Epilepsy and Depression, Comorbidity Problems of Treatment Tactics

Objective: Despite the availability of literary data on the treatment of comorbidity of epilepsy and depression, their therapy has not been fully resolved. However, epilepsy and depression are often combined. Materials and Methods: The aim of the study was development therapy in the comorbidity of epilepsy and depression in adults. The study included 100 patients with epilepsy. The severity of depression was studied by using the Hamilton scale, ICD-10 and DSM-5 criterions. Patients were observed at the Mental Health Center of the Ministry of Health of the Republic of Azerbaijan from January 2018 to January 2020 for 24 months. Patients took standard antiepileptic drugs (depakin-chrono 1000 mg/day, lamotrigine 150 mg/day, levitracetam 3000 mg/day) and antidepressant drug-citalopram was taken 10 mg twice a day, in the morning and in the evening. Results: Depression of varying severity was detected in 70 % of the examined patients 10 cases of mild, 40 moderate and 20 case of severe depression without psychotic symptoms. Conclusion: The combination of anticonvulsants with antidepressants Citalopram 10 mg in morning and evening (per os) reduces the frequency of seizures and reduces the severity of depression. The study of comorbidity of epilepsy and depression is of great theoretical and practical importance. First, it will contribute to the early detection of depression. Second, prevent suicides. Third, it will help reduce refractory epilepsy. Finally, improve their quality of life for patients with epilepsy.


Introduction
Around 400 BC, Hippocrates observed that "melancholy usually becomes epileptics and epileptics become melancholic" [1]. Recurrent seizures are associated with a number of harmful effects. Seizure-related deaths can account for up to 40% of all deaths in patients with chronic epilepsy. The rate of sudden death, which accounts for 7-17% of deaths among patients with epilepsy, is estimated to be 27 times higher in patients with seizures than those who do not have seizures [2].
The incidence of epilepsy in the European countries and the United States is about 40-70 cases per 100,000 population, while in developing countries the incidence is much higher. It is interesting that the incidence of epilepsy in men, especially in old and senile age, is higher than that of women [3].
Some authors indicates that depression deserves special attention due to its high frequency (10-30% of patients) and the risk of suicide occurring among epileptic patients is much more frequent than the average among population [4,5].
Further, the author believes that in addition to changes in the mood as a result of primary epileptic brain dysfunction, negative social stigmatization plays an important role in the development of depression, which leads to restrictions on education, occupation, social contacts, spending of free time.
According to various authors, depressive disorder in epilepsy occurs from 22% to 58% of patients [6].
In addition, the relationship between epilepsy and depression in the literature, the treatment of combined pathology, molecular basis etc. [7,8].

Materials and Methods
In accordance with the Helsinki Declaration of the World Medical Association "Recommendations for doctors engaged in biomedical research involving people", adopted by the 18th World Medical Assembly (Finland, 1964, revised in Japan in 1975, Italy-1983, Hong Kong-1989, the South African Republic-1996, Edinburgh-2000; The Constitution of the Republic of Azerbaijan, the Law "On Psychiatric Assistance" (adopted on 12 1) the conditions of the conducted researches corresponded to the generally accepted norms of morality, the requirements of ethical and legal norms, as well as the rights, interests and personal dignity of the participants of the studies were observed; 2) conducted research is adequate to the topic of research work; 3) there is no risk for the subject of research; 4) participants in the study were informed about the goals, methods, expected benefits of the study and associated with risk and inconvenience in the study; 5) the subject's informed consent about participation in the research was received; The decision of the Ethical Committee at the Azerbaijan Psychiatric Association on the article of NA. Aliev, Z. N.
Aliev "Epilepsy and depression, treatment tactics" submitted for publication in psychiatric journals: in connection with compliance with its legislative requirements and regulatory documents is to approve the article by N. A. Aliyev, Z. N. Aliev "Epilepsy and depression, treatment tactics" Epilepsy is one of the most common neuropsychiatric diseases. In the adapted version of the ICD-10 revision (put in place by order No. 170 of the Ministry of Health of the Russian Federation of May 27, 1997) in class VI, diseases of the nervous system-disorders related to epilepsy are provided for only 15 headings (G40 Epilepsy-G40.0-G40.9; G41 Epileptic status-G41.0-G41.9). In class V, mental and behavioral disorders associated with epilepsy are treated in a 17 rubric. In other words, the number of mental and behavioral disorders associated with epilepsy is greater than that of neurological. Therefore, we consider it expedient to consider epilepsy as a neuropsychic disorder.
Patients were observed at the Mental Health Center of the Ministry of Health of the Republic of Azerbaijan from January 2018 to January 2020 for 24 months. Patients took standard antiepileptic drugs (depakin-chrono 1000 mg/day, lamotrigine 150 mg/day, levitracetam 3000 mg/day) Antidepressant drug-citalopram was taken 10 mg twice a day, in the morning and in the evening.
We examined 70 patients with G40.3 Generalized idiopathic epilepsy and 30 patients G 40.0 Focal epilepsy (total=100). Patients were examined in the interictal period.
Clinical characteristics of enrolled patients was shown in the Table 1.

Results
Results of this study were presented in the Table 2. Table 2. Indicators beginning and end of the study.

Indicators
Beginning of the study End of the study Mild depression ICD-10; DSM-5 296.21 (8-16 points) 10 (5%) normal Moderate severe depression ICD-10; F32.0; DSM-5; 296.22 (17-23 points) 40 (20%) 10 patients of mild depression* Severe depression without psychotic symptoms ICD-10; F32.2;; DSM-5; 296. 23  As can be seen from Table 2, Depression of varying severity was detected in 70 % of the examined patients 10 cases of mild, 40 moderate and 20 case of severe depression without psychotic symptoms. Depression in generalized idiopathic epilepsy about 2.5 times more common than in focal epilepsy. In comparison with the general population, patients with epilepsy comorbid depression have more than twice as much depression as women.

Discussion
From literature it is known that among people with epilepsy, depression is extremely common and is associated with intense personal suffering and a sharp decline in the quality of life [10]. According to other systematic review, 23.1% of people with epilepsy suffer from depression during the past year, compared with 6.6% in the general population [11,12]. The lifetime prevalence of depression is estimated to be 30-35% among people with epilepsy, compared with 16.2% in the general population [13,14].
The results study of Swinkels, et al. [15] show a higher prevalence of mood and anxiety disorders in patients with epilepsy, compared with the general population. They found that the subgroup of temporal lobe epilepsy patients, in particular, suffer from these disorders. But they cannot exclude that some methodological short-comings in their design may have obscured more pronounced differences between the TLE and extra-TLE subgroups.
Depression can be diagnosed in: 1) from 20% to 30% of patients with recurrent seizures; 2) from 6% to 9% of patients in remission; 3) from 50% to 55% of patients attending hospital epilepsy clinics [16]. Men with epilepsy have a higher risk of developing depression, while in the general population, depression is more common in women [17].
According some literature data the prevalence of depression occurs 5 times more often in patients with controlled seizures and 10 times in patients with uncontrolled. It is not known whether depression in these patients can be considered primarily as part of the primary pathology of the central nervous system or as a clear response to an epileptic disorder with all the difficulties of daily coping [18].
In TLE affective disorders are important comorbidities, primarily due to suicidal potential in all its forms, including gestures, thoughts, or successful attempts, which range from 10% to 15% in patients versus 1-1.5% in the general population [19].
It is known that depression affects the results of seizure treatment. There is a high comorbidity between depression and seizures. Depression rates are higher in patients with epilepsy than in the general population (1% to 3% of men, 2% to 9% of women). [20]. Depression can be diagnosed in: 1) from 20% to 30% of patients with recurrent seizures; 2) from 6% to 9% of patients in remission; 3) from 50% to 55% of patients attending hospital epilepsy clinics [16]. Men with epilepsy have a higher risk of developing depression, while in the general population, depression is more common in women [17].
The relationship between the development of depressive disorders and the side effects of the use of a number of antiepileptic drugs is described. Long-term use of phenobarbital and other barbiturates most often leads to mnestic-intellectual decline, depression and even suicidal readiness in patients with epilepsy, which has been shown by both Russian and foreign researchers [21,22]. According to some authors, the appointment of antiepileptic drugs with GABAergic properties (vigabatrin and tiagabine, as well as gabapentin) is fraught with sedation and more often causes depression. Topiramate has a thymoleptic effect, but at the same time, it can cause anxiety, irritability and anxiety, and in some cases (mainly with rapid titration or starting from high doses)-psychosis [28,23,24]. In this regard, the purpose of this communication is to determine.
Treatment for epilepsy is not limited to achieving a seizure-free state. It should also include the management of common psychiatric and neurological comorbidities affecting an average of 30 to 50% of patients with epilepsy, which have a significant impact on their lives at various levels. Mood and anxiety disorders are the most common comorbid mental disorders, while stroke and migraine are among the most common neurological comorbidities. Primary mood disorders have a bidirectional relationship with these two neurological disorders. In addition, depression and migraine were associated with more severe epilepsy, while depression was associated with more severe stroke and migraine. And so, the treatment of epilepsy cannot be limited to achieving cessation of seizures, it must include the simultaneous treatment of concomitant neurological and psychiatric disorders. [25].
The typology of affective disorders in epilepsy is proposed, including preictal, ictal, interictal and postictal states. Various variants of affective states (depressive, dysphoric, manic) in epilepsy are considered. Depending on the severity of depressive symptoms, mild, moderate and severe depression in epilepsy was identified. The article presents clinical observations of patients with epilepsy, which show the effectiveness of anticonvulsants in relation to affective disorders. [26].
A number of authors attribute psychosocial factors (life problems, financial difficulties, difficulties in adaptation at work) to the main reasons for the development of depression in patients with epilepsy. The low level of physical activity of patients with epilepsy can be considered as a risk factor for the development of depression and anxiety [27]. It has been shown that the risk of developing epilepsy in a patient with depression is 4-7 times higher than in the population, and a history of suicide attempt increases the risk of developing epilepsy 5 times [28]. The available evidence, therefore, confirms the presence of common biological mechanisms of development of depression and epilepsy [29].
Depression is one of the most common diseases in epileptic patients, affecting 1 in 4 patients and is associated with psychological and neurobiological causes. The common neurobiological mechanisms of epilepsy and depression, and depression, have a complex one-way relationship that suggests that some epileptic syndromes may be a premorbid symptom. Sertraline and cytitalopram may be considered first-line treatment for moderate to severe depression, although psychological treatment should always be offered in mild to moderate degree [30].
The question may arise, why we used the antidepressant citalopram. The fact is that citalopram has the lowest risk of seizures. This is visible from the bottom table.
Antidepressants' seizure potential in any patient according to McConnell H, Duncan D. [31] and Barry JJ [32]. One of the mechanisms explaining the comorbidity of epilepsy with depression is the theory of Post R. M. [33] about kindlingю Kindling, in the classical sense, involves the gradual increase in sensitivity to the intermediate repetition of the same sub-electrical stimulation over time, with the amygdala being the most studied region. This is associated with repetitive sub-excitation stimulation: threshold reduction after electrical discharge; prolongation and spread of blood pressure; Progression of the seizure phase ending in full-scale tonic-clonic convulsions of the forelegs with ascent and descent; and from evolutionary stimuli to spontaneous seizures. This evolving process is immediately accompanied by changes in the spatiotemporal expression of early genes (IEG), neurotrophic factors, and late-action genes (LEG), as well as a related change in the efficacy model of various pharmacological interventions. Because pulse memorization is a paradigmatic behavioral manifestation, some pharmacological seizures are caused by local anesthesia, such as cocaine and lidocaine, and some epileptic syndromes are most likely homologously modeled with fomentation. However, since non-epileptiform syndromes, such as recurrent episodes of affective disorder and some pain syndromes, contain heterogeneous elements of evolution similar to sedation, some of the principles involved in the burning process may be related to the understanding and treatment of these syndromes. For example, it is possible to try to distinguish between secondary and adaptive genes involved in the initial pathological processes of the evolution of the syndrome. This differentiation can have a significant impact on the development of therapeutic approaches to suppress or enhance these changes, respectively. In these cases, the results obtained from the fomenting model are necessarily indirect and limited, because different neuroanatomical and biochemical processes are likely to affect the development of each neuropsychiatric syndrome. Given these well-known limitations of non-homologous models, recurrence may provide information on the longitudinal course, progression, and treatment of some neuropsychiatric syndromes that can then be tested directly in the clinically [33].
Thus, depending on the state of awakening of the neuron, different clinical manifestations occur: kindling, convulsions, affective disorders, hallucinations, pain syndrome and other neurological, psychopathological symptoms. In other words, it can be concluded that epilepsies, pain syndromes, and affective disorders have common kindling-like mechanisms.
The limitation of our work: 1) a small number of patients; 2) a short time observation.
Thus, for a group of examined patients with epilepsy in more than half of cases, depression is characterized to a certain degree of severity. The study of comorbidity of epilepsy and depression is of great theoretical and practical importance. First, it will contribute to the early detection of depression. Second, prevent suicides. Third, it will help reduce refractory epilepsy. Finally, improve their quality of life for patients with epilepsy.

Funding
The article carried out by own financial resource.

Author Disclosure
Authors declare that the manuscript is submitted on behalf of all authors. None of the material in this manuscript have been published previously in any form and none of the material is currently under consideration for publication elsewhere other than noted in the cover letter to the editor. Authors declare to have any financial and personal relationship with other people or organizations that could inappropriately influence this work. All authors contributed to and have approved the final manuscript.