jurnal internasional skizofrenia

ndian J Psychol Med . 2017 Nov-Des; 39 (6): 770-776. doi: 10.4103 / IJPSYM.IJPSYM_111_17 PMCID : PMC5733427 PMID: 29284810 Kemanjuran dan Tolerabilitas Clozapine versus Quetiapine dalam Skizofrenia yang resistan terhadap pengobatan Mitesh Kumar , BS Chavan , Ajeet Sidana , dan Subhash Das

Abstrak Tujuan: Untuk membandingkan kemanjuran dan tolerabilitas clozapine dan quetiapine pada pasien dengan skizofrenia yang resistan terhadap pengobatan (TRS). Pasien dan metode: Dalam studi label terbuka prospektif, acak, selama 14 minggu, 53 pasien dengan skizofrenia didiagnosis sesuai ICD-10 dan memenuhi versi modifikasi dari kriteria Conley dan Kelly tentang TRS secara acak ditugaskan untuk menerima clozapine atau quetiapine sesuai acak yang dihasilkan komputer meja. Setelah 2 minggu fase titrasi dosis, dosis ditetapkan pada dosis terapi minimum dan kemudian disesuaikan sesuai dengan perbaikan klinis. Semua pasien menerima dosis masing-masing obat dalam kisaran terapeutik. 13 pasien mangkir. Efikasi pengobatan dan efek samping dievaluasi dengan skala penilaian standar. Hasil: Kelompok clozapine (pengurangan skor total: rata-rata = 14,45, SD = 10,39) memiliki pengurangan yang lebih besar secara signifikan (P = 0,004; CI = 3,541-17,059) dalam skor total Skala Sindrom Positif dan Negatif (PANSS), subskala positif PANSS positif dan PANSS umum subskala psikopatologi pada 14 minggu dibandingkan dengan kelompok kuetiapin (pengurangan skor total: rata-rata = 4,15, SD = 10,71). Pengurangan signifikan dalam PANSS negatif subskala terlihat dengan kedua obat tetapi tidak ada perbedaan yang signifikan antara kedua obat. Pada 14 minggu, 30% pasien dalam kelompok clozapine dan 15% pasien dalam kelompok quetiapine menunjukkan respons. Clozapine menyebabkan efek samping yang secara signifikan lebih besar (P <0,001, CI = 2.241-6.059) pada Skala Efek Samping Antibodi Antropikotik (GASS) Glassgow daripada quetiapine. Kesimpulan: Clozapine ditemukan lebih efektif daripada quetiapine pada pasien dengan TRS tetapi dikaitkan dengan efek samping yang lebih besar. Kedua obat itu ternyata sama efektifnya dalam mengurangi gejala negatif.

Kata kunci: Clozapine , quetiapine , skizofrenia yang resisten terhadap pengobatan

Table 1.. Comparison between clozapine (Group A) and quetiapine (Group B) group on sociodemographic and clinical variables

Drug efficacy Twenty percent reduction in psychopathology score was taken as a response in the study.[3,7] In our study, six patients (30%) in clozapine group and three patients (15%) in quetiapine group showed a response (>20% reduction in PANSS from baseline) at the endpoint, i.e., 14 weeks. However, the difference between the two groups was not significant (P = 0.256). Comparison of Positive and Negative Syndrome Scale scores of two groups across assessments On within group analysis while there was statistically significant improvement in positive, negative, general subscale, and total score of PANSS in clozapine group, with regards to quetiapine such improvement, was present only in negative subscale of PANSS [Table 2].

Table 2 Comparison of Positive and Negative Syndrome Scale scores of two groups (Group A clozapine; Group B - quetiapine) across assessments

Change in Positive and Negative Syndrome Scale scores for clozapine and quetiapine group At the end of 14 weeks, the patients assigned to clozapine had significantly greater reductions in the PANSS total score (mean = 14.45, SD = 10.39) than the patients assigned to quetiapine (mean = 4.15, SD = 10.71, P = 0.004). A similar significantly greater reduction in clozapine group was seen on the PANSS positive subscale and PANSS general psychopathology subscale. However, on the negative subscale of PANSS, there was a significant reduction with both clozapine and quetiapine and the difference between two drugs was not significant [Tables [Tables22 and and33]. Table 3 Reduction in scores from baseline on Positive and Negative Syndrome Scale for clozapine (Group A) and quetiapine (Group B) group

Comparison of the side-effects in clozapine (Group A) and quetiapine (Group B) group There was statistically significant increase in GASS score at 6, 10, and 14 weeks from baseline in both groups [Tables [Tables44 and and5].5]. However, while comparing the two drugs, a statistically significant difference was seen at week 6, 10, and 14 and quetiapine was found to be superior to clozapine in terms of side-effect profile. The most common side effects observed in clozapine group were increased sleepiness/sedation (65%), feeling drugged (60%), drooling of saliva at night (45%) and dizziness (35%) and weight gain (45%). The most common side effects noted in quetiapine group were dry mouth (50%), difficulty in passing urine (45%), sleepiness/sedation (35%), dizziness (30%), and weight gain (20%).

Table 4 Comparison on Glasgow Antipsychotic Side-effect Scale between two groups (Group A clozapine, Group B - quetiapine)

Table 5 Effects of clozapine (Group A) and quetiapine (Group B) across assessments on Glasgow Antipsychotic Side-effect Rating Scale

DISCUSSION To the best of our knowledge, this is the first Indian study carried out to compare the efficacy and tolerability of clozapine and quetiapine in TRS. Forty patients who completed all four assessments were included in the final analysis. The two groups were comparable at baseline on sociodemographic and clinical variables. The mean dose of clozapine was 322.50 mg/day, and quetiapine was 790.0 mg/day. Clozapine group In this study, 6 (30%) patients in clozapine group showed response. This finding concurs with the multi-centric study conducted by Kane et al. which established clozapine as preferred drug for TRS[3] and another large randomized double-blind comparative study of clozapine and haloperidol in patients of refractory schizophrenia in which superior improvement was observed in the clozapine group.[16] Significantly, more patients in clozapine group had ≥20% reduction in symptoms than the comparator drugs in both these studies.[3,16] The response rate of 30% with clozapine in this study is somewhat similar to these two studies. The superiority of clozapine over typical and atypical antipsychotics has been reported in some systematic reviews and meta-analysis. However, studies comparing clozapine with quetiapine were not included in these. Furthermore, there was a high degree of heterogenicity in terms of duration of the study, dosage of drugs used, level of resistance to previous treatment and financial support from a drug company among various studies included in these

systematic reviews and meta-analysis, and hence it may not be appropriate to include these studies in a meta-analysis.[4,17,18,19] Quetiapine group In this study, patients with quetiapine had significant improvement only in negative symptoms and overall 3 (15%) patients showed response. These findings are in contradiction to an earlier study on 95 TRS patients, wherein 59% of quetiapine-treated patients were defined as PANSS responders compared to 38% of haloperidol-treated patients and quetiapine showed numerically greater but nonsignificant improvement at 8 weeks in all subscales and total score of PANSS in comparison to haloperidol.[7] The reason for greater improvement could be the inclusion of mildly ill patients (score of 3 or more on CGI), whereas all the patients in our study were moderately ill (score of 4 or more on CGI) and lower degree of treatment resistance. Findings of this study are also inconsistent with the findings of a smaller 4-week study which showed response in 50% of the cases as well as significant reduction in total PANSS scores in patients who were refractory to first-generation antipsychotics and were later treated with quetiapine.[20] Reasons for higher response rate in that study could be lower degree of treatment resistance, small sample size, single-blind design which can lead to bias. Moreover, unlike the current study, this study did not have a comparator group. The response rate to typical and atypical antipsychotics in other studies has not been as high as reported in the above-mentioned two studies.[3,16,21,22,23] Clozapine versus quetiapine group In this study, the difference between clozapine and quetiapine in term of response rate was not statistically significant which can be attributed to a smaller sample size of this study. Patients assigned to clozapine had significantly greater reductions on positive symptoms, general psychopathology and total PANSS score than the patients assigned to quetiapine. However, there was no significant difference between the two groups so far as reduction in negative symptoms was concerned; both drugs produced significant improvement in negative symptoms from the baseline assessment. These results are consistent with Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 2 investigations, where patients assigned to clozapine had significant reductions in the PANSS total score and PANSS general psychopathology subscale than the patients assigned to quetiapine. Reductions in positive and negative subscale scores in clozapine group were greater than quetiapine, but it was not statistically significant in that study.[24] Another noncommercially funded, pragmatic, open, multisite, and randomized controlled trial comparing clozapine with other SGA (including quetiapine) showed that the improvement seen in clozapine group was significantly higher in comparison to SGA group at 12, 26, and 52 weeks, although authors did not publish results for the different SGA.[25] However, findings of this study should be interpreted carefully because clozapine is associated with sedation, hyper-salivation, orthostatic hypertension and metabolic side effects[24,26] leading to poor tolerability. Other serious side effects such as agranulocytosis, [27] seizure,[28] and myocarditis[29] have been reported in the literature. Further important limitation arises from the need of slow titration and weekly blood counts which are laborious. [30] In addition, a significant proportion of TRS population is nonresponder to even clozapine.[5] Thus, there is still a prospect for using other molecules when clozapine is ineffective or intolerable though uncertainty exists regarding which molecule should be used in such a scenario.[30]

Negative symptoms predominate major portion of the course of illness and account for much of the long-term morbidity and poor functional outcome of patients with schizophrenia. [31,32,33] In such a scenario, quetiapine can be considered as a viable alternative as it showed a response in 15% of patients and was associated with significant improvement in negative symptoms. In fact, a metaanalysis conducted by Cochrane Schizophrenia group has found quetiapine to be more efficacious than clozapine on the negative symptom subscore. [34] The current study found that quetiapine was better so far as side effects of the two drugs were concerned as reflected by the GASS score. In addition, the side effects of both the drugs were mild in severity as only one patient in each group had dropped out due to side effects. However, the retention rate was better in the clozapine group as 4 patients dropped out from this group as compared to 9 patients in the other group. Clozapine was associated with sedation, hyper-salivation, and weight gain in greater proportion of the patients, whereas quetiapine caused anticholinergic side effects (dry mouth, difficulty in passing urine, etc.) in more number of patients and this finding are consistent with previous CATIE trials.[24,26] The current study, in fact, showed greater anticholinergic side effects due to quetiapine compared to a previous industry-sponsored study.[35] CONCLUSION Clozapine is still a good choice in TRS, and it was found to be more effective than quetiapine. However, clozapine was associated with greater side effects than quetiapine. Quetiapine, on the other hand, was also effective and equivalent to clozapine in the reduction of negative symptoms. Thus quetiapine might be a better choice in cases of TRS with predominant negative symptomatology, especially in instances where clozapine is ineffective or cannot be used. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Acknowledgments Patients who participated in the study, all faculty of the Department of Psychiatry, GMCH, Chandigarh, India. REFERENCES 1. Whiteford HA, Ferrari AJ, Degenhardt L, Feigin V, Vos T. The global burden of mental, neurological and substance use disorders: An analysis from the Global Burden of Disease Study 2010. PLoS One. 2015;10:e0116820. [PMC free article] [PubMed] [Google Scholar] 2. Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biol Psychiatry. 2001;50:898–911. [PubMed] [Google Scholar]

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