Which antidepressant is less likely to produce a decrease in seizure threshold?/nBackground: male p

Fråga: Which antidepressant is less likely to produce a decrease in seizure threshold?

Background: male patient, born 1964, brain damaged and psychotic from neonatal icterus, had a grand mal seizure in 1983 while receiving nortriptyline. A subsequent EEG was normal. Antidepressant treatment is considered necessary again. Present medication: haloperidol and thioridazine.

Sammanfattning: Though all antidepressants have been shown to decrease the seizure threshold, available information to date precludes the adequate estimation of relative risk for different drugs.

There is some evidence that maprotiline induces seizures more commonly than other antidepressants.

Svar: Reports of seizures occurring both with overdoses and at normal therapeutic doses have been published for most tricyclics andnewer antidepressants (1,2,3,4).

In a recent review (4), Edwards et al list all the cases of seizures in temporal relationship to antidepressants, and spontaneously reported to the Committee on Safety of Medicines (CSM) of the United Kingdom from 1964 to February 1984. A literature review is also presented (paper enclosed). However, though figures mentioned range from 0.1 To 4 per cent (3,4,5,12) thereal incidence is not known, as adequate epidemiological data is not available, and most trials are carried out in relatively small numbers of patients. This also renders impossible a comparison between different drugs. Since 1966 the Swedish Adverse Drug Reactions Reporting Committee has received reports of seizures related to the following antidepressants: zimelidine, five; maprotiline, three; dibenzepine, two; lofepramine, one; clomipramine, one; and tranylcypromine, one.

More reports have been received by the CSM for maprotiline than forany of the antidepressant drugs (though this contrasts with animal studies), and trimble, who followed up 92 of these reports between 1970 and 1980 has concluded that "early seizures may occur in patients with a lowered seizure threshold, but late seizures are more related to large doses of the drug" (6,7). He also states that "of the non maoi, non tricyclic antidepressants, l-tryphtophan, viloxazine, flupenthixol and nomifensine are least likely to provoke seizures" (2,6,8). Since then, viloxazine and nomifensine have been found unsuitable, due to unacceptable toxicity.

In another report of 41 cases of self-intoxication with maprotiline (of which 35 had taken other drugs or alcohol), 15 patients developed seizures; six of these had been given physostigmine as an antidote (16).

The convulsant activity of antidepressants has also been shown in many animal models of epilepsy, but the results are contradictory anddifficult to extrapolate to clinical reality (5,9,10).

Most authors agree that in the absence of risk factors, seizures occur infrequently at therapeutic doses of tricyclic antidepressants. Risk factors mentioned are:

1) family or personal history of seizures or EEG abnormality

2) brain damage

3) other predisposing conditions (unstable diabetes, alcohol abuse, etc)

4) polypharmacy (2,4,5,6,8,11,12).

Also, drug-related factors are:

1) initial period of the treatment (when seizures appear later it is probably due to higher dosage)

2) sudden dose changes

3) abrupt drug withdrawal

some authors recommend concomitant use of antiepileptic medication to control epileptic manifestations of antidepressant therapy when this cannot be discontinued (11,12). In these cases, as well as in known epileptics, interactions between antidepressants and antiepileptic agents should be considered. There is some evidence that serum phenytoin levels may be increased by nortriptyline, viloxazine, imipramine and nomifensine, though the effects were usually small and sometimes transient (7,12). On the other hand, antiepileptic drugs are potent liver enzyme inducers, and antidepressant serum levels may be reduced (7,12,13).

In the present case, the risk for seizures is increased not only by the patient´s pathology but by the use of neuroleptics which areknown to decrease the seizure threshold (14,15). Carbamazepine or alprazolam though not licensed for the indication of depression, have shown some antidepressant activity andcould be worth trying (17). 1 Side effects of drugs. Ed by MNG Dukes, Elsevier, Amsterdam. 1987; Annual 11: 16-23 2 Trimble M: Non-monoamine oxidase inhibitor antidepressants and epilepsy: a review. Epilepsia 1978; 19: 241-250 3 Messing RO, Closson RG, Simon RP: Drug-induced seizures: a 10-year experience. Neurology 1984; 34: 1582-1586 4 Edwards JG, Long SK, Sedgwick EM, Wheal HV: Antidepressants andconvulsive seizures: clinical, electroencephalographic, and pharmacological aspects. Clin neuropharmacol 1986; 9: 329-360 (bifogas) 5 Jabbari B, Bryan GE, Marsh EE, Gunderson CH: Incidence of seizures with tricyclic and tetracyclic antidepressants. Arch neurol 1985; 42: 480-481 6 Trimble MR: New antidepressant drugs and the seizure threshold. Neuropharmacology 1980; 19: 1227-1228 7 Richens A, Nawishy S, Trimble M: Antidepressant drugs, convulsions and epilepsy. Br j clin pharmacol 1983; 15: 295S-298S 8 Trimble MR: Antidepressant drugs and convulsions. Lancet 1980; I: 307 9 Peterson SL, Trzeciakowski JP, Mary JS ST: Chronic but not acute treatment with antidepressants enhances the electroconvulsive seizure response in rats. Neuropharmacology 1985; 24: 941-946 10 Krijzer F, Snelder M, Bradford D: Comparison of the (pro)convulsive properties of fluvoxamine and clovoxamine with eight other antidepressants in an animal model. Neuropsychobiology 1984; 12: 249-254

11 Itil TM, Soldatos C: Epileptogenic side effects of psychotropic drugs. JAMA 1980; 244: 1460-1463
12 Markowitz JC, Brown RP: Seizures with neuroleptics and antidepressants. Gen Hosp Psychiatry 1987; 9: 135-141
13 Drugline nr 05722
14 Drugline nr 04994
15 Drugline nr 03597
16 Knudsen K, Heath A: Effects of self poisoning with maprotiline. Br Med J 1984; 288: 601-603

17 Avery, Drug treatment. 1987; 3rd ed: 1172, 1178