Antidepressant treatment in epilepsy

Antidepressant Treatment in Epilepsy

A review has given guidance regarding the use of antidepressants in epilepsy. This is summarised below. For full guidance then more information is available here

Selective Serotonin Reuptake Inhibitors (SSRIs) are the preferred antidepressants (1)

• have a lower risk of causing seizures compared to other antidepressant choices
• is no first line choice of SSRI
  • choice of SSRI should be decided on a case-by-case basis

Considerations for SSRI options, in no order preference (listed alphabetically here), include (1):

• citalopram
  • can increase the risk of hyponatraemia with carbamazepine and valproate
  • can increase the risk of sedation with levetiracetam, lamotrigine and phenytoin
  • can cause dose dependant prolongation of QT interval
    • are maximum dose restrictions in people over 65 years
    • refer to the MHRA Drug Safety Update for the maximum daily dose schedules for citalopram and escitalopram in people over 65 years and people with liver impairment
• escitalopram
  • can increase the risk of hyponatraemia with carbamazepine and valproate
  • can increase the risk of sedation with levetiracetam, lamotrigine and phenytoin
  • can cause dose dependant prolongation of QT interval
    • are maximum dose restrictions in people over 65 years
    • refer to the MHRA Drug Safety Update for the maximum daily dose schedules for citalopram and escitalopram in people over 65 years and people with liver impairment
• fluoxetine and fluvoxamine
  • fluoxetine and fluvoxamine interact with more anti-seizure medications (ASMs) compared to citalopram, escitalopram and sertraline
  • fluoxetine and fluvoxamine can increase ASM blood levels
    • is a particular concern with ASMs such as carbamazepine and phenytoin which have a narrow therapeutic index
  • fluoxetine and fluvoxamine can increase the risk of sedation with levetiracetam, lamotrigine and phenytoin
  • a review of the use of antidepressants and ASMs notes (2):
    • fluoxetine and fluvoxamine are generally not recommended mainly because of the risk of drug-drug interactions and the complex pharmacokinetics
      • both of them have an inhibitory effect on the CYP2C9 which may be associated with an increased risk of pharmacokinetic interactions with ASMs metabolized by this enzymatic pathway like phenytoin and partially valproate
• sertraline
  • is associated with a low risk of seizure induction
  • can increase phenytoin levels
    • phenytoin has a narrow therapeutic index and symptoms of toxicity include slurred speech, confusion and hyperglycaemia
  • can increase the risk of hyponatraemia with carbamazepine and valproate
  • can increase the risk of sedation with levetiracetam, lamotrigine and phenytoin

Scottish Intercollegiate Guidelines network (SIGN) suggest that SSRIs appear to be safe to use in people with epilepsy and depression.

Other antidepressants

Other 'low to moderate risk' antidepressants, in no order of preference for use in epilepsy, are as below (1):

• selective and noradrenaline reuptake inhibitors
  • duloxetine is preferred over venlafaxine due to lower seizure risk
• mirtazapine
  • some specialists recommend mirtazapine use in people with epilepsy
  • carbamazepine, phenobarbital and phenytoin can decrease mirtazapine levels
• reboxetine, vortioxetine
  • reboxetine and vortioxetine are not known to lower seizure threshold but there is little experience in people with epilepsy
• monoamine oxidase inhibitors (moclobemide preferred over phenelzine, isocarboxazid and trancylcypromine, which are seldom used in practice due to the risk of interactions with food and drink)
  • MAOIs should not be started without a mental health specialist advice

Antidepressants to avoid

The following class of antidepressants should be avoided

• tricyclic antidepressants (particularly amitriptyline and clomipramine)
  • should be avoided as they lower the seizure threshold and are deemed the most pro-convulsive
  • doxepin has a lower risk of causing seizures than other tricyclic antidepressants (TCAs) but the evidence is very limited
  • TCAs should not be started without mental health specialist advice

Considerations when starting or switching antidepressants

• consider individual needs and epilepsy or seizure control when starting an antidepressant
• advise the person that there is a risk of seizure with all antidepressants, but some have a lower risk than others
• always take a full medication history and ask about over the counter medicine and complementary medicine use

ASM induced depression

Check the Summary of Product Characteristics (SmPC) if the person’s ASM could induce depression or mood changes.

Depression is a known side-effect of ASMs such as:

• levetiracetam
• phenytoin
• phenobarbitone
• primidone
• topiramate
• vigabatrin

Note that:

• if the ASM is associated with mood changes, check with their neurologist if changing the ASM could resolve the depression
  • do not stop ASMs abruptly as this may worsen mood or trigger a seizure
• some ASMs have mood stabilising properties such as carbamazepine, lamotrigine, oxcarbazepine and valproate
• if the person has a seizure after changing or reducing the dose of their ASM, they may have to reapply for their driver’s licence
  • further information about epilepsy and driving is available from GOV.UK

Other considerations when making a choice

Drug interactions

• drug interactions between current ASMs and the chosen antidepressant prior to initiation should be checked
  • use drug interaction resources such as The BNF Interaction checker to do this.
  • this is mandatory because complex drug interactions can occur; for example:
    • concomitant antidepressant treatment can increase ASM blood levels, affecting drugs with a narrow therapeutic range (e.g. carbamazepine, phenytoin, valproate)
    • concomitant ASM medication can lower antidepressant blood levels, possibly leading to treatment failure

Avoid using multiple antidepressants

• seizure risk increases with multiple concurrent antidepressants

Initiating the antidepressant

• Initiate the chosen antidepressant at a low dose and increase gradually until a standard therapeutic dose is achieved
  • review regularly thereafter as per NICE guidance
• do not exceed the maximum licensed dose of antidepressant without advice from a mental health specialist and neurologist

Use the lowest therapeutic dose possible

• there is a dose dependent relationship between antidepressants and seizures. The British National Formulary (BNF) contains information on licensed dosing.

Monitoring epilepsy and ASMs:

Monitor seizure frequency

• baseline seizure frequency must be recorded
• seizure diary - shared management should include requesting the patient to keep a record of seizure frequency

If seizures occur or seizure incidence increases

• seek specialist (neurologist advice)
• other suggestions are (1)
  • consider checking sodium levels for hyponatraemia
    • antidepressants (often SSRIs) can cause hyponatraemia and seizures may occur where this is severe
  • consider switching the antidepressant

Monitoring blood levels of ASMs

• for ASMs with narrow therapeutic range (e.g. carbamazepine, phenytoin)
  • consider blood monitoring, particularly if there are concerns of potential toxicity (e.g. the risk of an interaction with a newly started antidepressant).
• seek neurologist advice if dosage adjustment of the ASM may be required

Reference:

1. NHS Specialist Pharmacy Service (March 26th 2026). Using antidepressants for depression in people with epilepsy
2. Tallarico M et al. Antidepressant Drugs for Seizures and Epilepsy: Where do we Stand? Curr Neuropharmacol. 2023;21(8):1691-1713.