THE RELATIONSHIP BETWEEN SEROTONINE, HISTAMINE AND THE BRAIN`S ELECTRICAL ACTIVITY IN PATIENTS WITH DEPRESSION AND ENDOCRINE DISORDERS

Oana-Maria Nicola (Marioara)1, Alice Elena Ghenea2,3, Cristina-Nicoleta Vlădoianu4, Mara Carsote5,6, Mihaela Popescu7 1 Neurology, Municipal Hospital, Caracal, Romania 2 Departament of Bacteriology-Virology-Parasitology, University of Medicine and Pharmacy, Craiova, Romania 3 Clinical Emergency County Hospital, Craiova, Romania 4 Endocrinology, Filantropia Clinical Hospital, Craiova, Romania 5 “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 6 “C.I.Parhon” National Institute of Endocrinology, Bucharest, Romania 7 Department of Endocrinology, University of Medicine and Pharmacy, Craiova, Romania


INTRODUCTION
Depression is a persistent mental state of sadness that can affect an individual`s thoughts,behavior, emotion and well-being [1] and it is one of the most significant cause of decreasing the quality of life in adults [2]. Also, it is well known that it affect mainly females [2]. For diagnosis and evaluation of the attention and mood disorders, depression, encephalopathies and learning disability, an electroencephalogram (EEG) may be used.
Electroencephalogram is the graphical, mediated recording of electrical brain phenomena. Following peripheral stimulation, evoked potentials in the cortex may be observed.
These evoked potentials have been interpreted as the sum of the extracellular currents in the simultaneously activated cortical neurons. However, in the absence of peripheral stimulation spontaneous fluctuations of membrane potential can be recorded in all regions of the cortex. This recording was given the name of the electroencephalogram or EEG.
There are a series of EEG changes, depending on content, topography and neurochemistry [3].
The EEG is of great importance both for experimental neurophysiology and for clinical diagnosis. Althrough this changes on EEG are not specific for depression, they can be helpful in the diagnosis of this pathology.
Histamine is a biogenic amine synthesized in the posterior hypothalamus. It acts as a neuromodulator and neurotransmitter, being involved in processes such as thermoregulation, immunoregulation, food port, memory and sleep-wake cycle. Histamine is involved in some physiological processes (the gastric secretion). On the other hand, it is also involved in allergic pathologies [4].
Serotonine is a derivative of tryptophan, is synthesized in the central nervous system and in the mucosa belonging to the gastrointestinal tract. It is known for its implications in certain pathological aspects like mood disorders, vomiting, migrain and hypertension [5].

AIM OF THE STUDY
The purpose of our study was to establish if there is a connection between the values of serotonine, histamine and EEG in patients with depression and endocrine pathology based on the collected data.

Subjects
We included 50 individuals diagnosed with depression from Endocrinology Clinic of Craiova, over a period of 2 years (2018-2020). Serotonine and histamine were measured in blood and urine/24 hours in all the sample. Electroencephalography was performed to this patients.
The approval and informed consent have been obtained, from each participant. All study methods were conducted according to the principles expressed in the Declaration of Helsinki. Experiments have been performed in compliance with the ethical principles of the assigned institutional board or national committee.

Assessment of depression
Depressive symptoms were assessed with Hamilton scale. The Hamilton Depression Rating Scale is a questionnaire used to diagnose the severity of depression and it is also helpfull to evaluate the recovery process. This Scale use 17 to 21 items,depending of the type and the severity of depression, scored on 3 to 5 point scale. The items are: the depressed mood, feelings of guilty, insomnia (early in the night, middle of the night, early hours of the morning), work and activities, retardation, agitation, anxiety psychic, anxiety somatic, somatic symptoms gastro-intestinal, general somatic symptoms, genital symptoms, hypochondriasis, loss of weight,insight and diurnal variation, depersonalization/ derealization, paranoid symptoms, obsessional/ compulsive symptoms. Interpretation for the 17 items scale is (a higher total score indicate a more pronounced degree of depression) : the total score between 0 and 7 -normal, 8-17 mild depression, 17-25 moderate depression, > 25 severe depression [1].

Biochemical and hormone assays
Serum samples were assayed for hormones using an automated electrochemiluminescence assay system (ECLIA).
For measuring serotonine, it was used high-pressure liquid chromatography . patients were previously warned to avoid foods/medicines that may influence the quality of the analysis (monoamin-oxidase inhibitors, medicines containing lithium, methyldopa, morphine, reserpine. For urinary histamine -liquid chromatography coupled with mass spectrometry. Patients are advised to avoid eating foods rich in histamine (fermented foods, cheeses, soy, nuts, smoked sausages, alcoholic beverages, sweets, vinegar etc.). Sedatives and antidepressants were forbidden.

Electrical brain activity
Electroencephalography was realized with a machine adjusted with aplificators at the time constant of 0.3 seconds, the filter at 70 Hz, the international standard amplitude 1 cm = 100 ΡV, and the speed of the paper was 30 mm/sec.
For the realization of the electroencephalogram, the subject must be simultaneously at rest physically and mentally, with normal glycemic values, rested, without fever or painful sensations. Exploration is carried out with the patient being in comfort both thermally and acoustically and bright. It is also contraindicated to consume food/drinks/ medicines that can have exciting/depressing effects, such as: chocolate, coffee, alcohol, sedatives, vitamins, etc.

Statistical analysis
The acquired results in this study were processed and analyzed using the statistics program SPSS. Standard deviation (SD) is used for data which are "normally distributed" to provide information on how much the data vary around their mean. SD indicates how much a set of values is spread around the average. A range of one SD above and below the mean (abbreviated to ±1 SD) includes 68.2% of the values. Distributions of categorical variables are expressed as percentages.
Then we performed the statistical processing of their data. In all analyses, a p < 0.05 was considered as statistically significant.

FIGURE 1. Depression grades (Hamilton Scale) in our patients
In our study, 27 patients had mild depression, 17 had moderate depression and 6 had a severe disorder (Figure 1).
We studied 10 cases of each of the following gland pathologies: thyroid diseases, parathyroid disfunction, pituitary insufficiency, diabetes and adrenal gland pathology ( Figure 2).
For each electroencephalogram record, primary parameters represented by the rhythm index; the amplitude and wave frequency (for some situations extending the calculation and for pathological rhythms).

FIGURE 2. EEG abnormalities in depression
We also observed: wave morphology; modulation of alpha waves in spindles and their duration; the reaction of blocking the alpha rhythm when opening the eyes; the presence of pathological graphoelements, their index and location.
EEG abnormalities in patients with depression was represented by the presence of diffuse fast frequencies with hypovoltate route, decreased alpha incidence and increased beta index .The most significant change in EEG for patients with depression was alpha inher-hemispheric asymmetry. In our study, from 50 patients with depression, 42 had EEG abnormalities.
Patient T.E -F, 41 years, registration number 931/2019. Alpha index below 50%, alpha amplitude, to the lower limit of normal In our study, as it is observed (Figure 4), the urinary histamine values were high (normal value < 3.8 mg/24 h) in patients with depression and endocrine pathology. The mean value of urinary histamine was 6.04 mg/24 h (±1.91 DS) in patients with thyroid diseases, 4.94 mg/24h (±1.26DS) for those with parathyroid pathologies, 4.65 mg/24 h(±0.8DS) for those with pituitary insufficiency, 5.09 mg/24 h(±1.26DS) had patients with diabetes mellitus and 4.3 mg/24 h (±1.94DS) for those with adrenal gland disfunction.
We tried to fiind a link between EEG abnormalities and the variations of serotonine and histamine. In our study, this hypothesis was correct. We found a p value < 0.082 for serotonine and < 0.036 for urinary histamine.

DISCUSSION
Statistically, there are very strong correlations between serum serotonin and the degree of depression. According to the literature, a study conducted by Cowen and Browning clarified that low serum serotonin levels cause clinical symptoms of depression, and that sometimes despite drug treatment, patients may experience [6]. Also in our low serotonin study has direct link to depression.
Analyzing urinary histamine levels in patients studied, we obtained that they were even higher with the level of depression. Perez Garcia et al.  study suggests that histamine receptor blockage has no anxiolytic effect, but may have an antidepressant effect [7]. Kano et al. concluded that the decrease of brain H 1 R binding is connected with the severity of simptomes in patients with depression. Also, it is found that the histaminergic neuron system is the central piece in the pathological mechanism which leads to depression and it is an important thing when it cames to cure [8].
Also in our study, depressed patients are associated with a low frontal alpha asymmetry on the EEG and that may even be related to their suicidal behaviour [9,10]. As presented in the study of Jiang et al., oscillating brain activity in patients with depression occurs, posterior alpha power was negatively related to depression severity [11]. To distinguish between changes which appear in EEG at pacients with depression and other psychiatric disorders, more research needs to be done [12].
Interemispheric alpha asymmetry and the measurement of the severity of depression may be the basis of further research to strengthen the depression-EEG connection [13].

CONCLUSIONS
Depression is a frequent disease sometimes associated with endocrine pathology. It is reflected by changes in electrical brain`s activity with abnormal rhythms and waves.
In patients with EEG abnormalities occure significant changes in the values of serotonine and histamine (increased urinary histamine and decreased serotonine levels).
There are some limitations due to the small group, so further long-term studies on large cohorts of patients are needed to better clarify the link between the levels of serononine, urinary histamine and EEG. Follow-up studies are required to evaluate if long-term association is still available.