Choosing whether to prescribe at all
Antidepressants are not contra-indicated in stable epilepsy; however, the BNF advises caution when using antidepressants in people with epilepsy or a history of seizures, with very few exceptions.
The relatively low risk of antidepressants affecting seizure threshold rarely outweigh the risk of leaving depression untreated. Antidepressants can be used in people with epilepsy, although NICE suggest specialist advice (e.g. neurologist) should be sought for those taking Anti-epileptic drugs (AEDs).
Refer to NICE Clinical Knowledge Summary for management of depression in general. This page assumes the decision to prescribe antidepressants has already been made.
Choosing between antidepressants
There is no clear consensus across clinical guidelines on the best choice of antidepressant in people with epilepsy.
A Cochrane review has concluded that there is no high quality evidence to guide on the best choice of antidepressant in people with epilepsy. The Scottish Intercollegiate Guidelines network (SIGN) reached a similar conclusion although they suggest that in general antidepressants are safe in people with epilepsy.
Low to moderate risk antidepressants in epilepsy
These antidepressants are considered suitable options in epilepsy by a range of mental health resources including Bazire’s Psychotropic Drug Directory, Maudsley Prescribing Guidelines in Psychiatry and published papers.
Selective Serotonin Inhibitors (SSRIs)
Preferred options, in no order preference, are:
Scottish Intercollegiate Guidelines network (SIGN) suggest that SSRIs appear to be safe to use in people with epilepsy and depression. The NICE CKS guidance on depression recommends SSRIs, such as sertraline or citalopram, as being suitable for people with chronic health problems.
Other ‘low to moderate risk’ antidepressants, in no order of preference for use in epilepsy, are as below:
- Selective and Noradrenaline Reuptake Inhibitors (duloxetine is preferred over venlafaxine)
- Doxepin (preferred option of the tricyclic antidepressant group)
- 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)
High risk antidepressants to avoid in epilepsy
Tricyclic antidepressants (particularly amitriptyline and clomipramine) should be avoided as they lower the seizure threshold and are deemed the most pro-convulsive.
Other considerations when making a choice
- Check for potential drug interactions between current AEDs and the chosen antidepressant prior to initiation. Use drug interaction resources such as The BNF Interaction checker to do this.
- Complex drug interactions are possible; for example:
- Some antidepressants can increase AED blood levels, affecting drugs with a narrow therapeutic range (e.g. carbamazepine, phenytoin, valproate).
- Some enzyme inducing AEDs can lower antidepressant blood levels, possibly leading to treatment failure.
Avoid using multiple antidepressants
- The risk of seizure increases with multiple concurrent antidepressants.
Consider the need for neurologist input
- Where the patient’s AED has adverse psychiatric side-effects associated with depression (e.g. levetiracetam, phenytoin, phenobarbitone, primidone, topiramate, and vigabatrin).
- Where the patient might benefit from an AED with mood stabilising properties (e.g. carbamazepine, gabapentin, lamotrigine, oxcarbazepine, valproate).
Initiating the antidepressant
Use a low dose first
- Initiate the chosen antidepressant at a low dose and increase gradually until a standard therapeutic dose is achieved. Review regularly thereafter as recommended by NICE CKS guidance on depression.
- The recommendations on choices above assume use of antidepressants at standard doses.
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 AEDs
Monitoring seizure frequency
- Document the baseline
- Ask the patient to keep a seizure diary
If seizures occur or seizure incidence increases
- Consider checking sodium levels for hyponatraemia. Antidepressants (often SSRIs) can cause hyponatraemia and seizures may occur where this is severe. Our advice on Treating depression following anti-depressant induced hyponatraemia may help with subsequent choices.
- Consider the need for neurologist input.
- Consider switching the antidepressant.
Monitoring blood levels of AEDs
- For AEDs 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).
- If dosage adjustment of the AED may be required, seek advice from the neurologist.
Switching between antidepressants
Where people with stable epilepsy do not respond to their initial antidepressant, a switch in antidepressant may be necessary. Guidance on switching antidepressants specifically in epilepsy does not exist, but it may be helpful to:
Refer to NICE CKS Guidance
Refer to our drug switching content
Consult mental health specialists
- Complex scenarios of treatment failure may require specialist input.
The advice above has been generated using a range of literature. We’ve provided a brief summary to support our review below together with a full bibliography:
- Studies looking specifically at using antidepressants in people with epilepsy are limited. They are usually small, of low quality, and of retrospective design with varying definitions and degrees of depression, making comparison difficult.
- As such, some clinical data exist for these antidepressants in epilepsy: citalopram, fluoxetine, mirtazapine, sertraline.
- Of note, there are lack of clinical data in epilepsy for agomelatine, escitalopram, fluvoxamine, doxepin, duloxetine, paroxetine, MAOIs, venlafaxine, reboxetine, vortioxetine.
- A recent systematic review with broad study inclusion criteria (RCTs, observational studies and case reports in people with and without epilepsy) sought to determine the seizure risk associated with antidepressants. The review concluded that the risk of seizures is generally low for antidepressants used at therapeutic doses, but the risk is not zero for any of them.
- For fluoxetine and duloxetine the risk of seizure was deemed almost negligible
- For escitalopram, paroxetine, mirtazapine, sertraline and citalopram, a ‘low to moderate’ risk was assigned.
- There is generally a lack of published studies on antidepressant use in people with epilepsy; the relationship between antidepressants and seizure activity is often based on research in the general population as opposed to in people with epilepsy. A 5 year primary care cohort study of people with depression and no history of epilepsy or seizures (n=235,489) was conducted in the UK. At 5 years, 0.37% of those prescribed antidepressants had new seizures. All antidepressants except sertraline, escitalopram and mirtazapine were significantly associated with risk of epilepsy/seizures (compared to not using them). Trazodone, lofepramine and venlafaxine were associated with highest risk.
Thanks to Professor David Taylor, Director of Pharmacy at the Maudsley Hospital
Bazire S. Chapter 3.4 Epilepsy. Psychotropic Drug Directory 2020/21. Lloyd-Reinhold Publications.
Craig DP, Osborne C. Risk of seizures with antidepressants: what is the evidence? Drugs and therapeutics bulletin 2020; 58(9): 137-140.
Hill T, Coupland C, Morriss R et al. Antidepressant use and risk of epilepsy and seizures in people aged 20 to 64 years: cohort study using a primary care database. BMC Psychiatry 2015; 15:315.
Hovorka J, Herman E, Nemcová I. Treatment of interictal depression with citalopram in patients with epilepsy. Epilepsy and Behavior 2000; 1:444-447.
Kanner AM, Kozak AM, Frey M. The use of sertraline in patients with epilepsy: is it Safe? Epilepsy & Behavior 2000; 1: 100-105.
Kühn K-U, Quednow BB, Thiel M et al. Antidepressive treatment in patients with temporal lobe epilepsy and major depression: a prospective study with three different antidepressants. Epilepsy and Behavior 2003; 4:674-679.
Landmark CJ, Henning O, Johannessen SI. Proconvulsant effects of antidepressants – what is the current evidence? Epilepsy and Behavior 2016; 61:287-291.
Maguire MJ, Weston J, Singh J, Marson AG. Antidepressants for people with epilepsy and depression. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD010682. DOI: 10.1002/14651858.CD010682.pub2.
Münchau A, Langosch JM, Gerschlager W et al. Mirtazapine increases cortical excitability in healthy controls and epilepsy patients with major depression. J Neurol Neurosurg Psych 2005; 76:527-533.
NICE Clinical Knowledge Summary for depression. Updated March 2021.
Noe KH, Locke DEC, Sirven JI. Treatment of depression in patients with epilepsy. Curr Treat Opt Neurol 2011; 13:371-379.
Ojong M, Allen SN. Treatment of depression in patients with epilepsy. U S Pharmacist 2012; 37(11):29-32.
Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsy in adults. Guideline No. 143. Updated May 2015. Revised 2018.
Specchio LM, Iudice A, Specchio N et al. Citalopram as treatment of depression in patients with epilepsy. Clin Neuropharmacol 2004; 27(3):133-136.
Steinert T, Fröscher W. Epileptic seizures under antidepressive drug treatment: systematic review. Pharmacopsychiatry 2018; 51(4):121-135.
Taylor D, Barnes TRE, Young AH. Chapter 10: Drug treatment of psychiatric symptoms occurring in the context of other disorders. The Maudsley Prescribing Guidelines in Psychiatry. 13th Edition. Oxford: Wiley-Blackwell.