Choosing an antidepressant for people with epilepsy

Mood changes in epilepsy

The MHRA advises all antiseizure medicines (ASM) may be associated with an increase in suicidal thoughts and behaviour. Symptoms such as mood changes and distressing thoughts may be seen within 1 week of starting the ASM.

People with epilepsy have a high prevalence of mood disorders, including depression. The risk of suicide is 3 times greater than the general population.

Antidepressants and seizure risk

• Antidepressants are contra-indicated in unstable or poorly controlled epilepsy.
• Antidepressants are cautioned when used in people with epilepsy or a history of seizures.
• Some antidepressants may lower the seizure threshold and trigger a seizure.

Preferred antidepressants

Selective Serotonin Reuptake Inhibitors (SSRIs) are the preferred antidepressants. They have a lower risk of causing seizures.

Our recommendations assume all ASMs and antidepressants are used within their licensed indications and doses.

SSRIs

Both SIGN (opens in a new tab)  and NICE (opens in a new tab) suggest that SSRIs appear to be safe to use in people with chronic health problems such as epilepsy.

There is no first line choice of SSRI. The choice of SSRI should be decided on a case-by-case basis. See below for our considerations when starting or switching an antidepressant.

Safety concerns

SSRIs increase the risk of gastrointestinal (GI) bleeding(opens in a new tab), particularly in older people and in those who take aspirin, clopidogrel, direct oral anticoagulants (DOAC) or warfarin.

Consider if gastroprotection with a proton pump inhibitor (PPI) is needed in these scenarios.

Citalopram and escitalopram

Citalopram and escitalopram have few interactions with ASMs.

Potential interactions

Citalopram or escitalopram can increase the risk of hyponatraemia with carbamazepine and valproate.

Citalopram or escitalopram can increase the risk of sedation with levetiracetam, lamotrigine and phenytoin.

QT interval prolongation

Citalopram and escitalopram can cause dose dependant prolongation of QT interval. There 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.

See Identifying risk factors for developing a long QT interval (SPS page) for resources to identify medicines that prolong QT interval. Most ASMs do not affect QT interval.

Sertraline

Sertraline is associated with a low risk of seizure induction.

Potential interactions

Sertraline can increase phenytoin levels. Phenytoin has a narrow therapeutic index and symptoms of toxicity include slurred speech, confusion and hyperglycaemia.

Sertraline can increase the risk of hyponatraemia with carbamazepine and valproate.

Sertraline can increase the risk of sedation with levetiracetam, lamotrigine and phenytoin.

Fluoxetine and fluvoxamine

Fluoxetine and fluvoxamine interact with more ASMs compared to citalopram, escitalopram and sertraline.

Potential interactions

Fluoxetine and fluvoxamine can increase ASM blood levels. This 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.

Less preferred antidepressants

You should explore first whether a preferred antidepressant can be used; however, there may be a good reason why they cannot. 

There is either less data to demonstrate safe use of these antidepressants in people with epilepsy or they have demonstrated effects on the seizure threshold. 

Mirtazapine

Some specialists recommend mirtazapine use in people with epilepsy.

Potential interactions

Carbamazepine, phenobarbital and phenytoin can decrease mirtazapine levels.

Reboxetine and vortioxetine

Reboxetine and vortioxetine are not known to lower seizure threshold but there is little experience in people with epilepsy.

Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)

Duloxetine is preferred over venlafaxine due to lower seizure risk.

Monoamine Oxidase Inhibitors (MAOIs)

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.

Tricyclics antidepressants

Amitriptyline and clomipramine, should be avoided as they lower the seizure threshold and are considered to be 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

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.

Antidepressant considerations

If an antidepressant is required, check the person’s previous use of antidepressants and indications for use.

Understand the person’s baseline seizure risk and severity of their symptoms to ascertain the likely impact of introducing an antidepressant.

Check for drug interactions between the antidepressant and ASM, and any other medicines being taken. You may find our article on Drug interactions: resources to support answering questions (SPS page) useful.

Phenytoin, carbamazepine, phenobarbital and primidone can lower antidepressant blood levels and risk treatment failure.

Starting an antidepressant

Decide on an appropriate antidepressant using our advice and considerations.

Start the chosen antidepressant at the lowest licensed dose for the indication.

Review the initial symptoms of depression or mood at 4 weeks.

Adjust the antidepressant dose according and gradually.

Do not exceed the maximum licensed dose of antidepressant without advice from a mental health specialist and neurologist.

Switching between antidepressants

Switching people with epilepsy from their current antidepressant to another antidepressant may sometimes be necessary. Our advice switching between antidepressants (SPS page) includes establishing if a switch is needed, general considerations, how to plan the switch and what to monitor after switching.

Monitoring

Managing people with epilepsy who are initiated or maintained on an antidepressant requires careful monitoring.

Seizure frequency

Have clear documentation of the person’s seizure frequency before starting the antidepressant.

Ask the person to start or maintain their seizure diary.

If a seizure occurs or the person experiences a higher frequency of seizures after starting an antidepressant, consider withdrawing the antidepressant. See Addressing inappropriate use of antidepressants for depression and anxiety (SPS page) for useful resources.

Low sodium and seizures

Antidepressants, such as SSRIs, can cause hyponatraemia and seizures may occur where this is severe.

Consider checking sodium levels for hyponatraemia.

Consider switching the antidepressant using our advice on switching between antidepressants (SPS page).

ASMs with narrow therapeutic window

ASMs such as carbamazepine, phenytoin and valproate have a narrow therapeutic window.

Follow advice in the Medicines Monitoring (SPS page) when starting or changing antidepressants with these ASMs.

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