Clinical outcomes of patients with bipolar disorder in the manic phase on valproate and olanzapine versus valproate and risperidone

Clinical outcomes of patients with bipolar disorder in the manic phase on valproate and olanzapine versus valproate and risperidone | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical outcomes of patients with bipolar disorder in the manic phase on valproate and olanzapine versus valproate and risperidone Anusree P, Dr Bindu Menon, Remya Reghu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3757932/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Purpose Previous studies have shown that combining mood stabilizers and atypical antipsychotics is more effective than either treatment alone in bipolar disorder. The comparison of the two combinations is limited. We aim to compare the efficacy and adverse drug reactions of valproate plus olanzapine or risperidone combination treatment in the bipolar disorder, manic phase. Method In this 4-week study, 60 patients with DSM-V bipolar disorder in the psychotic manic phase were included and divided into either valproate plus olanzapine (n = 30) or risperidone (n = 30). The primary outcome was measured by the difference in mean total scores on the Young Mania Rating Scale (YMRS) and the Positive and Negative Syndrome Scale (PANSS). The secondary outcome for adverse effects was measured using the Naranjo ADR Probability Scale. The mean values obtained at weeks 0, 2, and 4 were compared. Results In our study, the mean difference in YMRS scores from baseline to week 4 in the olanzapine and risperidone groups was 13.9331.202 and 10.7671.164, respectively. These scores manifest significant changes within and between groups (p = < 0.001). A greater reduction was observed in the olanzapine group. There was no trend in the reduction of PANSS mean values between the groups, but a significant difference within the groups. However, a reduction was noted in the risperidone group. Adverse effects were observed more frequently during co-therapy with risperidone. Although, weight gain was notable in the olanzapine group. Conclusion All the results of our study showed that olanzapine in combination with valproate has slightly higher efficacy than risperidone. bipolar disorder mood stabilizer atypical antipsychotics co-therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. INTRODUCTION Bipolar disorder is a mental disorder characterized by two phases, depression, and mania, which last from days to weeks. Despite many studies conducted, the real cause of bipolar disorder is still unclear. Studies show dopamine and serotonin play a role in their pathophysiology. It has been believed that genetics and environmental variables contribute to the incidence of bipolar disorder. Patients are likely to face higher rates of recurrence, psychosocial handicaps, and increased use of health services if the illness is not appropriately treated (Simon, 2003 ). Untreated bipolar disorder has negative effects on the patient (Goetzel, & Wang, S. 2003). One of the most frequent reasons for the recurrence of mood episodes is high non-adherence rates (Colom & Scott, J. 2005). Lack of understanding, negative attitudes toward medication, and co-occurring personality disorders are among the causes of non-adherence (Colom & Gasto, C. 2000). Mood stabilizers and first-generation and second-generation antipsychotics have long been the primary mode of treatment of bipolar mania with and without psychotic features. An investigation has revealed that some guidelines for the management of bipolar disorder suggest monotherapy with mood stabilizers or second-generation antipsychotic drugs as frontline therapy, whereas others recommend a combination of both agents. Mood stabilizers widely used in bipolar disorder are lithium carbonate, and valproic acid/valproate. Olanzapine and risperidone are widely suggested atypical antipsychotic medications for individuals with bipolar disorder who experience acute manic episodes. A great deal of studies has been reported combination therapy of mood stabilizers and antipsychotics is more efficacious than monotherapy of either mood stabilizers or antipsychotics in bipolar disorder. The studies to compare two combination treatments are limited. This investigation seeks to assess and compare the effectiveness of the combination of valproate with olanzapine or risperidone in bipolar disorder in mania episodes. 2. METHODS We conducted a prospective observational study on 60 patients with DSM-V Bipolar disorder in manic episodes treated with a combination of valproate with olanzapine or risperidone over 8 months in a tertiary care hospital. All procedures were approved by the institutional research ethics committee, and performed in accordance with the recommendations of the Declaration of Helsinki on biomedical research involving human subjects. The total subjects were divided into two groups. Group A (n = 30) patients were treated with valproate-olanzapine, whereas Group B (n = 30) was with valproate-risperidone combinations. Written informed consent was obtained from all subjects. This study hypothesized that the clinical outcomes of valproate plus olanzapine therapy are non-inferior to valproate plus risperidone therapy in patients with bipolar mania. Inclusion criteria : Patients who meet DSM V criteria for bipolar disorder. Patients with age ≥ 18 years Patients with bipolar disorder who take valproate-olanzapine and valproate-risperidone treatments. Exclusion criteria : Pregnant and lactating women. Patients who have experienced seizures (including seizure disorder), stroke, severe head injury, or any other condition that increases their risk of seizures. Patients without psychotic symptoms. Demographic details, medication history, symptoms, and comorbidities were collected during admission or outpatient consult. All subjects were evaluated at weeks 0, 2, and 4. The effectiveness of two different treatment groups was measured with rating scales such as YMRS and PANSS during their follow-up. YMRS is used to assess the presence and severity of mania symptoms, and PANSS determines the severity of psychotic features in mania patients. The causality of ADRs in both groups was assessed by Naranjo ADR Probability Scale. But the study did not include the doses of either of any drugs. In the end, the chi-square test and student’s t-test were used to analyse the data; a P-value of 0.05 or lower was considered statistically significant. The conclusion was based on the limited sample size and study duration. 3. RESULTS 3.1 AGE AND GENDER Table 1 mean and standard deviation of age and gender distribution in group A and group B Characteristics Valproate-olanzapine Valproate-risperidone Age (Mean ± SD) 43.23 ± 16.91 44.50 ± 15.2 Female & male 60% & 40% 53.3% & 46.7% Note: The was no significant difference between the two groups in baseline characteristics (Table 1 ). The age distribution of both groups shows a maximum number of patients belonging to the age group 20–29 years, and female was the most prominent gender in both groups than male gender. 3.2 BIPOLAR MANIA SYMPTOMS Note In the current study, the major symptoms observed in patients in both group A and group B (Fig. 1 ) were irritability (86.7% & 80%), sleep disturbance (76.7% & 80%), and anxiety (80% & 76.7%). Irritability was observed as more significant than other symptoms. 3.3 MEDICAL COMORBIDITIES ASSOCIATED WITH BIPOLAR DISORDER Note In this study, patients in group A and group B had systemic hypertension (20% & 17%), type 2 diabetes mellitus (10% & 20%), and hypothyroidism (13% & 23%) as the highest common medical comorbidities associated with bipolar mania (Fig. 2 ). 3.4 MEAN YMRS SCORES Table 2 mean YMRS scores of patients in group A and group B No. Of weeks MEAN ± SD p-value Valproate-olanzapine Valproate-risperidone Week 0 17.13 ± 7.015 16.67 ± 7.406 .803 Week 2 9.13 ± 6.061 10.43 ± 5.811 .400 Note There was a trend in value reduction between week 0 and week 4 in both groups (p-value < 0.001), and reduction was shown higher in group A (Fig. 3 ). P < 0.05 indicated significance between the groups at the end of the study. 3.5 MEAN PANSS SCORE Table 3 mean PANSS score of patients in group A and group B No. Of weeks Vaproate-olanzapine Valproate-risperidone the p-value in between group mean ± SD p-value within group mean ± SD p-value within group Week 0 59.63 ± 14.109 - 55.50 ± 14.476 - .267 Week 2 47.60 ± 10.153 < 0.001 44.80 ± 11.544 < 0.001 .323 Week 4 38.87 ± 5.380 < 0.001 37.97 ± 9.550 < 0.001 .655 Note In Fig. 4 , statistically there was no trend in the value of reduction between the groups, but there was significance within the group (p value < 0.001). 3.6 BODY MASS INDEX (BMI) Table 4 mean BMI of patients in group A and group B No. Of weeks Valproate-olanzapine Valproate-risperidone P-value between group mean ± SD p-value within group mean ± SD p-value within group Week 0 25.34 ± 4.36 - 25.04 ± 4.058 - 0.785 Week 2 26.75 ± 4.48 < 0.001 25.88 ± 4.089 < 0.001 0.422 Week 4 28.136 ± 4.584 < 0.001 26.59 ± 4338 < 0.001 0.185 Note The p-value < 0.001 of BMI of study patients from week 0 to week 4 in group A and group B was found to be significant within the group. Group A showed more rise than group B (Fig. 5 ). 3.7 COMMON ADVERSE EFFECTS Table 5 common adverse effects observed in patients of group A and group B Adverse Effects Valproate-olanzapine (%) Valproate-risperidone (%) Weight gain 40 16.7 Daytime sleep 6.7 13.3 fatigue 10 13.3 constipation 6.7 10 Note: Weight gain, daytime sleep, fatigue, and constipation were the most common ADRs found in both groups A and B 4. DISCUSSION All subjects in this observational study have completed the course. The combination treatment of olanzapine and risperidone with valproate is well tolerated for up to 4 weeks. In addition to being D2 receptor antagonists, second-generation antipsychotics like olanzapine, quetiapine, and risperidone have an affinity for serotonin 5-hydroxytryptamine receptors and adrenergic receptors. Several studies show olanzapine combination therapy with valproate is more efficacious than olanzapine or valproate monotherapy (Xu, L., & Lin, Z. 2015). Likewise, risperidone combination therapy is more effective than risperidone monotherapy in reducing the severity of manic symptoms. According to Ghaemi et al.'s 1999 study risperidone has bidirectional mood-stabilizing properties (Ghaemi,1997), (Ghaemi, & S. N.,1999). In six investigations involving individuals with schizoaffective or bipolar disorder, both with and without psychosis, the mean response rate was reported to be 51% (Ghaemi, & S. N.,1997), (Jacobsen, F. M. (1995), (Tohen, M.,1996), (Ghaemi, S. N., & Sachs, G. S. (1997), (Dwight 1994), (Sajatovic, M.,1996). There were no reports of mania being induced in any of the four studies where risperidone was used in conjunction with mood stabilizers. Risperidone (1–6 mg/day) and placebo were compared as add-on-therapy to lithium or divalproex in a randomized, 3-week, double-blind, multicentre trial by Sachs et al. for the acute treatment of bipolar mania (Sachs, G. 1999 ). Patients who received risperidone in addition to a mood stabiliser experienced a statistically significant improvement in their YMRS scores (p = .009) compared to those who received a placebo and a mood stabiliser. Tohen et al. studied patients with bipolar disorder who had completed acute therapy with olanzapine integrated with lithium or valproate and discovered that during an 18-month trial, In contrast to 36.7% of patients taking olanzapine, 55.3% of patients receiving a placebo relapsed into either mania or bipolar depression (p = .149). Patients receiving a placebo had a considerably shorter time until a bipolar recurrence than those receiving olanzapine (Tohen, M. F., & Bowden, C. L. (2002). Findings from other studies suggest that in bipolar mania patients with inadequate responsiveness to monotherapy with mood stabilizers, their combination with olanzapine provides more efficacy (Tohen, M &. Chengappa, K. R., 2002). In this present study, the rapid onset of action in both groups is shown by the mean YMRS score at baseline and week 2. The YMRS score significantly decreased from week 2 to baseline, and this pattern was observed throughout the entire study in group A and group B (P < 0.001), and group A appears to have more reduction than group B (Fig. 3 ). The fact that group A showed more reduction than group B, indicated that valproate-olanzapine treatment was better for reducing mania. Studies show that olanzapine can produce efficacy in managing bipolar manic episodes as quickly as 1 week after the start of treatment (Vieta, E., 2008). In another study, YMRS scores in the risperidone group improved rapidly with greater reductions at week 1 (Yatham, L. N., 2003). The present study also found that olanzapine and risperidone combination therapies showed similar efficacy by YMRS score within 2 weeks of treatment but were more effective in olanzapine treatment. Except Sachs et al. study's visit-wise analysis and many other studies concluded that olanzapine and risperidone are equally efficacious and safe in the treatment of the manic phase of bipolar disorder. Results from studies conducted by Elionor Nehme et al. demonstrate that a significant number of patients with bipolar disorder experience at least one psychotic symptom during a manic episode (Nehme, E.,2018). Comparable to our study, Canuso et al. found that bipolar disorder with psychosis resulted in higher scores on the six PANSS scale items of grandiosity, delusions, lack of judgment/insight, excitement, persecution, and hostility (Canuso.,2008). On the PANSS positive scale, the mean scores exhibit a trend of value reduction from the baseline to the end of the study, and this trend is significant within the groups (P < 0.001). The PANSS negative scores show a decrease in value from week 0 to week 2 whereas a pattern of rise from week 2 to week 4 due to the psychotic symptoms masked was exhibited after week 2. There was significance within groups (P < 0.001) and a continuous decline in the PANSS total scores from baseline to week 4. The reduction was greater in group B indicating better effectiveness in reducing psychotic features in valproate-risperidone treatment than in the valproate-olanzapine group. Common treatment-emergent adverse events during this study were increased weight, daytime sleep, fatigue, and constipation. The olanzapine group experienced a significantly larger mean weight change. Antipsychotics primarily increase appetite, which is how it makes people gain weight. The complex process of controlling appetite and food intake is carried out by the region of the brain called the hypothalamus. Several researches had been established that neurotransmitter receptors in the brain appear to be influenced by the serotonin 5-HT2C and 5-HT1A receptors, histamine H1 receptor, and dopamine D2 receptor, among others (Fleischhacker, 2010). The ability of different antipsychotics to inhibit these receptors varies, which helps to explain how differently they may cause weight gain (Henderson, 2015), (Mitchell, J. E. (2011). The histamine H1 and serotonin 5-HT2C receptors are highly bound by the weight-gain-risky medications olanzapine and clozapine. Our study found that both the valproate-olanzapine group and valproate-risperidone group combination therapies are effective in patients with bipolar mania. YMRS scores showed the olanzapine-valproate group was more effective than the risperidone-valproate group in managing mania. Whereas the PANSS score manifested that risperidone-valproate is more effective in reducing psychotic symptoms. In terms of the incidence of ADRs, olanzapine has fewer ADRs than risperidone. The limitations of our study include the exclusion of the strength of the drugs and less sample population with only psychotic symptoms. The generalizability of this study is limited to 4 weeks. Future areas of research can be studied in multicenter with many populations incorporating drug dosage and patients with non-psychotic features. 5. CONCLUSION Considering all factors used in the study, we found that the valproate-olanzapine combination treatment is more effective than the valproate-risperidone combination treatment. Declarations Funding: Not applicable Conflicts of interest: The authors declare that they have no conflict of interest . Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethics Committee of Amrita Institute of Medical Sciences held on 22/10/2022 (IEC-AIMS-2022-PHARM-297). Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent for publication: Not applicable Author’s contribution: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Anusree P, Remya Reghu and Dr Bindu Menon. The first draft of the manuscript was written by Anusree P and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References Simon GE (2003) Social and economic burden of mood disorders. Biol Psychiatry 54(3):208–215 Goetzel RZ, Hawkins K, Ozminkowski RJ, Wang S (2003) The health and productivity cost burden of the top 10 physical and mental health conditions affected six large US employers in 1999. J Occup Environ Med, 5–14 Colom F, Vieta E, Tacchi MJ, Sánchez-Moreno J, Scott J (2005) Identifying and improving non‐adherence in bipolar disorders. Bipolar Disord 7:24–31 Colom F, Vieta E, Martinez-Aran A, Reinares M, Benabarre A, Gasto C (2000) Clinical factors associated with treatment noncompliance in euthymic bipolar patients. J Clin Psychiatry 61(8):549–555 Xu L, Lu Y, Yang Y, Zheng Y, Chen F, Lin Z (2015) Olanzapine–valproate combination versus olanzapine or valproate monotherapy in the treatment of bipolar i mania: a randomized controlled study in a Chinese population group. Neuropsychiatr Dis Treat, 1265–1271 Ghaemi SN, Sachs GS, Baldassano CF, Truman CJ (1997) Acute treatment of bipolar disorder with adjunctive risperidone in outpatients. Can J Psychiatry 42(2):196–199 Ghaemi SN, Goodwin FK (1999) Use of atypical antipsychotic agents in bipolar and schizoaffective disorders: review of the empirical literature. J Clin Psychopharmacol 19(4):354–361 Jacobsen FM (1995) Risperidone in the treatment of affective illness and obsessive-compulsive disorder. J Clin Psychiatry 56(9):423–429 Tohen M, Zarate CA Jr, Centorrino F, Hegarty JI, Froeschl M, Zarate SB (1996) Risperidone in the treatment of mania. J Clin Psychiatry 57(6):249–253 Ghaemi SN, Sachs GS (1997) Long-term risperidone treatment in bipolar disorder: 6-month follow up. Int Clin Psychopharmacol 12(6):333–338 Dwight M, Keck P, Stanton S, Strakowski S, McElroy S (1994) Antidepressant activity and mania associated with risperidone treatment of schizoaffective disorder. The Lancet 344(8921):554–555 Sajatovic M, DiGiovanni SK, Bastani B, Hattab H, Ramirez LF (1996) Risperidone therapy in treatment refractory acute bipolar and schizoaffective mania. Psychopharmacol Bull 32(1):55–61 Sachs G (1999), December Safety and efficacy of risperidone vs placebo as add-on therapy to mood stabilizers in the treatment of manic phase of bipolar disorder. In 38th annual meeting of the American College of Neuropsychopharmacology, Acapulco, Mexico Tohen MF, Chengappa KNR, Suppes P, Baker RW, Zarate CA Jr, Bowden CL (2002), May Olanzapine combined with lithium or valproate for relapse prevention of bipolar disorder: an 18-month study. In 155th annual meeting of the American Psychiatric Association Tohen M, Chengappa KR, Suppes T, Zarate CA, Calabrese JR, Bowden CL, Breier A (2002) Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 59(1):62–69 Vieta E, Panicali F, Goetz I, Reed C, Comes M, Tohen M (2008) Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study. J Affect Disord 106(1–2):63–72 Yatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A (2003) Mood stabilisers plus risperidone or placebo in the treatment of acute mania: international, double-blind, randomised controlled trial. Br J Psychiatry 182(2):141–147 Nehme E, Obeid S, Hallit S, Haddad C, Salame W, Tahan F (2018) Impact of psychosis in bipolar disorder during manic episodes. Int J Neurosci 128(12):1128–1134 Canuso CM, Bossie CA, Zhu Y, Youssef E, Dunner DL (2008) Psychotic symptoms in patients with bipolar mania. J Affect Disord 111(2–3):164–169 Fleischhacker WW, Heikkinen ME, Olié JP, Landsberg W, Dewaele P, McQuade RD, Kerselaers W (2010) Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 13(8):1115–1125 Henderson DC, Vincenzi B, Andrea NV, Ulloa M, Copeland PM (2015) Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. The Lancet Psychiatry 2(5):452–464 Roerig JL, Steffen KJ, Mitchell JE (2011) Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs 25:1035–1059 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 30 Jan, 2024 Reviewers agreed at journal 30 Jan, 2024 Reviewers invited by journal 30 Jan, 2024 Submission checks completed at journal 08 Jan, 2024 Editor assigned by journal 08 Jan, 2024 First submitted to journal 15 Dec, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3757932","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":265883150,"identity":"649a09db-b6f5-431f-9ea6-af176be8b741","order_by":0,"name":"Anusree P","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYLCCBIYDUFYFEDMzN5Ci5QxICyMRWhhgWhjbwCR+Lfyze8wkHvy5k2dw/uzDBx/n1UbztwO1/KjYhlOLxJ0zZhKJbc+KDW6kGxvO3HY8d8ZhxgbGnjO3cVtzI8fYILHhcOKGG2xs0rzbjuU2ALUwM7bh1iIP0pLwB6jl/DH233/nHMudT0iLwY0cwwcJbEAtB9LYgGFVk7uBkBbDG2mFDxLbDifOvJHGLNlz7EDuRqCWg/j8IncjecPBH0CH9Z0/xvjhR01d7rzzhw8++FGBx/to4DCYPEC0eiCoI0XxKBgFo2AUjBAAAMTsZUqBxSfvAAAAAElFTkSuQmCC","orcid":"","institution":"Amrita Vishwa Vidyapeetham University","correspondingAuthor":true,"prefix":"","firstName":"Anusree","middleName":"","lastName":"P","suffix":""},{"id":265883151,"identity":"1cc8d2f8-32fe-4fdf-88a8-d8601261a9d1","order_by":1,"name":"Dr Bindu Menon","email":"","orcid":"","institution":"Amrita Institute of Medical Sciences and Research Centre","correspondingAuthor":false,"prefix":"Dr","firstName":"Bindu","middleName":"","lastName":"Menon","suffix":""},{"id":265883152,"identity":"b01da98c-7dbd-46e3-af63-1a7b1a34b970","order_by":2,"name":"Remya Reghu","email":"","orcid":"","institution":"Amrita Vishwa Vidyapeetham University","correspondingAuthor":false,"prefix":"","firstName":"Remya","middleName":"","lastName":"Reghu","suffix":""}],"badges":[],"createdAt":"2023-12-15 09:44:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3757932/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3757932/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49440272,"identity":"15e16181-6272-4a21-98c3-9fa86a33a173","added_by":"auto","created_at":"2024-01-10 21:53:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":12974,"visible":true,"origin":"","legend":"\u003cp\u003epercentage of bipolar mania symptoms observed in group A and group B\u003c/p\u003e\n\u003cp\u003eNote: In the current study, the major symptoms observed in patients in both group A and group B (Figure 1) were irritability (86.7% \u0026amp; 80%), sleep disturbance (76.7% \u0026amp; 80%), and anxiety (80% \u0026amp; 76.7%). Irritability was observed as more significant than other symptoms.\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-3757932/v1/242f89079f5df0a4579ea656.png"},{"id":49439346,"identity":"84032436-c382-4011-84c9-d7a0d1da2c23","added_by":"auto","created_at":"2024-01-10 21:45:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":14336,"visible":true,"origin":"","legend":"\u003cp\u003epercentage of medical comorbidities associated with bipolar disorder in group A and group B\u003c/p\u003e\n\u003cp\u003eNote: In this study, patients in group A and group B had systemic hypertension (20% \u0026amp; 17%), type 2 diabetes mellitus (10% \u0026amp; 20%), and hypothyroidism (13% \u0026amp; 23%) as the highest common medical comorbidities associated with bipolar mania (Figure 2).\u003c/p\u003e","description":"","filename":"F2.png","url":"https://assets-eu.researchsquare.com/files/rs-3757932/v1/592babea4242344e8a11ed14.png"},{"id":49440273,"identity":"d0c60482-628d-43ab-abb5-9640c09e6a62","added_by":"auto","created_at":"2024-01-10 21:53:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":12733,"visible":true,"origin":"","legend":"\u003cp\u003emean YMRS scores of patients in group A and group B\u003c/p\u003e\n\u003cp\u003eNote: There was a trend in value reduction between week 0 and week 4 in both groups (p-value \u0026lt;0.001), and reduction was shown higher in group A (Figure 3). \u0026nbsp;P\u0026lt;0.05 indicated significance between the groups at the end of the study.\u003c/p\u003e","description":"","filename":"F3.png","url":"https://assets-eu.researchsquare.com/files/rs-3757932/v1/217e3da0cabb5a981a92fa7e.png"},{"id":49439348,"identity":"033dcbbd-27d3-48a2-8c93-80071d3a5bbd","added_by":"auto","created_at":"2024-01-10 21:45:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":13178,"visible":true,"origin":"","legend":"\u003cp\u003emean PANSS score of patients in group A and group B\u003c/p\u003e\n\u003cp\u003eNote: In Figure 4, statistically there was no trend in the value of reduction between the groups, but there was significance within the group (p value\u0026lt;0.001).\u003c/p\u003e","description":"","filename":"F4.png","url":"https://assets-eu.researchsquare.com/files/rs-3757932/v1/f8fd36a1bdda19ff50688069.png"},{"id":49439344,"identity":"8464e9ee-ceb6-4613-b373-560221cef40e","added_by":"auto","created_at":"2024-01-10 21:45:23","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":13324,"visible":true,"origin":"","legend":"\u003cp\u003emean BMI of patients in group A and group B\u003c/p\u003e\n\u003cp\u003eNote: The p-value \u0026lt;0.001 of BMI of study patients from week 0 to week 4 in group A and group B was found to be significant within the group. Group A showed more rise than group B (Figure 5).\u003c/p\u003e","description":"","filename":"F5.png","url":"https://assets-eu.researchsquare.com/files/rs-3757932/v1/1e674f34cc7bd8af29340746.png"},{"id":49439347,"identity":"2c8dc8fe-0201-41ca-af0c-67b16c235a1b","added_by":"auto","created_at":"2024-01-10 21:45:23","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":6936,"visible":true,"origin":"","legend":"\u003cp\u003ecommon adverse effects observed in patients of group A and group B\u003c/p\u003e","description":"","filename":"F6.png","url":"https://assets-eu.researchsquare.com/files/rs-3757932/v1/216121d4cdd0bbe77a01870b.png"},{"id":49440895,"identity":"6bd1157f-291a-4b4f-bd39-12324116eaec","added_by":"auto","created_at":"2024-01-10 22:01:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":422293,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3757932/v1/537aadaa-8de9-475f-be83-676823c86f44.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical outcomes of patients with bipolar disorder in the manic phase on valproate and olanzapine versus valproate and risperidone","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eBipolar disorder is a mental disorder characterized by two phases, depression, and mania, which last from days to weeks. Despite many studies conducted, the real cause of bipolar disorder is still unclear. Studies show dopamine and serotonin play a role in their pathophysiology. It has been believed that genetics and environmental variables contribute to the incidence of bipolar disorder. Patients are likely to face higher rates of recurrence, psychosocial handicaps, and increased use of health services if the illness is not appropriately treated (Simon, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). Untreated bipolar disorder has negative effects on the patient (Goetzel, \u0026amp; Wang, S. 2003). One of the most frequent reasons for the recurrence of mood episodes is high non-adherence rates (Colom \u0026amp; Scott, J. 2005). Lack of understanding, negative attitudes toward medication, and co-occurring personality disorders are among the causes of non-adherence (Colom \u0026amp; Gasto, C. 2000).\u003c/p\u003e \u003cp\u003eMood stabilizers and first-generation and second-generation antipsychotics have long been the primary mode of treatment of bipolar mania with and without psychotic features. An investigation has revealed that some guidelines for the management of bipolar disorder suggest monotherapy with mood stabilizers or second-generation antipsychotic drugs as frontline therapy, whereas others recommend a combination of both agents. Mood stabilizers widely used in bipolar disorder are lithium carbonate, and valproic acid/valproate. Olanzapine and risperidone are widely suggested atypical antipsychotic medications for individuals with bipolar disorder who experience acute manic episodes. A great deal of studies has been reported combination therapy of mood stabilizers and antipsychotics is more efficacious than monotherapy of either mood stabilizers or antipsychotics in bipolar disorder. The studies to compare two combination treatments are limited. This investigation seeks to assess and compare the effectiveness of the combination of valproate with olanzapine or risperidone in bipolar disorder in mania episodes.\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cp\u003eWe conducted a prospective observational study on 60 patients with DSM-V Bipolar disorder in manic episodes treated with a combination of valproate with olanzapine or risperidone over 8 months in a tertiary care hospital. All procedures were approved by the institutional research ethics committee, and performed in accordance with the recommendations of the Declaration of Helsinki on biomedical research involving human subjects. The total subjects were divided into two groups. Group A (n\u0026thinsp;=\u0026thinsp;30) patients were treated with valproate-olanzapine, whereas Group B (n\u0026thinsp;=\u0026thinsp;30) was with valproate-risperidone combinations. Written informed consent was obtained from all subjects. This study hypothesized that the clinical outcomes of valproate plus olanzapine therapy are non-inferior to valproate plus risperidone therapy in patients with bipolar mania.\u003c/p\u003e \u003cp\u003e \u003cem\u003eInclusion criteria\u003c/em\u003e:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePatients who meet DSM V criteria for bipolar disorder.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatients with age\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatients with bipolar disorder who take valproate-olanzapine and valproate-risperidone treatments.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eExclusion criteria\u003c/em\u003e:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePregnant and lactating women.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatients who have experienced seizures (including seizure disorder), stroke, severe head injury, or any other condition that increases their risk of seizures.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatients without psychotic symptoms.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eDemographic details, medication history, symptoms, and comorbidities were collected during admission or outpatient consult. All subjects were evaluated at weeks 0, 2, and 4. The effectiveness of two different treatment groups was measured with rating scales such as YMRS and PANSS during their follow-up. YMRS is used to assess the presence and severity of mania symptoms, and PANSS determines the severity of psychotic features in mania patients. The causality of ADRs in both groups was assessed by Naranjo ADR Probability Scale. But the study did not include the doses of either of any drugs. In the end, the chi-square test and student\u0026rsquo;s t-test were used to analyse the data; a P-value of 0.05 or lower was considered statistically significant. The conclusion was based on the limited sample size and study duration.\u003c/p\u003e"},{"header":"3. RESULTS","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 AGE AND GENDER\u003c/h2\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003emean and standard deviation of age and gender distribution in group A and group B\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValproate-olanzapine\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValproate-risperidone\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43.23\u0026thinsp;\u0026plusmn;\u0026thinsp;16.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44.50\u0026thinsp;\u0026plusmn;\u0026thinsp;15.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale \u0026amp; male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60% \u0026amp; 40%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53.3% \u0026amp; 46.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eNote: The was no significant difference between the two groups in baseline characteristics (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The age distribution of both groups shows a maximum number of patients belonging to the age group 20\u0026ndash;29 years, and female was the most prominent gender in both groups than male gender.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 BIPOLAR MANIA SYMPTOMS\u003c/h2\u003e\n \u003cp\u003e\u003cstrong\u003eNote\u0026nbsp;\u003c/strong\u003eIn the current study, the major symptoms observed in patients in both group A and group B (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) were irritability (86.7% \u0026amp; 80%), sleep disturbance (76.7% \u0026amp; 80%), and anxiety (80% \u0026amp; 76.7%). Irritability was observed as more significant than other symptoms.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 MEDICAL COMORBIDITIES ASSOCIATED WITH BIPOLAR DISORDER\u003c/h2\u003e\n \u003cp\u003e\u003cstrong\u003eNote\u0026nbsp;\u003c/strong\u003eIn this study, patients in group A and group B had systemic hypertension (20% \u0026amp; 17%), type 2 diabetes mellitus (10% \u0026amp; 20%), and hypothyroidism (13% \u0026amp; 23%) as the highest common medical comorbidities associated with bipolar mania (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 MEAN YMRS SCORES\u003c/h2\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003emean YMRS scores of patients in group A and group B\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo. Of weeks\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMEAN\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValproate-olanzapine\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValproate-risperidone\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeek 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.13\u0026thinsp;\u0026plusmn;\u0026thinsp;7.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.67\u0026thinsp;\u0026plusmn;\u0026thinsp;7.406\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.803\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeek 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.13\u0026thinsp;\u0026plusmn;\u0026thinsp;6.061\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.43\u0026thinsp;\u0026plusmn;\u0026thinsp;5.811\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.400\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cstrong\u003eNote\u0026nbsp;\u003c/strong\u003eThere was a trend in value reduction between week 0 and week 4 in both groups (p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and reduction was shown higher in group A (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated significance between the groups at the end of the study.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5 MEAN PANSS SCORE\u003c/h2\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003emean PANSS score of patients in group A and group B\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo. Of weeks\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eVaproate-olanzapine\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eValproate-risperidone\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003ethe p-value in between group\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value within group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value within group\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeek 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59.63\u0026thinsp;\u0026plusmn;\u0026thinsp;14.109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e55.50\u0026thinsp;\u0026plusmn;\u0026thinsp;14.476\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.267\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeek 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47.60\u0026thinsp;\u0026plusmn;\u0026thinsp;10.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44.80\u0026thinsp;\u0026plusmn;\u0026thinsp;11.544\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.323\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeek 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38.87\u0026thinsp;\u0026plusmn;\u0026thinsp;5.380\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e37.97\u0026thinsp;\u0026plusmn;\u0026thinsp;9.550\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.655\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cstrong\u003eNote\u0026nbsp;\u003c/strong\u003eIn Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, statistically there was no trend in the value of reduction between the groups, but there was significance within the group (p value\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.6 BODY MASS INDEX (BMI)\u003c/h2\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003emean BMI of patients in group A and group B\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo. Of weeks\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eValproate-olanzapine\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eValproate-risperidone\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eP-value between group\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value within group\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003emean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value within group\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeek 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25.34\u0026thinsp;\u0026plusmn;\u0026thinsp;4.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25.04\u0026thinsp;\u0026plusmn;\u0026thinsp;4.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.785\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeek 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.75\u0026thinsp;\u0026plusmn;\u0026thinsp;4.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25.88\u0026thinsp;\u0026plusmn;\u0026thinsp;4.089\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.422\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeek 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28.136\u0026thinsp;\u0026plusmn;\u0026thinsp;4.584\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.59\u0026thinsp;\u0026plusmn;\u0026thinsp;4338\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.185\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cstrong\u003eNote\u0026nbsp;\u003c/strong\u003eThe p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001 of BMI of study patients from week 0 to week 4 in group A and group B was found to be significant within the group. Group A showed more rise than group B (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.7 COMMON ADVERSE EFFECTS\u003c/h2\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ecommon adverse effects observed in patients of group A and group B\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdverse Effects\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValproate-olanzapine (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValproate-risperidone (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight gain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDaytime sleep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003efatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003econstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eNote: Weight gain, daytime sleep, fatigue, and constipation were the most common ADRs found in both groups A and B\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eAll subjects in this observational study have completed the course. The combination treatment of olanzapine and risperidone with valproate is well tolerated for up to 4 weeks. In addition to being D2 receptor antagonists, second-generation antipsychotics like olanzapine, quetiapine, and risperidone have an affinity for serotonin 5-hydroxytryptamine receptors and adrenergic receptors. Several studies show olanzapine combination therapy with valproate is more efficacious than olanzapine or valproate monotherapy (Xu, L., \u0026amp; Lin, Z. 2015). Likewise, risperidone combination therapy is more effective than risperidone monotherapy in reducing the severity of manic symptoms.\u003c/p\u003e \u003cp\u003eAccording to Ghaemi et al.'s 1999 study risperidone has bidirectional mood-stabilizing properties (Ghaemi,1997), (Ghaemi, \u0026amp; S. N.,1999). In six investigations involving individuals with schizoaffective or bipolar disorder, both with and without psychosis, the mean response rate was reported to be 51% (Ghaemi, \u0026amp; S. N.,1997), (Jacobsen, F. M. (1995), (Tohen, M.,1996), (Ghaemi, S. N., \u0026amp; Sachs, G. S. (1997), (Dwight 1994), (Sajatovic, M.,1996). There were no reports of mania being induced in any of the four studies where risperidone was used in conjunction with mood stabilizers. Risperidone (1\u0026ndash;6 mg/day) and placebo were compared as add-on-therapy to lithium or divalproex in a randomized, 3-week, double-blind, multicentre trial by Sachs et al. for the acute treatment of bipolar mania (Sachs, G. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). Patients who received risperidone in addition to a mood stabiliser experienced a statistically significant improvement in their YMRS scores (p\u0026thinsp;=\u0026thinsp;.009) compared to those who received a placebo and a mood stabiliser. Tohen et al. studied patients with bipolar disorder who had completed acute therapy with olanzapine integrated with lithium or valproate and discovered that during an 18-month trial,\u003c/p\u003e \u003cp\u003eIn contrast to 36.7% of patients taking olanzapine, 55.3% of patients receiving a placebo relapsed into either mania or bipolar depression (p\u0026thinsp;=\u0026thinsp;.149). Patients receiving a placebo had a considerably shorter time until a bipolar recurrence than those receiving olanzapine (Tohen, M. F., \u0026amp; Bowden, C. L. (2002). Findings from other studies suggest that in bipolar mania patients with inadequate responsiveness to monotherapy with mood stabilizers, their combination with olanzapine provides more efficacy (Tohen, M \u0026amp;. Chengappa, K. R., 2002).\u003c/p\u003e \u003cp\u003eIn this present study, the rapid onset of action in both groups is shown by the mean YMRS score at baseline and week 2. The YMRS score significantly decreased from week 2 to baseline, and this pattern was observed throughout the entire study in group A and group B (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and group A appears to have more reduction than group B (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The fact that group A showed more reduction than group B, indicated that valproate-olanzapine treatment was better for reducing mania.\u003c/p\u003e \u003cp\u003eStudies show that olanzapine can produce efficacy in managing bipolar manic episodes as quickly as 1 week after the start of treatment (Vieta, E., 2008). In another study, YMRS scores in the risperidone group improved rapidly with greater reductions at week 1 (Yatham, L. N., 2003). The present study also found that olanzapine and risperidone combination therapies showed similar efficacy by YMRS score within 2 weeks of treatment but were more effective in olanzapine treatment. Except Sachs et al. study's visit-wise analysis and many other studies concluded that olanzapine and risperidone are equally efficacious and safe in the treatment of the manic phase of bipolar disorder.\u003c/p\u003e \u003cp\u003eResults from studies conducted by Elionor Nehme et al. demonstrate that a significant number of patients with bipolar disorder experience at least one psychotic symptom during a manic episode (Nehme, E.,2018). Comparable to our study, Canuso et al. found that bipolar disorder with psychosis resulted in higher scores on the six PANSS scale items of grandiosity, delusions, lack of judgment/insight, excitement, persecution, and hostility (Canuso.,2008).\u003c/p\u003e \u003cp\u003eOn the PANSS positive scale, the mean scores exhibit a trend of value reduction from the baseline to the end of the study, and this trend is significant within the groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The PANSS negative scores show a decrease in value from week 0 to week 2 whereas a pattern of rise from week 2 to week 4 due to the psychotic symptoms masked was exhibited after week 2. There was significance within groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and a continuous decline in the PANSS total scores from baseline to week 4. The reduction was greater in group B indicating better effectiveness in reducing psychotic features in valproate-risperidone treatment than in the valproate-olanzapine group.\u003c/p\u003e \u003cp\u003eCommon treatment-emergent adverse events during this study were increased weight, daytime sleep, fatigue, and constipation. The olanzapine group experienced a significantly larger mean weight change. Antipsychotics primarily increase appetite, which is how it makes people gain weight. The complex process of controlling appetite and food intake is carried out by the region of the brain called the hypothalamus. Several researches had been established that neurotransmitter receptors in the brain appear to be influenced by the serotonin 5-HT2C and 5-HT1A receptors, histamine H1 receptor, and dopamine D2 receptor, among others (Fleischhacker, 2010). The ability of different antipsychotics to inhibit these receptors varies, which helps to explain how differently they may cause weight gain (Henderson, 2015), (Mitchell, J. E. (2011). The histamine H1 and serotonin 5-HT2C receptors are highly bound by the weight-gain-risky medications olanzapine and clozapine.\u003c/p\u003e \u003cp\u003eOur study found that both the valproate-olanzapine group and valproate-risperidone group combination therapies are effective in patients with bipolar mania. YMRS scores showed the olanzapine-valproate group was more effective than the risperidone-valproate group in managing mania. Whereas the PANSS score manifested that risperidone-valproate is more effective in reducing psychotic symptoms. In terms of the incidence of ADRs, olanzapine has fewer ADRs than risperidone.\u003c/p\u003e \u003cp\u003eThe limitations of our study include the exclusion of the strength of the drugs and less sample population with only psychotic symptoms. The generalizability of this study is limited to 4 weeks. Future areas of research can be studied in multicenter with many populations incorporating drug dosage and patients with non-psychotic features.\u003c/p\u003e"},{"header":"5. CONCLUSION","content":"\u003cp\u003eConsidering all factors used in the study, we found that the valproate-olanzapine combination treatment is more effective than the valproate-risperidone combination treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethics Committee of Amrita Institute of Medical Sciences held on 22/10/2022 (IEC-AIMS-2022-PHARM-297).\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInformed consent was obtained from all individual participants included in the study.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNot applicable\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contribution:\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Anusree P, Remya Reghu and Dr Bindu Menon. The first draft of the manuscript was written by Anusree P and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSimon GE (2003) Social and economic burden of mood disorders. Biol Psychiatry 54(3):208\u0026ndash;215\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoetzel RZ, Hawkins K, Ozminkowski RJ, Wang S (2003) The health and productivity cost burden of the top 10 physical and mental health conditions affected six large US employers in 1999. J Occup Environ Med, 5\u0026ndash;14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColom F, Vieta E, Tacchi MJ, S\u0026aacute;nchez-Moreno J, Scott J (2005) Identifying and improving non‐adherence in bipolar disorders. Bipolar Disord 7:24\u0026ndash;31\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColom F, Vieta E, Martinez-Aran A, Reinares M, Benabarre A, Gasto C (2000) Clinical factors associated with treatment noncompliance in euthymic bipolar patients. J Clin Psychiatry 61(8):549\u0026ndash;555\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu L, Lu Y, Yang Y, Zheng Y, Chen F, Lin Z (2015) Olanzapine\u0026ndash;valproate combination versus olanzapine or valproate monotherapy in the treatment of bipolar i mania: a randomized controlled study in a Chinese population group. Neuropsychiatr Dis Treat, 1265\u0026ndash;1271\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhaemi SN, Sachs GS, Baldassano CF, Truman CJ (1997) Acute treatment of bipolar disorder with adjunctive risperidone in outpatients. Can J Psychiatry 42(2):196\u0026ndash;199\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhaemi SN, Goodwin FK (1999) Use of atypical antipsychotic agents in bipolar and schizoaffective disorders: review of the empirical literature. J Clin Psychopharmacol 19(4):354\u0026ndash;361\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJacobsen FM (1995) Risperidone in the treatment of affective illness and obsessive-compulsive disorder. J Clin Psychiatry 56(9):423\u0026ndash;429\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTohen M, Zarate CA Jr, Centorrino F, Hegarty JI, Froeschl M, Zarate SB (1996) Risperidone in the treatment of mania. J Clin Psychiatry 57(6):249\u0026ndash;253\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhaemi SN, Sachs GS (1997) Long-term risperidone treatment in bipolar disorder: 6-month follow up. Int Clin Psychopharmacol 12(6):333\u0026ndash;338\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDwight M, Keck P, Stanton S, Strakowski S, McElroy S (1994) Antidepressant activity and mania associated with risperidone treatment of schizoaffective disorder. The Lancet 344(8921):554\u0026ndash;555\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSajatovic M, DiGiovanni SK, Bastani B, Hattab H, Ramirez LF (1996) Risperidone therapy in treatment refractory acute bipolar and schizoaffective mania. Psychopharmacol Bull 32(1):55\u0026ndash;61\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSachs G (1999), December Safety and efficacy of risperidone vs placebo as add-on therapy to mood stabilizers in the treatment of manic phase of bipolar disorder. In \u003cem\u003e38th annual meeting of the American College of Neuropsychopharmacology, Acapulco, Mexico\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTohen MF, Chengappa KNR, Suppes P, Baker RW, Zarate CA Jr, Bowden CL (2002), May Olanzapine combined with lithium or valproate for relapse prevention of bipolar disorder: an 18-month study. In \u003cem\u003e155th annual meeting of the American Psychiatric Association\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTohen M, Chengappa KR, Suppes T, Zarate CA, Calabrese JR, Bowden CL, Breier A (2002) Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 59(1):62\u0026ndash;69\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVieta E, Panicali F, Goetz I, Reed C, Comes M, Tohen M (2008) Olanzapine monotherapy and olanzapine combination therapy in the treatment of mania: 12-week results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) observational study. J Affect Disord 106(1\u0026ndash;2):63\u0026ndash;72\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A (2003) Mood stabilisers plus risperidone or placebo in the treatment of acute mania: international, double-blind, randomised controlled trial. Br J Psychiatry 182(2):141\u0026ndash;147\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNehme E, Obeid S, Hallit S, Haddad C, Salame W, Tahan F (2018) Impact of psychosis in bipolar disorder during manic episodes. Int J Neurosci 128(12):1128\u0026ndash;1134\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCanuso CM, Bossie CA, Zhu Y, Youssef E, Dunner DL (2008) Psychotic symptoms in patients with bipolar mania. J Affect Disord 111(2\u0026ndash;3):164\u0026ndash;169\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleischhacker WW, Heikkinen ME, Oli\u0026eacute; JP, Landsberg W, Dewaele P, McQuade RD, Kerselaers W (2010) Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 13(8):1115\u0026ndash;1125\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHenderson DC, Vincenzi B, Andrea NV, Ulloa M, Copeland PM (2015) Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. The Lancet Psychiatry 2(5):452\u0026ndash;464\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoerig JL, Steffen KJ, Mitchell JE (2011) Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs 25:1035\u0026ndash;1059\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"naunyn-schmiedebergs-archives-of-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nsap","sideBox":"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)","snPcode":"210","submissionUrl":"https://submission.nature.com/new-submission/210/3","title":"Naunyn-Schmiedeberg's Archives of Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"bipolar disorder, mood stabilizer, atypical antipsychotics, co-therapy","lastPublishedDoi":"10.21203/rs.3.rs-3757932/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3757932/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003ePrevious studies have shown that combining mood stabilizers and atypical antipsychotics is more effective than either treatment alone in bipolar disorder. The comparison of the two combinations is limited. We aim to compare the efficacy and adverse drug reactions of valproate plus olanzapine or risperidone combination treatment in the bipolar disorder, manic phase.\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eIn this 4-week study, 60 patients with DSM-V bipolar disorder in the psychotic manic phase were included and divided into either valproate plus olanzapine (n\u0026thinsp;=\u0026thinsp;30) or risperidone (n\u0026thinsp;=\u0026thinsp;30). The primary outcome was measured by the difference in mean total scores on the Young Mania Rating Scale (YMRS) and the Positive and Negative Syndrome Scale (PANSS). The secondary outcome for adverse effects was measured using the Naranjo ADR Probability Scale. The mean values obtained at weeks 0, 2, and 4 were compared.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn our study, the mean difference in YMRS scores from baseline to week 4 in the olanzapine and risperidone groups was 13.9331.202 and 10.7671.164, respectively. These scores manifest significant changes within and between groups (p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A greater reduction was observed in the olanzapine group. There was no trend in the reduction of PANSS mean values between the groups, but a significant difference within the groups. However, a reduction was noted in the risperidone group. Adverse effects were observed more frequently during co-therapy with risperidone. Although, weight gain was notable in the olanzapine group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAll the results of our study showed that olanzapine in combination with valproate has slightly higher efficacy than risperidone.\u003c/p\u003e","manuscriptTitle":"Clinical outcomes of patients with bipolar disorder in the manic phase on valproate and olanzapine versus valproate and risperidone","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-10 21:45:18","doi":"10.21203/rs.3.rs-3757932/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2024-01-30T14:58:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"12d5f768-2962-41b4-af69-b73267469d18","date":"2024-01-30T14:53:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-30T14:51:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-08T10:06:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-08T10:06:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Naunyn-Schmiedeberg's Archives of Pharmacology","date":"2023-12-15T09:42:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"naunyn-schmiedebergs-archives-of-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nsap","sideBox":"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)","snPcode":"210","submissionUrl":"https://submission.nature.com/new-submission/210/3","title":"Naunyn-Schmiedeberg's Archives of Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7b761478-b47b-49f1-886f-1dc1b613d137","owner":[],"postedDate":"January 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-01-10T21:45:19+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-10 21:45:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3757932","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3757932","identity":"rs-3757932","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}