Table 5.
Potential drug interactions between antiseizure medications and antidepressants and synthesis of results of available clinical studies and case reports.
| Antidepressants |
Effects of Antiseizure Medications on the Antidepressant Drug
(Affected Drug) |
Effects of the Antidepressant Drug
(Perpetrator) on Antiseizure Medications |
|||
|---|---|---|---|---|---|
| Older Antidepressants | |||||
| Desipramine | Information from Drug Compendia | ||||
| CYP3A4 induction | CYP3A4 inhibition | ||||
| Carbamazepine Phenytoin Phenobarbital Eslicarbazepine acetate Oxcarbazepine Rufinamide Topiramate |
↓↓ ↓↓ ↓↓ ↓ ↓ ↓ ↓ |
Cannabidiol | ↑↑ | ||
| No DDIs studies with ASMs in humans or case reports have been described | |||||
| Imipramine | Information from Drug Compendia | ||||
| CYP1A2 and CYP3A4 induction or by CYP3A4 and CYP2C19 inhibition | No predicted effects | ||||
| Carbamazepine Phenytoin Phenobarbital Rufinamide Topiramate Cannabidiol Felbamate Stiripentol Oxcarbazepine |
↓↓ ↓↓ ↓↓ ↓ ↓ ↑↑ ↑↑ ↑↑ ↓↑ |
- | |||
| Clinical data confirm the induction of imipramine by barbiturates and carbamazepine. Case reports of inhibition of phenytoin metabolism by imipramine have been described | |||||
| Clomipramine | Information from Drug Compendia | ||||
| CYP3A4 induction and CYP2C19 or CYP1A2 induction/inhibition | No predicted effects | ||||
| Carbamazepine Phenytoin Phenobarbital Rufinamide Topiramate Eslicarbazepine acetate Oxcarbazepine Stiripentol Cannabidiol |
↓↓ ↓↓ ↓↓ ↓ ↓ ↓↑ ↓↑ ↑ ↑ |
- | |||
| Case reports indicate a strong inhibition of clomipramine metabolism by valproic acid (not reported) | |||||
| Amitriptyline | Information from Drug Compendia | ||||
| CYP3A4 induction, CYP2C19 induction/inhibition or P-gp induction (distribution in the SNC) | No predicted effects | ||||
| Carbamazepine Phenytoin Phenobarbital Rufinamide Oxcarbazepine Felbamate |
↓↓ ↓↓ ↓↓ ↓ ↓↑ ↑↑ |
- | |||
| Pharmacokinetic and retrospective studies have shown that amitriptyline metabolism is induced by carbamazepine and inhibited by valproic acid | |||||
| Nortriptyline | Information from Drug Compendia | ||||
| CYP1A2 and CYP3A4 induction or inhibition | No predicted effects | ||||
| Carbamazepine Valproic acid (from SmPC) |
↓ ↑ |
- | |||
| Clinical studies and a case report confirm that nortriptyline metabolism is induced by carbamazepine and inhibited by valproic acid | |||||
| Doxepin | Information from Drug Compendia | ||||
| CYP3A4 inhibition | No predicted effects | ||||
| Stiripentol | ↑↑ | - | |||
| Findings from a retrospective study have indicated that doxepin metabolism may be inhibited by valproic acid | |||||
| No DDIs studies with ASMs in humans or case reports have been described | |||||
| Tranylcypromine | Information from Drug Compendia | ||||
| No predicted effects | CYP2C19 inhibition | ||||
| - | Phenobarbital Cannabidiol |
↑↑ ↑↑ |
|||
| A clinical case report has shown a lack of DDI with carbamazepine | |||||
| Mianserin | Information from Drug Compendia | ||||
| Unknown mechanism | No predicted effects | ||||
| Carbamazepine Phenobarbital |
↓↓ ↓↓ |
- | |||
| No DDIs studies in humans or case reports have been described | |||||
| Newer Antidepressants | |||||
| Citalopram | Information from Drug Compendia | ||||
| CYP3A4 and CYP2C19 induction and/or inhibition | No predicted effects | ||||
| Carbamazepine Phenytoin Phenobarbital Cenobamate Stiripentol Cannabidiol |
↓↓ ↓↓ ↓↓ ↓↓ ↓↑ ↑ |
- | |||
| A clinical study has confirmed a moderate inducing effect of carbamazepine on citalopram metabolism | |||||
|
Escitalopram
(S-citalopram) |
Information from Drug Compendia | ||||
| CYP3A4 and CYP2C19 induction and/or CYP2C19 inhibition | No predicted effects | ||||
| Carbamazepine Phenytoin Phenobarbital Cenobamate Stiripentol Cannabidiol Felbamate |
↓↓ ↓↓ ↓↓ ↓↓ ↓↓↑↑ ↑↑ ↑↑ |
- | |||
| No clinical data available (see citalopram) | |||||
| Fluoxetine | Information from Drug Compendia | ||||
| CYP3A4 induction or CYP2C9 inhibition | CYP2C9 or CYP2C19 inhibition | ||||
| Carbamazepine Cannabidiol |
↓↓ ↑↑ |
Phenytoin Cannabidiol |
↑↑ ↑↑ |
||
| Several case reports and studies on humans have confirmed that phenytoin, carbamazepine and valproic acid metabolism is inhibited by fluoxetine (not predicted by compendia) | |||||
| Fluvoxamine | Information from Drug Compendia | ||||
| CYP1A2 inhibition | CYP3A4 or CYP2C9 inhibition | ||||
| Stiripentol | ↑↑ | Carbamazepine Phenytoin Cannabidiol Zonisamide |
↑↑ ↑↑ ↑↑ ↑↑ |
||
| Inhibition of carbamazepine and phenytoin levels by fluvoxamine has been observed in case reports (not predicted by compendia) | |||||
| Paroxetine | Information from Drug Compendia | ||||
| No predicted effects | No predicted effects | ||||
| In a study on healthy volunteers, it has been observed that phenobarbital, phenytoin and carbamazepine decreased by 25% paroxetine levels while in a double-blind, cross-over study in patients with epilepsy, phenytoin, carbamazepine or valproate plasma levels were not affected by paroxetine | |||||
| Sertraline | Information from Drug Compendia | ||||
| CYP2C19 inhibition | CYP3A4 inhibition | ||||
| Cannabidiol Cenobamate Stiripentol |
↑↑
↑↑ ↑↑ |
Carbamazepine Phenytoin Cannabidiol |
↑↑ ↑↑ ↑↑ |
||
| A case report showed that sertraline could be induced by carbamazepine. Two controlled studies did not confirm that sertraline affects the metabolism of carbamazepine or phenytoin, while in case reports, inhibition of phenytoin or valproic acid metabolism by sertraline has been observed | |||||
| Trazodone | Information from Drug Compendia | ||||
| CYP3A4 induction or induction/inhibition | CYP3A4 inhibition and unspecified mechanisms | ||||
| Carbamazepine Oxcarbazepine Eslicarbazepine Phenobarbital Rufinamide Topiramate Stiripentol |
↓↓ ↓↓ ↓↓ ↓↓ ↓↓ ↓↓ ↓↑ |
Carbamazepine Phenytoin |
↑↑ ↑ |
||
| Trazodone-induced increase in carbamazepine levels has been described in a case report. Lack of DDI between trazodone and gabapentin has been demonstrated in a formal DDI study | |||||
| Viloxazine | No potential DDIs are reported in drug compendia | ||||
| Studies in patients with epilepsy have documented that viloxazine significantly inhibits the metabolism of carbamazepine and phenytoin and slightly increases concentrations of the oxcarbazepine active metabolite | |||||
| Mirtazapine | Information from Drug Compendia | ||||
| CYP3A4 induction or CYP3A4 and CYP1A2 induction/inhibition | No predicted effects | ||||
| Carbamazepine Phenytoin Phenobarbital Cenobamate Cannabidiol Stiripentol |
↓↓ ↓↓ ↓↓ ↓↓ ↓↑ ↓↑ |
- | |||
| Pharmacokinetic studies confirm that mirtazapine metabolism can be induced by carbamazepine and phenytoin | |||||
| Bupropion | Information from Drug Compendia | ||||
| CYP2B6 induction or CYP2B6 induction/inhibition | No predicted effects | ||||
| Carbamazepine Cenobamate Stiripentol Cannabidiol |
↓↓ ↓↓ ↓↓↑↑ ↓↓↑↑ |
- | |||
| Induction of bupropion by carbamazepine and lack of effect of valproate have been confirmed in a formal pharmacokinetic study. Lack of pharmacokinetic interactions with lamotrigine has been demonstrated in an open-label study | |||||
| Venlafaxine | Information from Drug Compendia | ||||
| CYP3A4 induction/inhibition | No predicted effects | ||||
| Stiripentol | ↓↓↑↑ | - | |||
| Data from therapeutic drug monitoring databases have shown that levels of venlafaxine active metabolite desmethylvenlafaxine are increased by valproic acid while valproic acid levels were not affected | |||||
| Milnacipran | Information from Drug Compendia | ||||
| No DDIs with ASMs have been reported | No predicted effects | ||||
| In a formal pharmacokinetic study, milnacipran metabolism has been induced by carbamazepine | |||||
| Reboxetine | Information from Drug Compendia | ||||
| CYP3A4 induction | CYP3A4 inhibition | ||||
| Carbamazepine Phenytoin Phenobarbital |
↓↓ ↓↓ ↓↓ |
Carbamazepine | ↑↑ | ||
| Case reports have confirmed that reboxetine metabolism is induced by phenobarbital and carbamazepine | |||||
| Duloxetine | Information from Drug Compendia | ||||
| CYP1A2 induction | No predicted effects | ||||
| Carbamazepine Phenobarbital Stiripentol Cannabidiol |
↓↓ ↓↓ ↓↑ ↓↑ |
- | |||
| No DDIs studies with ASMs in humans or case reports have been described | |||||
| Agomelatine* | CYP1A2 and, to a lesser extent, CYP2C9 and CYP2C19 induction (from SmPC) |
No predicted effects | |||
| No DDIs studies with ASMs in humans or case reports have been described | |||||
| Vilazodone | Information from Drug Compendia | ||||
| CYP3A4 induction or CYP3A4 induction/inhibition | No predicted effects | ||||
| Carbamazepine Phenytoin Phenobarbital Oxcarbazepine Eslicarbazepine acetate Stiripentol |
↓↓ ↓↓ ↓↓ ↓↓ ↓↓ ↓↓↑↑ |
- | |||
| Findings from a formal pharmacokinetic study have confirmed that carbamazepine induces vilazodone metabolism | |||||
| Vortioxetine | Information from Drug Compendia | ||||
| CYP3A4 induction or CYP3A4 induction/inhibition | No predicted effects | ||||
| Carbamazepine Phenytoin Phenobarbital Oxcarbazepine Eslicarbazepine acetate Stiripentol |
↓↓ ↓↓ ↓↓ ↓ ↓ ↓↑ |
- | |||
| No DDIs studies with ASMs in humans or case reports have been described | |||||
Note: All searches were performed through consultation of Medscape Interaction checker [9] and RxList [10] and in the SmPC or FDA PI of each drug. A more detailed description of clinical studies and relative references is reported in the text. There are DDIs not predicted by compendia that are clinically documented and also predicted DDIs that are not confirmed by clinical studies. Induction/inhibition means that a drug may have opposite effects on the metabolism of the victim drug.
* Drug not present in drug compendia
(↓): mild, (↓↓): moderate; (↓↓↓): severe decrease of plasma concentrations. (↑): mild, (↑↑): moderate, (↑↑↑): severe increase of plasma concentration; (↓↑): opposite effects on drug concentrations may be expected.