SSRI INDUCED SEXUAL

DYSFUNCTIONPRESENTER:-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 factors-

1. 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 disorder1. Loss or lack of desire2. Increased sexual desire

II. Sexual arousal disorder1. Erectile dysfunction 2. Decreased vaginal lubrication3. Priapism4. Persistent sexual arousal disorder

III. Orgasmic disorder1. Retarded or inhibited ejaculation/Anorgasmia2. Hyperorgasmia 3. Spontaneous orgasms (with yawning)4. 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 Sexual function before mental health problems Long-standing erectile failure

2 Severity of primary psychiatric disorder Current mild depressive episode

3 Severity of comorbid psychiatric disorder Current alcohol dependence

4 Presence of comorbid physical illness Hypertension

5 Co-prescribed psychotropic medication Antipsychotics

6 Prescribed medication for physical illness Atenolol

7 Over-the-counter or illicit drug use Benzodiazepine misuse

8 Overall relationship with sexual partner Frequent arguments and separations

Management • Strategies to reverse antidepressant-induced sexual dysfunction include 1. Waiting for tolerance to develop2. Lowering the drug dosage3. Drug holidays4. Delaying the intake of the medication until after coitus5. Changing to a different antidepressant6. 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-life2. 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. Mirtazapine 2. Bupropion3. Buspirone4. Dopamine agonists5. PDE inhibitors6. Cyproheptadine7. Yohimbine8. 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 period2. 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) 241–254

• 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.; Bolden-Watson, C.; Bass, K.I.; Donahue, R.M.; Jamerson, B.D.; Metz, A. Prevalence of sexual dysfunction among newer antidepressants. J. Clin. Psychiatry 2002; 63, 357-366.

• 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), 10-21.

• 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 Meta-analysis. 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 Author/year Study Result Comment

NEFAZODONE Ferguson JM,Et Al/2001

RCT compared to sertaline1 week wash-out period

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

• Sexually more stisfied• Similar and sustained improvement in Depressive symptoms

MIRTAZAPINE Gelenberg AJ,et al/2000

Open-label compared to SSRI

58% return to normal sexual functioningAnother 11% significant improvement

S/E :Initial sedation, irritability, muscle soreness and stiffness, wt gain

BUPROPION Walker PW et al/1993

Gardner EA et al/1985

Open-label2 week wash-out period

Case reports (TCA,MAOI,MAPROTILINE & TRAZODONE)

94% had complete or partial resolution81% Satisfied with sexual functioning81% ↑Libido

S/E resolved in 85%

•Well tolerated

DRUG Author/year Study Result Comment

MOCLEBOMIDE Montejo AI,et al/1996

Ramsubbu R/1999

Open label compared to SSRI

Open label compared to fluoxetine2 week wash-out period

77.7% total (7/9) improvement

In all patient, S/E resolved completely

• Well tolerated• Antidpressant effect comparable

AMINEPTINE Montejo AI,et al/1999

Open label,multicentric

S/E↓ from 100%(baseline) to 55.3%

• Antidpressant effect maintained