Epilepsy & Behavior 75 (2017) 237–240
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Effect of sleep patterns on levetiracetam induced mood changes☆ Randip Taneja a, Krystal Hunter b, Evren Burakgazi-Dalkilic a,c, Melissa Carran a,c,⁎ a b c
Department of Neurology, Cooper University Hospital, 1 Cooper Plaza, Camden, NJ 08103, United States Cooper Research Institute, Cooper University Hospital, 1 Cooper Plaza, Camden, NJ 08103, United States Department of Neurology, Cooper Medical School of Rowan University, 3 Cooper Plaza, Suite 320, Camden, NJ 08103, United States
a r t i c l e
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Article history: Received 30 May 2017 Revised 15 July 2017 Accepted 19 July 2017 Available online 18 August 2017 Keywords: Levetiracetam Sleep Mood Depression Anxiety Seizure Epilepsy
a b s t r a c t A common side effect of levetiracetam is the onset of neuropsychiatric symptoms such as mood changes including depression, anxiety, agitation, and sometimes psychosis. We performed a retrospective analysis to examine the effect of sleep pattern and chronotype on individual susceptibility to levetiracetam-induced mood changes. We reviewed records of 110 adults with epilepsy presenting to our clinic during a 3-month period, and categorized them into those currently on levetiracetam, and those no longer taking it because of mood-related adverse effects. Patients were administered Morningness–Eveningness Questionnaire (MEQ), Beck's Depression Inventory-II, and Neurological Disorders Depression Inventory in Epilepsy. Using various statistical methods, we analyzed the comparison of these 3 different scales amongst one another and between those subjects who tolerated levetiracetam and those who did not. Of 110 patients, 74 (67%) tolerated levetiracetam and 36 (33%) did not tolerate it because of mood changes with chronotype being a significant determining factor. Of those who tolerated the drug, 62% were intermediate chronotypes and 20.3% and 17.6% were morning and evening chronotypes, respectively. For those intolerant, 86.1% were morning chronotypes, 13.9% were intermediate chronotypes, and none were evening chronotypes (p b 0.001). Thirty-two percent of morning chronotypes, 100% of evening chronotypes, and 90.2% of intermediate chronotypes were tolerant of levetiracetam (p b 0.001). Chronotype significantly affected toleration of levetiracetam. Chronotype, but not depression, was a significant factor in determining tolerability of mood-altering side effects of levetiracetam, via statistically significant trend for an increasing ability to tolerate levetiracetam as chronotype would shift from morning to intermediate to evening. Additional research may help establish if this is related to possible underreporting of poor mood with evening chronotypes, and morning chronotypes having more stringent sleep schedules, genetic factors, or other reasons. © 2017 Elsevier Inc. All rights reserved.
1. Introduction Levetiracetam is one of the safest and most widely used anticonvulsants. The most frequently encountered and troubling side effect is the onset of neuropsychiatric symptoms such as mood changes of depression, anxiety, agitation, and sometimes psychosis [1,2]. This causes problems for patients and their family members, and often necessitates discontinuation of the medication. The ability to predict which patients will not tolerate levetiracetam would have a major impact on clinical decisions to successfully treat epilepsy. Chronotype refers to the circadian rhythm of a given organism that determines if alertness and productivity are greater in the hours of ☆ Statistical analysis was conducted by Krystal Hunter, MBA, Cooper Medical School of Rowan University, Statistician II — Cooper Research Institute, Cooper University Hospital. ⁎ Corresponding author at: Cooper Medical School of Rowan University Hospital, 3 Cooper Plaza, STE 320, Camden, NJ 08103, United States. E-mail addresses:
[email protected] (R. Taneja),
[email protected] (K. Hunter),
[email protected] (E. Burakgazi-Dalkilic),
[email protected] (M. Carran).
http://dx.doi.org/10.1016/j.yebeh.2017.07.038 1525-5050/© 2017 Elsevier Inc. All rights reserved.
early morning or later in the day [3]. When identifying a chronotype, three broad categories are often used: Morning type (informally known as “Lark”), Evening type (informally known as “Owl”), and Intermediate type [4]. The purpose of this study was to determine if there is a relationship between a patient's sleep pattern, i.e., chronotype, and their susceptibility to the mood deteriorating side effects of levetiracetam. We hypothesize that the individual chronotype may predict tolerance of the medication. In his thesis Charting Individual Daily Rhythms [5], O. Oquist from University of Goteborg, Sweden, Department of Psychology, introduced a questionnaire with the aim to separate “morningness” and “eveningness” [6]. This questionnaire was modified by Ostberg and Horne, who in 1976 had published the 19-item Morningness– Eveningness (ME) Questionnaire (MEQ) [4], which has been widely used in medical research. The scoring for the MEQ consists of a scale from 16 to 86, based on which an individual is determined to have one of five chronotypes: Definite Evening, Moderate Evening, Intermediate, Moderate Morning, or Definite Morning [Table 1]. There is accumulating research suggesting a link between chronotype and mood. Some studies show higher association with depression or
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Table 1 Morningness–Eveningness Questionnaire scoring.
Table 3 Neurological Disorders Depression Inventory in Epilepsy (NDDI-E) scoring.
Score
16–30
31–41
42–58
59–69
70–86
Chronotype
Definite Evening
Moderate Evening
Intermediate
Moderate Morning
Definite Morning
mood fluctuation in evening types, in the general population [7]. However, we suggest that since levetiracetam may cause increased sleepiness, morning types are more susceptible to mood and behavior effects since morning chronotypes sleep less overall [8,9]. Neurologists often utilize screen tools such as the Beck's Depression Inventory-II (BDI-II) and the Neurological Disorders Depression Inventory in Epilepsy (NDDI-E) to screen for depression and anxiety in clinical practice. We use these inventories to measure the presence and/or degree of mood problems in our epilepsy population. The BDI-II is one of the most widely used depression screening instruments used by clinicians and is in accordance with the depression criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). It consists of 21 items to assess for the presence and degree of depression in patients, with each item containing lists of 4 statements arranged in increasing severity about a particular depressive symptom [10]. Scoring for the BDI-II [Table 2] consists of a scale from 0 to 63, which corresponds to one of four severities of depression, including Minimal, Mild, Moderate, and Severe. The NDDI-E is a validated, rapid, self-rating, 6-item questionnaire for depression screening in patients with epilepsy [11]. Each item has an option for the patient to select one of 4 options (Never, Rarely, Sometimes, and Always or Often) with each respectively being scored from 1 to 4 [Table 3]. Scores of greater than 15 on the NDDI-E are suggestive of a diagnosis of depression.
2. Methods 2.1. Study design We reviewed the electronic records of patients with epilepsy who presented for follow-up at Cooper University Hospital's Neurology clinic during a 3-month period in 2016, in a sequential fashion. Inclusion criteria were adults with a diagnosis of epilepsy, ages 18 years and older, either taking levetiracetam currently or had taken it prior yet had to stop because of intolerable side effects, i.e., depression and/or anxiety. Exclusion criteria were diagnosis of developmental delay with intellectual disability or IQ b 70, a prior diagnosis of a mood disorder, or psychiatric diagnosis and on antipsychotic medication (prior to levetiracetam), presence of a sleep disorder, or having a diagnosis of dementia. Out of 110 subjects, all had completed an MEQ, 91 had also completed a BDI-II, and 101 had also completed an NDDI-E. These questionnaires were being administered to the patients prior to the study's inception. Extracted data included the subject's age, gender, whether or not actively taking levetiracetam, MEQ scale, BDI-II score, and NDDI-E score. For our study, we combined Definite Evening and Moderate Evening Chronotypes into “Evening Chronotype” and Definite Morning and Moderate Morning Chronotypes into “Morning Chronotype”.
Table 2 Beck Depression Inventory-II scoring. Score
Range
0–13 14–19 20–28 29–63
Minimal Mild Moderate Severe
Everything is a struggle Nothing I do is right Feel guilty I'd be better off dead Frustrated Difficulty finding pleasure
Always or Often
Sometimes
Rarely
Never
4 4 4 4 4 4
3 3 3 3 3 3
2 2 2 2 2 2
1 1 1 1 1 1
An NDDI-E score of greater than 15 is suggestive of a diagnosis of depression.
2.2. Statistical analysis There were three analyses done for this study: the comparison of the different scales (Morningness–Eveningness scale, BDI score, and NDDI score), the comparison between those who tolerated levetiracetam and those who did not, and the comparison between those who were classified as morning individuals and intermediate and evening individuals. The correlation of the different scales was figured by the Pearson and Spearman Rho Correlations. The analysis comparing factors by those who tolerated levetiracetam vs. those who did not were completed by using the independent t-test, Mann–Whitney U test to compare continuous factors (age and scores), and chi square tests to compare categorical factors. We used the MEQ and categorized those who were morning individuals vs. intermediate vs. evening individuals within our sample. When we compared those individuals with morning vs. evening characteristics (excluding those who were intermediate), we used independent t-tests, Mann–Whitney U test, and chi square tests. When we compared the factors between these three groups (including the intermediate group), we used One Way ANOVA to compare the means of the continuous variables and chi square tests to compare the proportions of categorical variables. We also used chi square tests to compare other scale ranges in the different analysis. For BDI-II, we categorized the score by minimal, mild, moderate, and severe depression, and for NDDI, we dichotomized by labeling one category “depressed” and the other category “not depressed”. These were compared between those who tolerated levetiracetam vs. those who did not and those who were morning vs. evening (vs. intermediate). The protocol was approved by the Cooper Health System Institutional Review Board.
3. Results Scores were collected for 110 patients. Of these, 74 (67%) tolerated levetiracetam, and 36 (33%) did not tolerate it because of mood changes [Table 4]. Chronotype was a significant factor in determining toleration Table 4 Association of factors with tolerability of levetiracetam. Factor
Age (mean/SD) Gender — male (n/%) BDI-II (median/SD) BDI-II (n/%) Minimal Mild Moderate Severe NDDI (mean/SD) NDDI — depressed (n/%) MEQ (n/%) Morning Evening Intermediate
Levetiracetam tolerated
Levetiracetam not tolerated
N
N
74 74 60 60
68 73 74
43.81 (17.10) 38 (51.3%) 5 (1–13.75) 45 (75%) 6 (10%) 2 (3.3%) 7 (11.7%) 11.06 (4.60) 10 (14.7%) 15 (20.3%) 13 (17.6%) 46 (62.2%)
36 36 31 36
33 36 36
47.56 (17.65) 14 (38.9%) 8 (4–14) 21 (67.7%) 7 (22.6%) 3 (9.7%) 0 (0%) 11.15 (3.47) 14 (38.9%) 31 (86.1%) 0 (0%) 5 (13.9%)
p value
0.289 0.219 0.234 0.057
0.919 0.246 b0.001
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Table 5 Association of factors with Morningness–Eveningness scale. Factor
Age (mean/SD) Gender — male (n/%) BDI-II (median/IQR) BDI-II (n/%) Minimal Mild Moderate Severe NDDI (mean/SD) NDDI — depressed (n/%)
Morningness
Eveningness
Intermediate
N
N
N
46 46 40 40
42 42
48.76 (16.42) 20 (43.5%) 6.5 (1–14) 29 (72.5%) 7 (17.5%) 3 (7.5%) 1 (2.5%) 10.79 (3.75) 4 (9.5%)
13 12 31 11
13 13
of levetiracetam. Of those who tolerated levetiracetam, 62% were of the intermediate chronotype while 20.3% and 17.6% were of the morning and evening chronotypes, respectively. For those who did not tolerate levetiracetam, 86.1% were of the morning chronotype while 13.9% were of the intermediate chronotype. There were no evening chronotypes who were intolerant of levetiracetam (p b 0.001). Thirtytwo percent of morning chronotypes, 100% of evening chronotypes, and 90.2% of those with an intermediate chronotype were tolerant of levetiracetam (p b 0.001). Table 5 displays association of factors assessed with ME score. When assessing the relationship between age, BDI-II, NDDI, and ME scale, it was found that there was a significant correlation between age and ME scale. There was a weakly positive linear relationship between these two (R = 0.232, p = 0.015) such that increasing age tended to have a higher ME score, correlating to morning chronotype. There was also a significant correlation between the BDI-II and NDDI-E scores. The relationship between these two assessments was a strong positive relationship indicating that as one goes up so does the other (R = 0.795, p b 0.001). Outside of chronotype, there were no other factors that significantly affected toleration of levetiracetam. 4. Discussion Our findings suggest that chronotype is a significant factor in determining tolerability of levetiracetam, in regard to mood-related side effects. We noted a statistically significant trend for an increasing ability to tolerate levetiracetam as individual chronotype would shift from morning to intermediate to evening. This finding was interesting and somewhat surprising in respect to additional findings in our study as well as others [7–9], which suggest that individuals with morning chronotypes tend to have lower depression scores than those with evening chronotypes. As we also found a higher incidence of depression in the evening chronotypes, it is uncertain if this is an underreported side effect of levetiracetam in our patients. It is possible that the personality style of evening chronotypes results in more internalization of depression, resulting in an underreporting of poor mood. This may make it important to have pre- and post levetiracetam depression inventories for all patients. The lack of this data is a limitation of our study. Although we found a weakly positive linear correlation with age and MEQ score (with increasing age tending to correlate with more morning chronotypes), there was no significantly significant correlation between age and BDI-II or NDDI-E depression score. In addition, our results suggest that the ability to tolerate levetiracetam was independent of underlying depression, or lack thereof, based on BDI or NDDI scores. Furthermore, we were able to establish validity of BDI-II and NDDI-E depression testing, as we found their results to have a statistically significant strongly positive correlation. This was consistent with prior studies. This finding also helps solidify the validity of the NDDI-E as a depression screen tool in patients with epilepsy, given the advantage of it being faster to administer.
41.92 (17.44) 5 (41.7%) 7 (1–27) 7 (63.6%) 1 (9.1%) 1 (9.1%) 2 (18.2%) 12.77 (4.27) 3 (23.1%)
51 51 31 40
46 46
p value
42.47 (17.72) 27 (52.9%) 6 (1–13.75) 30 (75%) 5 (12.5%) 1 (2.5%) 4 (10%) 10.89 (4.64) 6 (13%)
0.159 0.515 0.846 0.519
0.312 0.443
Although we consider our conclusions to be valid, there are limitations to our study. First, we had a relatively small sample size of 110 subjects. Second, for those patients we categorized as nontolerant of levetiracetam, we were not able to account for other variables contributing to their difficulty tolerating the medication when they were on it (such as other medications and social stressors). A subsequent study with larger sample sizes may help offset these variables. Studies have shown that levetiracetam may result in increase in total sleep time, and time spent in nonrapid eye movement (NREM) sleep stages 2 and 4 [12]. It is possible that the morning types who do tolerate levetiracetam do so partly from being more able to obtain extra sleep. A trial by Shorvon et al. [13] showed somnolence to be reported in 9.4% of patients taking 1000 mg daily of levetiracetam as an add-on therapy (vs. 5% of placebo) and 11.3% of patients taking 2000 mg daily (vs. 7% of placebo). Various other trials have also shown somnolence to be a common side effect reported by patients taking levetiracetam [14,15]. In addition, studies have shown that morning types tend to have more stringent sleep schedules than evening types, and that eveningness is associated with less time in bed during the week compared with ideal sleep needs with a tendency to compensate for this weekday sleep debt by sleeping more on the weekends [16]. Evening types tend to show more plasticity with respect to their length of sleep as well as their sleep/wake schedule compared with morning types [17], and may be less sensitive than morning types in regard to sleep restriction [18]. This may at least partly explain why our study found morning types to be more susceptible to the mood altering effect of levetiracetam. Genetic factors may also play a role in an individual's susceptibility to the mood altering effects of levetiracetam. Genomic studies have implicated the presence of several loci significantly associated with morningness, including several located near established circadian genes [19,20], however, more studies will be needed to validate this theory. In conclusion, degree of morningness via administration of the MEQ may be a good marker to use prior to initiation of levetiracetam for patients. Patients may be more appropriately counseled about their risk of mood problems, using these results. Declaration of interest None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. References [1] Medicine USNLo. Label: KEPPRA — levetiracetam tablet; 2010. [2] White JR, Walczak TS, Leppik IE, Rarick J, Tran T, Beniak TE, et al. Discontinuation of levetiracetam because of behavioral side effects: a case–control study. Neurology 2003;61:1218–21. [3] Chronotype. The American heritage medical dictionary. Houghton Mifflin Company; 2007.
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