ELSEVIER Epilepsy Research 25 (1996) 21-27

EPILEPSY RESEARCH

Vigabatrin and behaviour disorders: a retrospective survey

Laura Thomas a, Michael Trimble a,,, Bettina Schmitz b, Howard Ring c a Institute of Neurology, Queen Square, London WC1N 3BG, UK

b Abteilungfiir Psychiatrie, Klinikum Rudolf Virchow, Eschenallee 3, 14050 Berlin, Germany c The Royal London Hospital, Department of Psychiatry, 3rd Floor, Alexandra Wing, Whitechapel. London E1 2AA, UK

Received 28 July 1995; revised 1 March 1996; accepted 6 March 1996

Abstract

Vigabatrin is an anticonvulsant drug with a relatively favourable side-effect profile. However, in clinical trials behaviour disorders have been reported, including agitation, depression and psychoses. In this study, 136 cases of behavioural problems that had been reported to the manufacturers, or the authors, were followed up. Satisfactory clinical information could be obtained on 81 patients. Of these, 50 cases met the criteria for either a psychosis (n = 28) or depression (n = 22). These were compared with a group of Queen Square patients, with epilepsy and psychosis, who had never taken vigabatrin (n = 21) and another group, who received vigabatrin without experiencing any behavioural problems (n = 28). The main results from this study suggest that: (1) Psychosis as a treatment emergent effect of vigabatrin is seen in patients with more severe epilepsy, compared with those patients who never develop psychopathology, and those developing an affective disorder. The psychosis is related to a right-sided EEG focus, and suppression of seizures (64% became seizure free). (2) Depression as a treatment emergent effect of vigabatrin is associated with a past history of depressive illness. There was little or no change in seizure frequency in this group. Some suggestions for managing patients who may develop these behaviour disorders are given.

Keywords: Vigabatrin; Psychosis; Depression; Forced normalisation

1. Introduct ion

Vigabatrin (GVG) was introduced into clinical practice in the UK in 1989, following several years of patient trials. It was generally considered to be a highly effective anticonvulsant, with a favourable side-effect profile.

The first published cases of psychoses associated with vigabatrin came from Sander et al. [6]. They reported experience with 145 patients, suffering from

* Corresponding author.

intractable seizures, who received vigabatrin as add- on therapy. They noted that the most common ad- verse effects were behavioural disturbances. These ranged from irritability and confusion to psychotic reactions. They described seven of the latter (4.8%).

From an extended series of over 210 patients, Sander et al. [7] reported 14 cases (6.6%) who became psychotic after prescription of the drug, none being psychotic at the time of starting vigabatrin. However, of this group, 5 had a previous history of psychosis and 2 severe non-psychotic behaviour dis- orders. The mean dose of vigabatrin at the onset of the psychoses was 2.5 g daily (range 0 .5 -4 g).

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22 L. Thomas et a l . / Epilepsy Research 25 (1996) 21-27

Sander et al. [7] identified two patterns of rela- tionship between psychosis and seizures which per- tained to approximately 50% of the cases. In pattern 1, patients rapidly became seizure free, or virtually so, following the introduction of vigabatrin, only at a later date in time to develop a cluster of seizures, following which the psychosis erupted. In these cases, the psychosis was therefore a classical post-ictal psychosis and occurred within 48 h of the cluster. In all of these cases, the preceding period of seizure freedom was unusually long for the patients con- cerned.

Pattern 2 was one in which patients became seizure free on vigabatrin and then, whilst still seizure free, developed a psychosis, some 2-6 weeks later. In 7 patients, there was no pattern established between seizures and psychosis.

The clinical features of these psychoses were therefore either classical organic brain syndromes (delirium) or schizophrenia-like psychoses in the set- ting of clear consciousness.

Review of additional literature on vigabatrin re- veals occasional references to psychosis, but more frequently behaviour disorders, such as depression, irritability, agitation, psychic changes or confusion are documented [2,8]. The presence of pre-existing behavioural problems was noted in a high proportion of these cases.

Several groups have reported on individual pa- tients who have developed a psychosis following withdrawal of vigabatrin [1,4,7]. Post-ictal psychosis emerging in the setting of a cluster of withdrawal seizures may provide one explanation for these ob- servations.

Depression with vigabatrin has been reported by Ring et al. [5]. They describe 10 patients who devel- oped a major depressive illness while on vigabatrin. Six of these had previous depressive episodes but none became seizure free, or displayed the patterns described by Sander et al. [7] in their psychotic patients. The mean treatment dose was 2.8 g (range 1.5-4 g daily).

In contrast to these results where vigabatrin has been given as add-on therapy to difficult-to-control patients, post-marketing surveys (Mumford, in prep.; Cockerell et al., in press) and studies in monotherapy [3] indicate that these behaviour disorders occur with much less frequency, perhaps less than 1%. This

suggests that there may be a group of patients vul- nerable to develop these problems. One way to try to identify this cohort is to survey case material from patients treated with vigabatrin, who reported be- haviour disorders, and compare their features with comparison samples. Here we present such a study.

2. Materials and methods

We have examined the case records of 4 groups of patients. Group 1 were reported as having psy- chosis as a treatment emergent effect of vigabatrin (GVG/Psy); group 2 were patients who had epilepsy and psychosis and had never been treated with viga- batrin (Epi/Psy); group 3 had depression as a treat- ment emergent effect of vigabatrin (GVG/Dep); and group 4 were patients treated with vigabatrin who had reported no behavioural treatment emergent ef- fects (GVG/None).

Patients in the 3 vigabatrin treated groups were identified using the Marion Merrell-Dow (MMD) European safety database or were reported to us at The Chalfont Centre and the National Hospital for Neurology and Neurosurgery. The fourth group (Epi/Psy) was obtained from the database on psy- chotic patients with epilepsy held at the Institute of Neurology.

Those in the GVG/None group were a random selection of cases from the MMD database, who, on inspection of the case records, had shown no be- havioural problems with treatment. This group was taken from the European Safety database, and an approximate comparison number of 30 patients were used. On further analysis of the information, 2 pa- tients were subsequently excluded; one was a child, and the other may have experienced some minor psychopathology. The 2 other vigabatrin treatment groups come from a total of 136 cases of behaviour disturbance reported to the manufacturers. Following review of all the available data, satisfactory clinical information could be obtained in 81 cases. Of these, 50 met the criteria for either a psychosis (n = 28) or depression (n = 22). The remaining cases reflected a variety of behaviour problems, mainly anxiety and agitation. The latter were not analysed further.

The psychopathology was categorised on clinical grounds. A diagnosis of psychosis was given if

24 L. Thomas et a l . / Epilepsy Research 25 (1996) 21-27

Table 1

Demographic features

Male Female Age Epilepsy onset

cases cases (mean (mean yrs (S.D.))

(S.D.))

G V G / P s y 14 14 * 30 ( 7 ) 8 ( 7 ) * * *

E p i / P s y 18 3 4 2 ( 9 ) 11 ( 8 )

G V G / D e p 4 18 * * 37 (17) 10 (10)

G V G / N o n e 20 8 30 (10) 15 (11) * * *

* P < 0.05 G V G / P s y vs. E p i / P s y .

* * P < 0.01 G V G / D e p vs. G V G / N o n e .

* * * P < 0.01 G V G / P s y vs. G V G / N o n e .

(pattern 1), just prior to the onset of the psychosis (Fig. 1). One seizure-free patient was unclassifiable due to paucity of information recorded.

The mean dose of vigabatrin at the onset of the psychiatric episode was 2.6 g ( + 0.9) and the mean latency was 18 weeks ( + 27). It is important to note that in the vigabatrin group (n = 28), 28.6% of subjects had had a previous history of psychosis, and in 3 of these, the event had been related to the administration of clobazam, usually in association with seizure control.

A separate analysis comparing all variables of patients in the GVG/Psy group, with and without a past psychiatric history, revealed no significant dif- ferences.

In the second analysis we compared GVG/Psy with GVG/Dep. In the latter group, 18 were consid- ered to have had a major depressive episode and 4 a dysthymia.

Compared to the psychotic group (GVG/Psy), subjects with an affective disorder (GVG/Dep) were

Table 2

Features of seizures

Simple P Complex P Tonic- Other cases cases clonic seiz.

cases cases

G V G / P s y 2 24 22 * 7

E p i / P s y 11 11 18 5 G V G / D e p 2 19 4 0 G V G / N o n e 7 23 13 0

* P < 0.05 G V G / P s y vs. G V G / D e p and G V G / N o n e .

Table 3

EEG results

L foci R foci Bilateral Normal

cases cases cases cases

G V G / P s y 4 7 * 16 * * 0

E p i / P s y 4 0 15 1

G V G / D e p 9 6 3 0

* P < 0.05 G V G / P s y vs. E p i / P s y .

* * p < 0.05 G V G / P s y vs G V G / D e p .

significantly less likely to have a history of tonic- clonic seizures (chi-square with Yates' correction = 15.6 (1), P < 0.0001; OR = 0.06, CI = 0.01-0.25) (Table 2), and fewer bilateral abnormalities on the EEG (chi-square with Yates' correction = 6.4 (1), P < 0.05; OR = O.14, CI = 0.03-0.59 (Table 3).

With regards to seizure pattem, in contrast to the psychotic subjects, only one subject in the depressed group became seizure free, and none developed a cluster leading to the development of a florid post- ictal disorder (Fig. 1).

Both groups were receiving similar doses of viga- batrin (group 3:2.8 g + 1.7; group 1:2.6 g + 0.9) at the onset of the psychiatric episode. There was no significant difference in the time latency between the initiation of vigabatrin therapy and the onset of the psychiatric illness. The standard deviation was large but a breakdown reveals that most had problems in the first 10 weeks of therapy. A trend was noted for a longer interval between the onset of epilepsy and psychiatric illness with the depressed group, when the patients with a previous history of the same psychiatric disorder were removed from the analysis. However, the numbers were small (Table 4).

Finally, consideration of the psychiatric history reveals that none of the patients who developed a depression had a past history of psychosis. However,

Table 4 Age, epilepsy interval, and treatment latency to psychiatric onset

Psychiatric onset Interval < 10 wk > 10 wk

Cases * Mean (mean cases cases

(yrs) (S.D.))

G V G / P s y 12 29 19 ( 9 ) 15 12 G V G / D e p 9 41 26 (14) 12 10

* Subjects with previous psychiatric history excluded.

L. Thomas et aL / Epilepsy Research 25 (1996) 21-27 25

11 (50%) had a past history of depression, including three who had a depressive episode whilst previously taking barbiturates (primidone [1]; phenobarbitone [2]).

In the third analysis, group GVG/None were compared with GVG/Psy and GVG/Dep. First comparing GVG/Psy with GVG/None, the latter have less severe epilepsy with a significantly lower age of onset (Table 1), and significantly fewer tonic-clonic seizures (chi-square with Yates' correc- t ion=4 .9 (1), P < 0 . 0 5 ; OR=0 .24 , C I = 0 . 0 7 - 0.76) (Table 2). Unfortunately, EEG and scan data for this group were not available.

A significant difference was noted in the dose of GVG which was 2.8 g (GVG/Psy) compared to 2.0 g (GVG/None). Also there was a highly significant difference in seizure patterns, with none of GVG/None showing suppression of seizures, with or without clustering, compared to GVG/Psy (chi- square with Yates' correct ion=23.7 (1), P < 0.00001) (Fig. 1).

The second comparison, that between GVG/None and GVG/Dep, revealed that there were signifi- cantly more males in group GVG/None (chi-square with Yates' correction = 11.9 (1), P < 0.001; OR = 11.25, CI = 2.89-43.77) (see Table 1). Also, the dose of GVG reached significance, which was 2.6 g (GVG/Dep) compared to 2.0 g in GVG/None.

4. Discussion

In this paper we present a retrospective study of patients who have developed behaviour disorders on vigabatrin. Ideally, a prospective study should be carried out with full neurological and psychiatric evaluation of cases, but in the absence of such a study, we have attempted to accumulate sufficient numbers of well-defined cases to help clarify the clinical situation. However, our conclusions must be tempered by the reservations that pertain to all retro- spective investigations.

The cases chosen filled clinical diagnostic criteria. DSM-IIIR was not strictly applied because of the retrospective nature of the data but we are confident that the terms psychosis and depression have been appropriately applied to the two groups respectively.

We cannot explain the sex difference between the groups although perhaps to some extent this reflects sex differences in the epidemiology of psychiatric disorders, affective disorder being commoner in fe- males.

Following from the original paper of Sander et al. [6] the psychotic patients fell into two groups, namely those with an organic brain syndrome (delirium), and those with hallucinations or delusions in the setting of clear consciousness. In clinical terms, in the ab- sence of epilepsy, this latter clinical picture, if pro- tracted, would be referred to as a paranoid psychosis or schizophrenia.

The depressed patients were not simply miserable, unhappy patients with epilepsy. Clearly, they had a clinical affective disorder, yet, despite this, psychi- atric intervention was minimal. Where information could be ascertained (n = 12), only one patient was hospitalised and treated with antidepressants. By contrast, information on the psychotic group (n = 11) revealed a 70% hospitalisation rate. Once again, however, prescription of medication was infrequent, with only 3 subjects being treated with neuroleptics. In both groups, withdrawal from vigabatrin was the usual and, sometimes only, action taken in the event of a psychiatric episode. Further, in most cases the psychoses were of acute onset and remitted ;after a short time interval.

With regards to psychosis, our conclusions are that the vigabatrin group comes from a similar popu- lation as the comparison group, who have psychosis and epilepsy but never received the drug. It is impor- tant to note that, in comparison with data from other studies [9], there was no evidence that vigabatrin brought forward in time the onset of the psychosis in patients at risk. Thus, the latency between age of onset of epilepsy and the psychosis on vigabatrin was similar to that seen in patients with epilepsy and psychosis who had never received vigabatrin. In reaching this conclusion, we have specifically ex- cluded patients with a previous psychotic episode in the vigabatrin group. Thus in a survey of 14 studies, where the interval between the age of onset of epilepsy and the onset of psychosis could be ascer- tained, the mean was 15 years, with a normal distri- bution around the mean, and a range of 11-22 years [9]. The latency in the vigabatrin cases of 19 years is concordant with this distribution.

26 L. Thomas et aL / Epilepsy Research 25 (1996) 21-27

It is of interest that the vigabatrin psychotic group have more generalised tonic-clonic seizures, and more bilateral EEG abnormalities than the depressed group (GVG/Dep) , and the normal controls (GVG/None) where this could be examined. This suggests that psychosis is associated with more se- vere epilepsy, and in this database was found in patients with a high risk for the development of psychosis anyway [9].

Nearly 30% of those who became psychotic (GVG/Psy) had a previous history of psychosis, and in 5 patients this was related to the prescription of another anticonvulsant. In some of those cases, pa- tients also became seizure free. We believe the latter to be of utmost relevance. Thus, in the total vigaba- trin sample, 11 (39%) became seizure free and 6 (21%) developed their psychosis after a cluster of seizures, having been seizure free for a longer inter- val than their usual periodicity. This means that over 60% of the sample had a psychosis associated with freedom from seizures. This compares for example with 9 out of 128 (7%) who became seizure free without psychiatric morbidity in one clinical trial [7]. This is further verified in our comparison with the other groups, who fail to show the same seizure-free patterns (see Fig. 1). We cannot over-emphasise the importance of this finding and believe that the phe- nomenon of "forced normalisation" is relevant here [10]. It is also recognised clinically that patients can develop post-ictal psychoses following clusters of seizures and we believe that this is a significant biological precipitant for the development of psy- chosis in some of these patients.

In the group of patients who develop a psychosis following initial suppression of seizures and a break- through cluster, it is possible that they, having be- come seizure free, reduce their standard medications, and with such non-compliance lose control of their seizures and develop a post-ictal psychosis.

Patients with an affective disorder had an even higher incidence of past psychiatric history than the psychotic subjects. In both groups (GVG/Psy and GVG/Dep) , there was a strong congruence between the past psychiatric illness and the current disorder. Patients with a past history of affective disorder may thus be vulnerable to the development of depression as a treatment emergent effect with vigabatrin, and this should be carefully examined.

Patients developing the psychiatric complications of vigabatrin had significantly higher doses than those who were free from such complications. We think this may be an artefact of the steady dose of vigabatrin prescribed at 10 weeks in the clinical trials from which these patients were drawn. How- ever, it may be relevant, and the dose relationship to these problems should be explored further.

In summary, behaviour disturbances are a treat- ment emergent effect of vigabatrin, and a cause to stop the drug in some cases. However, we should note that in our series there are several patients who have had psychosis but continued on vigabatrin, albeit at lower doses, having a few more seizures but having no psychiatric consequences. We are also aware that some patients have received such good seizure freedom that they remain on both neurolep- tics and vigabatrin. We have no such cases in our study, but have some experience of this clinically.

5. Conclusions

It is clear that there is a strong relationship be- tween epilepsy and psychosis which has both histori- cal, clinical and experimental support [9]. Particular risk factors include long standing chronic, intractable partial epilepsy, particularly involving the temporal lobes as a site of origin of the seizures, with sec- ondary generalisation. The population of patients prescribed vigabatrin in the trials that have formed the database for this report come from this particular high risk group.

The main behaviour problems reported seem to be aggression, irritation, agitation, depression and psy- choses. In many cases, these do not lead to with- drawal of the drug, but the more severe ones, that have been the focus of this study, usually require stopping vigabatrin.

Identifiable risk factors for psychotic illness ap- pear to be: a history of psychotic illness, which may have been revealed following prescription of other drugs; a right-sided or bilateral focus; tonic-clonic seizures; and sudden cessation of seizures. This em- phasises the importance of seizure-related events in relationship to the development of psychoses and, to a certain degree, reflects on the powerful anticonvul- sant effects of vigabatrin.

L. Thomas et a l . / Epilepsy Research 25 (1996) 21-27 27

With regards to affective disorder, the most sig- nificant identifiable risk factor appears to be a past history of depression, again sometimes recorded in association with another anticonvulsant.

All vulnerable patients appear to be at greatest risk in the first 10 weeks of treatment and we would recommend vigilance in clinical monitoring during this time, especially in patients with the clinical characteristics identified above.

Our recommendations are that patients prescribed vigabatrin require a thorough psychiatric history evaluation and those with prior psychosis or a his- tory of depression should be carefully monitored. Medication should be introduced at a low dose and increased slowly, and those patients who become seizure free should be more closely monitored, espe- cially in the first 10 weeks of treatment.

If a patient on vigabatrin develops psychosis or depression we recommend that treatment is with- drawn slowly. In such cases, neuroleptics or antide- pressants are often not necessary. In some cases, a patient may continue vigabatrin with neuroleptics or antidepressants, but this is only possible with careful clinical monitoring and if it is necessary for the patient's wellbeing.

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