Addressing Psychiatric Comorbidities in Pediatric Epilepsy: Expert Opinions

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Children with a chronic physical illness have a substantially elevated prevalence of psychiatric illness.
Children with a chronic physical illness have a substantially elevated prevalence of psychiatric illness.

Children with a chronic physical illness have a substantially elevated prevalence of psychiatric illness. The odds of having a mental health disorder were 62% higher among children with vs without a chronic physical condition, even after adjusting for sociodemographic variables and access to health care, according to results from a study published in 2016.1 The risk for psychopathology is even greater among children who have chronic central nervous system (CNS) disorders.

In children with epilepsy, various studies have reported a prevalence of mental health problems ranging from 16% to 77%, and a 3-fold to 9-fold risk compared with controls.2 In a recent study of children and adolescents age 10 to 19 years who had epilepsy, the most commonly observed comorbid psychiatric disorders were attention-deficit/hyperactivity disorder (ADHD) and anxiety, and 26.8% of those with a psychiatric diagnosis demonstrated executive dysfunction. Independent risk factors for this comorbidity were executive dysfunction, male gender, and early seizure onset.3 Other research has also revealed higher rates of depression and autism-spectrum disorder in this population.4 

Cognitive and linguistic deficits have been cited as risk factors for psychiatric comorbidity in pediatric epilepsy, along with family factors such as parenting style and quality of the parent-child relationship.2 Although some research findings show a link between antiepileptic drugs (AEDs) and psychopathology in this patient group, results have been largely inconclusive.5

Psychiatric comorbidity has a significant impact on quality of life and psychosocial outcomes in this population, underscoring the importance of adequate screening and treatment measures.2 To elucidate the unique considerations involved in caring for these patients, Neurology Advisor spoke with Janelle L. Wagner, PhD, licensed clinical psychologist, research associate professor of nursing and pediatrics, and faculty member of the Comprehensive Epilepsy Center at the Medical University of South Carolina; and David W. Dunn, MD, the Arthur B. Richter professor of child psychiatry, professor of psychiatry and neurology, and director of the child and adolescent psychiatry section at Indiana University School of Medicine.

Neurology Advisor: How might the presence of epilepsy influence treatment of psychiatric comorbidities?

Dr Wagner: Up to 50% of persons with epilepsy also experience cognitive/neurodevelopmental and/or psychiatric comorbidities, and we are learning more about the bidirectional relationship between epilepsy and these psychiatric comorbidities, including neuroanatomic and neurotransmitter overlap, and providing support for epilepsy as a spectrum disorder.6 Epilepsy healthcare providers are being encouraged to screen for and potentially initiate medication management for these psychiatric symptoms in persons with epilepsy.

Studies support the use of selective serotonin reuptake inhibitors (SSRIs) to treat depression and anxiety and stimulants to treat ADHD in persons with epilepsy, and guidelines have been published for use of these medications in these patients.7 There is also a growing body of literature to support the use of behavioral health interventions such as cognitive behavioral therapy to alleviate depression, and in many cases, these interventions focus on evidence-based therapeutic strategies that have been adapted to fit epilepsy and the challenges it poses to individuals and their families.8

Dr Dunn: One of the first steps in treatment of psychiatric problems in people with epilepsy is to check on seizure control and AEDs. Frequent seizures can have a negative impact on attention, and nocturnal seizures may leave a patient feeling tired the following day. AEDs may have adverse effects that could contribute to ADHD, anxiety, or depression.

Most psychiatric medications are safe, but care should be taken in choosing psychotropic medication, and the response should be monitored. Stimulants such as methylphenidate or amphetamines can be used by people with epilepsy and ADHD without the risk of loss of seizure control. Antidepressants may be used without an increase in seizure frequency with certain exceptions — bupropion and the tricyclic antidepressants may lower seizure threshold and should be used with caution. Clomipramine may also lower seizure threshold. Of the antipsychotics, clozapine is most likely to cause seizures. Olanzapine and quetiapine have a lesser effect on increasing seizure number. [As] psychotropic medications may interact with AEDs, blood levels of AEDs should be checked after starting, changing doses, or discontinuing psychotropic medication.

Neurology Advisor: What is known about the influence of AEDs on psychiatric comorbidities?

Dr Wagner: Given the potential shared mechanisms between epilepsy and psychiatric disorders, it is not surprising that AEDs may influence psychiatric symptoms. For example, in a pediatric study, psychiatric or behavioral adverse effects to AEDs were more likely to develop in youth with medically refractory epilepsy and/or a history of psychiatric diagnosis.9 Similarly, higher hyperactivity/impulsivity in children with new-onset epilepsy at baseline predicted greater behavioral adverse effects to AEDs at 1 month post-AED initiation.10 In an adult study, Kanner and colleagues showed that comorbid depressive and anxiety symptoms can worsen the severity of adverse effects associated with AEDs.11 These studies raise an important consideration — the onset of psychiatric symptoms.

Dr Dunn: AEDs are also known mood stabilizers, and some AEDs are used to treat bipolar disorder. As with all medications, there are potential adverse effects of AEDs. The older drug phenobarbital has caused inattention, hyperactivity, and depression. Newer AEDs such as perampanel and brivaracetam can cause irritability. Behavioral adverse effects are less common with other second- and third-generation AEDs, but after starting an AED, the physician should monitor for anxiety, depression, inattention, or irritability.

Neurology Advisor: How might clinicians discern AED-related psychiatric comorbidities vs those unrelated to AEDs, and in either case, what is the optimal approach for treating these issues?

Dr Wagner: To tease apart AED-related psychiatric comorbidities and those unrelated to AEDs, clinicians must conduct baseline psychiatric screening prior to AED initiation and continue screening throughout the course of AED treatment. If significant psychiatric symptoms are present prior to AED initiation, clinicians are encouraged to treat those symptoms as comorbid as they move forward with AED initiation. If screening at baseline does not occur, these comorbid psychiatric symptoms may be confused with AED adverse effects, resulting in unnecessary changes to the AED regimen. It is important to note that these patients are at risk for worsening psychiatric symptoms with AED treatment.

If psychiatric symptoms are not present at baseline but present following AED initiation, these symptoms are likely adverse side effects to the AED and clinicians should consider dosing changes or alternative treatment options — such as a different seizure medication or diet — for seizures. In this case, it is very important to have a discussion with the patient and family about the severity of the psychiatric AED adverse effects and the alternative treatment options, as many patients report psychiatric symptoms as more burdensome than seizures themselves.12 If patients experience greater psychiatric symptoms, they are also at risk for poor adherence to their prescribed AED regimen.13

Dr Dunn: It can be difficult to decide if emotional and behavioral problems are due to seizures, AEDs, intrinsic emotional reactions of the person with epilepsy, or a response to the negative reaction of family or people in the community. In general, if the psychiatric problem seems to follow introduction of a new AED or an increase in AED dose, consider that psychiatric problems may be an adverse effect of AED. It may require stopping the AED to see if problems resolve. 

Neurology Advisor: What should be next steps in this area, in terms of research or otherwise?

Dr Wagner: As part of comprehensive epilepsy management, clinicians should consider treating both seizures and psychiatric symptoms, or at the least, screening for psychiatric symptoms and referring to a mental health professional if warranted. Screening for psychiatric symptoms is necessary at baseline, prior to AED initiation, and throughout the course of AED treatment.

Next steps for research include continued examination of shared mechanisms for epilepsy and psychiatric disorders, nonpharmacologic interventions for psychiatric disorders, and standardized assessment of AED adverse effects in routine epilepsy care.

Dr Dunn: We need to know who is at most risk for adverse effects from AEDs. Factors that might be important are the past history of the individual or a family history of emotional or behavioral problems. Pharmacogenomics research is assessing drug metabolism for clues to potential adverse effects or variable response to medications. The hope is to develop precision medication for the individual. There is still much research to be done.  

References

  1. Suryavanshi MS, Yang Y. Clinical and economic burden of mental disorders among children with chronic physical conditions, United States, 2008–2013. Prev Chronic Dis. 2016;13:150535.
  2. Plioplys S, Dunn DW, Caplan R. 10-year research update review: psychiatric problems in children with epilepsy. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1389-1402.
  3. Alfstad KÅ, Torgersen H, Van Roy B, et al. Psychiatric comorbidity in children and youth with epilepsy: an association with executive dysfunction?Epilepsy Behav. 2016; 56:88-94.
  4. Bolton PF, Carcani-Rathwell I, Hutton J, Goode S, Howlin P, Rutter M. Epilepsy in autism: features and correlates.Br J Psychiatry. 2011;198(4):289-294.
  5. Caplan R. Psychopathology in pediatric epilepsy: role of antiepileptic drugs. Front Neurol. 2012;3:163.
  6. Jensen FE. Epilepsy as a spectrum disorder: implications from novel clinical and basic science research. Epilepsia. 2011;52(Suppl 1):1-6.
  7. Kerr MP, Mensah S, Besag F, et al; International League of Epilepsy (ILAE) Commission on the Neuropsychiatric Aspects of Epilepsy. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy.Epilepsia. 2011;52(11):2133-2138.
  8. Michaelis R, Tang V, Wagner JL, et al. Cochrane systematic review and meta-analysis of the impact of psychological treatments for people with epilepsy on health-related quality of life. Epilepsia. 2018;59(2):315-332.
  9. Chen B, Detyniecki K, Choi H, et al. Psychiatric and behavioral side effects of anti-epileptic drugs in adolescents and children with epilepsy. Eur J Paediatr Neurol. 2017;21(3):441-449.
  10. Guilfoyle SM, Follansbee-Junger K, Smith AW, et al. Antiepileptic drug behavioral side effects and baseline hyperactivity in children and adolescents with new onset epilepsy. Epilepsia. 2018;59(1):146-154.
  11. Kanner AM, Barry JJ, Gilliam F, Hermann B, Meador KJ. Depressive and anxiety disorders in epilepsy: do they differ in their potential to worsen common antiepileptic drug-related adverse events. Epilepsia. 2012;53(6):1104-1108.
  12. Cramer JA, Blum D, Reed M, Fanning K; Epilepsy Impact Project. The influence of comorbid depression on seizure severity. Epilepsia. 2003;44(12):1578-1584.
  13. Ettinger AB, Good MB, Manjunath R, Faught RE, Bancroft T. The relationship of depression to antiepileptic drug adherence and quality of life in epilepsy. Epilepsy Behav. 2014;36:138-143.
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