SSRI INDUCED SEXUAL DYSFUNCTION

PRESENTER:-Ashutosh Singh CHAIRPERSON:-Mukund G. Rao

 Sexual dysfunction is frequently an integral symptom of a depressive disorder, making it difficult to ascertain whether the complaint is part of the syndrome being treated or the result of treatment itself. Approximately one third of nondrug-treated depressed patients report reduced sexual desire, delayed ejaculation, anorgasmia, or erectile dysfunction.

 SSRIs may negatively influence any or all phases of the sexual cycle with decreased or absent libido, impairment of arousal and erectile dysfunction but delayed ejaculation and absent or delayed orgasm are their most common effects (Rosen et al. 1999)

 Men experience significantly higher rates of desire and orgasm dysfunction compared with women, whereas women seem to have a higher arousal dysfunction than men.(Serretti et al. 2009) Possibly due to the greater weight of cognitive compared with physiologic aspects of arousal in women.(Clayton et al. 2006)

 Sexual dysfunction (SD) is commonly observed during SSRI therapy, occurring in approximately 20-70% of patients taking an SSRI (Bishop et al. 2009, Clayton et al. 2002, Montejo et al. 2001) Reasons for this marked variation in results could be explained by two factors1. Patients, if not directly questioned, tend to underreport sexual adverse effects 2. Sexual dysfunction is often associated with mood and anxiety disorders, even when untreated.

 THE SEXUAL RESPONSE CYCLE is a four-part phenomenon consisting of 1. Drive (sexual desire or libido), 2. Arousal (including erectile function in men and lubrication in women), 3. Orgasm (including ejaculation in men) 4. Resolution.

DESIRE
Dopamine Testosterone Estrogen Negative-prolactin, serotonin Stimulation of 5HT2A receptors in mesolimbic and hypothalamic areas decreases dopamine release. (Elisabeth et al. 2013)

 SSRI induced increased seretonergic activity leads to reduced central dopaminergic activity (Apathetic recovery seen with SSRIs) SSRIs may raise serum prolactin.

AROUSAL
Nitric oxide & Acetylcholine-facilitates
Anticholinergic action- erectile dysfunction NO inhibitor- erectile dysfunction

Alpha stimulation-inhibits
Alpha agonist-erectile dysfunction Alpha antagonist-priapism

Beta stimulation-facilitates
Beta antagonist-erectile dysfunction

 SSRIs may indirectly cause erectile dysfunction via modulation of adrenergic and cholinergic action. Paroxetine inhibits NOS Paroxetine has relatively prominent anticholinergic activity compared to other SSRIs.

ORGASM/EJACULATION
Alpha1
Agonism-facilitates Antagonism- retarded/delayed ejaculation.

Serotonin
5HT2A and possibly 5HT2C and 5HT3
Agonism-retarded/delayed ejaculation Antagonism-facilitates Stimulation of 5HT2A, 5HT2C and 5HT3 receptors in spinal cord may inhibit the spinal reflexes of orgasm and ejaculation.

5HT1A
Agonism-facilitates Antagonism-retarded/delayed ejaculation

 Vilazodone with partial 5HT1A agonism is associated with lesser sexual dysfunction. Agomelatine with 5HT2C antagonism without increased serotonin is associated with lesser sexual dysfunction. Fluoxetine too has 5HT2C antagonism but it also increases serotonergic neurotransmission. Mirtazapine has 5HT2A, 5HT2C and 5HT3 antagonism, net 5HT1A agonism, alpha2 antagonism, net alpha1 agonism with robust action on dopaminergic neurotransmission as well. Lesser sexual dysfunction.

SSRI INDUCED SEXUAL DYSFUNCTIONS

I. Sexual desire disorder
1. 2. Loss or lack of desire Increased sexual desire

II.

Sexual arousal disorder

1. 2. 3. 4. Erectile dysfunction Decreased vaginal lubrication Priapism Persistent sexual arousal disorder

III.

Orgasmic disorder
1. 2. 3. 4. Retarded or inhibited ejaculation/Anorgasmia Hyperorgasmia Spontaneous orgasms (with yawning) Painful orgasm

TOTAL SEXUAL DYSFUNCTION

Sertraline > venlafaxine > citalopram > paroxetine > fluoxetine > duloxetine > escitalopram > fluvoxamine > mirtazapine > bupropion > nefazodone > agomelatine

DESIRE DYSFUNCTION
Citalopram > paroxetine > fluoxetine > sertraline > venlafaxine > mirtazapine > fluvoxamine > duloxetine > nefazodone > agomelatine > bupropion > escitalopram

AROUSAL DYSFUNCTION
Citalopram > venlafaxine > paroxetine > sertraline > fluoxetine > duloxetine > mirtazapine > fluvoxamine > bupropion > escitalopram > nefazodone

ORGASMIC DYSFUNCTION
Paroxetine > sertraline > citalopram > venlafaxine > fluoxetine > escitalopram > mirtazapine > bupropion > fluvoxamine > agomelatine > nefazodone

Assessment of sexual dysfunction in a patient taking a SSRI

1 2 3 4 Sexual function before mental health problems Severity of primary psychiatric disorder Severity of comorbid psychiatric disorder Presence of comorbid physical illness Long-standing erectile failure Current mild depressive episode Current alcohol dependence Hypertension

5
6 7 8

Co-prescribed psychotropic medication

Prescribed medication for physical illness Over-the-counter or illicit drug use Overall relationship with sexual partner

Antipsychotics
Atenolol Benzodiazepine misuse Frequent arguments and separations

Management
Strategies to reverse antidepressant-induced sexual dysfunction include 1. Waiting for tolerance to develop 2. Lowering the drug dosage 3. Drug holidays 4. Delaying the intake of the medication until after coitus 5. Changing to a different antidepressant 6. Adding a new medication or pharmacologic antidote In most cases sexual dysfunction is fully reversed 1 to 3 days after withdrawal of an antidepressant and returns rapidly after reintroduction. However, fluoxetine may be an exception, with recovery occurring only 1 to 3 weeks after treatment withdrawal.

WATCHFUL WAITING
Spontaneous remission of symptoms may occur with time. An important aspect of antidepressant-induced SD is the time at which it is considered, with some evidence that only 15% of patients with treatment-emergent SD seem to obtain a moderate to total improvement between the third and sixth months, a percentage that reaches the 30% after 6 months.(Montejo et al. 2001, Detke et al. 2004, Haberfellner et al. 2004)

DOSE REDUCTION
Sexual dysfunction tends to be dose-related, so lowering the medication dose may be helpful. Care needs to be taken, though, not to go below the therapeutic threshold. In patients receiving fluoxetine, it may take several weeks to evaluate whether sexual dysfunction will respond to dosage reduction.

DRUG HOLIDAYS (Rothschild et al. 1995)

Patients take daily SSRI dose in the morning, discontinue after the Thursday morning dose, and restart on Sunday. Effective in approximately 50% of the patients for approximately half of the weekend period. Effective with sertraline and paroxetine Not with fluoxetine due to longer half life.

 Risk of significant discontinuation symptoms. Especially after the discontinuation of paroxetine, because of 1. Short half-life 2. Autoinhibition of metabolism 3. Anticholinergic properties Partial drug holidays for fluvoxamine-induced anorgasmia. Fluvoxamine 300 mg/day is reduced to 100 mg/day on weekends Resolution of sexual dysfunction on the days when decreased dosage is received

DOSING AFTER COITUS

Delayed ejaculation with paroxetine may be resolved in some by taking the evening dose after intended sexual intercourse. (Rothschild et al. 1995 )

DRUG SUBSTITUTION
Substituting bupropion, mirtazapine, or nefazodone (Agomelatine, Vilazodone) for SSRI that is causing sexual dysfunction However is may not adequately control psychiatric symptoms in all patients who have received SSRIs, particularly those with OCD or concomitant anxiety disorders. Furthermore, switching antidepressants is not always effective in alleviating sexual side effects.

ADJUNCTIVE MEDICATIONS
1. 2. 3. 4. 5. 6. 7. 8. Mirtazapine Bupropion Buspirone Dopamine agonists PDE inhibitors Cyproheptadine Yohimbine Granisetron

Mirtazapine
Pronounced antagonistic activity at 5-HT2A/2C, 5-HT3, and alpha2 receptors. 15-30mg/day

Bupropion
Combination of SSRIs and bupropion is associated with a lower incidence of sexual dysfunction than with either in monotherapy. Paroxetine and fluoxetine are potent inhibitors of CYP2D6 and fluoxetine is also a mild inhibitor of CYP3A4. Both the CYP3A4 and the CYP2D6 are involved in metabolism of bupropion. Anxiety and neurotoxicity are possible hazards of this combination (especially with fluoxetine) Tremor, anxiety and panic attacks, myoclonic jerks and bradykinesia, delirium, and seizures.

Buspirone
5-20 mg three times a day "as needed" use of buspirone on days when sexual relations were planned is equally effective. Increased irritability is noted in some patients. 1. activation of postsynaptic 5-HT (1A) receptors results in a shorter ejaculation latency period 2. may suppress SSRI-induced elevations of prolactin 3. interacts with dopamine receptors Coadministration of buspirone with SSRIs such as fluoxetine and paroxetine, which are potent inhibitors of CYP2D6, has produced effects ranging from manic reactions to seizures. Adjunctive buspirone may augment the therapeutic efficacy of SSRI treatment. Pindolol, an agonist at 5-HT1A receptors

Dopamine agonists
Low-dose dextroamphetamine (5 mg) or methylphenidate (5-25 mg) 1 hour before intercourse SSRI-induced inhibited orgasm or ejaculation However there is a therapeutic window, in which low dosages might enhance and higher doses inhibit orgasmic ability. Also known to improve SSRI antidepressant efficacy Amantadine has similarly been found to ameliorate SSRI-related sexual dysfunction in male and female patients.

PDE inhibitors
NO pathway-enhancing drugs Effective in treatment of erectile dysfunction, irrespective of etiology. Sildenafil 50-100mg(Both male and female patients) Tadalafil 10-20mg (Males) Risk of life threatening hypotension in patients taking nitrates.

Cyproheptadine
5HT2A antagonist 4 to 16 mg/day SSRI induced anorgasmia However, reported to negate the therapeutic response to SSRIs. Patients frequently report sedation and fatigue

Yohimbine
Alpha2 antagonist 5.4 mg 1 to 2 hours before intercourse SSRI-induced anorgasmia Associated with sympathomimetic reactions such as sweating, tremor, nausea, and anxiety

Granisetron
5-HT3 antagonist 1-2 mg 1 hour before coitus (Nelson et al. 2001, Jespersen 2004)

M.J. Taylor et al. / Journal of Affective Disorders 88 (2005) 241254

 The evidence currently available is rather limited. For men with antidepressant-induced erectile dysfunction, the addition of sildenafil or tadalafil appears to be an effective strategy. For women with antidepressant-induced sexual dysfunction the addition of bupropion at higher doses appears to be the most promising approach studied so far.

18. Bishop , J.R.; Ellingrod, V.L.; Akroush, M.; Moline, J. The association of serotonin transporter genotypes and selective serotonin reuptake inhibitor (SSRI)associated sexual side effects: possible relationship to oral contraceptives. Hum. Psychopharmacol. 2009; 24, 207-215. 19. Clayton, A.H.; Pradko, J.F.; Croft, H.A.; Montano, C.B.; Leadbetter, R.A.; BoldenWatson, C.; Bass, K.I.; Donahue, R.M.; Jamerson, B.D.; Metz, A. Prevalence of sexual dysfunction among newer antidepressants. J. Clin. Psychiatry 2002; 63, 357366. 20. Montejo, A.L.; Llorca, G.; Izquierdo, J.A.; Rico-Villademoros, F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J. Clin. Psychiatry 2001; 62 (Suppl. 3), 1021. 9. Rosen, R.C.; Lane, R.M.; Menza, M. Effects of SSRIs on sexual function: a critical review. J. Clin. Psychopharmacol. 1999; 19, 67-85. 10. Stahl, S.M. The psychopharmacology of sex, part 2: effects of drugs and disease on the 3 phases of human sexual response. J. Clin. Psychiatry 2001; 62, 147-148.

Clayton A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord. 2006;91:27Y32. Gerald et al. Comparative Benefits and Harms of Second-Generation Antidepressants for Treating Major Depressive DisorderAn Updated Metaanalysis. Annals of Internal Medicine. 2011 Dec;155(11):772-785. Montejo AL, Llorca G, Izquierdo JA, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62(suppl 3):10Y21. Detke MJ, Wiltse CG, Mallinckrodt CH, et al. Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur Neuropsychopharmacol. 2004;14: 457Y470. Haberfellner EM, Rittmannsberger H. Spontaneous remission of SSRI-induced orgasm delay. Pharmacopsychiatry. 2004;37: 127Y130. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry 1995;152:1514-6.

 Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 1999; 19:67-85.

 9. Rosen, R.C.; Lane, R.M.; Menza, M. Effects of SSRIs on sexual function: a critical review. J. Clin. Psychopharmacol. 1999; 19, 67-85. 10. Stahl, S.M. The psychopharmacology of sex, part 2: effects of drugs and disease on the 3 phases of human sexual response. J. Clin. Psychiatry 2001; 62, 147-148.

Switching
DRUG
NEFAZODONE Author/year Ferguson JM,Et Al/2001 Gelenberg AJ,et al/2000 Walker PW et al/1993 Study RCT compared to sertaline
1 week wash-out period

Result Reemergence of sexual S/E 26% V/S 76%

Comment
Sexually more stisfied Similar and sustained improvement in Depressive symptoms

MIRTAZAPINE

Open-label compared to SSRI Open-label

2 week wash-out period

58% return to normal sexual functioning Another 11% significant improvement 94% had complete or partial resolution 81% Satisfied with sexual functioning 81% Libido S/E resolved in 85%

S/E :Initial sedation,

irritability, muscle soreness and stiffness, wt gain Well tolerated

BUPROPION

Gardner EA et al/1985

Case reports
(TCA,MAOI,MAPR OTILINE & TRAZODONE)

DRUG
MOCLEBOMIDE

Author/year Montejo AI,et al/1996

Study Open label compared to SSRI

Result 77.7% total (7/9) improvement

Comment

Ramsubbu R/1999

Open label compared to fluoxetine

2 week wash-out period

In all patient, S/E resolved completely S/E from 100%(baseline) to 55.3%

Well tolerated Antidpressant effect comparable

AMINEPTINE

Montejo AI,et al/1999

Open label,multicent ric

Antidpressant effect maintained