Elsevier

Epilepsy & Behavior

Volume 76, November 2017, Pages 24-31
Epilepsy & Behavior

Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy

https://doi.org/10.1016/j.yebeh.2017.08.039Get rights and content

Highlights

  • Rates of psychiatric and behavioral side effect (PBSE) are compared between AEDs.

  • History of psychiatric condition and seizures failing to improve with ≥ 2 AEDs are associated with PBSEs.

  • History of absence and secondarily generalized seizures are associated with PBSEs.

  • Levetiracetam and zonisamide are associated with higher PBSEs.

  • Lower PBSE rates are seen in carbamazepine compared with that in lamotrigine.

Abstract

Purpose

Psychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.

Methods

As part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.

Results

Psychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P < 0.001, OR = 6.87). Levetiracetam was also significantly (P < 0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P < 0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P < 0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.

Conclusions

Psychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.

Introduction

Psychiatric and behavioral side effects (PBSEs) are highly prevalent in patients taking antiepileptic drugs (AEDs). These adverse effects can lead to suboptimal dosing for seizure control, as well as poor adherence to AEDs and early AED discontinuation in up 25% of patients [1], [2]. Between 15% and 20% of adult patients with epilepsy taking AEDs experience PBSEs; these include depressive mood, psychosis, increase in irritability, and aggressive behavior [3]. Psychiatric and behavioral side effects are some of the most common adverse effects associated with AED use and have a higher cost per patient per year compared with other adverse-effect categories [4], [5]. To our knowledge, no previous study has compared PBSEs of both newer and older AEDs while controlling for potential non-AED-related factors [6]. A better understanding of the PBSE profiles of different AEDs available today is important clinically, as it could help provide practical recommendations and guidelines for physicians to weigh the cost–benefit ratio when prescribing AEDs.

Of particular importance is that psychiatric and behavioral comorbidities result from the social and structural implications of epilepsy, as well as from the AEDs themselves [4]. Thus, individual susceptibility highlights the necessity of understanding patient-related, dose-independent factors that contribute to the onset of PBSEs [7], [8]. Yet, our knowledge of the influence of these factors is still very limited [9]. In the current study, we compared PBSE profiles of older and newer AEDs using a large patient database. We also looked at the influence of patient demographics and medical histories, as well as AED dose and drug load, on the onset of PBSEs.

Section snippets

Methods

We examined the medical records of 4085 adult patients (≥ 18 years old) using the Columbia and Yale Antiepileptic Drug Database. We included patients seen at both the Columbia Comprehensive Epilepsy Center and the Yale Comprehensive Epilepsy Center, all of whom had been newly started on one or more of the following AEDs between January 1, 2000 and January 1, 2015, and were followed up for at least 1 year: carbamazepine (CBZ), clobazam (CLB), felbamate (FBM), gabapentin (GBP), lacosamide (LCM),

Results

Our study population consisted of 4085 patients with epilepsy that started an AED at the age of 18 or older. Most of the patients were diagnosed with focal epilepsy (71.1%), followed by idiopathic generalized epilepsy (17.4%) and symptomatic generalized epilepsy (3.6%) (Table 1). A total of 79.8% (3261/4085) of our study population had seizures that failed to improve with two or more AEDs.

Overall, 17.2% (701/4085) of patients developed PBSE attributed to an AED, and 13.8% (565/4085) experienced

Discussion

Previous literature has shown that the presence of psychiatric history is a strong predictor of PBSE with AED use in adult patients with epilepsy [3], [4], [13], [14], [15]. This finding was confirmed by our study. In addition, our study also found that patients with intractable epilepsy (seizures failing to improve with two or more AEDs), secondarily generalized seizures, or absence seizures are more likely to have PBSE when taking AEDs. History of static encephalopathy was also moderately

Acknowledgments

The Columbia and Yale AED Database has been supported by Elan, GlaxoSmithKline, Ortho-McNeil, Pfizer, Lundbeck, Esai, and UCB Pharma. Dr. Hirsch has received honoraria, consultation fees, and/or speaker fees from all the supporting companies. Dr. Detyniecki and Dr. Choi have both received research support for investigator-initiated studies from Acorda Therapeutics.

Other coauthors have no relevant disclosures.

Dr. Gustavo Patino, Assistant Professor of Neuroscience at the Oakland University

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