To study the relationship between serotonin plasma and cerebrospinal fluid concentrations and clinical symptoms in patients with severe depression. Subjects and methods: Descriptive and cross-sectional studies.
Jourrnal of military pharmaco-medicine n09-2019 STUDY ON THE RELATIONSHIP BETWEEN SEROTONIN PLASMA AND CEREBROSPINAL FLUID CONCENTRATIONS AND CLINICAL SYMPTOMS IN SEVERE DEPRESSION PATIENTS Do Xuan Tinh1; Cao Tien Duc1; Nguyen Linh Toan2 SUMMARY Objectives: To study the relationship between serotonin plasma and cerebrospinal fluid concentrations and clinical symptoms in patients with severe depression Subjects and methods: Descriptive and cross-sectional studies This study was carried out on 72 patients with severe depression treated at the Department of Psychiatry, 103 Military Hospital from June 2016 to June 2018 Peripheral blood and cerebrospinal fluid samples of patients were collected for measurement of serotonin concentrations Some clinical symptoms of patients were also determined Results: There were correlations between decreased serotonin plasma (R = 0.452; p < 0.001) and cerebrospinal fluid concentrations (R = 0.534; p < 0.001) with the appearance of clinical features (age, male and number of hospitalizations ≥ times and duration of illness ≥ years), clinical symptoms (paranoia, emotional instability, low self-esteem and inferiority, unfortunate thoughts, suicidal behavior; R = 0.48; p < 0.001) in severely depressed patients; especially patients aged ≥ 45 years and male, having unfortunate ideas and unstable emotions Severe depression patients with suicidal behavior had a lower proportion of serotonin cerebrospinal fluid concentrations of ≤ 1.6 ng/mL (85.7%) than those without suicidal behavior (27.6%), p < 0.01 Conclusion: Serotonin plasma and cerebrospinal fluid concentrations were associated with the appearance of clinical features, clinical symptoms, in patients with severe depression, especially those gender, unstable emotions, unhappy idea and suicidal behavior * Keywords: Severe depression; Clinical symptoms; Serotonin concentration INTRODUCTION Serotonin is a neurotransmitter that plays an important role in depression, both as a cause and a consequence of depression A serotonin deficiency in the sinap cleft is considered a major cause of depression [1, 3, 4] The study on changes in serotonin concentration related to depressive patients has been analyzed, commented and confirmed by authors who showed that there was decrease of serotonin concentration in depressed patients Sadock B.J (2015) suggested that the lower the serotonin concentration in the sinap cleft, the worse the depression was [4] Numerous studies have demonstrated that the decrease in serotonin levels in the brain of depressed patients is very clear, even very low, only about 30% of the average person and the corresponding severity or mild of depressed patients [5, 6] 103 Military Hospital Vietnam Military Medical University Corresponding author: Do Xuan Tinh (doxuantinhbv103@gmail.com) Date received: 18/10/2019 Date accepted: 21/11/2019 262 Jourrnal of military pharmaco-medicine n09-2019 In Vietnam, there had been some researches on plasma serotonin concentration in depression, there has been no researches on serotonin changes in cerebrospinal fluid Since then, we have conducted the research with the aim: Study on the relationship between plasma and cerebrospinal fluid serotonin concentrations and clinical symptoms in patients with severe depression SUBJECTS AND METHODS Subjects A study of 72 patients diagnosed with severe depression, inpatient treatment at the Department of Psychiatry, 103 Military Hospital from June 2016 to June 2018 * Selection criteria: According to the standard of the 10th International Classification of Diseases (ICD-10) on mental and behavior disorders of WHO (1992), section F32 * Exclusion criteria: Patients with general body conditions that were related to the risk of lowering plasma serotonin concentration such as gastrointestinal, peripheral neuropathy, endocrine system diseases, heart diseases… Methods A prospective, cross-sectional study, and case-by-case analysis of individual case histories All patients were clinically examined and blood tested to quantify serum serotonin concentration, 36 patients underwent lumbar puncture to get cerebrospinal fluid Time of serotonin quantitative sampling: Patients in the acute phase, after admission from the 1st to 7th day Blood sampling time was from - am daily; lumbar puncture sampling of cerebrospinal fluid concentrations from - am daily Centrifuge plasma, store at -80oC until the test Quantitative serotonin test by ELISA was conducted at the Department of Pathophysiology, Military Medical University The unit of serotonin is ng/mL The criteria for the diagnosis of the severe depression stage following the diagnostic criteria of ICD-10F (1992), section F32 [3] were described with the following symptoms: - Main symptoms: + Mood decreases + Losing interest, enjoying + Reducing energy, easily tired - Common symptoms: + Decreased attention span; reduced self-esteem and confidence + There are ideas of being guilty and unworthy; looking at the gloomy and pessimistic future ideas and acts of self-destruction or suicide; sleep disorders; less appetite eating These conditions usually last at least weeks When severe depression often has common body symptoms: Weight loss, decreased exercise capacity, stupor, constipation, diarrhea, cardiovascular disorders Data were processed by using SPSS 20 software Evaluate the correlation between changes in plasma serotonin concentration and cerebrospinal serotonin with control group and some clinical manifestations by OR (Odds ratio) with 95% confidence interval (95%CI) 263 Jourrnal of military pharmaco-medicine n09-2019 RESULTS AND DISCUSSION Relationship between plasma serotonin concentration and cerebrospinal fluid with some characteristics of patients with severe depression In this study, we selected the plasma serotonin level ≤ 80 ng/mL and the cerebrospinal fluid serotonin ≤ 1.6 ng/mL to find the correlation and the relationship of serotonin with clinical features in the severe depression disease based on previous studies of plasma serotonin and cerebrospinal fluid serotonin in depressed patients, healthy non-depressed patients, and pathogenesis studies [5, 9, 10] Table 1: Relationship between decreased serum serotonin concentration (≤ 80 ng/mL) and a feature in severely depressed patients Correct prediction of reduced plasma serotonin Correlation coefficients R p 0.204 (R = 0.452) < 0.001 65.3% Factor OR Confidence interval (95%CI) p Age ≥ 45 3.22 0.924 - 11.25 > 0.05 Male 3.84 1.20 - 12.31 < 0.05 Number of hospitalizations ≥ times 3.18 0.87 - 11.56 > 0.05 Duration of illness ≥ years 1.38 0.45 - 4.24 > 0.05 The results showed a correlation between plasma serotonin reduction (≤ 80 ng/mL) and the appearance of clinical features in patients with severe depression: age, male and number of hospitalizations ≥ times and duration of illness ≥ years with a correlation coefficient R = 0.452 (p < 0.001); of which gender was closely related to decreased plasma serotonin concentration Table 2: Relationship between serotonin cerebrospinal fluid concentration (≤ 1.6 ng/mL) and clinical features in severely depressed patients Correct prediction of decreased serotonin cerebrospinal fluid Correlation coefficients R p 0.285 (R = 0.534) < 0.001 77.8% Factor 264 OR Confidence interval (95%CI) p Age ≥ 45 0.029 0.001 - 0.740 < 0,05 Male 0.075 0.007 - 0.808 < 0,05 Number of hospitalizations ≥ times 0.97 0.135 - 7.044 > 0,05 Duration of illness ≥ years 2.92 0.363 - 23.577 > 0,05 Jourrnal of military pharmaco-medicine n09-2019 The results showed a strong correlation between the decrease in cerebrospinal fluid serotonin concentration (≤ 1.6 ng/mL) and the combination of characteristics of severe depression patients such as age, male and hospitalizations ≥ times and illness duration ≥ years with correlation coefficient R = 0.534 (p < 0.001); in which patients in the age group > 45 years old and male gender were closely related to decreased cerebrospinal fluid serotonin concentration Many studies showed that factors such as age, gender, number of hospitalizations ≥ times, duration of disease ≥ years were clinical characteristics of patients with severe depression Kaplan H.I (1994) stated that depression was - times more common in women than in men, and the rate of depressive disorders increased by age group, which was the highest in the age group of 45 - 65 [2] Bui Quang Huy (2016) chose a disease landmark for more than years to decide whether the patients needed lifelong reinforcement or not [1] The research results showed that serum serotonin and cerebrospinal fluid concentration played an important role in the clinical characteristics of patients with severe depression These factors were consistent with the prognostic factors of many authors such as Gelder M (2010), Sadock B.J (2015) in depression when multiple clinical symptoms appeared [3, 4] It can be said that severe depression patients were older than 45 years old or that group of decreased cerebrospinal fluid serotonin Relationship between plasma serotonin and cerebrospinal fluid concentrations and clinical symptoms in patients with severe depression Table 3: Relationship between decreased serum serotonin concentration (≤ 80 ng/mL) and the appearance of clinical symptoms in severely depressed patients Correct prediction of reduced plasma serotonin Correlation coefficients R p 0.227 (R = 0.48) < 0.001 68.1% Factor OR Confidence interval (95%CI) p Self-charged paranoia 0.31 0.09 -1.09 > 0.05 Unstable emotions 0.24 0.06 - 0.92 < 0.05 Low self-deprecating thoughts 2.54 0.22 - 29.68 > 0.05 Unhappy idea 0.27 0.08 - 0.89 < 0.05 Suicidal behavior 0.75 0.21 - 2.60 > 0.05 The results showed a correlation between decreased plasma serotonin concentration (≤ 80 ng/mL) and the appearance of clinical symptoms: Self-accusatory paranoia, emotional instability, inferiority and inferiority, unfortunate ideas, suicidal behavior with correlation coefficient R = 0.48 (p < 0.05); in which the group having unfortunate ideas and unstable emotions had a strong correlation to decreased plasma This means that clinical symptoms also have different values in diagnosing and assessing the severity of depression 265 Jourrnal of military pharmaco-medicine n09-2019 This result was consistent with the diagnostic criteria of both ICD-10 and DSM-5 disease classification systems, which required the main symptoms and some or all of the dialectic symptoms to diagnose severity depression The recent research by Wayne C.D et al (2007) used PET and [carbonyl - 11 C] WAY-100635 (5-HT1A R selective radioactive PET method for pre-5-HT1A R bond first and after synaptic) to study the 5-HT1A R receptor (serotonin 1A receptor) in 16 subjects with severe depression and healthy controls, the results showed that 5-HT1A R decreased 26% in the Mussels (mesiotemporal cortex-MTC) (p < 0.005) and 43% in the gray core in severe depression compared to the prospective group (p < 0.001) and were closely related to 5-HT1A R reduction in depressed patients suicidal behavior [8] Table 4: Relationship between decreased cerebrospinal fluid serotonin concentration (≤ 1.6 ng/mL) and clinical symptoms in severely depressed patients Correct prediction of reduced cerebrospinal fluid serotonin Correlation coefficients R p 0.304 (R = 0.551) < 0.001 75.0% Factor OR Confidence interval (95%CI) p Self-charged paranoia 0.79 1.03 - 6.17 > 0.05 Unstable emotions 1.65 0.28 - 9.6 > 0.05 Low self-deprecating thoughts 0.71 0.05 - 10.24 > 0.05 Unhappy idea 1.88 0.34 - 10.379 > 0.05 Suicidal behavior 14.81 1.31 - 168.13 < 0.05 The results showed a strong correlation between the decrease in cerebrospinal fluid serotonin concentration (≤ 1.6 ng/mL) and the appearance of clinical symptoms in severely depressed patients such as self-accusatory delusions and unstable feeling, inferiority, unhappy idea, suicidal behavior In which, there was suicidal behavior closely associated with decreased cerebrospinal fluid serotonin Table 5: The change rate of reduction on serotonin serum and cerebrospinal fluid with psychotic symptoms in patients with severe depression Group Indicator Plasma serotonin ≤ 80 ng/mL Cerebrospinal serotonin ≤1.6 ng/mL 266 Patients with psychosis Patients without psychosis n % n % Reduction 13 41.9 29 70.7 No reduction 18 58.1 12 29.3 Reduction 40.0 38.1 No reduction 60.0 13 61.9 p < 0.05 > 0.05 Jourrnal of military pharmaco-medicine n09-2019 The results showed that the proportion between plasma serotonin and cerebrospinal of the group with reduced serotonin plasma serotonin in depressed patients Study of level ≤ 80 ng/mL without psychosis (70.7%) post-stroke depression patients, there was was higher than the psychotic group (41.9%), a good correlation between serum serotonin the difference was statistically significant concentration and cerebrospinal serotonin with OR = 0.30 (95%CI: 0.11 - 0.80); with correlation coefficient R = 0.664 p < 0.05 Whereas in patients with psychosis, (p < 0.001) and plasma serotonin concentration the rate of serotonin reduction in in some clinical symptoms substitutes for cerebrospinal fluid was higher than in the cerebrospinal fluid serotonin levels in the group without psychosis but the difference monitoring of depressed patients [5] In the was not statistically significant with p > 0.05 author’s study, serotonin concentration was Our results showed that psychotic symptoms lower than both in cerebrospinal fluid and were not associated with plasma in depressed patients with psychosis serotonin concentration in both plasma This may explain that our studied patients and cerebrospinal fluid This result was were still low, not enough to prove the inconsistent with other studies Heng- correlation between serotonin and psychotic Qiang Gao et al (2008) showed a correlation symptoms Table 6: The change rate in the plasma serotonin concentration, cerebrospinal fluid with suicidal behavior in patients with severe depression Group Indicator Plasma serotonin ≤ 80 ng/mL Cerebrospinal serotonin ≤ 1.6 ng/mL Suicidal behavior No suicidal behavior p n % n % Reduction 50.0 34 60.7 No reduction 50.0 22 39.3 Reduction 85.7 27.6 No reduction 14.3 21 72.,4 The results showed that patients with severe depression had a higher proportion of the group with decreased serotonin cerebrospinal fluid concentrations ≤ 1.6 ng/mL (85.7%) compared to the group without suicidal behavior (27.6%), the difference was statistically significant with p < 0.01 > 0.05 < 0.01 Similar to the study by Ruljancic N et al (2013) on serotonin concentration in platelets in 79 depressed suicidal patients and 101 depressed non-suicidal patients compared with 77 healthy subjects had been shown that serotonin concentration in platelets of depression group with and 267 Jourrnal of military pharmaco-medicine n09-2019 without suicidal behavior was lower than that of control group [6] Maria A.O et al (2015) suggested that the severity of suicidal intent in severe depression was related to the brain and serotonin 1A BP F frontal region and lower serotonin release at key projection sites of the brain, such as the anterior region, may be the main Self-paranoid paranoia crime, unstable emotions, inferiority thoughts, unhappy ideas, suicidal behavior; in which the group having unfortunate ideas and unstable emotions had a strong correlation to decreased plasma OR (95%CI) plasma concentrations of 0.27 and 0.24, respectively, with p < 0.05 cause of suicidal intent and, more serious, suicidal behaviors that cause high death for patients such as cutting blood vessels, jumping into wells, and strangulation, drinking poison, jumping on the floor [7] - Severe depression patients with suicidal behavior had a lower proportion of serotonin cerebrospinal fluid concentrations of ≤ 1.6 ng/mL (85.7%) than those without suicidal behavior (27.6%), p < 0.01 CONCLUSION By studying the correlation between changes in plasma serotonin concentration and cerebrospinal fluid with clinical characteristics in patients with severe depression, we found: - There were correlations between decreased serotonin plasma (R = 0.452; p < 0.001) and cerebrospinal fluid concentration (R = 0.534; p < 0.001) with the appearance of clinical features in patients with severe depression: age, male and number of hospitalizations ≥ times and illness duration ≥ years; in which the occurrence of patients ≥ 45 years old and male gender was strongly associated with decreased plasma serotonin or cerebrospinal fluid concentration - There were correlations between decreased serotonin serum (R = 0.48; p < 0.001) and cerebrospinal fluid concentration (R = 0.551; p < 0.001) with the appearance of clinical symptoms: 268 Thus, plasma serotonin and cerebrospinal fluid concentration are associated with the occurrence of clinical features and symptoms of patients with severe depression, especially those gender, unstable emotions, unhappy idea and suicidal behavior REFERENCES Bui Quang Huy, Dinh Viet Hung, Do Xuan Tinh Depression disorder Medical Publishing House Hanoi 2016 Kaplan H.I, Sadock B.J Synopsis of th Psychiatry edition William and Wilkins 1994, pp 903-911 Gelder M.G New Oxford Textbook of Psychiatry Second edition, Vol 1, 2010 Sadock B.J, Sadock V.A Synopsis of th Psychiatry 10 edition William and Wilkins 2015, pp.815-822 Gao H.Q, Zhu H.Y, Zhang Y.Q et al Reduction of cerebrospinal fluid and plasma serotonin in patients with post-stroke depression: A preliminary report Clin Invest Med 2008, 31 (6), pp.E351-E356 Jourrnal of military pharmaco-medicine n09-2019 Ruljancic N, Mihanovic M, Cepelak I et al Platelet serotonin and magnesium concentrations in suicidal and non-suicidal depressed patients Magnes Res 2013, Jan - Feb, pp.9-17 Maria A.O, Galfalvy H, Gregory M et al Positron emission tomographic imaging of the serotonergic system and prediction of risk and lethality of future suicidal behavior JAMA Psychiatry Original Investigation 2016, pp.1048-1055 Wayne C.D, Michael T, Eydie M et al Serotonin-1A receptor imaging in recurrent depression: Replication and literature review Nucl Med Biol 2007, October, 34 (7), pp.865877 Asberg M, Thoren P, Traskman L et al Serotonin depression: A bichemical subgroup within the affective disode? Science 1976, 06 Feb, Vol 191, Issue 4226, pp.478-480 10 Luykx J.J,,Bakker S.C, Geloven N.V et al Seasonal variation of serotonin turnover in human cerebrospinal fluid, depressive symptoms and the role of the 5-HTTLPR Transl Psychiatry 2013, 3, e311 269 ... have conducted the research with the aim: Study on the relationship between plasma and cerebrospinal fluid serotonin concentrations and clinical symptoms in patients with severe depression SUBJECTS... selected the plasma serotonin level ≤ 80 ng/mL and the cerebrospinal fluid serotonin ≤ 1.6 ng/mL to find the correlation and the relationship of serotonin with clinical features in the severe depression. .. severe depression patients were older than 45 years old or that group of decreased cerebrospinal fluid serotonin Relationship between plasma serotonin and cerebrospinal fluid concentrations and