Short communication

New antidepressant drugs and the seizure threshold

The effects of a range of antidepressants were investigated on neuronal voltage-gated Na⁺ and K⁺ channels. With the exception of phenelzine, all antidepressants inhibited batrachotoxin-stimulated ²²Na⁺ uptake, most likely via negative allosteric inhibition of batrachotoxin binding to neurotoxin receptor site-2 on the Na⁺ channel. Imipramine also produced a differential action on macroscopic Na⁺ and K⁺ channel currents in acutely dissociated rat dorsal root ganglion neurons. Imipramine produced a use-dependent block of Na⁺ channels. In addition, there was a hyperpolarizing shift in the voltage-dependence of steady-state Na⁺ channel inactivation and slowed repriming kinetics consistent with imipramine having a higher affinity for the inactivated state of the Na⁺ channel. At higher concentrations, imipramine also blocked delayed-rectifier and transient outward K⁺ currents in the absence of alterations to the voltage-dependence of activation or the kinetics of inactivation. These actions on voltage-gated ion channels may underlie the therapeutic and toxic effects of these drugs.

Dihydroergosine (50 and 100 mg/kg) enhanced the incidence of bicuculline (3 mg/kg)-induced convulsions in female rats, while 100 mg/kg of dihydroergosine given to female mice made 45% convulsive dose of bicuculline (2.5 mg/kg) to be subconvulsive. The same dose of dihydroergosine enhanced in mice the latency of bicuculline (4 mg/kg)-induced convulsions. Although, in $\text{in}$$\text{vitro}$ experiments dihydroergosine showed very weak ability to prevent the binding of ³H-muscimol, the drug was able to diminish and to augment the IC₅₀ of bicuculline and GABA when added to crude synaptosomal pellet of the rat and mouse brain respectively. Lower concentrations of dihydroergosine stimulated and higher inhibited ³H-TBOB binding to the crude synaptosomal pellet of the rat brain. In the preparation of mouse brain dihydroergosine produced only inhibition of ³H-TBOB binding. Only slight quantitative differences were observed in bicuculline-induced stimulation and in GABA- and diazepam-induced inhibition of ³H-TBOB binding between the two species. The results suggest that the opposite species-dependent effects of dihydroergosine on bicuculline-induced convulsions are due to the ability of this drug to modulate species-dependently the benzodiazepine/GABA receptor chloride channel complex.

1. Wistar rats of a strain presenting spontaneous petit mal-like seizures were injected intraperitoneally with graded doses of 14 non-monoamine oxidase inhibitor antidepressants and the immediate effects on behavior and the EEG were recorded.

2. Amineptine and nomifensine, the two drugs interacting with dopaminergic neurotransmission, reduced the duration of spontaneous spike-wave discharges (SWD) and were thus potentially antiepileptic.

3. Trazodone increased SWD duration.

4. The antidepressants, imipramine-like (imipramine, chlorimipramine, desipramine, metapramine and amitriptyline) and non-imipraminic (minaprine, maprotiline, viloxazine, mianserin, fluvoxamine and indalpine), and the 3 noted above, had potentially convulsive effects.

Seizures remain among the most serious side effects of psychotropic drugs. The authors review the literature associating neuroleptic and antidepressant medications with seizures, discussing the relative “seizurogenicity” of different medications, risk factors for seizures, and drugs of choice for high-risk patients. Case histories are presented. Available evidence suggests that molindone, fluphenazine, and haloperidol are among the least seizurogenic neuroleptics and that doxepin, monoamine oxidase inhibitors, or electroconvulsive therapy may be safest in treating the depressed patient at risk for seizures.

The effects of the chronic administration of antidepressants on threshold electroconvulsive (ECS) seizures were evaluated in rats. Initially, tonic-clonic seizures were induced in 90% of the animals. Of those animals responding with tonic-clonic seizures, 42% had hindlimb extension (extensors); the remainder showed only hindlimb flexion (flexors). No alteration in the pattern of seizures was observed 24 hr after a single oral dose of any of the antidepressant drugs. The rats were then treated with a total of 20 consecutive daily doses of antidepressants and threshold electroconvulsive seizure responses were evaluated 24 hr after the last dose. A significantly greater percentage of rats responded with extensor seizures after chronic treatment with amoxapine, chlorimipramine, pargyline and mianserin. There was no change in the pattern of seizures of the rats treated chronically with desipramine, but the duration of the clonic phase was reduced. After a 7 day period free of drugs a significantly greater percentage of animals had extensor seizures in the groups treated with amoxapine, chlorimipramine, pargyline and desipramine but not mianserin. In the light of evidence that chronic treatment with antidepressants reduces the activity of norepinephrine- or isoproterenol-sensitive adenylate-cyclase, and that the norepinephrine system is an important endogenous anticonvulsant factor in electroconvulsive seizures, these results suggest that the same mechanism may mediate both the therapeutic and proconvulsant effects of the chronic administration of antidepressants.