Great Effort From Dr.Badr. Sexual Side effect from antidepressant is quite common but not that well tackled in regular textbook.

1. Management of
Antidepressant-induced
Sexual Dysfunction
Literature Review
Prepared and Presented by:
Badr Saleh Alaseeri
Psychiatry R2
King Abdulaziz Medical City
National Guard Health Affairs
Jeddah
Reviewed by:
Dr. Tarek Sherif
Consultant Psychiatrist
King Abdulaziz Medical City
National Guard Health Affairs
Jeddah

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

3. 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.

4. Overview
What is meant by sexual dysfunction?
Sexual dysfunction could affect any of the
following phases of the sexual response
cycle:
 Desire  decreased libido
 Arousal/ erection  erectile
dysfunction
 Orgasm  anorgasmia
 Ejaculation  Delayed ejaculation

5. 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.

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

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

8. Epidemiology
Serretti and Chiesa (2009)

9. 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).

10. 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.

11. 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.

12. 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)

13. 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

14. 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.

16. 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).

17. 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)

18. Mechanisms by which antidepressants
cause sexual dysfunction
Desire:
 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)

19. 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).

20. 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).

21. 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)

22. Management

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

24. Management
Shafer L (2016)

25. Management
Shafer L (2016)

26. Management
Shafer L (2016)

27. Management
Shafer L (2016)

28. Management
Shafer L (2016)

29. 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.

30. Management: Strategies
 Wait for Spontaneous resolution
 19-30% 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).

31. 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.

32. 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).

33. Management
 Switch to another antidepressant:
Bupropion
Agomelatine
Mirtazapine
Nefazodone
Moclobemide
Selegiline

34. 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.

35. 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)

36. 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)

37. 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).

38. 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.

39. 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)

40. Management
 Augmentation:
 Bupropion
 Phosphodiesterase-5 inhibitors
 Others

41. 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)

42. 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

43. 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.

44. Management: Augmentation
 Phosphodiesterase-5 inhibitors:
The most favoured approach for men with erectile
dysfunction caused by antidepressants.
(Taylor 2013).

45. 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).

46. 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)

47. 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.

48. 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)

49. 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

50. 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)

51. 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

52. 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.

53. 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.

54. 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.

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