The association between dose of clozapine and panss scale in patients with schizophrenia poorly responsive to classic neuroleptiques – Phung Thanh Hai

Journal of military pharmaco-medicine n o 7-2018 151 THE ASSOCIATION BETWEEN DOSE OF CLOZAPINE AND PANSS SCALE IN PATIENTS WITH SCHIZOPHRENIA POORLY RESPONSIVE TO CLASSIC NEUROLEPTIQUES Phung Thanh Hai*; Bui Quang Huy**; Cao Tien Duc** SUMMARY Objectives: To evaluate the treatment result of clozapine in schizophrenic patients respond poorly to classic neuroleptiques. Subjects and methods: A prospective, cross-sectional, case- by-case analysis on 61 schizophrenic inpatients who responded poorly to classic haloperidol, aged 16 to 55 years and received treatment at National Psychiatric Hospital No 1 between 2014 and 2017. The data were processed by medical statistics using program SPSS Version 17. Result: PANSS scores were significantly different before and after clozapine treatment. Scores of P-PANSS, N-PANSS, G-PANSS and S-PANSS at three surveys were different with statistical significance. Haloperidol and clozapine had a positive correlation but very weak between dose and plasma levels. Conclusion: PANSS scores in patients with schizophrenia, who responded poorly to haloperidol, were significantly different before and after clozapine treatment. * Keywords: Schizophrenia; Classic neuroleptiques; Clozapine; PANSS scale. INTRODUCTION Schizophrenia is a group of severely psychotic disorders. The incidence of schizophrenia ranged from 0.3 to 1.5% of the population. Approximately 30 - 40% of patients with schizophrenia respond poorly or do not respond to classic neuroleptique. Symptoms in these patients did not improve after 4 weeks of treatment with classic antipsychotics. These patients must be treated with clozapine. Sadock B.J (2015) argues that there is a strong correlation between dose of clozapine and therapeutic efficacy [4]. Therefore, dose of clozapine should be carefully monitored so that dosages can be adjusted to improve therapeutic efficacy. In Vietnam, there haven’t even been any studies on the association between dose of clozapine and the results of treatment of schizophrenic patients who respond poorly to classic antipsychotics. We aimed: To evaluate the treatment results of clozapine in schizophrenic patients responding poorly to classic neuroleptiques. SUBJECTS AND METHODS The study included 61 schizophrenic inpatients, aged 16 - 55 years, who was received treatment at National Psychiatric Hospital No 1 between 2014 and 2017. * National Psychiatric Hospital No 1 ** 103 Military Hospital Corresponding author: Phung Thanh Hai (phungthanhhai18@yahoo.com) Date received: 11/04/2018 Date accepted: 31/08/2018 Journal of military pharmaco-medicine n o 7-2018 152 Patients were treated for the first 4 weeks with adequate dose of haloperidol but they improved less than 20% of PANSS score. Then, the patients were treated with clozapine. The results were collected at the time of three months, separated by 30 days. Use method of prospective, cross- sectional, case-by-case analysis. The data were processed by medical statistics using program SPSS version 17. RESULTS Table 1: Relationship between dose of clozapine and PANSS score. Dose of clozapine (mg/day) (n = 61) Dose PANSS score Time 2 (228.69 ± 48.48) Time 3 (228.69 ± 48.48) Time 4 (228.69 ± 48.48) p2-3 p2-4 ∑ PANSS total score 134.23 ± 5.68 87.21 ± 3.65 64.59 ± 2.88 p < 0.001 p < 0.001 ∑ P-PANSS 27.11 ± 4.24 13.62 ± 1.47 12.52 ± 1.29 p < 0.001 p < 0.001 ∑ N-PANSS 29.25 ± 1.90 26.97 ± 2.07 14.20 ± 1.60 p < 0.001 p < 0.001 ∑ G-PANSS 64.64 ± 2.87 40.38 ± 2.15 31.87 ± 1.87 p < 0.001 p < 0.001 ∑ S-PANSS 13.23 ± 1.12 6.25 ± 0.72 6.00 ± 0.00 p < 0.001 p < 0.001 ∑ Anergia 9.38 ± 1.82 7.47 ± 1.26 6.52 ± 0.81 p < 0.001 p < 0.001 ∑ Thought disturbance 15.13 ± 1.92 8.03 ± 0.94 7.26 ± 0.73 p < 0.001 p < 0.001 ∑ Activation 12.72 ± 0.95 6.49 ± 0.62 5.84 ± 0.37 p < 0.001 p < 0.001 ∑ Paranoid bellig 13.59 ± 1.28 6.59 ± 0.82 5.85 ± 0.36 p < 0.001 p < 0.001 ∑ Depression 12.54 ± 1.18 8.59 ± 1.19 7.82 ± 0.56 p < 0.001 p < 0.001 The association between the dose of clozapine and the PANSS scale in patients with schizophrenia showed that the all respondents were significantly different in the three surveys with p < 0.001. Varuni D.S and Raveen H (2010) studied 67 schizophrenic patients, who were started with clozapine due to resistance to at least two other antipsychotics. Although a minimum daily dose of 200 mg is recommended for clozapine, 12 patients (17.9%) were on a daily dose of 200 mg/day while 5 were on 150 mg/day. Of the sample, 43.3% were on 225 - 400 mg/day. Only 3 patients were on more than 600 mg/day. Mohammad S (2005) studied on 11 schizophrenic patients, who was received treatments with clozapine. Before treatment, the total PANSS score was 235, and after treatment it decreased to 123 (p < 0.0001); t = -7.83. Our results are consistent with the above authors. Journal of military pharmaco-medicine n o 7-2018 153 Table 2: Relationship between dose of clozapine and P-PANSS score. Dose of clozapine (mg/day) (n = 61) Dose P-PANSS Time 2 (228.69 ± 48.48) Time 3 (228.69 ± 48.48) Time 4 (228.69 ± 48.48) p2-3 p2-4 P1 Delusions 3.11 ± 1.97 1.56 ± 0.50 1.18 ± 0.39 p < 0.001 p < 0.001 P2 Conceptual disorganization 3.97 ± 0.89 2.46 ± 0.53 1.98 ± 0.13 p < 0.001 p < 0.001 P3 Hallucinations 2.98 ± 1.87 1.52 ± 0.50 1.20 ± 0.40 p < 0.001 p < 0.001 P4 Excitement 4.20 ± 0.51 2.05 ± 0.28 1.84 ± 0.37 p < 0.001 p < 0.001 P5 Grandiosity 3.69 ± 0.50 1.75 ± 0.47 1.36 ± 0.48 p < 0.001 p < 0.001 P6 Suspiciousness 4.72 ± 0.80 2.13 ± 0.34 1.88 ± 0.32 p < 0.001 p < 0.001 P7 Hostility 4.44 ± 0.59 2.15 ± 0.40 1.98 ± 0.13 p < 0.001 p < 0.001 There was a significant difference in P-PANSS among the three surveys with p < 0.001. According to Mohammad S (2005), P-PANSS pre-treatment was 34 ± 8.81 and after 3 months treatment, this figure was 17 ± 3.76. Our results were consistent with the Mohammad S. Table 3: Relationship between dose of clozapine and N-PANSS score. Dose of clozapine (mg/day) (n = 61) Dose N-PANSS Time 2 (228.69 ± 48.48) Time 3 (228.69 ± 48.48) Time 4 (228.69 ± 48.48) p2-3 p2-4 N1 Blunted affect 1.51 ± 0.81 1.87 ± 1.28 1.33 ± 0.47 p < 0.001 p < 0.001 N2 Emotional withdrawal 4.72 ± 0.55 4.21 ± 0.66 2.02 ± 0.13 p < 0.001 p < 0.001 N3 Poor rapport 4.62 ± 0.49 4.31 ± 0.59 2.02 ± 0.13 p < 0.001 p < 0.001 N4 Passive/ apathetic social withdrawal 4.84 ± 0.61 4.44 ± 0.53 2.23 ± 0.42 p < 0.001 p < 0.001 N5 Difficulty in abstract thinking 4.82 ± 0.39 4.47 ± 0.57 2.28 ± 0.45 p < 0.001 p < 0.001 N6 Lack of spontaneity and flow of conversation 4.56 ± 0.53 3.95 ± 0.28 2.33 ± 0.47 p < 0.001 p < 0.001 N7 Stereotyped thinking 4.18 ± 0.46 3.70 ± 0.49 2.00 ± 0.00 p < 0.001 p < 0.001 The three surveys of N-PANSS were very diverse. N2, N3, N5, N6 and N7 were statistically significant differences with p < 0.001. From the study by Mohammad S Journal of military pharmaco-medicine n o 7-2018 154 (2005), N-PANSS pre-treatment was 34.45 ± 8.8 and after 3 months treatment was 18.45 ± 5.62. Our results were consistent with the Mohammad S. Table 4: Relationship between dose of clozapine and G-PANSS. Dose of clozapine (mg/day) (n = 61) Dose G-PANSS Time 2 (228.69 ± 48.48) Time 3 (228.69 ± 48.48) Time 4 (228.69 ± 48.48) p2-3 p G1 Somatic concern 3.84 ± 0.66 3.39 ± 0.56 1.97 ± 0.36 p < 0.001 p < 0.001 G2 Anxiety 3.92 ± 0.59 3.38 ± 0.61 1.90 ± 0.30 p < 0.001 p < 0.001 G3 Guilty feelings 3.77 ± 0.50 4.31 ± 0.59 1.97 ± 0.18 p < 0.001 p < 0.001 G4 Tension 4.69 ± 0.53 2.85 ± 0.44 2.00 ± 0.00 p < 0.001 p < 0.001 G5 Mannerisms and posturing 3.84 ± 0.37 2.95 ± 0.22 2.00 ± 0.00 p < 0.001 p < 0.001 G6 Depression 3.87 ± 0.34 2.93 ± 0.36 1.98 ± 0.13 p < 0.001 p < 0.001 G7 Motor retardation 3.93 ± 0.31 2.29 ± 0.49 2.18 ± 0.43 p < 0.001 p < 0.001 G8 Uncooperativeness 4.43 ± 0.56 2.31 ± 0.50 1.98 ± 0.13 p < 0.001 p < 0.001 G9 Unusual thought content 4.49 ± 0.50 2.34 ± 0.48 2.00 ± 0.00 p < 0.001 p < 0.001 G10 Disorientation 1.00 ± 0.00 1.00 ± 0.00 1.00 ± 0.00 p < 0.001 p < 0.001 G11 Poor attention 4.57 ± 0.49 2.47 ± 0.50 2.33 ± 0.47 p < 0.001 p < 0.001 G12 Lack of judgment and insight 4.64 ± 0.52 2.74 ± 0.44 2.28 ± 0.45 p < 0.001 p < 0.001 G13 Disturbance of volition 4.28 ± 0.58 2.11 ± 0.32 2.00 ± 0.00 p < 0.001 p < 0.001 G14 Poor impulse control 4.82 ± 0.39 2.08 ± 0.28 2.03 ± 0.18 p < 0.001 p < 0.001 G15 Preoccupation 3.74 ± 0.44 2.16 ± 0.37 2.00 ± 0.00 p < 0.001 p < 0.001 G16 Active social avoidance 4.82 ± 0.39 2.51 ± 0.54 2.25 ± 0.43 p < 0.001 p < 0.001 The relationship between the dose of clozapine and the G-PANSS showed significant differences among the 3 surveys with p < 0.001. Our results were consistent with the Mohammad S (2005), G-PANSS pre-treatment was 64.27 ± 16.1 and after 3 months treatment was 32.16 ± 11.1. Journal of military pharmaco-medicine n o 7-2018 155 Table 5: Relationship between dose of clozapine and S-PANSS. Dose of clozapine (mg/day) (n = 61) Dose S-PANSS Time 2 (228.69 ± 48.48) Time 3 (228.69 ± 48.48) Time 4 (228.69 ± 48.48) p2-3 p2-4 S1 Anger 4.43 ± 0.56 2.11 ± 0.32 2.00 ± 0.00 p < 0.001 p < 0.001 S2 Exasperated when satisfaction of requests was delayed 4.21 ± 0.49 2.08 ± 0.28 2.00 ± 0.00 p < 0.001 p < 0.001 S3 Unstable mood 4.59 ± 0.50 2.05 ± 0.22 2.00 ± 0.00 p < 0.001 p < 0.001 For the three surveys of S-PANSS, there were significant differences with p < 0.001. Our results were consistent with the Mohammad S (2005); S-PANSS pre-treatment was 25.45 ± 6.28 and after 3 months treatment was 12.18 ± 1.99. Table 6: Relationship between dose of clozapine and five groups PANSS score. Dose of clozapine (mg/day) (n = 61 Dose PANSS Time 2 (228.69 ± 48.48) Time 3 (228.69 ± 48.48) Time 4 (228.69 ± 48.48) p2-3 p2-4 ∑ Anergia 9.38 ± 1.82 7.47 ± 1.26 6.52 ± 0.81 p < 0.001 p < 0.001 ∑ Thought disturbance 13.20 ± 1.87 8.08 ± 0.94 7.26 ± 0.73 p < 0.001 p < 0.001 ∑ Activation 12.72 ± 0.95 6.49 ± 0.62 5.84 ± 0.37 p < 0.001 p < 0.001 ∑ Paranoid bellig 13.59 ± 1.28 6.59 ± 0.82 5.85 ± 0.36 p < 0.001 p < 0.001 ∑ Depression 12.54 ± 1.18 8.59 ± 1.19 7.82 ± 0.56 p < 0.001 p < 0.001 There was a clear and significant difference between dose of clozapine and five groups PANSS in all surveys with p < 0.001. In the study by Mohammad S (2005), PANSS score for anergia pre-treatment was 31.87 ± 5.64 and after 3 months treatment with clozapine was 9.27 ± 2.72; thought disturbance pre-treatment was 18.72 ± 3.46 and after 3 months treatment was 9.63 ± 2.57; activation pre-treatment was 11.9 ± 3.35 and after 3 months treatment was 6 ± 1.34; paranoid bellig before treatment was 14.18 ± 3.54 and after treatment was 7.27 ± 1.27; depression before treatment was 14.63 ± 3.26 and 8.18 ± 1.83 after treatment. Our results were consistent with the Mohammad S. Journal of military pharmaco-medicine n o 7-2018 156 Table 7: Relationship between dose and plasma level of clozapine. Name of medicine n Average dosage (mg/day) Plasma level (ng/ml) Correlation coefficients (r) Haloperidol first time 61 12.67 ± 2.63 10.60 ± 6.06 0.3757 Clozapine second time 30 228.69 ± 48.48 272.68 ± 143.37 0.3144 Clozapine third time 30 228.69 ± 48.48 319.35 ± 129.81 0.0746 Clozapine fourth time 30 228.69 ± 48.48 319.34 ± 138.71 0.1166 Linear correlations between dose and plasma level of haloperidol and clozapine during each survey period showed: - For haloperidol, there was a linear but very weak correlation (r = 0.3757). - The second survey of clozapine found that the correlation coefficient was very weak (r = 0.3144); third and fourth survey of clozapine was found to be unrelated (r = 0.11666 and 0.0746). Pierre-Michel L, Christophe L, Béatrice D (2002) studied twenty-seven men and 10 women with schizophrenia. The mean dosage of clozapine at endpoint was 486.5 mg/day for mean plasma levels of 543.8 ng/mL for clozapine. There was a significant correlation between daily dosage of clozapine and clozapine plasma level (p < 0.05). Our results were consistent with the above authors. Dragan B.R, Slavica M.D.D, Vladimir J et al (2009) conducted a prospective, active-controlled study with 325 adult outpatients of both genders (140 females), with mean age of 34.8 year (range 21 - 57), suffering from chronic schizophrenia. The patients were allocated to receive haloperidol (105 subjects, dose range 2 - 15 mg), chlorpromazine (n = 105, 100 - 400 mg) or clozapine (n = 115, 75 - 600 mg). The statistically significant differences in all psychometric scores was found, for both schizophrenic syndrome, in preference for clozapine. Clozapine was safer and had fewer adverse effects than haloperidol and chlorpromazine. Our results were consistent with the above authors. CONCLUSION - Total PANSS scores were significantly different before and after clozapine treatment at three surveys. - Scores of P-PANSS, N-PANSS, G-PANSS and S-PANSS at three surveys were different with statistical significance (p < 0.001). - The PANSS scores for the five groups of impaired symptoms, mental disorders, motor impairment, paranoid and depression among the participants were statistically different with p < 0.001. - Haloperidol and clozapine had a positive but very weak correlation between dose and plasma concentration. Journal of military pharmaco-medicine n o 7-2018 157 REFERENCES 1. Dragan B.R, Slavica M.D.D, Vladimir J et al. Effectiveness of clozapine, haloperidol and clopromazine in schizophrenia during five-year period. Arq Neuropsiquiatr. 2009, 67 (2-A), pp.195-202. 2. Mohammad S. Comparison of classical and clozapine treatment on schizophrenia using positive and negative syndrome scale of schizophrenia (PANSS) and SPECT Imaging. 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