PAPERS:
Ping Qin, Huilan Xu, Thomas Munk Laursen, Mogens Vestergaard, and Preben Bo Mortensen

Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study
BMJ 2005; 331: 23 [Abstract] [Full text]

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Re: Schizophrenia and Epilepsy: Untenable Link from Flawed Research Design

The recently published BMJ article by Qin et al, “Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: Population based cohort study” offers an untenable conclusion.(1) The first sentence of the authors’ discussion asserts, “…this large population study shows that people with a history of epilepsy have nearly 2.5 times the risk of developing schizophrenia and nearly three times the risk of developing a schizophrenia-like psychosis compared with the general population.” While it is possible that the authors’ declaration of risk might have future validity, it is unsupportable based upon their current research. An analysis of their work, partially funded by the USA-based Stanley Medical Research Institute, ignores the effects of antiepileptic medication-induced neuropsychiatric sequelae in an epileptic cohort.

The oversight is significant. It is a problem addressed briefly by Dinah KC Murray, London, in her previous response to the Qin article.(2) The authors failed to account for the putative role of anticonvulsant medications in the production of psychotic symptoms, including psychoses that resemble schizophrenic-like disorders. This omission erroneously assumes that anticonvulsant-treated epilepsy in Denmark, and elsewhere, has the same natural course as unmedicated epilepsy. The evidence regarding anticonvulsant-mediated adverse side-effects suggests otherwise.

In 1994, Srinivasan and Richens described a ‘schizophrenia-like syndrome' in vigabartin.(3) That paper outlined at least three subtypes of psychosis associated with vigabartin, an irreversible inhibitor of GABA transaminase whose net effect is to enhance regional GABAergic activity.(4) In similar fashion, but not to the same degree, all of the major anticonvulsants list psychosis or psychotic-like symptoms in their presentation of adverse effects.

The number one and number two best-selling anti-seizure drugs in the United States (according to the 21 April 2005 story in the Wall Street Journal, “FDA Request Reviews of Epilepsy Drugs-Paper”) dramatize the problem.(5) Best-seller gabapentin (Neurontin-Pfizer), a GABAergic anticonvulsant similar to vigabartin but whose different mechanism of action also enhances GABA activity, induces comparable problems. The adverse event data for gabapentin, as observed and recorded during all clinical trials in adults and adolescents with epilepsy, according to 2004 Physicians’ Desk Reference(PDR), pages 2562-3, reveals the following neuropsychiatric side-effects: Apathy, hallucinations, agitation, depression, paranoia, depersonalization, euphoria, emotional lability, nervousness, abnormal thinking, encephalopathy, suicidal gestures and psychosis.(6)

The second most widely prescribed anticonvulsant in the United States, topiramate (Topamax-Ortho-McNeil; division of Johnson and Johnson), has a mechanism of action similar to vigabatrin and gabapentin, suggesting that it also potentiates the activity of the inhibitory neurotransmitter, GABA. The 2004 PDR(pages 2486-88) lists its adverse neuropsychiatric events as follows: Psychomotor slowing, impaired concentration, encephalopathy, personality disorder, speech or language problems, confusion, exacerbation of mood disturbances(including irritability and depression), hallucinations, aggressive reaction, paranoid reaction, delusions, paranoia, manic reactions, suicidal gestures, suicide attempts and psychosis.(6)

A similar picture of adverse neuropsychiatric side-effects has been reported with all of the other major anticonvulsants, including carbamazepine, valproic acid, the oxazolidinediones, the succinimides, and the hydantoins. In many cases, the co-administration of these anticonvulsants increases the risk of neurotoxicity and the production of psychotic symptoms.(4)

In order to substantiate their putative link between epilepsy and schizophrenia-like psychosis, Qin et al. would have to affirm three assumptions: (a) that medicated and unmedicated epileptic cohorts are separable and have natural history courses that are comparable, (b) that antiepileptic drugs, otherwise known to produce psychotic sequelae, do not produce long-term clinical conditions similar to schizophrenia-like psychosis, and, (c) that antiepileptic drugs, despite producing serious mood and thought disturbances as side-effects, do not induce those conditions in sufficient numbers in a given cohort to be addressed in linkage studies. Since these assumptions have not been addressed, the author’s conclusions are not valid.

Stefan P. Kruszewski, M.D.

Harrisburg, Pennsylvania 17112 USA

joeysdogma@comcast.net

1. Qin P, Huilan X, Laursen TM, et al. 2005(17 June) Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. BMJ Publishing Group Ltd. BMJ, doi:10.1136/bmj.38488.462037.8F.

2. Murray, D, July 3, 2005 response to: Qin P, Huilan X, Laursen TM, et al. 2005(17 June). Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. BMJ Publishing Group Ltd. BMJ, doi:10.1136/bmj.38488.462037.8F.

3. Srinivasan, J & Richens A. (1994) A Risk-Benefit Assessment of Vigabartin in the treatment of neurological disorders. Drug Saf. 10: 395-405.

4. Brown TM, Stoudemire A. (1998) Psychiatric Side Effects of Prescription and Over-the-Counter Medications: Recognition and Management. Washington, DC. American Psychiatric Press, Inc.

5. Dow Jones Newswire .2005(21 April). FDA Requests Reviews of Epilepsy Drugs-Paper. The Wall Street Journal Online. WSJ.com

6. Murray, Lori, Senior Ed. (2004) PDR 58 Edition 2004: Physicians’ Desk Reference. Montvale, NJ, Thompson PDR.

Competing interests: None declared