What are the next steps for a patient with depression or anxiety, already taking bupropion (300mg extended release) and mirtazapine (15mg), who is experiencing ongoing insomnia and sexual dysfunction despite current medication?

Management of Persistent Insomnia and Sexual Dysfunction Despite Bupropion-Mirtazapine Combination

For a patient experiencing ongoing insomnia and sexual dysfunction despite taking bupropion 300mg ER and mirtazapine 15mg, the most evidence-based next step is to increase the mirtazapine dose to 30-45mg, as higher doses enhance noradrenergic effects that improve sexual function while maintaining sedating properties for insomnia. 1, 2

Understanding the Current Regimen's Limitations

Your patient is already on an optimal combination theoretically—bupropion has the lowest sexual dysfunction rates among antidepressants, and mirtazapine at 15mg should provide sedation for insomnia 3, 1. However, mirtazapine's dose-dependent pharmacology is critical here: at 15mg, antihistaminic (H1) effects predominate causing sedation, but sexual benefits emerge more robustly at 30-45mg when noradrenergic enhancement increases 1, 2.

Primary Recommendation: Optimize Mirtazapine Dosing

Increase mirtazapine to 30-45mg at bedtime as the first intervention:

• Sexual dysfunction improvement: Studies demonstrate that mirtazapine improves sexual function in depressed patients, with women showing 41% improvement in desire, 52% in arousal/lubrication, and 48% in orgasm satisfaction; men showed 10% improvement in desire, 23% in arousal/erection, and 14% in orgasm satisfaction 2
• Insomnia management: Mirtazapine maintains sedating properties at higher doses through 5-HT2 and 5-HT3 receptor antagonism, though paradoxically somnolence may decrease slightly at higher doses due to increased noradrenergic activity 1
• Mechanism: The 5-HT2 and 5-HT3 receptor blockade prevents serotonin-related sexual dysfunction while alpha-2 antagonism enhances noradrenergic transmission beneficial for sexual function 1, 2

Critical Caveat About Mirtazapine Dosing

The 15mg dose may be subtherapeutic for addressing sexual dysfunction—the antihistaminic effects dominate at this dose, providing sedation but insufficient noradrenergic enhancement for sexual function 1. This explains why your patient still experiences sexual dysfunction despite being on a medication known to have low sexual side effects.

Secondary Strategy: Add Targeted Pharmacotherapy for Persistent Symptoms

If optimizing mirtazapine to 30-45mg fails to resolve symptoms after 4-6 weeks:

For Persistent Sexual Dysfunction (Particularly Erectile Dysfunction in Men)

Add a phosphodiesterase-5 (PDE5) inhibitor:

• Sildenafil: Improves ability to achieve erections (MD 1.04,95% CI 0.65 to 1.44) and maintain erections (MD 1.18,95% CI 0.78 to 1.59)—a one-point improvement equals frequency change from "sometimes" to "most times" 4
• Tadalafil: Significantly improves erectile function (RR 11.50,95% CI 3.03 to 43.67) 4
• Critical contraindication: Never combine with nitrates due to life-threatening cardiovascular interactions 3

For Persistent Insomnia

Follow the American Academy of Sleep Medicine's sequential approach 5:

1. First-line: Short-intermediate acting benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon) or ramelteon 5
2. Important principle: Pharmacotherapy should be supplemented with cognitive behavioral therapy for insomnia (CBT-I) when possible, as this facilitates eventual medication tapering 5
3. Avoid: Over-the-counter antihistamines are not recommended for chronic insomnia due to lack of efficacy and safety data 5

Alternative Consideration: Switching Antidepressants

If the above strategies fail and depression remains adequately controlled:

Consider switching from the current regimen to an SSRI/SNRI with lower sexual dysfunction rates:

• Sertraline or fluoxetine have lower sexual dysfunction rates than paroxetine, though still higher than bupropion 5
• Critical evidence gap: The STAR*D trial showed that switching antidepressants (bupropion, sertraline, venlafaxine) resulted in only 25% achieving symptom-free status, with no difference among agents 5
• Major caveat: This approach risks destabilizing mood control and should only be attempted if depression is in solid remission

What NOT to Do

Do not add buspirone despite its mention in some guidelines—evidence is extremely limited with only "a few trials involving non-cancer populations" and insufficient safety/efficacy data 3

Do not use drug holidays—no randomized trial evidence supports this approach 4

Do not switch to nefazodone—while one trial showed benefit (RR 0.34,95% CI 0.19 to 0.60), this medication is no longer clinically available 4

Monitoring and Follow-Up

• Reassess within 2-4 weeks after mirtazapine dose increase for both sexual function and sleep quality 5
• Screen for mood destabilization as dose changes can affect depressive symptoms 3
• Monitor for increased sedation initially with higher mirtazapine doses, though this often improves with continued use 1
• Assess seizure risk factors if considering bupropion dose escalation above 300mg (history of seizures, eating disorders, alcohol use) 3, 6

Evidence Quality Considerations

The recommendation to optimize mirtazapine dosing is based on understanding its pharmacodynamic profile 1 and pilot study data showing sexual function improvement 2, though these are not the highest-quality randomized controlled trials. However, the PDE5 inhibitor data for erectile dysfunction represents robust evidence from multiple controlled trials 4, making this the strongest augmentation strategy if mirtazapine optimization alone is insufficient.

The insomnia management recommendations come from consensus-based American Academy of Sleep Medicine guidelines 5, as head-to-head trials showed similar efficacy among various antidepressants for depression with insomnia 5.