The Clinical And Experimental Research On Therapy Of Tic Disorders By Aripiprazole And The Change Of Immune Function

【Objective】1.To investigate the role of immune function in tic disorder (TD)through the animal model built by iminodipropionitrile and evaluate the efficacy of aripiprazole comparing with haloperidol in treating TD animal model. 2.To compare the clinical efficacy and safety of the aripiprazole comparing with tiapride in treating tic disorder through the case-control and experimental study.【Methods】1.Experimental Study: TD animal model ( P21 male SD rats) was established by Diamond . According to behavioral test, the rats with TD were randomly divided into the haloperidol group, the aripiprazole group and the untreated group, while the behavior of normal control group was investigated. There were 8 rats in each group. The 8th day from the experiment, P28 rats in the haloperidol group, aripiprazole group were separatedly given haloperidol (0.5mg/kg.d) and aripiprazole (10mg/kg.d) for 7 days, the untreated group, while the rats in normal control group were treated by NS. The changes of behavior were assessed on P34 rats. The scores of stereotyped behavior of rats was evaluated by Diamond's method and the suspension test and the balance test were used to detect rat muscle strength and body coordination in both haloperidol group and aripiprazole group. After the behavioral tests, the brain, thymus and spleen of rats were detected. The pathological changes of the striatum of rat brain were observed under the light microscope. Thymus index and spleen index were used to evaluate the immune function of rats. And the level of IL-6,TNF-αin rat brain were measured by ELASE. 2.Clinical Research: A randomized, case-controlled clinical trial was designed. The children with TD were diagnosis by the diagnostic criteria according to the revised fourth edition of "Psychiatric Diagnostic and Statistical Manual" in 2000 (DSM-IV-TR). 65 Han Chinese children aged 6～14 years old with chronic tic disorder (CTD) (n = 34) or Tourett syndrome (TS) (n = 31) were randomly divided into two groups-the aripiprazole group (n = 33) and the tiapride group (n = 32).The clinical efficacy was assessed by YGTSS and the adverse reactions were assessed with adverse reactions scale in the following 12 weeks.【Results】1.Experimental Study:1.1 The efficacy of aripiprazole on rats with TD: Before the drug intervention, there was no significant difference in tic behavior score among the aripiprazole group, haloperidol group and the untreated group. After adminstration, tic behavior score of rats in aripiprazole group (1.75±0.71 points) was significantly lower than that in untreated group (3.00±0.53 points,P <0.05), which was no significant difference comparing to that in haloperidol group (2.12±0.35 points, P>0.05).1.2 The adverse reactions of aripiprazole on rats with TD: In the balance test, the score in the aripiprazole group (6.38±0.74 points) were much more than that in haloperidol groups (4.63±0.74 points, P<0.05), which was no significant difference comparing to the untreated group (6.50±0.53 points) and normal control group (6.88±0.35 points, P>0.05). In suspension experiments, the suspended time of rats in the aripiprazole group (19.75±7.29 seconds) was longer than that in the haloperidol group (9.63±2.20 seconds, P<0.05), which showed no statistically significant compared with both in untreated group (18.38±10.13 seconds) and normal control group (18.38±8.23 seconds, P>0.05).1.3 The change of immune function: Both spleen index (0.33±0.02) and thymus index (0.27±0.01)of rats in the untreated group were significantly lower than those in the normal control group (0.42±0.08, 0.38±0.25, P<0.05). After aripiprazole or haloperidol adminstration, spleen index and thymus index were increased, which were (0.40±0.08) and (0.36±0.05) in the aripiprazole group, and (0.43±0.06) and (0.34±0.04) in the haloperidol group. The spleen index and thymus index both in the aripiprazole group and in the haloperidol group were significantly higher than those in the untreated group (P<0.05), which were similar to those in the normal group (0.42±0.08, 0.38±0.25, P> 0.05). There was no significant difference between aripiprazole group and the haloperidol group (P>0.05).1.4. The change of cytokine levels: The concentration of IL-6 and TNF-αin the rat brain in the untreated group (2081.63±528.26, 146.53±5.66 pg/ml) were significantly higher than those in normal control group (879.13±318.42, 120.83±2.15pg/ml, P<0.05). In aripiprazole group and haloperidol group, the concentration of IL-6 and TNF-αwere increased to (733.50±250.70, 125.36±9.88 pg/ml) or (921.00±60.00, 129.42±10.77 pg/ml), which was significantly higher than that in the untreated group (P<0.05) and no significantly different from that in normal control group (879.13±318.42, 120.83±2.15 pg/ml, P>0.05). There was no significant difference between the aripiprazole group and the haloperidol group (P> 0.05).1.5 The result of correlation analysis:It showed that tic behavior score was negatively correlated to the spleen index (r =-0.473, P<0.05) and the thymus index (r=-0.710, P<0.05), positive correlated to IL-6 and TNF-α(r = 0.529, P<0.05; r= 0.764, P<0.05).2.Clinical Research: YGTSS score in the aripiprazole group and in tiapride group decreased from the second week after treatment. Comparing with that in the tiapride-treated group (16.11±13.76%),the decline rate of YGTSS score in aripirazole-treated group (28.99±12.86%) was significantly lower in the second week after treatment(P<0.001). After 12 weeks'following treatment,the overall effictive rates of the aripirazole group and the tiapride group were separately 90.91% and 83.87%. There was no significant difference between the two groups (P>0.05), The incidences of adverse reactions in the two groups were separately 9.09% and 9.68%, which was no significant difference (P>0.05). There were also no serious adverse reactions in the two groups.【Conclusion】1.Experimental Study:1.1 Aripiprazole can effectively treat the tic symptoms, which efficacy is similar to haloperidol. And the adverse reactions of aripiprazole is less than that of haloperidol. It provides laboratory evidence for clinical use of aripiprazole inTD.1.2.There are immune disorder in TD, particularly the lower levels of cytokines (IL-6 and TNF-α) in the central nervous system. The reduction of TD symptoms are also accompanied with the improvement of immune function. It suggests immune dysfunction may be involved in the pathogenesis of TD. 2.Clinical Research: The lower dose (2.5mg/d～10mg/d)of aripiprazole is safe and effective for children with tic disorder, which provides a new drug option for the clinical treatment of children with tic disorder.