Abstract
Introduction:
Pharmacokinetic and pharmacodynamic drug interactions (DIs) can occur between antiepileptics (AEDs) and second-generation antipsychotics (SGAPs). Some AED and SGAP pharmacodynamic mechanisms are poorly understood. AED–SGAP combinations are used for treating comorbid illnesses or increasing efficacy, particularly in bipolar disorder.
Areas covered:
This article provides a comprehensive review of the interactions between antiepileptics and second-generation antipsychotics. The authors cover pharmacokinetic AED–SGAP DI studies, the newest drug pharmacokinetics in addition to the limited pharmacodynamic DI studies.
Expert opinion:
Dosing correction factors and measuring SGAP levels can help to compensate for the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone. Further studies are needed to establish the clinical relevance of combining: i) AED strong inducers with amisulpride, asenapine, iloperidone, lurasidone and paliperidone; ii) valproate with aripiprazole, asenapine, clozapine and olanzapine; iii) high doses of oxcarbazepine (≥ 1500 mg/day) or topiramate (≥ 400 mg/day) with aripiprazole, lurasidone, quetiapine, risperidone, asenapine and olanzapine. Two pharmacodynamic DIs are beneficial: i) valproate–SGAP combinations may have additive effects in bipolar disorder, ii) combining topiramate or zonisamide with SGAPs may decrease weight gain. Three pharmacodynamic DIs contributing to decreased safety are common: sedation, weight gain and swallowing disturbances. A few AED–SGAP combinations may increase risk for osteoporosis or nausea. Three potentially lethal but rare pharmacodynamic DIs include pancreatitis, agranulocytosis/leukopenia and heat stroke. The authors believe that collaboration is needed from drug agencies and pharmaceutical companies, the clinicians using these combinations, researchers with expertise in meta-analyses, grant agencies, pharmacoepidemiologists and DI pharmacologists for future progression in this field.
Acknowledgments
The authors acknowledge L Maw, M.A., and MT Susce, R.N., M.L.T. at the Mental Health Research Center at Eastern State Hospital, Lexington, KY, who helped in editing the article.
Notes
This box summarizes key points contained in the article.
Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004;5:553-64 Brodie MJ. Antiepileptic drug therapy: the story so far. Seizure 2010;19:650-5 Brodie MJ. Antiepileptic drug therapy: the story so far. Seizure 2010;19:650-5 Fountoulakis KN, Vieta E. Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol 2008;11:999-1029 Fountoulakis KN, Vieta E. Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol 2008;11:999-1029 Fountoulakis KN, Vieta E. Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol 2008;11:999-1029 Harwood AJ, Agam G. Search for a common mechanism of mood stabilizers. Biochem Pharmacol 2003;66:179-89 Mula M, Pini S, Cassano GB. The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence. J Clin Psychopharmacol 2007;27:263-72 Johannessen Landmark C. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs 2008;22:27-47 Kennedy GM, Lhatoo SD. CNS adverse events associated with antiepileptic drugs. CNS Drugs 2008;22:739-60 Kennedy GM, Lhatoo SD. CNS adverse events associated with antiepileptic drugs. CNS Drugs 2008;22:739-60 Kennedy GM, Lhatoo SD. CNS adverse events associated with antiepileptic drugs. CNS Drugs 2008;22:739-60 Zaccara G, Gangemi PF, Cincotta M. Central nervous system adverse effects of new antiepileptic drugs. A meta-analysis of placebo-controlled studies. Seizure 2008;17:405-21 Mula M, Trimble MR. Antiepileptic drug-induced cognitive adverse effects: potential mechanisms and contributing factors. CNS Drugs 2009;23:121-37 Kennedy GM, Lhatoo SD. CNS adverse events associated with antiepileptic drugs. CNS Drugs 2008;22:739-60 Sirven JI, Fife TD, Wingerchuk DM, Second-generation antiepileptic drugs' impact on balance: a meta-analysis. Mayo Clin Proc 2007;82:40-7 Kennedy GM, Lhatoo SD. CNS adverse events associated with antiepileptic drugs. CNS Drugs 2008;22:739-60 Sirven JI, Fife TD, Wingerchuk DM, Second-generation antiepileptic drugs' impact on balance: a meta-analysis. Mayo Clin Proc 2007;82:40-7 Beydoun A, D'Souza J, Hebert D, Doty P. Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures. Expert Rev Neurother 2009;9:33-42 Mula M, Sander JW. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf 2007;30:555-67 Brandt C, Fueratsch N, Boehme V, Development of psychosis in patients with epilepsy treated with lamotrigine: report of six cases and review of the literature. Epilepsy Behav 2007;11:133-9 Brodtkorb E, Mula M. Optimizing therapy of seizures in adult patients with psychiatric comorbidity. Neurology 2006;67(Suppl 4):S39-44 White JR, Walczak TS, Marino SE, Zonisamide discontinuation due to psychiatric and cognitive adverse events: a case-control study. Neurology 2010;75:513-18 Dinkelacker V, Dietl T, Widman G, Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases. Epilepsy Behav 2003;4:537-47 White JR, Walczak TS, Marino SE, Zonisamide discontinuation due to psychiatric and cognitive adverse events: a case-control study. Neurology 2010;75:513-18 Boussemart T, Flurin V, Labay-Bruneau F, Heat stroke and topiramate. Arch Pediatr 2008;15:416-18 Shimizu T, Yamashita Y, Satoi M, Heat stroke-like episode in a child caused by zonisamide. Brain Dev 1997;19:366-8 Nolla-Salas J, Gracia MP, Martin JC, Heatstroke during topiramate treatment. Med Clin (Barc) 2007;128:677-8 Gerstner T, Busing D, Bell N, Valproic acid-induced pancreatitis: 16 new cases and a review of the literature. J Gastroenterol 2007;42:39-48 Buzan RD, Firestone D, Thomas M, Valproate-associated pancreatitis and cholecystitis in six mentally retarded adults. J Clin Psychiatry 1995;56:529-32 Yatham LN, Goldstein JM, Vieta E, Atypical antipsychotics in bipolar depression: potential mechanisms of action. J Clin Psychiatry 2005;66(Suppl 5):40-8 Maher AR, Maglione M, Bagley S, Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA 2011;306:1359-69 Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 2009;166:980-91 Yatham LN, Goldstein JM, Vieta E, Atypical antipsychotics in bipolar depression: potential mechanisms of action. J Clin Psychiatry 2005;66(Suppl 5):40-8 Blier P, Szabo ST. Potential mechanisms of action of atypical antipsychotic medications in treatment-resistant depression and anxiety. J Clin Psychiatry 2005;66:30-40 Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 2009;166:980-91 Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 2009;166:980-91 Prieto E, Mico JA, Meana JJ, Neurobiological bases of quetiapine antidepressant effect in the bipolar disorder. Actas Esp Psiquiatr 2010;38:22-32 Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. J Clin Psychiatry 2003;64(Suppl 19):6-12 Sachs GS, Ice KS, Chappell PB, Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2011;72:1413-22 Buchanan RW, Kreyenbuhl J, Kelly DL, The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010;36:71-93 Gonzalez JM, Thompson PM, Moore TA. Review of the safety, efficacy, and side effect profile of asenapine in the treatment of bipolar 1 disorder. Patient Prefer Adherence 2011;5:333-41 Weiden PJ, Cutler AJ, Polymeropoulos MH, Safety profile of iloperidone: a pooled analysis of 6-week acute-phase pivotal trials. J Clin Psychopharmacol 2008;28(Suppl 1):S12-19 Samalin L, Garnier M, Llorca PM. Clinical potential of lurasidone in the management of schizophrenia. Ther Clin Risk Manag 2011;7:239-50 Buchanan RW, Kreyenbuhl J, Kelly DL, The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010;36:71-93 Gonzalez JM, Thompson PM, Moore TA. Review of the safety, efficacy, and side effect profile of asenapine in the treatment of bipolar 1 disorder. Patient Prefer Adherence 2011;5:333-41 Cutler AJ, Kalali AH, Weiden PJ, Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol 2008;28:S20-8 Samalin L, Garnier M, Llorca PM. Clinical potential of lurasidone in the management of schizophrenia. Ther Clin Risk Manag 2011;7:239-50 de Leon J, Sandson NB, Cozza KL. A preliminary attempt to personalize risperidone dosing using drug-drug interactions and genetics: part I. Psychosomatics 2008;49:258-70 de Leon J, Sandson NB, Cozza KL. A preliminary attempt to personalize risperidone dosing using drug-drug interactions and genetics: part I. Psychosomatics 2008;49:258-70 Kane JM, Sharif ZA. Atypical antipsychotics: sedation versus efficacy. J Clin Psychiatry 2008;69:18-31 Gonzalez JM, Thompson PM, Moore TA. Review of the safety, efficacy, and side effect profile of asenapine in the treatment of bipolar 1 disorder. Patient Prefer Adherence 2011;5:333-41 Weiden PJ, Cutler AJ, Polymeropoulos MH, Safety profile of iloperidone: a pooled analysis of 6-week acute-phase pivotal trials. J Clin Psychopharmacol 2008;28(Suppl 1):S12-19 Weiden PJ, Preskorn SH, Fahnestock PA, Translating the psychopharmacology of antipsychotics to individualized treatment for severe mental illness: a roadmap. J Clin Psychiatry 2007;68(Suppl 7):1-48 de Leon J. Paying attention to pharmacokinetic and pharmacodynamic mechanisms to progress in the area of anticholinergic use in geriatric patients. Curr Drug Metab 2011;12:635-46 Thornton AE, Van Snellenberg JX, Sepehry AA, The impact of atypical antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: a quantitative review. J Psychopharmacol 2006;20:335-46 Thornton AE, Van Snellenberg JX, Sepehry AA, The impact of atypical antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: a quantitative review. J Psychopharmacol 2006;20:335-46 Alper K, Schwartz KA, Kolts RL, Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry 2007;62:345-54 Torta R, Monaco F. Atypical antipsychotics and serotoninergic antidepressants in patients with epilepsy: pharmacodynamic considerations. Epilepsia 2002;43(Suppl 2):8-13 Serretti A, Chiesa A. A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics. Int Clin Psychopharmacol 2011;26:130-40 Serretti A, Chiesa A. A meta-analysis of sexual dysfunction in psychiatric patients taking antipsychotics. Int Clin Psychopharmacol 2011;26:130-40 de Leon J, Sandson NB, Cozza KL. A preliminary attempt to personalize risperidone dosing using drug-drug interactions and genetics: part I. Psychosomatics 2008;49:258-70 de Leon J. Paying attention to pharmacokinetic and pharmacodynamic mechanisms to progress in the area of anticholinergic use in geriatric patients. Curr Drug Metab 2011;12:635-46 Buchanan RW, Kreyenbuhl J, Kelly DL, The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010;36:71-93 Curran MP, Perry CM. Amisulpride: a review of its use in the management of schizophrenia. Drugs 2001;61:2123-50 Gonzalez JM, Thompson PM, Moore TA. Review of the safety, efficacy, and side effect profile of asenapine in the treatment of bipolar 1 disorder. Patient Prefer Adherence 2011;5:333-41 Citrome L. Iloperidone, asenapine, and lurasidone: a brief overview of 3 new second-generation antipsychotics. Postgrad Med 2011;123:153-62 Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract 2011;65:189-210 Martin-Latry K, Goumy MP, Latry P, Psychotropic drug use and risk of heat-related hospitalisation. Eur Psychiatry 2007;22:335-8