A review of some early studies

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Animal data

A number of laboratory and clinical investigations were carried out to assess the effect of tricyclic drugs on seizures and the seizure threshold. The early laboratory

Table 20.1. Classification of psychotic drugs

Antidepressants Antipsychotics Minor tranquillizers Mood stabilizers Psychostimulants Others (beta blockers etc.)

investigations essentially revealed the proconvulsant effect of these agents, and it emerged from these studies that clomipramine, amitriptyline and maprotiline were probably the most proconvulsant compounds (Trimble, 1987).

Luchins et al. (1984) used spike activity in perfused guineapig hippocampal slices as an indication of epileptogenicity and reported the effect of a variety of antidepressants. Imipramine, amitriptyline, nortriptyline, desipramine and maprotiline generally increased spike activity, while viloxazine, protriptyline and trimipramine appeared to decrease neuronal excitability. Nomifensine, a drug no longer available, had a biphasic effect, increasing excitability initially, and then producing cessation of spikes. Similarly, doxepin produced a significant increase in excitability, and then significant decreases. In this model mianserin had no effect.

Using the photosensitive baboon, Papio papio, Trimble et al. (1977) compared two tricyclic drugs, namely clomipramine and imipramine, and the quadricyclic maprotiline with the nontricyclic nomifensine. The first three all lowered the seizure threshold, while nomifensine had little effect and in some animals was anti-convulsant.

One interesting drug examined in these early studies was viloxazine. In two animal models (Luchins et al., 1984; Meldrum et al., 1982) it was observed, if anything, to have a seizure-protective effect.

These early animal studies therefore suggested the potential for both anticonvul-sant and proconvulsant effects of these drugs; in some compounds the potential was a dose-related effect.

Clinical data

The clinical data at that time came mainly from reports of government agencies such as the Committee for the Safety of Medicines (CSM), and from clinical trial data. Several reviews emphasized the poor quality of the available information (Edwards, 1985). However, from the clinical studies the highest reporting of seizures was with maprotiline and clomipramine, and the lowest reporting with pro-triptyline.

The estimated risk of seizures with tricyclic drugs was around 0.06 to 0.1% (Burley, 1977; Jick et al., 1983) The incidence of seizures with imipramine was 0.7%, and with clomipramine 3.0%.

Garvey and Tollefson (1987) drew attention to myoclonic seizures that could occur in relationship to tricyclic drug prescribing, and suggested that as many as 40% of patients reported some kind of myoclonic event after starting them. They calculated the frequency of the effect with the different drugs in descending order from maprotiline, trazodone, nortriptyline, desipramine, amitriptyline to imipramine. Doxepin was not associated with this effect.

Other information that emerged from the early clinical studies was the low reporting of seizures with viloxazine (Edwards and Glen-Bott, 1984), and for pro-convulsant drugs a relationship of seizure reporting to the therapeutic dose, with higher doses of the drug having a higher frequency of seizures, a clear relationship to overdose, and the relationship of seizures to the number of psychotropic drugs prescribed.

The time relationship between commencing the drug and the seizures varies considerably between studies. The attack may occur from 24 hours to several weeks after starting an antidepressant, although early seizures (less than a week later) would seem to be associated with lower dosing schedules and possibly more patient-related factors that lower the seizure threshold (Trimble, 1980) than later-onset seizures.

It was generally concluded that patients were more likely to have seizures (if they did not have epilepsy) if they had a family history of seizures, or a past history of relevant medical conditions such as a head injury or a cerebrovascular accident.

Few of the above antidepressant drugs were tried in patients with epilepsy. Viloxazine was studied, but it was shown to easily lead to anticonvulsant drug toxicity, and was therefore not recommended in epilepsy (Pisani et al., 1984).

Paradoxically, there were some clinical reports of tricyclic antidepressants being anticonvulsant. Ojemann et al. (1983) reported retrospective data, which suggested that doxepin improved seizure frequency in 15 of 19 patients who were prescribed the drug. This included a diminution of both partial and generalized tonic-clonic seizures.

Conclusions from these earlier clinical studies were that, in general, antidepress-ant drugs were proconvulsant, although they were not all proconvulsant to the same degree, and some may not alter the seizure threshold or have a biphasic effect, sometimes revealing some anticonvulsant effects. Table 20.2 shows factors which were thought to be interlinked with lowering of the seizure threshold, emphasizing that this is a problem of the use of these drugs which is not confined only to epilepsy. There are many patients without epilepsy, who have a lowered seizure threshold, who are susceptible to psychotropic-induced seizures.

Table 20.2. Factors that lower the seizure threshold

A family history of epilepsy

Head injury, especially with a prolonged posttraumatic amnesia, or intracranial injury Neurological illness

Table 20.3. Newer antidepressants

Noradrenergic uptake inhibitors - reboxetine Serotonin-noradrenaline uptake inhibitors - venlafaxine Serotonin antagonist/reuptake inhibitor - nefazodone Noradrenaline selective serotonin uptake inhibitors - mirtazapine

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