Effects of Chronic Alcohol Exposure on Dopaminergic and Serotonergic Neurotransmission System in Rat / 대한정신약물학회지

OBJECTIVE: This study investigates the effects of chronic alcohol exposure on rat brain THmRNA expression, TH (tyrosine hydroxylase) acitivity, and TPH (tryptophan hydroxylase) activity which are important in synthesis of dopamine and serotonin and other components of both the dopaminergic and serotonergic systems of the rat brain. METHODS: Rats were fed a liquid diet containing alcohol for 4 weeks. We investigated effects of chronic alcohol exposure on dopaminergic systems as follows. We evaluated expression of THmRNA in LC, VTA and substantia nigra by using in-situ hybridization and measured activity of TH by using immunoassay. We used HPLC for simultaneous measurement of dopamine, DOPAC and HVA in the cerebral cortex, striatum, hypothalamus, hippocampus, mid brain, hind brain, and cerebellum. Also we investigated serotonergic systems as follows. We evaluated expression of TH mRNA in the dorsal raphe nucleus by using radioprobe and measured the activity of TPH by using enzyme immunoassay. We used HPLC for simultaneous measurement of 5-HT and 5-HIAA in the cerebral cortex, striatum, hypothalamus, hippocampus, mid brain, hind brain, and cerebellum. RESULTS: Alcohol exposure for 4 weeks increased the expression of TH mRNA in the ventral tegmental area and the locus ceruleus but not in the substantia nigra. The 4 weeks of alcohol exposure did not cause significant changes in levels of dopamine and metabolites in the different areas of the brain, nor was it associated with changes in the maximal binding and affinity (Kd) of anterior striatal dopamine D2 receptor. Alcohol exposure for 4 weeks had no effect on the expression of TPH mRNA or on the activity of TPH in the dorsal raphe nucleus and the hypothalamus. CONCLUSION: We reported at first that chronic alcohol exposure could increase TH mRNA in the locus ceruleus. In a previous study of acute alcohol treatment, there is increase of dopamine metabolism but in this study, we did not observe any changes in dopamine metabolism in the different areas of the brain. Also we did not see any significant changes in the synthesis and metabolism of serotonin after 4 weeks of chronic alcohol exposure compared with control. Therefore, synthesis and metabolism of serotonin was affected in the acute phase. And, as previous reports have suggested, any changes caused by alcohol returned to previous levels via adaptation and regulatory mechanisms.

Association of Antipsychotic-Induced QTc Prolongation with 5-HTTLPR

OBJECTIVE: A Comparison of QTc prolongation for various antipsychotics and an analysis of QTc prolongation for the various types of serotonin transporter polymorphism were performed. METHOD: EKG was checked, followed by QTc measurement as Bazett's correction, and the serotonin transporter polymorphism was examined in 110 chronic schizophrenia patients were performed EKG before 24 weeks ago. We defiened QTc prolongation as over 450ms. The risk factor of sudden cardiac death were defiend as QTc prolongation and or 60ms in delta value. RESULT: The prevalence of QTc prolongation in this study was 7.3%, and the prevalence of over 60ms was 4.5%. Patients who had the risk factors were 10(9.1%). 6/52 who prescribed atypical antipsychotics and 2/58 who prescribed haloperidol showed QTc prolongation. The prevalence who had the risk factor of sudden cardiac death were 16% in atypical antipsychotics group, 3.4% in haloperidol group. QTc prolongation were observed more frequently in l/l type than s/s type. l allele frequency were 50% in QTc prolongated group, 19% in not prolongated group. l allele had an association with QTc prolongation(p<0.01). CONCLUSION: The prevalence of QTc prolongatin was frequent in chronic schizophrenia patients who were prescribed atypical antipsychotics. It has strong association with l allele of 5-HTTLPR.

Clinical Psychiatric Drug Trials in Korea: 1962~1998 / 대한정신약물학회지

OBJECTIVE: This investigation was performed to uncover the nature of the clinical drug trials in the past in Korean psychiatry and to prepare some guidelines for the good clinical practice in the future. METHOD: We reviewed total 212 papers of the clinical drug trials in the major Korean psychiatric journals from April 1962 to December 1998. RESULTS: From the year 1985, when the pharmacological and biological organizations in psychiatry were found in our country, the clinical drug trials are rapidly expanding. Although open clinical trials in small sample size less than 30 subjects were the most frequent in the past, some well-designed clinical trials such as multicenter double-blind cross-over study were performed recently. Majority of these 212 clinical trials was done in patients with schizophrenia and mood disorders. Haloperidol was just the drug most frequently evaluated in the clinical trials in our country. As expected, among several clinical rating scales, Brief Psychiatric Rating Scale was the most frequently used. Prolactin and homovanillic acid were the materials frequently measured in the patients with schizophrenia. A few of these clinical trials were performed under the financial supports from the industry, and only one biological research had gained a fund from a national academic institute. To evaluate the researchers' concepts for the medical ethics in the clinical drug trials, we reviewed the description about the informed consent and the approval of institutional review board in all papers. Surprisingly, we found no descriptions about the informed consent in 113 papers(65.8%). Only one clinical trial was performed after the approval of the institutional review board. CONCLUSIONS: We confirmed that the majority of the clinical psychiatric drug trials in the past were performed in lacks of the concept of Good Clinical Practice(GCP). The KGCP guideline did not influenced on the researchers' concepts and performance for the medical ethics at all. Although all of the clinical trials may not need to be done under the guidelines of GCP, clinical researchers' efforts for the medical ethics should be continued for both, the patient and the researcher.

The Relationship between Tardive Dyskinesia and both Negative Symptoms and Cognitive Dysfunctions in Chronic Schizophrenic In-patients / 신경정신의학

OBJECTIVES: The purpose of present study was to determine the prevalence rate of tardive dyskinesia and to search for its risk factors in chronically institutionalized schizophrenic subjects. We also examined the relationship between tardive dyskinesia and both negative symptoms and cognitive impairments in the same subjects. METHODS: Subjects were 271 in-patients (174 males, 97 females) at Masan Dongsuh Hospital. They met DSM-IV criteria for schizophrenia and had been taking fixed doses of antipsychotics for at least 3 months. Tardive dyskinesia was assessed by Abnormal Involuntary Movement Scale (AIMS). Cases of tardive dyskinesia were ascertained by the criteria of Schooler and Kane (1982) and DSM-IV. The rating of psychopathology was acquired using Brief Psychiatric Rating Scale (BPRS) and Schedule for the Deficit Syndrome (SDS) and the assessment of cognitive function using Mini-Mental State Examination (MMSE). RESULTS: The prevalence of tardive dyskinesia is 50.9% and the frequency of tardive dyskinesia was high est in male above the age of fifty. But there was no statistically significant relationship between the frequency of tardive dyskinesia and both the length of hospitalization and the daily dose of antipsychotics. The frequency order of abnormal movement in the patients with tardive dyskinesia was as follows: tongue, upper extremities, lips and perioral area. We couldn't find any significant difference in the total and subscale scores of BPRS between the groups with and without tardive dyskinesia. There were no differences in MMSE scores between the groups with and without tardive dyskinesia. CONCLUSION: This study gave us that the prevalence of tardive dyskinesia was high in chronically institutionalized schizophrenic inpatients and that age was the most significant risk factor of tardive dyskinesia. The relationship between tardive dyskinesia and both negative symptoms and cognitive impairment, however, was not revealed.

Pharmacotherapy of Vascular Dementia

Although many drugs are currently available in the treatment of vascular dementia, there are no licensed drugs for it with proven efficacy. The major treatment efforts are therefore focused on the management of the underlying causes and control of risk factors. Antiplatelet agents or anticoagulants such as a low dose of aspirin or warfarin should be used in all patients where there is no contraindication. Hypertension should be properly controlled not to make the patient hypotensive. Blood cholesterol and triglyceride, especially LDL cholesterol, should be assessed and, if raised, treated using diet or drugs. And if the patient is diabetic, it should be controlled also. If the patient is a smoker, they should be encouraged to stop smoking. Supportive measures such as gait retraining, prophylaxis against limb contractures, and speech therapy are indicated in selected patients. Pathophysiological processes common to both vascular dementia and dementia of Alzheimer's type may include microglial activation, increased production of cytokines, free radicals and glutamate. Propentofylline, a neuroprotective glial cell modulator, has been shown to be effective in the management of the patients with Alzheimer's disease or vascular dementia. Other therapies such as estrogen, non-steroid anti-inflammatory drugs and anti-oxidants such as vitamin E/selegiline (MAO-B inhibitor), Gingko biloba are sometimes used and show promise in delaying the progression of dementia. But several further clinical trials are needed to determine whether these new therapies can be successfully used in patients with vascular dementia or dementia of Alzheimer's type.