The prevalence of depression is significantly higher in patients suffering from epilepsy compared to the general public. The condition often remains undiagnosed and untreated due to the belief that antidepressant drugs are proconvulsant. Many of the antidepressants are known to lower the seizure threshold, which may provoke a seizure in patients, particularly in those that have predisposing risk factors for seizures. Of the available antidepressants bupropion has been the best documented with regards to increasing the risk of seizure. However, when used at low doses the antidepressants possess anticonvulsant properties and at therapeutic doses the risk of seizure activity is low. When selecting an antidepressant to be used in a patient with epilepsy, consideration should be made with regards to drug-drug interactions with the antiepileptic drugs, the potential for seizure activity, and the depressive symptoms displayed by the patient. In general, selective serotonin reuptake inhibitors (SSRIs) are considered first line therapy.
Treatment of Depression in Patients with Epilepsy
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The Prevalence of depression is significantly higher in patients suffering from epilepsy compared to the general public; it is the highest comorbid disorder in epilepsy. However the incidence and prevalence are difficult to establish secondary to the under reporting of depressive symptoms, underdiagnosis, and diversity in methodologies and sample populations across studies.1 Depression is more common and severe in patients with epilepsy than in patients with chronic or neurological disorder. 2 Compared to the general population the rate of depression in recurrent seizures is 20% to 55% and 3% to 9% in patients with controlled epilepsy.1 Community-based studies of epilepsy populations report rates of depression from 9% to 22% and hospital based samples report high rates from 27% to 58% of depression. 2 The health-related quality of life has been reported to be worse in patients suffering from frequent seizures compared to those not having suffered any seizures in many years.3 Patients who suffer from reoccurring seizures are 5 times more likely to suffer from depression when compared to patients who did not experience any seizures in the previous year.3 According to Gilliam and Kanner, suicide is one of the highest causes of death in patients suffering from epilepsy; It is estimated to be about 10 times higher compared to the general population.1 The condition often remains undiagnosed and untreated due to the belief that anti depressant drugs are proconvulsant.4
The Diagnostic and Statistical Manual of Mental Disorder (DSM-IV-TR) identifies major depressive disorder as one or more major depressive episodes (at least 2 weeks of depressed mood or loss of interest accompanied by at least four additional symptoms of depression such as weight/appetite changes, sleep disturbances, psychomotor, fatigue, worthlessness, executive function deficit (EFD), or suicidal ideation. 5 Symptoms must cause significant impairment in social, occupational or other important areas of functioning and cannot be attributed to the psychological effects of a substance or bereavement.
Epilepsy is defined as the occurrence of two unprovoked seizure separated by 24 hours.6 Seizures disturb the electrical activity in the brain leading to changes in attention or behaviors.6,7 In epilepsy, permanent changes in brain tissue cause the brain to be too excitable which sends out abnormal signals leading to unpredictable seizures.6
Changes in serotonin (5HT) and noradrenaline (NE) have been shown to play a key role in the pathology of major depression and epilepsy.1 Although the exact pathology of depression is unknown, studies have shown that depression involves catecholamines (dopamine, noradrenaline and serotonin), glutamate, and Gama-Aminobutyric acid (GABA).8 Similarly, decreased activity of serotonergic, and noradrenergic functions has been shown to worsen seizure severity and intensify the likelihood of seizures occurring in some animal models of epilepsy.1
Risk of Seizure with Antidepressants
Many of the antidepressants are known to lower the seizure threshold, which in turn may provoke a seizure in patients, especially those that already have predisposing risk factors for seizures. The mechanism by which antidepressants cause seizures is not fully understood.9 Initially it was thought that, because antidepressants inhibit the reuptake of serotonin and/or norepinephrine, the convulsant properties are secondary to its antidepressant effects. This has since been shown to be unlikely and in fact accounts for the anticonvulsant properties of the antidepressants at lower doses. For example, amitriptyline has been shown to reduce spike activity at lower concentrations in experimental setting.10,11 Other proposed mechanisms for the convulsant properties of antidepressants include effects on glutamatergic, GABAergic, and histaminergic neurotransmission, G coupled K+ channels, and brain derived neurotrophic factor. There is insufficient data to confirm that these proposed mechanisms are the definitive cause of the convulsant properties of the antidepressants.10
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The first antidepressant reported to cause seizures in with depressive illness was imipramine, a tricyclic antidepressant (TCA).10 At therapeutic doses the TCAs seizure rate ranges from 0.4% to 2%. In general the risk should be considered similar between each of the TCAs.9 The tetracyclic antidepressants, maprotiline and amoxapine, have been associated with a higher rate of seizures. Post marketing data indicated that maprotiline had a strong dose relationship and as a result the therapeutic dose range was lowered (maximum dose 225 mg/day). The monoamine oxidase inhibitors (MAOIs) are believed to have a relatively low risk of seizures. Trazodone is considered to have a low risk of seizures although there have been reports of seizures with its use.9 The newer generation antidepressants are considered safe and more tolerable. The incidence of seizure for the newer generation antidepressants is lower than that seen for TCAs and tetracyclic antidepressants (0-0.4%).9 The risks of seizures with the newer antidepressants have been reviewed in several review and research articles (Table 1).
In a review of the World Health Organization- Adverse Drug Reaction (WHO-ADR) database, Vigibase, between the years of 1986 and 2006, and Kumlien et al. assessed the number of convulsions reported to the database associated with antidepressants and other neuroleptic agents. The reports for antidepressants and convulsions ranged from 1.23% to 14.43% with the highest number reported for maprotiline (14.43%), followed by escitalopram (9.78%), bupropion (9.48%), amoxapine (8.74%), trimipramine (5.69%), and clomipramine (5.6%).14 A limitation to the Vigibase data is a causal relationship between the drug and the reported ADR are not formed. Instead the report acts as an early detection of unwanted drug side effects.14 Additionally, Alper et al. did an analysis of the Food and Drug Administration (FDA) Summary Basis of Approval (SBA) reports which is a review of the pre-clinical and clinical data from a drugâ€™s New Drug Application. All antidepressants approved between the years 1985 and 2004 were included and compared to each other for analysis. In their analysis bupropion IR was found to have the highest incidence of seizure (0.6%) followed by citalopram (0.3%). There was not a significant difference amongst the other antidepressants. 15
Supportive therapy should be offered to the patients and family members of newly diagnosed epileptic cases. 16 Supportive therapy will help educate patients and their family about epilepsy, and will help determine a patientâ€™s state of mind and emotional reaction to the disease. Supportive therapy will also help reduce the risk of false belief pertaining to epilepsy and will teach patients and their family to know how to make the best of their disease. Depressive reactions should be treated with supportive therapy, counseling, and rehabilitation .16 More severe reaction may require psychotherapy such as cognitive-behavior therapy.16 Psychotherapy can also be used to help improve patientsâ€™ coping skills.16
Depressive symptoms should be classified according to their occurrence in relation to the onset of the seizures.17 In precital depression, the depressed mood occurs hours to days prior to a seizure episode and is relieved by the onset of convulsions.16 In cital depression, the depressed mood occurs minutes prior to the onset of a complex partial seizure.17 Cital depression is often described as an aura to the onset of the seizure.17 Precital and cital depression are seen by some patients as a warning sign that a seizure is about to occur.16 This allows them to warn others, and get to a safe place. Fast acting drugs such as benzodiazepine can also be used to prevent the onset of the seizure.16 Postictal depression is characterized by depressed mood developed hours to days following a seizure episode. Interictal depression tends to present itself as chronic depression in patients with epilepsy.17
When treating a patient suffering from epilepsy and depression, optimal control of seizures should be attained first with appropriate anticonvulsant treatments.2 Some anticonvulsant drugs such a valproate, carbamazepine, lamotrigine and gabapentin have demonstrated mood improvement in epileptic patients, and have shown efficacy in prevention of manic and depressive episodes in bipolar patients.2 These drugs may thus be beneficial in those patients suffering from depression.
Prior to beginning treatment of depression in epileptic patients, it is important to rule out that the depressive episodes are caused by pharmacotherapy used to treat the epilepsy. For example, discontinuation of carbamazepine, valproic acid, or lamotrigine, which are antiepileptic drugs with mood stabilizing properties can lead to depressive episode.1 In such cases, reintroduction of that antiepileptic drug or of a mood stabilizer agent may be sufficient to reach a euthymic state .1 Another example would be patients suffering from a depressive episode following the introduction or dose increment of an antiepileptic drug with known negative psychotropic properties. If possible, lowering the dose or discontinuing the drug will lead to symptom remission.1 However, if a patient is on an antiepileptic drug with negative psychotropic properties such as phenobarbital, promidone, tiagabine, topiramate, and vigabatric, that are known to yield superior seizure control, the depressive episode can be treated with antidepressants from the selective serotonin reuptake inhibitors (SSRI) group, such as sertraline or paroxetine.17
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The drug of choice used to treat depression in an epileptic patient depends on the most prominent symptoms of depression the patient is exhibiting (e.g., insomnia, anxiety, suicidal ideation), efficacy, interaction with antiepileptic drugs, and side effect profile.16 Effective anti-depressive treatment may indirectly improve seizure control due to the fact that adequately treated patients have improve sleep pattern and are more adherent to their antiepileptic drug regimen.18 In general, selective serotonin reuptake inhibitors (SSRIs) are considered first line treatment in patients suffering from depression and seizures.2 SSRIs are very unlikely to exacerbate onset of seizures, less likely to result in death following an overdose, and have a good adverse-effects profile.17 Tricyclic antidepressants (TCA) have also been shown to yield good clinical response in the treatment of depression in epileptic patients.16 TCAs have a low risk for exacerbating seizures when used within therapeutic range.2 However, due to potential cardiotoxic effects and severe complications seen with overdose, these drugs are used as second line agents.1 Therapy should be continued for four months after the last symptoms of depression to decrease chances of relapse.16
Electroconvulsive therapy (ECT) is well tolerated in epileptic patients and may be considered for epileptic patients who are severely depressed.17
Drug -Drug Interactions
Most antidepressants are inhibitors of one or more cytochrome P450 isoenzymes and are metabolized in the liver.2 SSRIâ€™s inhibition of P450 can result in toxic levels of antiepileptic drugs such as phenytoin, phenobarbital and carbamazepine. Elevated levels of carbamazepine have been observed when given with fluoxetine, fluvoxamine and nefazodone. 2 The administration of fluoxetine and carbamazepine can lead to toxic serotonin syndrome (TSS) which is characterized by uncontrollable shivering, agitation, incoordination, restlessness in feet when sitting, involuntary contractions progressing to myoclonic like leg movements and hyperreflexia.16 Citalopram is an SSRI that does not have any pharmacokinetic interactions with the antiepileptic drugs and can thus be given as an alternative.17
Antiepileptic drugs such as phenytoin, carbamazepine, phenobarbital and primidone are potent cytochrome P450 enzyme inducers.2 This leads to the accelerated metabolism of antidepressant drugs.17 This is especially seen when given with TCAs and paroxetine. 2,16 but not with newer antiepileptics such as gabapentin, lamotrigine and levetiracetam.17
Some anti-depressant such as SSRI and antiepileptic drugs such as barbiturates and benzodiazepine cause sedation and cognitive impairments.2 This can lead to patient suffering from daytime drowsiness and impaired psychomotor function.16
Depression is a common comorbid disorder in patients with epilepsy.1 Although the mechanism is not fully understood, antidepressants are associated with lowering of the seizure threshold, which may induce or provoke seizure, particularly in those that have a predisposed risk. As a result, prescribers may be hesitant to use antidepressants in epileptic patients. Further research has shown that, at lower doses, antidepressants possess anticonvulsant properties and at therapeutic doses the risk of seizure activity is minimal. It is suggested that patients with epilepsy and depression be treated with psychotherapy and, if medication is indicated, SSRIs are generally considered first line because of their safety, tolerability, and side effect profile. Alternatively ECT is a viable treatment option for patients with severe depression and epilepsy who are unable to take antidepressant therapy. When selecting an antidepressant to be used in a patient with epilepsy consideration should be made with regards to drug-drug interactions with the antiepileptic drugs, the potential for seizure activity, and the prominent depressive symptoms displayed by the patient.