As stated in the preceding text, antidepressant medications are commonly used currently for the management of major depressive disorders, panic disorders, generalized anxiety disorders and obsessive-compulsive disorders, and, finally, ADHD in children and adults who cannot tolerate or do not respond to CNS stimulants. An increased serotonergic (5-hydroxytryptamine [5-HT]) with or without noradrenergic (norepinephrine [NE]) and dopaminergic (dopamine [DA]) CNS activity have been the basic mechanisms of action of most classes of antidepressant drugs. Some of the antidepressants have a mixed serotonergic/noradrenergic action (i.e., imipramine, venlafaxine, duloxetine), whereas others have a pure serotonergic (fluoxetine, sertraline, paroxetine, citalopram) or noradrenergic (desipramine) effect while acting on dopaminergic and noradrenergic receptors (i.e., bupropion). It is of note that there is a growing body of literature that suggests an antiepileptic effect mediated by noradrenergic and serotonergic mechanisms (Chapter 3). For example, increments of either NE or 5-HT transmission with the selective serotonin reuptake inhibitor (SSRI) sertraline resulted in a dose-dependent seizure-frequency reduction in the genetically epilepsy-prone rats (GEPRs) that correlated with the extracellular thalamic serotonergic thalamic concentration (17). In addition, the 5-HT precursor 5-HTP has been shown to have anticonvulsant effects in GEPRs when combined with a monoamine oxidase inhibitor (MAOI) (18), whereas SSRIs and MAOIs have been found to exert anticonvulsant effects in genetically prone epilepsy mice (19) and baboons (20,21) and in non–genetically prone cats (22), rabbits (23), and rhesus monkeys (24). Conversely, drugs that interfere with the release or synthesis of NE or 5-HT exacerbate seizures in the GEPRs. These include NE storage vesicle inactivators, reserpine or tetrabenazine, the NE false transmitter α-methyl-m-tryosine, the NE synthesis inhibitor α-methyl-Δ-tyrosine, and the 5-HT synthesis inhibitor Δ-chlorophenylalanine.

In humans, the evidence is less robust; however, in a double-blind crossover study, imipramine therapy resulted in a significant reduction in seizure frequency in patients with absence and myoclonic-astatic epilepsy despite the discontinuation of other antiepileptic medications (25). Open trials with the tricyclic drugs doxepin and nortriptyline and the SSRIs fluoxetine and citalopram have also suggested a significant reduction in seizure frequency in patients with refractory epilepsy (26,27,28), but
these results need to be confirmed in controlled studies.

The first two classes of antidepressant medications to be developed were the tricyclic antidepressants (TCAs) and tetracyclic antidepressants (TTAs). The former class includes eight drugs: amitriptyline, imipramine, desipramine, doxepin, clomipramine, nortriptyline, protriptyline, and trimipramine maleate, whereas the TTAs include amoxapine and maprotiline. These two classes of antidepressants were reported to cause seizures in nonepileptic patients, primarily in the setting of overdoses or in patients who have high serum concentrations attributed to a genetically determined slow metabolic rate. Among the family of TCAs, however, clomipramine was identified as an agent with a significantly higher incidence of seizures (1%), and therefore it is not recommended for use in people with epilepsy (29). Jobe estimated the risk ratio for epilepsy in patients taking TCAs to be 1.5, compared with a risk ratio of 3.7 for people with depression (30). On the other hand, the two TTAs, amoxapine and maprotiline, were also found to have higher incidence of seizures and are also not recommended in this patient population (31). A low initial dose and slow titration is recommended with the use of TCAs in patients with epilepsy. Furthermore, serum concentrations of most antidepressants of this class are available, and it is recommended that they be measured once the desired dose is reached to identify those patients who may be “slow metabolizers.”

The next class of antidepressant drugs to come onto the market was the MAOIs, which include four drugs: phenelzine, isocarboxazid, tranylcypromine, and selegiline. At present, MAOIs have been restricted to the management of certain patients with atypical depressions or borderline personality disorders, and since the advent of the SSRIs, they have been used as a third-line treatment drug. These medications have been found to be safe in people with epilepsy and their limited use pertains rather to the potential adverse events associated with the ingestion of certain tyramine-containing foods that can result in hypertensive crisis (32).

The third class of antidepressants, which is currently preferred as a first line treatment for mood and anxiety disorders is the SSRIs, which includes six drugs: fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram. In line with the evidence cited in the preceding text linking 5-HT anticonvulsant effects, there are some animal data that have suggested a positive pharmacodynamic synergistic interaction (anticonvulsant) between SSRIs such as fluoxetine and AEDs such as phenytoin or carbamazepine (33,34,35). However, other studies have failed to confirm these observations. Rapeport et al. did not find a meaningful pharmacodynamic interaction between the serotonin reuptake inhibitor sertraline and either phenytoin or carbamazepine (36,37). Whereas evidence for a positive, synergistic dynamic interaction is lacking, there does not appear to be evidence to support a substantial risk of adverse, proconvulsant interaction between SSRIs and AEDs.

In line with the observations that patients with depression may have a 3% to 7% higher risk of developing unprovoked seizures or epilepsy, Kahn et al. completed a study in which they compared the incidence of seizures among patients randomized to three SSRIs (escitalopram, fluoxetine, and fluvoxamine) with placebo as part of the regulatory studies for the treatment of depression (38). They found that patients randomized to the antidepressants were significantly less likely to have had an epileptic seizure compared with controls (24).

The experience with the newer antidepressant drugs in the family of serotonin norepinephrine reuptake inhibitor (SNRI), venlafaxine and duloxetine, is very limited, but the incidence of seizures in the regulatory studies compared with placebo-exposed patients does not appear to be increased.

Another class of drugs is the NE and DA reuptake blocker bupropion, which has relatively weak reuptake properties of DA and NE, but its active hydroxylated metabolite has strong reuptake properties of these neurotransmitters and seems to be responsible
for the efficacy of this agent. This a drug used for a certain type of depressive order (i.e., retarded depression) and for the management of ADHD. In an early study, bupropion appeared to be relatively safe, even at dosages above 450 mg per day (39). However, in a study of 69 patients with bulimia, 4 patients developed generalized tonic-clonic seizures (40). A rate of seizure frequency ranging from 0.36% to 0.48% has been reported in patients exposed to bupropion at a dosage of 450 mg per day or less (41). Lower doses, however, were identified with extended release formulations at doses of 300 mg per day or less in a study of 3,100 patients, yielding a seizure frequency of 0.15% (42). This lower frequency of seizures suggests that avoidance of a peak of dose effect may have an important role in minimizing the proconvulsant properties of this antidepressant medication. If this medication is to be used presently in patients with epilepsy, it should be started at a low dose and not exceed doses of 300 mg per day. In general, it is recommended that the drug be avoided.

In summary, to date, antidepressant medications can be safely used in patients with epilepsy, with drugs of the SSRIs being among the safest ones. TCAs can be safely used but can be started at low doses and increased slowly, and serum concentrations should be monitored to identify patients who may be slow metabolizers. Clomipramine, maprotiline, and amoxapine should, however, be avoided in patients with epilepsy. MAOIs can be safely used in patients with epilepsy, whereas bupropion should be avoided, unless there is no other option. If it were to be used, the dose should not surpass 300 mg per day.

The CNS stimulants used for ADHD include methylphenidate in its different formulations (immediate release methylphenidate, extended release methylphenidate, Concerta) dextroamphetamine in its immediate and extended release formulations, and pemoline, which is used as a last choice currently because of its identified hepatotoxicity. There has been a concern among clinicians that the use of CNS stimulants may be associated with an increased risk of epileptic seizures, and hence these drugs are often avoided by pediatricians, pediatric neurologists, and neurologists, in patients with epilepsy. It should be remembered, however, that ADHD is the other psychiatric condition with a bidirectional relationship with epilepsy and children with ADHD were found to have a 2.5% higher risk of developing incident seizures or epilepsy (14). As stated in the preceding text, this bidirectional relationship obviously raises the question as to whether the witnessed seizures reported in the literature in patients started on CNS stimulants were an expression of the inherent risk of the ADHD and not the consequence of the treatment with a CNS stimulant. In fact, Wernicke reviewed the seizure risk in patients with attention deficit disorder who were treated with an NE agent atomoxetine, methylphenidate, and placebo (43). In the review of 31 studies that totaled 5,831 patients on atomoxetine, 1,015 patients randomized to placebo, and 523 patients randomized to methylphenidate, there were no statistical differences in the incidence of seizures among the three groups. The incidence of seizures was of 0.06% during the control phases. Currently, the consensus among pediatric epileptologists and neurologists is that the use of CNS stimulants in children and adults with epilepsy is safe.