There are experimental, clinical and epidemiological methods of assessing the epileptogenic potential of psychotropic drugs. In the laboratory it has been shown that there is a range of cellular and synaptic processes in the cerebral cortex and hippocampus that give rise to epileptiform neuronal activity. In addition to the classical suppression of GABA-mediated inhibitory synaptic mechanisms, in vitro studies in animal models of epilepsy and on human tissue suggest a prominent role for the N-methyl D-aspartate (NMDA) subtype of excitatory amino acid receptors. Any mechanism that leads to the depolarization of the neurones is likely to result in a facilitation of the NMDA-receptor involvement in excitatory neurotransmission. This is particularly true in the cortex and hippocampus where the densities of the NMDA-receptor are highest. Data are presented in this paper on how this epileptogenic mechanism can be studied in vitro. In humans, the importance of an accurate diagnosis is stressed and the advantages and disadvantages of routine EEG recordings and ambulatory monitoring discussed. Descriptions of large-scale systems of drug safety monitoring and their application to the assessment of the epileptogenic properties of psychotropic drugs are given.
Abbott R.J., Browning M C K, Davison D L W (1980) Serum prolactin and cortisol concentrations after grand mal seizures. J Neurol Neurosurg Psychiatr43: 163-167
2.
Alger B.E. (1984). Characteristics of the slow hyperpolarised synaptic potential in the rat hippocampal pyramidal cell in vitro. J Neurophysiol52: 892-910
3.
Alger B.E., Nicoll R.A. (1982) Feedforward dendritic inhibition in rat hippocampal pyramid cells studied in vitro. J Physiol328: 105-143
4.
Andreasen M., Lambert J D C, Skovgaard Jensen M. (1988) Direct demonstration of an N-methyl-D-aspartate receptor mediated component of excitatory synaptic transmission in area CA1 of the rat hippocampus. Neurosci Lett93: 61-66
5.
Andreasen M., Lambert J D C, Skovgaard Jensen M. (1989) Effects of new non-N-methyl-D-asparate antagonists on synaptic transmission in the in vitro rat hippocampus. J Physiol414: 317-336
6.
Ashwood T.J., Wheal H.V. (1986a) Extracellular studies on the role of N-methyl-D-aspartate receptors in epileptiform activity recorded from the kainic acid lesioned hippocampus. Neurosci Lett67: 147-152
7.
Ashwood T.J., Wheal H.V. (1986b) Loss of inhibition in the CA1 region of the kainic acid lesioned hippocampus is not associated with changes in postsynaptic responses to GABA. Brain Res367: 390-394
8.
Ashwood T.H., Wheal H.V. (1987) The expression of N-methyl-D-aspartate-receptor mediated component during epileptiform synaptic activity in the hippocampus . Br J Pharmacol91: 815-822
9.
Ashwood T.J., Lancaster B., Wheal H.V. (1986) Intracellular electrophysiology of CA1 pyramidal neurones in slices of kainic acid lesioned hippocampus of the rat. Exp Brain Res62: 189-198
10.
Avoli M., Olivier A. (1987) Bursting in human epileptogenic neocortex is depressed by an N-methyl-D-aspartate antagonist. Neurosci Lett76: 249-254
11.
Binnie C.D. (1988) Electroencephalography. In Laidlow J, Richens A, Oxley J (eds), A textbook of epilepsy, Third edn. Churchill Livingstone, Edinburgh , pp. 236-306
12.
Cilasun J., Edwards J.G., Sedgwick E.M. (1986) Electroencephalographic changes during treatment with clovoxamine fumarate. Neuropharmacology25: 665-667
13.
Colino A., Halliwell J.V. (1987) Differential modulation of three separate K conductances in hippocampal pyramidal cells by serotonin. Nature328: 73-76
14.
Cornish S.M., Mitchell J., Wheal H.V. (1988) A loss of non-pyramidal cells in the kainic acid (KA) lesioned rat hippocampus. J Physiol400: 63
15.
Dunnell K., Cartwright A. (1972) Medicine takers, prescribers and hoarders. Routledge and Kegan Paul, London
16.
Dutar P., Nicoll R.A. (1988) A physiological role for GABA B receptors in the central nervous system. Nature33: 156-158
17.
Ebersole J S, ed. (1989) Ambulatory EEG monitoring. Raven Press, New York
18.
Edwards J.G., Glen-Bott M. (1983) Mianserin and convulsive seizures. Br J Clin Pharmacol15(suppL 2): 299-311
19.
Edwards J.G., Glen-Bott M. (1984) Does viloxazine have epileptogenic properties? J Neurol Neurosurg47: 960-964
20.
Edwards J.G., Long S.K., Sedgwick E.M., Wheal H.V. (1986) Antidepressants and convulsive seizures: clinical, electroencephalographic and pharmacological aspects. Clin Neuropharmacol9: 329-360
21.
Edwards J.G., Inman W H W, Pearce G.L., Rawson N S B (1991) Prescription-event monitoring of 10,895 patients treated with alprazolam. Br J Psychiatr158: 387-392
22.
Edwards J.G., Inman W H W, Wilton L., Pearce G.L. (1992). Prescription-event monitoring of 10,401 patients treated with fluvoxamine. for publication
23.
Gahwiler B.H., Brown D.A. (1985) GABA B receptor activated K+ current in voltage clamped CA3 pyramidal cells in hippocampal culture. Proc Natl Acad Sci USA82: 1558-1562
24.
Hablitz J.J., Thalmann R.H. (1987) Conductance changes underlying the late synaptic hyperpolarisation in hippocampal CA3 neurons. Physiology58: 160-179
25.
Henry J.A., Woodruff G H A (1978) A diagnostic sign in states of apparent unconsciousness . Lancet2: 290-291
26.
Hill D.R., Bowery N.G. (1981) 3H Baclofen and 3H GABA bind biculline insensitive GABA B sites in the brain. Nature290: 149-152
Inman W H W (1980) Monitoring for drug safety in the United Kingdom . In Inman W H W (ed.), Monitoring for drug safety. MTP Press, Lancaster, pp. 9-47
29.
Inman W H W, Vessey M.P. (1968) Investigation of death from pulmonary, coronary and cerebral thrombosis and embolism in women of child bearing age. Br Med J2: 192-199
30.
Inman W H W, Vessey M.P. (1978) Monitoring adverse drug reactions. In Bennett A E (ed.), Recent advances in community medicine. Churchill Livingstone, Edinburgh, pp. 215-230
31.
Jick H., Dinan B.J., Hunter J.R., Stergaachis A., Ronning A., Perera D.R., Marsden S., Nudelman P.M. (1983) Tricyclic antidepressants and convulsions. J Clin Psychopharmacol3: 182-185
32.
Jick H., Miettinen O.S., Shapiro S., Lewis G.P., Siskind V., Slone D. (1970) Comprehensive drug surveillance. J Am Med Assoc213: 1455-1460
33.
Kerihuel J.C., Dreyfus J.F. (1991) Meta-analysis of the efficacy and tolerability of the tricyclic antidepressant lofepramine. J Int Med Res19: 183-201
34.
Kosaka T., Wu J-Y., Benoit R. (1988) GABAergic neurons containing somatostatin-like immunoreactivity in the rat hippocampus and dentate gyrus. Brain Res71: 388-398
35.
Lancaster B., Wheal H.V. (1982) A comparative histological and electrophysiological study of some neurotoxins in the rat hippocampus. J Comp Neurol211: 105-114
36.
Lancaster B., Wheal H.V. (1984) Chronic failure of inhibition of the CA1 area of the hippocampus following kainic acid lesions of the CA3/4 area. Brain Res295: 317-324
37.
Lawson D.H. (1980) Intensive monitoring in hospitals. I: Boston Collaborative Drug Surveillance Program. In Inman W H W (ed.), Monitoring for drug safety. MTP Press, Lancaster, pp. 213-240
38.
Margerison J.H., Corsellis Y A N (1966) Epilepsy and the temporal lobes. A clinical electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain89: 499-530
39.
Marsan A.C., Zivin L.S. (1970) Factors related to the occurrence of typical paroxysmal abnormalities in the EEG records of epileptic patients. Epilepsia11: 361-381
Newberry N.R., Nicholl R.A. (1985) Comparison of the action of baclofen with gamma aminobutyric acid on rat hippocampal pyramidal cells in vitro. J Physiol360: 161-185
42.
Peck A.W., Stern W.C., Watkinson C. (1983) Incidence of seizures during treatment with tricyclic antidepressant drugs and bupropion. J Clin Psychiatr44: 197-201
43.
Phelps S., Mitchell J., Wheal H.V. (1991) Changes to synaptic ultrastructure in field CA1 of the rat hippocampus following intraventricular injection of kainic acid . Neuroscience40: 687-699
44.
Rawson N S B, Pearce G.L., Inman W H W (1990) Prescription-event monitoring: methodology and recent progress. J Clin Epidemiol43: 509-522
45.
Scheibel M.E., Crandall P.H., Scheibel A.B. (1974) The hippocampal-dentate complex in temporal lobe epilepsy. Epilepsia15: 55
46.
Schneiderman J.H., MacDonald J.F. (1989) Excitatory amino acid blockers differentially affect bursting of in vitro hippocampal neurons in two pharmacological models of epilepsy. Neuroscience31: 593-603
47.
Sedgwick E.M., Edwards J.G. (1983) Mianserin, maprotiline and the electroencephalogram . Br J Clin Pharmacol15(suppl2): 255-262
48.
Sedgwick E.M., Edwards J.G. (1984) Assessment of electroencephalographic changes during treatment with psychotropic drugs. Neuropharmacology23: 265-267
49.
Sedgwick E.M., Cilasun J., Edwards J.G. (1987) Paroxetine and the electroencephalogram. J Psychopharmacol1: 31-34
50.
Segal M. (1990) Serotonin attenuates a slow inhibitory postsynaptic potential in rat hippocampus neurons. Neuroscience36: 631-641
51.
Shepherd M., Cooper B., Brown A.C., Kalton G., Clare A. (1980) Psychiatric illness in general practice. 2nd edn. Oxford University Press, Oxford
52.
Simpson L.H., Wheal H.V., Williamson R. (1991) The contribution of non-NMDA and NMDA receptors to graded bursting activity in the CA1 region of the hippocampus in a chronic model of epilepsy. Can J Physiol Pharmacol (in press)
53.
Sloviter R.S., Damiano B.P. (1981) On the relationship between kainic acid-induced epileptiform activity and hippocampal neuronal damage. Neuropharmacology20: 1003-1011
54.
Smith A., Traganza E., Harrison G. (1969) Studies of the effectiveness of antidepressant drugs. Psychopharmacol Bull (Suppl) 1-53
55.
Sperk G., Lassman H., Baran H., Kish S.J., Seitelberger F., Hornykiewicz O. (1983) Kainic acid induced seizures: Neurochemical and histopathological changes. Neuroscience10: 1301-1315
56.
Sperk G., Weiser R., Widmann R., Singer E.A. (1986) Kainic acid induced seizures: Changes in somatostatin, substance P and neurotensin. Neuroscience17: 1117-1126
57.
Spiers C.J., Griffin J.P., Weber J C P, Glen-Bott M (1984) Demography of the UK adverse reactions register of spontaneous reports. Health Trends16: 49-52
58.
Stanford I.M., Chad J.E., Wheal H.V. (1990) The role of GABAA and B receptors in mediating inhibitory synaptic mechanisms in the rat hippocampus. Neurosci Lett38: 582
59.
Thalmann R.H. (1987) Pertussis toxin blockade of the late inhibitory synaptic potential in hippocampal CA3 neurons. Neurosci Lett82: 41-46
60.
Thomson A.M., West D.C. (1986) N-methylaspartate receptors mediate epileptiform activity evoked in some, but not all, conditions in rat neocortical slices . Neuroscience19: 1161-1177
Trimble M.R. (1978) Serum prolactin in epilepsy and hysteria. Br Med J2: 1682
63.
Turner D.A., Wheal H.V. (1991) Excitatory synaptic potentials in partially denervated CA1 pyramidal neurones in the rat hippocampus in vitro. J Neurosci (in press)
64.
Weissman M.M., Klerman G.L. (1977) Sex differences in the epidemiology of depression . Arch Gen Psychiatr34: 98-111
65.
Wheal H.V. (1990) NMDA-receptors are involved in synaptic plasticity following partial denervation of CA1 pyramidal cells. In Ben-Ari Y (ed.), Excitatory amino acids and neuronal plasticity. Plenum Press, London, pp. 461-469
66.
Wheal H.V., Simpson L., Phelps S., Stockley E.W. (1991) Excitatory amino acid receptor sub-types and their roles in epileptiform synaptic potentials in the hippocampus. In Wheal H V, Thomson A M (eds), Excitatory amino acids and excitatory transmission. Academic Press, pp.239-264
67.
Wheal H.V., Bruce R.C., Best N., Garden O., Mitchell J. (1992) Failure of synaptic inhibition and changes in the populations of some non-pyramidal cells in a chronic model of temporal lobe epilepsy. In Speckmann E J, Gutnick M (eds), Inhibition and epilepsy. Urban & Schwarzenberg, Munchen- Wien-Baltimore (in press)
68.
Zielinsky J.J. (1988) Epidemiology. In Laidlow J, Richens A, Oxley J (eds), A textbook of epilepsy, third edn. Churchill Livingsone, Edinburgh , pp. 21-48
