What antidepressants have the lowest risk for producing seizures? Is there an interaction between l

Fråga: What antidepressants have the lowest risk for producing seizures? Is there an interaction between lamotrigine and antidepressants?

Sammanfattning: Seizures occasionally occur with therapeutic doses of both older and newer antidepressants although this is a rare side-effect. The incidence increases with high doses and is especially increased following overdose. Clomipramine and maprotiline appear to have a higher risk of seizures compared to fluoxetine, fluvoxamine and the monoamine oxidase inhibitors.The existence of a number of reports on epileptic seizures in connection with citalopram treatment is probably due to the greater use of this drug in Sweden compared to other newer antidepressants. In contrast, nefazodone and venlafaxin are very new drugs with few cases of seizures probably due a limited use of these drugs so far. It is suggested to monitor blood levels of antidepressant drugs in order to avoid high drug levels and reduce seizure risk.

Svar: Antidepressant drugs from all major classes can produce seizures in humans as well as lower the seizure threshold in animal studies(1). Comparison of the potential seizure risks for different antidepressant drugs is difficult because available data are not comparable (1,2). Seizures are uncommon during treatment with antidepressants, but most frequently reported in patients with predisposing factors such as previous seizures, family history of a seizure disorder, brain damage, concurrent medications active on the central nervous system and substance abuse and withdrawal (1).

Estimates of the incidence of antidepressant-related seizures studied for imipramine, amitriptyline and maprotiline range from 0.1 per cent to 4.0 per cent (1). Fluoxetine, sertraline, fluvoxamine and the monoamine oxidase inhibitors appear to have a lower incidence of seizures than the older antidepressant drugs (1,2). Both clomipramine and maprotiline are regarded as drugs with a higher risk of seizures (1,2).

In general, risk of seizures is increased with overdose for all antidepressants and is associated with blood levels that are greater than usual therapeutic drug concentrations (1). However, it is unclear if there are specific blood level thresholds common to most individuals above which seizures are more likely (1).

The files of Swedish Adverse Drug Reactions Advisory Committee (SADRAC) contain in total 422 cases of neurological side effects related to the newer antidepressants. Among 20 reports on fluoxetine, 27 reports on sertraline and 148 reports on paroxetine there is one single case of convulsions and one case of epileptic seizure judged as a possible cause for each drug. Fluvoxamine has two cases of epileptic seizures and three cases of convulsions among 71 reported neurological side effects. Citalopram is the most reported drug with regard to these side effects. Eight cases of epileptic seizures, two cases of aggravated epilepsy, all judged as possible and three cases of convulsions were found among 121 reports. During the period 1992-1996 approximately 126 million DDD (defined daily doses) of citalopram were sold, which corresponds to one case reported per 10 million DDD or one case per 27400 patient years.

The very new SNRI´s venlafaxine and nefazodone have 14 and 21 reports associated with neurological side effects respectively. Two cases in connection with venlafaxine have been judged as a possible cause of epileptic seizures. The first case was a 76-year-old depressed woman who took 37.5 mg and developed an epileptic seizure within the first week of treatment. As venlafaxine was discontinued and treatment with fenytoin was started no furher seizure was observed. The other case concerned a 55-year-old man with a previous history of an episode of epilepsy fifteen years ago. After four weeks treatment with venlafaxin 75 mg per day he developed another epileptic episode. EEG showed no epileptic activity. Only one report of convulsions was found on nefazodone treatment.

Despite an extensive literature search in Medline no data are available on nefazodone and venlafaxine. Nor could we find any data concerning an interaction between lamotrigine and antidepressant drugs. Several of the tricyclic antidepressants are metabolized through demethylation and hydroxylation followed by glucuronide conjugation. Lamotrigine is mainly excreted in urine as a glucuronide.