What are the potential interactions between metformin, duloxetine, mirtazapine, lemborexant, aripiprazole (Abilify), trazodone, zopiclone, clonazepam, and bupropion?

Drug Interactions in This Polypharmacy Regimen

This medication combination carries significant risk for multiple clinically important interactions, particularly CNS depression from combining sedating agents (mirtazapine, trazodone, zopiclone, clonazepam, lemborexant), serotonin syndrome from combining serotonergic drugs (duloxetine, mirtazapine, trazodone), and seizure risk from bupropion interactions with other CNS agents.

Critical High-Risk Interactions

CNS Depression and Fall Risk

• Combining three or more CNS-active agents substantially increases fall risk, which is explicitly cautioned against in geriatric guidelines 1
• This regimen contains seven CNS depressants (duloxetine, mirtazapine, lemborexant, trazodone, zopiclone, clonazepam, and potentially bupropion)
• The combination of benzodiazepines (clonazepam) with multiple other sedating agents creates compounded risk for oversedation, respiratory depression, delirium, and falls 1
• Benzodiazepines combined with high-dose antipsychotics (Abilify) have resulted in fatalities from oversedation and respiratory depression 1

Serotonin Syndrome Risk

• Duloxetine (SNRI), mirtazapine (NaSSA), and trazodone (serotonergic antidepressant) create a triple serotonergic combination that substantially elevates serotonin syndrome risk 1, 2
• Serotonin syndrome presents with agitation, confusion, tremor, hyperthermia, hyperreflexia, and can be life-threatening 1
• While mirtazapine has a different mechanism than SSRIs/SNRIs, it still enhances serotonergic neurotransmission through 5-HT1 receptors 3
• The combination of any SNRI (duloxetine) with other serotonergic agents requires careful monitoring 1, 2

Seizure Risk

• Bupropion lowers seizure threshold, and this risk is amplified when combined with multiple CNS-active medications 4
• Combining bupropion with benzodiazepines (clonazepam) and other sedatives creates unpredictable CNS effects 2

Pharmacokinetic Interactions

CYP2D6 Metabolism

• Bupropion is a moderate CYP2D6 inhibitor and can increase levels of drugs metabolized by this pathway 4
• Duloxetine is metabolized by CYP2D6 and CYP1A2, and may interact with other drugs using these pathways 1, 4
• Aripiprazole (Abilify) is metabolized by CYP2D6 and CYP3A4; dose reduction is required in poor CYP2D6 metabolizers or when combined with strong CYP2D6 inhibitors like bupropion 1
• Combining bupropion with aripiprazole may increase aripiprazole levels, potentially causing extrapyramidal symptoms, akathisia, or other adverse effects 1

Minimal Interaction Potential

• Mirtazapine is unlikely to inhibit metabolism of coadministered drugs metabolized by CYP1A2, CYP2D6, or CYP3A4 at therapeutic doses 3, 4
• Metformin has minimal pharmacokinetic interactions with this regimen, as it is not significantly metabolized by CYP enzymes and is primarily renally eliminated 5
• Metformin interactions are primarily pharmacodynamic (glucose-lowering effects) rather than pharmacokinetic 5

Specific Drug Pair Concerns

Duloxetine + Mirtazapine + Trazodone

• This triple antidepressant combination creates redundant serotonergic activity 2, 4
• Mirtazapine and trazodone both cause significant sedation, which is additive 3, 4
• Duloxetine may cause hypertension and increased pulse, while mirtazapine and trazodone cause orthostatic hypotension—creating unpredictable cardiovascular effects 1

Multiple Hypnotics (Lemborexant + Zopiclone + Clonazepam + Trazodone + Mirtazapine)

• Using five sedating agents simultaneously is excessive and dangerous 1
• Lemborexant (orexin antagonist), zopiclone (Z-drug), and clonazepam (benzodiazepine) all target sleep through different mechanisms but create additive CNS depression 1
• Trazodone and mirtazapine are frequently used off-label for sleep, adding further sedation 3, 4

Bupropion + CNS Depressants

• Bupropion is activating and may counteract sedation, but this creates unpredictable net CNS effects 4
• Combining bupropion with benzodiazepines has been associated with adverse CNS reactions 2

Cardiovascular Considerations

• Aripiprazole may cause QTc prolongation, though less than first-generation antipsychotics 1
• Duloxetine can increase blood pressure and heart rate 1
• Mirtazapine and trazodone cause orthostatic hypotension 3, 4
• Clonazepam and zopiclone may cause dizziness and hypotension 1

Discontinuation Syndrome Risk

• Both duloxetine and mirtazapine require slow tapering to avoid discontinuation syndrome if stopped 1
• Abrupt discontinuation of duloxetine causes adrenergic hyperactivity, dizziness, and flu-like symptoms 1
• Benzodiazepines (clonazepam) require very gradual tapering to avoid potentially dangerous withdrawal 1

Monitoring Recommendations

• Monitor closely for excessive sedation, falls, confusion, and respiratory depression given the multiple CNS depressants 1
• Watch for serotonin syndrome signs: agitation, tremor, hyperreflexia, hyperthermia, confusion 1, 2
• Monitor blood pressure (duloxetine may increase; mirtazapine/trazodone may decrease) 1, 3
• Assess for extrapyramidal symptoms from aripiprazole, potentially worsened by bupropion interaction 1
• Monitor for seizures given bupropion use with multiple CNS agents 4

Common Pitfalls

• Underestimating cumulative CNS depression from multiple agents, each seemingly "safe" individually 1
• Failing to recognize that mirtazapine, while not an SSRI/SNRI, still contributes to serotonin syndrome risk 3, 2
• Not adjusting aripiprazole dose when adding bupropion (a CYP2D6 inhibitor) 1, 4
• Assuming metformin interacts significantly—it does not with this regimen 5