Etiology of depression in epilepsy

Forced normalization

In the 16th century, Cardenus (Whitwell 1936) wrote about a case of melancholia alternating with epilepsy, describing what is possibly the first case of forced normalization associated with epilepsy. The term forced normalization was coined by Heinrich Landolt (Landolt 1953) and defines a phenomenon characterized by the fact that with the occurrence of psychotic states, the EEG becomes normal or more normal compared to previous recordings.

Although forced normalization clinically usually manifests as a schizophrenia-like psychosis, prepsychotic dysphoria and depression have also been reported (Wolf 1984). Several studies have also reported a decrease in seizure frequency prior to the onset of depressive illness (Dongier 1959/60, Flor-Henry 1969).

A decrease in the seizure frequency and thus forced normalization can be brought about by (Robertson 1998):

* 1) a spontaneous reduction in seizures,
* 2) antiepileptic drugs,
* 3) temporal lobectomy.

The phenomenon of forced normalization forms an interesting interface between neurology and psychiatry, with various theories being suggested to explain the same. While (Wolf et al. (1991) suggested the condition to be a form of active but restricted subcortical seizure activity, various others have postulated that amygdaloid and limbic kindling might play a role in the development of this phenomenon (Krishnamoorthy, 1998). The roles of the glutamate and the GABA receptors in the mechanisms of epilepsy and psychosis also suggest the possibility of the involvement of various neurotransmitters in forced normalization (Krishnamoorthy 1999). One of the most recent hypotheses put forward to explain the same, digresses towards a more physiological view involving dysfunctions of the ion channels, and suggests that the phenomenon of forced normalization could be a unique kind of channelopathy (Krishnamoorthy 2002).

AEDs and depression

Anti-epileptic drugs may cause significant psychiatric side effects. Kanner (Kanner et al. 2000) studied 100 patients who were treated for depression in epilepsy. In almost a third of these patients, the depression was considered iatrogenic, provoked by AEDs. The AEDs, which have been commonly reported as depressogenic, are vigabatrin (10%), tiagabine (5%), topiramate (15%) and phenobarbitone (Trimble 1998). Levetiracetam therapy was associated with depression in 2.5% individuals; this was dose-dependent and was also related to a past history of febrile seizures and status epilepticus (Mula et al. 2003).

Laterality hypothesis

In the late 1960s, Flor-Henry (Flor-Henry 1969) postulated that affective disorders were more common in patients with right-sided temporal lobe epilepsy. Many investigators have subsequently reported mixed and overall equally balanced results, favouring neither the right nor the left hemisphere. Modern laterality hypotheses relate to the connectivity of the mesial temporal lobes; left temporal epilepsy may lead to frontal lobe dysfunction (hypofrontality) and clinical depression (Schmitz 2002). Evidence from FDG-PET (Bromfield 1992) and HMPAO-SPECT (Schmitz et al. 1997) studies also suggest a difference in the psychopathology of depression in left-sided TLE as compared to right-sided TLE. Victoroff (Victoroff et al. 1994), suggested that in individuals with left-sided epileptogenicity, there is a progressive vulnerability to depressive “decompensation”. This “laterality hypothesis” has, however been challenged by Quiske (Quiske et al. 2004), who noted a similar preponderance of depressive symptoms in both right and left-sided pathologies. Depression in left-sided epilepsy has been hypothesized to be a consequence of seizure activity. This has been confirmed (as above) by Reuber (Reuber et al. 2004), who found that following left-sided lobectomy, only patients who became seizure-free improved with respect to mood. Patients with left-sided epilepsies who did not become seizure-free and patients with right-sided TLE however, did not improve.