Several factors may contribute to the underrecognition of depression in epilepsy and lack of adequate therapeutic intervention. These may include the failure to appreciate the impact of depression on quality of life (Wiegartz et al., 1999 : Gilliam, 2002) , concerns over the epileptogenic potential of the antidepressants
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Extent of MR spectroscopy abnormality (mm2)
FIGURE 6.3 Correlation of severity of depression symptoms with spatial extent of hippocampal dysfunction defined by 1H-MR spectroscopic creatine/N-acetylaspartate ratio maps (n = 31). Source: Gilliam et al. (2007).
(Pisani et al, 1999), and uncertainty in regards to the efficacy of standard antidepressant therapy in patients with epilepsy (Kanner, 2003a ; Gilliam et al, 2004b).
Widespread concern in regards to the potential for antidepressants to worsen seizures appears to be mostly unsubstantiated. There are no reports in the literature of TCA-induced seizures at therapeutic serum levels. Patients who suffered seizures at therapeutic doses were discovered to be slow metabolizers of the drug. Rapid increases in medication, an abnormal EEG, the presence of CNS pathology, and personal and family history of epilepsy were other risk factors for developing seizures in non-epileptic patients (Kanner, 2003a).
The actual risk of causing seizures to worsen in patients with epilepsy by the use of antidepressant medications appears to be low. In a prospective study by Kanner et al. of 100 patients with epilepsy treated with sertraline, an SSRI, only one patient was found to have definite worsening of seizure rate and severity, and five others with probable but not definite worsening. Four of these patients remained on sertraline, and none of the patients suffered further seizure exacerbation after adjustment of their AEDs. Resolution of depressive symptoms was achieved in 54% of patients (Kanner et al., 2000) . In a retrospective 2-month study of the TCA doxepin in 19 patients with epilepsy, Ojemann et al. (1983) reported two patients with increased seizures, and 15 experiencing a reduction in seizures (Ojemann )t al., 1983) . As discussed earlier, some antidepressant medications may also exhibit anticonvulsant effects, particularly in low doses, in experimental models of epilepsy and in humans.
The actual treatment of depression in persons with epilepsy is largely based on empiric evidence and anecdotal experience. A practical approach has been proposed by Kanner: Attempts should be made to exclude iatrogenic causes of depressive symptoms, such as the withdrawal of mood stabilizing AEDs such as CBZ, VPA, or LTG, or initiation or titration of an AED with known negative psycho-tropic properties such as phenobarbital, primidone, tiagabine, topiramate, felbamate, and vigabatrin. In the setting of an AED with negative psychotropic properties, the medication may need to be decreased in dose, discontinued, or replaced with an alternative medication. In patients for whom these options are not available, the initiation of an SSRI may be considered. The patient should be started on a small dose of medication, with small incremental increases until desired clinical effect, in order to minimize potential exacerbation of seizures (Kanner, 2003a).
As first line pharmacologic therapy, SSRIs with minimal effects on CYP450 isoenzymes may be preferred, such as citalopram and sertraline. Open trials of the SSRIs sertraline, paroxetine, and fluoxetine and the SNRI venlafaxine suggest that many patients with epilepsy may experience remission of their symptoms of depression (Kanner et al., 2000).
The only prospective randomized, double-blind, placebo-controlled trial of antidepressants in epilepsy was reported in 1985 by Robertson and Trimble (1985). The efficacy of amitriptyline, nomifensine, and placebo were compared in 42 patients with epilepsy and depression. Despite a 50% improvement in the mean BDI and Hamilton Depression Rating Scale (HAMD) scores after treatment, similar degrees of improvement in the placebo arm resulted in no significant difference between groups at 6 weeks. Small patient sample sizes in each treatment group limited the interpretation of the trial results. Of note, no difference was observed in seizure rates between groups placed on TCA or placebo.
Blumer conducted an open label, uncontrolled study involving the addition of an SSRI to patients with interictal affective disorder previously refractory to a TCA, followed over a 20-month period (Blumer, 1997). Within the limitations of the study, treatment was felt to be highly satisfactory with 15 of 22 patients becoming good to excellent responders.
An uncontrolled study by Hovorka et al. (2000) sought to assess the efficacy and safety of the SSRI citalopram in 43 depressed patients with epilepsy. A significant decrease in HAMD scores was observed after 4 weeks and 8 weeks of treatment. There were 28 (65.1%) responders after 8 weeks, all with a decrease on the HAMD of greater than 50%. No seizure worsening was observed in any patient.
Kuhn et al. (2003) conducted a post hoc analysis of 75 adult patients with TLE and MDD treated prospectively with antidepressant medications. Of these, 33 patients were treated with citalopram, 27 with mirtazapine, and 15 with rebox-etine. Depressive symptoms were rated at baseline, at 4 weeks, and between weeks 20 and 30. The rates of response to treatment, defined as a reduction in the HAMD score of greater than 50% between baseline and weeks 20—30, were not significantly different at 51.9% for mirtazapine, 36.4% for citalopram, and 53.3% for reboxetine. Dropout rates were notably high at 74.1% for mirtazapine, 48.5% for citalopram and 40.0% for reboxetine by weeks 20—30, and significantly different only for mirtazapine. There was no increase in frequency or severity of seizures as assessed by clinical judgment.
In an open, multicentered, uncontrolled study by Specchio et al. (2004) ; patients with epilepsy and depression underwent treatment with citalopram for 4 consecutive months (Specchio et al.; 2004). Clinical assessments were performed at baseline, and at 2 and 4 months of therapy. Of 45 enrolled patients, none had a deterioration of seizure frequency. An overall improvement in seizure frequency was observed in the 39 patients who completed the study. Most patients (67%) experienced a marked or moderate improvement of depressive symptoms during the treatment period.
Thome-Souza e t al. (2007) sought to evaluate the influence of SSRIs on the severity and frequency of seizures in children with epilepsy and MDD, in addition to the efficacy of SSRIs in the treatment of depressive symptoms. In their uncontrolled study of 36 children with epilepsy and depression treated with fluoxetine or sertraline, seizures worsened in only two patients within 3 months after beginning an SSRI. All patients remaining on an SSRI had clinical improvement in their depressive symptoms. The authors concluded that SSRIs were a good therapeutic option in children with epilepsy, efficacious in the remission of depressive symptoms, generally associated with sustained maintenance of seizure control, and had few adverse effects.
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