MINISTRY OF EDUCATION AND TRAINING - MINISTRY OF DEFENSE MILITARY MEDICAL UNIVERSITY DAM DUC THANG RESEARCH ON CLINICAL FEATURES OF DEPRESSIVE DISORDER IN PATIENTS WITH GENERALIZED TONIC – CLONIC SEIZURES AND RESULTS OF TREATMENT FOR DEPRESSIVE DISORDER WITH FLUOXETINE Specialism: Neuroscience Code: 9720159 SUMMARY OF MEDICAL DOCTORAL THESIS HANOI – 2018 THE WORK HAS BEEN SUCCESSFULLY COMPLETED AT MILITARY MEDICAL UNIVERSITY Science Supervisors: Associate.Prof PhD BUI QUANG HUY Associate.Prof PhD NGO NGOC TAN Opponent 1: Prof PhD Nguyen Van Chuong Opponent 2: Associate.Prof PhD Tran Van Cuong Opponent 3: Associate.Prof PhD Nguyen Hoang Ngoc The thesis will be protected before the doctoral thesis review Board in Military Medical University - Ministry of Defense By the hour,day month 2018 The thesis can be found at the library: Military Medical University library- Ministry of Defense National library of Vietnam BACKGROUND Urgency of the project Epilepsy is a syndrome of the brain due to many causes, the rate of epilepsy accounts for 0.5 -1% of the world population In Vietnam, there are 5-8 people with epilepsy per 1000 people Generalized seizures make up a high proportion among epilepsy patients, in which generalized tonic-clonic seizures is the most common Depressive disorder in patients with epilepsy accounts for about 20-40% However, clinical symptoms of depression are often atypical and therefore difficult to diagnose and evaluate The frequency of seizures, some antiepileptic drugs, community stigma, etc., are associated with depressive disorder in patients with epilepsy The concentration of Serotonin in plasma is considered be related to depressive disorder and it is often significantly reduced compared with healthy people Recent research has shown that selective Serotonin reuptake inhibitors are the first choice for the treatment of depressive disorder in patients with epilepsy In particular, Fluoxetine is approved by the Food and Drug Administration (the United States) for the treatment of depressive disorder In Vietnam, there have been some sporadic scientific reports about depressive disorder in patients with epilepsy Depressive disorder in patients with epilepsy has not been carefully investigated and studied yet Purposes of the thesis - Study clinical characteristics of depressive disorder in patients with generalized tonic - clonic seizures patients - Evaluate of plasma Serotonin levels and risk factors associated with depressive disorder in patients with generalized tonic - clonic seizures - Comment on the results of treatment for depressive disorder inthe patients suffering from generalized tonic - clonic seizures with Fluoxetine combined with antiepileptic drugs Practical significance and new contributions of the thesis - The thesis is the first systematic study on clinical features, plasma Serotonin levels and associated risk factors, especially on the treatment of depressive disorder in patients with generalized tonic clonic seizures (GTCs) with Fluoxetine combined with antiepileptic drugs (AEDs) applied in Vietnam - The study found that moderate depressive disorder in patients with GTCs had the highest rate of 71.57%.The seizures are more frequent in the patients with GTCs associated with depression 38.24% of patients used more than AEDs, in which those used both Phenobarbital (PB) and Phenytoin (PTH) at the same time accounted for 74.36% Average dosage of Fluoxetin 20.61 ± 3.45 mg per day was effective for treating - The research opens a new direction for the selection of antidepressants, especially Fluoxetine combined with AEDs for treatment of depressive in epilepsy Structure of the thesis The thesis is presented in 164 pages, 44 tables of data, 11 charts and illustrations The content includes: background 2pages; Chapter 1: Overview 38pages; Chapter 2: Subject and Methodology 20 pages; Chapter 3: Study results 36 pages; Chapter 4: Discussion 45pages and Pagesof Conclusion;1 page of proposal; List of research works of thesis:1 page; 19 pages of references (21 Vietnamese documents and 145 foreign documents) CHAPTER 1: OVERVIEW 1.1 Generalized tonic - clonic seizures The GTCs is a typical generalized seizure caused by the sudden electrostatic discharge that spreads both hemispheres in clinical manifestations from the first episode Clinical manifestations are typically characterized by successive phases: tonique, clonique and resolutive, lasting about 40 to 70 seconds or up to 90 seconds The ictal Electroencephalogram (EEG) is often obscured by muscle artifact During the tonic phase, fast, rhythmic, low - amplitude spike are seen in all leads, wich evolve to a spike- wave or polyspike- andwave pattern during the clonic phase Postically, there is diffuse suppression of electrical activity, followed by generalized slowing The interictal EEG is often seen with cerebral arrhythmia, alternating with slow waves (delta, theta) high amplitude or spike, can be seen as ictal paroxysmal series 1.2 Depressive disorder in patients with epilepsy Currently, pathogenic mechanisms of depressive disorder in patients with epilepsy have not been completely elucidated Structural abnormalities, monoamine pathways, cerebral glucose metabolism, the hypothalamic-pituitary-adrenal (HPA) axis, and interleukin-1b all play a role in the common pathogenesis of these conditions Clinical features of depressive disorder in patients with epilepsy are often atypical Depressive symptoms in patients with epilepsy can be classified in categories: major depressive disorder, atypical depression or dysthymia, or a dysthymic-like disorder with intermittent symptoms that can be milder than those of major depression Serotonin levels in plasma and cerebrospinal fluid of depressed patients are often lower than normal There are many risk factors associated with depressive disorder in patients with epilepsy such as some AEDs, frequency of seizure, stigma, social psychology etc 1.3 Treatments for depressive disorder in patients with epilepsy Antidepressants, selective inhibition of serotonin reuptake (SSRIs) are the first choice of treatment for depressive disorder in patients with epilepsy Fluoxetine is one of the SSRI group of antidepressants approved by FDA for the treatment of depressive disorder in patients with epilepsy Fluoxetine doses start with 10 mg per day, the maximum dose is 80mg per day Fluoxetine suppresses cytochrome P-450 enzymes which may increase the concentration of AEDs in the cerebrospinal fluid and plasma, thereby increasing the anticonvulsant capacity of AEDs The second option is SNRI antidepressants including venlafaxine, mirtazapine and duloxetine In developing countries tricyclic antidepressants are also selected, but they are less tolerant and highly toxic in overdose In addition, combining psychotherapy, vagus nerve stimulation and medicine application is more effective in treatment than using antidepressants only CHAPTER 2: SUBJECTS AND METHODOLOGY 2.1 Subjects 2.1.1 Characteristics of the subjects A study of 102 GTCs patients diagnosed with depression Patients were treated at the Hai Phong Psychiatric Hospital between April 2013 and October 2015 2.1.2 Selection criteria - Diagnosis criteria for GTCsare based on ILAE (1981) and ICD-10 (1992): standard G40.30 - Diagnosisfor organic depressive disorder isaccording to the ICD-10 (1992): standard F06.32 2.2 Study method 2.2.1 Study design - Prospective and cross-sectional study -Clinical trial with treatment 2.2.2 Study sample size In this study we applied the "scaled estimate in a population" according to the formula: p = 0.427 (in the study of Lopez-Gomez M (2005), Δ =0.1 We calculated n= 94 patients (minimum size) In our study, we chose 102 GTCs patients 2.2.3 Clinical assessment tool and results of treatment for depressive disorder in patients with GTCs The clinical assessment and results oftreatment for depressive inpatients with GTCsare based on the following materials: - Detailed medical records, meeting the research objectives - ILAE Classification of Epilepsy (1981) - International Classification of Diseases ICD-10 (1992): section G40.30 for the diagnosis of GTCs, section F06.32 for the diagnosis of organic depressive disorder - Hamilton Depression Rating Scale (HAM-D) - Quantification of Serotonin concentrations in plasma 2.2.4 Clinical features of depressive disorder in patients with GTCs - Clinical evaluation of depressive disorder - Clinical evaluation ofmental disorders in the research group - Some laboratory tests supporting the differential diagnosis 2.2.5 Evaluation of Serotonin levels in plasma and risk factors related to depressive disorder inpatients with GTCs + Serotonin plasma concentrations at the time of admission (T0) and after weeks of treatment (T8) 88 patients in the study group + Risk factors include: - Duration of epilepsy, age at onset of seizure, causes of epilepsy, frequency of seizure, sex, ect - Dosage and duration of using AEDs (alone or combined) 2.2.6 The results of treatment for depressive disorder inpatients with GTCs by Fluoxetine combination with AEDs -The dosage of Fluoxetine (Oxeflu) - The dosage of AEDs - Evaluation of clinical course and Hamilton scale 2.3 Data processing method and assessment of research results The data was processed and analyzed on the Stata 12.0 program and we used statistical algorithms applied in medicine CHAPTER 3: RESULTS 3.1 General characteristics of the research subject Table 3.1 Age of the study subjects No Statistics index Age group (year) Quantity Proportion % < 20 4.90 20 - 29 27 26.47 30 - 39 24 23,53 40 - 49 22 21.58 50 - 59 12 11.76  60 12 11.76 102 male; 50.00% 100.00 Total female; 50.00% Average age 38.59 ± 14.14 year old Table 3.1 the youngest is 18 years old and the oldest is 79 years old, an average age is 38.59 ± 14.14 years old Figure 3.1 Gender of study group Figure 3.1 shows that 51 male patients accounting for 50.00%, there by male/female ratio = 12 3.4.1 Use of drugs to treat depressive disorder in patients with GTCs Table 3.30 Dosage of Fluoxetine Statistics index No Dosage Quantit % y 20mg/day 96 96.97 40mg/day 3.03 Average dose (mg/day) 20.61 ± 3.45 Table 3.30 shows that the average dosage of Fluoxetine (Oxeflu) used for treatment was 20.61 ± 3.45 mg/day Table 3.31 Dosage anti epileptic drugs Statistics index Dosage (mg/day) Phenobarbit al ( n=68) Phenytoin (n =59) Natri Carbamazepi Valproat n ( n=7) (n=1) 169.74 ± 45.82 181.48±48.3 1200.00 With drugs 125 ± 44.09 162.07±56.1 800 ±346.41 With drugs 200.00 233.33±57.7 733.33±115.47 600 152.21 ± 49.95 174.58±54.4 828.57±269.0 600 Alone Medium Table 3.31 shows that 69 patients received PB with an average dosage of 152.21 ± 49.95mg/day, PTH with an average dosage of 174.58 ± 54.44mg/day, VPA with an average dosage of 828.57 ± 269.04mg/day, CBZ is 1BN with a dosage of 600mg/day 3.4.2 Results of treatment of depressive disorder in patients with GTCs by each different time 13 Table 3.32 Development of typical symptoms of depression T0 Time Symptoms Depressed mood Loss of interest and enjoyment Reduced energy leading to increased fatiguability n 9 7 T8 % 95.96 69.70 77.78 n pT0,T8 % 46.46