The Study Of Drug Prophylaxis On PTSD

Objectives This study was designed to examine the effect of drug prophylaxis on PTSD. In specific, examine the effect of chronic administration (orally) of quetiapine and an herbal(FEWP) on the behavioral manifestation of anxiety and cognition, and the level of cerebral phosphorylated p44/42 extracellular- regulated protein kinase (p-ERK1/2) activation in rats subjected to a modified single prolonged stress (SPS&S), an animal model that is widely used to study post-traumatic stress disorder (PTSD). Meanwhile, to examine the effect of paroxetine on some survivors who experienced a serious stress and to characterize psychopathological, biological, and neuroimaging profiles in the survivors.Methods In animal test, SPS&S was used used as an animal model of PTSD to test two drugs mentioned in objectives. For quetiapine test, the rats were randomly divided into four groups: (1) the"Sham+Veh"group in which the animals were not subjected to SPS&S stress and only received vehicle administration to serve as a normal control; (2) the"SPS&S+Veh"group and (3)"SPS&S+QUE"group in which animals underwent SPS&S treatment, followed by quetiapine administration for 14 days, 10 mg/kg/d; and (4) the"QUE+SPS&S"group in which quetiapine was administered before SPS&S treatment for 14days, 10 mg/kg/d. For FEWP test, the rats were randomly divided into five groups: the"Sham+Veh"group; the"SPS&S+Veh"group; and the"SPS&S+FEWP"group consisting of SPS&S treatment followed by FEWP administration. The"SPS&S+FEWP"group was divided into three subsets corresponding to the different doses (FEWP1: 2.5 mg/kg/d, FEWP2: 5 mg/kg/d, FEWP3: 10 mg/kg/d, for 14days). In the model of SPS&S, rats were first restrained for 2 h, followed immediately by 20 min of forced swimming, after 15 min of recuperation, the rats were exposed to diethyl ether until they lost consciousness, and then they were kept in the shock chamber until they had recovered, at last a single electric foot shock was exerted through the metal grid installed at the bottom of the chamber. After 14 days of the SPS&S, the open field test used to assess spontaneous locomotor activity, Morris water maze used to assess learning and memory, and elevated plus maze used to assess anxiety behavior in rats were test. An immunohistochemical method was used to observe alterations in the level of phosphorylated (p) ERK1/2 in the brain. Psychopathalogical evaluations with the Clinician- Administered PTSD scale (CAPS), the 17-item Hamilton Rating Scale for Depression (17-HAMD) and the Symptom Check List-90-R (SCL-90-R), and measurement of plasma cortisol and adrenocorticotropic hormone (ACTH) were conducted at 3 and 6 months postdisaster. Magnetic resonance imaging (MRI) detection was performed at 6 months.Results The results showed that performances in the Elevated Plus Maze (EPM), Morris Water Maze (MWM), and Open Field (OF) were changed significantly in rats, and chronic administration of quetiapine (10 mg/Kg/d) for 2 weeks, either before or after stress, significantly ameliorated anxiety-like symptoms and attenuated learning and memory impairments in stressed animals. The effect of herbal which was administrated after the stress was similar to quetiapine.In the EPM test of quetiapine, the differences in OA entries (%) were significant among the four groups. The designed Post-hoc test showed that following stress the OA entries (%) for the SPS&S+Veh group decreased significantly in comparison with those for the group not suffering from stress (p<0.01, vs. Sham+Veh). On the other hand, administration of quetiapine, either before or after stress, significantly inhibited the reduction in OA entries (%). There were no significant differences among the SPS&S+QUE, QUE+SPS&S, and Sham+Veh groups. Regarding the OA time (%), it was also revealed significant effects on either the SPS&S or quetiapine group, and the interaction between the groups. Post hoc analysis revealed that OA time (%) exhibited by the SPS&S+QUE and QUE+SPS&S groups was higher than that of the SPS&S+Veh group. There were no significant differences among the SPS&S+QUE, QUE+SPS&S, and Sham+Veh groups. In the test of FEWP, Differences among open arm (OA) entries (%) were significant among the five groups. The designed post hoc test showed that following stress, the OA entries (%) for the SPS&S+Veh group decreased significantly in comparison with those obtained for the non-stressed group. On the other hand, all three administrations of FEWP significantly inhibited the reduction in OA entries (%). There were no significant differences among the FEWP1, FEWP2, FEWP3, and Sham+Veh groups. As for the percentage of time spent in the open arms the significant interaction between SPS&S and FEWP was showed. Post hoc analysis revealed that the percentages of open arm time in the Sham+Veh and FEWP groups were higher than that obtained for the SPS&S+Veh group.In the MWM test of quetiapine, it was indicated that Group, Day, and Trial all had significant effects on the escape latency. The Designed Post-hoc test revealed that the escape latency of the SPS&S+Veh group increased significantly, while both types of quetiapine administration reversed this effect. There were no significant differences among the SPS&S+QUE, QUE+SPS&S, and Sham+Veh groups. The results also demonstrated that SPS&S significantly impaired spatial memory. The designed Post-hoc test showed that quetiapine treatment significantly reversed the SPS&S-induced decrease in time spent in the target quadrant. There were no significant differences among the SPS&S+QUE, QUE+SPS&S, and Sham+Veh groups. In the test of FEWP, Three way ANOVA indicated that Group, Day and Trial had significant effect on the escape latency and the pathlength to the platform. The designed post hoc test showed that the escape latency of the SPS&S+Veh group increased significantly, while all three administrations of FEWP reversed this effect on day 2, 3. There were no significant differences among the FEWP1, FEWP2, FEWP3, and Sham+Veh groups. One way ANOVA was used to analyze the percentage of time spent in the target quadrant. The designed post hoc test showed that the two higher dosages of FEWP treatment significantly reversed the SPS&S-induced decrease in time spent in the target quadrant. In OF test of quetiapine, with the result of 5min, there was a significant difference of horizontal distance among the SPS&S+QUE, QUE+SPS&S, SPS&S+Veh, and Sham+Veh groups. There was also a significant difference of activity time among four groups。In the test of FEWP, Two-way ANOVA showed no significant effect of SPS&S and FEWP administration on horizontal distance, and no interaction between SPS&S and FEWP administration, indicating that neither SPS&S nor chronic FEWP intervention significantly affected spontaneous locomotor activity. But for 5 min test, there was a significant difference among five groups.Furthermore, the p-ERK1/2 levels in the prefrontal cortex, medial amygdaloid nucleus, and cingulate gyrus of the rats drastically decreased 14 days after SPS; however, quetiapine inhibited this decrease.In the clinical study, forty-eight survivors aged 16-50 years were assessed. The prevalence of PTSD was 35.4% (17/48) at 3 months and 31.3% (15/48) at 6 months postdisaster, with high rates of comorbid symptoms. Risk factors for PTSD included traumatic experience, less than 5 years of being a miner, in an extremely exhausted or sick during the disaster, poor interpersonal relationship and sleep quality. Plasma cortisol levels were significantly higher in subjects with than without PTSD at 6 months, but not at 3 months, and positively correlated with the severity of several comorbid symptoms. The whole and regional brain volumes were indifferent between subjects with and without PTSD, but subjects with PTSD had significantly reduced fractional anisotropy (FA) values in the right posterior cingulum and bilateral hippocampal body than subjects without PTSD. The administration of paroxetine showed a beneficial effect on the survivors.Conclusions The findings indicate that drug prophylaxis with quetiapine may be beneficial in PTSD for anxiety-like symptoms and cognition deficit, and the increase in ERK1/2 activity in the brain may play a role in this effect. After a serious stress, there is a high risk of development of PTSD in people, and paroxetine may be beneficial for this people.