Management of Antidepressant-Induced Sexual Dysfunction

1
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
2
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.

3
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

4
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

5
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
  
• - Im not much in the mood for sex
• - Also, Im having trouble reaching orgasm

6
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, 2893095-3105 2
Leon et al., Arch Fam Med 1995, 10857-861
7
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,
58395-401.
8
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/depre
ssion.htm
9
Antidepressant Prescribing in Primary Care

• Data from National Ambulatory Medical Care
  Survey1
• Examined data from 89,424 adult primary care
  visits from 1989-2000 (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, 5153-157.
10
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
11
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)

12
Antidepressant Adverse Effects

• Anticholinergic effects
• Sedation
• Activation
• Weight gain
• Orthostatic hypotension
• GI Effects
• Insomnia
• Sexual dysfunction
• Miscellaneous others

?
13
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

14
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 -
Premature ejaculation - 21
Source Laumann et al., JAMA, 1999, 281537-544
15
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

16
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

17
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
Delayed ejaculation - 22
Source Kennedy et al., J Affective Disorders,
1999, 56201-208.
18
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,
65959-965.
19
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,
63357-366.
20
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

21
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

22
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

23
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?
24
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
25
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.

26
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,
6562-67 Masand et al., Am J Psychiatry, 2001,
158805-807.
27
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, 28956-64.
28
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

29
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

30
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