oxidise inhibitor (non-MAOI) ADs, including the newer selective serotonin-reuptake inhibitors (SSRIs), have been associated with the occurrence of seizures (5–7). SSRIs, however, have been thought to be safer than other classes of ADs. Yet, some authors have warned against becoming too complacent, given the conflicting nature of the data on the epileptogenic potential of SSRIs (8).

Because of their overall safety profile, SSRIs are currently the ADs of first choice in the treatment of MDD, dysthymic disorder (DD), and obsessive–compulsive disorder (OCD) (9). Seizure occurrence has been estimated to range from 0.1 to 0.2% among nonepileptic patients treated with SSRI; sertraline (SRT) had the lowest reported seizure occurrence (10). The risk of seizure worsening with SRT among patients with epilepsy is yet to be established, however.

The purpose of this study was to assess the impact of SRT on the severity and frequency of seizures in 100 consecutive patients with epilepsy and depression or OCD. We chose SRT among the different SSRIs because of its insignificant pharmacokinetic interaction with antiepileptic drugs (AEDs), as well as for the reported "apparent" paucity of epileptic seizures in nonepileptic patients (10).

METHODS

We prospectively monitored the seizure frequency of 100 consecutive patients with epilepsy after being started on SRT for the treatment of a depressive (n 5 97) or obsessive–compulsive (n 5 3) disorder. Children and adults were started on SRT at daily doses of 25 and 50 mg, respectively. The dose was increased by the same amount at 3-week intervals until patients became symptom-free, reached a maximal daily dose of 200 mg, or developed adverse events (AEs). During SRT titration, AED doses were kept stable, unless an increase in seizure frequency was reported. Patients who initially responded to SRT, but then developed tolerance, underwent additional 50-mg dose increments until they became again symptom-free, reached a daily dose of 200 mg, or developed AEs. If symptoms had not remitted at that dose, patients were switched to the SSRI paroxetine at a dose of 20 mg/ day.

Assessment of Seizure Frequency

During titration of SRT, patients were followed in the outpatient clinic every 4 to 8 weeks. Once patients reached their final dose, they were followed every 12

weeks. All patients kept a record of their seizures in a seizure calendar, which was checked at every visit and transcribed to their medical chart. Seizure frequency for the 12 months preceding the start of SRT was also available in the medical records of all patients who had been seen at approximately 3-month intervals. We calculated each patient’s monthly mean and maximal seizure frequencies for the 3 and 12 months preceding the start of SRT, which we used for comparison with the monthly mean and maximal seizure frequencies recorded during the SRT trial. A comparison with the seizure frequencies of the preceding 12 months was necessary to minimize false-positive conclusions of seizure worsening, given the natural fluctuation of seizure frequency in patients with uncontrolled seizures. For patients whose seizures usually occurred in clusters (defined as more than one seizure in a 24-hour period), we calculated the mean and maximal monthly number of clusters for the same time periods.

Seizure Worsening Criteria

We developed two sets of criteria to establish whether causality between seizure worsening and SRT was "probable" or "definite." A definite causality was considered in the following circumstances: (1) occurrence of de novo primary or secondarily generalized tonic– clonic seizure (GTC) in patients with only absence seizures or simple and complex partial seizures, respectively; (2) recurrence of a GTC following a period of at least 1 year without this seizure type; and (3) an increase in the seizure frequency beyond the maximal recorded frequency during both the 3- and 12-month periods preceding the start of SRT. A probable causality between seizure worsening and SRT was considered in the case of an increase in seizure frequency beyond the maximal frequency recorded during the 3 month, but not the 12-month, period preceding the start of SRT. All analyses were done on an intent-to-treat basis.

Psychiatric Assessment

Every patient underwent a psychiatric evaluation by one of the authors (A.K.), who is board certified in neurology and psychiatry. Each patient received a DSM-IV diagnosis (11) that was based on a semistructured interview derived from the SCID-I (12). Since a significant number of patients with epilepsy experience depressive disorders that fail to meet any DSM criteria (13), we identified the DSM-IV diagnostic category with which the clinical phenomenon had the closest similarities. In addition, we determinedK

whether the depressive disorder was spontaneous or iatrogenic. The latter was considered when symptoms followed the introduction or dose increase of an AED. At the end of each psychiatric evaluation, we generated a list of symptoms of depression identified as a target for SRT therapy. At all follow-up visits each symptom was rated as follows: (i) present, unchanged; (ii) present, partially improved; (iii) completely resolved.

RESULTS

Seizure Disorder Profile

Among the 100 patients, 49 were women and 51 men. Their mean age was 29.9 ± 13.5 years (range, 6–62). The mean duration of their seizure disorder was 16.2 ± 8.5 years (range, 8–40). Ninety-five patients suffered from partial epilepsy and five from primary generalized epilepsy. Sixty-two patients had intractable epilepsy and 38 were seizure-free at the start of SRT. The latter group included the five patients with primary generalized epilepsy. Forty-two patients were on one AED, 51 on two, 5 on three, and 1 on four. One patient was off all AEDs. In 28 patients, the psychiatric disorder was considered to be iatrogenic, and was attributed to the introduction of vigabatrin (VGB) in 14 patients, primidone (PRM) in 12, and phenobarbital (PB) and topiramate (TPM) in 1 each.

SRT Dose and Impact on Seizure Frequency

The mean dose of SRT taken by the 100 patients was 108 ± 56.9 mg/day (range, 25–200). The mean duration of treatment was 10.3 ± 10.1 months, and the median duration, 6 months (range, 0.2–38 months). Six patients (6%) experienced an increase in seizure frequency during their SRT trial. A definite causality between seizure worsening and SRT could be established in only one patient, however. This patient experienced a flurry of secondary GTCs while taking SRT at a daily dose of 50 mg. At that time he was on a regimen of carbamazepine at daily doses of 800 mg with a serum concentration of 10.8 mg/liter. This patient had a single seizure during the year preceding the start of SRT on the same AED regimen. He was taken off SRT and no further seizures recurred. In the other five patients (5%) we established a probable causality between seizure increase and SRT, as their monthly seizure frequency was higher than the maximal monthly frequency recorded during the 3 months

but not the 12 months preceding the start of SRT. All five patients required an adjustment of their AED dose. Four patients were kept on SRT at the same doses without further seizure exacerbation, while one patient opted to be taken off SRT. Seizure worsening occurred during the first 2 months of treatment at SRT doses significantly lower than those reached by the other 94 patients (57.1 ± 23.8 mg/day vs 111.8 ± 56.8 mg/day; F = 6.35, P = 0.01). The six patients who experienced seizure worsening failed to differ from the 94 other patients with respect to the following variables: type of seizure disorder (F = 0.4, P = 0.5), baseline seizure frequency (F = 0, P = 0.98), number of AEDs (F = 0.1, P = 0.8), and whether the psychiatric event was iatrogenic or spontaneous (F = 0.01, P = 0.97). For the entire group of 100 patients, the mean monthly seizure frequency during the 3 months preceding the start of SRT failed to differ from that recorded while on the drug (3.7 ± 9.1 vs 3.3 ± 9.0, t = 1.6, P = 0.2).

Psychiatric Profile

Among the 100 patients, three met DSM-IV criteria for OCD. One of these patients developed an OCD as part of Tourette’s syndrome triggered by lamotrigine. The other 97 patients had a depressive disorder: 28 met DSM-IV criteria for MDD. The depressive symptoms of the remaining 69 patients did not meet criteria of any of the DSM-IV recognized categories of affective disorders (i.e., MDD, DD, cyclothymia, or bipolar disorder); therefore, they were classified under the category of Depressive Disorder Not Otherwise Specified.

These 69 patients presented a pleomorphic clinical picture consisting of anhedonia, with or without hopelessness, fatigue, anxiety, irritability and poor frustration tolerance, and mood liability with bouts of crying. Changes in appetite and sleep patterns and problems with concentration were also reported by some patients. In 33 of these 69 patients (34%), the predominant and most disabling symptom was anhedonia, while in the remaining 36 patients, irritability and poor frustration tolerance were the most disabling symptoms. Most symptoms presented with a waxing and waning course, with repeated interspersed symptom- free periods of one to several days’ duration. Nevertheless, symptomatology was severe enough in all patients to disrupt their activities, interpersonal relations, and overall quality of life and to make them seek treatment.

These clinical phenomena had the strongest similarity with DD; accordingly, we referred to these symptom clusters as "dysthymic-like disorder of epilepsy"

tration tolerance (9). Complete resolution of these symptoms was reported by 59 (59%) of our patients. Improvement was noted to occur within the first 2 weeks of therapy and preceded the response to therapy of other symptoms of depression.

Fourteen patients developed tolerance to the effect of SRT. Five responded to further dose increments, while nine patients had to be switched to another SSRI, paroxetine, resulting in complete symptom resolution in all patients at a dose of 20 mg/day. No seizure worsening was observed in these nine patients during their trial with paroxetine.

Response to SRT was significantly more frequent among patients with a past history of MDD (F = 4.81, P = 0.03) and among patients on one AED only (F = 5.8, P = 0.018). It was significantly less likely among patients with prior psychopharmacologic treatment of any psychiatric disorder [not necessarily depression (F = 7.3, P = 0.008)]. On the other hand, response to SRT was not associated with dose (109.5 6 53.9 mg/ day vs 106.5 ± 60.7 mg/day, F = 0.06, P = 0.8), baseline seizure frequency (F = 1.4, P = 0.25), type of psychiatric disorder (F = 0.5, P = 0.47), or whether the event was spontaneous or iatrogenic (F = 0.89, P = 0.35).

Adverse Events

Sedation was the most frequent AE (n = 9), followed by hypomanic symptoms (n = 7). One patient experienced rheumatic pain in her wrists and another patient had myoclonus. AEs disappeared following discontinuation of SRT in all patients. Hypomania occurred in four patients who were taking VGB, one patient on LTG, and two on carbamazepine. A family history of depression was identified in six of the seven patients who experienced a hypomanic episode.

DISCUSSION

This is the first study, to the best of our knowledge, to examine the impact of SRT in a large group of patients with epilepsy and depression or OCD. The findings of this study suggest that SRT carries a minimal risk of worsening seizures among these patients. We were able to establish a definite causality between the worsening of seizures and SRT in only one patient. In five other patients, the change in seizure frequency met our criteria for a probable causality. Yet, in all five patients this seizure increment was easily controlled with an adjustment of the AED dose. Accordingly, discontinuation of SRT can be averted and should not

be automatically advocated if the patient is deriving a therapeutic benefit. We also have to recognize our inability to exclude the possibility that the increase in seizures in these five patients resulted from the natural fluctuation of their seizure frequency, as this is a very common phenomenon in patients with intractable epilepsy.

Complete resolution of depressive symptoms was achieved in 54% of our patients without having to proceed to high doses of SRT. This percentage would have increased to 60% had we excluded the 10 patients who discontinued the drug very early in the course of therapy because of AEs. These percentages are identical to those reported in most double-blind, placebocontrolled studies of most ADs in nonepileptic depressed patients (14). The SRT dose did not have an impact on seizure worsening, as the 6 patients who experienced this problem were on significantly lower doses than those with unchanged seizure frequency. The opposite relationship has been reported with tricyclic antidepressants (TCAs), which can increase the risk of seizure occurrence at high doses in nonepileptic patients (15). Nevertheless, we must view these results with caution, given the small number of patients in our study who experienced an increase in seizure frequency.

The use of SRT in depressive disorders of epileptic patients has several advantages over other families of ADs. First, SRT has been found to be effective in the treatment of DD (9) and hence should yield a therapeutic effect in DLDE. Our preliminary treatment response data appear to support this hypothesis. Yet, the efficacy of SRT in DLDE can only be demonstrated in a double-blind placebo-controlled study. Second, its therapeutic effect on irritability and poor frustration tolerance is an additional advantage (9), as these are two prominent symptoms of spontaneous and iatrogenic DLDE. In our trial, complete remission of irritability with SRT was observed in two-thirds of patients and occurred early in the course of therapy, preceding the remission of other symptoms of depression, such as anhedonia and feelings of hopelessness and helplessness. We recognize that we can derive only limited information from the treatment response to SRT, since this was an open trial, and placebo effect is relatively high in psychopharmacologic therapies. Accordingly, we consider the treatment response data as preliminary or pilot data. On the other hand, knowledge of the treatment response was necessary to place in a proper perspective the doses of SRT reached by patients. Double-blind placebo-controlled studies are necessary to confirm these observations as well. Finally, the safer AE profile of SSRIs compared with that

of TCAs and MAOIs has placed this class of ADs as the drugs of first choice for the treatment of depressive disorders in epileptic and nonepileptic patients (9).

Our data clearly show that the majority of patients with symptoms of depression did not meet criteria of MDD. Instead, they presented with a pleomorphic cluster of symptoms that resemble DD, which we referred to as DLDE. Others have reported similar observations. For example, among the depressive episodes identified in a study by Mendez et al., 50% had to be classified as Atypical Depression, according to DSM-III criteria (16). Kraepelin described this form of depression in 1923 (17), and in recent years, Blumer coined the term interictal dysphoric disorder (IDD) in referring to this disorder (18, 19). Blumer considers that almost one-third to one-half of patients with epilepsy seeking medical care suffer from IDD of sufficient severity to require pharmacologic treatment (19).

Only one-third of our patients with a depressive disorder of more than 1-year duration were treated within 6 months of the onset of their symptoms. Delay in the start of pharmacotherapy was not related to the severity of the depressive disorder, as the same proportions of patients with chronic MDD and DLDE went without ADs for more than 1 year. Underrecognition of depressive disorders has been described by others (3).

One-third of our patients were treated for an iatrogenic depressive disorder caused by an AED. In general, we advocate treating such iatrogenic processes by lowering the dose or discontinuing the culprit AED. However, in some patients with refractory epilepsy, this AED may be the only drug that improves seizure control. Such was the case in 25 of the 28 patients we included in the trial with SRT. In 13 of these 25 patients, all symptoms remitted with SRT, and we were not forced to discontinue the one AED that had provided them with the best seizure control.

In conclusion, the risk of worsening seizures with SRT is minimal in patients with epilepsy. Further, in this open-label study, symptoms of depression responded favorably with SRT. Accordingly, treatment with SRT should not be delayed in depressed patients with epilepsy requiring AD treatment.

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