A SHORT HISTORY OF ANTIEPILEPTIC DRUG USE IN PSYCHIATRY. ‡

By, N. Frank Feiner, Ph.D, M.D.

© N. Frank Feiner, Ph.D., M.D., 1998

Historically, agents introduced for the treatment of epilepsy have also been turned to almost simultaneously for psychiatric indications. The original 'first-generation' antiepileptic drug (AED), a bromide salt, which appeared in 1857, [2012] was also known for its tranquilizing properties. After phenobarbital came into use for epilepsy in 1912, [2012] there soon followed reports of its psychopharmacologic application. [2013, 2014, 492] Phenytoin was introduced as an AED in 1938 by Putnam and Merritt, [2015] who then immediately described its psychotropic advantages. [2016] Hayes, who has extensively reviewed the use of AEDs in psychiatry, [621, 701, 690] writes that the modern psychopharmacologic usage of AEDs began with phenytoin in 1942,[492] although relatively few psychiatric uses for AEDs were reported over the next decade [1127, 2065-2067, 1158, 2068] and beyond.

In the early 1960s, there was near-simultaneous introduction of carbamazepine (CBZ)[1121] and valproic acid (VPA)and its derivatives, [490, 1150] as new treatments for epilepsy. Although VPA had been first prepared by Beverly S. Burton, an American working in Europe, in 1882, [1873] its antiepileptic utility was not appreciated until this was serendipitously discovered 80 years later by Meunier in France.[501] CBZ was not first synthesized until 1960, in the United States, by Schindler ­ who had a decade earlier patented the structurally closely related imipramine[1831a] ­ and it was found to have antiepileptic properties. [1831, 1914]

When concurrent remedial effects on mood and behavior were noted with both CBZ [487, 1122, 1121] and VPA [490] in the very early epilepsy trials, both drugs were soon appropriated by psychiatrists, first by Lambert, [490] in France (1966), using the amide derivative of VPA, and, shortly thereafter, by Takezaki and Hanaoka (1971)[1159] and then Okuma (1973)[1151] in Japan, both employing CBZ. These authors both reported significant acute and prophylactic mood stabilization within manic-depressive populations. The psychotropic effects of CBZ were also noted early on (1971) by a neurologist, Dalby, working with TLE patients and publishing in the neurologic literature, [487] in what eventually came to be a highly influential paper. However, since most of the early psychiatric publications appeared either in Japanese,[1159,1981] French, [490, 1976, 1977] or Spanish[1978] and/or in less widely circulated journals, [1130, 1979, 1139, 1121] it is likely that many psychiatrists were not aware of the dawning of the AED era until the subsequent reports of the work of Balleneger and Post (1978, 1980),[1157, 536] followed by the reviews (1983) of Kishimoto [534] and Okuma, [542] and then (1984) a highly informative early compilation text published in Europe.[1150] Only then did the floodgates begin to open.

In the United States, these 'second generation' AEDS, CBZ and VPA, held center stage for the next 3 decades. It has only been since the mid 1990s that the FDA has begun approving a series of novel AEDs, the clinical study of which had actually begun a decade earlier. There are currently available 5 of these agents, which might then be termed the 'third generation' AEDs. These are felbamate, [2083] lamotrigine,[2084] gabapentin, [2085] topiramate, [2086] and tiagabine, [2087] As seen in previous generations, the psychiatric application of these new agents has quickly followed suit, [2088-2091] principally for bipolar spectrum disorders.

N. Frank Feiner, Ph.D., M.D.
Medical Psychiatry & Psychotherapy Associates
105 Medway Street, Providence, RI 02906 USA
[401] 274 -7020/23 (telephone)
[401] 274-7551 (fax)
nfrank@pol.net

REFERENCES
‡ Reproduced from Feiner NF: The Affective Illness-Epilepsy Connection. I. Historical and Modern Perspectives. Manuscript in preparation.

487. Dalby MA: Antiepileptic and Psychotropic Effects of Carbamazepine (Tegretol(r)) in the Treatment of Psychomotor Epilepsy. Epilepsia 1971; 12: 325-334 & (ii) #1122 Dalby MA: Behavioral effects of Carbamazepine, in Penry JK, Daly DD (ed): Advances in Neurology, Vol 11. New York, Raven, 1975. Chapter 18, pp. 331-344

490. Lambert PA, Carraz G, Carbel S: Action neuro-psychotrope d'un nouvel anti-épileptique: le dépamide. Ann Méd-Psycholog 1966; 124: 707-710

492. Lindsley DB, Henry CE: The effect of drugs on behavior and the electroencephalograms of children with behavior disorders. Psychosomatic Med 1942; 4: 140-149

501. McElroy SL, Keck PE Jr: Antiepileptic Drugs, in Schatzberg A, Nemeroff CB (ed): American Psychiatric Press. Textbook of Psychopharmacology. American Psychiatric Press, Washington, D.C., 1995. Chapter 17, pp 351-375

534. Kishimoto A, Ogura C, Hazama H, Inoue K: Long-term prophylactic effects of carbamazepine in affective disorder. Brit J Psychiatr 1983; 143: 327-331

542. Okuma T: Therapeutic and prophylactic effects of carbamazepine in bipolar disorders. Psychiatr Clin North Amer 1983; 6: 157-174

536. Ballenger JC, Post RM: Carbamazepine in Manic Depressive Illness: A New Treatment. Am J Psychiatry 1980; 137: 782-790

621. Hayes SG: Acetazolamide in Bipolar Affective Disorders. Ann Clin Psychiatr 1994 ; 6: 91-98

690. Hayes SG, Goldsmith BK: Psychosensory symptomatology in anticonvulsant-responsive psychiatric illness. Ann Clin Psychiatr 1991; 3: 27-35

701. Hayes SG: Barbiturate Anticonvulsants in Refractory Affective Disorders. Ann Clin Psychiatr 1993; 5: 35-44

1121. Sillanpää M: Carbamazepine. Pharmacology and clinical uses. Acta Neurolog Scand 1981; 64 (Suppl 88): 9-109

1122. Dalby MA: Behavioral effects of carbamazepine, Adv Neurol 1975; 11: 331-344

1127 Kalinowsky LB, Putnam TJ: Attempts at treatment of schizophrenia and other nonepileptic psychoses with Dilantin. Arch Neurol Psychiatr 1943; 49: 414-420

1130. Okuma T, Kishimoto A, Inoue K, Matsumoto H, Ogura A: Anti-manic and prophylactic effects of carbamazepine (Tegretol) on manic depressive psychosis. A preliminary report. Folia Psychiatr Neurol Jpn 1973; 27: 283-297

1139. Okuma T, Inanaga K, Otsuki S, Sarai K, Takahashi R, Hazama H, Mori A, Watanabe S: A preliminary double-blind study on the efficacy of carbamazepine in prophylaxis of manic-depressive illness. Psychopharmacol 1981; 73: 95-96

1150 Emrich HM, Okuma T, Müller AA, Forward, in Emrich HM, Okuma T, Müller AA (eds): Anticonvulsants in Affective Disorders, Excerpta Medica, Amsterdam, 1984. pp 1-2

1151. Okuma T: Therapeutic and prophylactic efficacy of carbamazepine in manic depressive psychosis, in Emrich HM, Okuma T, Müller AA (eds): Anticonvulsants in Affective Disorders, Excerpta Medica, Amsterdam, 1984. pp 76-87

1157. Ballenger JC, Post RM: Therapeutic Effects of Carbamazepine in Affective Illness: A Preliminary Report. Commun Psychopharm 1978; 2: 159-175

1158. Kubanek JL, Rowell RC: The use of Dilantin in the treatment of psychotic patients unresponsive to other treatment. Dis Nerv Sys 1946; 7: 47-50

1159. Takezaki H, Hanaoka M: The use of carbamazepine (Tegretol) in the control of manic-depressive psychosis and other manic, depressive states. Seishin Igaku 1971; 13: 173-183

1831. Budavari S (ed): The Merck Index. 11th Edition. Merck, Rahway, NJ, 1989. p 269

1831a. Budavari S (ed): The Merck Index. 11th Edition. Merck, Rahway, NJ, 1989. p 780

1873. Burton Beverly S: On the propyl derivatives and decomposition products of ethyl acetoacetate. Am Chem J 1882; 3: 385-395

1914.Schindler Walter; 5H-Dibenz[b,f]azepines. US pat. 2,948, 718 (1960 to Geigy). Chemical Abstracts 1960; 55:P 1671c.

1976. Lambert PA, Borselli S, Marcou G, Bouchardy M, Cabrol G: Long-term thymo regulative action of Depamide in manic-depressive psychoses. Ann Med Psychol (Paris) 1971; 2(3) 442-448

1977. Lambert PA, Carraz G, Borselli S, Bouchardy M: Dipropylacetamide in the treatment of manic-depressive psychosis. Encephale 1975; 1: 25-31

1978. Lambert PA, Garraz G, Borselli S, Bouchardy M: Dipropylacetamide in the treatment of manic depressive psychoses. Actas Luso Neurol Psiquiatr Cienc Afines 1978; 6: 33-36

1979. Okuma T, Inanaga K, Otsuki S, Sarai K, Takahashi R, Hazama H, Mori A, Watanabe M: Comparison of the antimanic efficacy of carbamazepine and chlorpromazine: a double-blind controlled study. Psychopharmacol 1979; 66: 211-217

1981. Okuma T, Kishimoto A, Inoue K, Matsumoto H, Ogura A: Anti-manic and prophylactic effects of carbamazepine (Tegretol) on manic depressive psychosis. Seishin-igaku 1975; 17: 617-630

2012 Dreifuss FE: Other antiepileptic drugs, in Levy RH, Mattson RH, Meldrum BS (ed): Antiepileptic Drugs. 4th Edition. Raven Press, New York, 1995. pp 949-962

2013. Meerloo AM: On the action of barbituric acid compounds: a contribution to the prolonged narcosis treatment of mental symptoms. J Ment Sci 1933; 79: 336

2014. Cutts KK, Jasper HH: Effect of benzedrine sulphate and phenobarbital on behavior problem children with abnormal electroencephalograms. Arch Neurol Psychiatr 1939; 41: 1138

2015. Merritt HH, Putnam TJ: Sodium diphenyl hydantoinate in the treatment of convulsive disorders. J Amer Med Ass 1938: 111: 1068 2016. Merritt HH, Putnam TJ: Dullness as an epileptic equivalent. Arch Neurol Psychiatr 1941; 45: 797

2065. Silverman D: The electroencephalograph and therapy of criminal psychopaths. Criminal Psychopathology 1944; 5: 439-457

2066. Brill NQ, Walker EF: Psychopathic behavior with latent epilepsy. J Nerv Ment Dis 1945; 101: 545-549

2067. Freyhan FA. Effectiveness of diphenylhydantoin in management of non-epileptic psychomotor excitement states. Arch Neurol Psychiatr 1945; 53: 370-374

2068. Pasamanick B: Anticonvulsant drug therapy of behavior problem children with abnormal electroencephalograms. Arch Intern Med 1951; 104: 752-766

2083. Wilensky AJ, Friel PN, Ojemann LM, Kupferberg HJ, Levy RH: Pharmacokinetics of W-554 (ADD 03055) in epileptic patients. Epilepsia 1985 Nov;26(6):602-606

2084. Cohen AF, Ashby L, Crowley D, Land G, Peck AW, Miller AA: Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam. Br J Clin Pharmacol 1985 Dec;20(6):619-629

2085. Saletu B, Grunberger J, Linzmayer L: Evaluation of encephalotropic and psychotropic properties of gabapentin in man by pharmaco-EEG and psychometry. Int J Clin Pharmacol Ther Toxicol 1986 Jul;24(7):362-373

2086. Maryanoff BE, Nortey SO, Gardocki JF, Shank RP, Dodgson SP: Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate and related compounds. J Med Chem 1987 May;30(5):880-887

2087. Pierce MW, Suzdak PD, Gustavson LE, Mengel HB, McKelvy JF, Mant T: Tiagabine. Epilepsy Res Suppl 1991;3:157-160

2088. Walden J, Hesslinger B: Value of old and new anticonvulsants in treatment of psychiatric diseases. Fortschr Neurol Psychiatr 1995; 63 (8): 320-335

2089. Dimond KR, Pande AC, Lamoreaux L, Pierce MW: Effect of gabapentin (Neurontin) [corrected] on mood and well-being in patients with epilepsy. Prog Neuropsychopharmacol Biol Psychiatry 1996 Apr;20(3):407-417

2090. Ketter TA, Malow BA, Post RM, Theodore WH: Psychiatric effects of felbamate. J Neuropsychiatry Clin Neurosci 1997; 9 (1): 118-119

2091. Dodrill CB, Arnett JL, Shu V, Pixton GC, Lenz GT, Sommerville KW Effects of tiagabine monotherapy on abilities, adjustment, and mood. Epilepsia 1998 Jan;39(1):33-42

Return to Depression Central