Convulsive threshold

Convulsions can be induced in rodents by electric shock applied directly across the cerebrum (ECS), by chemical agents administered peripherally, or even by exposure to noise in specific strains of animals. In safety pharmacology it is particularly important to detect proconvulsant activity. On the other hand, although anticonvulsant activity does not in itself constitute a risk, many substances with anticonvulsant activity, for example, benzodiazepines, induce sedation and memory impairment, which have obvious implications for CNS safety. Both kinds of activity can be seen 

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The anticonvulsant activity of a drug may also be evaluated by measuring its ability to raise the convulsive threshold, i.e. the amount of applied current or infused PTZ required to just evoke a seizure. Comparison of the efficacy of drugs in the threshold and maximal seizure tests may distinguish between their abilities to raise seizure threshold or reduce seizure spread and development. 

Extensive brain damage or lesions are certainly not essential for convulsions. These merely require appropriate conditions. Everyone is capable of having a convulsion, indeed their induction has been a common treatment for depression. The convulsive threshold of an epileptic, or more precisely that of some of their neurons, is just lower than normal. 

Hypomania Hypomania has been the most common severe psychiatric side effect reported. This has been largely limited to patients in whom disorders characterized by hyperkinetic symptoms coexist with, but are obscured by, depressive affect. Diabetes There is conflicting evidence as to whether MAOIs affect glucose metabolism or potentiate hypoglycemic agents. Consider this if used in diabetics. Epilepsy The effect of MAOIs on the convulsive threshold may vary. Do not use with metrizamide discontinue MAOl 48 hours or more prior to myelography and resume 24 hours postprocedure. 

Seizure disorders These drugs can lower the convulsive threshold and may precipitate seizures. Use cautiously in patients with a history of epilepsy and only... 

Seizures Methylphenidate may lower the convulsive threshold in patients with history of seizures, in patients with prior EEG abnormalities in the absence of a history of seizures, and, very rarely, in the absence of a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, discontinue the drug. Hypertension and other cardiovascular conditions Use cautiously in patients with hypertension. Monitor blood pressure at appropriate intervals in all patients taking dexmethylphenidate, especially those with hypertension. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate (eg, pre-existing hypertension, heart failure, recent Ml, hyperthyroidism). 

McCall WV, Shelp EE, Weiner RD, et al Convulsive threshold differences in right unilateral and bilateral ECT. Biol Psychiatry 34 606-611, 1993a McCall WV, Reid S, Rosenquist P, et al A reappraisal of the role of caffeine in ECT. Am J Psychiatry 150 1543-1545, 1993b... 

The present Section describes basic protocols satisfying ICH S7A recommendations for core battery CNS studies. Included are protocols for measuring general behavioral signs induced by test substances (Irwin Test), effects on spontaneous locomotion (Activity Meter Test), effects on neuromuscular coordination (Rotarod Test), effects on the convulsive threshold (Electroconvulsive Shock (ECS) Threshold and PTZ Seizure Tests), interaction with hypnotics (Barbital Interaction Test) and effects on the pain threshold (Hot Plate Test). 

Tests for the convulsive threshold estimate whether a test substance induces changes in the probability of convulsions occurring either spontaneously or, more importantly, in association with other treatments. Although overt convulsions can usually be detected using the Irwin procedure, proconvulsant activity can occur in the absence of overt convul-... 

It is generally accepted that there is a good correlation between potentiation or antagonism of experimentally induced convulsions in animals and effects observed in man (Kupferberg 2001). Most substances with antiepileptic properties in man antagonize experimental convulsions, whereas many substances which either induce convulsions or lower the convulsive threshold in man (certain CNS stimulants, some neuroleptics) show similar effects in animals. There are nonetheless differences in the efficacy of certain substances in antagonizing experimental convulsions. For example, sodium valproate appears to be more widely effective in different experimental models than benzodiazepines (Loscher 2002). 

Fig. 3. Convulsive threshold in the Rat PTZ Test. Effects of Ro 15-4513 and diazepam (p.o.) on the latency to tonic convulsions induced by PTZ in the rat.

More elaborate procedures can be employed to assess whether drug withdrawal induces changes in fearfulness, pain sensitivity, convulsive threshold or even memory. On the other hand, it is frequently difficult to demonstrate effects on these parameters and the tests involved are particularly time-consuming. The procedure described below represents an initial screen which has been shown to be sensitive to several dependence-inducing drugs such as opioids and benzodiazepines (Goudie et al. 1993). 

It has been suggested that the less potent sedative neuroleptic drugs (aliphatic or piperidine phenothiazines) lower the convulsive threshold more than the potent neuroleptic drugs (piperazine phenothiazines) (170). Variable and unpredictable effects on seizure activity related to butyrophenones have been reported (171). 

Tricyclics and SSRIs can lower the convulsion threshold making epilepsy more difficult to control by anti-epilepsy drugs and lengthening seizure time in electroconvulsive therapy. The situation is further complicated by the ability of carbamazepine to accelerate (induce) the metabolism of antidepressants and inhibition of carbamazepine metabolism by certain antidepressants (below). 

Seizures associated with imipenem + cilastatin have repeatedly been reported (5-7). As with other beta-lac-tam antibiotics, it is difficult to assess clearly the cause of a seizure in patients with a cluster of other predisposing factors for neurotoxicity (8) and hence to reach clear estimates of frequency. In a review of 1754 patients there was a similar incidence of seizures with imipenem -I- cilastatin as with other antibiotic regimens usually containing another beta-lactam (9). In rabbits imipenem -I- cilastatin and another carbapenems were more neurotoxic than benzylpenicillin (10). In mice, ataxia and seizures were seen, with much lower blood concentrations of imipenem than cefotaxime or benzylpenicillin (1900 pg/ml versus 3400 qg/ml and 5800 qg/ml) (11). In mice imipenem also lowered the convulsive threshold of pentetrazol (pentylenetetrazole) more than cefazolin or two other carbapenems (12). Cilastatin alone was not proconvulsant, but it increased the effects of co-adminis-tered imipenem. 

Particularly likely to occur when a tricyclic drug, a phenothiazine, and a antiparkinsonian drug are prescribed concurrently Tricyclic drugs can interfere with the metabolism of oral anticoagulants Convulsive threshold lowered Hepatic microsomal enzyme induction Hypertension should be controlled with diuretics, p-blockers, or vasodilators before treatment of depression... 

Primidone When used with escitalopram, convulsive threshold is decreased. 

Voskuyl R A, Hoogerkamp A, Danhof M. Properties of the convulsive threshold determined by directcortical stimulation in rats. Epilepsy Res 1992 12 111-120. 

Otani K, Yamatodani A, Wada H, Mimaki T, Yabuuchi H. Effect of ketogenic diet on convulsive threshold and brain monoamine levels in young mice. No To Hattatsu 1984 16 196-204. 

Overdosage toxidty Poisoning with antipsychotics other than thioridazine is not usually fatal. Hypotension often responds to fluid replacement. Neuroleptics lower the convulsive threshold and may cause seizures, which are usually managed with diazepam or phenytoin. Thioridazine overdose, because of cardiotoxicity, is more difficult to treat. 

Seizures Because the convulsive threshold is lowered by tricyclic drugs and by MAO inhibitors, seizures may occur with overdoses of these agents. Overdoses of maprotiline and the SSRls have also caused seizures. 

It has the reputation for being the most effective succinimide analog in petit mal therapy. It acts by suppressing the EEC pattern of petit mal epilepsy perhaps by depression of the motor cortex and raising the convulsive threshold. Combined drug therapy with either phenobarbital or phenytoin sodium is common in cases where petit mal co-exists with grand mal or other types of epilepsy. 

Detailed information about adverse interactions between nefopam and other drugs does not seem to be available. The manufacturer advises caution if nefopam is given with a tricyclic antidepressant because they lower the convulsive threshold convulsions have been seen in some patients taking nefopam. In addition, the antimuscarinic adverse effects of nefopam may be additive with those of tricyclics and other drugs with antimuscarinic effects. For example, the CSM in the UK has a number of reports of urinary retention caused by nefopam, which would be expected to be worsened by drugs with antimuscarinic activity. Nefopam appears to have sympathomimetic activity and the manufacturer therefore says it should not be given with the MAOIs (see MAOIs or RIMAs + Sym-pathomimetics Indirectly-acting , p.l 147). 

The serum phenytoin levels of an epileptie patient were redueed by loxapine, and showed a marked rise when it was withdrawn. The general im-portanee of this case is uncertain, but bear this interaction in mind, particularly as loxapine can lower the convulsive threshold. 

The CSM in the UK has publicised 27 reports of convulsions and one of worsening epilepsy with tramadol, a reporting rate of 1 in 7000 patients. Some of the patients were given doses well in excess of those recommended, and some were taking SSRIs (5 patients) or tricyclic antidepressants , (p.l87), both of which are known to reduce the convulsive threshold. Similarly, of 124 seizure cases associated with tramadol reported to the FDA in the US, 20 included the concurrent use of SSRIs. ... 

The plasma levels of amitriptyline, imipramine and nortriptyline can be reduced by the barbiturates. A reduced therapeutic response would be expected. The tricyclics also lower the convulsive threshold and may be inappropriate for patients with convulsive disorders. 

Note that the tricyclics lower the convulsive threshold and may therefore be inappropriate for patients with convulsive disorders. 

The reduction in the serum levels of amitriptyline, desipramine, doxepin, imipramine and nortriptyline caused by the interaction with carbamazepine appears to be established but the clinical importance is very much less certain. Evidence from one study, that achieved a beneficial response in patients taking tricyclics and carbamazepine suggests that it is possibly not necessary to increase the tricyclic dosage to accommodate this interaction. The fact that a retrospective study found that increased imipramine doses were being given to those taking carbamazepine suggests that this interaction will be naturally accounted for. If carbamazepine is added to treatment with any of these tricyclics, be aware that the dose of the tricyclic may need to be titrated up to achieve the desired therapeutic response. Remember too that the tricyclics can lower the convulsive threshold and should therefore be used with caution in patients with epilepsy. 

It has been su ested, but not confirmed, that because increased levels of carbon dioxide in the tissues can increase the sensitivity to oxygen-induced convulsions, carbonic anhydrase inhibitors, such as acetazolamide, are contraindicated in those given hyperbaric oxygen, because they cause carbon dioxide to persist in the tissues. Nor should hyperbaric oxygen be given during opioid or barbiturate withdrawal because the convulsive threshold of such patients is already low. ... 

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