| Depression is one of main types of affective mental disorders. It is a syndrome mainly characterized by a series of obvious consistent mood depressions. The pathogenesis of depression is not clear yet. The categorization of depression is only symptom-descriptive type presently. Based on the Global Burden of Disease in 2000, the point occurrence of single depression accounted for 1.9% in male and 3.2% in female, of which 5.8% male and 9.5% female experienced one onset of depression within one year. The occurrence of depression goes up year by year due to the quickening of life rhythm, working pressure, family life, society reformation, accidences and other factors. Depression brings great burden for the society and is the forth major cause for all diseases. It is the main cause of disability adjusted life year and accounts for 11.9% of all disability adjusted life year. Therefore, it has very important society and economy double significance to strengthen the study on this disease and find out effective therapeutic measures.The pathogenesis of depression is not clear yet. The patients have multi-system pathological changes in the nervous system, endocrine system, immune system and so on. It is believed that the biochemical performance disorder of the central nervous system is highly correlated with it, especially noradrenalin (NE), 5-Hydroxytryptamine (5-HT) and other neurotransmitters. New antidepressants at present in the world mainly act by two ways: 1) to inhibit the re-uptake of 5-HT and NE to elevate the level of them in the brain;2) to inhibit the activity of monoamine oxidase to reduce the degradation of 5-HT and NE. These drugs can be categorized as tricyclic, tetracyclic and monoamine oxidase inhabitants (MAOI). The study in the world is focused on 5-HT re-uptake inhabitants (SSRI). However the clinic application of them is restricted due to the severe side effects, poor curative effect, poor compliance and high cost. Depression is typical disease caused by biological, psychological and social factors and that can induce multi-system and multi-hierarchy pathological reactions. Thus mono-action and mono-target medication has some shortcomings inevitably and multi-hierarchy and multi-target traditional Chinese drug therapy may have some advantages. Because Chinese herb medicine compound has great advantage in multi-system and multi-target therapy, it is promising to study the application of Chinese herb medicine in the treatment of depression. Yushu Granule has been developed by Professor Zhou Shaohua based on his decade's clinic experiences and got good curative effect in clinic. In order further to confirm the curative effect and the action mechanism, we designed this clinic and experimental study.Part I An Observation on the Clinic Curative Effect of Yushu Granule in theTreatment of DepressionThis study is a random single-blind positive medicine controlled trial. The selected patients must met the diagnostic standards of CCMD-3 criterions for unipolar depressive episode or bipolar affective disorder depressive episode, screen and baseline Hamilton depressive scale (HAMD) 17 items >16 and belonging to stagnation of the liver-qi for TCM differentiation of symptoms and signs. All patients were outpatients or inpatients of China Academy of Chinese Medical Sciences. The subjects were enrolled to test group and control group randomly and received 6wk single-blind treatment. Visited the patients before the drug administration (screen and baseline) and at the end of the second, forth and sixth week after the drug administration to get data for the evaluation of the safety and effectiveness of the drug.The patients in the test group were given Yushu Granule (0.48g/tablet), 6 tablets each time, each morning and evening, and the patients in the control group were given fluoxetine hydrochloride capsule, 20mg/day, with 6wk for a therapeutic course.Effective indexes scale evaluation was carried out at screen, baseline, at the end of the second, forth and sixth week after the drug administration respectively. Evaluated Hamilton depressive scale (HAMD) at the screen and evaluated HAMD, Hamilton anxiety scale (HAMA), self rating depressive scale (SDS), HAMD factors (anxiety/somatization factor, body weight lost factor, cognitive disorder factor, retardation factor and sleep disorder factor) at other visiting times. Evaluated the effectiveness based on the changes of these scales.The evaluation criterions were the reduction of HAMD score and the reduction rate of HAMD score at the end of the treatment and the evaluation point was at the end of 6wk. Total HAMD score ^ was considered as clinical cure, reduction rate ^0% as effective and reduction rate <50% as ineffective.Per-protocol analysis (PP, i.e. therapeutic duration was over 6wk, the study protocol was complied with, they had good compliance and had filled out the contents required) and intention-to-treat analysis (ITT, i.e. all the randomly enrolled patients who had received the drug and visited at least once after the baseline) were applied as effective evaluation indexes.Total 70 patients with depression were enrolled, of which 62 patients completed the study and 8 patients withdrew (who participated in the effective evaluation in ITT specimen). Total withdrawal rate was 11.43%, 3 from the test group and 5 from the control group, 2 due to the lost in the follow-up (1 from the test group), 3 due to adverse event (3 from the control group) , 1 due to no marked clinical effect 2 wk after the treatment, 1 due to violating the study protocol 2 wk after the treatment (1 from the test group) and 1 due to the aggravation of the symptoms 2wk after the treatment (1 from the test group).There were total 35 patients in the test group, male 15, female 20, with the average age of 45.28±7.58 and 35 patients in the control group, male 17, femalel8, with the average age of47.66±8.25.The effectiveness rate and the clinical cure rate of Yushu Granule reached 75.00% and62.50% respectively 6wk after the treatment. There was no significant difference in total HAMD deduction value, effectiveness rate, clinical cure rate, HAMD factor score (anxiety/ somatization, body weight lost, cognitive disorder, retardation factor and sleep disorder) and total SDS score between the groups 6wk after Yushu Granule administration, which indicates that Yushu Granule is effective to depression and the efficacy is equivalent to that of fluoxetine. Based on HAMA comparative score, the anxiety relieving effect is equivalent in the two groups. Yushu Granule has excellent effect on the depression companied with anxiety symptom.Deep breath tendencc and distention and pain in the chest were relieved after Yushu Granule administration and there was significant difference between the two groups. Depression, vex, hard to drop asleep, early waking, shallow sleep, easy to be awaked and other symptoms were improved as well.There were 1 clinical controlled, 6 clinical obvious effective, 17 clinical effective and 11 clinical ineffective patients in the test group and there were 1 clinical controlled, 5 clinical obvious effective, 16 clinical effective and 13 clinical ineffective patients in the control group at the end of the treatment. The difference had no statistical significance between the two groups.The difference in TCM symptom score before and after the treatment in the two groups was significant (P<0.01) but there was no statistical significance in the difference before and after the treatment in the two groups (P>0.05).No adverse event was observed in the test group. Anxiety, nervousness, insomnia, dry mouth, constipation, anorexia or inappetite was observed in some patients in the control group, of which 3 patients withdrew the study due to dry mouth, constipation and insomnia respectively (The withdrawal was possibly caused by the control drug) and some other patients completed the study as they had only mild symptom.This random single-blind positive medicine controlled study confirms that Yushu Granule has good curative effect to Depression and is safe to use and no adverse reaction and side effect are observed.Part II Experimental StudyExperiment I The Effects of Yushu Granule on the Mouse Model of DepressionCaused by ReserpineUse investigational reserpine to develop the mouse model of depression and observe the effect of Yushu Granule on eyelid ptosis, automatic activities and the content of noradrenaline(NE), 5-Hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the brain of mice.The animals were enrolled into 6 groups: control group, model group, fluoxetine hydrochloride 5mg/kg group, Yushu Granule crude drug 4g/kg group, Yushu Granule crude drug 8g/kg group and Yushu Granule crude drug 16g/kg group.The experiment showed that the mice in the model group showed eyelid ptosis, had less automatic activities, low content of NE and 5-HT and high content of 5-HIAA after having been given reserpine. The experiment confirms that Yushu Granule can markedly inhibit-7-mouse eyelid ptosis and less automatic activities caused by reserpine and increase the content of NE and 5-HT, especially the content of NE. It indicates that Yushu Granule can antagonize Depression and regulate mood. The action mechanism is possibly related to monoamine neurotransmitters but the definite mechanism of the antidepression of it is to be studied.Experiment II The Effect of Yushu Granule on the Rat Model of Depression Causedby Chronic StressThis experiment observed the effect of Yushu Granule on the relevant indexes of the rat model of depression developed by 24days unexpected stress.The animals were randomly enrolled into 6 groups: control group, model group, fluoxetine hydrochloride 3.5mg/kg group, Yushu Granule crude drug 2.5g/kg group, Yushu Granule crude drug 5g/kg group and Yushu Granule crude drug lOg/kg group.The results of open field test showed that the rats in the model group had less horizontal and vertical activities after unexpected stimulation and there was significant difference between the test group and the control group (P<0.01). After 24 day drug intervention, compared with the rats in the model group, the rats in the fluoxetine hydrochloride group had much more horizontal and vertical activities (P<0.01). Horizontal activities in three dose groups of Yushu Granule and vertical activities in Yushu Granule crude drug lOg/kg group and 5g/kg group increased markedly.The results of MORRIS water maze test showed that the rats had a low exploring and learning ability after chronic stress and would stay a much longer time and had a muchlonger total distance in MORRIS water maze. There was significant difference between the test group and the control group (PO.01). Compared with that of the model group, the time of staying in the water maze and the total distance shortened significantly in the Yushu Granule crude drug lOg/kg group and 5g/kg group (PO.05-PO.01). The two indexes also shortened in the Yushu Granule crude drug 2.5g/kg group but there was no statistical significance.The results of the experiment on the effect to sleep showed that the rats in the model group had much less sleep and there was significant difference between the model group and the control group (PO.05). Compared with the model group, the fluoxetine hydrochloride group and Yushu Granule crude drug had much longer sleep time. The test did not observed obvious change in sleep time and the sleep time in the treatment groups had not marked change compared with the model group.This experiment, based on the data of 24days intervention on the rat model of depression developed by 24days unexpected stress, indicates that Yushu Granule can markedly improve Depression, increase horizontal and vertical activities and shorten the time staying in water maze and the distance. The experiment showed that Yushu Granule extended the sleep time of the rats in the model group. It confirms that Yushu Granule has certain preventive and treatmental effect to depression.Experiment III The Effect of Yushu Granule on Despair and Inactive Behavior ofMiceMouse immobility times in forced swimming test and tail suspension test were used as indexes of despair and observed after the administration of Yushu Granule.In the forced swimming test, the mice exerted the utmost strength to swim and try their best to climb up tub wall. After a piece of time, the activities of the mice decreased and there were long immobility intervals between active times. During the intervals, the mice took bend upward posture to keep their nosed above the water surface. With time extension, the interval time increased. Compared with the mice in the model group, after 28 day drug administration, the immobility times in 6min in the fluoxetine group and in the three Yushu Granule groups shortened significantly (PO.01).The tail suspension test showed that the immobility time in 6min in the fluoxetine group shortened significantly (p<0.01) and that in the three Yushu Granule groups shortened as well (p<0.05-0.01) after 28 day drug administration compared with that in the model group.In the test, the mice were put in a limited inescapable place to swim or under an inescapable stress condition to induce immobility of the mice. Mouse immobility times in forced swimming test and tail suspension test were used as indexes of despair. There are many animal models of depression. Mouse tail suspension test and mouse forced swimming test are simple, low cost, sensitive and reliable. After 28 days Yushu Granule administration through gastric canal, the immobility times in mouse tail suspension test and in mouse forced swimming test shortened markedly and were correlated to the dose given, which indicates that Yushu Granule has anti-depressant effect.Experiment IV Sedative Effect of Yushu GranuleGive pentobarbital sodium by intraperitoneal injection and observe the sedative-hypnotic effect of Yushu Granule.The animals were randomly enrolled into 5 groups, 13 mice in each group: control group, fluoxetine hydrochloride 5mg/kg group, Yushu Granule crude drug 16g/kg group, Yushu Granule crude drug 8g/kg group and Yushu Granule crude drug 4g/kg group.The animals received the drug 20mg/kg (the animals in the control group received the same quantity of normal water), once each day for 28 days. The mice were given pentobarbital 60mg/kg through intraperitoneal injection after the last drug administration. The time when righting reflex disappeared was recorded as drop-asleep time and the duration from drop-asleep to the recovery of righting reflex was recorded as sleep-time. Statistical process was performed on the recorded data.The results indicate that fluoxetine can shorten mouse drop-asleep-time and prolong sleep-time compared with the control group significantly (P<0.05-0.01). The three doses of Yushu Granule have no significant influence on mouse drop-asleep-time and sleep-time, which suggests that Yushu Granule has not obvious sedative-hypnotic effect to normal animals. The sleep improvement effect to depression patients of Yushu Granule observed in clinic may be caused by relieving depression rather than by inhibiting the central nervous system.Experiment V Acute Toxicity of Yushu GranuleMouse acute toxicity test of Yushu Granule was performed according to New Drug Approval Method. As LD50 was undetectable, determination of maximal dose was made to observe the acute toxic reaction of Yushu Granule.The animals were randomly enrolled into two groups, 20 mice in each group, male and female half and half. The animals could drink but could dot eat any food for 18 hrs. Yushu Granule was given through gastric canal, with the concentration of 3.57g crude drug/ml and the volume of 40ml/kg, twice in 24hrs and the total dose was 285.6 g crude drug/kg. The same volume of distilled water was given for the animals in the control group. Observed and recorded the toxic reaction and the changes in the body weight, the appearance, behavior, secretion and excretion and mortality for 14 days after the drug administration.The mice had upright hairs and became indolent from the drug administration to 2hrs after the drug administration. From 4 hrs after the drug administration to 14days after the drug administration, the mice had normal movement, food and water uptake, no upright hairs, no polysialia or vomit, no dyspnea, no nasal obstruction, normal eye, no lacrimation, no pupil contraction or dilation, no eyelid ptosis. The stool of the mice was colorized by the drug color 1 day after the drug administration and became normal lately. No animal was dead. There was no significant difference in the body weight between the treatment group and the control group. The maximal dose for the mice was 285.6g crude drug/kg, equivalent to 295.7 times of the effective dose in clinic. No obvious toxic reaction was observed. This experiment indicates that Yushu Granule is safe and low toxic at this dose.CONCLUSIONClinical and experimental study on the effect of Yushu Granule in the treatment of depression indicate that the drug has certain antidepressant effect and the curative effect is equivalent to fluoxetine capsule but has no side effect and adverse reaction. The action mechanism is possibly related to monoamine neurotransmitters but the definite mechanism of the antidepression of it is to be studied.
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