Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study
BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.38488.462037.8F (Published 30 June 2005) Cite this as: BMJ 2005;331:23All rapid responses
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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
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
Competing interests: No competing interests
The authors appear not to have considered the possible impact of
medication on the association between epilepsy and
schizophrenia they find in their study. It seems to me premature to
speculate about cause without taking into account potential
interactions between psychotropic medications and prior
dispositions.
Yours truly,
Dinah Murray
Competing interests:
None declared
Competing interests: No competing interests
Sir: The authors of this study having used initially ICD-8 and then
ICD-10 to make diagnoses of schizophrenia seem to have ingnored the ICD-8
diganostic category of 'psychosis associated with other cerebral
condition' (e.g. epilepsy) and the ICD-10 exclusion criterion for a
diagnosis of schizophrenia in the presence of epilepsy. The authors are
not alone in this oversight as the BNF cautions against the use of
atypical drugs licensed for schizophrenia in the presence of epilepsy when
no such diagnosis can be made if a higher order diagnosis (organic brain
disorder)is present.
Competing interests:
None declared
Competing interests: No competing interests
Thank you for a most interesting study showing an increased risk of
developing a psychotic illness in those with epilepsy.
The results of this study do go against the conventional psychiatric
wisdom and well-established fact that inducing a seizure provides relief
in psychotic symptoms. Therefore one would have expected those with
epilepsy to have had a lower incidence a psychotic illness.
Having said that from my own experience (having worked in psychiatry
for 6 years now) one does meet a number of patients with a psychotic
illness who also suffer from epilepsy. Certainly from now on whenever I
see patients with psychosis and epilepsy I will be bearing the results of
this study in mind.
To compound matters further, treating psychosis in those with
epilepsy can be quite tricky on occasion. The reason for this is that as
most anti-psychotics lower the seizure threshold they can potentially
cause problems in the symptom-control of epilepsy. In this group of
patients it is therefore important to carefully select an anti-psychotic
with a lower epileptogenic side-effect profile. It is also of importance
to optimise the dose of anti-epileptic medications if needed and have
input from a Neurology Consultant whose advice can be invaluable in the
care of such patients.
Competing interests:
None declared
Competing interests: No competing interests
In describing the realationship between these two diseases, the
historical concept of antagonism of diseases first introduced by Wagner-
Jauregg in 1917 - the concept of treating a mental disease by introducing
another disorder- (treating Dementia Paralytica with Malaria), should be
mentioned.
In 1930 Ladislaw Meduna applied this theory, based on his observation that
patients who developed epileptic seizures, showed a relief of the symptoms
of Dementia Praecox, thus introducing the injection of Camphor to produce
an epileptic seizure. This was tried on the 23 January 1934 in a
psychiatric hospital in Budapest on a schizophrenic patient who had been
psychotic, mute and negativistic. He repeated the camphor injections at
three days intervals and after the fifth injection the patient got up from
his bed and began to talk for the first time in four years.
This led to the later introduction of the Electroconvulsive therapy by U.
Cerletti and L. Bini in 1938 in Rome.
Competing interests:
None declared
Competing interests: No competing interests
The authors conclude from the study that epilepsy and psychosis may
share common environmental and / or genetic causes.
The authors also report however, that the increased risk associated
with both personal and familial history of epilepsy is stronger among
people with no family history of psychosis.
This suggests a curious interaction, in that a family history of
psychosis seems to infer some sort of protection against psychosis in
people with epilepsy.
Such a result is in exactly the opposite direction that one might
expect from the received wisdom, and the other evidence presented in the
study, and suggests that seizures and genetic and environmental influences
do not produce a simple cumulative risk for psychosis.
It is possible that a family history allows for an environment where
reality-distortion symptoms are recognised and referred to a clinician
before they become full-blown psychosis, or perhaps that a genetic
susceptibility to psychosis and the presence of seizures are somehow
antagonistic.
Either way, the cause of this interaction would seem to be a
particularly valuable point of enquiry that could lead to some important
clinical interventions.
Competing interests:
None declared
Competing interests: No competing interests
Re: Epilepsy excludes diagnosis of schizophrenia
Sir
First of all this was a very interesting study. A number of issues deserve
mention however.
As Andrew Al-Adwani noted a diagnosis of epilepsy
precludes a diagnosis of schizophrenia according to ICD-10 diagnostic
criteria. ICD-10 states that "Schizophrenia should not be diagnosed in the
presence of overt brain disease or during states of drug intoxication or
withdrawal. Similar disorders developing in the presence of epilepsy or
other brain disease should be coded under F06.2 and those induced by drugs
under F1x.5." We are unaware how many of the individuals with epilepsy in
this large cohort had ictal or post-ictal psychosis and if these
individuals were diagnosed as Schizophrenia or Schizophrenia-like
psychosis. Understandably this was beyond the remit of Qin and colleagues
study.
The authors noted that there was an increased risk of schizophrenia
for those with a personal history of epilepsy and the risk was stronger
among people with no family history of psychosis. From their results
presented in Table 3. this does not appear to be so. For those with no
family history of psychosis, and a personal history of epilepsy the
relative risk is 2.61 (95%CI 2.29-2.99). This is not markedly different to
those with a family history of schizophrenia - the relative risk is 2.60
(95%CI 1.78 - 3.80). Individuals with only a family history of epilepsy
and no psychiatric family history the relative risk is 1.17 (95%CI 1.05-
1.31) compared with 0.96 (95%CI 0.72-1.29) for those individuals with a
family history of epilepsy . I feel that the authors can make this
statement for those patients with a family history of epilepsy.
Competing interests:
None declared
Competing interests: No competing interests