1. 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. 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 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.I am not a consultant or paid speaker for any pharmaceutical companies.

3. 3 Learning Objectives Brief review of diagnosis and treatment of depression by primary care physiciansBrief review of diagnosis and treatment of depression by primary care physicians Brief review of sexual dysfunctionBrief review of sexual dysfunction Prevalence and hypothesized mechanisms of antidepressant-induced sexual dysfunctionPrevalence and hypothesized mechanisms of antidepressant-induced sexual dysfunction Strategies for managing antidepressant-induced sexual dysfunctionStrategies for managing antidepressant-induced sexual dysfunction

4. 4 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)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 himselfAt 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 outDifferential diagnosis rules out medical/medication causes for the depression; substance abuse also ruled out Diagnosis: first episode of major depression, moderate severityDiagnosis: first episode of major depression, moderate severity Case Study

5. 5 Initial treatment: paroxetine 20 mg daily for one week followed by dose increase to 30 mg; referral to psychologistInitial 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 depressionPatient 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 sweatsSide 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 … ”“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” Case Study

6. 6 Major Depression in Primary Care General population estimates for major depression in the U.S. 1 :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 problems 2Prevalence of depression in adult primary care patients tends to be higher especially in the presence of chronic health problems 2 Depression is associated with poor self-care and poor adherence to medical treatmentsDepression 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 settingsSecond 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

7. 7 Major Depression in Primary Care Primary care physicians are the gatekeepers of medical care including depressionPrimary care physicians are the gatekeepers of medical care including depression Primary care physicians (PCPs) outnumber psychiatrists 7 to 1; PCPs prescribe the majority of antidepressantsPrimary 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 physicians 1Outcomes for depression treatment of primary care patients do not differ for psychiatrists and primary care physicians 1 1 Simon et al., Arch Gen Psychiatry 2001, 58:395-401.

8. 8 UW Health: Treating Major Depression In Adults in Primary Care (2002) Source: http://www.hosp.wisc.edu/crit/guides/depression.htm Medication recommended “for essentially all patients” with MDDMedication recommended “for essentially all patients” with MDD Mild MDD: medication or psychotherapy Mild MDD: medication or psychotherapy Moderate/severe MDD: medication with or without 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)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 remissionTreatment 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 resolvePatient should continue on medication for at least 6 months after symptoms resolve

9. 9 Antidepressant Prescribing in Primary Care Data from National Ambulatory Medical Care Survey 1Data from National Ambulatory Medical Care Survey 1 Examined data from 89,424 adult primary care visits from 1989- 2000 (approximately 260 million visits per year)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 visitsFrom 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: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.

10. 10 Current Antidepressants Chemical Class Example#Avail. Selective Serotonin Reuptake Inhibitors (SSRI) Citalopram6 Norepinephrine Dopamine Reuptake Inhib. (NDRI) Bupropion1 Selective Serotonin-Norepi. Reuptake Inhib. (SNRI) VenlafaxineDuloxetine2 Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) TrazodoneNefazodone2 Noradrenergic/Specific Serotonergic Agent (NaSSA) Mirtazapine1 Tricyclics / tetracyclics (mixed reuptake Inhibitor / receptor blockers) ImipramineMaprotiline10 Irreversible monamine oxidase-A-B inhibitors (MAOI) Phenelzine3 Main Source: Bezchlibnyk-Butler et al. (Eds.). Clinical handbook of psychotropic drugs, 13 th revised ed., 2003 Total = 25

11. 11 Antidepressant Efficacy All antidepressants appear to be equally efficaciousAll antidepressants appear to be equally efficacious Choice of antidepressant depends on several factors: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. 12 Antidepressant Adverse Effects Anticholinergic effectsAnticholinergic effects SedationSedation ActivationActivation Weight gainWeight gain Orthostatic hypotensionOrthostatic hypotension GI EffectsGI Effects InsomniaInsomnia Sexual dysfunctionSexual dysfunction Miscellaneous othersMiscellaneous others 

13. 13 Sexual Dysfunction DESIRE: Inhibited or hypoactive sexual desireDESIRE: Inhibited or hypoactive sexual desire AROUSAL in males: erectile dysfunctionAROUSAL in males: erectile dysfunction AROUSAL in females: inadequate lubrication and/or diminished/absent physiological changes associated with sexual excitement (e.g., swelling of genitalia)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 orgasmORGASM: premature, delayed, or absent orgasm PAIN: painful intercourse; vaginisimusPAIN: painful intercourse; vaginisimus Classifications:lifelong (primary), acquired (secondary), generalized, and situational

14. 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 FemalesMales Low sexual desire 22%5% Arousal problems / ED 14%5% Sexual pain 7%- Premature ejaculation -21% Source: Laumann et al., JAMA, 1999, 281:537-544

15. 15 Possible Causes of Sexual Dysfunction Medical conditions (e.g., vascular disease, endocrine disorders, neurological conditions)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)Psychological/psychiatric factors (e.g., history of sexual trauma, stress, relationship factors, psychiatric disorders such as depression, substance abuse) Medications: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. 16 Sexual Dysfunction in Major Depression Sexual functioning is often impaired in MDD due to diminished ability to experience pleasureSexual functioning is often impaired in MDD due to diminished ability to experience pleasure Antidepressant treatment of MDD can cause or worsen sexual dysfunctionAntidepressant treatment of MDD can cause or worsen sexual dysfunction Antidepressant-induced sexual dysfunction can exacerbate depression and may influence the patient to discontinue antidepressant treatmentAntidepressant-induced sexual dysfunction can exacerbate depression and may influence the patient to discontinue antidepressant treatment

17. 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 yearsKennedy 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 treatmentAssessed past month sexual functioning prior to initiation of antidepressant treatment 39 women (49%) and 14 men (26%) reported no sexual activity in past month39 women (49%) and 14 men (26%) reported no sexual activity in past month Source: Kennedy et al., J Affective Disorders, 1999, 56:201-208. Sexual Dysfunction FemalesMales Decrease in sexual drive 50%42% Arousal problems / ED 50%46% Delayed ejaculation -22%

18. 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)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 treatmentAssessed 17 SSRI side effects including sexual dysfunction in a phone interview 75 to 105 days of starting SSRI treatment Source: Hu et al., J Clin Psychiatry, 2004, 65:959-965. 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

19. 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 enjoymentClayton 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: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.

20. 20 General Findings Regarding Antidepressant-Induced Sexual Dysfunction Difficult to disentangle depression-related sexual dysfunction (SD) from medication-related SDDifficult to disentangle depression-related sexual dysfunction (SD) from medication-related SD Package inserts for antidepressant medications typically underestimate the prevalence of SDPackage inserts for antidepressant medications typically underestimate the prevalence of SD SD is more likely in patients who do not respond well to antidepressant treatmentSD is more likely in patients who do not respond well to antidepressant treatment Tolerance to sexual side effects unlikelyTolerance to sexual side effects unlikely SD often leads to discontinuation of medicationSD often leads to discontinuation of medication SSRIs are more likely than non-SSRIs to cause problemsSSRIs are more likely than non-SSRIs to cause problems Some studies suggest that males are more likely than femalesSome studies suggest that males are more likely than females to experience problems to experience problems

21. 21 Why Are SSRIs More Likely to Cause SD? Probable role of neurotransmitters and hormones in normal sexual functioning: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:Hypothesized mechanisms of SSRI-related SD: - serotonin reputake blockade may reduce dopamine activity - serotonin reputake blockade may reduce dopamine activity - SSRIs may increase prolactin levels - SSRIs may increase prolactin levels - SSRIs may interfere with spinal reflex centers involved in ejaculation and orgasm ejaculation and orgasm

22. 22 Management of Antidepressant-Induced Sexual Dysfunction Prior to initiation of antidepressant treatment:Prior to initiation of antidepressant treatment: - assess baseline sexual functioning (non-depressed) - assess current sexual functioning After antidepressant treatment has started:After antidepressant treatment has started: - re-assess sexual functioning to identify any changes If SD present, ascertain possible causes and treat accordinglyIf SD present, ascertain possible causes and treat accordingly

23. 23 Assessing Sexual Functioning 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?” Assess baseline (usual sexual interest and functioning) and current sexual functioning; continue to monitor during treatment

24. 24 Management of SSRI-Induced Sexual Dysfunction If SD is SSRI-induced, consider treatment options: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. 25 Management of SSRI-Induced Sexual Dysfunction: Switching to Another Antidepressant Antidepressants with lowest incidence of sexual side effects (in order of preference):Antidepressants with lowest incidence of sexual side effects (in order of preference): - Bupropion: potentiates dopamine neurotransmission, no serotonergic effects - Nefazodone: blocks post-synaptic 5-HT 2 receptors - Mirtazapine: blocks 5-HT 2 and 5-HT 3 receptors; increases norepinephrine neurotransmission Note that the evidence base for switching to any of these medications is quite limited.Note that the evidence base for switching to any of these medications is quite limited.

26. 26 Management of SSRI-Induced Sexual Dysfunction: Adding An “Antidote” Medication Adding bupropion SR to SSRI treatment:Adding bupropion SR to SSRI treatment: - one randomized clinical trial 1 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 benefit 2 - 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.

27. 27 Management of SSRI-Induced Sexual Dysfunction: Adding An “Antidote” Medication Adding sildenafil to SSRI treatment for erectile dysfunction (ED):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 SSRIs 1 - 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.

28. 28 Management of SSRI-Induced Sexual Dysfunction: Adding An “Antidote” Medication Other medications have been proposed for treating SD: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 baseNone of these medications have an adequate evidence base

29. 29 Summary Antidepressant-induced sexual dysfunction (SD) is very commonAntidepressant-induced sexual dysfunction (SD) is very common SSRIs have the highest incidence of treatment-emergent SD 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 medicationsWhen 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 SDConsider initial use of antidepressants with lower incidence of SD Follow-up with patients to monitor medication efficacy and side effectsFollow-up with patients to monitor medication efficacy and side effects Carefully assess and treat SD no matter what the cause(s)Carefully assess and treat SD no matter what the cause(s) The evidence base for most SD treatments is quite limitedThe evidence base for most SD treatments is quite limited

30. 30 Primary care physician (PCP) recommended that the patient continue on paroxetine for another month to see if SD would improvePrimary 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 medicationNo improvement in SD after two months on medication PCP recommended switching to nefazodonePCP recommended switching to nefazodone Patient stayed on nefazodone for one week; discontinued medication due to side effects; not interested in trying other antidepressantsPatient stayed on nefazodone for one week; discontinued medication due to side effects; not interested in trying other antidepressants Patient continuing in psychotherapyPatient continuing in psychotherapy Case Study