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Psychoactive Medications and Seizures—Challenges and Pitfalls Deepti Anbarasan, MD The Neurological Institute of New York, Columbia University Medical Center, New York, New York A REPORT FROM THE 69th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY © 2016 Direct One Communications, Inc. All rights reserved. 1 Epilepsy and Depression People with depression are 3–7 times more likely to develop epilepsy than those without depression. People with a history of depression are also more likely to experience intractable epilepsy. People with epilepsy are more likely to report higher rates of depression than those without epilepsy. People with epilepsy also have significantly higher rates of mood and anxiety disorders and of suicidal ideation. Blum D et al. Neurology. 2002;Suppl 3:A175; Ettinger A et al. Neurology. 2004;63:1008; Tellez-Zenteno JF et al. Epilepsia. 2007;48:2336 © 2016 Direct One Communications, Inc. All rights reserved. 2 Epilepsy and Depression continued Prevalence of depression and other psychiatric conditions in patients with and without epilepsy: Tellez-Zenteno JF et al. Epilepsia. 2007;48:2336 © 2016 Direct One Communications, Inc. All rights reserved. 3 Epilepsy and Bipolar Affective Disorder A 2005 population-based study 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. Ettinger A et al. Neurology. 2005;65:535 © 2016 Direct One Communications, Inc. All rights reserved. 4 Evaluation for Psychiatric Comorbidities The severity and probably the duration of epilepsy may be risk factors for psychiatric comorbidities, such as depression and anxiety. When compared with extratemporal-lobe epilepsy, temporal-lobe epilepsy traditionally has been associated with higher rates of psychiatric disorders; however, this finding has not been noted consistently. Patients with mesial temporal sclerosis may have a higher prevalence of major depressive disorder. Kobau R et al. Epilepsia. 2006;47:1915; Quiske A et al. Epilepsy Res. 2000;39:121; Sanchez-Gistau V et al. Epilepsia. 2012;53:386 © 2016 Direct One Communications, Inc. All rights reserved. 5 Psychiatric Effects of AEDs Putative psychiatric effects associated with the use of antiepileptic drugs (AEDs): © 2016 Direct One Communications, Inc. All rights reserved. 6 Psychiatric Effects of AEDs continued Depressive side effects is associated with the use of AEDs that have prominent properties associated with g-aminobutyric acid (GABA), such as barbiturates, topiramate, tiagabine, and vigabatrin. 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. Ketter T et al. Neurology. 1999;53(5 Suppl 2):S53 © 2016 Direct One Communications, Inc. All rights reserved. 7 AEDs and Suicidality A meta-analysis of 199 randomized, placebo-controlled trials evaluating 11 AEDs led the FDA to issue an alert in 2008 that the use of these drugs was associated with a statistically significant 1.8-fold increased risk of suicidality. The methodology of this study drew criticism, and several studies subsequently investigating whether AEDs may increase the risk of suicidality have yielded inconsistent results. The current consensus is that the benefits of AED therapy in patients with epilepsy outweigh the risks of uncontrolled seizures. Hesdorffer DC, Kanner AM. Epilepsia. 2009;50:978; Arana A et al. N Engl J Med. 2010;363:542; Olesen JB et al. Pharmacoepidemiol Drug Saf. 2010;19:518 © 2016 Direct One Communications, Inc. All rights reserved. 8 Antidepressants and Epilepsy In the general population, use of antidepressants confers a 7-fold risk of unprovoked seizures, whereas the incidence of seizures associated with the use of antipsychotics has been reported to be 1.2%–1.3%. 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. Therapy with selective serotonin reuptake inhibitors (SSRIs) generally is believed to be safe with regard to seizures; however, hyponatremia, an idiosyncratic side effect of SSRIs, may lower the seizure threshold. Pisani F et al. Drug Saf. 2002;25:91; Alldredge BK. Neurology. 1999;53(Suppl 2):S68 © 2016 Direct One Communications, Inc. All rights reserved. 9 Antidepressants and Epilepsy continued Bupropion is associated with an approximate 0.4% incidence of seizures in patients receiving less than 450 mg/d; however, the risk of seizures increases with higher daily doses. Phenylpiperazines, such as trazodone and nefazodone, are probably safe in patients with epilepsy, although these drugs should be used cautiously with AED inducers. Tricyclic antidepressants (TCAs) can lower the seizure threshold, and use of certain TCAs have a known dose-dependent effect on seizure incidence. Peck AW et al. J Clin Psychiatry. 1983;44(5 pt 2):197 © 2016 Direct One Communications, Inc. All rights reserved. 10 Other Psychotropic Medications Both typical and atypical antipsychotics may cause seizures, although the risk varies: » Clozapine and chlorpromazine are associated with a relatively high risk of seizures. » Olanzapine and quetiapine are associated with a relatively moderate risk of seizures. » Fluphenazine, haloperidol, risperidone, and ziprasidone are associated with a relatively low risk of seizures. Administration of anxiolytics and sedative-hypnotic medications in general is associated with a low risk of seizures; however, abrupt withdrawal of these psychoactive medications is not recommended. Pisani F et al. Drug Saf. 2002;25:91; Lee F et al. Expert Opin Drug Saf. 2003;3:233 © 2016 Direct One Communications, Inc. All rights reserved. 11 Other Psychotropic Medications continued 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. 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. Lee F et al. Expert Opin Drug Saf. 2003;3:233 © 2016 Direct One Communications, Inc. All rights reserved. 12 Other Psychotropic Medications continued Nine critical guiding principles to consider before using psychotropic medications in patients with epilepsy: 1. Check carefully for predisposing factors 2. Use the minimal effective dose 3. Minimize polytherapy 4. Start low and go slow 5. Avoid abrupt discontinuation or dose changes 6. Consider using antiepileptic drugs with psychotropic properties 7. Monitor plasma drug concentrations 8. Pay attention to sudden electroencephalographic changes 9. Consider changing the psychotropic drug or optimizing the antiepileptic drug regimen if seizures worsen © 2016 Direct One Communications, Inc. All rights reserved. 13 Antipsychotic Medications and the Metabolic Syndrome The metabolic syndrome is associated with a variety of health issues, including hypertension, renal disease, atherosclerotic cardiovascular disease, stroke, and type 2 diabetes. Patients with mental illness, many of whom are on psychotropic medications, may be especially susceptible to the metabolic syndrome, which 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. Grundy S et al. Circulation. 2005;112:285; De Hert M et al. World Psychiatry. 2011;10:138; Simon G et al. Gen Hosp Psychiatry. 2008;30:32 © 2016 Direct One Communications, Inc. All rights reserved. 14 Antipsychotic Medications and the Metabolic Syndrome continued Antipsychotic medications, especially when used with other psychotropic agents, can significantly increase the prevalence of metabolic syndrome. Clozapine and olanzapine confer the highest risk of inducing the metabolic syndrome. Starting in July 2016, all patients who are prescribed antipsychotics will need to undergo a structured metabolic screening test that includes an annual: » Lipid panel; » Fasting glucose or hemoglobin A1c measurement; » Blood pressure readings; and » Determination of the patient’s body mass index. De Hert M et al. World Psychiatry. 2011;10:138; Steylen P et al. Clin Neuropsychiatry. 2012;9:75 © 2016 Direct One Communications, Inc. All rights reserved. 15 Changes in Heart Rhythm Antipsychotics also may cause QTc prolongation, a predisposing factor for torsades de pointes (TdP). Other factors that can increase the risk of TdP include hypokalemia, female gender, drug-drug interactions, advancing age, genetic predisposition, hypomagnesemia, heart failure, and bradycardia. Chlorpromazine, haloperidol, and thioridazine is associated with a definite risk of TdP Aripiprazole, clozapine, iloperidone, olanzapine, risperidone, and paliperidone are associated with a possible risk of TdP. European Medicines Agency (EMEA). ICH Topic E14 (November 2005) © 2016 Direct One Communications, Inc. All rights reserved. 16 Adverse Drug Interactions The recent increase in adverse events related to drug-drug interactions has been attributed to several factors, including: » An aging population with more complex medical needs; » Increased availability of more medications; and » Increased use of more than one pharmacy by patients to fill their prescriptions. Both pharmacokinetic and pharmacodynamic factors need to be monitored in patients using psychotropic drugs and/or AEDs. © 2016 Direct One Communications, Inc. All rights reserved. 17