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Home , Haloperidol, Risperidone

JOURNAL OF CRITICAL REVIEWS

ISSN- 2394-5125 VOL 7, ISSUE 13, 2020

COMPARISON BETWEEN COMBINATION OF AND THERAPY WITH COMBINATION OF RISPERIDONE AND THERAPY ON CLINICAL SYMPTOM IMPROVEMENT OF

Saidah Syamsuddin1, Erlyn Limoa2, Ismariani Mandan3, Sonny T. Lisal4

1Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia. 2Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia. 3Postgraduate, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia. 4Department of Psychiatry, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia.

Received: 21.04.2020 Revised: 23.05.2020 Accepted: 18.06.2020

ABSTRACT: Background: Risperidone, haloperidol and chlorpromazine are that can easily be found in most hospitals but its use in combination does not yet have strong evidence especially to clinical symptom of schizophrenia patients. Objectives: This research aimed to know the difference between the combination of risperidone and haloperidol therapy with a combination of risperidone and chlorpromazine therapy on clinical symptom improvement of schizophrenia. Materials and methods: It used observational analytic design with prospective cohort approach. 30 subjects were divided into 2 groups where on 15 subjects who received a combination of risperidone and haloperidol therapy and 15 subjects received a combination of risperidone and chlorpromazine therapy. Improvement of clinical symptoms rated by Positive and Negative Syndrome Scale – Excited Component (PANSS-EC) instrument at baseline and on the 1st day, on the 2nd day and on the 3rd day of therapy and Positive and Negative Syndrome Scale – Excited Component (PANSS) instrument at baseline and on the 1st week, on the 2nd week on the 4th week, and on the 6th week of therapy. Results: The results showed that the decrease of PANSS-EC score was significant in both groups since the 1st day, the 2nd day and the 3rd day (p<0.001). Statistical analysis showed comparison of the change in PANSS-EC score were significant at every time that was on the 1st day p=0. 026; on the 2nd day p=0. 041, and on the 3rd day p=0.03. The decrease of total PANSS score was significant in both groups since the 1st week, the 2nd week the 4th week, and the 6th week (p<0.05). Statistical analysis showed, comparison of the change in PANSS score were not significant at every time that was on the 1st week p=0. 811; on the 2nd week p=0.201; on the 3rd week p=0. 728, and on the 4th week p=0.637. Conclusions: Improvement of the agitation symptoms of schizophrenia subjects in acute exacerbations was significantly better in the group receiving a combination of risperidone and chlorpromazine therapy than the group receiving a combination of risperidone and haloperidol therapy. The addition of small doses of antipsychotics was quite effective in the first days of treatment of acute exacerbation of schizophrenia subjects, but not for long-term treatment. KEYWORDS: Schizophrenia, Risperidone, Haloperidol, Chlorpromazine, -combination. © 2020 by Advance Scientific Research. This is an open-access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.31838/jcr.07.13.268

I. BACKGROUND Schizophrenia is one of the most debilitating diseases that cause long-term disability to more than 50% of its sufferer. World Health Organization (WHO) stated that schizophrenia affected 7 from 1000 adults worldwide. According to Indonesian Basic Health Research data conducted by Indonesian Health Service (2013) showed that the prevalence of Indonesian severe mental disorders was 1.7 per mil and in South, Sulawesi was 2.6 per

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ISSN- 2394-5125 VOL 7, ISSUE 13, 2020 mil. It is a challenge for clinicians to decide on the best treatment for schizophrenia based on the risks and benefits. [1, 2, 3] It is common for clinicians who work in the Emergency Department to encounter acutely agitated and aggressive patients. Agitation control is the first step in the treatment of acute exacerbation schizophrenia patients. It is necessary to consider the best choice not only for the rapid control of agitation symptoms but also for the long- term implications of the therapy, such as efficacy, side effects, , and the average time for cessation. Optimizing drug selection from the beginning will affect treatment in a stable phase, with the hope of increasing the effectiveness of treatment. [4,5,6] Oral medications, if possible, are preferred over intramuscular or intravenous drugs. In a study in Turin, Italy, 93% of subjects preferred oral medications during the agitation period. [7] Fortunately, treatments commonly used for agitation are available on oral routes, including haloperidol, , , and risperidone. Some oral drug combinations have been shown to be at least as effective as intramuscular injected with lower side-effect profiles. [7,8] Atypical antipsychotics (AAP) are the treatment of choice for schizophrenia today due to their lower side effects and superior efficacy. Among atypical antipsychotics, risperidone is the most widely prescribed antipsychotic agent in the United States. [9,10] Likewise in Indonesia, risperidone is the most commonly used . At Cipto Mangunkusumo Hospital, Jakarta, around 71.7% of schizophrenia patients received risperidone therapy similarly in Ratumbuysang Hospital, Manado more than 70% of patients received risperidone therapy both in a single form and in combination with other antipsychotics. [11,12] Generally, recommended guidelines therapy for schizophrenia is using mono-therapy antipsychotic. However, the use of poly-pharmacy antipsychotics (at least two antipsychotics at the same time) had increased over the past decade. In general, the most common type of oral combination used worldwide is the combination of first-generation antipsychotics and the second-generation antipsychotics. [13] Previous research by Jarut, et.al (2013), at Ratumbuysang Hospital in Manado found that the administration of risperidone was often combined with chlorpromazine. In Makassar, the combination of risperidone with low potential antipsychotics such as chlorpromazine or is also often found. One of the purposes is to overcome agitation which is the most frequently complained symptom from schizophrenia patients who were hospitalized. Because the price is affordable compared to other antipsychotics, risperidone, haloperidol, and chlorpromazine are antipsychotics that can easily be found in most hospitals. Haloperidol is the most widely used in Indonesia but until now that is often used as an adjuvant is low-dose chlorpromazine. This made the researchers interested to see if risperidone added with a small dose of haloperidol were also effective to clinical symptom improvement in patients receiving risperidone, specifically to overcome the symptoms of agitation and general symptoms of schizophrenia. Based on this background, the researchers were interested in conducting a study that aimed to determine differences of the combination of risperidone and haloperidol therapy with the combination of risperidone and chlorpromazine therapy to improve clinical symptoms of schizophrenia subjects.

II. MATERIALS AND METHODS This study was an observational analytic study with a prospective cohort design. This study was conducted at the Special Hospital of South Sulawesi Province, Indonesia, in the period from May to September 2018. The study included 30 subjects diagnosed with schizophrenia based on the Diagnostic and Statistical Manual of , Fifth Edition (DSM-5) and in acute exacerbation phase.

Inclusion Criteria All subjects enrolled if their ages are between 18 and 50 years. Subjects family were adequately informed of all aspects regarding the participation and the purpose of the study and provide written informed consent. We excluded the subjects if they have severe neurological disorders, severe systemic diseases or psychiatric diagnosis due to other general medical condition or substance abuse. The subjects were further divided into two groups, namely the group received a combination of risperidone and haloperidol therapy (treatment group I), and the group received a combination of risperidone and chlorpromazine therapy (treatment group II). Each sample from both groups was assessed by Positive and Negative Syndrome Scale PANSS and Positive and Negative Syndrome Scale – Excited Component (PANSS-EC) scores before starting the treatment. PANSS-EC score was assessed in both groups on the 1st day, on the 2nd day and on the 3rd day. PANSS scores were assessed in both groups on the 1st week, on the 2nd week, and on the 4th week and on the 6th week. Data were processed and analyzed by the statistical program.

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ISSN- 2394-5125 VOL 7, ISSUE 13, 2020

III. RESULTS During the study period, 30 subjects joined the study and were divided into 2 groups, namely the group receiving a combination of risperidone and haloperidol therapy with the group receiving a combination of risperidone and chlorpromazine therapy. PANSS-EC scores in both groups showed a significant decrease on the 1st day, on the 2nd day and on the 3rd day (p <0.05) (Table 1).

Table 1: Positive and Negative Syndrome Scale – Excited Component (PANSS-EC) Scores Decrease in Both Group Length of PANSS-EC Decrease Group P* treatment Mean (SD) Mean difference % Mean difference 18,00(15/27) The 1st day 3,00 16,67 % 0.001 15,00(13/21) Risperidone + 18,00(15/27) The 2nd day 6,00 33,33% 0.001 Haloperidol 12,00(10/19) 18,00(15/27) The 3rd day 8,00 44,44% 0.001 10.00(9/15) 23,00(15/33) The 1st day 5,00 21,74% 0.001 18,00(13/22) Risperidone + 23,00(15/33) The 2nd day 9,00 39,13% 0.001 Chlorpromazine 14,00(10/16) 23,00(15/33) The 3rd day 13,00 56,52% 0.001 10.00(9/13) *Wilcoxon test; p = significance.

Mann Whitney Test analysis results showed a significant difference in the changes of PANSS-EC score 108 between the group receiving a combination of risperidone and haloperidol therapy and the group receiving a 109 combination of risperidone and chlorpromazine therapy with p <0.05. Changes of the Total Positive and Negative Syndrome Scale (Total PANSS) scores in both groups showed a significant decrease in the 1st week, on the 2nd week, on the 4th week, and on the 6th week (p <0.05) ( Table 2).

Table 2: Total PANSS Scores Decrease in Both Group Length of Total PANSS Decrease Group P* treatment Mean (SD) Mean difference % Mean difference 104.47(20.91) The 1st Week 13.60(14.2) 12.5(11.5) % 0.022 90.87(19.28) 104.47(20.91) The 2nd Week 26.13(14.50) 24.3(11.9)% <0.001 Risperidone + 78.33(16.66) Haloperidol 104.47(20.91) The 4th Week 44.67(17.00) 41.9(11.2)% <0.001 59.80(13.66) 104.47(20.91) The 6th Week 55.87(19.57) 52.4(11.3)% <0.001 48.60(11.90) 116.27(24.67) The 1st Week 15.40(22.00) 11.3(15.4)% 0.017 100.87(16.69) 116.27(24.67) The 2nd Week 22.87(23.34) 17.8(15.3)% 0.002 Risperidone + 93.40(17.34) Chlorpromazine 116.27(24.67) The 4th Week 49.27(22.94) 40.5(10.9)% <0.001 67.00(8.03) 116.27(24.67) The 6th Week 60.20(22.29) 50.6(10.2)% <0.001 58.07(11.08) *Paired t test; p= significance

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Independent t-test analysis results did not show a significant difference in the changes of the Total PANSS scale between the group receiving a combination of risperidone and haloperidol therapy with the group receiving a 124 combination of risperidone and chlorpromazine therapy with p > 0.05. IV. DISCUSSION Statistical analysis showed that both groups had a significant decrease in PANSS-EC scores (p <0.05) on the 1st day, on the 2nd day and on the 3rd day after treatment. In another study of schizophrenia subjects who used risperidone with a 6 weeks treatment duration, there were a significant decrease in PANSS-EC by 8 points (p < 0.001). [14] Comparison of changes in PANSS-EC scores showed that the group receiving combination of risperidone and chlorpromazine therapy was greater than the groups receiving combination of risperidone and haloperidol with of p<0.05. Another study which observed the effectiveness of haloperidol, risperidone and olanzapine showed that on the 1t day and on the 2nd day olanzapine were superior to risperidone and Haloperidol, but on the 3rd day and on the 5th day haloperidol is superior than the others. Although it wasn’t clear yet, reduction of agitation on the 1st day by olanzapine might be associated its effect. [15] Sedation effect of chlorpromazine might also help diminished agitation of schizophrenia subjects, especially in the initial stages of treatment. Assessment of total PANSS scores in both groups, showed significant changes in PANSS scores at each measurement, i.e. on the 1st week, on the 2nd week, on the 4thweek and on the 6th week of study (p <0.05). Atypical antipsychotic, risperidone, worked as a D2 antagonist and also works on other neurotransmitter in the brain. While conventional antipsychotic drugs such as haloperidol and chlorpromazine have a high affinity for dopamine D2 receptors in the basal ganglia and limbic areas. The mechanism of action, especially to dopamine in mesolimbic and mesocortical are considered the most influential in the improvement of clinical symptoms of schizophrenia. [16] For long treatment, there were a trend toward a greater change in the total PANSS score in the group that received combination of risperidone and haloperidol therapy compared to the group that received combination of risperidone and chlorpromazine therapy although there were no significant differences (p>0.05). In a study comparing 15 antipsychotics in schizophrenia, haloperidol were 13- 16% more effective than ziprasidone, chlorpromazine, and , and as effective as quetiapin and aripiprazol, and 10% less effective than palliperidone. [17] Haloperidol and chlorpromazine are conventional antipsychotic drugs which have a high affinity for dopamine receptors D2 in basal ganglia and limbic areas. Larger doses are needed if the affinity of the drug for D2 receptors is relatively weak. Compared to other typical antipsychotics, chlorpromazine has a lower D2 receptor affinity. This explains why the addition of haloperidol to risperidone improve the effectiveness to overcome clinical symptoms of schizophrenia better than chlorpromazine. [18]

V. CONCLUSIONS AND RECOMMENDATIONS In a conclusion, improvement of the agitation symptoms of schizophrenia subjects in acute exacerbations were significantly better in the group receiving combination of risperidone and chlorpromazine therapy than the group receiving combination of risperidone and haloperidol therapy. No significant changes of clinical symptoms between risperidone added with small dose haloperidol antipsychotic or small dose chlorpromazine. The addition of small doses of antipsychotics was quite effective in the first days of treatment of acute exacerbation of schizophrenia subjects, but not for long term treatment.

VI. FUNDING There is no source of funding for the research.

Ethics Approval and Consent to Participate The study was approved from the Institutional Ethics Committee of Faculty of Medicine, Hasanuddin University (430/H4.8.4.5.31/PP36-KOMETIK/-2018). A written consent was taken from all of the participants after explaining the details, benefits, and risks to them.

Consent for Publication

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This has been obtained from the participants involved in the study to report their individual patient data.

Competing Interests The authors declare that they have no competing interests. VII. REFERENCES [1] Laursen TM. Life expectancy among persons with schizophrenia or bipolar affective disorder. Schizophrenia research. 2011 Sep 1; 131(1-3): 101-4. [2] Indonesian Health Service. Basic Health Research; 2013. [3] Murray RM, Kendler KS, McGuffin P, Wessely S, Castle DJ, editors. Essential psychiatry. Cambridge University Press; 2008 Sep 18. [4] Battaglia J. Pharmacological management of acute agitation. Drugs. 2005 Jun 1; 65(9): 1207-22. [5] Buckley PF, Correll CU. Strategies for dosing and switching antipsychotics for optimal clinical management. The Journal of clinical psychiatry. 2008; 69: 4-17. [6] Kane JM, Sharif ZA. Atypical antipsychotics: sedation versus efficacy. The Journal of clinical psychiatry. 2008; 69: 18-31. [7] Villari V, Rocca P, Fonzo V, Montemagni C, Pandullo P, Bogetto F. Oral risperidone, olanzapine and versus haloperidol in psychotic agitation. Progress in Neuro-Psychopharmacology and . 2008 Feb 15; 32(2): 405-13. [8] Currier GW, Trenton A. Pharmacological treatment of psychotic agitation. CNS drugs. 2002 Apr 1; 16(4): 219-28. [9] Sadock BJ, Sadock VA. Kaplan and Sadock's synopsis of psychiatry: Behavioral sciences/clinical psychiatry. Lippincott Williams & Wilkins; 2011 Dec 26. [10] Keefe RS. Cognitive deficits in patients with schizophrenia: effects and treatment. The Journal of clinical psychiatry. 2007; 68: 8-13. [11] Wiguna T, Ismail RI, Noorhana SR, Kaligis F, Aji AN, Belfer ML. Family responses to a child with schizophrenia: An Indonesian experience. Asian journal of psychiatry. 2015 Dec 1; 18: 66-9. [12] Jarut YM, Fatimawali F, Wiyono WI. Tinjauan penggunaan antipsikotik pada pengobatan skizofrenia di rumah sakit prof. dr. vl ratumbuysang manado periode januari 2013-maret 2013. Pharmacon. 2013 Aug 1; 2(3). [13] Gallego JA, Bonetti J, Zhang J, Kane JM, Correll CU. Prevalence and correlates of antipsychotic polypharmacy: a and meta-regression of global and regional trends from the 1970s to 2009. Schizophrenia research. 2012 Jun 1; 138(1): 18-28. [14] Chan HY, Lin AS, Chen KP, Cheng JS, Chen YY, Tsai CJ. An open-label, randomized, controlled trial of and risperidone for acutely ill, hospitalized, schizophrenic patients with symptoms of agitation. Journal of clinical psychopharmacology. 2013 Dec 1; 33(6): 747-52. [15] Walther S, Moggi F, Horn H, Moskvitin K, Abderhalden C, Maier N, Strik W, Müller TJ. Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater- blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine. Journal of clinical psychopharmacology. 2014 Feb 1; 34(1): 124-8. [16] Gardner DM, Baldessarini RJ, Waraich P. Modern antipsychotic drugs: a critical overview. Cmaj. 2005 Jun 21; 172(13):1703-11. [17] Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet. 2013 Sep 14; 382(9896): 951-62. [18] Hancock S, McKim W. Drugs and Behavior: An Introduction to Behavioral . Pearson; 2017 Mar 3.

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