Sexual Dysfunction With Antidepressants – Pathophysiology | Assessment | Management

MECHANISMS OF SEXUAL DYSFUNCTION WITH ANTIDEPRESSANTS

Serotonergic Effects: 

• 80% of serotonin is localised in the periphery. SSRIs and SNRIs increase serotonin levels. Serotonin directly reduces sensation in the reproductive system’s anatomical structures and diminishes erection, vaginal lubrication, ejaculation, and orgasm.
• 5HT2 and 5HT3 receptor activation: Cyproheptadine (5HT2A antagonist); Mirtazapine (5HT2A, 5HT2C and 5HT3 antagonist), and Granisetron (5HT3 antagonist) have benefits in SSRI induced SD.
• Serotonin inhibits nitric oxide production, which normally has a role in relaxing the smooth muscle of the vasculature (including the vasculature of the reproductive structures), thus enabling vasodilation and allowing sufficient blood supply to the sexual organs during the sexual response cycle.
• 5HT1A agonist activity increases Dopamine and noradrenaline, which are essential neurotransmitters in sexual desire. Therefore, the absence of significant 5HT1A activity with some SSRIs compared to others may account for the differential risk of SD with SSRIs. Buspirone, Vilazodone and Flibanserin (in women only) are 5HT1A agonists used in Antidepressant related SD.

Dopaminergic effects: 

• Reduced mesolimbic dopaminergic activity (reward pathway) as a result of inhibitory serotonergic midbrain raphe nuclei projections. [Pfaus, 2009]

Cholinergic and Adrenergic effects:  

• Ejaculation is mediated by α1-adrenergic receptors.
• Many antidepressants have some efficacy at cholinergic and α1-adrenergic receptors, thereby inhibiting the autonomic nervous system and consequently inhibiting normal sexual function.

Molecular Effects: 

• Long-term exposure may impact catecholaminergic and endocrine systems at the genetic level, affecting semen quality and DNA integrity. This effect may be due to confounding by indication (i.e. presence of depression). [Beeder & Samplaski, 2020]

SEXUAL SIDE-EFFECTS WITH ANTIDEPRESSANTS

Treatment-emergent sexual dysfunction (TESD) is commonly underestimated. The prevalence of sexual dysfunction with antidepressants is estimated to be 2-16%; however, this is likely to be underestimated due to these estimates being part of the self-report. [Montejo et al., 2019], [Higgins et al., 2010]

When patients are actively asked about sexual side effects, this prevalence increases significantly. [Higgins et al., 2010]

• SSRIs have a prevalence of 25-73% with side effects of decreased libido, delayed inability to reach orgasm.
• SNRIs have a prevalence of 58-70%.
• TCAs prevalence (Approx 30%) and MAOIs (approx 40%)

Women: [Lorenz et al., 2016] [Higgins et al., 2010]

• The most commonly reported adverse sexual effects in women taking antidepressants are problems with sexual desire (72%) and sexual arousal (83%).
• SSRIs: 42% of women report problems having an orgasm.
• SNRIs: associated with delayed or absent orgasm.

Men

• SSRIs: Delayed ejaculation and erectile dysfunction (ED). The erectile dysfunction risk with SSRIs is higher with paroxetine, citalopram and venlafaxine.
• SNRIs: Erectile dysfunction and abnormal ejaculation

Post-SSRI sexual dysfunction (PSSD) [Rothmore, 2020)] , [Giatti et al., 2018]

• PSSD includes decreased libido, feeling of a lack of connection between the brain and penis, genital anaesthesia, pleasureless or weak orgasm, erectile dysfunction, delayed ejaculation, loss of lubrication in women, and anorgasmia that persists despite cessation of SSRI or SNRI.
• The most characteristic triad consists of genital anaesthesia, loss of libido, and erectile dysfunction.
• The prevalence is unknown.
• PSSD is associated with suicide due to persistent distress. [Hogan et al., 2014]
• The postulated mechanisms include persistent downregulation of 5HT1A receptors, serotonergic axonal toxicity, inhibitory effect on dopamine and downregulation of HPA axis and lower testosterone levels. (A similar syndrome occurs with the antiandrogen 5-α-reductase inhibitor, Finasteride )
• Consider the possibility of PSSD in patients in whom sexual dysfunction was absent before starting antidepressants but develops during or soon after antidepressant treatment and persists after remission from depression and discontinuation of the drug.

ASSESSMENT OF SEXUAL DYSFUNCTION

Clinical assessment should take into account medical, psychological and substance-related factors.

The PAM-D approach provides an easy stepwise approach to the issue. [Prof Anita Clayton Interview]

• Plan – Plan in advance that you’re going to talk about sexual dysfunction with everybody
• Ask -If you ask the question it gives patients the opportunity to talk about it (Remember in the study that 70% of people wanted to talk about it)
• Monitor -Monitor sexual side effects at each visit after the medication has been initiated.
• Discuss – Discuss the pros and cons of different medications – this allows the patient to make the decision according to their needs

Clinical History 

1. Medical history

• Chronic medical conditions; example, hypertension, diabetes, brain or spinal cord injury, cancer (past or present), including a history of chemotherapy or radiation

2. History of Past sexual dysfunction

1. How is your sexual life been since you started medication.
2. Have you noticed any change that worries you.
3. Have you noticed any problems with your sexual desire, orgasm or arousal capacity.
4. It is not uncommon for men to experience issues with their sexual desire, orgasm or arousal after starting antidepressants. Have you experienced any of this? (Normalising statement)

3. Past surgical procedures

• Pelvic surgery, prostatectomy

4.  Current medications:

• Antihypertensive medication
• Propranolol
• Spironolactone
• Opioids
• Metformin
• Antihistamines
• Hormone treatments (5-Alpha reductase inhibitors for benign prostatic hypertrophy)
• Oral contraceptive pill

5. Substance Use History:

• Alcohol and drug use

6. Psychiatric History: 

• Depression
• Social phobia
• Anxiety
• Obsessive-compulsive disorder
• ADHD
• Distraction
• Performance anxiety
• Body image
• Sexual trauma/abuse
• Relationship issues / divorce
• Sexual skills

6. Menopause

7. Rating Scales : 

• ASEX (Arizona Sexual Experience Scale) is a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm
• Changes in Sexual Functioning Questionnaire
• Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ)
• Sex-Effect Scale

Important points in the assessment include:

• Establish temporality between the initiation of antidepressant and sexual dysfunction
• Gradual erectile dysfunction generally indicates vascular or neurological issues. Sudden loss of sexual desire or ability to get erections is likely to indicate medication-related issues.
• Impact of sexual dysfunction on the relationship and mood.
• A medical evaluation, substance use history, physical examination and investigations.
• Ask if there are any genital abnormalities; if yes, refer for physical examination.
• Investigations
• Rule out hypoactive sexual disorder. In females, approximately 8-14% of women have a hypoactive sexual desire disorder (HSDD) characterised by distress due to a decreased interest in sex.

PREVENTION OF ANTIDEPRESSANT-INDUCED SEXUAL DYSFUNCTION

1. Detailed Sexual History: 

• Sexual function
• Any erectile problems
• Questions around the phases of the sexual response cycle
• Frequency of sexual acts

2. Commence medication with a low incidence of sexual dysfunction

• Agomelatine, Bupropion or Mirtazapine. Bupropion has the most scientific evidence for low treatment-emergent sexual dysfunction and can also improve sexual function. [Montejo et al., 2019]

Following are antidepressants having no significant effect on sexual functioning :

• Agomelatine
• Desvenlafaxine
• Moclobemide
• Trazodone
• Vilazodone
• Vortioxetine

• The evidence for Duloxetine, Levomilnacipran and Mirtazapine is inconclusive in relation to their propensity to cause sexual dysfunction.   [Chokka & Hankey, 2018]
• If SSRIs are to be prescribed, consider fluvoxamine, which is considered to have the least incidence of sexual dysfunction under doses < 100mg per day.
• If a medication with a noradrenergic effect is required in addition to the serotonergic effect, consider desvenlafaxine in doses < 150mg per day and Vortioxetine 10-15mg per day.

MANAGEMENT OF ANTIDEPRESSANT-INDUCED SEXUAL DYSFUNCTION

1. Wait and watch:

Some patients experience partial or total improvement of their treatment-emergent sexual dysfunction in a few weeks to months.

Most (80%) do not present any improvement after six months. [Montejo et al., 2019]

2. Dose reduction:

Halving the dose of an antidepressant improved treatment-emergent sexual dysfunction in 75% of cases with total recovery. [Nurnberg & Levine, 1987]

Dose reduction, however, can be associated with relapse of depression, and hence close monitoring is essential.

3. Augmentation:

Antidepressant augmentation: 

• Adding bupropion, mirtazapine or mianserin.
• Augmentation with agomelatine

Augmentation with phosphodiesterase 5 inhibitors (PDE-5)

• Sildenafil, tadalafil and vardenafil. They do not improve low sexual desire or delayed ejaculation/orgasm. Sildenafil (25-100mg single dose no more than once a day, 1 hour before sexual intercourse); Tadalafil (10-20 mg /day. Longer effect up to 72 hrs)
• Known to potentiate antidepressant activities of antidepressants.

Aripiprazole augmentation

• Adding aripiprazole improves sexual desire and sexual satisfaction in refractory depression.

Dopamine agonists

• Dexamphetamine
• Ropinirole
• Amantadine

Serotonin antagonists

• Cyproheptadine (5HT2A antagonist)

5HT1A receptor stimulants

• Buspirone

Adrenergic agonists

Cholinergic agonists

4. Drug holidays:

• Withdrawing antidepressants 48-72 hours before the sexual activity. This strategy can, however, increase the risk of withdrawals.
• The alternative is to lower the dose to half in the 24 hours before sexual relations may help erectile or orgasmic dysfunction but not desire.

5. Switching strategies:

Fluvoxamine:

• Lower incidence of anorgasmia/ejaculation dysfunction

Bupropion: [Read about the mechanism of action]

• Low incidence of sexual dysfunction and can also improve sexual function.
• When switching from SSRI, gradual reduction to avoid discontinuation syndrome.
• A combination of SSRI plus bupropion can lessen TESD when a switch is not possible.

Agomelatine: [Read more on the mechanism of action]

• Risk of sexual dysfunction similar to placebo with evidence of improved sexual function in the longer study. [Kennedy et al., 2008]

Mirtazapine: [View video on the mechanism of action]

• Mirtazapine improved TESD in 70-90% of patients in a small study of 11 patients; however, weight gain and sedation can be side effects. [Koutouvidis et al., 1999]

• A significant improvement was observed in a six-month study across all five dimensions of the PRSexDQ questionnaire (low libido, orgasm retardation, anorgasmia, erectile dysfunction/vaginal lubrication, acceptance of dysfunction) from the first month of mirtazapine treatment continuing until the end of the study. [Montejo et al., 2002]

Moclobemide

• Low incidence of sexual dysfunction (<10%)
• 73.3% of patients who switched to moclobemide showed improvement in sexual function at doses of 450-600mg a day. [Schweitzer et al., 1989]

  Amongst MAOIs, Phenelzine may have a higher incidence of TESD with a 28.6% libido decrease and 42.8% ejaculatory dysfunction.

Reboxetine and Trazodone are also suitable switching options.

Switching to partial serotonergic antidepressant

Desvenlafaxine:

• Lower incidence of TESD at doses < 100 mg/day.

Vortioxetine: [Read about the mechanism of action]

SUMMARY OF RECOMMENDATIONS

Low Sexual Desire

Option 1

• Switch to Agomelatine
• Switch to non-serotonergic drug
• Add Bupropion

Option 2

• Switch to Desvenlafaxine (50 mg/day) or vortioxetine (< 15 mg/day)
• Dose reduction
• Adding Aripiprazole

Orgasm Reduction

Option 1

• Switch to Agomelatine
• Switch to non-serotonergic drug or fluvoxamine

Option 2

• Switch to Desvenlafaxine (50 mg/day) or Vortioxetine (< 15 mg/day)
• Dose reduction

Anorgasmia

Option 1

• Switch to Agomelatine
• Switch to non-serotonergic drug or fluvoxamine

Option 2 :

• Switch to Desvenlafaxine (50 mg/day) or vortioxetine (< 15 mg/day)
• Dose reduction or weekend holiday protocol

Erectile dysfunction

• Switching to Agomelatine
• Switching to a non-serotonergic drug

Option 2 :

• Switch to Desvenlafaxine (50 mg/day) or Vortioxetine (< 15 mg/day)
• Add PD-5 inhibitors

Scarce vaginal lubrication:

• Switching to Agomelatine
• Switching to a non-serotonergic drug

Option 2:

• Switch to Desvenlafaxine (50 mg/day) or Vortioxetine (< 15 mg/day)
• Dose reduction
• Using vaginal lubricants

NON-PHARMACOLOGICAL TREATMENTS

SUMMARY

Antidepressant induced sexual dysfunction is often underestimated. SSRIs and SNRIs are associated with SD and can affect all phases of the sexual response cycle due to their effect on serotonin receptors, dopamine, cholinergic and noradrenergic systems.

Clinicians should proactively ask about sexual dysfunction in patients started on ADs and include this side effect as part of shared decision making when choosing ADs.

Agomelatine, Bupropion and Mirtazapine have a lower incidence of SD.

Below is a summary algorithm in managing sexual dysfunction.

Learn more: 

View the following brief interviews with Prof Anita Clayton.

1. Mechanisms of Sexual Dysfunction with Antidepressants – Conversations with Prof Anita Clayton
2. Sexual Dysfunction with Antidepressants – Conversations with Prof Anita Clayton
3. Key Points in the Assessment of Sexual Dysfunction – Conversations with Prof Clayton
4. Assessment and Management the Issue of Sexual Dysfunction with Antidepressants in Clinical Practice – Conversations with Prof Clayton