Depression is the most frequently occurring comorbid psychiatric disorder in patients with epilepsy, with prevalence rates of 10% to 20% among patients with controlled seizures and 20% to 60% among those with refractory epilepsy (1,2). Suicide accounts for one of the highest standardized mortality rates of all causes of death in persons with epilepsy and is 10 times more common in patients with epilepsy than in the general population (3).

Studies of depression and health-related quality of life have shown that depression is a better predictor of quality of life than are verbal memory, psychomotor function, cognition, seizure frequency, and seizure severity (4, 5, 6, 7).

Depressive symptoms vary according to the temporal relation to seizure occurrence. Symptoms may arise prior to seizure onset (preictal), as an expression of the seizure (ictal), following seizures (postictal), or unrelated to seizure occurrence (interictal). The clinical presentation in up to 50% of depressed patients with epilepsy does not meet any of the Diagnostic and Statistical Manual of Mental Disorders (DSM) Axis I categories (8,9).

Interictal depression is the most common presentation. It mimics a dysthymic disorder, with endogenous features and an intermittent course, and has been termed interictal dysphoric disorder by Blumer (9). Prominent symptoms include irritability, anhedonia, feelings of hopelessness and helplessness, fear, and anxiety.

Ictal depression manifests as the clinical expression of a simple partial seizure (SPS) in which depression is the sole symptom. The most common ictal psychiatric symptoms are anhedonia, guilt, and suicidal ideation. Preictal depression is characterized by a dysphoric mood that precedes a seizure by hours or days (10) and that usually ends with the seizure. Postictal depression has long been recognized but its frequency of occurrence is unknown. Symptoms often persist for hours to several days.

Depression is both underrecognized and undertreated in patients with epilepsy. A number of reasons have been proposed, including lack of clinical recognition, the consideration that depression is an expected, or “normal,” reaction to having epilepsy and therefore not necessary to treat separately, and concern that all antidepressants may exacerbate seizures. A further limiting factor is the lack of controlled trials for depression in patients with epilepsy.

Before treatment is begun, iatrogenic factors should be considered, such as the recent discontinuation of an antiepileptic therapy with mood-stabilizing properties (e.g., carbamazepine, lamotrigine, valproate, and vagus nerve stimulation); the recent introduction or dosage increase of an antiepileptic drug (AED) with potential negative psychotropic properties (e.g., primidone, phenobarbital, topiramate, vigabatrin, and tiagabine); or the recent remission of seizures (i.e., “forced normalization”).

In the absence of controlled trials, the choice of an antidepressant should be based on safety, tolerability, and ease of use (i.e., frequency of dosage, likelihood of drug-drug interactions). It is prudent to avoid bupropion, maprotiline, and amoxapine because of their potential for exacerbating seizures (11). By contrast, selective serotonin reuptake
inhibitors (SSRIs) are unlikely to worsen seizure frequency or severity, and are generally effective for dysthymic disorders, symptoms of irritability, and poor frustration tolerance. Furthermore, an overdose of an SSRI is unlikely to be fatal, interactions with AEDs are minimal, and side effects are manageable.

Among the SSRIs, sertraline has been best studied. Kanner and associates used sertraline to treat depression in 100 patients with epilepsy. Depressive symptoms improved in the majority of patients, with seizures definitely worsening in only one patient (12). Sertraline can be initiated at 25 to 50 mg per day and increased every 3 weeks as needed, to 200 mg per day or the maximum tolerated dose.

Other pharmacologic options include venlafaxine, tricyclic antidepressants (TCAs), and antiepileptic therapies with mood-stabilizing properties. Monoamine oxidase (MAO) inhibitors require dietary vigilance to minimize the risk for hypertension, and lithium is a proconvulsant in nonepileptic patients and is associated with electroencephalographic changes. Electroconvulsive therapy is not contraindicated and should be considered for patients with pharmacologically refractory depression.

Psychotherapy can help patients cope with limitations imposed by epilepsy and may result in significant improvements in rating scales of depression and anxiety, as well as seizure frequency (13).

A bidirectional relationship between epilepsy and psychosis was proposed during the 19th century. The likelihood of an episode of psychosis occurring in patients with epilepsy varies according to the epilepsy syndrome, seizure severity, and seizure frequency. Consequently, the frequency of psychosis among patients with epilepsy is 14%, compared with 3% in patients with idiopathic generalized epilepsy. In addition, psychosis is reported in 0.6% to 7% of patients with epilepsy in the community versus 19% to 27% of hospital-derived populations (14).

Psychotic symptoms present according to the temporal relation to seizures. The most common form of psychosis in patients with epilepsy occurs between seizures (interictal). Postictal psychosis is less common, and ictal psychotic ideation is rare.

Hill and colleagues observed that patients with interictal psychosis did not display lack of affect, or “asocial or withdrawn attitude” (15). Slater and colleagues confirmed these atypical features, while noting that psychotic episodes included paranoid delusions with visual and auditory hallucinations (16). Consequently, he coined the term “schizophrenia-like psychosis.” Compared with the psychosis of schizophrenia, patients with interictal psychosis have an absence of negative symptoms, better premorbid state, less deterioration of personality, and better response to pharmacotherapy. Possible contributing factors include postictal psychosis, AED toxicity, and AED withdrawal (17).

Postictal psychosis typically begins within several days of a cluster of complex partial or secondarily generalized seizures and includes hallucinations, paranoia, and delusions (18, 19, 20, 21, 22).

In general, psychotropic agents that are associated with a high incidence of seizures in nonepileptic patients should be avoided. These include certain antipsychotics (i.e., clozapine, chlorpromazine, and loxapine) and certain antidepressants (i.e., clomipramine, amoxapine, maprotiline, and bupropion).

Therapies that are less likely to exacerbate seizures include olanzapine 5 to 25 mg per day (major side effects are somnolence, weight gain, and glucose intolerance); risperidone 0.5 to 6 mg per day (associated with weight gain and extrapyramidal side effects); molindone 50 to 200 mg per day; haloperidol (particularly if intramuscular or intravenous administration is needed); and lorazepam 0.5 to 2 mg per day (in conjunction with an antipsychotic to reinforce a sleep schedule) (23).