In a male patient with persistent irritability who has tried citalopram, escitalopram, fluoxetine, sertraline, vilazodone, lamotrigine, low‑dose aripiprazole, low‑dose olanzapine, and desvenlafaxine without adequate response, what medication can be used to reduce irritability while minimizing sexual side effects?

Medication Options for Irritability in Males That Minimize Sexual Side Effects

For a male patient with persistent irritability who has failed multiple SSRIs, SNRIs, lamotrigine, and low-dose antipsychotics, bupropion (Wellbutrin) is the optimal next choice, as it is the only antidepressant that consistently demonstrates prosexual effects rather than sexual dysfunction, with 77% of patients reporting enhanced sexual function and only 14% experiencing any adverse sexual effects. 1

Evidence-Based Rationale for Bupropion

Bupropion stands apart from all other antidepressants in its sexual side-effect profile:

• Bupropion-treated patients reported significant increases in libido, arousal intensity, orgasm intensity, and orgasm duration beyond premorbid baseline levels 1
• 86% of bupropion patients had no adverse sexual effects, compared to only 27% of SSRI-treated patients 1
• The mechanism involves dopaminergic and noradrenergic activity rather than serotonergic inhibition, which is responsible for SSRI-induced sexual dysfunction 2

Why Previously Tried Medications Failed This Patient

SSRIs (citalopram, escitalopram, fluoxetine, sertraline) and vilazodone all cause high rates of sexual dysfunction:

• Overall SSRI sexual dysfunction rates range from 57.7% to 72.7%, with paroxetine highest at 70.7% and fluoxetine at 57.7% 3
• The prospective multicenter study of 1,022 patients found fluoxetine 57.7%, sertraline 62.9%, and citalopram 72.7% sexual dysfunction rates 3
• SSRIs significantly decrease libido, arousal, orgasm duration, and orgasm intensity below premorbid levels 1
• Sexual dysfunction with SSRIs appears to be the rule rather than the exception and may be substantially underreported unless specifically assessed 1

Desvenlafaxine (Pristiq) carries similar sexual dysfunction risk:

• Venlafaxine (the parent compound of desvenlafaxine) causes sexual dysfunction in 67.3% of patients, comparable to SSRIs 3
• SNRIs share the serotonergic mechanism that inhibits sexual function 2

Dosing Algorithm for Bupropion

Start bupropion SR 150 mg once daily in the morning for 3-4 days to assess tolerability, then increase to 150 mg twice daily (total 300 mg/day). 4

• If inadequate response after 4 weeks at 300 mg/day, increase to bupropion SR 200 mg twice daily (total 400 mg/day), which is the maximum recommended dose 4
• Bupropion XL formulation can be used as a once-daily alternative: start 150 mg daily, increase to 300 mg daily after 3-4 days, with maximum dose 450 mg daily 4

Alternative Medications With Lower Sexual Dysfunction Risk

If bupropion is contraindicated or ineffective, consider these alternatives in order:

Mirtazapine

• Mirtazapine causes sexual dysfunction in only 24.4% of patients, significantly lower than SSRIs 3
• Start 15 mg at bedtime, increase to 30 mg after 1 week if tolerated 5
• Caveat: Mirtazapine causes significant sedation and weight gain, which may limit tolerability 5

Nefazodone

• Nefazodone causes sexual dysfunction in only 8% of patients 3
• Start 100 mg twice daily, titrate to 300-600 mg/day in divided doses 4
• Critical warning: Nefazodone carries a black-box warning for hepatotoxicity and requires baseline and periodic liver function monitoring 4

Medications to Avoid

Do not retry any SSRI or SNRI, as this patient has already failed multiple agents in these classes and all carry 58-73% sexual dysfunction rates. 3

Avoid tricyclic antidepressants (TCAs), as they cause sexual dysfunction through multiple mechanisms including anticholinergic, antihistaminic, and alpha-adrenergic blockade. 2

Do not use MAO inhibitors, as they are among the most powerful serotonergic medications and cause high rates of sexual dysfunction comparable to SSRIs. 2

Monitoring and Follow-Up

Assess response at 4 weeks and 8 weeks using standardized measures for both irritability and sexual function:

• Specifically ask about libido, arousal, erectile function (if applicable), orgasm intensity, and orgasm duration at each visit 3
• Sexual dysfunction is substantially underreported unless patients are specifically questioned about various aspects of sexual function 1

If inadequate response after 8 weeks at maximum tolerated bupropion dose, consider adding cognitive-behavioral therapy or reassessing the underlying diagnosis (e.g., unrecognized bipolar disorder, which would require mood stabilizer rather than antidepressant). 5

Critical Pitfalls to Avoid

Never assume sexual side effects will resolve after discontinuation—persistent sexual dysfunction after SSRI discontinuation has been documented in multiple case reports, with symptoms including permanent erectile dysfunction, genital anesthesia, and ejaculatory anhedonia lasting years after stopping the medication. 6

Do not add sildenafil or other PDE5 inhibitors to treat SSRI-induced erectile dysfunction without first attempting a medication switch, as these agents only address erectile function and do not restore libido, arousal, or orgasm quality. 6

Avoid combining bupropion with stimulants, as there are no controlled studies demonstrating safety of this combination and the Physicians' Desk Reference does not provide guidance on this interaction. 7