A survey on doctors’ cognition of depression in patients with epilepsy

Abstract Objective This survey aimed to assess doctors’ cognition on depressive symptoms in patients with epilepsy in Shanghai China. Methods Questionnaires were handed out to doctors who have taken part in the epilepsy care, covering those from all third‐grade hospitals and several second‐grade hospitals in Shanghai China. Respondents were asked to make choices for their demographic profiles, clinical practices, acquired knowledge of, and attitudes toward the comorbidity of epilepsy and depression. Results A total of 282 questionnaires were collected from 16 hospitals in Shanghai China, of which 280 copies were included in the statistical analysis. Respondents were mainly less than 50 years (260, 92.8%), mostly residents and attendings (206, 73.6%), and mostly master and doctor's degrees (225, 80.3%). The ratio of epileptologists and nonepileptologists was 56 (20.1%):224 (79.9%). Compared to nonepileptologists and residents, epileptologists and doctors with higher professional titles were more likely to answer that they received a higher percentage of patients with the comorbidity of epilepsy and depression (≥30%), and they knew very well about the knowledge, and held the view that depression exacerbated seizures (p < .05). Surprisingly, most doctors including chief doctors and epileptologists answered that they had difficulties in prescribing antidepressants. Quite a few doctors from lower class hospitals even preferred to use tricyclic antidepressants for controlling depressive symptoms in patients with epilepsy. Significance Doctors, especially younger doctors and nonepileptologists, need more training to get knowledge of the comorbidity of epilepsy and depression. However, the therapeutic methods for depressive symptoms in patients with epilepsy were still limited and in a challenge.


INTRODUCTION
Epilepsy is a chronic brain disorder characterized not only by recurrent seizures but also by its neurobiological, cognitive, psychological, and social consequences as pointed out by the International League Against Epilepsy (ILAE) in 2014 (Fisher et al., 2014). Psychiatric disorders are very common comorbidities in patients with epilepsy, of which depression has the highest prevalence (Tellez-Zenteno et al., 2007).
According to a recent meta-analysis, the pooled prevalence of depressive disorders in patients with epilepsy until July 2016 was 22.9% (Scott et al., 2017). In some tertiary epileptic centers, the prevalence of depression in patients with epilepsy was even as high as 50% (Ring et al., 1998;Victoroff et al., 1994). A cross-sectional study from four cities in China established that the prevalence rate of self-reported depressive symptoms in patients with epilepsy was 24.1% (Fu et al., 2006).
Depressive symptoms in patients with epilepsy are usually relatively mild that might not meet the Diagnostic and Statistical Manual criteria of major depressive disorders (Krishnamoorthy et al., 2007), and symptoms such as suicidal idea, frustration intolerance, irritability, and motor agitation are unstable and alternated with symptom-free periods. For this reason, Blumer et al. refer to it as interictal dysphoric disorder (IDD) (Blumer et al., 2004), and depressive symptoms in patients with epilepsy are usually unrecognized by clinicians due to the atypical features. For another, since most antidepressants are at a high risk of provoking seizures, especially when used in a rapid dose increase or at excessively high doses (Steinert & Froscher, 2018), the treatments for depressive symptoms in patients with epilepsy are still limited.
Increasing evidence shows that there are bidirectional relationships between epilepsy and depression (Hesdorffer et al., 2012;Josephson et al., 2017;Salpekar, 2017). A large-scale clinical investigation by Hesdorffer et al. found that epilepsy was associated with an increased onset of psychiatric disorders and suicide before and after epilepsy diagnosis (Hesdorffer et al., 2012). An observational study of a population-based cohort by Josephson et al. even found that treated depression (a surrogate for more severe depression than untreated depression) was associated with worse epilepsy outcome (Josephson et al., 2017). Clinically, seizure severity, seizure frequency, antiepileptic drugs (AEDs) taking, and social psychological factors were risk factors that promoted depression in patients with epilepsy (Peng et al., 2014;Thapar et al., 2005;Yildirim et al., 2018). Basic studies further demonstrated that common mechanisms including disturbance of neurotransmitters in the central nervous system, a hyperactive hypothalamic-pituitary-adrenal axis, brain structural changes, and inflammatory mechanisms were involved in the comorbidity of epilepsy and depression (Kanner et al., 2014).
Despite the high prevalence, depression in patients with epilepsy is commonly underdiagnosed and untreated (Kanner & Balabanov, 2002).
The probable reasons in China are as follows: (1) Neurologists and neurosurgeons who take part in epilepsy care concern more about seizure control than underlying neuropsychiatric disorders. An online doctor survey on behalf of the Task Force of the ILAE Commission on Neuropsychiatry identified some key areas for improvement in managing the psychiatric comorbidities of epilepsy, suggesting that there are educational needs for clinicians taking part in epilepsy care in many countries . (2) The stigma of patients with epilepsy and their relatives may prevent them from turning to psychiatrists for help (Yildirim et al., 2018). Most patients are reluctant to see a psychiatrist or a psychologist in the specialized Mental Health Center in case of being looked in a peculiar way. To understand the current situation of attitudes toward and knowledge of the comorbidity of epilepsy and depression in doctors taking part in the epilepsy care in Shanghai, China, we designed a questionnaire in honor of the Shanghai Medical Association. Based on the questionnaire-based doctor survey, we analyzed the underlying reasons for the undercognition of depression in patients with epilepsy.

Questionnaire development
We Xin Wang who is the chairman of the epilepsy group affiliated to the Shanghai Medical Association.

Participants
There is a three-level hierarchical medical system in Shanghai, which is representative of the way the health system is organized in big

Questionnaire handing out and recollecting
Doctors who were the standing committee members of the epilepsy group affiliated to the Shanghai Medical Association handed out the questionnaire in their hospitals. The same person recollected the questionnaires after 1 week.

Statistical data analysis
For the convenience of statistics, the multichoice options for these questions were set as categorical or ordinal variables, such as "yes/no/not clear," "always/sometimes/occasionally/never," and "<30%/30-60%/>60%." The IBM SPSS version 21.0 (IBM Inc., Armonk, NY, USA) software was used to perform the statistical analysis. The chi-square test or Fisher's exact test was conducted to compare parameters between specific groups, and the linear-by-linear association was adopted when the data fit the ordinal distribution.
At last, a binary logistic regression was performed to establish the independent factors that affect doctors' decision on whether to treat depressive symptoms in patients with epilepsy.

Overall impression of doctors' attitudes toward and cognition for the comorbidity of epilepsy and depression
All the doctors have taken part in epilepsy care, and 85.6% of them confirmed that they received epilepsy patients with depressive symptoms.
About 37.4% of doctors said that they regularly asked the patients if

Factors that affect doctors' cognition and decision on treatments for the comorbidity of epilepsy and depression
We compared the doctors' opinions based on their specialties, professional titles, and the level of their hospitals. Compared with residents and attendings, chief doctors and associate chief doctors were more likely to think the percentage of depression in patients with epilepsy is greater than 30% (Figure 1a At last, a binary logistic regression was conducted to establish the key factors that significantly affected doctors whether to prescribe antidepressants for controlling depression in patients with epilepsy. Whether doctors prescribed antidepressants for patients with comorbidity of epilepsy and depression was set as the dependent variable. The following independent factors were included for analysis that had significances performed by t-tests: age (<30/30∼/40∼/50∼years), epileptologists or not (yes/no), percentage of patients with epilepsy they have received (<10%/10%∼/20%∼/30%∼), having received patients with the comorbidity of epilepsy and depression or not (yes/or), regularly asking patients' moods problems (always/sometimes/occasionally/never), how well they know the diagnosis and treatments for the comorbidity of epilepsy and depression (very well or moderately/very few or completely do not know), whether antidepressants exacerbate seizures (yes/no), whether depression exacerbates seizures (yes/no/not clear), whether to use TCAs (yes/no). The step of "enter" was selected. The result showed that age, epileptologists or not, how well doctors know the diagnosis and treatments for the comorbidity of epilepsy and depression, and opinions on whether to use TCAs were key factors that mostly affected a doctor's decision on whether to use antidepressants for controlling depressive symptoms in patients with epilepsy (see Table 2). In the article written by Kanner et al., over 50% of depression in epilepsy has not been recognized by neurologists (Kanner & Balabanov, 2002), which might be attributed by multiple reasons. The first is that depressive symptoms in patients with epilepsy are sometimes not so typical and hardly differentiated with symptoms of seizures.

DISCUSSION
It is reported that up to 50% of patients with the comorbidity of epilepsy and depression presented psychiatric symptoms that could not meet DSM or International Classification of Disease systems, which were referred to as IDD or peri-ictal dysphoric syndrome (Mula, 2016). In this survey, the depressive symptoms of "insomnia," "daytime somnolence," and "somatic symptoms" were considered frequently occurred in patients with epilepsy, which had a consistency with the clinical study by Shen et al. (Shen et al., 2017), as insomnia was tightly associated with depression (Roberts & Duong, 2013), and treatments with AEDs might cause sleep disorders either (Jain & Glauser, 2014).
The symptom of "impulsiveness" was considered to be popular in F I G U R E 1 (a) Compared with attendings and residents, chief doctors and associate chief doctors were more likely to consider that the percentage of depression in patients with epilepsy was greater than 30% (*p < .05); (b) epileptologists chose that they received a higher percentage (30%∼) of patients with the comorbidity of epilepsy and depression than nonepileptologists (*p < .05); (c) most chief doctors chose that they always asked the patients' moods problems, much higher than the residents (*p < .05); (d) no difference between epileptologists and nonepileptologists; (e) there were no differences among doctors with different professional titles who held the view that depression exacerbated epilepsy; (f) higher percentage of epileptologists believed depression exacerbated epilepsy compared with nonepileptologists (*p < .05) F I G U R E 2 (a,b) As for the question "How well do you know the diagnosis and treatments for comorbidity of epilepsy and depression," epileptologists and doctors with higher rank professional titles frequently chose "know very well or moderately," while nonepileptologists, residents, and attendings mostly chose "know a few or completely do not know" (*p < .05); (c,d) most doctors chose to use antidepressants or recommend patients to a psychologist, but surprisingly, quite a few chief doctors including epileptologists chose that they did not know how to select antidepressants (*p < .05) was relatively low (most doctors thought it is less than 30%), which might be due to stigma or inferiority.

Variables in the equation a
Two main aspects of therapeutic methods for controlling depressive symptoms in patients with epilepsy have been recommended: pharmacological and psychological treatments. Except for antiseizure properties, AEDs have the effect of modulating moods and behavior as well (Perucca & Mula, 2013). Some of AEDs have been used as mood stabilizers such as valproate, lamotrigine, pregabalin, and clobazam, while some others are associated with mood deterioration or aggressive behavior (Brodie et al., 2016;Mula & Sander, 2007). Therefore, clinicians should thoroughly collect the psychiatric history and avoid prescribing AEDs that might aggravate mood problems. Adding on antidepressants is another choice of pharmacological therapy. SSRIs and serotonin and norepinephrine reuptake inhibitors are first recommended in patients with epilepsy (Mula, 2017), but still with potential risks of increasing seizures. Sertraline and citalopram are considered to be the first-line choice, since other SSRIs such as fluoxetine may have pharmacological interactions with AEDs (Mula et al., 2008).
Traditional antidepressants such as TCAs may induce epileptic discharges in electroencephalographic studies, especially when taken in high dose (>200 mg) (Alper et al., 2007;Mula, 2017 At last, in our study, factors that affected doctors' decision on whether to use antidepressants to treat depression in patients with epilepsy were as follows: age, epileptologists or not, how well doctors know the diagnosis and treatments for the comorbidity of epilepsy and depression, and opinions on whether to use TCAs. As age is positively correlated with doctors' professional titles, it is reasonable that doctors with elder age have more experiences using antidepressants than younger doctors. It is worth mentioning that nonepileptologists prefer to prescribe antidepressants than epileptologists, but they use TCAs frequently, which indicates that they do not have as much knowledge of the comorbidity of epilepsy and depression as epileptologists.

CONCLUSIONS
This questionnaire-based investigation indicates that most doctors taking part in epilepsy care, especially epileptologists, realize that there is a high prevalence of the comorbidity of epilepsy and depression, depression exacerbates seizures, and depressive symptoms should be controlled in patients with epilepsy. Epileptologists have more knowledge about the comorbidity of epilepsy and depression than nonepileptiologists. However, how to choose antidepressants is still a dilemma for most doctors including epileptologists. This survey in Shanghai reflects the current condition of diagnosis and treatments for the comorbidity of epilepsy and depression in big cities of China, which highly indicates that making related guidelines may contribute to set a consensus for doctors to recognize and treat depressive symptoms in patients with epilepsy.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.

ACKNOWLEDGMENTS
We are grateful to all the doctors who participated in the survey. This survey was funded by Shanghai Wu-Mengchao Medical Science and Technology Fund (JJHXM-2017009).

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.