Neuropsychiatric Symptoms of Epilepsy

2 Depression
27
developing unprovoked seizures or epilepsy among patients who had been hospitalized
for a psychiatric disorder ( n = 1885) to a group of controls, matched for gender,
and year of diagnosis selected randomly from the register of the Stockholm County
population [ 12 ]. The age-adjusted odds ratio for development of unprovoked seizures
was 2.5 for people with major depressive disorder, 2.7 for patients with bipolar
illness, 2.7 for anxiety disorder, and 2.6 for suicide attempt. Three other
population-based studies published between 1990 and 2006 demonstrated that
patients with a depressive disorder had a threefold to sevenfold higher risk of developing
epilepsy [ 13 – 15 ].
The above findings cannot be attributed to the use of psychotropic drugs despite
the long-held belief that antidepressants have proconvulsive properties. In fact,
there is increasing data from experimental animal studies that this type of medications
may have a protective effect against the development of seizures. In humans
with primary mood disorders, one study suggested that antidepressants (with two
exceptions) may have a protective effect against seizure occurrence. This study
investigated the incidence of seizures in patients with primary major depressive and
obsessive compulsive disorders during the course of multicenter-randomized
placebo- controlled trials of antidepressants carried out for regulatory purposes in
the United States and compared the incidence of seizures between those randomized
to a psychotropic drug and those given placebo [ 16 ]. Data for this study
included Phase II and III multicenter-randomized placebo-controlled trials that
encompassed 75,873 patients between 1985 and 2004. The trials included antidepressants
of the tricyclic, selective serotonin-reuptake inhibitor (SSRI) and
serotonin- norepinephrine reuptake inhibitor (SNRI) families as well as bupropion.
The investigators found a higher incidence of seizures in patients randomized to
clomipramine and bupropion in its immediate release form. On the other hand, subjects
randomized to the other antidepressants were 52 % less likely (69 % less likely
when excluding bupropion immediate release formulation) to develop seizures
compared to those randomized to placebo. In addition, patients randomized to placebo
were 19 times more likely to experience a seizure, compared to the expected
incidence in the general population.
As indicated above, antidepressant drugs of the SSRI and tricyclic families have
been found to display antiepileptic effects in several animal models of epilepsy [ 17 ],
while reduction in seizure frequency has been suggested in three open trials with
SSRIs in patients with treatment-resistant epilepsy [ 18 – 20 ]. In fact, the long-held
belief of a proconvulsant effect of antidepressant drugs is derived from observations
of seizures resulting from their use at very high doses (e.g., in overdoses). The only
four antidepressants with known proconvulsant properties at therapeutic doses are
amoxapine, clomipramine, maprotiline, and bupropion. Furthermore, since a psychiatric
history has been associated with an increased risk of the development of
epilepsy, seizure occurrence during their pharmacologic management may in fact
reflect the “natural course” of the psychiatric disorder and not an iatrogenic effect
of the psychotropic drug.