This document discusses drug-induced sexual dysfunction and its management. It covers the nosology of sexual dysfunction, etiology focusing on medication-induced and substance-induced causes. It evaluates epidemiology of sexual side effects of various classes of medications like antidepressants, antipsychotics, mood stabilizers, etc. based on controlled studies and clinical observations. Specific substances like alcohol, opioids, cannabis are discussed in relation to sexual dysfunction. Evaluation, approach and management strategies are also mentioned.

1. Drug induced sexual dysfunction
and Management
Dr.Udayan Majumder, JR 2nd yr
Chairperson : Prof. N. Heramani Singh (HOD)
Department of Psychiatry, RIMS

2. Outline
• Brief Nosology (DSM V), APA 2013.
• Etiology of Sexual Dysfunction.
• Special Focus on :
1. Medication induced
2. Substance induced
• Evaluation, approch and management.

3. Nosology of Sexual Dysfunction
3

4. Presumed Etiology
 Primary
Developmental dysfunctions
 Secondary
Metabolic, Neurological, Endocrine, Genitourinary, psychiatric
Situational/Psychosocial
Substance-induced
Psychotropics, Non-Psychotropics , drugs of abuse
 Genetic basis
4

5. Secondary causes of Sexual Dysfunction

6. Secondary causes of Sexual Dysfunction

7. Medication induced sexual dysfunctions

8. Medication induced sexual dysfunctions

9. Psychiatric causes of sexual dysfunctions
1. Depression and Anxiety
2. Obsessive compulsive disorders
3. Schizophrenia spectrum disorders

10. Substance/Psychotropic drug induced causes
1. Alcohol
2. Opioids
3. Cannabis
4. Nicotine
5. Stimulants
6. Cocaine are the common, alcohol being the
highest.

11. Genetic predisposition
• D4 receptor polymorphisms significantly contribute to
differences in libido, arousal and orgasm in humans
(Zion et al , 2006)
• SSRI-induced sexual dysfunction is associated with the GG
genotype of 5-HT2A receptor–1438 single nucleotide
polymorphisms vs. GA or AA genotype
(Bishop et al , 2006)
11

13. Antidepressant induced sexual dysfunctions

14. History
1.1971 :first report of female orgasm delay on
monoamine oxidase inhibitors
2.1976-Reports of orgasm delay on antipsychotics
3.1985 :double-blind study indicated high rate of
orgasm/libido problems on both phenelzine and
imipramine
4.1987 :Double-blind study indicated orgasm
problems on benzodiazepines
Harrison et al, PB, 1985; Monteiro et al, BJP, 1987; Segraves et al,JCP, 2000

15. 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)
• 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).

16. Contd.
• 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.
Zajecka et al (1991) in Serretti and Chiesa (2009)

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

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

19. Evidence Concerning Rates of Drug-
induced Sexual Dysfunction
1. Controlled trials
2. Large clinical series
3.Efficacy in treatment of rapid ejaculation

20. Controlled Studies with Direct Inquiry
1. Clomipramine (Anafranil ) > Placebo
2. Sertraline (Zoloft) > Nefazodone (Serzone)
3. Sertraline (Zoloft) > Bupropion (Wellbutrin)
4. Paroxetine (Paxil) > Duloxetine (Cymbalta)>
placebo
5. Fluoxetine (Prozac) > Bupropion (Wellbutrin)
6.Citalopram (Celexa) = Paroxetine (Paxil)
1.Monteiro et al, BJP,1987; 2. Harrison et al, JCP,1986; 3. Feiger et al, JCP,1996
,Ferguson et al, JCP, 2001; 4. Segraves et al, JCP,200; Kavoussi et al, JCP, 2001,
Croft et al, JCP, 1999; 5. Delgado et al, JCP,2005; 6. Landen et al, JCP, 2005

21. Controlled Comparisons
1. Clomipramine > Sertraline > Fluoxetine
2. Paroxetine > Fluoxetine > Sertraline
3. Fluvoxamine = Placebo
4. 40mg fluoxetine = 50mg sertraline
5. Paroxetine = Clomipramine = Sertraline
1. Kim & Sue, JU, 1998; 2. Waldinger et al, JCP,1998;
3. Murat et al, AEU,1999

22. Large Clinical Series
Observation in Clinical Settings
1. 5 year open label prospective study of
treatment emergent sexual dysfunction
2. 1022 patients ( 610 women, 412 men)
3. Average age 39.8 years
4. Standard questionnaire used at multiple
clinical sites in Spain
Montejo et al, J Clin Psychiatry,2001

23. Sexual Side Effect Profile
• Citalopram (Celexa) 73%
• Paroxetine (Paxil) 71%
• Venlafaxine (Effexor CR) 67%
• Sertraline (Zoloft) 63%
• Fluoxetine (Prozac) 58%
• Mirtazapine ( Remeron) 24%
• Nefazodone ( Serzone) 8%
Montejo et al, J Clin Psychiatry,2001

24. Additional Observations
1. Sexual side effects more frequent in men
2. Sexual side effects more severe in women
3. Spontaneous remission at 6 months 10%
4. Most common problems-delayed orgasm or
ejaculation and decreased libido
Montejo et al, J Clin Psychiatry,2001

25. Controlled studies on Ejaculatory latency
1. Placebo 1.5 fold increase
2. 100 mg Fluvoxamine 1.9 fold increase
3. 20mg Fluoxetine 6.6 fold increase
4. 20mg Paroxetine 7.8 fold increase
5. 50mg Sertraline 4.4 fold increase
Waldinger & Olivier, J Clin Psychopharmacol.1998

26. Paroxetine vs Citalopram
1. Intravaginal ejaculatory latency time
2. Stop watch, 6 weeks treatment
• 20mg Paroxetine 8.9 fold
• 20mg Citalopram 1.8 fold
Waldinger, J Clin Psychopharmacol, 2001

27. Ejaculatory Disturbances
Causes significant delay ejaculation
1. Paroxetine (Paxil)
2. Sertraline (Zoloft)
3. Fluoxetine (Prozac)
4. Clomipramine (Anafranil)
5. Citalopram (Celexa)
1. Waldinger et al, AJP, 1994, Waldinger at al, BJU, 1997; McMahon et al, JU, 1999
2. Waldinger et al, JCP, 1998;Mendels et al, JCP,1995;McMahon , JU, 1998;
3. Waldinger etal, JCP,1998;kara et al, JU,1996;Haensel et al, JCP,1998; Biri et al, IVN,1999
4. Strassberg et al, JSMT,1999;Segraves et al, JSMT,1993;Althof et al, JCP,1995
5. Atmaca et al, IJIR,2002

28. Contd.
Minimal or no delay
– 1.Fluvoxamine (Luvox)
– 2.Nefazodone (Serzone)
– 3.Mirtazapine (Remeron)
– 4.Citalopram (Celexa) at 20mg dose
1. Waldinger et al, JCP,1988; 2. Waldinger et al, JCP,1998
2. Waldinger etal, JCP,2001 3. Waldinger , JU, 2002
3. Waldinger, JCP,2001

29. Bottom line
1. Good data that bupropion, nefazodone, mirtazapine
have low levels SD
2. Good data that clomipramine & paroxetine have
high rates of SD
3. Citalopram at usual dose levels has high rates of SD
4. Duloxetine probably has intermediate rates of SD

30. Benzodiazepines
1. Numerous case reports of anorgasmia on
benzodiazepines
2. One double-blind, placebo-controlled study
3. Orgasm by vibrator in laboratory
4. Dose response delay in orgasm by diazepam
Riley & Riley, SMT,1986;Fossey & hammer, 1994;Segraves & Balon, In Press

31. Lithium and Sexual Dysfunction
1. Case reports suggest that lithium may impair libido and
erectile function
2. One double blind study found that 2/10 of bipolar
patients developed erectile problems on therapeutic
doses of lithium
3. It is difficult to discriminate between a drug side effect,
phase of the disease, and a treatment effect.
Vinarova et al , 1976, Aizenberg et al, 1996

32. Anticonvulsants
1. Case reports of anorgasmia on gabapentin and
carbamazepine
2. Case reports of decreased libido, impaired arousal and
anorgasmia on valproate monotherapy
3. Case reports of improved erectile function in epileptics
on lamotrigine
4. Carbamazepine (Tegretol) increases serum hormone
binding globulin and thus decreases bioavailabilty of
androgens
5. Oxcarbamazpine (Trileptal) does not influence androgen
bioavialabilty
Schnech et al, JCP,2002; Husain et al, SMJ,2002; Leris et al,
BJU,1997;Labbate & Rubey,AJP,1999

33. Antipsychotics and Sexual Dysfunction

34. Updates
1. In general evidence suggests that newer prolactin
sparing antipsychotics are less likely to cause
sexual dysfunction that older agents causing
prolactin elevation
2. Evidence is not consistent

35. Early Case Report
• Sexual interviews, n=87
• Difficulty with erections in 44% of patients on
thioridazine (Mellaril) versus 19% on other
antipsychotics
• Ejaculatory problems in 49%
Kotin et al, 1975

36. Antipsychotics and SD
 Open label study of 106 outpatients
• Risperidone (Risperdal) 82% ( 5.5mg/d )
• Haloperidol (Haldol) 25% ( 5.8mg/d)
• Olanzapine (Zyprexa) 2% ( 9.4 mg/d)
• Clozapine (Clozaril) 0% (115mg.d )
Montejo et al, 1998 APA NR

37. Newer Antipsychotics
0
10
20
30
40
50
60
70
Risperidone
Olanzapine
Quetiapine
Pimozide
n=66
n=21
n=13
n=41
%
Knegtering et al, 2002

38. SD and Antipsychotic Drug Therapy
0
10
20
30
40
50
60
70
1st Qtr
Classical
Risperidone
Olanzapine
Knegtering et al, 2002
5-6mg
N=90
6.5mg
10mg

39. Risperidone vs Olanzapine
0
5
10
15
20
25
30
35
40
45
50
Risperidone
Olanzapine
Knegtering et al, 2002
3-4 mg
9.2 mg
N=46
3.4mg
9.2mg

40. Frequency of Sexual Side Effects
• Risperidone (Risperdal) 43%
• Haloperidol ( Haldol) 38%
• Olanzapine (Zyprexa) 35%
• Quetiapine (Seroquel) 18%
Bobes et al, JSMT,2003

41. Other Findings
• Most common problem erectile dysfunction
and loss of sexual desire in men
• In women, lost of sexual desire most common
• Frequency of side effects appeared to be dose
related
Bobes et al, JSMT,2003

42. Intercontinental Schizophrenia Outpatient
Health Outcome Study
• 570 patients started on clozapine, olanzapine,
quetiapine, riperidone, haloperidol
• Sexual dysfunction assessed at baseline, 3rd and
6th months
• Less sexual dysfunction on OLANZAPINE.
Bitter et al, ICP, 2005

43. Bottom Line
• Risperidone (Risperdal) and traditional
antipsychotics probably have highest incidence
of sexual side effects
• Olanzapine(Zyprexa) and Quetiapine
(Seroquel) probably have the lowest incidence
of sexual side effects

44. Sexual dysfunction and Substance use :
Facts and figures
• Often leads to treatment non-adherence and sexual or marital
disharmony .
• In case of alcohol dependence, the SD rates have varied from
 51% to 58% for low sexual desire
 1659% for erectile impotence
 415.9% for premature ejaculation
 17.825.4% for retarded ejaculation.
• Studies in heroin dependents or on MMT or Buprenorphine
have demonstrated higher rates of SD than in the general
population.
 3485% for heroin addicts
 1481% for MMT
 3683% for Buprenorphine

45. Alcoholism
• Leading cause of erectile dysfunction and other
disturbances.
• Negatively impact on a persons’ libido.
• Long-term use interferes with the HPA axis
 reduced testosterone and feminization in men
 decreased sex drive and performance.
• Alcohol 's harmful effect on testosterone
production
reduced level of nitric oxide (NO), a local
vasodilator.

46. Opiates
• Heroin reduces sexual feelings and may decrease desire,
and cause erectile and ejaculatory dysfunction.
• Opioids reduce testosterone level  decreased libido
and erectile dysfunction.
• Chronic administration of opioids for nonmalignant
pain result in tonic decrease  total (TT) and free (FT)
testosterone levels in an apparent dose-dependent
fashion.
• Women also experience similar hormonally linked side
effects of opioids dysmenorrhea and decreased libido.
• Reduced estrogen levels in women on methadone
maintenance.

47. Cannabis
• The delta 9THC chemicals in weed inhibit acetylcholine function
 impotence and premature ejaculation problems.
• A 2010 study published in the Journal European Urology found that
marijuana may contribute to ED by inhibiting the nervous system
response that causes an erection in the first place.
• Marijuana use to lower testosterone levels, contributing to ED as
well anorgasmia.
• Recent studies shows marijuana use along with alcoholism triggers
ED than alcoholism alone.

48. Cocaine
• Acts as a monoamine transporter blocker, with similar
affinities for dopamine, serotonin, and norepinephrine
transporters.
• Two opposite effects on sexual functioning according to its acute
or chronic abuse.
• New or infrequent cocaine users may report that cocaine
induces spontaneous erection and ejaculation.
• MacDonald et al. (1988) found that of men who had used cocaine
for 1 year or longer, 66% reported to have erection difficulties.

49. Stimulants
• Increase sexual desire in the short term, but
long-term use may result in reduced sex drive.
• Amphetamine use is also associated with
ejaculatory disturbance in the long term.
• Ecstasy alters libido and can increase sex
drive at the expense of impaired sexual
performance (delayed orgasm and erectile
dysfunction), possibly due to increased
prolactin secretion.

50. Tobacco
• Inconsistent studies about the effect of
smoking on sexual dysfunction.
• Massachusetts Male Aging Study found that
the incidence of ED doubled in a sub-group
of men smokers free from vascular-disease
• Excess risk of ED in past smokers decreases
substantially in the initial 2-3 years; thereafter
the risk reduction slows down.
• Higher rate of ED in former smokers may be
related to smoking induced vascular diseases.

51. Bottom line
• Alcoholism remains the major predisposing
factor leading to sexual dysfunction among all
substasnces.
• Recent studies promisingly support role of
opioids in anorgasmia and other dysfunctions,
also in therapeutic settings (methadone,
buprenorphine).
• Inconsistent studies and discrete case reports
regarding other substances.

52. References
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55. THANK YOU
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