International Journal of Neuropsychopharmacology (2014), 17, 169–186. doi:10.1017/S146114571300093X
© CINP 2013
REVIEW
Modelling olanzapine-induced weight gain in rats E. M. van der Zwaal1, S. K. Janhunen2, S. E. la Fleur3* and R. A. H. Adan4* 1
Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands 2 CNS Research, Research and Development, Orion Corporation Orion Pharma, Turku, Finland 3 Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands 4 Department of Neuroscience and Pharmacology, Rudolf Magnus Institute for Neuroscience, University Medical Center, Universiteitsweg 100, 3584 GC, Utrecht, The Netherlands
Abstract The second-generation antipsychotic drug olanzapine has become a widely prescribed drug in the treatment of schizophrenia and bipolar disorder. Unfortunately, its therapeutic benefits are partly outweighed by significant weight gain and other metabolic side effects, which increase the risk for diabetes and cardiovascular disease. Because olanzapine remains superior to other antipsychotic drugs that show less weight gain liability, insight into the mechanisms responsible for olanzapine-induced weight gain is crucial if it is to be effectively addressed. Over the past few decades, several groups have investigated the effects of olanzapine on energy balance using rat models. Unfortunately, results from different studies have not always been consistent and it remains to be determined which paradigms should be used in order to model olanzapine-induced weight gain most accurately. This review summarizes the effects of olanzapine on energy balance observed in different rat models and discusses some of the factors that appear to contribute to the inconsistencies in observed effects. In addition it compares the effects reported in rats with clinical findings to determine the predictive validity of different paradigms. Received 22 October 2012; Reviewed 31 December 2012; Revised 4 July 2013; Accepted 21 July 2013; First published online 8 October 2013 Key words: Antipsychotic, energy balance, olanzapine, rat models, weight gain.
Introduction Olanzapine-induced weight gain Upon its introduction to the market in 1996, olanzapine quickly became a widely prescribed drug in the treatment of schizophrenia and bipolar disorder (Scherk et al., 2007; Leucht et al., 2009). Unfortunately, its therapeutic benefits were soon overshadowed by metabolic side effects: significant weight gain, dyslipidemia and hyperglycemia are major causes for concern, because they increase the risk for diabetes and cardiovascular disease in patients taking this drug chronically (Newcomer, 2007; Rummel-Kluge et al., 2010). Furthermore, because of the esthetic consequences and social stigmatism associated with being overweight or obese, patient compliance is reduced, which increases the risk of relapse and re-hospitalization (Lieberman et al., 2005). Although several other antipsychotics on the market today are less likely to induce weight gain (especially
Address for correspondence: E. M. van der Zwaal MD, PhD, Department Nuclear Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Tel.: ++ 31 (0) 20 5663572 Fax: ++31 (0) 20 5669092 Email:
[email protected] * These authors contributed equally to this work.
ziprasidone and aripiprazole), none has proved to be as therapeutically effective as olanzapine (Leucht et al., 2009; Komossa et al., 2010). It is, therefore, necessary to develop novel treatment strategies that obtain an equal therapeutic response without increasing body weight. Insight into the mechanisms responsible for olanzapineinduced weight gain is crucial if it is to be effectively addressed, and an important first step in this process is to assess the effects on energy balance.
Regulation of energy balance In normal-weight individuals, compensatory mechanisms match energy intake to changes in energy expenditure (Fig. 1). However, if energy intake persistently exceeds energy expenditure, weight gain inevitably occurs (Schwartz et al., 2000). Total energy expenditure (TEE) is determined for a large part (±60–75%) by resting energy expenditure (REE), which is independent of physical activity (Donahoo et al., 2004) and in a ‘thermoneutral’ environment consists mainly of the energy required to maintain normal function of cells – basal metabolic rate (BMR) – which in turn is largely determined by the body’s fat-free mass (Ravussin et al., 1986). At lower ambient temperatures, however, a significant portion of REE is determined
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E. M. van der Zwaal et al. Energy balance
Maintenace FFM
NEAT
Exercise
PPT
Meal size
Meal Frequency
Food preference
Food motivition
Energy intake
Thermogenesis
REE
NREE
Energy expenditure
Fig. 1. Simplified model of the different components of energy balance. FFM, fat-free mass; NEAT, non-exercise activity thermogenesis; NREE, non-resting energy expenditure; PPT, postprandial thermogenesis; REE, resting energy expenditure.
by the thermogenic processes necessary to maintain body temperature (Silva, 2006). Non-resting energy expenditure (NREE) – consists of three components: (1) postprandial thermogenesis (PPT) – which occurs during digestion, absorption and storage of food (±10% of TEE), (2) volitional exercise (e.g. sports and fitness-related activity) – which is determined by conscious decisions and (3) non-exercise activity thermogenesis (NEAT) – which is due to all other physical activity (D’Alessio et al., 1988; Novak and Levine, 2007). The contribution of NEAT ranges from ±3–50% of TEE. It is partly determined by occupational duties, but also by subconscious processes, such as fidgeting, spontaneous muscle contractions and changes of posture (Ravussin et al., 1986; Rising et al., 1994; Levine, 2002). Total energy intake depends on the amount of food ingested: the product of meal size and meal frequency. In this respect, an important distinction is made between (1) ‘satiation’ – which refers to the processes that promote meal termination, and thereby limit meal size – and (2) ‘satiety’ – which refers to the absence of hunger and determines the interval to the next meal, thereby regulating meal frequency (Blundell and Halford, 1994). Total caloric intake also depends on food preference, as this can influence the energy-density of the ingested food markedly. However, food choice is not only determined by its palatability (‘liking’), it is also determined by the motivation to obtain it (‘wanting’) (Berridge, 1996). Therefore, food motivation is the final significant contributor to total caloric intake. It is now widely acknowledged that the brain plays a key role in the regulation of energy balance (Fig. 2)
(Schwartz et al., 2000). It does so by integrating multiple peripheral signals that convey information concerning the presence and type of nutrients available in the environment and within the alimentary tract, the quantity of fuels circulating within the blood and the amount of energy stored as fat (Morton et al., 2006). In response to this input, energy expenditure is influenced through autonomic and endocrine control of basal metabolic rate, thermoregulation and physical activity (Bamshad et al., 1999; Lechan and Fekete, 2006; Novak and Levine, 2007). Conversely, the different components of energy intake are influenced by complex interactions between cortical and subcortical structures, the hypothalamus and the hindbrain, that ultimately either initiate or terminate feeding behaviour (Berthoud, 2002). As olanzapine readily enters the central nervous system after peripheral administration, it is likely that olanzapine induces weight gain by affecting the neural circuits controlling energy balance (Aravagiri et al., 1999). However, the exact underlying mechanisms remain to be elucidated. Investigation of olanzapine-induced weight gain in rats Because animal models offer additional opportunities to elucidate the mechanisms responsible for olanzapineinduced weight gain compared to clinical studies (e.g. the possibility to standardize environments, to precisely quantify different aspects of energy balance and to perform certain experimental manipulations) several rodent-models have been developed in recent years. Unfortunately, the results from different studies have not always been consistent in terms of the effects observed
Modelling olanzapine-induced weight gain in rats 171
Environmental, emotional & cognitive factors
Sight, taste & smell Rewarding aspects
Catabolic + – Brain – + anabolic Food intake
Energy expenditure
Ghrelin
- Metabolic rate - Thermogenesis - Physical activity
Gastro-intestinal tract Fat stores Adiposity signals: Leptin Insulin
Metabolic signals: Glucose Amino acids Free fatty acids
Neural & humoral satiation signals: Gastric distension CCK, PYY, GLP-1 etc.
Fig. 2. Neural control of energy balance. Simplified model showing different types of signals that activate either anabolic or catabolic pathways in the brain. These pathways have opposing effects on energy intake and energy expenditure, and work together to maintain energy balance in healthy normal-weight individuals (adapted from Schwartz et al., (2000)).
on energy balance, and it remains to be determined which experimental paradigms model the effects of therapeutic doses of olanzapine in humans most accurately. Previous animal studies have already implicated certain neural mechanisms in olanzapine-induced weight gain. For instance, olanzapine caused an increase in mRNA levels of the orexigenic neuropeptides agoutirelated protein (AGRP) and neuropeptide Y (NPY) in the arcuate nucleus of rats treated sub-chronically with 3 mg/kg bi-daily (Ferno et al., 2011). This may have been due to activation of NPY/AGRP-expressing neurons by increased levels of ghrelin (Wang et al., 2002), as olanzapine caused an increase in plasma levels of this stomach-derived hormone after acute (1 mg/kg) and sub-chronic treatment (up to 6 mg/kg) (WestonGreen et al., 2011; van der Zwaal et al., 2012b). However, in different studies olanzapine failed to affect mRNA levels of NPY and AGRP after both acute (1 mg/kg) and sub-chronic administration (1 mg/kg once or bi-daily) (Davoodi et al., 2009; Guesdon et al., 2010). Similarly, increased activation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK) by antagonism at histamine H1 receptors was proposed to
mediate olanzapine-induced weight gain by studies that administered 10 mg/kg olanzapine acutely and 2 mg/kg once-daily for 2 wk (Kim et al., 2007; Martins et al., 2010; Sejima et al., 2011). However, the opposite effect (reduced activation of AMPK) was observed by others after administering 3 mg/kg bi-daily for 6 d (Ferno et al., 2011). Other central mechanisms previously implicated include the increased activation of orexin-expressing neurons and increased expression of receptors for the orexigenic neuropeptide melanin-concentrating hormone (MCH) in the nucleus accumbens (Wallingford et al., 2008; Stefanidis et al., 2009; Guesdon et al., 2010). Unfortunately, the rat models previously used to investigate the neural mechanisms underlying olanzapine-induced weight gain differed significantly regarding their methodology and – as will be discussed in this paper – this may partly explain their sometimes contradictory results. The aim of this review is to summarize the effects of olanzapine on energy balance observed in different experimental paradigms, and to discuss some of the factors that may contribute to the inconsistencies in observed effects. In addition, findings reported in rats are compared to those observed in clinical studies in order to determine
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the predictive validity of different paradigms. Hopefully this will help improve the design of future studies that aim to further investigate the neural mechanisms underlying olanzapine-induced weight gain. Although a number of studies used mice, rats were used in the majority of studies and are, therefore, the focus of this paper.
Effects of olanzapine on energy balance Body weight and composition Whether olanzapine induced body weight gain in a rat model was largely gender-dependent, as most studies using females reported weight gain (see Table 1), whereas most studies using males did not (see Table 2). Nevertheless, increased adiposity measures were repeatedly reported in both females and males, even in the absence of weight gain (see Tables 1 and 2). Interestingly, in males increased adiposity was mostly observed in paradigms offering a medium-fat diet containing 25–50 %kcal fat and/or establishing fairly constant drug exposure – either by administering olanzapine more than once a day, continuously via minipumps, or mixed with food/drinking water (Minet-Ringuet et al., 2006a; Cooper et al., 2007; Victoriano et al., 2009; Guesdon et al., 2010; Muller et al., 2010; Shobo et al., 2011a, b; van der Zwaal et al., 2010; Smith et al., 2011). Furthermore, total body weight gain was only observed in male rats maintained on a medium-fat diet (Minet-Ringuet et al., 2006a; Shobo et al., 2011a; Smith et al., 2011). This may have been a consequence of hyperphagia, which also occurred more frequently in males offered a medium-fat diet (a finding that may be due to synergistic effects – see ‘total food intake’ section). However, an additional explanation may lie in the fact that less energy is required to store an excess of calories in adipose tissue when they are ingested as fat than if overfeeding occurs with a low-fat, carbohydrate-rich diet (Horton et al., 1995). The fact that male rats appear to require more constant drug exposure in order to induce increased adiposity levels is most likely due to the short half-life of olanzapine in rats: only 2.5 h compared to ±30 h in humans (Callaghan et al., 1999). In male rats, a reduction in muscle mass was reported in combination with increased adiposity (Cooper et al., 2007; van der Zwaal et al., 2010). This may be due to the olanzapine-induced reduction in testosterone levels (Cooper et al., 2007), as castrated rats show a marked reduction in body weight gain that is mostly due to a reduction in lean body mass (Allan et al., 2007). Because a reduction in lean mass may compensate for a simultaneous increase in adipose tissue, this might explain why total body weight gain is not frequently observed in males. Unfortunately, only a limited number of studies determined effects on body composition in females. Interestingly, in some cases significant body weight gain
in female rats was not accompanied by a significant effect on adiposity measures (Fell et al., 2007, 2008; Han et al., 2008). Furthermore, although reduced lean mass was observed in one study treating female Wistars bi-daily with 5 mg/kg for 14 d (Kalinichev et al., 2005), no effect on gastrocnemius muscle weight was observed in a different laboratory treating Sprague–Dawleys oncedaily with 4 mg/kg for 20 d (Albaugh et al., 2006). Conversely, a third group treating Han Wistars bi-daily with 2 mg/kg for 12 d observed an increase in lean mass that was larger than the increase in adipose tissue (Liebig et al., 2010). Therefore, the effect on lean mass in females appears inconsistent, and it cannot be excluded that the increase in body weight observed in certain studies was (partly) due to effects on lean mass instead of adiposity. Although a meta-analysis of studies in humans reported an average weight gain of 11.1 lb after shortterm treatment with olanzapine, significant weight gain (defined as > 7% of baseline body weight) was observed in only 48% of patients after 1 yr of treatment, and approximately 7% even showed significant weight loss (Parsons et al., 2009). Thus, weight gain is not observed in all patients. An individual’s susceptibility to antipsychotic-induced weight gain appears to be influenced by genetic factors, and differences in susceptibility to olanzapine-induced weight gain have also been reported between ethnic groups (Basson et al., 2001; Zipursky et al., 2005; Gebhardt et al., 2010). This appears to be reflected in a difference in susceptibility between strains of rats, as female Wistars gained more weight than female Sprague–Dawleys after olanzapine treatment (Kalinichev et al., 2005). Genetic variability within outbred strains of rats is likely to further contribute to individual differences in susceptibility. Indeed, we frequently observed considerable variability in behavioural responses to olanzapine between individual rats in our paradigms. This variability in response due to genetic differences reduces the statistical power to detect effects and may partially underlie the fact that previously observed effects are not always significant in a repeat experiment, even under similar dosing and housing conditions within the same lab (Hartfield et al., 2003 and Davoodi et al., 2008; Fell et al., 2004 and Fell et al., 2005a). Clinical studies investigating the effects of olanzapine treatment on body composition did not describe any reductions in lean muscle mass (Eder et al., 2001; Graham et al., 2005). This may be due to the fact that schizophrenic patients exhibit highly sedentary lifestyles (Gothelf et al., 2002; Jolley et al., 2006), causing lean muscle mass to already be reduced before initiation of antipsychotic medication (contrary to rats used in experiments, which show normal baseline activity levels). Nevertheless, antipsychotic-induced weight gain in humans has been attributed mainly to an increase in body fat (Eder et al., 2001; Graham et al., 2005) and the effect of olanzapine on adiposity levels, therefore,
Modelling olanzapine-induced weight gain in rats 173 appears to be adequately modelled in rats, irrespective of gender. Energy expenditure Locomotor activity In most studies that determined effects on locomotor activity, a reduction in activity was observed after olanzapine treatment (see Tables 1–3 ). As rats are mostly inactive during the light phase, a ‘floor effect’ may have prevented detection of a significant effect when locomotor activity was investigated during the light phase only (Kirk et al., 2004; Han et al., 2008; Snigdha et al., 2008; Muller et al., 2010; Skrede et al., 2012). Furthermore, due to the short half-life of olanzapine in rats, effects occurring at peak plasma levels (∼30 min) may disappear rapidly after the drug is cleared from the blood (Aravagiri et al., 1999). This most likely explains why the effect on locomotor activity disappeared in the light phase in studies in which olanzapine was administered in the dark phase (Arjona et al., 2004; Stefanidis et al., 2009; Evers et al., 2010) or was not significant when averaged over a 24 h period (Albaugh et al., 2011). The effect on locomotor activity appears to occur at doses that fail to affect feeding behaviour (van der Zwaal et al., 2010; Weston-Green et al., 2011). It is most likely a reflection of the sedative properties of olanzapine, for which rats appear very sensitive (Ahnaou et al., 2003). Considering the potential impact of spontaneous locomotor activity on NREE it is likely that energy expenditure was markedly reduced as a consequence (Rising et al., 1994; Novak and Levine, 2007). Surprisingly, most of the clinical studies that investigated effects of olanzapine on activity levels failed to detect any significant effects (Gothelf et al., 2002; Fountaine et al., 2010; Vidarsdottir et al., 2010), although reduced locomotor activity was observed in a study performed in anorexia patients (Hillebrand et al., 2005). This discrepancy may be due to limited statistical power and/or methodological differences. In the study by Gothelf et al. (2002), for instance, moderate to vigorous activity (measured by accelerometer at the hip) decreased by ±30%, but the effect did not reach significance (p = 0.13), most likely due to the limited number of subjects (n = 10) combined with baseline levels of activity that were already low. Furthermore, accelerometers were mostly carried on the wrist (an extremity), whereas telemetry, video tracking and ‘beam breaks’ are mostly used to assess locomotor activity in rats – measurements that are less influenced by movement of an individual limb (Fountaine et al., 2010; Vidarsdottir et al., 2010). Although it is possible that the effect of olanzapine on locomotor activity differs between rats and humans, somnolence and sedation are side effects that were reported by 18–81% of olanzapine-treated individuals in clinical studies (Biswasl et al., 2001; Lambert et al., 2003; Roerig et al., 2005; McEvoy et al., 2007; Scherk
et al., 2007; Gao et al., 2008) and caused a ±20% increase in drug discontinuation compared to placebo (Costa e Silva et al., 2001). It is, therefore, likely that olanzapine does affect activity levels in humans and thereby reduces energy expenditure, at least in the subset of patients that experience sedative side effects. Thermogenesis The effect of olanzapine on body temperature appears to depend on the dosing schedule applied (see Tables 1–3). After acute administration, a transient reduction in body temperature was observed, followed by an increase in body temperature several hours later (Evers et al., 2010; van der Zwaal et al., 2012b). Continuous administration via osmotic minipumps for 9 d did not produce significant effects, most likely because plasma levels did not rise as high as after acute injections (van der Zwaal et al., 2010). Conversely, administration via drinking water for 4 wk resulted in a gradual reduction in body core temperature in the dark phase (van der Zwaal et al., 2010), perhaps due to changes that only occur after long-term administration (e.g. receptor downregulation), which might also explain the observation of withdrawal-induced hyperthermia observed after discontinuation of olanzapine after 18 d (Goudie et al., 2007). A drug-induced decrease in body core temperature can occur due to downregulation of neural and humoral pathways involved in heat production, thereby resulting in reduced energy expenditure (Silva, 2006). Indeed, a reduction in thermogenic activity of brown adipose tissue was reported in female rats treated chronically with olanzapine (Stefanidis et al., 2009; Skrede et al., 2012). Conversely, a decrease in body core temperature can also occur due to redistribution of blood from the warm body core to the colder periphery, resulting in increased heat loss via the skin. In order to restore body core temperature, pathways involved in heat production need to be activated, which would result in increased energy expenditure (Kent et al., 1991). The rapid decline in body temperature observed after acute administration of olanzapine, followed by an increase in body temperature several hours later (Evers et al., 2010; van der Zwaal et al., 2012b), suggests that redistribution due to peripheral vasodilatation probably played a role (e.g. by antagonism at adrenergic receptors), with compensatory mechanisms subsequently being activated to increase heat production, resulting in increased body temperature after olanzapine was cleared from the plasma (Kent et al., 1991; Morrison et al., 2008). Taken together, based on body core temperature alone, it is not possible to establish the effect of olanzapine on thermogenesis and REE. Although effects of olanzapine on body temperature have not been systematically assessed in clinical studies, there are several reports of hypothermia occurring in patients (Fukunishi et al., 2003; Blass and Chuen, 2004). If olanzapine causes a decrease in thermogenesis in
174
Strain
Weight
Dose Diet (d) (mg/kg)
Route
ZT
Weight gain
Adipose tissue
Food intake
Albaugh et al., 2006–1 Albaugh et al., 2006−2 Albaugh et al., 2006−3 Arjona et al., 2004–1 Arjona et al., 2004−2 Belanoff et al., 2011 Chintoh et al., 2008
SD SD SD SD SD SD SD
220–225 220–225 220–225 250 250 8 wks 225–275
lf lf lf lf CP lf lf
33 20 5 10 10 18 25
CD p.o. CD p.o. p.o. p.o. MP s.c.
? ? ? 12 12 ? –
> (4–12 mg) – > > d8–10 > d8–10 > n.s. > (7.5 mg)
– > WAT-PM > WAT-PM – – – > WAT-m (7.5 mg)
Choi et al., 2007–1 Choi et al., 2007–2
SD SD
275–300 275–300
lf lf
11 5 11 5
MP s.c. MP i.p.
– –
n.s. > >
– –
> d1–12 – – > d6–8 – > n.s.>7.5 mg, (p = 0.08) > n.s.>(p = 0.07)
Cooper et al., 2005
HW
200
lf
20 bid: 1/2/4 i.p.
2+9
> (1/2/4 mg)
> WAT-P (2 + 4 mg) > 1st wk (2 + 4 mg)
Davoodi et al., 2009–1 Davoodi et al., 2009–2 Evers et al., 2010
SD SD Wi
200–225 200–225 232
lf lf mf
7 bid: 1 7 bid: 1 14 bid: 5
p.o. p.o. i.g.
4 + 11 4+ 11 12 + 18
> d3–7 > d7 > d6–14
– – –
> d2–7 > cum < da, >li
Fell et al., 2004
HL
200
lf
21 0.5/1/4
i.p.
5–7
> WAT-A: 4 mg
Fell et al., 2005a Fell et al., 2007
HL HL
165 250
lf 21 4 CPF 21 2
i.p. i.p.
5–7 5–7
> d3–10 (4 mg); > d3–5 (1 mg) > d3–21 > d1–21
> WAT-A n.s. >
wk1: (4 mg); wk2: > (1 + 4 mg) n.s. > > cum
Fell et al., 2008
HL
250
mf
28 2
i.p.
5–7
> d1–3; n.s. < d28
= WAT-A
Ferno et al., 2011 Goudie et al., 2002 Han et al., 2008–1 Han et al., 2008–2
SD Wi SD SD
230–250 258–355 220–250 220–250
lf lf lf lf
6 20 7 84
p.o. i.p. Ch Ch
3+9 ? ±5 + 9 8 + 16 +24 8 + 16 +24
> d2–6 > d2–20 > > wk1–8
– – > WAT-PM/P/S n.s. > WAT– PM/P/S
4–20* 4 4 1.2 1.2 bid: 1.2 2/7.5
bid: 3 bid: 4 tid: 0.5 tid: 0.5
< wk 3–4 n.s.< cum > dy 2–6 – n.s. > > wk1–3
Meal size
Meal freq.
– – – – – – –
– – – – – – –
– –
– –
– –
– –
–
–
– – – –
– – – –
Remarks Sedation at 20 mg/kg = Gastrocnemius muscle weight = Gastrocnemius muscle weight TM: FE d4–8 No effect on food preference < Act li 2 + 2.75 mg (beam breaks for 2 h)
Serum olanzapine levels MP i.p. group approx. 50% of MP s.c. group – – n.s. > WAT-PM (p = 0.14); weight gain less pronounced in 4 mg group; cumulative food intake > 1 mg only > n.s.< < Feeding rate – – PF: = BWG < da; n. n.s. < TM: < act da; temp s. < li da > li li; = total food intake – – 6-hsd 6-hsd 2-hsd; >P; < F diet; < act li (beam breaks for 1 h; 30 min p.i.); carcass composition: n.s. > fat % 2-hsd PF: = BWG = act li (5 min videotracking)
E. M. van der Zwaal et al.
Table 1. (Sub)chronic studies administering olanzapine to female rats
Huang et al., 2006 Kalinichev et al., 2005–1 Kalinichev et al., 2005–2 Kalinichev et al., 2006 Kirk et al., 2009–1 Kirk et al., 2009−2 Liebig et al., 2010
SD Wi
> > d3–14
> WAT-P/T > WAT-T
> cum > cum: d6–14
– –
– –
–
–
–
–
4 + 11 ±4 ±4 3
> (Wi>SD); < d1 (10 mg) > d7 > d2–4 > d3–4 > d4–12
– – – > WAT-A/S
– – – > d2–9
– – – –
– – – –
MP
–
> d5–28
> WAT-S/M/R
–
–
2.5/
p.o.
12 + 18
–
–
–
3 3 3
W p.o. p.o. p.o. PB
– 2–4 2+8 2+8 7 + 24
> all wks (2.5 mg) >wk2 (10 mg) > at wk 8 > d14 > d4–13 > d4–13 > d2–24
> WAT– M/R – – > WAT-PM/M –
> d3–5; >cum: d27 > all wks (2.5 mg) > d1–14 > d12–14 > d4–13 > d4–13 > d1–12
– – – – –
– – – – –
MP
> d8 + 12
–
> d5–14
–
–
> FE all wks (2.5 mg), wk 2 (10 mg) < act da (beam breaks) – 3-hsd; PF: = BWG and=WAT; < Thermogenic markers BAT < act da (TM); < BAT temp da; PF: > BWG vs. controls > FE
14 ±6
MP
> d11–14
–
> d10–14
–
–
> FE
14 tid: 0.25/ 0.5/1/2
CD
> d4–14 (0.5–2 mg)
2 mg > WAT-R/S; 1 > d8−14 (2 mg) mg > WAT-S
–
–
n.s.>WAT-R (1 mg), n.s. > WAT-S (0.5 mg), n.s> WAT-PM (2 mg); = BAT > FE (0.5–2 mg) Lean mass and > fat
abs = absolute food intake per day or week; act = locomotor activity; BAT = brown adipose tissue; bid/tid=bi/tri-daily administration of this dose; BWG = body weight gain; CD = in portion of cookie dough; Ch: in chocolate; CP = choice diet offering a high-carbohydrate diet (63% sucrose +20% cornstarch) and a high-protein diet (chow containing 23% casein); CPF = macronutrient choice diet offering separate pastes of high- carbohydrate diet (corn flour, maltodextrin + sucrose), protein (soya protein isolate) and fat (lard + soya oil); cum = cumulative food intake; D = mixed with diet; DEXA = dual energy X-ray absorpsiometry; da = dark phase; d = day; F = fat portion of CPF diet; FE = feeding efficiency; FI = food intake; FM = in portion of fortimel; h = hour(s); HL = Hooded Lister; HW = Han Wistar; i.g. = via intragastic cannula; i.p. intraperitoneal injection/administration; lf = less than 15% of kCal from fat; li = light phase; mf = 25–50% kCal from fat; MP = osmotic minipump; MRI = magnetic resonance imaging; MW = Mol:Wistar Hannover; n.s. = non-significant; P = protein portion of CPF diet; PB = in peanut butter; PF = pair-fed group; p.i. = post injection; p.o. = oral gavage; s.c. = subcutaneous injection/administration; SD = Sprague–Dawley; temp = body temperature; TM = telemetry data; W = in drinking water; WAT = white adipose tissue fat depot (-A = intra-abdominal, -M = mesenteric; -PM = parametrial, -S = subcutaneous, -R = retroperitoneal/perirenal, -T = sum of fat pad weights); Wi = Wistar; wk = week(s); ZT = Zeitgeber time of administration of dose(s); 2/5/6-hsd = housed per 2/5/6; *Stepwise dosing: wk 1: 4, wk 2: 8, wk 4: 12, wk 5: 20 mg/kg; > higher/more in treatment group; < lower/less in treatment group; ? = not indicated precisely; − = not assessed.
Modelling olanzapine-induced weight gain in rats 175
250 200–270
176 E. M. van der Zwaal et al.
Table 2. (Sub)chronic studies administering olanzapine to male rats
Strain
Weight
Diet
(d)
Dose (mg/kg)
Route
ZT
Weight gain
Adipose tissue
Food intake
Meal size
Meal freq
Albaugh et al., 2006 Albaugh et al., 2011
SD SD
220–225 200–225
lf lf
14 35
4–20* 4–12#
CD CD
? ?
= =
– > wk1–5
= =
– –
– –
Choi et al., 2007 Cooper et al., 2007
SD HW
315–345 260
lf lf
11 21
5 bid: 1/2/4
MP i.p.
– 2+9
= < (4 mg)
– > WAT-P (all doses)
= =
– –
– –
Guesdon et al., 2010 Minet-Ringuet et al., 2005 Minet-Ringuet et al., 2006a−1
Wi SD
250 300–320
mf CPF
13 42
1 1
D FM
– 2
= =
> Sum of WAT-S/E/R n.s. > WAT-S
> cum =
– –
– –
SD
175–200
mf
42
0.01/0.1/ 0.5/2
D
–
> WAT-S (0.5 + 2 mg)
–
–
–
Minet-Ringuet et al., 2006a−2
SD
200–220
mf
21
1
D
–
> d15–42 (0.5 + 2 mg) > d4–21
–
> wk3
–
–
Minet-Ringuet et al., 2006b
SD
175–200
CPF
42
1
PR
–
=
> WAT-S/E/R
=
–
–
Muller et al., 2010−1 Muller et al., 2010−2 Pouzet et al., 2003
Wi
3 mths
lf
120
1.5
W
–
=
> WAT-M/E
–
–
–
No effect food choice; n.s. < carcass weight Powdered food n.s. > carcass weight n.s. > WAT-E/R/M Powdered food wk 1 + 2; food intake measured in 3rd wk using liquid diet no effect food choice n.s. < carcass weight > BAT retroperitoneal + interscapular 5-hsd; = act li (2 h videotracking)
Wi
3 mths
mf
120
1.5
W
–
=
n.s. > WAT-E
–
–
–
5-hsd; = act li (2 h videotracking)
MW
200
lf
21
bid: 2.5/10
p.o.
12 + 18
= (2.5 mg); < (10 mg)
–
=
–
–
< FE (10 mg dose)
Remarks
Body composition MRI: lean mass < wk 3 + 5. n.s. < activity (24 h beam breaks); = FE Similar results with i.p. MP < Gastrocnemius muscle mass (all doses); n.s. > WAT-E
Shobo et al., 2011a
SD
2 mths
mf
42
5/7.5/10
D
–
> d13 + 17 (5 mg)
Shobo et al., 2011b Smith et al., 2011−1 Smith et al., 2011−2 Smith et al., 2011−3
SD SD SD SD
207–262 ±175 ±175 ±175
mf lf mf lf+mf$
42 42 42 42
1/1.5 10 10 10
EP s.c. s.c. s.c.
– 1 −6? 1 −6? 1 −6?
Victoriano et al., 2009−1 Victoriano et al., 2009−2 van der Zwaal et al., 2008 van der Zwaal et al., 2010−1 van der Zwaal et al., 2010−2
SD
175–220
mf
26
2
D
SD
175–220
mf
46
2
Wi
±337
lf
28
Wi
275–300
lf
Wi
275–300
Wi
275–300
van der Zwaal et al., 2010−3
> cum (5 mg)
–
–
Powdered food
= < > –
> WAT-S/E/R (5 mg) > WAT-S/E (7.5 mg) > WAT-S (10 mg) > WAT-S/E/R (1.5 mg) < > –
= < > >
– – – –
– – – –
Powdered food
–
=
=
=
D
–
=
> WAT-E
–
–
–
1/2.75/7.5
MP
–
=
=
=
–
–
9
1/2.75/7.5
MP
–
=
=
> (7.5 mg)
>
=
>
Preference for mf over lf diet, more pronounced in ola-group Meal patterning with ‘mash’ diet after 21 dys powdered diet
< Act (running wheel activity, 2.75 mg +7.5 mg) TM: < act; = temp (li + da); n.s. < gastrocnemius weight TM: < act; >Temp da (2.75 + 7.5 mg); < Temp li (7.5 mg) n.s. < gastrocnemius weight TM: < act; < Temp da wk3 + 4 < Gastrocnemius weight
Modelling olanzapine-induced weight gain in rats 177
abs = absolute food intake per day or week; act = locomotor activity; BAT = brown adipose tissue; bid = bi-daily administration of this dose; CD = in portion of cookie dough; CPF = macronutrient choice with separate sources of high-carbohydrate (53% cornstarch, 37% sucrose, powdered) /-protein (91% milk protein, powdered) /-fat (paste of 36% lard +54% soya bean oil) diet; cum = cumulative food intake; D = mixed with diet; d = day(s); da = dark phase; EP = electrical microinfusion pump; FE = feeding efficiency; FM = in portion of fortimel; h = hour(s); HFHS = high fat, high sucrose choice diet (saturated fat and 30% sucrose solution in addition to chow); HW = Han Wistar; i.p. = intraperitoneal injection; lf = less than 15% of kCal from fat; li = light phase; mf = 25–50% kCal from fat, mths = months; MP = subcutaneous osmotic minipump; MRI = magnetic resonance imaging; MW = Mol:Wistar Hannover; n.s. = non-significant; ola = olanzapine; p.o. = oral gavage; PR = in protein macronutrient diet; s.c. = subcutaneous injection; SD = Sprague–Dawley; temp = body temperature; TM = telemetry data; W = in drinking water; WAT = white adipose tissue fat depot (-A = abdominal, -E = epidydimal, -M = mesenteric/omental, -R = retroperitoneal/perirenal, -S = subcutaneous): Wi = Wistar; wk = week; ZT = Zeitgeber time of administration of dose(s); 5-hsd = housed per 5; *stepwise dosing: wk1: 4, wk2 + 3: 8, wk4: 12, wk5: 20; #stepwise dosing: wk1: 4, wk 2: 8, wk3: 12; $choice between lf and mf diet in homecage; >higher/more in treatment group vs. control; 1 > 0 mg
Davoodi et al., 2008
M
HL
350–385
ad lib
WS
0.3
i.p.
−30 min (li)
30 min intake of 10% intralipid emulsion
=
Hartfield et al., 2003
M
HL
270–420
ad lib
WS
0.1/0.3/1
i.p.
−30 min (li)
> (all doses)
Kirk et al., 2004
M
HL
350
85–90% BW
G
0.5
i.p.
−30 min (li ?)
30 min intake of 10% intralipid emulsion runway to food pellets (5 × 3 × 3 min blocks)
Lee and Clifton, 2002 Shobo et al., 2011a
M
HL
350–400
ad lib
WS
0.3/1/3
i.p.
−30 min (da)
M
SD
178–231
Chow 4 h/day
G
0.5/1/2
i.p.
−30 min
Snigdha et al., 2008
F
HL
250
ad lib
G
1
i.p.
−60 min (li)
60 min intake of palatable mash
>
Thornton-Jones et al., 2002
M
HL
‘adult’
85% BW
G
0.5
i.p.
−30 min (li)
runway to food pellets (5 × 3 × 3 min blocks)
van der Zwaal et al., 2012b
M
Wi
275–300
ad lib
WS
1
i.p.
−30 min (da)
1st meal size chow
> 1st trial block n.s. > total FI (p = 0.055) >
Test
pellet intake first 6 h dark phase 4 h chow intake
Effect on intake
> Total FI; > 1st trial block
= > (2 mg)
Remarks Dose-dependent > resting, especially 4 mg/kg (indicative of sedation) Ola reversed the thioperamide-induced reduction in intake > Interlick interval (indicative of sedation) at 0.3/1 mg dose n.s.
