1.44)An 8-week trial found that sildenafil (50 to 100 mg on

demand) helped women who have disturbed orgasm due to antidepressants more than placebo (72 vs 27 %).

Nurnberg et al. 2008

Management: Augmentation

Phosphodiesterase-5 inhibitors:Tadalafil:

An RCT (Evliyaoğlu Y et al 2011) showed greater improvement in each domain of sexual activity than placebo.

A pooled analysis of 19 RCTs (Segraves RT et al 2007) showed greater improvement than placebo in erectile dysfunction caused by antidepressants.

Management: Augmentation

Phosphodiesterase-5 inhibitors:The most favoured approach for men with

erectile dysfunction caused by antidepressants.

(Taylor 2013).

Management: Augmentation

Mirtazapine:A systematic review and meta-analysis (Taylor MJ et

al 2013) found no benefit of mirtazapine as an augmenting agent.

Another two studies showed reduction of sexual side‐effects in patients treated with duloxetine or SSRIs when mirtazapine was added.

Ravindran LN et al (2008) and Ozmenler NK et al (2008).

Management: Augmentation

Busprione:2 trials were done, one showed no more

improvement in sexual functioning than placebo. The other one showed a difference, favouring buspirone, that was statistically insignificant.

Michelson D et al (2000) and Landen M et al (1999)

Management: Augmentation

Ginkgo biloba:Kang (2002) showed no significant difference

between Gingko biloba and placebo.‘Satisfaction to orgasm’ was better in placebo.

(Kang 2002)Wheatley (2004) concluded that Gingko biloba

added no more benefit than placebo.

Management: Augmentation

Exercise:30 minutes of moderate strength training and

cardiovascular exercise immediately before sexual activity improved sexual desire and global sexual function in women compared to exercise separate from sexual activity.

High dropout rate (46 %).(Lorenz TA and Meston CM 2014)

Management: Augmentation

Maca root:

A small RCT (Dording et al 2015) showed higher remission rates for the maca versus placebo group were associated with postmenopausal status.

Lepidium meyenii

Management: Augmentation

Saffron:

Improved overall sexual satisfaction in SSRI-induced sexual dysfunction in both men and women.

Modabbemia et al (2012) and Kashani et al (2013)

Management: Augmentation

A systematic review and meta-analysis (Taylor MJ et al 2013) failed to prove the benefit of augmentation with: Amantadine Bethanechol Cyproheptadine Ephedrine Granisetron Mirtazapine Olanzapine Yohimbine

Summary

Sexual dysfunction is one of the most frequent and problematic side effects of antidepressants.

It can affect not only sexual functioning, but also worsen the depressive illness and quality of life.

SSRIs and SNRIs have the highest risk for sexual dysfunction, while bupropion, agomelatine, mirtazapine has the lowest risk.

It's prevalence is underreported. Direct questioning is essential to pick up patients with

this side effect.

Summary

Assessment for baseline sexual functioning helps accurately assessing any subsequent change in sexual functioning.

Depression and sexual dysfunction has a reciprocal relationship.

A thorough assessment for risk factors contributing to the sexual dysfunction is important to improve overall outcomes.

Many strategies have been suggested to manage antidepressant-induced sexual dysfunction, many of which are with insufficient body of evidence.

Summary

Those strategies include: watchful waiting, drug holiday, reduction of the dose, switch or augmentation.

Augmentation with bupropion seems to have the best evidence yet.

Augmentation with Phosphodiesterase-5 inhibitors seems helpful specially for men with erectile dysfunction related to antidepressants.

Further research is highly needed to reach a clearer consensus about management.

References

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