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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). From the National Electronic Library for Medicines. www.nelm.nhs.uk 2
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
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