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1 Internet Journal of Medical Udate July;11(2): doi: /ijmu.v11i2.5 Internet Journal of Medical Udate Journal home age: htt:// Original Work Metabolic effects of Olanzaine versus Iloeridone: A 24 weeks randomized, rosective, interventional study Shivangna Singh, Shalini Chandra, A K Kaoor ᴪ, H K Singh, Rohit Kant Rohilkhand Medical College and Hosital, Bareilly, Uttar Pradesh, India (Received 12 Setember 2015 and acceted 22 November 2015) ABSTRACT: Atyical antisychotics have become the mainstay of theray for sychosis. Though extrayramidal side effects have been reduced with atyical antisychotics, yet there are increased concerns over metabolic effects. The resent study is aimed to comaratively evaluate the metabolic rofile of olanzaine and iloeridone in cases of sychosis. A rosective, randomized, oen label, observational study of duration was conducted in the Deartment of Pharmacology and Deartment of Psychiatry, Rohilkhand Medical College and Hosital, Bareilly. A total of 62 atients of both sexes newly diagnosed with sychosis (ICD-10, F20- F29) were included in the study, 31 each in olanzaine and iloeridone grous. Demograhic arameters were recorded, following which the atient s body weight, BMI, fasting blood sugar and liid rofile were estimated at baseline. Follow-u of the atients was done eriodically after one month, three months and six months. Olanzaine treated atients showed markedly significant rise in body weight u to 7 kg at the endoint () at each follow-u, with a significant increase in BMI. Rise in fasting blood sugar (FBS), total cholesterol (TC), triglycerides (TG) and low-density liorotein (LDL) levels werealso statistically significant. At the same time, significant decrease in HDL levels was also observed. Iloeridone treated atients showed statistically significant less rise in body weight (uto 1kg, 0.05) and BMI. No significant changes in fasting blood sugar, total cholesterol, LDL and HDL levels were noted, while TG levels were significantly reduced. Iloeridone caused numerically less rise in bodyweight and BMI, and fewer metabolic adverse effects as comared to olanzaine, and hence should be referred. KEY WORDS: Atyical antisychotics; Weight gain; Blood sugar level; Dysliidemia INTRODUCTIONV Psychosis is a symtom of mental illness characterized by distorted or non-existent sense of reality. Psychotic disorders have different etiologies, each of which demands a unique treatment aroach. 1 The ICD-10, F20-F29 grou of sychiatric disorders includes mental and behavioral disorders characterized by rominent disturbances of thought, ercetion, affect and behavior. The disorders in this section include schizohrenia, schizotyal disorder, ersistent delusional disorders, acute and transient sychotic ᴪ Corresondence at: Deartment of Pharmacology, Rohilkhand Medical College and Hosital, Bareilly , Uttar Pradesh, India; Mobile: ; drakkaoor@rediffmail.com disorders, induced delusional disorder and schizoaffective disorders. 2 Psychosis is rimarily treated with antisychotic drugs. Antisychotic drugs are classified as tyical and atyical agents. Atyical antisychotic agents, in addition to their moderate otencies at doamine recetors, interact with varying affinities at several other classes of recetors like alha1 and alha2 adrenergic, 5-HT1A, 5-HT2A, 5-HT2C, M and H1. 3 The clinically effective doses of atyical antisychotics comared with tyical antisychotic exhibit markedly reduced extrayramidal symtoms risk. 3 Atyical antisychotics ossess the advantage of treating negative symtoms. Yet there have been increased concerns over metabolic effects like weight gain, hyerglycemia, diabetes mellitus and liid abnormalities. 3 A comarative evaluation between olanzaine versus iloeridone has not been investigated 17

2 thoroughly. A few studies have assessed the adverse effect rofile of olanzaine with iloeridone, though not in an Indian oulation. The aims of the resent study were to comaratively evaluate olanzaine (OLZ) which is a more commonly used antisychotic for the treatment of sychosis with iloeridone (ILO) with regard to metabolic rofile and assess whether there exists any major advantage of one drug over the other for the Indian oulation. METHODOLOGY A rosective, randomized, observational study of 6months duration (October 2013 to March 2014) was conducted to comaratively evaluate the metabolic safety rofile of iloeridone versus olanzaine in the deartments of harmacology and sychiatry of Rohilkhand Medical College and Hosital, Bareilly, Uttar Pradesh. Aroval for the study rotocol was obtained from the institutional ethics committee. The CTRI registration number of the study is CTRI/2014/10/ Each subject signed an informed consent form and could withdraw without rejudice at any time. Patients years and of both genders attending the sychiatry outatient deartment during the study eriod diagnosed with sychosis falling under the grou (F20-F29) as er ICD-10 criteria and rescribed monotheray with olanzaine or iloeridone were eligible to articiate in the study. The exclusion criteria included history of diabetes mellitus, severe cardiovascular disease, heatic, renal or untreated thyroid disease, current medication such as antieiletics (valroate or carbamazeine), antiarkinsonian agents (levodoa), birth control ills, steroids, roranolol and thiazide diuretics and agents that induce weight loss, regnancy or breast-feeding and irregular comliance. A total of 62 atients (OLZ31 and ILO31) comrised the samle; of these two atients droed out of the olanzaine grou (n 29) due to extrayramidal side effects. All atients were allotted a reference number; the odd numbers were assigned to the olanzaine and even numbers to the iloeridone grou. A redesigned, structured and retested questionnaire was used to collect demograhic information. A comlete clinical examination was conducted on all study subjects to rule out any chronic ailments referred to in the exclusion criteria. Data regarding age, sex, socio-economic status, family history, and other demograhic arameters were recorded. For calculating BMI, the atient s height and weight were recorded. Blood ressure was measured using a standard rotocol. Other relevant investigations were also erformed. The atient s bodyweight (BW), body mass index BMI, fasting blood sugar (FBS) and liid rofile (TC, LDL, TG, HDL) was estimated at baseline and on each subsequent follow-u. Flexible doses of both iloeridone (8-12 mg/day) and olanzaine (10-20mg/day) were administered. No other anti-sychiatric drug theray was given during the study eriod though rescue medications like tablets/injections of lorazeam, tablet trihexyhenidyl, tablet clonazeam were administered for managing emergency and side effects, if any. Patients were subsequently monitored and reassessed after one, three and six months with resect to alterations in biochemical arameters and adverse effects. Blood ressure was recorded to evaluate orthostatic hyotension. The consultant sychiatrist erformed sychiatric evaluation of the atients during each visit. Statistical analysis was erformed using the software SPSS, Windows version 20. Mean s of change in BW, BMI, FBS and liid rofile at baseline and after one, three and six months were comared between two grous by using unaired t- test and, in the grous, by aired t-test. RESULT Table 1 shows demograhic characteristics. Out of 62 cases of sychosis (31 atients in each grou), 45 (72.58%) were males and 17 (27.42%) females. M: F ratio is 2.65:1. The mean age in the olanzaine grou was 29.4 ± 9.55 years and the mean age in iloeridone grou was 30.81± Fifty (80.64%) atients out of 62 cases belonged to rural areas whereas 12 (19.35%) were from urban areas (rural:urban ratio 4.17:1). Thirty-four atients (54.83%)were illiterate while 28 (45.16%) were literate. Thirty-two (51.61%) atients had low socioeconomic status while 30 (48.38%) belonged to the middle class. Table 2 shows BW, BMI, FBS, TC, TG, LDL, and HDL levels after one, three and six months with olanzaine. All the arameters were significantly altered. There was statistically significant increase () in BW (uto7kg), BMI (2.49 kg/m 2 ), FBS (8.18 mg/dl), TC (9.86 mg/dl), TG (8.89 mg/dl) and LDL (5.48 mg/dl) after six months of theray. HDL s were significantly decreased (0.05) after three and six months from baseline. Table 3 deicts a statistically significant rise in body weight (uto 1 kg) and BMI (0.43 kg/m 2 ) overtime with iloeridone treatment (0.05 after 6 months). However, there were no significant alterations (>0.05) between the baseline s and follow-u s of FBS, TC, LDL and HDL. Only TG showed a statistically significant decrease (0.05) after one, three and six months. Table 4 shows the comarative s of BW and BMI between olanzaine and iloeridone in followus. The two grous were well matched at baseline (>0.05). After one month, treatment bodyweight 18

3 showed no significant change (0.1179). After three months, the olanzaine grou showed a statistically significant increase in bodyweight (0.0109) and bodyweight recorded a further more significant rise (0.0006) after six months. In short, olanzaine showed an increase of aroximately 7kg over six months comared to 1kg with iloeridone. Regarding BMI, there was comaratively no significant changes after one month and three months of theray ( and , resectively). However, after there was markedly significant increase in BMI with olanzaine as comared to iloeridone (0.0025). Table 5 comares the alterations in FBS between olanzaine and iloeridone treated grous from baseline to one, three and six months. Both grous were comarable at baseline (>0.05) and after 1 month (>0.05). However after statistically marked significant increase in FBS ( , 88.72±7.41 mg/dl in olanzaine grou versus 83.77±5.60 mg/dl in iloeridone) was noted, FBS after became statistically highly significant (, 92.90±1.72 mg/dl in the olanzaine grou versus 83.90±5.34 mg/dl in the iloeridone grou). Table 6 shows comarative changes in liid rofile between olanzaine versus iloeridone. Statistically no significant difference in LDL and HDL levels (>0.05) was noted. Though, TC and TG levels were comarable at baseline after one month and three months (>0.05), yet the olanzaine grou showed statistically significant increase in TC (150± mg/dl, 0.05) and TG (134.41± mg/dl, P0.05) after six months. Table 1:Distribution of demograhic arameters S.N. PARAMETERS OLZ ILO TOTAL NO. (%) Test Value P-Value 1 Male (72.58%) X² Female (27.41%) t 3 Mean age ± SD ± ± ± Rural (80.64%) X² Urban (19.35%) 6 7 Literate Illiterate (45.16%) 32 (51.61%) X² Low Socio-economic (51.61%) status X² Middle Class (48.38%) OLZ Olanzaine; ILO Iloeridone; > 0.05 not significant Table 2:Effect of olanzaine on BW, BMI, FBS and liid rofile Parameters Bodyweight (kg) BMI (kg/m 2 ) FBS TC TG LDL HDL Mean±S.D ± ± ± ± ± ± ±4.94 Mean ± S.D. t 3 months Mean ± S.D ± ± ± ± ± ± ±5.16 t ± ± ± ± ± ± ± significant; > 0.05 not significant Mean±S.D ± ± ± ± ± ± t ±

4 Table 3:Effect of iloeridone on BW, BMI, FBS and liid rofile Parameters Bodyweight (kg) BMI (kg/m 2 ) FBS TC TG LDL HDL Mean ± S.D ± ± ± ± ± ± ±4.26 Mean ±S.D. t 3 months Mean ± S.D. t ± ± ± ± ± ± ± ± ± ± ± ± ± 43.87± significant; > 0.05 not significant 6 months Mean ±S.D ± ± ± ± ± ± ± 3.81 t Table 4:Comarative evaluation of olanzaine and iloeridone on body weight and BMI OLZ (Mean ± 55.17± 6.12 WEIGHT (kg) BODY MASS INDEX (kg/m 2 ) ILO(Mean ± 54.12± 5.08 t OLZ (Mean ± ±1.20 ILO(Mean ± ± 1.29 t ± ± ± ± ± ± ± ± ± ± month ± ± significant; > 0.05 not significant Table 5:Comarative effects of olanzaine and iloeridone on fasting blood sugar FASTING BLOOD SUGAR OLZ (Mean ± ILO (Mean ± t - Value 84.72± ± ± ± ± ± ± ± significant; > 0.05 not significant

5 Table 6:Comarative evaluation of liid rofile with olanzaine and iloeridone OLZ (Mean ± 140.9±22.53 TOTAL CHOLESTEROL ILO (Mean ± ±22.45 t OLZ (Mean ± ± LOW DENSITY LIPOPROTEIN ILO (Mean ± ± t Value ± ± ± ± ± ± ± ± ± ± ± ± ± TRIGLYCERIDES ± ±4.94 HIGH DENSITY LIPOPROTEIN ± ± ± ± ± ± ± ± month ± ± ± ± ± significant; > 0.05 not significant DISCUSSION Workers in the field have documented that most atyical antisychotic agents, excet a few, cause significant raid increase in bodyweight ranging from 2 14 kg which occurs within 12 weeks of treatment and is one of the imortant adverse effects leading to dro out from the study. 4-7 In the resent study, a raid markedly significant increase in bodyweight was noted with olanzaine, after one () three (), and six months () whereas iloeridone caused comaratively less increase in weight during similar eriods. The mean change in weight from baseline to endoint was 7kg with olanzaine comared to 1 kg with iloeridone. Allison et al 8 and Conley et al 4 observed that olanzaine caused weight gain of 4.15 kg at 10 weeks from baseline and 3.26 kg at 8 weeks resectively. Similarly, in the CATIE trial, 5 atients taking olanzaine gained an average of 0.9kg /month and a greater roortion of these atients gained 7% or more of their body weight at 18 months. Besides, Ganguli et al 9, Garyfallos et al 10, Volavka et al 6, Bobes et al 7, Brier et al 11 also observed significant weight gain and BMI increase after treatment with olanzaine and riseridone. Atmaca et al 12 have also noted that olanzaine and clozaine caused marked increase in weight. In a meta-analysis of 48 studies, Rummel-Kluge et al 13 have noted that olanzaine roduced more weight gain than all other second generation antisychotic agents. The results of the resent study with resect to olanzaine are in line with revious findings. De Hert et al 14 in a meta-analysis observed statistically significant weight gain with iloeridone (0.001) greater than lacebo. Cutler et al 15 in a 25-week clinical trial with iloeridone (12 mg BD) noted weight gain (9.2%). Weiden et al 16 observed that iloeridone caused a mild weight increase ( kg) similar to riseridone (1.5kg). Hochfeld et al 17 in a meta-analysis of 3200 atients who were administered iloeridone noted an average weight gain of about 2kg following treatment for greater than one year and most weight gain occurred within first six weeks of the studies. Thus, the results of the resent study are comarable with these studies for iloeridone and that weight gain has been noticed after 1month of theray (0.0019). The recise mechanism of weight gain due to atyical antisychotics is not clearly understood 21

6 and aears to be a multifactorial henomenon involving basically effects on recetors and neuroendocrine athways (hyothalamic neurotransmitters and neuroetides). Serotonin enhances satiety by stimulating Prooiomelanocortin (POMC) secretion by an effect mediated by 5-HT2c recetors; antagonists of 5- HT2c recetors revent or delay the onset of satiety, thereby increasing the size of the meal. Histamine H1 recetor blockade activates hyothalamic AMP-activated rotein kinase (AMPK), increasing aetite. Additionally, D2 recetor antagonism has also been imlicated in antisychotic associated weight gain. Further cells in the arcuate nucleus of the hyothalamus exress neuroetide Y (NPY) and Agouti-related rotein (AgRP), two highlyorexigenic (aetite enhancing) etides whose exression is increased by ghrelin and inhibited by letin. 18 In the resent study we observed a highly significant increase in body mass index (BMI) after one, three and six months () with olanzaine. In contrast iloeridone caused statistically significant increase in BMI only after three (0.0089) and six months (0.0229). Thus, comaratively iloeridone has shown a lower and delayed increase in BMI than olanzaine. Allison et al 8 have noted that olanzaine also increased mean BMI by 1.1 kg/m 2. Robinson et al 19 have noted that the estimate of adjusted mean of BMI increased from 24.3 (95%, CI ) at baseline to 28.2 (95%, CI ) at 4 months with olanzaine. Ingole et al 20 in a short term trial have similarly observed that bodyweight and BMI show significant increase from baseline with both olanzaine and riseridone. Besides, other workers in the field 6-12 also have observed that an increase in BMI occurred after treatment with olanzaine. Thus the findings in our study on BMI in resect to olanzaine are consistent with that of the above noted workers. Data ertaining to iloeridone are not available. In our study mean FBS s with olanzaine have shown statistically significant rise in each follow-u and ( ) after six months. While iloeridone showed no significant alterations in FBS even after, Lindenmayer et al 21 and Atmaca et al 12 noted that olanzaine roduced more increase in glucose levels than riseridone, zirasidone and ariirazole. Ingole et al 21 observed that mean blood sugar significantly increased in a short term trial with olanzaine (). The results of the resent study are in line with the above studies. Fuller et al 22 and Farewell et al 23 also demonstrated that after one year of theray, olanzaine use was a significant redictor of develoing new onset diabetes and that develoment of diabetes mellitus takes more than 15 months. In Phase I of the CATIE trial 5, olanzaine was associated with a significant increase in mean HbA1c. Similar to weight gain, olanzaine and clozaine aear to have the greatest risk for diabetes. A significant association between olanzaine and diabetes mellitus and insulin resistance in olanzaine subjects has also been observed De Hert et al 14 in a meta-analysis haveobserved significant changes in glucose levels during shortterm treatment with iloeridone ( mg/dl; 95% CI 2.4,11.8, 0.01). Hochfeld et al 17 observed fasting mean (SD) glucose changes with iloeridone 6.6 (24.0) from baseline to end of study, while Cutler et al 15 in a 25-week clinical trial with iloeridone noted that levels of serum glucose, liids and rolactin were essentially unchanged or decreased during the treatment. Our observations in resect to FBS are in conformity with these authors. Atyical antisychotics have been shown to cause dysliidemia These changes are largely related to concomitant weight gain; therefore, agents associated with the greatest weight gain may have the greatest roensity to cause dysliidemia 28. In our study, changes in liid metabolism were observed in both olanzaine and iloeridone grous. Olanzaine significantly altered liid arameters (TC, TG, LDL and HDL). TC levels significantly increased from baseline to endoint (). Initially TG levels did not change till one month but rose significantly after three months () and six months (). LDL s also increased significantly after each follow u. Cardiorotective HDL levels significantly decreased after three months (0.05) and six months (): these findings are similar to those of other workers who have also documented similar change in liid metabolism with olanzaine. Lindenmayer et al 21 observed significant increase in mean TC at 14 weeks of 20.1mg/dl (0.002) in atients taking olanzaine. Atmaca et al 12 observed that olanzaine roduced more changes in TC than riseridone, ariirazole and zirasidone besides there beinga marked increase in serum TG and letin levels. Previous studies have documented a relation between atyical antisychotics clozaine and olanzaine and serum letin levels. Letin has been associated with atyical antisychotic induced weight gain. Besides, atyical antisychotics esecially clozaine and olanzaine are associated with higher risk of metabolic syndrome. 28 Iloeridone however, showed no significant changes in TC, LDL, HDL levels from baseline to endoint of theray. An interesting result observed in this study was that TG levels were significantly decreased with iloeridone after one (P0.05), three (P0.001) and six months (P0.05). Hochfeld et al 17 observed that non-fasting cholesterol showed decrease from baseline to time oints after 4 weeks 22

7 and neither short term nor long term treatment with iloeridone led to develoment of high or borderline high cholesterol in the overall study oulation. Fasting mean (SD) triglycerides changes were -0.83(82.3) mg/dl. Thus, iloeridone showed small changes in liids that are unlikely to be of clinical concern. A decrease in TG levels is in line with our observations. Limitations of the resent study include the following: First, as the duration of the resent study was relatively short, it was not ossible to elicit further changes in bodyweight, BMI, glucose levels and liid rofile. Second, the number of atients included was small. CONCLUSION Comarative data are still too sarse to evaluate the metabolic safety rofile of the two drugs used. Thus, there is a clear need for further controlled studies to comaratively evaluate which of the two agents is less roblematic for short term safety and tolerability for treatment, with resect to weight gain and metabolic disturbances. Our study suorts the safety and tolerability of iloeridone over olanzaine for the treatment of sychosis. REFERENCES 1. Sadock BJ, Sadock VA. Schizohrenia. Kalan and Sadock s Synosis of Psychiatry 10 th Edition. Liincott Williams & Wilkins Publication, 2007: WHO, ICD-10 classification of mental and behavioral disorders 10 th Edition. AITBS Publishers. 2007: Jonathan M. Pharmacology of sychosis and mania. Goodman & Gilman s The Pharmacological Basis of Theraeutics12 th Edition. McGraw Hill ublication.2011: Conley RR, Mahmoud R. A randomized double blind study of riseridone and olanzaine in the treatment of schizohrenia or schizoaffective disorder. Am J Psychiatry. 2001;158: Lieberman JA, Strou TS, Mc Envoy JP, Swartz MS, et al. Effectiveness of antisychotic drugs in atients with chronic schizohrenia. N Engl J Med. 2005;353: Volavka J, Czobor P, Sheitman B, Lindenmayer JP, et al. Clozaine, olanzaine, riseridone, and haloeridol in the treatment of atients with chronic schizohrenia and schizoaffective disorder. Am J Psychiatry. 2002;159: Bobes J, Rajas J, Garcia-Garcia M, Rico VF, Garcia-Portilla MP, et al. Weight gain in atients of schizohrenia treated with riseridone, olanzaine, quetiaine, or haloeridol: results of the EIRE study. Schizohr Res. 2003;62: Allison DB, Mentore JL, Heo M, Chandler LP, Caelleri JC, Infante MC, et al. Antisychotic-induced weight gain: a comrehensive research synthesis. Am J Psychiatry. 1999;156: Ganguli R, Barar JS, Ayrton Z. Weight gain over 4 months in schizohrenia atients: a comarison of olanzaine and riseridone. Schizo Res. 2001;49(3): Garyfallos G, Dimelis D, Kauniakis P. Olanzaine versus riseridone: weight gain and elevation of serum triglyceride levels. J Euroean Psychiatry, 2003;18: Breier A, Berg PH, Thakore JH, Naber D, et al. Olanzaine versus zirasidone: results of 28 week double blind study in atients with schizohrenia. Am J Psych. 2005;162: Atmaca M, Kuloglu M, Tezcam E, Ustundag B. Serum letin and triglyceride levels in atients on treatment with atyical antisychotics. J Clin Psychiatry. 2003;64(5): Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, et al. Head to head comarisons of metabolic side effects of second generation antisychotics in the treatment of schizohrenia: a systemic review and meta analysis. Schizohr Res. 2010;123: DeHert M, Yu W, Detraux J, Sweers K, et al. Body weight and metabolic adverse effects of asenaine, iloeridone, lurasidone and alieridone in the treatment of schizohrenia and biolar disorder: a systematic review and exloratory meta-analysis. CNS drugs. 2012;26(9): Cutler AJ, Kalali AH, Mattingly GW, Kunovac J, et al.long-term safety and tolerability of iloeridone: results from a 25-week, oen-label extension trial. CNS Sectr. 2013;18(1): Weiden PJ, Cutler AJ, Polymerooulous MH, Wolfgang CD. Safety rofile of iloeridone: a ooled analysis of 6-week acute hase ivotal trials. J Clin Psychoharmacol. 2008;28(2): Hochfeld M, Ahmed S, Meng X, Winseck A. Changes in weight and metabolic arameters following long term iloeridone use: a metaanalysis of data from 9 hase II and III trials of iloeridone. Oen J Psychiatry. 2012;2: Balt SL, Galloway GP, Baggott ML, Schwatrz Z, et al. Mechanisms and genetics of antisychotic associated weight gain. Clin Pharmacol Ther. 2011;90(1):

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