4. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. The following drug-drug interactions summarized in Table 16 are considered clinically relevant for antidepressants. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level # |
|---|---|---|---|---|
| bupropion | systemic corticosteroids | concurrent administration may increase seizure risk as both agents lower seizure threshold | reduce initial doses and titrate doses upward slowly; monitor closely for seizure activity | Moderate (CP) |
| cyclic antidepressants, SNRIs, bupropion, levomilnacipran, milnacipran, nefazodone, trazodone, vilazodone, vortioxetine | monoamine oxidase inhibitors (MAOIs) | increased risk of serotonin syndrome (e.g., mental status changes, hyperpyrexia, restless, shivering, hypertonia, tremor) due to serotonin metabolism inhibition by monoamine oxidase | allow 14 days after MAOI discontinuation before initiating other antidepressant therapy; wait 5 weeks after discontinuing fluoxetine before initiating MAOIs | Contraindicated (CP) |
| MAOIs | select CNS stimulants (amphetamines, atomoxetine, methylphenidate, and derivatives) | increased risk of hypertensive crisis due to additive effects on catecholamine neurotransmitters | avoid concurrent use; allow two weeks between discontinuing MAOIs and initiating CNS stimulant | contraindicated (CP) |
| MAOIs | cyclobenzaprine | increased risk of hyperpyretic crisis, seizures, and death potentially due to additive adrenergic activity | avoid concurrent use; allow two weeks between discontinuing MAOIs and initiating cyclobenzaprine therapy | contraindicated (CP) |
| MAOIs | morphine | increased risk of hypotension and enhanced CNS/respiratory depression as MAOIs amplify morphine pharmacologic effects | avoid concurrent use; allow two weeks between discontinuing morphine and initiating MAOI therapy | contraindicated (CP) |
| MAOIs | sympathomimetics | increased risk of hypertensive crisis as MAOIs increase norepinephrine availability at neuronal storage sites as well as enhance adrenergic effects | avoid concurrent use; allow two weeks between discontinuing sympathomimetics and initiating MAOI therapy | contraindicated (CP) |
| nefazodone (NZD) | carbamazepine | reduced NZD serum levels/antidepressant effects and increased carbamazepine (CBZ) serum levels and potential for toxicity due to induced CYP3A4-mediated NZD metabolism and inhibited CYP3A4-mediated CBZ metabolism | avoid concurrent use | contraindicated (CP) |
| NZD | pimozide | enhanced pimozide pharmacologic effects and potential for cardiovascular toxicity due to NZD-mediated CYP3A4 inhibition | avoid concurrent use | contraindicated (CP) |
| SNRIs, vilazodone, vortioxetine | anticoagulants | co-administration may increase bleeding risk due to impaired platelet aggregation most likely resulting from platelet serotonin depletion | patients should be monitored for signs/symptoms of bleeding (including INR) if combined therapy necessary | moderate (CP) |
| SNRIs, vortioxetine, vilazodone | antiplatelet agents | adjunctive administration may increase bleeding risk due to impaired platelet aggregation most likely resulting from platelet serotonin depletion | patients should be monitored for signs/symptoms of bleeding if combined therapy necessary | moderate (CP) |
| SNRIs | drugs with serotonergic properties (e.g., antipsychotics, dextromethorphan, tramadol, triptans) or dopamine antagonist properties (e.g., phenothiazines, metoclopramide) | combined use may increase risk of serotonin syndrome or neuroleptic malignant syndrome (NMS) | cautiously administer concurrently and closely observe for signs/symptoms of serotonin syndrome or NMS, especially with treatment initiation or dosage increases | contraindicated (CP) |
| Vilazodone Vortioxetine |
drugs with serotonergic properties (e.g., antipsychotics, dextromethorphan, tramadol, triptans) or dopamine antagonist properties (e.g., phenothiazines, metoclopramide) | combined use may increase risk of serotonin syndrome or neuroleptic malignant syndrome (NMS). Platelet aggregation may be impaired due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication | cautiously administer concurrently and closely observe for signs/symptoms of serotonin syndrome or NMS, especially with treatment initiation or dosage increases | Moderate (CP) |
| SNRIs, vortioxetine | tramadol | increased risk of serotonin syndrome and seizures due to increased nervous system serotonin concentrations (additive effects on serotonin, SSRI inhibition of CYP2D6-mediated tramadol metabolism) as well as potential reduced seizure threshold with SNRIs, SSRIs | avoid concurrent use | Moderate (CP) |
| TCAs | pimozide | increased risk of pimozide toxicity including cardiotoxicity (QT prolongation) due to elevated plasma concentrations or additive effects on QT interval | avoid concurrent use | contraindicated (CP) |
| TCAs, duloxetine | select phenothiazines (thioridazine) | increased risk of somnolence, bradycardia and serious cardiotoxicity (QT prolongation, torsades de pointes) due to potential additive effects on QT interval prolongation; increased thioridazine serum concentrations/decreased thioridazine elimination and potential for serious cardiac arrhythmias due to CYP2D6 inhibition by duloxetine, fluoxetine, or paroxetine | avoid concurrent use; if adjunctive use necessary, monitor for increased pharmacologic/toxic effects; adjust dose as necessary | contraindicated (CP) |
| vilazodone | CYP3A4 inducers | combined administration may result in reduced vilazodone serum levels and decreased pharmacologic effects, as vilazodone is primarily metabolized by CYP3A4 | monitor for decreased pharmacologic effects and adjust doses as necessary | moderate (CP) |
| vilazodone | CYP3A4 inhibitors | adjunctive administration may result in increased vilazodone serum levels and enhanced pharmacologic/adverse effects, as vilazodone is primarily metabolized by CYP3A4 | monitor for increased pharmacologic/adverse effects; reduce vilazodone dose to 20 mg daily when prescribed concurrently with strong (e.g., ketoconazole) CYP3A4 inhibitors; reduce vilazodone dose to 20 mg daily when co-administered with moderate (e.g., erythromycin) CYP3A4 inhibitors and intolerable adverse effects are present | major (CP) |
| vortioxetine | strong CYP2D6 inducers | combined administration may result in reduced vortioxetine serum levels and decreased pharmacologic effects, as vortioxetine is primarily metabolized by CYP2D6 as well as QTC prolongation with concurrent use of Thioridazine | monitor for decreased pharmacologic effects; increase the vortioxetine dose (by no more than 3x the recommended dose) if strong CYP2D6 inducer administered concurrently for more than 14 days; reduce vortioxetine dose to original dose within 14 days of CYP2D6 inducer discontinuation | major (CP) |
| vortioxetine | strong CYP2D6 inhibitors | adjunctive administration may result in increased vortioxetine serum levels and enhanced pharmacologic/adverse effects, as vortioxetine is primarily metabolized by CYP2D6 | Reduce vortioxetine dose by 50% when administered concurrently with strong CYP2D6 inhibitor; reduce vortioxetine dose to original dose when CYP2D6 inhibitor discontinued | major (CP) |
| Amitripityline/Perphenazine | cisapride | increased risk of QT prolongation and increased risk for arrythmia | avoid concurrent use | Contraindicated (CP) |
Legend:
- #CP = Clinical Pharmacology
- CNS = central nervous system
- SNRIs = serotonin and norepinephrine reuptake inhibitors
- TCAs = tricyclic antidepressants