The recent editorial by Toone1 serves to highlight the deficiencies in our understanding of the relation between epilepsy and psychosis. Although some aspects of this association are now better established than they were at the time of Slater's classic report,2 insights into the pathophysiological processes underlying these psychoses seem to have advanced very little. A major reason for this, in my opinion, is that the greater focus of research has been on chronic schizophrenia-like psychoses rather than on the episodic psychoses, which are more likely to yield testable hypotheses.

It can be argued that postictal psychoses present the best opportunity to examine some of the pathophysiological mechanisms that underlie the relation. These psychoses occur in patients who have generally been examined in their prepsychotic states, are likely to develop in hospital while the patient is being monitored for epilepsy, and can be closely studied up to their termination and possible recurrence. That they usually occur in relation to partial complex epilepsy that is secondarily generalised suggests the importance of bilateral involvement of limbic structures in their genesis. The fact that postictal psychoses often follow a cluster of seizures must bring into focus the role of neural inhibitory processes in their development. Epileptic conditions are presumed to involve a chronic imbalance of excitatory and inhibitory influences,3 whereas increased inhibition plays an important part in the development and maintenance of the interictal state.4 Human temporal lobe epilepsy is associated with enhanced inhibition,5 which contrasts it from neocortical epilepsy in which the epileptogenic regions demonstrate reduced afterdischarge thresholds.6 The role these inhibitory processes have in the genesis of psychosis has not been adequately examined. Active inhibitory processes may produce focal reversible deficits—such as Todd's paralysis—which may persist for long periods. Is it possible that postictal psychoses are a manifestation of similar processes bilaterally in the limbic cortex? The question lends itself to examination using electrophysiological and neuroimaging techniques, and even in vivo neurotransmitter measurement using microdialysis in patients being monitored with depth electrodes.7

The inhibitory processes not only bring about the postictal state but are also necessary for maintaining the interictal state. Postictal and brief interictal psychoses may therefore not be so different from each other as is generally thought. As the development of seizures may be due to either disinhibition or hypersynchrony involving enhanced disinhibition,3 the occurrence of a seizure during psychosis may have different pathogenetic mechanisms and may indicate either disinhibition or increased inhibition. The effect on psychosis of a seizure could thereby be either an amelioration of symptoms or their exacerbation. This may explain why seizures during postictal psychosis often exacerbate the psychosis whereas those during brief interictal psychosis may improve the psychiatric status. Different patterns of excitation and inhibition may also explain why the EEG may show “forced normalisation” in some cases of interictal psychosis. These speculations can be tested by the longitudinal examination of patients with brief psychoses, using neurophysiological and neuroimaging methods.

The important neurotransmitters involved in the inhibitory processes are GABA, opioids, and adenosine, whereas glutamate is the key excitatory amino acid. Both GABA8 and glutamic acid9 have been implicated in the development of psychosis. Glutamate is also important for the maintenance of brain plasticity and surges in its concentrations may be responsible for mossy fibre sprouting in the hippocampus in temporal lobe epilepsy. These plastic brain changes associated with epilepsy raise the question whether repeated postictal psychoses eventually lead to chronic psychosis. There is a suggestion that this may indeed be the case in some patients,10 but few follow up studies have been published.

The above mechanisms may explain some episodic psychosis, but the enigmatic question is: Why is it that only some patients with recurrent partial complex epilepsy develop psychosis? Is it the “right” mix of inhibition and excitation that is responsible? Is it the involvement of some key anatomical structures? Does the development of psychosis require a substratum of a structural abnormality on which the interplay of these processes comes about? Unless we begin to consider these questions empirically, the relation between psychosis and epilepsy will continue to remain mysterious.