Brain Dysfunction and Behavior - Research Paper Example

Brain Dysfunction and Behavior CLOZAPINE DOSE-RESPONSE ABSTRACT Schizophrenia is a psychic behavioural disorder characterized by typical impairments in the perception and expression of reality with significant social or occupational dysfunction. A person suffering from schizophrenia demonstrates disorganized thinking and experiences delusions or auditory hallucinations.Clozapine is an atypical antipsychotic drug widely used in refractory Schizophrenia. However, drug toxicity, side effects, mortality and tolerability of the drug is a matter of concern in the clinical treatment of Schizophrenia. Hence, Clozapine therapy needs stringent monitoring not only for agranulocytosis but also possible lethal side effects like seizure and myocarditis. This study is an attempt to explore the possibility of obtaining a positive correlation with dose, effects and side effects of the drug using EEG recording so that a minimum and maximum dose range of the drug can be obtained for effective treatment of Schizophrenia. Key words: Clozapine, Schizophrenia, EEG assessment, Drug dose. INTRODUCTION Clozapine is a tricyclic dibenzodiazepine derivative 8-chloro-11- (4-methyl-1-piperazinyl)-5H-dibenzo [b, e] [1,4] diazepine. It is available as 25mg and 100 mg tablets for oral administration. Clozapine is widely used in refractory Schizophrenia. There seems to be a cultural and geographical variations in dose response relationship and tolerability to the drug making the dose response unpredictable. The effective and tolerable range is between 100 mg to 900 mg, which makes it difficult to make a predictive, significant and valid correlation. There has been no positive correlation with serum level too. Thus, there is a need to search for a clinically viable and simple method for growth response monitoring of the drug. The present study is an attempt to evolve such a method. Thus, the study focuses on the effect of clozapine on EEG pattern of the Schizophrenia. patients to explore the possibility of obtaining a positive correlation with dose, effects and side effects so that a minimum and maximum dose range of the drug can be obtained for effective treatment of Schizophrenia. MATERIALS AND METHODS The study was done in the year 2000 at a tertiary care center. This open level prospective cohort naturalistic study was done on patients selected randomly after informed consent.50 patients referred to clozapine therapy were studied for a period of three months. A conventional 10 channel EEG with international 10-20 system of montages was recorded during a fixed time of 5-7 PM at baseline, 4, 8 and 12 weeks. RESULTS AND DISCUSSION Any attempt on obtaining a correlation of EEG data with clozapine dose response should be substantiated by a review of current research findings on clozapine therapy associated EEG abnormalities to evaluate the relevance and significance of the recorded data. Electroencephalogram (EEG) slowing has been shown to be associated with clozapine side effects and can be used as a marker to predict treatment response during clozapine treatment. (Wichniak A et.al, 2005). Patients with schizophrenia have been found to show N1, P3 and Late Slow Wave abnormalities indicating impairment in early stimulus evaluation and subsequent working memory functions. Subsequent treatment with clozapine seem to have induced normalization of the P3 and Late Slow Waves, indicating improvement in working memory updating and executive processing. There also seems to be a partial normalization of N1 amplitude, suggesting improvement in early stimulus evaluation. ( Galletly CA et.al ,2005). In patients treated with electro convulsive therapy along with parallel administration of antipsychotic medication, Antipsychotic drugs have been found to influence both seizure threshold and seizure activity in different ways. Most of the antipsychotics like Olanzapine, Clozapine and Zuclopenthixol have been found to have epileptogenic properties. (Gazdag G, 2004). Table 1.1 showing the EEG Recording data EEG MALE FEMALE BASE 4 WEEKS 8 WEEKS 12 WEEKS No abnormality 50 % 45 % 42 30 15 9 Abnormality found 54 % 52 % 8 20 35 41 Equivocal 6 % 3 % 0 0 0 0 Background alpha 34 24 20 12 Frequency 4-6 CPS 32 % 34 % 41 32 30 21 Amplitude (more than normal range) 42 % 45% 0 21 31 40 Sharp waves (appearance) 32% 42% 0 1 9 21 Spikes (first appeared) 35% 45% 0 6 7 12 Slow waves (significant) 29% 23% 11 28 34 37 Table 1.2 Mean Clozapine dose in mg BASELINE 4 WEEKS 8 WEEKS 12 WEEKS 250 350 400 450 Table 1.3 ‘t’, ‘r’ and ‘p’ values Between Weeks ‘t’ value ‘r’ value ‘p’ value 4-8 19. 86 0.9974 not = 0 8-12 0.28 0.1 = 0 4-12 0.36 0.13 = 0 The data generated have been tested for their for level of significance and correlation analysis statistically. This enables us to generalize the results of the sample population, their validity and degree of confidence. A t-test for testing the significance of an observed sample correlation coefficient in which r is the correlation between 4 weeks and 8 weeks of the clozapine therapy and recorded EEG data yielded a t value 19.86 which is much higher than the tabulated t value of 2.31.This takes us to a conclusion that the t is significant at 5 percent level of significance and there is a positive correlation between the variables of the EEG data and the number of patients showing abnormalities recorded from 4 and 8 weeks of clozapine therapy. This also takes us to the conclusion that EEG recording can be a marker to study the clozapine dose response. A further Analysis of Variance to substantiate the conclusion that there is no deviation in the correlation arrived from the 4th and 8th week till the 12th week also takes us to the conclusion that there is no significant difference between the correlation arrived. That is to say, the therapeutic results show the same trend displayed in the 4th week till the 12th week of the therapy. The calculated value at 5 percent level 3.96 is less than the tabulated value, which means that there is no significant difference between the correlations arrived between weeks. To be specific, the data generated by the EEG recording indicate that the drug causes abnormalities in the EEG and the abnormalities in all the 12 weeks have a correlation and indicate the same statistical hypothesis that Clozapine therapy induces EEG abnormalities. Table 1.3 ANOVA data Source of Variation Sum of Squares Df Mean Squares F Between weeks 674 3 224.6 1.93 A study on the relationships between clozapine serum level, quantitative EEG parameters and performance in vigilance and memory tasks have shown that the atypical antipsychotic clozapine causes EEG alterations indicating memory impairments due to its anticholinergic properties. Negative correlations between clozapine serum levels and the amount of high-frequency EEG activity and positive correlations between high-frequency EEG activity and memory performance obtained suggest that clozapine treatment brings about dose-dependent impairments of vigilance and memory indicated by reduction of high-frequency EEG activity (Adler G et.al, 2002 ).A study which investigated the incidence and nature of clozapine-associated electroencephalographic (EEG) abnormalities and the relationship between EEG abnormality and clozapine dosage in Korean schizophrenic patients has shown that the majority of EEG abnormalities presented as nonspecific slow waves (SW), Spikes (or spike and wave complexes; SP) and frontal intermittent rhythmic delta activity (FIRDA). The probability of EEG abnormality has been found to be linearly dependent on the daily dose of clozapine and patient's age. The studies have shown that a substantial proportion of patients treated with clozapine develop EEG abnormalities and the EEG abnormalities occur in a dose-dependent manner ( Chung SJ et.al, 2002 ). Duggal HS et.al have elaborated on clozapine-induced seizures as evidenced by EEG abnormalities. It is well known that Clozapine produces EEG abnormalities and dose-dependent risk of epileptic seizures. Specific electroencephalogram (EEG) changes during clozapine therapy have also been studied with reference to clozapine serum level ranges. Patients in a typical study have shown EEG changes during the 10-week study period with seizures and slowing on EEG at clozapine serum level 320 ng/mL (Freudenreich O, 1997). The present study has also confirmed the appearance of abnormal amplitude waves with 21 patients in the 4th week, 31 in the 8th week and 40 patients in the 12th week of the therapy. Sharp wave appearances have been recorded in 1 patient in the 4th week, 9 patients in the 8t week and 21 patients in the 12th week of the clozapine therapy. Spikes have been recorded in 6 patients in the 4th week, 7 in the 8th week and 12 in the 12th week. Significant slow waves have been recorded in 28 patients in the 4th week, 34 in the 8th week and 37 patients in the 12th week. Although a non-linear analysis on multi-channel EEG data drawn from patients before and after a therapeutic trial of clozapine has shown that the correlation dimension is difficult to extract from a limited time series EEG data to find a meaningful association with clozapine use (Kang UG, et al 2001), the present study has given scope for utilizing EEG recording as a marker of dose-response relationship to detect maximum tolerable dose so that dose escalation can be stopped to avoid other serious side effects like myocarditis, seizure etc. Clozapine can induce a number of adverse effects, most of which are preventable and manageable by a number of simple clinical procedures. The use of EEG abnormalities as a marker to decide on the Clozapine drug dose will have a marked effect on the well being of patients receiving Clozapine therapy. REFERENCE Adler G, Grieshaber S, Faude V, Thebaldi B, Dressing H. 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