How seizure disorders change depression treatment

Seizure risk. Seizures are a rare but serious adverse effect of most antidepressants (Table 2).¹³ Compared with the incidence of first seizures in the general population (4 Generalized tonic-clonic seizures are associated with increased mortality in tricyclic antidepressant (TCA) overdose, especially with amitriptyline, maprotiline, and clomipramine.

Desipramine, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and trazodone are preferred options for depressed epilepsy patients because these drugs lower the seizure threshold less than other antidepressants, with a 1% to 1.5% incidence of seizures during the first 2 years of treatment.¹⁴ Because most seizures reported with these medications are dose-related, blood level monitoring is helpful. Avoid bupropion, which has a seizure rate double that of other antidepressants.⁶

Clinical trial experience and EEG studies suggest that the SSRIs are less epileptogenic than TCAs. MAOIs also are less likely than TCAs to cause seizures but can cause excessive sedation when coadministered with barbiturates. The only double-blind trial of antidepressants (amitriptyline, nomifensine, and placebo) to treat comorbid depression and epilepsy found no significant differences among drugs or placebo.⁸

Drug-drug interactions. Consider the cytochrome P450 enzyme system when choosing an antidepressant for an epilepsy patient.⁶ Antidepressants can alter serum levels of phenobarbital and carbamazepine, and AEDs usually reduce antidepressant levels.⁸ For example, carbamazepine could lower TCA levels, valproic acid might elevate TCA levels,¹⁵ and imipramine and nortriptyline might increase phenytoin levels. Similarly, monitor TCA levels during AED withdrawal, as increased TCA concentrations can result in toxicity and concomitant behavioral effects.¹³

SSRIs may cause a dramatic rise in AED levels, leading to dizziness, ataxia, confusion, and somnolence. Sertraline and citalopram seem less likely to increase AED levels than fluvoxamine or fluoxetine.⁶ Fluvoxamine inhibits carbamazepine and phenytoin metabolism.³ Among SSRIs, most case reports of drug-drug interactions involve fluoxetine, which inhibits cytochrome enzymes and may increase carbamazepine or phenytoin levels, sometimes with clinical consequences.⁶ Monitor electrolytes when prescribing carbamazepine or oxcarbazepine with an SSRI because the combination may cause hyponatremia.

Start antidepressants at doses lower than used in patients without epilepsy, and gradually increase until depression remits. Periodically check AED levels during antidepressant treatment, and adjust dosages to maintain a therapeutic level.

Algorithm

Stepwise approach to treating
comorbid psychiatric disorders and epilepsy

Step 1
Determine the etiology of depression
↓
Step 2
Assess AED regimen Avoid polytherapy Consider the adverse psychotropic effects with phenobarbital and primidone Consider changing to carbamazepine or valproic acid, if clinically appropriate; modified release preparations usually are better tolerated Monitor total plasma levels of AEDs Screen erythrocyte folate levels
↓
Step 3
Start the antidepressant at a low dose and then increase slowly Start with drugs of choice such as selective serotonin reuptake inhibitors Bupropion, maprotiline, and clomipramine are contraindicated in patients with a history of seizures, brain injury, or EEG abnormality Assess for antidepressant-AED interactions Continue to monitor plasma levels of AEDs Remember that all antidepressants can lower the seizure threshold
↓
Step 4
Consider ECT for refractory or severe depression
↓
Step 5
Recommend support groups and cognitivebehavioral therapy Communicate regularly with patient’s neurologist, primary care physician, and other specialists involved in his or her care
AEDs: antiepileptic drugs; ECT: electroconvulsive therapy;
EEG: electroencephalography

Table 2

Antidepressants’ seizure potential in any patient

Antidepressant	Risk of seizures (%)
High risk (not indicated for epilepsy patients)
Bupropion     450 to 650 mg	0.4 0.6 to2.19
Clomipramine	0.5 to 1.66
Maprotiline	0.4 to 15.6
Intermediate risk
Tricyclics	0.1 to 15.6
Amitriptyline	0.4 to 0.5
Imipramine	0.6 to 0.9
Low risk
Citalopram
Fluoxetine
Fluvoxamine	0.2
Paroxetine	0.1
Sertraline
Trazodone
Venlafaxine	0.1 to 0.2
Mirtazapine
Duloxetine	0.2
Source: References 6,3

Nondrug therapies

ECT. Consider ECT for patients with refractory or severe depression. ECT can be lifesaving—especially in patients with psychotic depression—and is a viable and safe alternative to antidepressants for patients with epilepsy.³

ECT can raise a patient’s seizure threshold.¹³ Unilateral nondominant electrode placement is recommended to minimize the combined cognitive side effects of AEDs and ECT. Except for those at high risk of status epilepticus, advise patients not to take their AEDs the morning of ECT treatments.

Support groups. Epilepsy can affect many aspects of a patient’s life, including education, employment, family life, and selfesteem.¹³ Epilepsy support groups can provide emotional support by introducing patients to others with a seizure disorder. Patients often experience a sense of relief when they discover that they are not alone and other group members share similar dilemmas. Becu et al¹⁶ reported that self-help group intervention characterized by education, support, and socialization significantly reduced depression scores in epilepsy patients. These groups often offer education about the nature of the patient’s illness.