Evaluation of the Efficacy of Depressive Disorders Pharmacotherapy Using Quantitative Pharmaco-EEG

Rostov State Medical University, 29 Nakhichevansky Lane, Rostov-on-Don, 344022, Russian Federation Своевременная диагностика и эффективная фармакотерапия депрессивных расстройств является актуальной проблемой в медицинской практике. Метод количественной фармако-электроэнцефалографии позволяет дифференцированно оценить эффективность лечения данного аффективного расстройства. Цель работы: проведение сравнительного анализа фармакологической активности двух схем лечения соматизированного депрессивного расстройства средней степени тяжести у пациентов с патологией желудочно-кишечного тракта: монотерапии антидепрессантом из группы селективных ингибиторов обратного захвата серотонина — флуоксетином и его комбинированного применения с лекарственным препаратом, содержащим мелатонин. Методы: с помощью шкалы Гамильтона (HDRS-17) проводилась оценка степени тяжести депрессивного расстройства у пациентов и эффективности применения обозначенных схем фармакотерапии. Методом количественной фармако-электроэнцефалографии (фармако-ЭЭГ), использовавшимся как до начала лечения, так и на фоне проведения соответствующего режима фармакотерапии, осуществлялся анализ влияния вышеуказанных лекарственных средств на функциональное состояние головного мозга пациентов с депрессивным расстройством. Результаты: показано, что комбинация флуоксетина с мелатонином способствует более быстрому регрессу депрессивной симптоматики согласно шкале HDRS-17. Метод количественной фармако-ЭЭГ позволил выявить характерные различия во влиянии флуоксетина при монотерапии или комбинированном применении с мелатонином на биоэлектрическую активность головного мозга пациентов. Выводы: проведенный анализ относительного значения мощности ритмов головного мозга пациентов методом количественной фармако-ЭЭГ показал, что восстановление нормальных значений ритмов ЭЭГ на фоне комбинации флуоксетина с мелатонином происходит быстрее, чем при монотерапии флуоксетином, прием которого не привел к полной ремиссии текущего депрессивного эпизода у ряда пациентов при лечении в течение 42 сут. Ключевые слова: депрессивное расстройство; количественная фармако-электроэнцефалография (фармако-ЭЭГ); шкала Гамильтона (HDRS-17); флуоксетин; мелатонин

3. Фармако-ЭЭГ анализ ОЗМ в группе Ф+М продемонстрировал, что восстановление нормальных значений ритмов ЭЭГ на фоне комбинации флуоксетина с мелатонином более значимое и происходит с небольшим опережением по сравнению с показателями монотерапии флуоксетином.At present depressive disorders (DDs) are quite widespread in both the developing and developed countries.This is a rather serious psychoemotional disorder which affects up to 21 % of people around the world [1].According to clinical studies, the number of depressed patients among patients with a chronic somatic disease amounts to 22-33 % and leaves behind such a widespread condition as arterial hypertension [2].The most widespread chronic diseases with recurrent somatic symptoms are gastrointestinal diseases.They may be accompanied by affective disorders capable of producing and sustaining somatic symptoms [3,4].
The challenges associated with DD pharmacotherapy are quite pressing despite a wide range of existing antidepressant medicines [5].The use of selective serotonin reuptake inhibitors (SSRIs), as compared to tricyclic antidepressants, has a number of advantages in practical terms: safe use, better tolerability and the possibility of targeted treatment of the underlying cause of the psychiatric condition.At present one of the major medicines among SSRIs is fluoxetine [6].
In order to improve the efficacy of pharmacotherapy, SSRIs are often used in combination with other types of medicines.The literature describes the use of antidepressants in combination with antipsychotic medicines [7].Combination therapy of DD may benefit from the use of a pineal hormone -melatonin (MT) which ensures nonspecific protection against stress and regulates circadian rhythms [8].
Analysis of the brain electrical activity is a highly specific tool for studying the neurobiology of mental impairment in the context of various central nervous system disorders [9, 10].One of the most informative methods of assessing the efficacy of psychotropic medicines is quantitative pharmaco-electroencephalography (pharmaco-EEG).This non-invasive technique is helpful for analysis of psychotropic medicines activity and monitoring the efficacy of pharmacotherapy [11][12][13].
The aim of the present paper is to perform comparative assessment of the efficacy of modern antidepressants used for the treatment of moderate somatic DD by quantitative pharmaco-EEG.

MATERIALS AND METHODS
Forty seven subjects took part in the study.The study was approved by the Regional Independent Ethics Committee (RIEC) of Rostov State Medical University (extract from the minutes of the RIEC meeting No. 34 of 7 July 2011).
Th control (C) group included presumably healthy subjects (n = 17).The D group (n = 30) comprised patients with confirmed DD.The diagnosis of DD was made based on clinical examination according to the ICD-10 classification criteria, and the severity of the disorder was assessed using the 17-item Hamilton Scale (HDRS-17).
The patients included into the D group were further subdivided into two clinical groups depending on the prescribed pharmacotherapy regimen: the patients in the F group (n = 15) took fluoxetine (a single dose of 20 mg/day), and the patients in the F+M group (n = 15) took fluoxetine (a single dose of 20 mg/day) and melatonin (a single dose of 3 mg/day one hour prior to bedtime).
Before the treatment the mean HDRS-17 score of the patients in both clinical groups was equivalent to moderate DD: 19.6 ± 2.5 scores in the F group, and 19.3 ± 2.1 scores in the F+M group.
The patients who took any psychotropic medicines in the pretreatment period did not take any drugs for seven days prior to initiating therapy in order to rule out the possibility of drug interaction.None of the patients received any psychotherapy.
The efficacy of the therapy was assessed by comparing the HDRS-17 scores before the treatment, and on the 14 th , 28 th , and 42 nd days of the treatment, as well as by comparing the quantitative pharmaco-EEG data obtained before the treatment and on the 42 nd day of the treatment.Electroencephalograms (EEGs) of the patients were recorded using an electroencephalograph-analyser EEGA-21/26 «Encephalan 131-03» (Russia) with 8 channels.The relative power (RP, %) was computed in the δ (delta, 1-4 Hz), θ (theta, 5-7 Hz), α (alpha, 8-12 Hz), and β (beta, 13-30 Hz) EEG frequency bands.The statistical significance of differences in the RP of EEG rhythms in patients belonging to the С, D, F and F+M groups was assessed using Student's t-test and the significance levels p < 0.05 and p < 0.01.

RESULTS AND DISCUSSION
The patients who took both fluoxetine and melatonin (the F+M group) said they were feeling better on the 14 th day of the treatment, but they still had complaints about low mood.When interviewed they complained of difficulties falling asleep and early awakening, but they did not complain of nocturnal awakening.They still had complaints about fatigue, weakness, decreased libido, reduced appetite or loss of appetite, heaviness in the stomach, weight loss.
On the 28 th day of the treatment more than half of the patients belonging to this group voiced a much lower number of complaints and reached the threshold level by scoring 7 or less on the HDRS-17 scale, which was regarded as remission of the depressive episode.
The patients of the F group said they started to feel better only on the 28 th day of the treatment, and their mean HDRS-17 score decreased 1.7 times (р < 0.01).Some patients continued to complain of seemingly unfounded fatigue, weakness, low mood, decreased libido.There still remained a problem with falling asleep and anxiety caused by early awakening, but the patients were less worried about insomnia and less preoccupied with their health problems.
The patients of the clinical groups continued to have a positive response to DD therapy at a later stage.On the 42 nd day of the treatment the mean score in the F group decreased 2.5 times (р < 0.01), and in the F+M group -3.6 times (р < 0.01) as compared to the initial mean score before initiation of treatment (table 1).
At the end of the monitoring period all patients in the F+M group reached the threshold level of less than 7 scores on the HDRS-17 scale, and, in general, all of them felt fine, however during interviews some of them still complained of decreased libido.
Sixty percent of the patients in the F group had a HDRS-17 score equivalent to mild depression (7-16 scores), and the rest scored below 7.At the same time most patients in this group still had some DD symptoms, such as occasional impaired productivity and fatigue.Some patients still had problems with early awakening and difficulties falling asleep again, they also had some manifestations of somatic anxiety related to their health problems.
Thus, at the end of the 42-day course of DD treatment the patients in the clinical F+M group demonstrated sustained improvement in the existing affective state, which is not the case with the patients of the F group who took fluoxetine alone -they still needed care and continuation of pharmacotherapy.
The severity of DD was assessed using the HDRS-17 scale and, in addition, judging by the EEG readings.The assessment of the RP of EEG rhythms in different brain areas gave a fuller picture of the pharmacotherapy ef-fect on the bioelectric activity of the brain.The obtained data were compared to the results of the control C and D groups.
Alpha rhythms normally dominate in the back of the head in a healthy person (C group) and tend to subside closer to the frontal lobes.Beta rhythms, by contrast, are predominant in the frontal and central areas of the brain [10].This distribution of RP was observed in the C group (table 2).
However, the EEG pattern of the patients with confirmed DD before initiation of treatment (D group) was different, it showed desynchronization of fast rhythms and changes in the amplitude of EEG rhythms (table 2).The RPs of alpha rhythms increased from the frontal area towards the central area and were 1.8 and 1.4 times higher than the corresponding values for these areas in the C Note.Statistically significant differences in the RP of EEG rhythms in the patients of the D group (before initiation of treatment), F group (fluoxetine monotherapy) and F+M group (fluoxetine and melatonin combination therapy) as compared to the RP of EEG rhythms in the patients of the C group (healthy subjects) for * -р < 0.05; ** -р < 0.01.Statistically significant differences in the RP of EEG rhythms in the patients of the F and F+M groups as compared to the RP of EEG rhythms in the patients of the D group for # -р < 0.05; ## -р < 0.01.group.There was a significant reduction in the power of alpha rhythms in the parietal region, and a 64.2 % decrease (р < 0.01) in occipital alpha rhythms as compared to the initial data.The beta rhythm also underwent some changes: it decreased in all analysed areas of the brain, in particular, its RP was 7.9 times lower (р < 0.01) in the frontal region as compared to that of the patients in the C group.The delta power increased 80 % (р < 0.01) in all analysed areas of the brain, and it was even more prominent than the alpha rhythm in the occipital and parietal regions.The theta rhythm also increased, but to a lesser extent than the delta rhythm.At the end of the treatment period (on day 42) the RP values of patient EEG rhythms changed considerably (table 2).
The analysis of EEG parameters of the patients receiving the fluoxetine monotherapy showed that the bioelectric activity of the brain in the F group was very close to normal, however it differed a little from that of the patients in the C group (healthy subjects) and D group (patients before initiation of treatment) (table 2).The administration of fluoxetine had a significant effect on the power of the alpha rhythm which began to dominate in the occipital and parietal regions, but at the same time it was 1.4 times (р < 0.05) and 1.2 times (р < 0.05) lower than that of the patients in the C group, respectively.As for the central and frontal regions, the alpha rhythm reached a level showing no statistically significant differences with that of the patients in the C group of healthy subjects.The beta rhythm was also close to normal, but its RPs were still rather low in the central and frontal regions of the brain.Fluoxetine had a different effect on the delta rhythm than on alpha or beta rhythms.The RPs of the delta rhythm remained at a level twice as high as the norm (р < 0.01) in all the analysed regions all through the period of treatment.The theta rhythm dropped to the normal level and did not show any fluctuations thereafter.
A similar pattern of EEG rhythm distribution was observed in the patients who received the combination therapy with two drugs (the F+M group) (table 2).For instance, on the 42 nd day of the pharmacotherapy, the RP values of the alpha rhythm (given its normal distribution) were found to be lower in the occipital and parietal regions of the brain than those in the C group of healthy subjects.
The beta rhythm complied with the norm only in the occipital and parietal regions, but its RP values remained at a low level in the central and frontal regions.The delta rhythm values were two or three times as high in all of the analysed regions as the corresponding values in the C group, and the theta rhythm reached the pretreatment level on the 14 th day of the treatment and showed no changes afterwards.
Summarising the results of the study it may be concluded that according to the HDRS-17 scale the therapeutic effect was achieved in the patients, who received the combination therapy with fluoxetine and melatonin, already on the 28 th day of the treatment.At the same time less than half of the patients who received the monotherapy with fluoxetine showed a similar response on the 42 nd day of the treatment, and the rest of the patients in the latter group needed further care and continuation of the pharmacotherapy.The analysis of EEG RP by pharmaco-EEG demonstrated quite fast restoration of normal EEG rhythms in the patients who took fluoxetine and melatonin, which is not the case with the fluoxetine monotherapy, which did not result in complete remission of the existing depressive episode in a number of patients after the 42-day treatment course.

CONCLUSION
1.The administration of both fluoxetine and melatonin resulted in a more rapid regression of depressive symptoms and helped more than half of the patients score 7 or less on the HDRS-17 scale (which is equivalent to DD remission) already on the 28 th day of the treatment.By contrast, 40 % of the patients who took fluoxetine alone still needed therapy and observation even on the 42nd day of the treatment.
2. Pharmaco-EEG helped to demonstrate that fluoxetine contributed to partial restoration of the alpha rhythm in the occipital region of the brain and beta rhythm in the frontal part of the brain, but not to the extent comparable to the healthy subjects in the C group.
3. Pharmaco-EEG analysis of RP values in the F+M group showed a more significant and a little more rapid restoration of normal EEG rhythms after treatment with fluoxetine and melatonin as compared to the fluoxetine monotherapy.
4. The obtained results indicate that the combination therapy with fluoxetine and melatonin used for patients with gastrointestinal diseases with comorbid moderate DD leads to a more rapid recuperation of concomitant psychoemotional disorder as compared to the fluoxetine monotherapy.

Table 2 .
Mean RP values of EEG rhythms in the C, D, F and F+M groups on the 42 nd day of treatment