Chronic olanzapine administration in rats: Effect of route of administration on weight, food intake and body composition

Pharmacology, Biochemistry and Behavior 103 (2013) 717–722

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Chronic olanzapine administration in rats: Effect of route of administration on weight, food intake and body composition☆,☆☆ Steve Mann a, Araba Chintoh b, Adria Giacca b, Paul Fletcher b, Jose Nobrega b, Margaret Hahn a, b, Gary Remington a, b,⁎ a b

Schizophrenia Program, Centre for Addiction and Mental Health (CAMH), Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada

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Article history: Received 31 July 2012 Received in revised form 10 November 2012 Accepted 1 December 2012 Available online 9 December 2012 Keywords: Animal models Drug formulation Olanzapine Weight gain

a b s t r a c t Atypical antipsychotics are associated with increased risk of weight gain, and researchers have turned to rodent models to better understand underlying mechanisms. Weight gain has been inconsistent in these studies though, possibly related to the rapid metabolism of antipsychotics in rodents. This study investigates olanzapine, an atypical antipsychotic with high liability for weight gain in humans, administered to rats by continuous infusion via osmotic minipump versus daily subcutaneous (s.c.) or intraperitoneal (i.p.) injections. We examined body weight, food intake and body composition for olanzapine (7.5 mg/kg/day) versus placebo (n=8/group) in female Sprague–Dawley rats using the 3 routes of administration over 14 days. For olanzapine treated animals, weight gain was significantly greater in the minipump sample compared to both s.c. and i.p. injections. Twice as many animals (i.e. 75%) gained ≥7% body weight compared to either daily s.c. or i.p. injections. Olanzapine treated animals consumed more kilocalories than vehicle, and the minipump group consumed more than either daily injection group, although the difference with the s.c. sample was nonsignificant. Significantly more visceral fat was amassed in olanzapine treated animals versus vehicle, again greatest in the minipump sample, although differences between groups did not reach significance. The magnitude of increase across all groups fits with other evidence suggesting change in body composition may represent a more sensitive measure than body weight in assessing antipsychotic related changes. We conclude that the rodent model is tenable in evaluating the effects of antipsychotics on weight/body composition. © 2012 Elsevier Inc. All rights reserved.

1. Introduction ‘Atypical’ antipsychotics have supplanted their older counterparts as the treatment of choice for psychotic disorders such as schizophrenia (Hollingworth et al., 2010; Weinbrenner et al., 2009; Yang et al., 2008). As a class, the atypical antipsychotics have claimed a number of clinical advantages over the typical or conventional antipsychotics (Remington, 2003); however, there also have been limitations identified, including a marked increase in risk of weight gain and related metabolic sequelae (Allison and Casey, 2001; Henderson, 2007; Newcomer, 2005, 2007; Parsons et al., 2009). It is not clear how these drugs lead to the rapid and substantial weight gain that can be observed clinically and while a number of mechanisms have been proposed (Allison and Casey, 2001; Baptista, 2002; Baptista et al., 2004b; Henderson, 2007; Matsui-Sakata

☆ This work constituted graduate requirements for a M.Sc. (S.M.). ☆☆ None of the authors identify actual or potential conflicts of interest (financial, personal, and other) within three years of this investigation. ⁎ Corresponding author at: Schizophrenia Program, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada M5T 1R8. Tel.: +1 416 535 8501; fax: +1 416 979 4292. E-mail address: [email protected] (G. Remington). 0091-3057/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pbb.2012.12.002

et al., 2005; Muller and Kennedy, 2006; Newcomer, 2005, 2007; Parsons et al., 2009), the underlying processes remain poorly understood. Not surprisingly, animal models have been employed for this purpose and a number of labs, including our own, have turned to rodents, specifically rats, to pursue this line of investigation. To mirror the clinical situation, we have utilized chronic administration as this reflects how these drugs are administered in humans, the goal being one of attaining steady state levels and maintaining treatment long-term (Javaid, 1994; Jeste et al., 1999). However, antipsychotic pharmacokinetics differ considerably in rodents, where drugs like olanzapine are metabolized much more quickly; for example, its plasma half-life in rats is in the range of 2–3 h versus > 24 h in humans (Aravagiri et al., 1999; Callaghan et al., 1999; Chiu and Franklin, 1996; Kassahun et al., 1997). At least some labs have employed osmotic minipumps to address these pharmacokinetic differences and allow for continuous administration over prolonged intervals (Chintoh et al., 2008b; Choi et al., 2007; Shobo et al., 2011; van der Zwaal et al., 2008), with one report achieving this through a more recently developed electrical microinfusion pump (Shobo et al., 2011). However, many publications report other routes of administration, including oral (Albaugh et al., 2006; Kalinichev et al., 2005, 2006; Minet-Ringuet et al., 2005, 2006a, 2006b; Raskind et al., 2007), daily injections (Cooper et al., 2005, 2007; Fell et al., 2004,

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2005, 2007, 2008; Goudie et al., 2002; Hartfield et al., 2003; Lee and Clifton, 2002; Patil et al., 2006), and gavage (Pouzet et al., 2003), strategies that do not address the rapid metabolism of antipsychotics identified in rodents. What influence this may have on reported findings has not been specifically examined to our knowledge, and we therefore set out to evaluate olanzapine-induced changes in a rodent model that directly compared results using osmotic minipumps with two other widely used strategies for drug administration i.e. subcutaneous (s.c.) and intraperitoneal (i.p.) injections. We hypothesized that measures such as weight gain and food intake would show significantly greater effects in those animals receiving olanzapine via osmotic minipump, while findings would be comparable for the two injection strategies.

sterilized with isopropyl alcohol and then inserted subcutaneously slightly posterior to the scapulae according to the manufacturer's specifications. The incision was closed using 9 mm surgical staples, and analgesia included topical bupivacaine 0.12% and i.m. ketoprofen 5 mg/kg. Post-operative animals recovered from the anesthetic in a heated Plexiglas cage.

2. Material and methods

2.2.3. Body weight, food intake, and body composition Food intake and body weight were measured daily between 1000 h and 1200 h. Food intake was calculated as difference between the weight of food that was placed in the hopper and weight of food remaining at the time of measurement the following day. On day 14, the animals were sacrificed by CO2 inhalation. To measure visceral adiposity, omental fat pads were dissected out and weighed.

2.1. Animals

2.3. Data analysis

Forty-eight female Sprague–Dawley rats (Harlan, Indianapolis, USA), initially weighing 200–225 g, were singly housed in 48.3× 26.7 × 20.3 cm transparent polycarbonate cages (Lab Products Inc., Seaforth, Delaware, USA) on a 12-h light:12-h dark cycle with lights on at 0800 h in a temperature controlled room (21 ±2 °C). The use of females reflects evidence that they demonstrate a greater risk of antipsychotic-induced weight gain in rodent models than males (Baptista et al., 2004a; Pouzet et al., 2003), a point that will be revisited in the Discussion. Rats had free access to standard rodent chow (Lab Diet, Indiana, USA; 3.02 kcal/g) and water throughout the duration of the experiment. All procedures conformed to the guidelines of the Canadian Council on Animal Care and were approved by the Centre for Addiction and Mental Health (CAMH) Animal Care Committee.

Statistical analyses were performed using SPSS Version 15.0 and SAS System v.9.1.3. Results are expressed as mean ± SD and statistical significance for all analyses was set at P b 0.05. ANOVAs were used to determine the effect of treatment on the dependent variables, total food intake and visceral fat. Repeated measures ANOVA was used to determine the effect of treatment on the dependent variable, weight gain.

2.2. Procedure 2.2.1. Drug treatment Three groups of rats were randomly assigned to receive 7.5 mg/kg/ day of olanzapine (Toronto Research Chemicals, Toronto, ON) for 14 days via Alzet minipumps (Alzet model 2ML2, Durect Corp., Cupertino, CA), once daily s.c. injection, or once daily i.p. injection. There was a vehicle arm for each, using the same routes of administration. The duration of the study is in line with recent recommendations from our own lab related to trial duration when employing olanzapine administered through osmotic minipump (Remington et al., 2011). It is also in line with the finding that rodent studies of less than a month duration are more likely to detect drug-induced weight gain (Boyda et al., 2012), which is in keeping with human data indicating there is somewhat of a ceiling effect to antipsychotic-related weight gain (Zipursky et al., 2005). Olanzapine dose was selected to reflect 70% D2 occupancy as established using positron emission tomography (PET), a threshold associated in humans with optimal chance of antipsychotic efficacy (Kapur and Remington, 1996, 2001; Kapur et al., 2003; Remington et al., 2011) and one that has been incorporated by other studies of this sort (Chintoh et al., 2008a, 2008b; Shobo et al., 2011). Olanzapine was dissolved in 2% acetic acid solution, buffered with 1 N NaOH, while vehicle was a 2% acetic acid solution, buffered with 1 N NaOH. Osmotic minipumps were 2 mL and primed to infuse 31.25 μg/μL over the 15 day interval. Both s.c. and i.p. injections were administered daily (1 mL/kg) between 1000 h and 1200 h, after body weight and food intake were measured. 2.2.2. Osmotic minipump surgery After 1 week of habituation to the animal facility, each rat was anesthetized briefly using the inhalant anesthetic isoflourane. Once anesthetized, a small portion of the animal's back was shaved and sterilized with both isopropyl alcohol and betadine solution. An incision was made within the shaved area followed by dissection of connective tissue with blunt-tipped forceps. The minipumps were

3. Results 3.1. Weight gain Findings (Fig. 1) revealed a significant route main effect (ANOVA: F(2,42) = 7.91, P = 0.0012), a significant treatment main effect (ANOVA: F(1,42) = 38.33, P b 0.0001), a significant time main effect (ANOVA: F(13,546) = 10.23, P b 0.0001), a significant route × time interaction, (ANOVA: F(26,546) = 1.87, P = 0.0058), and a significant treatment× time interaction, (ANOVA: F(13,546)= 3.28, P b 0.0001). Controlling for route and time, weight gain was significantly greater in the olanzapine treated group than in the vehicle treated group (P b 0.0001). Controlling for treatment and time, Bonferroni-adjusted pairwise comparisons revealed that weight gain was significantly higher in the osmotic minipump group compared to both the s.c. and i.p. injection groups (P = 0.0166 and P = 0.0014, respectively). The s.c. injection and i.p. injection groups did not differ from each other (P = 1.0). The 3-way interaction between route, treatment, and time demonstrated trend level significance only and was not investigated further through pairwise comparisons. However, the olanzapine treated minipump group showed the most weight gain, followed by the s.c. and i.p. injection groups. 3.2. Food intake Those animals treated with olanzapine consumed more kilocalories than the vehicle treated groups. A 3 × 2 ANOVA indicated a significant treatment main effect (P b 0.001), a significant route of administration main effect (P b 0.001), but no significant treatment× route of administration interaction (P = 0.470) (Fig. 2). Bonferroni-adjusted post pairwise comparisons revealed that the osmotic minipump group consumed more kilocalories than the i.p. injection group; those receiving s.c. injections fell between, and were not significantly different from the minipump group (Fig. 2). 3.3. Visceral fat There was a significant main effect for treatment (P b 0.01), although this was not the case for route of administration (P = 0.709) or interaction effect (P = 0.439). Thus, olanzapine treated animals amassed

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Treatment Fig. 2. Effects of olanzapine versus placebo on food intake (mean ± SD, n = 8/group) based on route of administration. Analysis indicated a significant treatment main effect (P b 0.001) and significant route of administration main effect (P b 0.001), but no significant treatment × route of administration interaction (P = 0.470). Animals receiving olanzapine via osmotic minipump consumed more kilocalories than the i.p. group, while those receiving s.c. injections fell between and were not significantly different from the minipump group.

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Fig. 1. Effects of olanzapine versus placebo on weight gain (mean±SD, n=8/group) based on route of administration: a, osmotic minipump; b, subcutaneous (s.c.); and, c, intraperitoneal (i.p.). Controlling for route and time, weight gain was significantly greater in olanzapine-treated animals. Controlling for treatment and time, weight gain was significantly higher in those animals receiving olanzapine via osmotic minipump than both the s.c. (P=0.0166) and i.p. (P=0.0014) groups, which were not significantly different from each other (P=1.0).

that it is not viable because findings do not mirror what is observed in humans. In particular, it has been highlighted that results often fail to demonstrate significant weight gain (Baptista et al., 2002a; Cooper et al., 2007, 2008; Fell et al., 2008; Minet-Ringuet et al., 2005, 2006a) and/or the weight gain is confined to females (Albaugh et al., 2006; Baptista et al., 1987; Choi et al., 2007; Pouzet et al., 2003). An excellent review of this topic has recently been published, highlighting a number of factors (e.g., diet, age, and route of administration) which may contribute to these differences (Boyda et al., 2010). We propose that these findings, at least in part, reflect differences in antipsychotic exposure attributable to the very rapid metabolism that occurs with antipsychotics in rodents. Like other groups, we have employed osmotic minipumps to circumvent this issue, and the data presented here underscore its importance. More specifically, weight gain was significantly greater in the minipump group versus either the daily s.c. or i.p. groups; as we also

Visceral Fat

significantly more visceral fat compared to those treated with placebo, although there were no significant differences based on olanzapine's route of administration (Fig. 3).

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Having animal models to evaluate underlying mechanisms that lead to the increased weight gain associated with atypical antipsychotics like olanzapine is critically important (Remington, 2009). Over and above the controlled environment that can be provided, such models afford us access to interventions (e.g., use of specific drugs and examination of tissue) that are simply not tenable in humans. The rodent model has been widely embraced in the field of antipsychotics and proven extremely useful on a number of levels, from the identification of putative antipsychotics using conditioned avoidance response (CAR) to examination of side effects like tardive dyskinesia (TD) utilizing antipsychoticinduced vacuous chewing movements (VCMs) (Geyer and Ellenbroek, 2003; Kulkarni and Dhir, 2011). These are now standard preclinical measures in antipsychotic drug development. The rodent model has, however, been challenged as a model for antipsychotic-induced weight gain, with various reports concluding

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Treatment Fig. 3. Effects of olanzapine versus placebo on visceral fat (mean±SD, n=8/group) based on route of administration. There was a significant treatment main effect (Pb 0.01), with olanzapine treated animals amassing significantly more visceral fat. However, there was no route of administration main effect (P=0.709) or interaction effect (P=0.439).

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hypothesized, there were no significant differences between the latter two on this measure. Similarly, total food intake was greater in the animals receiving olanzapine via osmotic minipump compared to the i.p. group, although here, this was not seen in the s.c. animals where food intake was slightly higher (but still below the minipump sample). Interestingly, in terms of visceral fat measurement there was a significant effect for olanzapine versus placebo but no differences across the three routes of administration. Specific to the issue of gender differences, in humans more rapid clearance has been reported in males (Callaghan et al., 1999). Whether this is the case in rodents is not clear as the pharmacokinetic studies to date have been confined to males (Aravagiri et al., 1999; Chiu and Franklin, 1996), and we are presently undertaking work to clarify this. From the standpoint of weight gain, how do the results of the osmotic minipump sample compare to weight gain observed in humans treated with olanzapine? Clinically significant weight gain defined as an increase of ≥7% is consistent with the US Food and Drug Administration guidelines (Sachs and Guille, 1999), and represents a threshold that has been employed by human studies evaluating olanzapine (Citrome et al., 2009; Kinon et al., 2006; Zipursky et al., 2005). Whereas the weight gain associated with both s.c. and i.p. olanzapine fell short of this threshold (b 6%), those animals administered olanzapine via osmotic minipump demonstrated overall weight gain in excess of 10%, almost twice that observed with the other two routes of administration. Looking individually at the 7% threshold, this occurred in 75% (6/8) of animals receiving olanzapine by means of minipump, versus 37.5% (3/8) in each of the s.c. and i.p. groups. The results related to visceral fat accumulation are certainly interesting and warrant further comment. On one hand, they contradict our hypothesis that those animals receiving olanzapine via osmotic minipump will show significantly greater increases than the s.c. and i.p. groups. From another perspective though, these data suggest that visceral fat accumulation may actually be more sensitive to olanzapine-induced changes than body weight per se. While the comparisons were versus vehicle and not within subject, the magnitude of the increase for all groups versus their comparative vehicle group (osmotic minipump, 48%; s.c., 42%; i.p. 13%) was notable. Of note, other researchers did not identify increases in other fat pads (inguinal, retroperitoneal, and periovarian), highlighting the possibility of a regionally specific effect on fat accumulation (Boyda et al., 2012). Returning to a point made earlier, the use of a rodent model to investigate antipsychotic-induced weight gain has been challenged based on data indicating inconsistent weight gain with the model. Further, inducing weight gain in males has proven particularly difficult; while there is some evidence in humans that weight gain is a greater risk in females (Aichhorn et al., 2006; Basson et al., 2001), it is also common in males. However, it has been reported that both clozapine and olanzapine-induced changes in adiposity are less gender-specific and can even occur in the absence of increased food intake or weight gain (Cooper et al., 2007, 2008). While we did not see significantly greater visceral fat in the osmotic minipump group versus s.c. or i.p. groups here, it did reflect the greatest increase of the three formulations when compared to vehicle (0.97 g, 0.92 g, and 0.30 g, respectively) and, taken together, those receiving olanzapine recorded a significantly greater increase in visceral fat compared to vehicle-treated animals. We have as well reported similar results for females, also receiving 7.5 mg/kg via osmotic minipump over one month (Chintoh et al., 2008b). This raises the issue of whether changes in visceral adiposity may represent a more sensitive marker of antipsychotic-induced changes. Offering support for this position, in humans increased visceral fat has been noted as early as 6 weeks following the initiation of olanzapine (Eder et al., 2001); moreover, it has been reported that weight gain with olanzapine is mainly attributable to increase in body fat (Gilles et al., 2010). The major limitation to this investigation is its scope. We confined our assessment to females although, as noted earlier in rodents, a clear difference between males and females has been established in terms

of antipsychotic-induced weight gain. Our results indicate use of osmotic minipumps appears to address the more rapid metabolism of antipsychotics observed in rodents, as evidenced by greater weight gain with its use compared to either s.c. or i.p. injections. We did not address how this impacts males, although other studies using minipump administration of olanzapine in males did not induce significant weight gain (Choi et al., 2007; Shobo et al., 2011; van der Zwaal et al., 2008). Of note though, lower daily doses were used in two of these investigations (Choi et al., 2007; Shobo et al., 2011) — this may be relevant as the higher dose employed here was chosen based on established D2 occupancy levels in humans. Similarly, we have relied on other sources for data involving males and olanzapine-induced changes in visceral adiposity. There is a report, for example, demonstrating that even low-dose olanzapine (1.5 mg/day) induces significant adiposity in the absence of weight gain (Shobo et al., 2011). Further indirect evidence indicates increased insulin sensitivity in sulpiride-treated rats that did not show weight gain compared to vehicle; however, In terms of other limitations, our study, like others, used dissection techniques to assess adiposity. Going forward, though, more sophisticated noninvasive strategies (e.g. DEXA, microCT, and microMRI) warrant consideration for assessing longitudinal changes (Luu et al., 2009). We raise one caveat that warrants comment. The focus here has been antipsychotic-induced weight gain, clearly a factor in the increased rates of metabolic disturbances reported more recently in schizophrenia (Citrome et al., 2006; Cohn et al., 2004; Henderson et al., 2005; Ramaswamy et al., 2006; Reist et al., 2007). It is of note though that the illness itself may play a contributory role (Cohn et al., 2006; Kirkpatrick et al., 2012; Kohen, 2004; Ryan et al., 2003; Spelman et al., 2007); in addition, there is evidence that these newer antipsychotics can influence variables such as insulin sensitivity and glucose dysregulation independent of weight gain (Baptista et al., 2002b; Chintoh et al., 2008a, 2009; Hahn et al., 2011; Houseknecht et al., 2007). 5. Conclusions Our findings suggest that use of rodents may, in fact, represent a viable model to examine the widespread problem of antipsychoticinduced weight gain that has taken on such prominence with the newer antipsychotics. We recommend that antipsychotics be administered via osmotic minipump to address their more rapid metabolism in rodents, a strategy that appears to result in greater weight gain. Perhaps the most notable discrepancy with what occurs in humans is the marked difference in weight gain as a function of gender, although incorporating a measure of visceral adiposity parallels what is observed in humans and at least partly speaks to the gender differences reported in rodents. There is still much to be learned regarding underlying mechanisms, and the argument that the rodent model is untenable seems premature. References Aichhorn W, Whitworth AB, Weiss EM, Marksteiner J. Second-generation antipsychotics: is there evidence for sex differences in pharmacokinetic and adverse effect profiles? Drug Saf 2006;29:587–98. Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B, et al. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity (Silver Spring) 2006;14:36–51. Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry 2001;62(Suppl. 7):22–31. Aravagiri M, Teper Y, Marder SR. Pharmacokinetics and tissue distribution of olanzapine in rats. Biopharm Drug Dispos 1999;20:369–77. Baptista T. Mechanisms of weight gain induced by antipsychotic drugs. J Clin Psychiatry 2002;63:245–6. Baptista T, Parada M, Hernandez L. Long term administration of some antipsychotic drugs increases body weight and feeding in rats. Are D2 dopamine receptors involved? Pharmacol Biochem Behav 1987;27:399–405. Baptista T, Araujo de Baptista E, Ying Kin NM, Beaulieu S, Walker D, Joober R, et al. Comparative effects of the antipsychotics sulpiride or risperidone in rats. I: bodyweight, food

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