Psychoactive Medications and Seizures: Challenges and Pitfalls

Psychoactive Medications and Seizures: Challenges and Pitfalls

Deepti Anbarasan, MD

The Neurological Institute of New York, Columbia University Medical Center, New York, New York

The use of psychoactive medications in patients with epilepsy may affect the seizure threshold, influence electroencephalographic test results, and result in pharmacokinetic drug interactions. Speakers at this Special Interest Group meeting at the 2015 annual gathering of the American Epilepsy Society underscored the importance of identifying psychiatric comorbidities in patients with epilepsy and treating them appropriately. In addition, they discussed the different pharmacologic issues that arise when psychotropic medications are used concomitantly with antiepileptic drugs.

Deepti Anbarasan, MDDuring the 69th Annual Meeting of the American Epilepsy Society in Philadelphia, Pennsylvania, the Neuropharmacology Special Interest Group highlighted the challenges and pitfalls related to the use of psychoactive medications in patients with epilepsy. Psychiatric comorbidities often complicate the treatment of this patient population; a fuller understanding of the possible pharmacologic interactions between antiepileptic drugs (AEDs) and other psychoactive medications and the effects of these medications on seizure threshold is crucial for optimal management of patients with epilepsy and concomitant psychiatric illnesses.

This Neuropharmacology Special Interest Group meeting was coordinated by Laura Strom, MD, and Mitra Habibi, PhD. Speakers at the meeting discussed the EEG changes related to the use of antipsychotics, antidepressants, stimulants, and other psychoactive drugs. In addition, they reviewed the development of seizures in patients with and without epilepsy who are treated with psychoactive medications and the risk factors these drugs pose for increased seizure activity.

THE OVERLAP BETWEEN EPILEPSY AND MOOD DISORDERS
Based on a presentation by Archana Shrestha, MD, Assistant Professor of Neurology, University of Colorado School of Medicine, Denver.

Dr. Shrestha discussed the bidirectional relationship between epilepsy and mood disorders. When compared with other chronic medical illnesses such as diabetes and asthma, epilepsy predisposes people to relatively higher rates of depression.1,2 Various studies have demonstrated that patients with depression are 3–7 times more likely to develop epilepsy than are those not affected by this mood disorder and that people with a history of depression are more likely to experience intractable epilepsy than other individuals. In an analysis of results from the Canadian National Health Survey, Tellez-Zenteno and colleaugues3 reported that patients with epilepsy are more likely to report higher rates of depression than do those without epilepsy. Patients with epilepsy also have significantly higher rates of mood and anxiety disorders and of suicidal ideation.3 Table 1 compares the prevalence of depression and other psychiatric conditions in patients with and without epilepsy.3

Table 1

Less has been written about the incidence of bipolar affective disorder in patients with epilepsy. A 2005 population-based study by Ettinger et al4 compared the prevalence of bipolar symptoms between patients with epilepsy and those with other conditions such as migraine, diabetes, or asthma. Bipolar symptoms were 1.6–2.2 times more common among patients with epilepsy than among patients with other chronic illnesses.

Evaluation of Patients for Psychiatric Comorbidities
Several contributing factors must be considered when evaluating psychiatric comorbidities in patients with seizure disorders. Various studies have shown the severity of epilepsy to be a risk factor for psychiatric comorbidities.5 Duration of epilepsy may be another risk factor for such psychiatric comorbidities as depression and anxiety, although this has not been a consistent observation across studies. When compared with extratemporal-lobe epilepsy, temporal-lobe epilepsy traditionally has been associated with higher rates of psychiatric disorders; however, this finding also has not been noted consistently. Structural abnormalities may be another contributing factor—patients with mesial temporal sclerosis may have a higher prevalence of major depressive disorder.6,7

Several psychosocial factors (eg, perceived stigma of having epilepsy, fear of seizures, limitations in social support, and unemployment) may contribute to depression in patients with epilepsy. From the psychologic perspective, patients with epilepsy struggle to manage anxieties associated with the unpredictable nature of seizures. This lack of control over one's condition could worsen the risk of depression and deepen the individual's sense of helplessness, especially in patients with medically refractory epilepsy. Forced normalization, in which psychiatric symptoms worsen in the context of improved seizure control, may be considered when worsening mood symptoms are preceded by decreased seizure frequency.

Effect of AEDs on Psychiatric Status
Dr. Shrestha also tackled the subject of AED-related iatrogenic psychiatric issues in patients with epilepsy. Table 2 summarizes the putative psychiatric effects associated with the use of AEDs. Generally, depressive side effects are associated with the use of AEDs having more prominent properties associated with γ-aminobutyric acid (GABA), such as barbiturates, topiramate, tiagabine, and vigabatrin.8 In contrast, glutaminergic AEDs, such as felbamate, perampanel, and lamotrigine, have activating, anxiogenic, and antidepressant effects. Both sodium- and calcium-channel blockers may have mood-stabilizing effects.

Table 2

Whether AED therapy increases the risk of suicidality has been debated often. In 2005, the US Food and Drug Administration (FDA) requested clinical trial data from all AED manufacturers. A meta-analysis of 199 randomized, placebo-controlled trials testing a total of 11 AEDs was performed.9 Based on the results of this analysis, the FDA issued an alert that AED use was associated with a statistically significant 1.8-fold increased risk of suicidality.10 The methodology of this study drew several criticisms, including key issues that suicidality was not a primary endpoint in this meta-analysis and that the study did not assess the data in a systematic manner using validated measures.11 Since then, several studies investigating whether AED use may be associated with an increased risk of suicidality have yielded variable results.12,13

The consensus has been that the benefits of AED therapy in patients with epilepsy outweigh the risks, since untreated seizures may result in status epilepticus, sudden unexplained death in epilepsy, and injuries. As such, when managing AEDs, clinicians should educate patients about potential psychiatric symptoms and monitor them for emerging depression, suicidality, and other potential psychiatric effects of AEDs.

PSYCHOTROPIC THERAPY AND EPILEPSY
Based on a presentation by Mesha-Gay Brown, MD, Assistant Professor of Neurology, University of Colorado School of Medicine, Denver.

Dr. Brown discussed the challenges associated with using psychotropic medications in patients with epilepsy, a population that often requires treatment for various psychiatric comorbidities.

Among the general population, use of antidepressants confers a 7-fold increased risk of unprovoked seizures, whereas the incidence of seizures associated with the use of antipsychotics has been reported to be 1.2%–1.3%.14 However, seizures are a relatively rare side effect of psychotropics; when used properly, the risk of seizures associated with the administration of these drugs approaches that in the general population.

Assessment of studies seeking to elucidate the risk of seizures associated with the use of psychotropic medications has been challenging. For example, methodologic challenges have included small sample sizes (with inadequate power to assess for significance); variable inclusion and exclusion criteria; differences in trial design; and inadequate accounting for drug dosages, drug interactions, and duration of exposure.

Antidepressants
Among the antidepressants, use of selective serotonin reuptake inhibitors (SSRIs) generally is believed to be safe with regard to seizures.15 For instance, premarketing trials have shown a 0.2% incidence of new-onset seizures in patients taking fluoxetine, comparable to their incidence in patients who received placebo. However, hyponatremia, an idiosyncratic side effect that has been associated with the use of SSRIs, may lower the seizure threshold. Bupropion therapy is associated with an approximate 0.4% incidence of seizures in patients receiving less than 450 mg a day; however, the risk of seizures increases with higher total daily doses.16 Use of phenylpiperazines such as trazodone and nefazodone is probably safe in patients with epilepsy, although these drugs should be used cautiously with AED inducers. Treatment with tricyclic antidepressants (TCAs) can lower the seizure threshold, and use of certain TCAs has a known dose-dependent effect on seizure incidence. At this time, limited information is available regarding the seizure-inducing activity of venlafaxine or monoamine oxidase inhibitors.

Antipsychotics
Seizures have been reported with the use of both typical and atypical antipsychotics. Treatment with clozapine and chlorpromazine is related to a relatively higher risk of seizures, whereas use of olanzapine and quetiapine has been associated with a relatively moderate risk of seizures.14 A reduced risk of seizures is associated with the administration of fluphenazine, haloperidol, risperidone, and ziprasidone.17

Anxiolytics, Sedative-Hypnotics, and Mood Stabilizers
Administration of anxiolytics and sedative-hypnotic medications is associated with a low risk of seizures; however, abrupt withdrawal of these psychoactive medications is not recommended. Lithium therapy should not be withheld if other mood stabilizers are ineffective or poorly tolerated, as the evidence for lithium's putative proconvulsant effects is conflicting.

Table 3Summary
Preferred agents to manage depression in patients with epilepsy are SSRIs, trazodone, mirtazapine, and (possibly) venlafaxine. Risperidone therapy is preferred for long-term treatment of psychosis, whereas use of haloperidol is acceptable for short-term treatment of psychosis in patients with epilepsy. Table 3 lists nine critical guiding principles to consider when contemplating the use of psychotropic medications in patients with epilepsy.

ANTIPSYCHOTIC USE AND INCREASED SEIZURE ACTIVITY:
RISK FACTORS
Based on a presentation by Jacquelyn Bainbridge, PharmD, FCCP, Professor of Clinical Pharmacy and Neurology, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Denver.

Dr. Bainbridge discussed properties that contribute to the increased seizure risk associated with the use of antipsychotics. These properties include the overactive physiologic selectivity for specific dopamine receptors in the mesolimbic region, the relative tightness of dopamine D2-receptor blocking between antipsychotics, and the dose-dependent effects of antipsychotics.18,19 Specifically, signaling from D1-like receptors in the limbic system may exert a pro-epileptogenic effect, whereas signaling from D2-like receptors may provide an anti-epileptogenic effect. Thus, the use of such D2-blocking agents as antipsychotics may predispose patients to an increased risk of seizures.

Antipsychotics and the Metabolic Syndrome
The metabolic syndrome has been associated with a variety of health issues, including hypertension, atherosclerotic cardiovascular disease, stroke, renal disease, and type 2 diabetes.20 Patients with mental illness, many of whom are on psychotropic medications, may be especially susceptible to the metabolic syndrome. This syndrome is 1–2 times more prevalent in patients with depression, 1.5–2 times more prevalent in patients with bipolar disorder, and 2–3 times more prevalent in patients with schizophrenia than in control groups.21,22

Antipsychotic medications, especially when used with other psychotropic agents, can significantly increase the prevalence of metabolic syndrome.23 In particular, treatment with the atypical antipsychotics clozapine and olanzapine confers the highest risk of inducing the metabolic syndrome.21 These findings highlight the importance of following patients using psychotropics for the development of the metabolic syndrome. Accordingly, starting in July 2016, all patients who are prescribed antipsychotic medications will be required to undergo a structured metabolic screening test that includes a lipid panel, a fasting glucose or hemoglobin A1c measurement, blood pressure readings, and a determination of the patient's body mass index every 12 months. Insurance reimbursements from the Centers for Medicare and Medicaid Services will be based on whether these measurements were collected.

Changes in Heart Rhythm
Antipsychotic use also may raise concern about QTc prolongation, a predisposing factor for torsades de pointes (TdP). Aside from QTc prolongation, several factors can increase the risk of TdP, including hypokalemia, female gender, drug-drug interactions, advancing age, genetic predisposition, hypomagnesemia, heart failure, and bradycardia. Intravenous administration of an antipsychotic agent can further increase the risk of QTc prolongation.

Use of the antipsychotics chlorpromazine, haloperidol, or thioridazine is associated with a definite risk of TdP, whereas use of aripiprazole, clozapine, iloperidone, olanzapine, risperidone, or paliperidone is associated with a possible risk of TdP. As such, medical professionals must learn about medications that may result in QTc prolongation, limit combined agents that prolong the QTc, and monitor the electrocardiograms of patients who need to be on more than one QTc-prolonging agent.24

Adverse Drug Interactions
A recent increase in adverse events related to drug-drug interactions has been attributed to several factors, including an aging population having more complex medical needs, increased availability of medications, and patients' increased use of more than one pharmacy to fill prescriptions. Both pharmacokinetic and pharmacodynamic factors need to be monitored for patients using psychotropic drugs and/or AEDs.

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Dr. Anbarasan is a Clinical Neurophysiology Fellow at The Neurological Institute of New York, Columbia University Medical Center, New York, New York.

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