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Management of
Antidepressant-Induced
Sexual Dysfunction
Stevens S. Smith, Ph.D.
Assistant Professor (CHS)
Department of Medicine / General Internal Medicine
Center for Tobacco Research and Intervention
University of Wisconsin Medical School
Primary Care Conference Presentation
Wednesday, 25 August 2004
1
Disclaimer
•
I have received smoking cessation research
support from pharmaceutical companies (Elan
Corporation; GlaxoSmithKline) that market
antidepressants or other medications discussed
in this presentation.
•
I am not a consultant or paid speaker for any
pharmaceutical companies.
2
Learning Objectives
•
Brief review of diagnosis and treatment of depression
by primary care physicians
•
Brief review of sexual dysfunction
•
Prevalence and hypothesized mechanisms of
antidepressant-induced sexual dysfunction
•
Strategies for managing antidepressant-induced
sexual dysfunction
3
Case Study
•
50 year-old male; married and sexually active; no medical
complications other than a 10-year history of hypertension
(controlled with enalapril 10 mg daily)
•
At routine check with his primary care physician (PCP), the patient
mentions feeling depressed for several months with increasing
problems at work and at home; he admits to occasional suicidal
ideation but has no active plans to harm himself
•
Differential diagnosis rules out medical/medication causes for the
depression; substance abuse also ruled out
•
Diagnosis: first episode of major depression, moderate severity
4
Case Study
•
Initial treatment: paroxetine 20 mg daily for one week followed by
dose increase to 30 mg; referral to psychologist
•
Patient returns after 4 weeks for medication check; patient reports
a small but noticeable improvement in symptoms of depression
•
Side effects noted by the patient include: nausea (improving),
drowsiness, night sweats
•
“And, oh, by the way, my psychologist said that I should mention
these other side effects to you … ”
- “I’m not much in the mood for sex”
- “Also, I’m having trouble reaching orgasm”
5
Major Depression in Primary Care
•
General population estimates for major depression in the U.S.1 :
- Lifetime prevalence: 16.2%
- 12-month prevalence rate: 6.6%
•
Prevalence of depression in adult primary care patients tends to
be higher especially in the presence of chronic health problems2
•
Depression is associated with poor self-care and poor adherence
to medical treatments
•
Second only to hypertension as the most common chronic
condition encountered in primary care settings
1
Kessler et al., JAMA 2003, 289:3095-3105; 2 Leon et al., Arch Fam Med 1995, 10:857-861
6
Major Depression in Primary Care
•
Primary care physicians are the gatekeepers of medical care
including depression
•
Primary care physicians (PCPs) outnumber psychiatrists 7 to 1;
PCPs prescribe the majority of antidepressants
•
Outcomes for depression treatment of primary care patients do
not differ for psychiatrists and primary care physicians1
1
Simon et al., Arch Gen Psychiatry 2001, 58:395-401.
7
UW Health: Treating Major Depression
In Adults in Primary Care (2002)
•
Medication recommended “for essentially all patients” with MDD
Mild MDD: medication or psychotherapy
Moderate/severe MDD: medication with or without
psychotherapy
•
Acute phase (first 12 weeks of Tx): Patient should be seen a
minimum of 3 times (at least once with prescriber)
•
Treatment response should be assessed every 4-6 weeks during
drug therapy; assess every 4-12 weeks after remission
•
Patient should continue on medication for at least 6 months after
symptoms resolve
Source: http://www.hosp.wisc.edu/crit/guides/depression.htm
8
Antidepressant Prescribing in Primary Care
•
Data from National Ambulatory Medical Care Survey1
•
Examined data from 89,424 adult primary care visits from 19892000 (approximately 260 million visits per year)
•
From 1989 to 2000, primary care physicians increased their
prescribing of antidepressants from 2.6% of visits to 7.1% of visits
•
Antidepressant prescriptions in 2000 in primary care:
- 18% older agents (e.g., tricyclics, MAOIs, trazodone)
- 17% newer, non-SSRIs (e.g., bupropion, venlafaxine)
- 65% SSRIs
1
Pirraglia et al., Primary Care Companion J Clin Psychiatry 2003, 5:153-157.
9
Current Antidepressants
Chemical Class
Example
#Avail.
Selective Serotonin Reuptake Inhibitors (SSRI)
Citalopram
6
Norepinephrine Dopamine Reuptake Inhib. (NDRI)
Bupropion
1
Selective Serotonin-Norepi. Reuptake Inhib. (SNRI)
Venlafaxine
Duloxetine
2
Serotonin-2 Antagonists/Reuptake Inhibitors (SARI)
Trazodone
Nefazodone
2
Noradrenergic/Specific Serotonergic Agent
(NaSSA)
Mirtazapine
1
Tricyclics / tetracyclics (mixed reuptake Inhibitor /
receptor blockers)
Imipramine
Maprotiline
10
Irreversible monamine oxidase-A-B inhibitors
(MAOI)
Phenelzine
3
Total = 25
Main Source: Bezchlibnyk-Butler et al. (Eds.). Clinical handbook of psychotropic drugs, 13th revised ed., 2003
10
Antidepressant Efficacy
•
All antidepressants appear to be equally efficacious
•
Choice of antidepressant depends on several factors:
- pharmacokinetics
- lethality in overdose
- prior response in patient or family members
- potential medication interactions
- medical contraindications
- presence of co-morbid conditions (e.g., social anxiety)
- side effect profile (e.g., more sedating vs. less sedating)
11
Antidepressant Adverse Effects
•
•
•
•
•
•
•
 •
•
Anticholinergic effects
Sedation
Activation
Weight gain
Orthostatic hypotension
GI Effects
Insomnia
Sexual dysfunction
Miscellaneous others
12
Sexual Dysfunction
•
DESIRE: Inhibited or hypoactive sexual desire
•
AROUSAL in males: erectile dysfunction
•
AROUSAL in females: inadequate lubrication and/or
diminished/absent physiological changes associated with
sexual excitement (e.g., swelling of genitalia)
•
ORGASM: premature, delayed, or absent orgasm
•
PAIN: painful intercourse; vaginisimus
Classifications: lifelong (primary), acquired (secondary),
generalized, and situational
13
Past-Year Prevalence of Sexual Dysfunction
•
1992 National Health and Social Life Survey
•
Sampled 1749 women and 1410 men aged 18-59 years
•
Assessed presence of sexual problems in past 12 months
•
43% of women and 31% of men reported sexual dysfunction
Sexual Dysfunction
Females
Males
Low sexual desire
22%
5%
Arousal problems / ED
14%
5%
Sexual pain
7%
-
-
21%
Premature ejaculation
Source: Laumann et al., JAMA, 1999, 281:537-544
14
Possible Causes of Sexual Dysfunction
•
Medical conditions (e.g., vascular disease, endocrine disorders,
neurological conditions)
•
Psychological/psychiatric factors (e.g., history of sexual trauma,
stress, relationship factors, psychiatric disorders such as
depression, substance abuse)
•
Medications:
- antihypertensives (e.g., clonidine, beta-blockers, CCBs)
- sedatives (e.g., alprazolam)
- anticonvulsants (e.g., phenytoin, carbamazepine,
- neuroleptics (e.g., chlorpromazine, fluphenazine)
- miscellaneous (cimetidine, niacin, digoxin, ketoconazol)
- antidepressants, especially SSRIs, tricyclics, and MAOIs
15
Sexual Dysfunction in Major Depression
•
Sexual functioning is often impaired in MDD due to
diminished ability to experience pleasure
•
Antidepressant treatment of MDD can cause or
worsen sexual dysfunction
•
Antidepressant-induced sexual dysfunction can
exacerbate depression and may influence the patient
to discontinue antidepressant treatment
16
Impaired Sexual Functioning in MDD
Prior to Antidepressant Treatment
•
Kennedy et al. (1999) studied 55 male and 79 female patients
who met DSM-IV criteria for MDD; ages 18-64 years
•
Assessed past month sexual functioning prior to initiation of
antidepressant treatment
•
39 women (49%) and 14 men (26%) reported no sexual activity in
past month
Sexual Dysfunction
Females
Males
Decrease in sexual drive
50%
42%
Arousal problems / ED
50%
46%
-
22%
Delayed ejaculation
Source: Kennedy et al., J Affective Disorders, 1999, 56:201-208.
17
Impaired Sexual Functioning in MDD
Subsequent to SSRI Treatment
•
Hu et al. (2004) studied 401 patients, 18-40 years old, receiving
SSRI treatment (paroxetine, fluoxetine, sertraline, or citalopram)
•
Assessed 17 SSRI side effects including sexual dysfunction in a
phone interview 75 to 105 days of starting SSRI treatment
Sexual Dysfunction (SD) Measure
Percentage
% experiencing SD
34%
% experiencing bothersome SD
17%
SD occurred during first two weeks*
70%
SD continued for 3 months*
83%
*Includes only patients reporting SD
Source: Hu et al., J Clin Psychiatry, 2004, 65:959-965.
18
Prevalence of Antidepressant-Induced
Sexual Dysfunction
•
Clayton et al. (2002) examined a target population of 802 primary
care patients who met the following criteria: 18-40 years old; no
sexual side effects from previous antidepressant tx; on
medication at least 3 months; no medications or illnesses causing
SD; history of at least “some” sexual enjoyment
•
Percentage of target population reporting sexual dysfunction:
30% - citalopram and venlafaxine
27% - sertraline and paroxetine
22% - fluoxetine
 7% - bupropion
Source: Clayton et al., J Clin Psychiatry, 2002, 63:357-366.
19
General Findings Regarding
Antidepressant-Induced Sexual Dysfunction
•
Difficult to disentangle depression-related sexual dysfunction
(SD) from medication-related SD
•
Package inserts for antidepressant medications typically
underestimate the prevalence of SD
•
SD is more likely in patients who do not respond well to
antidepressant treatment
•
Tolerance to sexual side effects unlikely
•
SD often leads to discontinuation of medication
•
SSRIs are more likely than non-SSRIs to cause problems
•
Some studies suggest that males are more likely than females
to experience problems
20
Why Are SSRIs More Likely to Cause SD?
•
•
Probable role of neurotransmitters and hormones in normal
sexual functioning:
- Desire/libido:
dopamine, testosterone, estrogen 
prolactin 
- Arousal:
acetylcholine, dopamine, nitric oxide 
- Orgasm:
norepinephrine 
serotonin 
Hypothesized mechanisms of SSRI-related SD:
- serotonin reputake blockade may reduce dopamine activity
- SSRIs may increase prolactin levels
- SSRIs may interfere with spinal reflex centers involved in
ejaculation and orgasm
21
Management of Antidepressant-Induced
Sexual Dysfunction
•
Prior to initiation of antidepressant treatment:
- assess baseline sexual functioning (non-depressed)
- assess current sexual functioning
•
After antidepressant treatment has started:
- re-assess sexual functioning to identify any changes
•
If SD present, ascertain possible causes and treat accordingly
22
Assessing Sexual Functioning
Assess baseline (usual sexual interest and functioning) and current
sexual functioning; continue to monitor during treatment
Sexual Phase Possible Questions
Desire
Baseline: “What is your usual interest in sex? Do you
have sexual thoughts or fantasies?”
Current: “Has there been any recent changes in your
interest in or desire for sex?”
Arousal
Female: “Do you usually have (or ‘Have you had any’)
problems getting wet or lubricated when aroused?”
Male: “Do you usually have (or ‘Have you had any’)
problems getting or keeping an erection?”
Orgasm
“Do you usually have (or ‘Have you had any’) difficulty
reaching orgasm?”
23
Management of SSRI-Induced
Sexual Dysfunction
•
If SD is SSRI-induced, consider treatment options:
SD Management Strategy
Comments
Wait for tolerance to develop
Low success rate
Reduce the dose
Risk for relapse of depression
Drug holiday
Pt may discontinue drug
Switch to another medication
Limited evidence
Add another medication
e.g., bupropion; sildenafil
Combinations of the above
Limited evidence base
24
Management of SSRI-Induced Sexual Dysfunction:
Switching to Another Antidepressant
•
Antidepressants with lowest incidence of sexual side effects (in
order of preference):
- Bupropion: potentiates dopamine neurotransmission, no
serotonergic effects
- Nefazodone: blocks post-synaptic 5-HT2 receptors
- Mirtazapine: blocks 5-HT2 and 5-HT3 receptors; increases
norepinephrine neurotransmission
•
Note that the evidence base for switching to any of these
medications is quite limited.
25
Management of SSRI-Induced Sexual Dysfunction:
Adding An “Antidote” Medication
•
Adding bupropion SR to SSRI treatment:
- one randomized clinical trial1 showed statistically significant
increases in desire for and frequency of sexual activity but no
differences in arousal or orgasm
- a second randomized clinical trial showed no benefit2
- use caution in combining bupropion with SSRIs
1
Clayton et al., J Clin Psychiatry 2004, 65:62-67; Masand et al., Am J Psychiatry, 2001, 158:805-807.
26
Management of SSRI-Induced Sexual Dysfunction:
Adding An “Antidote” Medication
•
Adding sildenafil to SSRI treatment for erectile dysfunction (ED):
- Nurnberg et al. (2002) reviewed 3 randomized clinical trials and
retrospective data pooled from 10 clinical trials; trials included
depressed men treated or untreated with SSRIs1
- Sildenafil was found to be efficacious for SSRI-induced ED and
for ED unrelated to SSRI treatment
- Beneficial effects of sildenafil were generally replicated in a
newer study by Nurnberg et al. (2003)2
1
Nurnberg et al., Urology 2002, 60 (Suppl 2B), 58-60; 2 Nurnberg et al., JAMA 2003, 289:56-64.
27
Management of SSRI-Induced Sexual Dysfunction:
Adding An “Antidote” Medication
•
Other medications have been proposed for treating SD:
- cyproheptadine and other serotonin antagonists
- amantadine and other dopamine agonists
- buspirone (anxiolytic)
- yohimbine (alpha-2 adrenergic receptor antagonist)
- ginko biloba
- dextroamphetamine and other stimulants
•
None of these medications have an adequate evidence base
28
Summary
•
Antidepressant-induced sexual dysfunction (SD) is very common
•
SSRIs have the highest incidence of treatment-emergent SD
•
When treating depressed patients with or without antidepressants,
it is important to assess usual sexual functioning as well as any
changes in sexual functioning associated with the onset of
depression and/or the use of medications
•
Consider initial use of antidepressants with lower incidence of SD
•
Follow-up with patients to monitor medication efficacy and side
effects
•
Carefully assess and treat SD no matter what the cause(s)
•
The evidence base for most SD treatments is quite limited
29
Case Study
•
Primary care physician (PCP) recommended that the patient
continue on paroxetine for another month to see if SD would
improve
•
No improvement in SD after two months on medication
•
PCP recommended switching to nefazodone
•
Patient stayed on nefazodone for one week; discontinued
medication due to side effects; not interested in trying other
antidepressants
•
Patient continuing in psychotherapy
30