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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 34  |  Issue : 1  |  Page : 28-32

Antipsychotics-induced diabetes mellitus in rats: it is time to change


Department of Forensic Medicine & Clinical Toxicology, Faculty of Medicine; Lecturer of Forensic Medicine & Clinical Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission22-Jul-2016
Date of Acceptance09-Jan-2017
Date of Web Publication24-May-2017

Correspondence Address:
Shimaa M Motawei
Faculty of Medicine, El-Gomhoria street, Mansoura city, P.O. 35516
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-208X.206897

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  Abstract 


Introduction
The use of antipsychotics has progressively increased in the last 50 years. Despite the fact that second-generation antipsychotics have shown marked therapeutic benefits in treatment of psychosis than earlier typical ones, they produce many metabolic side-effects.
Aim
This study aimed to measure the metabolic effects of three classes of atypical antipsychotics on albino rats.
Materials and methods
A total of 40 albino rats including 16 males and 24 females were grouped into four groups: group I (control group) received the control diet and tap water ad libitum; group II received olanzapine 10 mg/kg intraperitoneally, group III received respiridone 0.2 mg/kg intraperitoneally; and group IV received aripiprazole 20 mg/day intraperitoneally. Blood glucose and insulin as well as serum cholesterol, triglycerides, malondialdehyde, high-density lipoprotein, and low-density lipoprotein were measured before treatment and 60 days after continuation of treatment.
Results
Significant elevation in blood glucose levels, disturbance in insulin levels, and elevation in malondialdehyde, low-density lipoprotein, and total serum cholesterol levels in atypical antipsychotics-treated animals, as compared with vehicle-treated rats, were found. These effects were more prominent with olanzapine, which is a very commonly used antipsychotic, followed by respiridone. Aripiprazole produced the least disturbance in these parameters.
Conclusion
Individual second-generation antipsychotics disturb blood glucose and insulin levels and produce different degrees of other metabolic derangements. There is a need to introduce safer agents for clinical use.

Keywords: hyperglycemia, metabolic derangements, rats, second-generation antipsychotics


How to cite this article:
Motawei SM. Antipsychotics-induced diabetes mellitus in rats: it is time to change. Benha Med J 2017;34:28-32

How to cite this URL:
Motawei SM. Antipsychotics-induced diabetes mellitus in rats: it is time to change. Benha Med J [serial online] 2017 [cited 2017 Sep 19];34:28-32. Available from: http://www.bmfj.eg.net/text.asp?2017/34/1/28/206897




  Introduction Top


Antipsychotics are widely used to treat several psychiatric disorders in pediatric and adult populations. Antipsychotics are categorized into two drug classes – first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs). Although FGAs provide treatment for psychotic symptoms, they can cause extrapyramidal symptoms, dry mouth, and sedation [1].

Although SGAs are thought to be safer, they are associated with significant weight gain, hyperglycemia, and lipid and prolactin elevation. Other adverse effects are neuroleptic malignant syndrome, sudden cardiac death, and coagulopathies. These side-effects vary and are medication specific. In addition, certain evidences show that SGAs are not identical in their effects on weight and insulin sensitivity [2].


  Aim Top


This study aimed to investigate the metabolic side-effects of three SGAs in rats as inducers of secondary diabetes mellitus and other metabolic derangements.


  Materials and methods Top


After approval of local ethics committee, the study was conducted. The effects of three distinct classes of SGA drugs on glucose tolerance, insulin sensitivity, and lipid metabolism were compared in rats [3].
  1. Olanzapine (originally branded Zyprexa): Product of Lilly Pharmaceutical Company (USA, Office in Misr Elgadida, Cairo, Egypt). It was administered at a dose of 10 mg/kg intraperitoneally for 60 days.
  2. Respiridone (trade name Risperdal): Product of Janssen of Johnson & Johnson Pharmaceutical Company (Multinational, Office Mohamed Tawfiq Diab St. Off Makram Ebaid St, Nasr City, Cairo, Egypt). It was administered at a dose of 0.2 mg/kg for 60 days.
  3. Aripiprazole (trade name Abilify): Product of Bristol–Myers Squibb Company (USA, Office in Studio Misr street, ElHaram, Giza, Egypt). It was administered at a dose of 20 mg/day intraperitoneally for 60 days.


Animal grouping

Forty albino rats of both sexes were used in this study (16 male and 24 female). Their weight ranged from 170–190 g. They were maintained in the same housing and feeding conditions and were divided into four groups of 10 rats each.

Group I (control group) received the control diet and tap water ad libitum.

Group II received olanzapine 10 mg/kg intraperitoneally.

Group III received respiridone 0.2 mg/kg intraperitoneally.

Group IV received aripiprazole 20 mg/day intraperitoneally.

This was continued for 60 days, and then the animals were killed by cervical decapitation. Blood samples were collected, were allowed to clot, and then centrifuged. Serum was separated and preserved at −20°C until assay of the study parameters. An oral glucose tolerance test was carried out 2 days before the animals were killed. The rats were fasted overnight and 30% glucose was administered (2 g/kg body weight). Blood samples were collected before glucose supplementation and every half an hour after glucose supplementation for 90 min. Blood glucose levels were immediately measured.

Methods

  1. Serum glucose was measured according to the enzymatic glucose oxidase method of Trinder [4].
  2. Fasting serum insulin was measured using enzyme-linked immunosorbent assay kits and human insulin as standard.
  3. Insulin resistance was measured by the Homeostasis Model Assessment of Insulin Resistance using the formula [insulin (µU/ml)×glucose (mmol/l)/22.5] [5].
  4. Total serum cholesterol was measured using kits from Biomerieux Company (Multinational, bioMérieux Egypt Office in Aly Rashed Street, Star Capital Tower A2, Heliopolis West, Cairo, Egypt) according to Richmond [6]; serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were measured according to Burstein et al. [7] using kits from Biomerieux Company. Triglycerides were measured according to Fossati and Prencipe [8].
  5. Determination of thiobarbituric acid-reactive substances: malondialdehyde was assayed by kits purchased from Biodiagnostic Chemical Company (Egyptian, 29 El-Tahrer Street, Dokki, Giza, Egypt) according to Walker and Shah [9].


Statistical analysis

All data were tabulated, coded, and then analyzed using the computer program statistical package for social science, version 17.0 (SPSS Inc. 233 S. Wacker Drive, Chicago, IL 60606-6307, USA). Descriptive statistics were calculated as mean±SD. For statistical comparison between the different groups, the significance of difference was tested using one of the following tests.
  1. Student’s t-test (paired) was used to compare the mean values of two related groups of numerical (parametric) data. It is known that this test is very sensitive to minimal changes.
  2. Analysis of variance was used to compare more than two groups of numerical (parametric) data followed by post-hoc test.


A P-value less than 0.05 was considered statistically significant.


  Results Top


Results are shown in [Table 1] and [Table 2].
Table 1 Levels of serum glucose, serum insulin, insulin sensitivity index, and other tested biomarkers in all groups of the studied animals before and after drug treatment

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Table 2 Fasting blood glucose and other measured parameters before and after treatment in all groups

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  Discussion Top


Antipsychotics are well-known for their harmful effects. Although SGAs, which emerged in the 1980s, have lower risk of motor side-effects that are prominent features of FGAs, they are associated with significant weight gain, disruption of lipid metabolism, and the development of type 2 diabetes [2].

In the present study, the metabolic effects of three distinct classes of SGA drugs were studied and compared in rats. The drugs used were olanzapine, respiridone, and aripiprazole.

Rats are often used experimentally draw conclusions on what occurs in humans − for example, reaction to poisonous substances. Rats are often considered to be a ‘closer’ model for human drug response and behavior than mice. The collective effect of many experiments on rats makes more data available about the validity of the animal model, thus making further experiments − for example, development of a less-toxic drug − easier to interpret, as scientists know more about how good a model a rat is for particular biological processes in humans [10].

To assess the metabolic effects of the three tested antipsychotics, the following parameters were measured: fasting blood glucose, fasting blood insulin, insulin resistance index, total serum cholesterol, HDL, LDL, triglycerides, and thiobarbituric acid-reactive substance. There were no significant differences between the four groups at the beginning of the study ([Table 1]).

Sixty days after treatment with specific antipsychotic drugs, there were highly significant within-group differences in levels of the measured biomarkers compared with baseline ([Table 2]), as well as between the four groups ([Table 1]).

The highest significance as compared with the control group (which was fed normal diet and no drug) was found for group II (which was given olanzapine). The difference was less when compared with group III (given respiridone), and the least significant difference was found for group IV (which was given aripiprazole).

Therefore, olanzapine was found to be highly associated with elevation of blood glucose levels, decrease in insulin sensitivity, and disturbance in lipid metabolism, followed by risperidone. Aripiprazole is thought to have the smallest effects on weight and insulin resistance.

These results are in agreement with the results of van der Zwaal et al. [11] who found an association between olanzapine and risk of induced diabetes mellitus and weight gain in rats, and that these findings can be used to predict the risk of these drugs in clinical settings. Boyda et al. [12] and Weston-Green et al. [13] agree to the same findings and state that benzepines (like olanzapine) can cause fatal diabetic complications such as diabetic ketoacidosis or hyperglycemic hyperosmolar nonketotic coma.

Chintoh et al. [14] who tested the metabolic effects of different antipsychotics in an animal model found that risperidone disturbs insulin secretion and induces hyperglycemia and metabolic disturbances.

Kalinichev et al. [15] found that aripiprazole disturbs fat metabolism and causes obesity, although to a lesser degree compared with olanzapine, but these harmful effects can cause patient noncompliance to the drug therapy and risk of relapse and medical complications.

Bogdan et al. [16] agree with the above findings, and furthermore they found that aripiprazole causes less disturbance of total cholesterol, LDL and HDL, and triglycerides.

Time has come to abandon the terms FGAs and SGAs, as they do not merit this distinction. Identification of genes that are involved in psychotic disorders and in antipsychotic action, which cause glucose and cellular metabolic disturbances, opens insights for drug discovery and patient biomarker development to provide safer drugs than current SGA [17].

Recommendations

  1. Time has come to abandon the use of SGAs because of their many harmful metabolic side-effects.
  2. Olanzapine caused a large and highly significant glucose intolerance compared with vehicle-treated rats and both resperidone and aripiprazole.
  3. Studies have shown that prescriptions for psychotropics including antipsychotics have increased during the last 20 years in children and youth.
  4. Newer drug classes can be developed in the future (i.e. third-generation antipsychotics) to avoid all these drawbacks of currently available drugs.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Hulshof TA, Zuidema SU, Ostelo RW, Luijendijk HJ. The mortality risk of conventional antipsychotics in elderly patients: a systematic review and meta-analysis of randomized placebo-controlled trials. J Am Med Dir Assoc 2015; 16:817–824.  Back to cited text no. 1
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Rojo LE, Gaspar PA, Silva H, Risco L, Arena P, Cubillos-Robles K, Jara B. Metabolic syndrome and obesity among users of second generation antipsychotics: a global challenge for modern psychopharmacology. Pharmacol Res 2015; 101:74–85.  Back to cited text no. 2
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Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM. Dose equivalents for second-generation antipsychotics: the minimum effective dose method. Schizophr Bull 2014; 40:314–326.  Back to cited text no. 3
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Trinder P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 1969; 6:24.  Back to cited text no. 4
    
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Richmond W. Preparation and properties of a cholesterol oxidase from Nocardia sp. and its application to the enzymatic assay of total cholesterol in serum. Clin Chem 1973; 19:1350–1356.  Back to cited text no. 6
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Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982; 28:2077–2080.  Back to cited text no. 8
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Walker PD, Shah SV. Evidence suggesting a role for hydroxyl radical in gentamycin-induced ARF in rats. J Clin Invest 1988; 81:334–341.  Back to cited text no. 9
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Lindke A, Tremper-Wells B, Miller MW. Generation and use of primary rat cultures for studies of the effects of ethanol. Methods Mol Biol 2008; 447:125–136.  Back to cited text no. 10
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Van der Zwaal EM, Janhunen SK, la Fleur SE, Adan RA. Modelling olanzapine-induced weight gain in rats. Int J Neuropsychopharmacol 2014; 17:169–186.  Back to cited text no. 11
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Boyda HN, Ramos-Miguel A, Procyshyn RM, Töpfer E, Lant N, Choy HH et al. Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats. Int J Neuropsychopharmacol 2014; 17:77–90.  Back to cited text no. 12
    
13.
Weston-Green K, Huang XF, Lian J, Deng C. Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels. Eur Neuropsychopharmacol 2012; 22:364–373.  Back to cited text no. 13
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Chintoh AF, Mann SW, Lam L, Giacca A, Fletcher P, Nobrega J, Remington G. Insulin resistance and secretion in vivo: effects of different antipsychotics in an animal model. Schizophr Res 2009; 108:127–133.  Back to cited text no. 14
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Kalinichev M, Rourke C, Daniels AJ, Grizzle MK, Britt CS, Ignar DM, Jones DN. Characterisation of olanzapine-induced weight gain and effect of aripiprazole vs olanzapine on body weight and prolactin secretion in female rats. Psychopharmacology (Berl) 2005; 182:220–231.  Back to cited text no. 15
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Bogdan M, Silosi I, Surlin P, Tica AA, Tica OS, Balseanu TA et al. Salivary and serum biomarkers for the study of side effects of aripiprazole co-prescribed with mirtazapine in rats Int J Clin Exp Med 2015; 8:8051–8059.  Back to cited text no. 16
    
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