Medicines Q&As

Medicines Q&As
Q&A 24.3
What is the most appropriate antidepressant to use in epileptics?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Expiry: 31 st March 2010
Background
The prevalence of epilepsy in the general population has been suggested to be 0.5-5% (1). Patients
with epilepsy are prone to depression and the incidence rates quoted in the literature range from 20 to
55% (2), which are significantly higher than in the general population (1-9%) (3). A higher incidence
of depression is estimated in patients with severe epilepsy, 50-55% (4), whilst a lower incidence is
estimated in those patients with controlled epilepsy, 3-9% (1). The use of antidepressant medication
in patients with epilepsy is a common clinical dilemma, as most antidepressants, especially the
tricyclic antidepressants (TCAs), are well known to lower the seizure threshold. It is important to treat
depression in patients with epilepsy as they have attempted suicide rates three to five times higher
than that of the general population (2).
Answer
Most antidepressants can lower the seizure threshold, and precipitate epileptic seizures (1;5).
Antidepressants may exert proconvulsive effects by antagonising the actions of GABA (gamma
amino-butyric acid), an inhibitory neurotransmitter in the brain that suppresses seizure activity. At
therapeutic dosages, seizures are a rare but serious complication of antidepressant therapy (6). Data
for the pro-convulsant effect of antidepressants comes largely from overdose studies (4;6). There is a
lack of human data on the pro-convulsant effects of antidepressants at therapeutic doses and even
less data in patients with epilepsy.
Tricyclic Antidepressants (TCAs)
All TCAs appear to lower the seizure threshold (7). Seizures have been reported in patients treated
with TCAs for depression, both with and without a past history of epilepsy at both therapeutic and
toxic doses (6). The overall incidence of seizures at therapeutic doses of TCAs has been estimated
as being between 3-4% (8;9) though the incidence for individual TCAs varies markedly (see Table 1).
The incidence of seizures following TCA overdose has been reported to be between 3-41% (10).
Table 1: Seizure incidence rates and manufacturers advice for individual TCAs.
Drug Incidence Manufacturers Advice
Amitriptyline 0.3% (therapeutic doses) (6;11).
Clomipramine
1.0-12.2% (therapeutic doses,
dose dependent) (11).
Use with caution in patients with history of epilepsy
(12).
Use with extreme caution in epilepsy (13).
Dosulepin Limited data. Avoid in patients with history of epilepsy (14).
Doxepin 0.1% (therapeutic doses) (3).
Imipramine
Lofepramine
Nortriptyline
Trimipramine
0.1% (≤200mg/day) – 1.1%
(>200mg/day) (3;10;16).
Limited data
Limited data
Limited data
Use with caution in patients with history of epilepsy
(15).
Use with extreme caution in epilepsy (seizure
occurrence appears to be dose dependent) (17).
Use with extreme caution in patients with a history
of epilepsy or recent convulsions (18).
Avoid if possible in patients with a history of
epilepsy (19).
Avoid if possible in patients with a history of
epilepsy (20).
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Medicines Q&As
Doxepin is considered to have the lowest incidence of seizures (5;7;9;21) and therefore is considered
the TCA of choice. The manufacturers of amitriptyline and clomipramine have advised that these
antidepressants should be used with caution in epilepsy but other sources recommend that they
should be avoided completely in epilepsy (22).
Selective Serotonin Reuptake Inhibitors (SSRIs)
In general, the SSRIs have been suggested to have a low pro-convulsive effect (7;22), a favourable
side effect profile and to be less problematic in overdose (6). SSRIs are associated with a lower
incidence of seizures when compared with TCAs (1;11). However, little data are available
concerning the use of SSRIs in patients with epilepsy. Early clinical trials suggested that the SSRIs
were not associated with seizures (6). Seizures have now been reported with all SSRIs (16) and the
risk is considered to be dose related (22). Data on how these antidepressants induce seizures is still
controversial, one theory is that a decreased turnover of serotonin in the central nervous system
(CNS) might be associated with seizures (23). There is some evidence that SSRIs increase the
seizure duration once a seizure has commenced (6).
Fluoxetine is the most studied SSRI and was suggested to exert an anticonvulsant effect in rats, this
has been further supported by data from small-scale controlled studies in humans (23). Fluoxetine
has a probable seizure incidence of 0.2% (7;11;16) and has a long half-life (24). The manufacturers
recommend it should be avoided in patients with unstable seizure disorders and patients with
controlled epilepsy should be monitored (24).
One small-scale study (n=28) reported that fluvoxamine was not epileptogenic at doses ranging from
50 to 200mg, when given to depressed epileptic patients (25) however there have been case reports
of seizures following therapeutic doses of fluvoxamine in patients with and without a previous history
of seizures (26). More recently, a retrospective survey of prescriptions (n=10,401) suggested the
incidence of seizure with fluvoxamine to be 0.2% in the general population (27). It has also been
suggested that fluvoxamine is associated with a higher incidence of seizures in overdose when
compared to other SSRIs but the evidence for this is poor (6). Fluvoxamine should be avoided in
patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored
(28).
Paroxetine appears to have a minimal potential for producing seizures at therapeutic doses (7) but
the manufacturers suggest that it should be used with caution in patients with epilepsy (29). Reviews
suggest paroxetine has a seizure incidence of 0.1% (6;11;30). Seizures have occurred rarely in trials
and no cause-effect relationship has been proven (7).
Citalopram and escitalopram have not been reported to have a pro-convulsive effect (7). In a recent
open label study citalopram 20mg/day was associated with an improvement in depressive symptoms
and a reduction in seizure frequency in 39 patients who had epilepsy and depression (31). A study of
43 patients with epilepsy showed citalopram to be an effective antidepressant without affecting
seizure frequency (32). It is considered one of the first line options due to it is perceived safety in
these patients and lack of interactions with the anticonvulsant agents (11;22) .
Early clinical trials with sertraline suggested that seizures occurred at a similar frequency to placebo
and only in people with a history of seizures (7). The above study in 43 patients showed only 6% of
epileptics taking sertraline had worsening of seizures, which were corrected by adjusting the
antiepileptic dosage (4;32).
Overall, it has been suggested that the risk of seizures with SSRIs at therapeutic doses lies between
0.1-4% (23) but the incidence varies between individual agents. SSRIs are considered the first line
antidepressant option in patients with epilepsy (3;4;11;22;27). Fluoxetine, fluvoxamine and paroxetine
are all potent inhibitors of the cytochrome P450 enzymes (11;22), which means they have interaction
potential with the anticonvulsant agents, which needs to be considered. Citalopram and sertraline
may be considered the safest options due to their lack of interaction potential with the anticonvulsants
(11). The manufacturers of these agents recommend to avoid their use in patients with unstable
epilepsy (33;34).
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Medicines Q&As
Monamine Oxidase Inhibitors (MAOIs)
MAOIs have for many years been considered to be the least pro-convulsive antidepressants for
patients with epilepsy (6;32). However MAOIs are seldom used now due to their interactions with
certain foods and drugs and the fact that there are safer alternatives available. Moclobemide is a
reversible inhibitor of monoamine oxidase type A (RIMA) which is less likely to interact with foods and
drugs, and is associated with a low incidence of seizures in patients with depression (6). It is
considered a good choice in patients with epilepsy and is not cautioned or contraindicated in these
patients (22;35).
Lithium
Evidence suggests that lithium can reduce the seizure threshold but no studies have been conducted
in patients with epilepsy. Animal studies suggest that prolonged lithium therapy may reduce seizure
threshold (6). It is known that toxic serum levels of lithium are associated with seizures and the
majority of reports have described seizures that are transient but some have persisted (6). Lithium
has been thought to induce EEG abnormalities though data is conflicting (6;11). Encephalopathy or
severe brain oedema can occur in patients taking lithium who have a seizure (6;11). At therapeutic
doses it is considered to have a low pro-convulsive effect or have no effect on the seizure threshold
(7;22).
Miscellaneous Antidepressants
Mianserin has a relatively low incidence of seizures compared to TCAs at therapeutic doses in
patients with brain damage, and following an overdose (6). It is often quoted as being relatively safe in
epilepsy (7) however the manufacturers recommend to avoid if possible in patients with epilepsy (36).
The incidence of seizures quoted in the literature for trazodone (a serotonin agonist) is

Medicines Q&As
In addition, some antidepressants may interact with anticonvulsants; this potential for interactions
would need to be considered when choosing a suitable antidepressant agent for the patient. Plasma
concentrations of the anticonvulsants should be carefully monitored if appropriate, particularly during
the early phase of treatment with the antidepressant and doses adjusted accordingly (6;11;22).
As a general rule, the more sedating a drug is, the more likely it is to induce seizures (22). There is a
dose dependent relationship between antidepressant use and seizures. Patients should be
commenced on a low dose, and this should be increased slowly until a therapeutic dose has been
achieved, to reduce the risk of seizures (7;22). In addition, maximum recommended doses of
antidepressants should not be exceeded.
Summary
• The first consideration should always be to check the patients’ anticonvulsant regimen for
potential drug-induced depression. It may be that the patient would benefit from changing the
anti-convulsant to another agent with a more favourable effect on mood rather than adding in
an antidepressant.
• The risk of seizures with most antidepressants is low, but is probably not zero for any of them,
and patients should be made aware of this when prescribing. The risk of seizures increases
with increasing doses.
• SSRIs are considered the first line antidepressant option in patients with epilepsy. Published
data do not support the recommendation of a specific SSRI, although fluoxetine is not the
best choice due to its long half-life, a possibly greater incidence of seizures and an increased
risk of drug interactions. Citalopram or sertraline may be considered the better option due to
safety and reduced interaction potential with the anticonvulsants.
• Moclobemide, is a good alternative, as it has a low incidence of seizures but due to limited
data it should be reserved as a second choice.
• TCAs should be used cautiously in patients with epilepsy and reserved for patients who
poorly respond to or are intolerant of other antidepressants. Where a TCA is needed, doxepin
would be the agent of choice.
• Clinicians should be aware of the possibility of interactions between antidepressants and
anticonvulsants and should monitor carefully patients with epilepsy who are prescribed
antidepressants.
• Introducing the antidepressant gradually, starting with a low dose, and not exceeding the
maximum recommended doses may reduce the risk of a seizure.
Limitations
In general, very little specific information is available about the use of antidepressants in epilepsy.
Most studies investigating the relationship between antidepressants and seizure activity have
examined the effects of antidepressants in overdose in the general population, making it difficult to
extrapolate the findings to patients with epilepsy. Seizure rates quoted are based on the incidence in
patients with depression rather than patients with epilepsy, and this latter figure would be expected to
be higher. Many of the early estimates of seizure incidence were based on case reports where there
were many influencing variables and poor definitions for what constituted a convulsive event.
Patients were also often taking concomitant medication, which may have affected seizure threshold,
or, through inhibition of antidepressant metabolism, caused higher antidepressant plasma levels.
Newer antidepressants have undergone clinical trials with improved methodology and with systematic
reporting of adverse events. However, even these do not allow accurate comparisons to be made
between the antidepressants. There are few systematic studies of antidepressants in people with
epilepsy. Unless a large-scale trial is conducted, which is unlikely, the best antidepressant in epilepsy
will remain unknown (7).
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Medicines Q&As
Disclaimer
♦ Medicines Q&As are intended for healthcare professionals and reflect UK practice.
♦ Each Q&A relates only to the clinical scenario described.
♦ Q&As are believed to accurately reflect the medical literature at the time of writing.
♦ See NeLM for full disclaimer.
References
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(3) Anon. Prompt diagnosis and treatment of depression in patients with epilepsy essential for
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Neuropsychiatry Clin Neurosci 2005; 17(1):20-28.
(12) Summary of Product Characteristics. Amitriptyline Oral Solution 25mg/5ml. Rosemont
Pharmaceuticals Limited. Accessed via http://emc.medicines.org.uk. Date of access:
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From the National Electronic Library for Medicines. www.nelm.nhs.uk 5

Medicines Q&As
(16) Duncan D, Taylor D. Which is the safest antidepressant to use in epilepsy? Psychiatric
Bulletin 1995; 19:355-356.
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Medicines Q&As
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From the National Electronic Library for Medicines. www.nelm.nhs.uk 7

Medicines Q&As
Quality Assurance
Prepared by
Varinder Rai, London Medicines Information Service (Northwick Park Hospital)
Based on earlier work by Caroline Fletcher and Iram Husain
Date Prepared
13 th March 2008
Checked by
Helen Rowlandson, London Medicines Information Service (Northwick Park Hospital)
Date of check
8 th April 2008
Search strategy
• Embase "((ANTIDEPRESSANT-AGENT#.DE.) AND (EPILEPSY#.W..DE.) AND
(DEPRESSION-DT#.DE.)) AND HUMAN=YES". Information added since 09/02/2006.
• Medline "((EPILEPSY#.W..DE.) AND ((ANTIDEPRESSIVE-AGENTS#.DE.) OR
(ESCITALOPRAM) OR (DULOXETINE) OR (FLUPENTIXOL) OR (MIRTAZAPINE) OR
(REBOXETINE) OR (VENLAFAXINE))) AND HUMAN=YES". Information added since
09/02/2006.
• In-house resources
• Electronic Medicines Compendium
• Pharmline ( EPILEPSY and ANTIDEPRESSANT)
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