patient emotions and perceptions of antiepileptic drug changes and titration during treatment for epilepsy

Epilepsy & Behavior 69 (2017) 44–52 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh Patient emotions and perceptions of antiepileptic drug changes and titration during treatment for epilepsy Jesse Fishman a,⁎, Greg Cohen a, Colin Josephson b, Ann Marie Collier c, Srikanth Bharatham a, Ying Zhang a, Imane Wild a a b c UCB Pharma, 1950 Lake Park Drive SE, Smyrna, GA 30080, USA Department of Clinical Neurosciences, University of Calgary, Cummings School of Medicine, Foothills Medical Center, 1403 29th St NW, Calgary, Alberta T2N 2T9, Canada St Mary's Hospital, 750 Wellington Ave, Grand Junction, CO 81501, USA a r t i c l e i n f o Article history: Received 17 November 2016 Revised 30 January 2017 Accepted 31 January 2017 Available online xxxx Keywords: Titration Antiepileptic drug Emotion Valence Physician empathy a b s t r a c t Objective: To investigate the impact of antiepileptic drug (AED) change and dose titration on the emotional wellbeing of patients with epilepsy Methods: Members of an online epilepsy community were invited to voluntarily participate in an online survey The cross-sectional anonymous survey consisted of 31 multiple choice questions balanced in terms of variety and positivity/negativity of emotions concerning participants' most recent AED change To substantiate survey results, spontaneous comments from epilepsy-related online forums and social media websites that mentioned participants' experiences with AED medication changes (termed passive listening statements) were analyzed and categorized by theme Results: All 345 survey participants (270 [78.3%] female; 172 [49.9%] were 26–45 years old) self-reported an epilepsy/seizure diagnosis and were currently taking seizure medication; 263 (76.2%) were taking ≥2 AEDs and 301 (87.2%) had ≥1 seizure in the previous 18 months All participants reported a medication change within the previous 12 months (dose increased [153 participants (44.3%)], medication added [105 (30.4%)], dose decreased [49 (14.2%)], medication removed [38 (11.0%)]) Improving seizure control (247 [71.6%]) and adverse events (109 [31.6%]) were the most common reasons for medication change Primary emotions most associated (≥10% of participants) with an AED regimen change were (before medication change; during/after medication change) hopefulness (50 [14.5%]; 43 [12.5%]), uncertainty (50 [14.5%]; 69 [20.0%]), and anxiety (35 [10.1%]; 45 [13.0%]), and were largely due to concerns whether the change would work (212/345 [61.4%]; 180/345 [52.2%]) In the text analysis segment aimed at validating the survey, 230 participants' passive listening statements about medication titration were analyzed; additional seizure activity during dose titration (93 [40.4%]), adverse events during titration (71 [30.9%]), higher medication dosages (33 [14.3%]), and drug costs (25 [10.9%]) were the most commonly noted concerns Conclusion: Although the emotional well-being of patients with epilepsy is complex, our study results suggest that participants report their emotional well-being as negatively affected by changes in AED regimen, with most patients reporting uncertainty regarding the outcome of such a change Future research is warranted to explore approaches to alleviate patient concerns associated with AED medication changes © 2017 Published by Elsevier Inc Introduction Patient emotions may play a vital role in communication and satisfaction with the patient–clinician relationship and in adherence to treatment regimens Owing to the broad availability of medical ⁎ Corresponding author E-mail addresses: jesse.fishman@ucb.com (J Fishman), gregory.cohen@ucb.com (G Cohen), cbjoseph@ucalgary.ca (C Josephson), marietxmd@gmail.com (A.M Collier), srikanth.bharatham@ucb.com (S Bharatham), ying.zhang5@ucb.com (Y Zhang), imane.wild@ucb.com (I Wild) http://dx.doi.org/10.1016/j.yebeh.2017.01.032 1525-5050/© 2017 Published by Elsevier Inc information via the Internet, patients are more informed about their medical condition and treatments than previous generations, prompting a change in the nature of the patient–physician relationship [1–3] Indeed, patients are becoming more involved in making decisions and managing their disease [4,5], which is dependent upon a solid partnership with their physician However, evidence suggests that a division exists between physicians and their patients in the importance of different aspects of disease treatment and management [5,6] In one survey, two-thirds of patients versus one-third of physicians reported avoiding depression, anxiety, and treatment-related behavior changes as important considerations in making treatment decisions [5] Although half of patients rated reducing the titration period and changes to the J Fishman et al / Epilepsy & Behavior 69 (2017) 44–52 treatment plan owing to adverse events as important factors in treatment decisions, less than 20% of physicians rated these as important factors However, both patients and physicians regarded reducing seizure frequency and severity as the most important aspects of treatment [5] An improved physician–patient dynamic may foster better assessment of patient emotions and perceptions of antiepileptic drug (AED) use, which may impact the treatment adherence so critical for seizure control In one study, nonadherence to AED therapy was influenced by patient doubts regarding the need for AEDs, negative perceptions of AEDs, and concerns about adverse events [7] In another study, the majority of surveyed patients blamed forgetfulness for medication nonadherence, while physicians overwhelmingly attributed nonadherence to poor tolerability or patient complacency [6] Further, intentional nonadherence has been described in patients with chronic conditions, with nonadherence commonly attributed to feeling good and deciding not to dose, or a fear of side effects [8] Because emotions are intrinsically involved in an individual's decision-making [9] and treatment adherence requires daily decision on the patient's part, addressing patient emotions that may hinder AED titration may help remove barriers to adherence Ultimately, a better understanding of patient considerations, perceptions, and emotions may help improve the discussion between patients and their physicians, leading to improved treatment outcomes Modification to AED regimens often require a titration period that differs depending upon the individual AED and the titration approach (e.g., titration of a new AED to full dose before tapering the first AED, or simultaneously titrating and tapering AEDs [10]) During this titration period, the physician and patient must once again evaluate the benefits of the new medication versus potential side effects In addition to side effects, the possibility of seizures occurring during AED changes may also be concerning for patients during this timeframe Changing AED treatment indicates suboptimal seizure control or unacceptable side effects, and changes to optimize AED treatment introduces a new period of uncertainty to the patient as to whether the new treatment will help them achieve seizure control Although AED treatment changes may negatively affect patients' quality of life [11], patients' emotions regarding an AED regimen change are not well explored, and represents a possible opportunity for addressing patient needs Additionally, understanding patient emotions during AED treatment changes may better explain other reasons for nonadherence, whether intentional or unintentional, that are typically attributed to forgetting or adverse events Accordingly, the objective of this survey-based study was to better understand the effect of AED change and dose titration on epilepsy patients' emotional well-being as well as their perceptions during this period of change Methods 2.1 Patient survey This study was an open, prospective, cross-sectional survey of adult members with epilepsy from the Epilepsy Advocate disease-state patient community This online community (www.epilepsyadvocate com; supported by UCB Pharma) provides patients and their families with an open forum for epilepsy-related information, patient blogs, social networking opportunities, and links to other support sources An invitation to participate in the survey was posted to the Epilepsy Advocate Facebook page (i.e., “Have you and your physician ever modified your medication plan? We are looking for your perspective on the emotions and mindsets you experienced during a proposed medication change.”) with a link to the survey Names, Facebook IDs, or other personally identifiable information (e.g., e-mails) were not collected Each respondent provided informed consent, and all responses were automatically captured and tabulated by SurveyMonkey® (SurveyMonkey 45 Inc, Pala Alto, CA, www.surveymonkey.com) Surveys were completed from September 4, 2015 to October 30, 2015 Clinical trial experts and a clinical psychologist developed and evaluated the survey based on prior experience, and incorporated guidance for reporting of online surveys [12] The survey consisted of 31 multiple choice questions that focused on patient experiences and emotions before and during/after the patient's most recent AED medication change in the past 12 months (e.g., change in AED dose or drug, reason for change, duration of change, seizure activity, communication with the clinician, emotions experienced and positivity/negativity) as well as patient demographics and epilepsy characteristics (e.g., age, sex, insurer, number of AEDs, time since diagnosis) The survey did not capture time from the most recent AED change, but all changes were to have occurred in the prior 12 months All questions about emotion were balanced in terms of variety and valence, a common dimension of emotions (positivity or negativity) used to explain behavior [13] Emotions were selected based, in large part, on Plutchik's theory of emotions [14] For comparison purposes, emotion terms were operationally grouped into basic emotion groups as follows (primary emotion terms in parentheses): anticipation (confident, intrigued, optimism), trust (certain, compliant), joy (courageous, eager, hopeful), anger (disbelief, resistant), sadness (anxiety, hopelessness, worry), distrust (afraid, fear, hesitant, uncertain), and none Anticipation, joy, and trust were considered as having positive valence, while anger, sadness, and distrust were attributed negative valence Valence (degree of positivity or negativity) is an integral aspect of emotion research [15–17] used to evaluate if something is perceived as helpful or harmful, and was assessed with respect to the primary emotion reported To confirm assignment of emotion terms (and by extension, basic emotion groups) as being positive or negative, emotion terms were weighted by reported valence (1 = very positive, = slightly positive, = neutral, = slightly negative, = very negative; Supplementary Table 1) Positive or negative emotion groups were expected to be consistent with emotion research [14] The reason for the emotion before and during/ after the medication change also was assessed Antiepileptic drugs categorized as sodium-channel blocking [SCB(+)] AEDs were carbamazepine, lamotrigine, lacosamide, oxcarbazepine, and phenytoin; nonsodium-channel blocking [SCB(−)] AEDs were levetiracetam, perampanel, topiramate, and divalproate Antiepileptic drugs with mood-stabilizing properties were those approved by the US Food and Drug Administration for the treatment of bipolar disorder (carbamazepine, lamotrigine, and sodium valproate) 2.2 Passive listening text analysis In an effort to assess the generalizability of the patient survey findings, a passive listening text analysis was undertaken to extract data from online sources outside of the Epilepsy Advocate community IMS Health™: Nexxus™ Social Media used longitudinal tracking of patient data on social media platforms to ascertain epilepsy status and extract conversations related to the terms dose, doses, dosage, titrate, or titration in the context of epilepsy or epileptic seizures Conversations were cross-referenced between websites to ensure epilepsy status Results were qualitatively analyzed to produce a set of comments related to titration aspects of AED treatment A set of categorical filters specific to emotional, physical, and general health, adapted from the Quality of Life in Epilepsy Inventory-31 (QOLIE-31) questionnaire [18], was used to probe the final dataset Questions from the QOLIE-31 were selected based upon applicability to the dose titration phase and probability of being addressed in social media data; in some cases, language was slightly modified based on the patient lexicon and for ease of understanding An additional category concerning financial issues due to drug expense was included Based on the information provided in the subject statements, each question was assigned a categorical answer of “Yes,” “No,” or “Not mentioned.” Patients' experiences with the medication change process within emotional, physical, and general 46 J Fishman et al / Epilepsy & Behavior 69 (2017) 44–52 health categories were analyzed to better understand the emotions and experiences surrounding an AED change (dose titration phase) 2.3 Statistical analyses For statistical analyses, emotions captured in the Epilepsy Advocate survey were categorized as positive (certain, compliant, confident, courageous, eager, hopeful, intrigued, and optimism) and negative (afraid, anxiety, disbelief, fear, hesitant, hopelessness, resistant, uncertain, and worry); responses of “none” were excluded Analysis by individual emotion term was not undertaken due to small sample sizes across the 18 emotion terms After term grouping, a McNemar's test was used to assess the agreement between before an AED change and matched responses during/after the AED change on positive and negative categories A binomial test (H0: proportion of negative emotions = 0.5) was employed for data during/after an AED change to compare positive versus negative emotion categories Chi-square tests were used to assess the impact of duration of AED change (titration), type of AED change (add or remove AED, increase or decrease in dose), number of Table Demographic and clinical characteristics n (%) Survey patients (N = 345) Female Male Age, years 18–25 26–35 36–45 46–55 56–65 N66 Highest education level ≤High school Some collegea ≥College graduate Annual household income b$30,000 $30,000–$50,000 $50,000–$75,000 N$75,000 Prefer not to say Insurer Commercial Medicare Medicaid Federal (other than Medicare/Medicaid) None Time since epilepsy or seizure diagnosis b2 years previously 2–3 years previously N3 years previously Number of current seizure medications N3 Current seizure/epilepsy medicationb Levetiracetam Lamotrigine Topiramate Divalproex Lacosamide Oxcarbazepine Carbamazepine Phenytoin Eslicarbazepine Perampanel Other Experienced ≥1 seizures in the past 18 months 270 (78.3) 75 (21.7) a b 69 (20.0) 87 (25.2) 85 (24.6) 68 (19.7) 33 (9.6) (0.9) 104 (30.1) 170 (49.3) 71 (20.6) 143 (41.5) 47 (13.6) 35 (10.1) 39 (11.3) 81 (23.5) 130 (37.7) 68 (19.7) 78 (22.6) 51 (14.8) 18 (5.2) 38 (11.0) 23 (6.7) 284 (82.3) 82 (23.8) 133 (38.6) 88 (25.5) 42 (12.2) 135 (39.1) 109 (31.6) 83 (24.1) 54 (15.7) 54 (15.7) 42 (12.2) 35 (10.1) 31 (9.0) 13 (3.8) 10 (2.9) 148 (42.9) 301 (87.2) Included Associate's degree, some college, and technical school Participants could select up to three current seizure medications AEDs, household income, education status, and insurer on positive/ negative categories during/after the AED change Descriptive statistics were used for the remaining outcomes (e.g., comparisons by SCB or mood-stabilizing property) Results Overall, 345 patients with a self-reported epilepsy/seizure diagnosis completed the survey The majority of respondents had been diagnosed for more than years (82.3%), were taking more than one AED (76.2%), had a seizure in the previous 18 months (87.2%), and were predominately female (78.3%; Table 1) All patients were currently taking a prescription medication for seizures or epilepsy and reported that their seizure/epilepsy medication(s) had changed within the past 12 months An increase in AED dose, addition of another AED, decrease in AED dose, or removal of an AED were reported by 44.3%, 30.4%, 14.2%, and 11.0%, respectively Reasons for AED change (more than one reason could be selected) included: to improve seizure control (71.6% of patients), side effects (31.6%), remove current medication (13.6%), could not afford medication (3.2%), and insurance change (1.2%) Of 345 respondents, 68 (19.7%) selected “Other” as a reason for medication changes Of these, nearly half described adverse events, approximately 30% noted loss/lack of efficacy, and smaller percentages reported AED regimen changes because of planned pregnancy, surgery, long-term seizure freedom, or other reasons Patients reported a range of primary emotions before and during/ after medication changes (Table 2) Some emotions fluctuated following the change, with the largest relative changes observed for basic emotion groups of anticipation (30.2% relative decrease), joy (23.9% relative decrease), and trust (52.6% relative increase) Emotions were categorized as positive, negative, and none for 125 (36.2%), 209 (60.6%), and 11 (3.2%) of respondents, respectively, before an AED change During/ after an AED change, emotions were positive, negative, or none for 103 (29.9%), 223 (64.6%), and 19 (5.5%) of respondents, respectively Analysis of matched responses revealed that 40.8% of respondents who initially reported a positive emotion reported a negative emotion during/after the AED change, while 16.3% who initially reported a negative emotion shifted to a positive emotion during/after the AED change The shift between matched responses did not show statistical Table Primary emotion before and during/after change in seizure medication (N = 345) Basic emotion group Primary emotion Before AED change n (%) During/After AED change n (%) Anticipation Confident Intrigued Optimism Joy Courageous Eager Hopeful Trust Certain Compliant Anger Disbelief Resistant Sadness Anxiety Hopelessness Worry Distrust Afraid Fear Hesitant Uncertain None 40 (11.6) 20 (5.8) (1.2) 16 (4.6) 72 (20.9) (0.3) 21 (6.1) 50 (14.5) 13 (3.8) (1.7) (2.0) (2.0) (1.2) (0.9) 80 (23.2) 35 (10.1) 23 (6.7) 22 (6.4) 122 (35.4) 26 (7.5) 21 (6.1) 25 (7.2) 50 (14.5) 11 (3.2) 28 (8.1) 16 (4.6) (0.6) 10 (2.9) 55 (15.9) (0.6) 10 (2.9) 43 (12.5) 20 (5.8) 10 (2.9) 10 (2.9) (1.7) (0.9) (0.9) 93 (27.0) 45 (13.0) 16 (4.6) 32 (9.3) 124 (35.9) 20 (5.8) 12 (3.5) 23 (6.7) 69 (20.0) 19 (5.5) J Fishman et al / Epilepsy & Behavior 69 (2017) 44–52 2 months (n = 112) 1–2 months (n = 61) 33.0 32.8 28.3 28.8 30 Respondents, % 47 25.0 21.7 19.6 20.0 19.7 20 16.3 15.2 15.0 13.1 14.3 19.6 20.0 13.1 21.3 12.5 10.9 10 Very positive Slightly positive Neutral Slightly negative Very negative Valence Fig Valence of primary emotions associated with an antiepileptic drug regimen change, by duration of change (N = 345) significance using McNemar's test (p = 0.065) However, significantly more respondents reported negative than positive category emotions (p b 0.001) during/after an AED change Assessment of basic emotion groups as positive or negative was confirmed based on patient-reported valence for emotions; basic emotion groups of anticipation, joy, and trust aligned with a positive valence, while anger, sadness, and distrust aligned with a negative valence (Supplementary Table 1) The valence reported with the primary emotion at the time patients were informed of a change to their AED regimen versus during/after the change did not substantially differ (very positive, slightly positive, neutral, slightly negative, or very negative emotion reported by 17.4%, 17.7%, 19.1%, 27.8%, and 18.0%, respectively, before the AED change vs 16.8%, 14.5%, 22.9%, 28.1%, and 17.7% during/after the AED change) Valence of emotion during/after a medication change remained more negative than positive regardless of how long the change in AED regimen took to occur (Fig 1) The most commonly reported concern associated with changes in the AED regimen was lack of confidence that a change in AED regimen would work (Table 3) Several aspects of treatment were further analyzed, including titration duration, type of AED change, and number of concomitant AEDs Across durations of a regimen change (e.g., at b2 weeks or at 2–4 weeks), basic emotion groups were mainly more negative than positive (Fig 2) Distrust was the most common basic emotion group across all time durations Statistical analysis of the during/after responses revealed no significant difference (p = 0.989) in positive/negative categories (approximately 65% negative, 30% positive, and remaining reported as None for each titration duration) across titration durations Table Reasons for concerns with AED change associated with primary emotion (N = 345) Reasona Before n (%) During/after n (%) I was not sure if the change will work (could make things better or worse) I was confident in my doctor's decision to make the change Other reason I was sure I would have fewer seizures (thought it would work) I did not have all the information I needed about change I didn't think I could afford new medicine or that my insurance would pay for it (would not be covered) 212 (61.4) 180 (52.2) 128 (37.1) 122 (35.4) 68 (19.7) 99 (28.7) 96 (27.8) 84 (24.3) 35 (10.1) 37 (10.7) 36 (10.4) 21 (6.1) a Respondents could select a primary and secondary reason, which were combined All respondents provided at least one reason, whether primary or secondary For respondents receiving AED monotherapy (n = 73), primary emotions associated with duration of medication change were consistent with the overall population, with the negative category emotions most commonly reported Analysis by type of medication change (addition or removal of AED, increase or decrease in dose) showed that distrust and sadness were the two most commonly reported basic emotion groups across types of medication change (before vs during/after; Fig 3), with the sole exception of decreased dose before the AED change, where distrust and joy were most common Generally, similar results were observed regardless of number of concomitant AEDs (Fig 4) When emotions were categorized as positive or negative, there was a consistently higher percentage of negative versus positive basic emotion groups, with no significant differences across categories of type of AED change (p = 0.261) or number of AEDs taken (p = 0.365) The impact of type of AED on emotional response was examined in the subset of patients receiving monotherapy Negative category emotions were reported approximately twice as often as positive category emotions regardless of the class of AED taken (sodium-channel blocking [SCB](+) vs SCB(−)) (Fig 5A) AEDs approved by the US Food and Drug Administration for bipolar disease were categorized as having mood-stabilizing properties [19–21] Comparison of these AEDs versus those without mood-stabilizing properties revealed three times as many respondents receiving AEDs without mood-stabilizing properties reported negative versus positive category emotions, while AEDs with mood-stabilizing properties had a less than two-fold difference (Fig 5B) Finally, the impact of socioeconomic factors on reporting of primary emotions was considered In an analysis of the overall positive/negative category, the patterns of emotion category were consistent with the overall study results (i.e., negative reported twice as often as positive), with no significant pattern differences noted across levels of annual household income (p = 0.484), attained education (p = 0.411), or insurer (p = 0.398) For the passive listening text analysis, 17 social media forums contained relevant data (Supplementary Table 2) Of 8051 data points extracted, 521 comments were identified as relevant (i.e., confirmation of epilepsy through direct mention or usage of AEDs along with titration), of which 230 comments addressed titration aspects of AED treatment Data from the passive listening statements revealed that the emotional category of worry (about additional seizures) and apprehension (when titrating to a higher dose) were noted as impacting well-being in 40.4% and 14.3% of statements, respectively (Table 4) Of 136 statements mentioning the potential for additional seizures during titration, 93 (68.4%) responses noted worry regarding this possibility Similarly, of 47 statements regarding titration to a higher AED 48 J Fishman et al / Epilepsy & Behavior 69 (2017) 44–52 2 months (n = 112) – months (n = 61) 36.3 34.4 40.2 19.6 3.8 1.6 2.7 Anger Sadness Distrust During/After change 80 60 38.0 37.5 40 21.3 19.6 20 6.5 8.8 3.3 12.5 11.6 25.0 27.5 12.5 10.0 4.4 3.3 5.4 5.4 3.8 6.6 6.3 1.1 0.0 1.6 3.6 None Anger Anticipation Joy Trust 31.1 32.8 34.8 25.9 Sadness Distrust Basic emotion group Fig Basic emotion groups (from combined primary emotions) associated with antiepileptic drug change, by duration of regimen change for the overall population (N = 345) Added AED (n = 105) Respondents, % 100 Removed AED (n = 38) Increased dose (n = 153) Decreased dose (n = 49) Before change 80 60 38.1 39.5 40 21.0 20 10.5 10.5 11.8 15.8 14.3 20.9 24.5 1.9 7.9 5.2 0.0 Anticipation 100 Joy 32.7 34.7 22.9 23.7 23.5 22.4 Trust 3.8 0.0 3.3 4.1 None 1.9 2.6 2.6 0.0 Anger Sadness Distrust During/After change Respondents, % 80 60 40.0 40 29.5 23.7 20 13.2 6.7 16.2 8.5 6.1 18.4 13.1 2.9 5.3 8.5 4.1 4.8 5.3 7.8 Anticipation Joy Trust 0.0 None 0.0 0.0 35.3 36.7 32.7 26.3 23.5 26.3 3.3 2.0 Anger Sadness Distrust Basic emotion group Fig Basic emotion groups (from combined primary emotions) associated with antiepileptic drug (AED) change, by type of medication change (N = 345) J Fishman et al / Epilepsy & Behavior 69 (2017) 44–52 AED (n = 82) Respondents, % 100 AEDs (n = 133) AEDs (n = 88) >3 AEDs (n = 42) Before change 80 60 41.5 40 20 22.6 19.0 11.0 10.5 10.2 23.9 26.2 21.8 20.5 16.7 12.2 Anticipation 100 37.6 35.2 28.6 25.6 3.7 3.8 4.5 2.4 4.9 2.3 3.4 2.4 4.8 1.2 1.5 2.3 Trust None Anger Respondents, % 49 Joy Sadness Distrust During/After change 80 60 41.5 40 25.6 20 19.5 7.3 8.3 10.2 4.8 19.0 12.5 12.2 3.7 7.5 5.7 4.8 7.3 7.1 3.8 5.7 Joy Trust 31.6 37.5 35.7 23.8 2.4 0.8 1.1 4.8 Anticipation 28.6 27.3 None Anger Sadness Distrust Basic emotion group Fig Basic emotion groups (from combined primary emotions) associated with antiepileptic drug (AED) change, by the number of concomitant AEDs (N = 345) dose being detrimental if taken for a long duration, 33 (70.2%) noted apprehension about this change Finally, of 123 statements noting side effects (headaches, insomnia, tremors, weight issues), 71 (57.7%) were bothered by side effects during titration Negative category Discussion In our study, negative emotions were more commonly reported than positive emotions surrounding changes in AED regimen, regardless of Neutral Positive category A Respondents on monotherapy, % 100 80 63.2 68.6 63.2 7.9 2.9 7.9 28.9 28.6 28.9 60 40 20 71.4 8.6 20.0 SCB(+) (n = 38) SCB(–) (n = 35) SCB(+) (n = 38) SCB(–) (n = 35) B Respondents on monotherapy, % 100 80 60.0 69.8 60 40 20 3.3 60.0 72.1 6.7 7.0 36.7 23.2 33.3 9.3 18.6 Mood stabilizing (+) (n = 30) Mood stabilizing (–) (n = 43) Mood stabilizing (+) (n = 30) Mood stabilizing (–) (n = 43) Before AED change During/After AED change Fig Emotion categories (positive vs negative) associated with antiepileptic drug (AED) monotherapy (N = 73), by type of AED: (A) SCB(+) or SCB(−) AED category, (B) AED with versus without mood-stabilizing properties SCB(+): sodium-channel blocking AED; carbamazepine, lamotrigine, lacosamide, oxcarbazepine, phenytoin SCB(−): non–sodiumchannel blocking AED; levetiracetam, perampanel, topiramate, divalproex AEDs with mood-stabilizing properties were those approved by the US Food and Drug Administration for the treatment of bipolar disorder (carbamazepine, lamotrigine, sodium valproate) 50 J Fishman et al / Epilepsy & Behavior 69 (2017) 44–52 Table Passive listening statements about medication titration (N = 230) During dose titration, patients were… Emotional health Physical health General health Response category Worried about additional seizure activity? Apprehensive due to higher dose of medication as it will be bad if taken for a long time? Bothered about side effects such as headaches, insomnia, tremors, and weight issues? Bothered about memory problems; difficulty with reasoning and solving problems? Sad about disruption of their social activity? Concerned about financial issues due to expensive drug therapy? the duration of the change, or factors such as type of AED or type of medication change The most common reason given for an emotion reported by respondents was uncertainty regarding whether the medication change would make things better or worse, which was reflected in the high levels of reported distrust (fear, hesitation, uncertainty, being afraid) and sadness (anxiety, hopelessness, worry) The negative patient perceptions surrounding AED changes were further supported by results from the passive listening text analysis of unsolicited comments on social media, in which worry regarding additional seizures was noted in 40.4% of statements A similar emotional element was reported in a study of patients with well-controlled epilepsy but moderate AED-related complaints who were given an intervention (change in AED dose or AED) or remained on their current regimen [22] Of patients assigned to the intervention group (n = 56), 42% subsequently refused the intervention, with investigators citing social implications and fear of seizures as likely contributing to the refusal Our findings suggesting that changes in AED treatment may negatively affect patients' emotional well-being are perhaps not surprising considering that patients with epilepsy experience a range of negative emotions, including anxiety and worry about their disease [23] as well as depression, which can diminish both quality of life [24] and treatment adherence [25,26] Owing to the unpredictable nature of seizures, persons with epilepsy are prone to learned helplessness, whereby negative effects are attributed as being outside of one's control, particularly for patients with a pessimistic attributional style [27] A negative attributional style also has been associated with the development of depression in patients with epilepsy, as well as in the general population [28] However, these aspects of patients with epilepsy may not often be considered during routine clinical care It should be noted that the interpretation of the data in this study is limited by a number of factors, including the nature of the online survey, which targeted only members of the Epilepsy Advocate website, and dependence upon the accuracy of patients self-reporting diagnosis and management of their epilepsy However, a study examining the agreement between patient self-reports and patient records found good sensitivity and specificity, supporting the validity of self-identifying cases of epilepsy in community surveys [29], and indeed, a number of surveys rely upon patient self-reports [30,31] Because respondents were not required to report their specific epilepsy diagnosis, the population likely reflects various epilepsy types and associated treatment approaches The survey requested emotions from the most recent medication change during the prior 12 months, but not the specific timeframe within those 12 months Because patients with epilepsy are prone to memory disturbances [32] that may have influenced their recall of emotions or events over the prior 12 months, the recall period poses a challenge in interpreting the results However, it should be noted that physicians similarly rely on patient reports from visit to visit, rendering some degree of recall bias in normal clinical practice Indeed, patient diaries, questionnaires, and interviewers are common methods for obtaining self-report data in emotion research [18] Our analysis focused on emotions during/after an AED change, as emotions reported directly after an event are more likely to be valid than emotions reported for events that occurred in the past [15] and because Yes n (%) No n (%) Not mentioned n (%) 93 (40.4) 33 (14.3) 71 (30.9) 14 (6.1) 15 (6.5) 25 (10.9) 43 (18.7) 14 (6.1) 52 (22.6) (2.6) (3.0) (1.3) 94 (40.9) 183 (79.6) 107 (46.5) 210 (91.3) 208 (90.4) 202 (87.8) recollection of emotions before an AED change may have been influenced by their emotions after the AED change These limitations suggest that future research into emotional aspects of treatment would benefit from the use of an intervention, such as daily diaries, to capture immediate perceptions Because the survey did not capture psychiatric comorbidities, respondents with a negative emotional valence before an AED change (e.g., as a result of concurrent depression or anxiety disorder) may have biased the results Our respondent sample reflected high rates of polytherapy and gender imbalance that may have influenced the results The predominance of patients on polytherapy (76.3%) in our survey suggests a population with difficult-to-treat seizures, as most patients with epilepsy will achieve seizure control with initial AED monotherapy [33,34] Of interest, the survey had an overrepresentation of female respondents (78.3%), consistent with another study of an online patient community (PatientsLikeMe®) [35], suggesting that other methods may be needed to engage male patients Studies have also reported that depression is more common among female than male patients with epilepsy [36], which may further impact our results Furthermore, results may not be generalizable to the overall adult epilepsy population, to patients who did not respond to the survey, or to patients who are not enrolled in the Epilepsy Advocate community, although this site was the largest epilepsy-related page on Facebook at the time of the survey Because the results of this study are a reflection of a specific online community, our survey results cannot be assumed to represent the wider population of patients with epilepsy, and the passive listening segment was an attempt to assess generalizability Because patients with epilepsy frequently experience negative emotions (including the dilemmas of living with epilepsy, perceived stigma, risks, and injury related to their seizures, as well as other comorbid conditions [37,38]) and our study was not designed to assign causation, care should be used in interpreting survey results As noted earlier, patients with epilepsy often experience negative emotions [23,39] Therefore, although the survey explicitly inquired about emotions associated with a medication change in the context of their initial discussion or time of making a change, we cannot establish causation as the retrospective study design and residual confounding may distort the strength and direction of this association Furthermore, the survey was not designed to evaluate the duration of emotional response to medication change Any putative effect of medication change on emotion is likely to be acute rather than chronic Hence, future studies should prospectively document the type, valence, and duration of emotional change Finally, validation of a survey measure in future research would provide a basis for more rigorous data capture and analysis The concept of holistic medicine and patient empowerment in improving the quality of life in patients with epilepsy is beginning to receive more attention [40,41] Patients should feel informed and empowered to adhere to their treatment and to seek answers to questions Because treatment adherence in epilepsy can be diminished by lack of patient involvement in making treatment decisions [42], patient perceptions regarding AEDs and adverse events [7], and comorbid depression [25,26], addressing a patient's needs in a holistic manner may help ensure treatment success Patients should receive drug counseling to provide a solid understanding of medication schedules J Fishman et al / Epilepsy & Behavior 69 (2017) 44–52 and possible side effects before initiating an AED regimen change Titration of AEDs to effective doses are taken in stepwise fashion every to days up to every weeks, depending upon the individual AED product information [43] However, consensus guidelines for titration of AEDs recommend a dose increase at 1- to 2-week intervals [44] Although slow titration starting at a low dose is often implemented to minimize or avoid adverse events while optimizing efficacy, more aggressive or no titration may be warranted when there is an immediate need for seizure control [45–47] and if patient profile permits [45] Ultimately, appropriate selection and titration of an AED is critical to attaining seizure control, with benefits also manifesting in psychological, social, and vocational areas of functioning [48] An important element of making an AED change is the discussion between clinician and patient Studies highlight areas for improvement in the discourse between patients and their physicians [6] Patients with epilepsy desire more attention and discussions with their physicians [49,50] and place a high value on communication, information, and knowledge with their physicians [51] To this end, clinicians should discuss with their patients the potential risks and benefits of treatment changes before initiating any changes in order to address patient concerns and ascertain understanding [52] This approach aligns with quality improvement measures recommending that patients be asked and counseled about AED side effects, as well as about safety issues appropriate to the patient's situation [53] However, implementation of quality improvement measures may fall short, with discussions of adverse events and comorbid depression receiving inadequate attention [54] A best practice and goal of patient-centered communication includes exploring and responding to patient emotions during each medical encounter [55] Such efforts may help physicians identify areas in need of further support, reassurance, or assistance Studies have shown that clinician empathy to a patient's experience has a profound impact on patient outcomes [56,57] In a study of physicians treating patients with diabetes, high physician clinical empathy scores were significantly associated with patients having good control of glycated hemoglobin and low-density lipoprotein cholesterol levels [57] Similarly, in a study of physicians treating patients with the common cold, physicians scoring high in empathy were associated with significant improvements in patients' interleukin-8 levels and neutrophil counts, which manifested as reduced cold severity and duration [56] Further, a growing body of evidence suggests that empathy directly enhances therapeutic efficacy Engaged communication has been linked to decreasing patient anxiety and, for a variety of illnesses, decreasing anxiety has been linked to physiologic effects and improved outcomes [58] The impact of human interaction and empathy on improved clinical outcomes may reflect better decision-making because of transparent communication and increased understanding between patients and physicians [56,57] Efforts to improve epilepsy treatment outcomes include optimizing AED therapy, minimizing adverse events, improving patient– physician communication, and providing patients with education, self-management strategies, and referral to other sources of support Initiatives geared toward patient-centered care and self-management education can help patients identify risks, maintain emotional health, and provide strategies for managing stress, fears, and coping with other aspects of their disease [59] Improving patient outcomes will require closer collaboration and improved communication between clinicians and their patients with epilepsy, and recognition that the emotional component must be addressed at each interaction [55] An improved patient– physician dynamic may have a positive impact on patient experience, and potentially improve patient adherence to a medication regimen and any necessary changes [60] Future studies should consider the impact of medication titration on patient well-being 4.1 Conclusion In summary, the results from this survey of respondents with selfreported epilepsy or seizures suggest that titration or change of AED 51 treatment may negatively affect patients' overall well-being on different levels However, future research studies using robust data sources and validated instruments are needed to confirm the signal observed in our study Meanwhile, it is noteworthy that patient perceptions are an underappreciated aspect of medical encounters that should be addressed in the clinic Evaluating the emotional state of patients with epilepsy is complicated by several factors including the stigma of living with epilepsy, fear of injury, and concerns over the effects of medications The results of this survey provide additional insights to the challenges patients with epilepsy face on a day-to-day basis Only by probing for emotional status, providing educational information, remaining available for patients to ask questions, thoroughly discussing AED changes, and considering patient emotions during AED selection, can clinicians help alleviate patient concerns and foster improved clinical outcomes Conflicts of interest Srikanth Bharatham, Greg Cohen, Jesse Fishman, Imane Wild, and Ying Zhang are employees of UCB Pharma Ann Marie Collier and Colin Josephson have nothing to disclose Acknowledgments This study was sponsored by UCB Pharma The authors thank the survey respondents who contributed to this study The authors acknowledge Lynne Isbell, PhD, CMPP (Evidence Scientific Solutions, Philadelphia, PA) for writing and editorial assistance, which was funded by UCB Pharma Appendix A Supplementary data Supplementary data to this article can be found online at http://dx doi.org/10.1016/j.yebeh.2017.01.032 References [1] Akerkar SM, Bichile LS Doctor patient relationship: changing dynamics in the information age J Postgrad Med 2004;50:120–2 [2] Truog RD Patients and doctors—evolution of a relationship N Engl J Med 2012;366: 581–5 [3] Sacristan JA Patient-centered medicine and patient-oriented research: improving health outcomes for individual patients BMC Med Inform Decis Mak 2013;13:6 [4] Robinson A, Thomson R Variability in patient preferences for participating in medical decision making: implication for the use of decision support tools Qual Health Care 2001;10(Suppl 1):i34–8 [5] Ross J, Stefan H, Schauble B, Day R, Sander JW European survey of the level of satisfaction of patients and physicians in the management of epilepsy in general practice Epilepsy Behav 2010;19:36–42 [6] Groenewegen A, Tofighy A, Ryvlin P, Steinhoff BJ, Dedeken P Measures for improving treatment outcomes for patients with epilepsy—results from a large multinational patient-physician survey Epilepsy Behav 2014;34:58–67 [7] Chapman SC, Horne R, Chater A, Hukins D, Smithson WH Patients' perspectives on antiepileptic medication: relationships between beliefs about medicines and adherence among patients with epilepsy in UK primary care Epilepsy Behav 2014;31: 312–20 [8] Willey C, Redding C, Stafford J, Garfield F, Geletko S, Flanigan T, et al Stages of change for adherence with medication regimens for chronic disease: development and validation of a measure Clin Ther 2000;22:858–71 [9] Lerner JS, Li Y, Valdesolo P, Kassam KS Emotion and decision making Annu Rev Psychol 2015;66:799–823 [10] Jobst B The art of switching antiepileptic medications: keep trying or just let it be Epilepsy Curr 2013;13:76–7 [11] Wassenaar M, Leijten FS, Sander JW, Uijl SG, Egberts AC, OPPEC study group Antiepileptic drug changes and quality of life in the community Acta Neurol Scand 2016;133:421–6 [12] Eysenbach G Improving the quality of web surveys: the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) J Med Internet Res 2004;6:e34 [13] Shuman V, Sander D, Scherer KR Levels of valence Front Psychol 2013;4:261 [14] Plutchik R The nature of emotions Am Scientist 2001;89:344 [15] Mauss IB, Robinson MD Measures of emotion: a review Cogn Emot 2009;23: 209–37 [16] Kron A, Pilkiw M, Banaei J, Goldstein A, Anderson AK Are valence and arousal separable in emotional experience? Emotion 2015;15:35–44 52 J Fishman et al / Epilepsy & Behavior 69 (2017) 44–52 [17] Kensinger EA Remembering emotional experiences: the contribution of valence and arousal Rev Neurosci 2004;15:241–51 [18] Lopatovska I, Arapakis I Theories, methods and current research on emotions in library and information science, information retrieval and human–computer interaction Inf Process Manag 2011;47:575–92 [19] Equestro [package insert] Parsippany, NJ: Validux Pharmacetuicals LLC; 2012 [20] Lamactal [package insert] Research Triangle Park, NC: GlaxoSmithKline; 2015 [21] Depakote [package insert] North Chicago, IL: AbbVie Inc.; 2016 [22] Uijl SG, Uiterwaal CS, Aldenkamp AP, Carpay JA, Doelman JC, Keizer K, et al Adjustment of treatment increases quality of life in patients with epilepsy: a randomized controlled pragmatic trial Eur J Neurol 2009;16:1173–7 [23] Jacoby A, Snape D, Lane S, Baker GA Self-reported anxiety and sleep problems in people with epilepsy and their association with quality of life Epilepsy Behav 2015;43:149–58 [24] Shallcross AJ, Becker DA, Singh A, Friedman D, Montesdeoca J, French J, et al Illness perceptions mediate the relationship between depression and quality of life in patients with epilepsy Epilepsia 2015;56:e186–90 [25] McAuley JW, Passen N, Prusa C, Dixon J, Cotterman-Hart S, Shneker BF An evaluation of the impact of memory and mood on antiepileptic drug adherence Epilepsy Behav 2015;43:61–5 [26] Ettinger AB, Good MB, Manjunath R, Edward Faught R, Bancroft T The relationship of depression to antiepileptic drug adherence and quality of life in epilepsy Epilepsy Behav 2014;36:138–43 [27] Gehlert S Attributional style and locus of control in adults with epilepsy J Health Psychol 1996;1:469–77 [28] Hermann BP, Trenerry MR, Colligan RC Learned helplessness, attributional style, and depression in epilepsy Bozeman Epilepsy Surgery Consortium Epilepsia 1996;37: 680–6 [29] Brooks DR, Avetisyan R, Jarrett KM, Hanchate A, Shapiro GD, Pugh MJ, et al Validation of self-reported epilepsy for purposes of community surveillance Epilepsy Behav 2012;23:57–63 [30] Kobau R, Zahran H, Grant D, Thurman DJ, Price PH, Zack MM Prevalence of active epilepsy and health-related quality of life among adults with self-reported epilepsy in California: California Health Interview Survey, 2003 Epilepsia 2007;48:1904–13 [31] Roberts JI, Patten SB, Wiebe S, Hemmelgarn BR, Pringsheim T, Jette N Health-related behaviors and comorbidities in people with epilepsy: changes in the past decade Epilepsia 2015;56:1973–81 [32] Hoppe C, Elger CE, Helmstaedter C Long-term memory impairment in patients with focal epilepsy Epilepsia 2007;48(Suppl 9):26–9 [33] Kwan P, Brodie MJ Early identification of refractory epilepsy N Engl J Med 2000; 342:314–9 [34] French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society Neurology 2004;62:1252–60 [35] de la Loge C, Dimova S, Mueller K, Phillips G, Durgin TL, Wicks P, et al PatientsLikeMe(R) Online Epilepsy Community: patient characteristics and predictors of poor health-related quality of life Epilepsy Behav 2016;63:20–8 [36] Karouni M, Arulthas S, Larsson PG, Rytter E, Johannessen SI, Landmark CJ Psychiatric comorbidity in patients with epilepsy: a population-based study Eur J Clin Pharmacol 2010;66:1151–60 [37] Strine TW, Kobau R, Chapman DP, Thurman DJ, Price P, Balluz LS Psychological distress, comorbidities, and health behaviors among U.S adults with seizures: results from the 2002 National Health Interview Survey Epilepsia 2005;46:1133–9 [38] Quintas R, Raggi A, Giovannetti AM, Pagani M, Sabariego C, Cieza A, et al Psychosocial difficulties in people with epilepsy: a systematic review of literature from 2005 until 2010 Epilepsy Behav 2012;25:60–7 [39] Pulliainen V, Kuikka P, Kalska H Are negative mood states associated with cognitive function in newly diagnosed patients with epilepsy? Epilepsia 2000;41:421–5 [40] Bennett L, Bergin M, Wells JS The social space of empowerment within epilepsy services: the map is not the terrain Epilepsy Behav 2016;56:139–48 [41] Kerr MP The impact of epilepsy on patients' lives Acta Neurol Scand Suppl 2012; 1–9 [42] Chapman SC, Horne R, Eade R, Balestrini S, Rush J, Sisodiya SM Applying a perceptions and practicalities approach to understanding nonadherence to antiepileptic drugs Epilepsia 2015;56:1398–407 [43] Schmidt D Drug treatment of epilepsy: options and limitations Epilepsy Behav 2009;15:56–65 [44] Garnett WR, St Louis EK, Henry TR, Bramley T Transitional polytherapy: tricks of the trade for monotherapy to monotherapy AED conversions Curr Neuropharmacol 2009;7:83–95 [45] Perucca E, Dulac O, Shorvon S, Tomson T Harnessing the clinical potential of antiepileptic drug therapy: dosage optimisation CNS Drugs 2001;15:609–21 [46] Vimpat [package insert] Smyrna, GA: UCB Inc; 2014 [47] Dilantin [package insert] New York, NY: Pfizer; 2011 [48] Sander JW Ultimate success in epilepsy—the patient's perspective Eur J Neurol 2005;12(Suppl 4):3–11 [49] Cohen G, Leymon-Porter B, Fishman J Survey of online patient communities to analyze perceptions of healthcare value Epilepsy Curr 2015;15:P2.031 [50] Fishman J, Cohen G, Leymon-Porter B Patient perceptions of healthcare value in epilepsy management extend beyond costs to humanistic aspects Epilepsy Curr 2016;15:P1.334 [51] Wiebe N, Fiest KM, Dykeman J, Liu X, Jette N, Patten S, et al Patient satisfaction with care in epilepsy: how much we know? Epilepsia 2014;55:448–55 [52] Smith BJ, St Louis EK, Stern JM, Green C, Bramley T Concerns with AED conversion: comparison of patient and physician perspectives Curr Neuropharmacol 2009;7: 120–4 [53] Fountain NB, Van Ness PC, Swain-Eng R, Tonn S, Bever Jr CT, American Academy of Neurology Epilepsy Measure Development Panel and the American Medical Association-Convened Physician Consortium for Performance Improvement Independent Measure Development Process Quality improvement in neurology: AAN epilepsy quality measures: report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology Neurology 2011;76:94–9 [54] Wasade VS, Spanaki M, Iyengar R, Barkley GL, Schultz L AAN Epilepsy Quality Measures in clinical practice: a survey of neurologists Epilepsy Behav 2012;24:468–73 [55] King A, Hoppe RB "Best practice" for patient-centered communication: a narrative review J Grad Med Educ 2013;5:385–93 [56] Rakel D, Barrett B, Zhang Z, Hoeft T, Chewning B, Marchand L, et al Perception of empathy in the therapeutic encounter: effects on the common cold Patient Educ Couns 2011;85:390–7 [57] Hojat M, Louis DZ, Markham FW, Wender R, Rabinowitz C, Gonnella JS Physicians' empathy and clinical outcomes for diabetic patients Acad Med 2011;86:359–64 [58] Halpern J What is clinical empathy? J Gen Intern Med 2003;18:670–4 [59] Shafer PO, Buchhalter J Patient education: identifying risks and self-management approaches for adherence and sudden unexpected death in epilepsy Neurol Clin 2016;34:443–56 [60] Fuertes JN, Mislowack A, Bennett J, Paul L, Gilbert TC, Fontan G, et al The physicianpatient working alliance Patient Educ Couns 2007;66:29–36  ... I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy. .. patient experiences and emotions before and during/ after the patient'' s most recent AED medication change in the past 12 months (e.g., change in AED dose or drug, reason for change, duration of. .. reasons Patients reported a range of primary emotions before and during/ after medication changes (Table 2) Some emotions fluctuated following the change, with the largest relative changes observed for