Pharmacologic Management of Behavioral Challenges and Psychiatric Comorbidities in People With Epilepsy

People with epilepsy experience higher rates of psychiatric and behavioral comorbidities than the general population. A variety of factors can contribute to the severity of these comorbidities including specific antiseizure medication(s) (ASM) used, epilepsy type, overall seizure burden, interictal EEG abnormalities, and genetics. Failure to adequately address mood disorders and maladaptive behavior can affect levels of executive functioning, development, medication adherence, and quality of life, which can in turn affect seizure control. Therefore, it is essential that epilepsy care include identification and management of psychiatric and behavioral challenges. 

Accessing psychiatric care may be challenging for some individuals. Therefore, neurologists can better serve their patients by familiarizing themselves with first-line pharmacologic treatments for the most common psychiatric and behavioral comorbidities of epilepsy. The Figure illustrates the relationship among epilepsy, its most common associated conditions, and the behavioral challenges with which they can present.

Figure. The relationship among epilepsy, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and depression or anxiety, and the constellation of symptoms with which these co-occurring conditions may present.

Selective Serotonin Reuptake Inhibitors
Anxiety and depression are common in people with epilepsy and more common in people with epilepsy than in the general population.^1,2 Mood disorder symptoms include excessive worry, loss of interest in activities, irritability, restlessness or decreased energy, changes in sleep patterns, and changes in appetite. Depression and anxiety in children can present with anger, aggression, disruptive behavior, somatic complaints, and decreased academic performance.³ Mood disorders should be considered when assessing and treating maladaptive behavior, particularly in children and people with global developmental delay or intellectual disability.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for anxiety or depression in people with epilepsy. SSRIs are considered safe for people with seizures and may even have an anticonvulsant effect.³ Among the SSRIs, fluoxetine and escitalopram are approved by the Food and Drug Administration (FDA) for people aged ≥6 years and ≥7 years, respectively. Sertraline and fluvoxamine are generally considered safe for children, although they do not have specific FDA approval for pediatric use. 

SSRIs are typically well-tolerated, with common side effects being gastrointestinal upset, headache, insomnia, and agitation. Side effects occur most frequently at treatment initiation and resolve with continued dosing. It is recommended to start an SSRI at a low dose and titrate up every 2 weeks to the minimum effective dose to reduce the risk of side effects. Less commonly, activation syndrome (hyperactivity, irritability, insomnia, disinhibition, restlessness, and anxiety) can occur, typically around the third or fourth week after treatment initiation.⁴ Patients should be counseled on activation syndrome and potential side effects before starting an SSRI and monitored for symptoms that do not resolve within a few days of treatment initiation or dose increase. 

Table 1 lists recommended starting doses and half-lives for commonly prescribed SSRIs. Starting at half the recommended initial dose may be considered if patients are worried about potential side effects. In addition, escitalopram, sertraline, and citalopram have the greatest overall tolerability and may also be considered for patients who have experienced side effects on other SSRIs. Those who experience intolerable side effects may be switched to second-line medications such as venlafaxine, duloxetine, or mirtazapine for depression, or hydroxyzine or buspirone for anxiety.⁴

In 2004, the FDA issued a Boxed Warning for SSRIs for increased risk of suicidal thoughts and behaviors in adolescents. It has since been found that reasons for increased rates of reported suicidal ideation (SI) in adolescents taking SSRIs are likely multifactorial and confounded by mood disorder type, symptom severity, and previous SI.⁵ Studies of populations showing substantially decreased rates of pediatric SSRI prescription following the issuance of this Boxed Warning demonstrate that while rates of reported SI decreased, the rate of suicide attempts increased.⁶ This suggests that SSRI use may increase the reporting of preexisting SI, thus enabling more successful interventions. People who express SI while taking an SSRI should immediately be referred to a psychiatrist. 

Rapid withdrawal of SSRIs is not recommended—even in cases of SI—due to risks of rebound symptoms. SSRIs should be tapered off over 2 to 4 weeks. People on higher doses of SSRIs or SSRIs with shorter half-lives (particularly sertraline and fluvoxamine) as well as those who have had a longer duration of SSRI treatment (>6 months) or a history of rebound symptoms should be tapered off over at least 4 weeks. 

Antipsychotics
The reported frequency of autism spectrum disorder (ASD) in people with epilepsy is between 15% and 74% depending on the etiology and type of epilepsy.7 People with ASD who have epilepsy experience more challenging behaviors than those with ASD who do not have epilepsy.^7,8

Aripiprazole and risperidone are first-line treatments for challenging behavior in people with epilepsy with co-occurring ASD.⁹ These agents are approved by the FDA for treatment of emotional dysregulation and irritability in people with ASD aged ≥6 years and ≥5 years, respectively. Both medications have demonstrated greater efficacy than placebo in treating emotional dysregulation, aggression, irritability, and hyperactivity in people with ASD regardless of seizure history. However, their effectiveness in people with epilepsy may be reduced in the presence of a high seizure burden, global developmental delay, intellectual disability, or an underlying genetic syndrome. In addition, certain ASMs, such as phenytoin, carbamazepine, and topiramate, may affect blood levels of antipsychotics.¹⁰ Other second-generation antipsychotics (eg, quetiapine, olanzapine, ziprasidone, lurasidone) have limited studies supporting their efficacy in treating challenging behaviors in people with ASD and are not recommended.¹¹

Studies have found that aripiprazole and risperidone do not carry an increased seizure risk,¹² although it is unclear whether the analysis included people with preexisting seizure disorders. Therefore, concern for increased seizure risk is not a contraindication when prescribing aripiprazole or risperidone to people with epilepsy, although it may still warrant close monitoring. Weight gain and sedation are the most common reported side effects of aripiprazole and risperidone treatment.^9,11 People on aripiprazole exhibit less weight gain than those on risperidone in the first 2 months of therapy, but there is no significant difference in the amount of weight gained in the long term.⁹

Routine monitoring of weight, blood glucose level, and lipid metabolism is recommended for people taking antipsychotic medications. Table 2 outlines the recommended laboratory tests and monitoring schedule. People should be asked about any personal or family history of diabetes, hypertension, or cardiovascular disease before starting treatment because they may require more frequent monitoring. 

People experiencing side effects may be tapered off their medication over 1 to 2 weeks. Alternatively, people whose behavior improves on aripiprazole or risperidone but are experiencing excessive weight gain or metabolic derangements may consider starting metformin rather than discontinuing the medication.¹¹ There is also emerging evidence supporting the use of glucagon-like peptide-1 (GLP-1) receptor agonists to combat weight gain, hyperglycemia, and hyperlipidemia associated with antipsychotic medication.^13,14 People should be referred to their primary care physician or an endocrinologist if they are interested in starting metformin or a GLP-1 receptor agonist.

Table 3 provides dosing guidelines for aripiprazole and risperidone. As with SSRIs, individuals should be started on low doses of antipsychotics and titrated up every 1 to 2 weeks to the minimal effective dose. Before starting an antipsychotic, individuals should be screened for mood disorders and attention-deficit/hyperactivity disorder (ADHD), which may be better treated with an SSRI or stimulant or nonstimulant medication. Increasing irritability while on aripiprazole or risperidone may be a sign of drowsiness, in which case guanfacine may be considered (see discussion of α-agonists in the next section).

Stimulants and Nonstimulants
ADHD is the most common comorbidity in pediatric epilepsy with a higher prevalence among adults with epilepsy than the general population.¹⁵ In addition, poor seizure control is associated with higher risk of ADHD.¹⁶ ADHD symptoms include hyperactivity, impulsivity, inattentiveness, lack of focus, and disorganization. Methylphenidate (Cotempla XR-ODT; Neos Therapeutics, Grand Prairie, TX) is the most prescribed stimulant medication for ADHD in people with epilepsy aged ≥6 years and has been shown to be efficacious and well-tolerated.¹⁶ In contrast, data on the efficacy of amphetamines in people with epilepsy are limited.^15,16 Some evidence suggests that there is a small risk of a transient increase in seizure frequency when starting methylphenidate, warranting close monitoring. However, studies showed that these increases were typically mild, with only a small percentage of people discontinuing methylphenidate due to seizure exacerbations.¹⁶

Among nonstimulant ADHD medications, atomoxetine and guanfacine are shown to be more beneficial than placebo in treating hyperactivity and impulsivity in people with epilepsy. Some data show increased efficacy of atomoxetine over long-acting guanfacine.¹⁷ α-Agonists such as guanfacine and clonidine also improve impulsivity and emotional dysregulation in people with ASD.¹⁸ Guanfacine may therefore be considered in people with epilepsy aged ≥6 years with impulsivity and emotional dysregulation who do not respond to, cannot tolerate, or wish to avoid antipsychotic medication. Although clonidine has been shown to reduce hyperactivity and other challenging behaviors, it has a short half-life and a considerable sedating effect. This makes clonidine difficult to use for daytime symptom management but useful in treating insomnia in people with epilepsy with comorbid sleep disorders (with or without ADHD).¹⁸

Overall, it is important to consider the individual’s ADHD symptom profile (hyperactive vs inattentive) and comorbidities (eg, anxiety, emotional dysregulation, insomnia) when selecting an ADHD medication. Table 4 lists the commonly prescribed stimulant and nonstimulant medications for ADHD in people with epilepsy aged ≥6 years.

Antiseizure Medication
Numerous studies show that lamotrigine improves irritability, aggression, and mood symptoms in children and adolescents with epilepsy. This is thought to be due to its effectiveness in decreasing interictal epileptic discharges—which evidence suggests are correlated with irritability and aggression—on EEG.¹⁹ Lamotrigine has also been shown to reduce aggression in people with temporal lobe and other partial epilepsies^20,21 and to reduce depression symptoms in older adults with epilepsy.²² Therefore, adding lamotrigine to an individual’s ASM regimen to treat challenging behaviors or mood disorders may be considered in some people with epilepsy. 

Some studies report greater improvement in behavior and epileptic discharges on EEG with valproate compared with placebo in children with ASD as well as seizures,¹⁹ although the evidence is less conclusive than that for lamotrigine. However, when considering valproate for seizure management, its potential benefits in treating challenging behaviors may also be considered. Small studies have shown the efficacy of oxcarbazepine as a mood stabilizer for people with ASD,²³ suggesting it may also be beneficial for those with co-occurring epilepsy. Although data on the efficacy of oxcarbazepine in improving behaviors in this population are inconclusive, oxcarbazepine has been shown to carry a low risk of exacerbating challenging behaviors or mood symptoms.^24,25 Therefore, oxcarbazepine may be preferred over other ASMs when treating seizures in people with irritability, emotional dysregulation, or aggression.

Conclusion
Behavioral and psychiatric comorbidities occur at much higher rates in people with epilepsy than in the general population. Treating these challenges requires careful consideration of underlying etiologies, symptom profile, ASMs, and epilepsy type. A multidisciplinary approach may be warranted to optimize the care of individuals with psychiatric and behavioral comorbidity with epilepsy, including consultation with psychiatrists and other mental health professionals and consideration of evidence-based nonpharmacologic interventions such as psychotherapy and lifestyle interventions.²⁶ A discussion of these topics is outside of the scope of this article. SSRIs are first-line treatment for anxiety and depression in people with epilepsy aged ≥6 years. Aripiprazole and risperidone are preferred treatments for emotional dysregulation, agitation, aggression, and disruptive behavior in people with ASD with epilepsy. SSRIs may also be considered, particularly when these behaviors are thought to stem from or are accompanied by anxiety or depression. Guanfacine can be considered as an alternative behavioral medication in people who are hesitant to use antipsychotics. Guanfacine and atomoxetine are the most effective nonstimulant ADHD medications in people with epilepsy with ADHD. Clonidine may also improve hyperactivity and impulsivity, but is more beneficial as a sleep aid because of its sedating effects. Methylphenidate is the most effective stimulant and overall ADHD medication in people with epilepsy. For people with comorbid behavioral or psychiatric concerns, lamotrigine, valproate, or oxcarbazepine may be considered as primary or adjunctive ASMs due to their favorable or neutral effects on behaviors and mood.