Comparative Efficacy, Safety and Tolerability of Olanzapine and Blonanserin in Patients with Schizophrenia: a Parallel Group Study

10.2478/AMB-2021-0023

COMPARATIVE EFFICACY, SAFETY AND TOLERABILITY OF OLANZAPINE AND BLONANSERIN IN PATIENTS WITH SCHIZOPHRENIA: A PARALLEL GROUP STUDY

S. Chattopadhyay1, U. Roy2, S. Biswas1, P. Roy3, P. Mandal4

1Department of Pharmacology, Burdwan Medical College and Hospital – India 2Department of Pharmacology, Raiganj Govt. Medical College and Hospital – India 3Department of Psychiatry, Burdwan Medical College and Hospital – India 4Department of Pharmacology, Raiganj Govt. Medical College and Hospital – India

Abstract. Background: The antipsychotic olanzapine is a fi rst-line drug in the treatment of schizophrenia while blonanserin is indicated in resistant cases of schizophrenia when the fi rst line antipsychotics have failed. There are very limited studies available world- wide as well as in India that compare blonanserin with other antipsychotics in the setting of schizophrenia. Aims: To study the effi cacy, safety and tolerability of olanzapine and blonanserin in Schizophrenia. Settings and Design: The study was a prospective, observational, parallel group study done on schizophrenia patients aged between 18-50 years of both sexes at an outpatient Department of Psychiatry, in a tertiary medical college. The study was conducted from February 2015 to October 2016, with follow ups at weeks 4, 8 and 12. Materials and Methods: The effi cacy parameters were measured by the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) rating. The safety parameters included the vital signs, haematological profi le, lipid profi le, blood sugar monitoring. Adverse drug reactions and compliance to therapy was observed through- out the study period. Appropriate statistical tests were applied to detect any signifi cant within and between group diff erences using Microsoft Excel 2007 and SPSS version 17. Results: There was signifi cant decrease in the mean total score on the BPRS and CGI-S in the blonanserin arm at the 2nd and last follow up visit (p value < 0.001). Com- pliance was good in both groups (≤ 20% missed pills). Overall, 77 treatment-emergent adverse events were present from 56 patients. Twenty three subjects of the blonanserin arm and 33 subjects in the olanzapine arm at least experienced one adverse event (p = 0.006), metabolic adverse eff ects were more common with olanzapine, whereas insomnia, headache and somnolence were more often seen with blonanserin. Conclusions: In the present study, blonanserin provided signifi cantly better outcomes than olanzapine with respect to BPRS, CGI-S scores.

Key words: blonanserin, eﬃ cacy, olanzapine, safety, schizophrenia, tolerability

Corresponding Author: Dr. Uttam Kumar Roy, Dilip Das Sarani, Hill View Main, Paschim Bardha- man, Pin-713304, West Bengal, India, Phone numbers: 9434163225, E-mail: [email protected]

RECEIVED: 11 August 2020, ACCEPTED: 29 September 2020

Acta Medica Bulgarica, Vol. XLVIII, 2021, № 2 // Original article 45 INTRODUCTION Being an observational study, CTRI approval was not required. Ethics Committee approval was ob- chizophrenia is a chronic psychiatric disorder tained prior to study from the appropriate Clinical characterised by positive symptoms, negative Research Ethics Committee [BMC/PG/190/1(1), Ssymptoms and cognitive impairment. Global Dated10/01/2015]. Patients presenting with history prevalence of schizophrenia is 1% and the incidence re- or symptoms of schizophrenia were screened and mains 1.5 per 10000 population [1]. In India, the weight- recruited as per subject selection criteria. Recruit- ed prevalence of schizophrenia is 0.64% [2]. Schizophre- ment was subjected to satisfactory completion of the nia patients suff er of higher morbidity and mortality [3]. informed consent process. Laboratory parameters Though pharmacotherapy is the mainstay of therapy, were assessed at baseline and at end of 4 weeks. psychotherapy is also important. Antipsychotics like Inclusion criteria olanzapine used as 1st line agent for pharmacotherapy of schizophrenia, provide eff ective control for positive All patients aged between 18 and 50 years of both symptoms but the negative symptoms and cognitive im- sexes diagnosed with schizophrenia by the Struc- pairment remain a challenge for social functioning, sub- tured Clinical Interview for DSM IV Axis-1 Disor- jective well-being and long-term adherence to therapy. ders (SCID) and. The SCID has been used by most Second generation antipsychotic drugs should then be of the studies for diagnosis of schizophrenia. The prescribed according to Canadian guidelines [4] which SCID is an effi cient, user-friendly and reliable clini- categorized recommendations into six areas. cal interview for making DSM diagnosis [14]. Pa- tients with normal complete blood counts, blood The other challenges for therapy are non-adherence sugar, lipid profi le and normal ECG were included to therapy, social stigma, substance abuse, suicidal in the study. tendency and comorbidities. Atypical antipsychotics like blonanserin, having high affi nity for D2, D3 and Exclusion criteria 5HT2A receptors, are helpful in controlling negative Pregnant and lactating women, immunosuppression symptoms and cognitive impairment as shown in ani- due to drug or disease, severe psychosis and vio- mal studies as well as in humans [5, 6]. But these lent behaviour; patients who have already taken any drugs are not free from adverse eff ects that limit ef- other antipsychotic or antidepressant medication, fectiveness and compliance [7]. The atypical antipsy- presence of renal or hepatic impairment, substance chotic drugs have better safety profi le [8]. Olanzapine abuse, participation in any other clinical trial within is commonly used as a fi rst-line drug in the treatment past 3 months, patients unable or not willing to give of acute symptoms and for maintenance therapy but consent, diseases of vital organs, those receiving its role in treating negative symptoms remains unclear medications known to prolong QT-interval or capable [9]. Recent studies have shown that this drug is likely of otherwise having drug-drug interaction with study to induce weight gain and an increased risk for obe- medication. sity-related diseases, as well as metabolic syndrome [10]. Olanzapine usewas associated with hypergly- Time schedule of visits and activities at each visit caemia [11]. Blonanserin is unlikely to cause metabolic Subjects were screened in the psychiatry outpa- side eff ects, is generally well tolerated and can cause tient department and the diagnosis was done by the less prolactin elevation [12]. It also improves cogni- Structured Clinical Interview for DSM IV Axis-1 Dis- tive function in patients with fi rst-episode and chronic orders (SCID) [14]. In addition, the selection crite- schizophrenia [13]. But there is a need of comparing ria were checked and written informed consent was blonanserin with other antipsychotics in schizophre- obtained from the patient. Laboratory examination nia in Indian patients. Global reports are also limited. included parameters such as haemoglobin (Hb), to- Thus, the aim of this study was to compare effi cacy, tal leucocyte count (TLC), diff erential count (DLC), safety and tolerability of blonanserin for long term erythrocyte sedimentation rate (ESR), random blood management compared with a standard atypical anti- sugar (RBS), blood lipid profi le, plus blood pressure psychotic such as olanzapine. and ECG. Concomitant medication was noted and non-permit- MATERIALS AND METHODS ted medications were withdrawn prior to the study. The baseline visit was scheduled fi ve days after the Study design and subjects screening visit to allow for any antipsychotic that had The study was a prospective, observational, con- been taken to be washed out. The period of fi ve days trolled, parallel group, comparing blonanserin versus refl ected the fi ve half-lives of the commonly prescribed a standard atypical antipsychotic, Olanzapine. antipsychotic agents [15]. The dosage of Blonanserin

46 S. Chattopadhyay, U. Roy, S. Biswas et al. was 8-12 mg daily in two divided doses – with titration Among them 80 were fi nally randomised – 40 in each up to 24 mg [16]. The clinical pharmacokinetic profi le group. Of these, three patients were lost to follow- of olanzapine supported once-daily oral administration, up, of which two from the blonanserin group and starting with a dose of 5-10 mg, with a target dose of 10 one from the Olanzapine group. 77 patients (39 in mg/day, and a maximum dose of 20 mg/day [17]. blonanserin group and 38 in Olanzapine group) ful- Patients were asked to report immediately any un- fi lled modifi ed-intention-to-treat criteria [23] and their wanted and unexpected reactions. They were followed parameters were analyzed (Fig. 1). The demographic up at weeks 4, 8 and 12 with possibility for interim fol- characteristics (Table 1) of both groups were compa- low up for assessing adverse events, if needed. rable at baseline. The clinical characteristics of the Measurements subjects in both groups were comparable at baseline. The Brief Psychiatric Rating Scale (BPRS) [18] and (Mann-Whitney U-test). the Clinical Global Impression (CGI) Severity [19] Within group analysis showed that the mean to- were measured at baseline, 4th week, 8th week and tal score of BPRS decreased signifi cantly in both 12th week. The BPRS assesses several symptom groups: with blonanserin from baseline (61.18 + domains due to the multidimensional nature of the 4.29) to week 12 (27.10 +3.57, p < 0.001), olanzap- scale. Psychometric investigations of various BPRS ine from baseline (60.13 + 4.23) to week 12 (31.61 + versions provide evidence for satisfactory to excel- 4.04, p < 0.001) (fi g. 2). The CGI-S score decreased lent inter-rater reproducibility [20]. from baseline (5.13+ 0.61) at 12 weeks (1.72 + 0.51) CGI Severity and improvement scales off er a read- in Blonanserin group (n = 39) (p value < 0.001). In the ily understood, practical measurement tool, thus Olanzapine Group (n = 39) the reduction was from can be easily administered by a clinician in a busy 5.03 + 0.59 at baseline to 2.16 + 0.49 at 12 weeks (p clinical practice setting to document the details, track < 0.001 (fi g. 3). responses to interventions and monitor and quantify patient progress [21]. Inter-group analysis (Independent-Sample t test) re- Recorded adverse events included treatment-emer- vealed that the BPRS score and CGI-S score were gent events reported spontaneously by subjects at declining over the treatment period in both groups. any time during the 12-week treatment. Causality This decline was statistically signifi cant (p < .001) analysis of adverse events was done by using the when compared between visits of the both treat- WHO-UMC Scale [22]. Compliance with therapy was ment arms in second and end follow up visit [Tables assessed by the pill counting method. 2 and 3].The end-of-study compliance (per protocol) Adherence to therapy was considered satisfactory if assessment indicateed excellent adherence to treat- ≤ 20% pills were missed [23]. ment for all patients in both treatment groups (≤ 20% missed dose). Statistical considerations Not a single participant encountered a serious ad- The target sample was 33 in each group. This was calculated to detect a diff erence between groups of verse event and there were no hospitalizations. 6 in the Brief Psychiatric Rating Scale (BPRS) score During the 12-week study period a total of 68 with 80% power and 5% probability of Type 1 error, subjects were suspected of having at least one assuming a standard deviation of 10 for the same pa- adverse drug reaction (ADR). On causality as- rameter. Considering a 20% drop-out rate, the num- sessment, 12 of these 68 cases (17.65%) were ber of patients required to be recruited in each group considered with WHO-UMC causality status” un- is 40 or 80 subjects overall. likely”. From the remaining 56 subjects, 77 ADRs Students independent t-tests were applied for age, (93.5%) belonged to the “probable” category, and chi-square test for sex distribution, residence, whereas 5 (6.49%) were of “possible” type ac- literacy, occupation. Within-group analysis was done cording to the WHO-UMC scale. No case could by Friedman ANOVA followed by post hoc analysis be labelled “certain”, as re-challenge was not with Multiple Wilcoxon Signed Ranks test with a Bon- attempted by the attending psychiatrist, once a ferroni correction. drug was withdrawn. Overall, out of 77 treatment- emergent adverse events from 56 patients: 23 RESULTS subjects in the Blonanserin arm and 33 subjects A total of 110 patients attending the out-patient De- in the Olanzapine arm reported at least one event. partment of Psychiatry were screened for this study. (Table 2) (p = 0.006 by chi-square test).

Comparative eﬃ cacy, safety and tolerability of olanzapine... 47 Table 1. Demographic proﬁ le of the study population (N = 77)

Categry Blonanserin group (n = 39) Olanzapine group (n = 38) Age (Years) 18 to 50 18 to 50 Mean ± SD 31.51 ± 5.86 32.66 ± 7.14 Gender Male 56.4% 47.4% Female 43.6% 52.6%

Table 2. Changes in the BPRS score over 12 weeks

BPRS Blonanserin group Olanzapine group p value (n = 39) (n = 38) (between groups) Mean ± SD Mean ± SD Baseline 61.18 ± 4.29 60.13 ± 4.23 0.284

1st follow-up 54.00 ± 3.33 54.53 ± 3.65 0.511

2nd follow-up 38.10 ± 3.06 44.11 ± 4.11 < 0.001

End of study 27.10 ± 3.57 31.61 ± 4.04 < 0.001

Table 3. Changes in the CGI-S score over 12 weeks

Blonanserin group Olanzapine group p value CGI-S (n = 39) (n = 38) (between groups) Mean ± SD Mean ± SD Baseline 5.13 ± 0.61 5.03 ± 0.59 0.452 1st follow-up 4.41 ± 050 4.42 ± 0.50 0.924 2nd follow up 2.87 ± 0.41 3.45 ± 0.50 < 0.001 End of study 1.72 ± 0.51 2.16 ± 0.49 < 0.001

Table 4. Individual reported adverse drug reactions

Blonanserin group Olanzapine group p value Adverse event (n = 39) (n = 38) (between groups) Insomnia 8 4 0.227 Somnolence 7 4 0.352 Nausea 2 7 0.087 Tremor 2 4 0.431 Anxiety 5 5 1.000 Headache 4 0 0.115 Vomiting 1 6 0.056 Constipation 0 2 0.240 Weight gain 3 10 0.675 Increased salivation 0 1 0.494 Akathisia 0 2 0.240

(Chi-square test for insomnia and somnolence and Fisher’s exact test for the rest)

48 S. Chattopadhyay, U. Roy, S. Biswas et al. Fig. 1. Study subjects recruitment ﬂ ow chart

Fig. 2. The BPRS score at diﬀ erent visits in two treatment arms

Fig. 3. The CGI-S score at diﬀ erent visits in two treatment arms

DISCUSSION ics are the best options when effi cacy, safety and tolerability profi les are concerned [24] and this study is trying Schizophrenia is a functionally and socially debilitating to fi nd a new option. We found no study that compared chronic psychiatric illness that necessitates long term the two drugs olanzapine and blonanserin in the treat- therapy at a high cost. Second generation antipsychot- ment of schizophrenia globally and in our country.

Comparative effi cacy, safety and tolerability of olanzapine... 49 Patients having severe psychosis or severe disease of the two treatment arms. No other studies corrobo- condition were excluded from our as those subjects rated with this observations [6]. would be very diffi cult to handle. The study subjects In respect to lipid profi le tests there were signifi cant were assessed in four visits which helped thorough increases of post treatment mean values of total assessment of the patients regarding effi cacy, safe- cholesterol, triglycerides, LDL-cholesterol, VLDL- ty and adverse drug reactions. There were no sig- cholesterol and a signifi cant decrease of post treat- nifi cant diff erence in the duration of illness of both ment mean values of HDL-cholesterol in both treat- groups (blonanserin – 21.15 ± 5.48 months, olan- ment arms. In between groups comparisons all the zapine – 22.37 ± 5.29 months, p value 0.270). The biochemical parameters were comparable except for majority of subjects in our study belonged to younger serum total cholesterol, which was increased more at age groups because of the wide prevalence of the study end by olanzapine than by Blonanserin. This disease in younger age [1] and so other co-morbid- highlighted the need for checking their lipid profi le ev- ities associated with advanced age were avoided. ery 3 months when administering these medications. Our study showed that most of the patients were in Studies done by Huh L, Lee BJ (2019) [34] and Lally their thirties with a nearly equal gender distribution. J, MaCabe JH (2015) [8] support our fi ndings. The The WHO statistics also found a greater incidence random blood glucose levels at baseline and study- of schizophrenia in the third decade of life, though end were comparable – both within and in-between males were shown to be suff ering more often from the two treatment arms. However, many studies the disease [1]. This diff erence can be due to a small showed a strong association of olanzapine with the sample size in our population. Other demographic incidence of type 2 diabetes mellitus [34]. profi les were comparable in both treatment arms. The treatment-emergent side eff ects are depicted in The vital signs recorded at baseline were analogous table 4. The patients in both groups complained of in both the treatment arms. The laboratory param- many adverse events from which 93.5% were ADRs eters were within normal limits in both groups. belonging to the “probable“ category, whereas 6.5% Regarding effi cacy, the BPRS scale (a short version fell in the “possible” category, according to the WHO- of PANSS) [25] and the CGI-S showed signifi cant UMC causality assessment scale [35]. The incidence improvement from 2nd follow-up visits to end of study of adverse events was signifi cantly higher in the olan- visit in the blonanserin group compared to the olanzapine arm in which weight gain, GI disturbances zapine group. Woo YS (2019) showed signifi cant re- were more common. On the other hand, insomnia, duction in BPRS that support our study fi ndings [26]. somnolence, headache were more frequently report- Another study of Woo YS (2016) showed signifi cant ed by Blonanserin treated patients. The incidence of reduction in CGI-S with blonanserin [27]. anxiety was equal in both treatment arms. The RCT Blonanserin induced improvement in the negative done by Gründer, Gerhard & Heinze in 2016 revealed symptoms and cognitive impairment with less ad- similar fi ndings also [24]. verse eff ects in various short and long term studies Blonanserin, an atypical antipsychotic with dopamine [28]. It has been shown that cognition improvement D3, D2, 5HT2A receptor antagonism has proved to more than 0.5 SD improves quality of life [29]. In the be eff ective in the management with least metabolic, present study, blonanserin induced a signifi cantly extrapyramidal and hyperprolactinaemic side eff ects. better outcome as assessed by the BPRS and CGI- Blonanserin does not produce sedation due to its S scores. We found no study compared blonanserin low affi nity for the 5HT2C, adrenergic alpha1, hista- with olanzapine in therapy of schizophrenia, but other mine H1 and muscarinic M1 receptors [36]. Switching studies with other antipsychotics showing superior ef- to blonanserin can reverse medication – induced hy- fi cacy of blonanserin compared with haloperidol [30], perprolactinemia found in female patients making it is risperidone [31], aripiprazole [32], amisulpuride [33]. a suitable antipsychotic [12]. When safety parameters were considered (vital signs Study subjects showed good compliance to therapy such as the pulse rate, systolic and diastolic blood as there were ≤ 20% missed doses in both groups. pressure), they were comparable at baseline and at The lack of troublesome adverse events helped in treatment end in both medication groups. In the cur- this regard. Also, most of them (both patients and rent study, an increase in haemoglobin in both the family members) were well educated to understand treatment groups was registered, however between the nature of the disease and the medication eff ect. groups comparisons did not reveal any relation. The In addition, good communication could be estab- mean values of other haematological parameters did lished before signing the consent form. This may be not vary at baseline and end of study visits in either also due to small sample size. Such compliance in

50 S. Chattopadhyay, U. Roy, S. Biswas et al. the patients favours the adherence to therapy with serin in healthy subjects: A positron emission tomography either of the medications [23]. study with [11C]-(+)-PHNO. Int J Neuropsychopharmacology. 2018; 21(6):522-7. The limitations of our study include the small sample 6. Tenjin T, Miyamoto S, Ninomiya Y, et al. Profi le of blonanserin size was calculated on the basis of a relatively large for the treatment of schizophrenia. Neuropsychiatr Dis Treat. eff ect size with respect to BPRS score. A larger sam- 2013; 9:587-594. ple may have shown a clear statistical diff erence be- 7. Stroup TS, Gray N. Management of common adverse eff ects of antipsychotic medications. World Psychiatry. 2018; 17(3): tween groups in other measures such as CGI-S and 341-356. CGI-I rating. Antipsychotic drugs may increase se- 8. Lally J, MacCabe JH. 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52 S. Chattopadhyay, U. Roy, S. Biswas et al.