Table 2.

Chronic preclinical studies examining antipsychotic effects on weight, adiposity and glucose metabolism.

A. Female Models
STUDY	MODEL	AP DOSE	EFFECT OF WEIGHT GAIN, FOOD INTAKE, ADIPOSITY METABOLISM
Albaugh et al. (2006) [33]	• Female C57Bl/6J and A/J mice • Female Wistar and Sprague-Dawley rats	• Olanzapine (mice); oral; ramped dosing 4–8 mg/kg; 10 days • Olanzapine (rats); oral; 4 mg/kg-20 mg/kg; 20 days • Clozapine (rats); oral; 4 mg/kg-8 mg/kg; 12 days • Clozapine + olanzapine (rats); oral; 4 mg/kg clz- 8 mg/kg clz + 4 mg/kg ola 27 days	(Olanzapine 10 days mice): • No significant change in body weight (trend for weight loss, and decreased food intake) (Olanzapine 20 days rats): • Increased body weight (plateau at 710 days without ramped dosing) • Increased food intake (starting after 24 h) • Increased fasting insulin levels (not fasting glucose) • No effect on glucose tolerance, increased insulin during OGTT (Clozapine − rats): No effect on body weight, food intake (Clozapine + Olanzapine-rats): Increased weight gain, increased food intake
Arjona et al. (2004) [34]	Female Sprague-Dawley rats	• Olanzapine; oral gavage; 1.2 mg/kg/day; 10 days • Haloperidol; oral gavage; 0.04 mg/kg/day; 10 days	• Olanzapine: Significant increase in body weight and food intake • Decreased total motor activity • Haloperidol: No effect on body weight or food intake
Coccurello et al. (2009) [59]	Female CD-1 mice	Olanzapine; 30 day mini-osmotic pump infusion; 4 mg/kg, 8 mg/kg	• Weight gain, hyperphagia, hyperglycemia, hyperinsulinemia, • Increased pancreatic insulin, increased insulin resistance, i.e., increased HOMA-IR • Increased periuterine adipose tissue • Decreased RER, decreased metabolic rate
Cooper et al. (2005) [35]	Female Han Wistar rats	Olanzapine; I.P.; 1,2,4 mg/kg/day; Twice daily, 20 days	• Increased body weight at 1 and 2 mg/kg (not 4 mg/kg) • Increased total food intake (1 mg/kg) • Increased perirenal fat pad mass (2 and 4 mg/kg) • No change in fasting glucose levels • Increased fasting insulin, HOMA-IR (1 mg/kg)
Cooper et al. (2008) [36]	• Female Wistar rats	• Clozapine I.P.; 1,2,4 mg/kg/day Twice daily 20 days • Clozapine; I.P.; 0.25–0.5 mg/kg	• Weight loss • No change in food intake, muscle mass, levels of glucose, insulin • Increased visceral adiposity
Ersland et al. (2015) [57]	Female Sprague Dawley rats	• Olanzapine; intramuscular injection; 100 mg/kg; Once • Risperidone; intramuscular injection; 30 mg/kg; Once • Olanzapine; intramuscular; 10 mg/kg; 3 doses; 35 days • Risperidone; intramuscular; 15 mg/kg; 3 doses; 35 days	• Single treatment: Increased food intake and weight gain • Repeated dosing: Increased food intake and weight gain
Ersland et al. (2019) [37]	Female Sprague Dawley rats	Olanzapine; intramuscular; 100 mg/kg; 13 months	Increased body weight gain; Glucose intolerance, insulin intolerance
Fell et al. (2004) [38]	Female hooded-Lister rats	Olanzapine; I.P.; 0.5–4 mg/kg 21 days	• Increased body weight and food intake • Increased intra-abdominal fat • No effect on wet/dry uterine weights
Ferno et al. (2011) [51]	Female Sprague-Dawley rats	Olanzapine; oral gavage; 3 mg/kg Twice daily	• Induced body weight gain • Increased food intake • Visual decrease in locomotor activity • Weight gain was not different from vehicle in pair-fed animals
Goudie et al. (2002) [39]	Female Wistar rats	Olanzapine; B.I.D.; 4 mg/kg 20 days	• Increased body weight • No effect of baseline body weight on weight gain response
Hu et al. (2014) [40]	Female Sprague-Dawley rats	Olanzapine; 4 mg/kg 7 days + 8 mg/kg; 7 days	• Increased weight gain, adiposity and food intake compared to vehicle treated rats • Olanzapine decreased BAT weight
Lykkegaard et al. (2008) [41]	Female Sprague-Dawley rats	Olanzapine; S.C. mini pumps; 1.75 mg/24 h; 28 days	• Increased food intake, body weight, adiposity • Impaired glucose tolerance (OGTT)
Mann et al. (2013) [42]	Famale Sprague-Dawley rats	Olanzapine; osmotic minipump, S.C., i.p.; 7.5 mg/kg/day 14 days	• Increase in body weight • increased food intake • Increased adiposity
Pouzet et al. (2003) [43]	Female Mol:Wistar Hannover rats	• Haloperidol; oral gavage; 0.08 and 0.31 mg/kg/day • Olanzapine; oral; 5.0 and 20 mg/kg/day; 21 days	• Haloperidol and olanzapine (5 mg/kg) increased body weight • Olanzapine (20 mg/kg) only significantly increased body weight at 2 weeks; • Olanzapine (5 mg/kg) increased cumulative food intake • All treatments decreased water intake
Skrede et al. (2012) [45]	Female Sprague-Dawley rats	• Olanzapine; oral gavage; 6 mg/kg • Aripiprazole; oral gavage; 6 mg/kg 13 days	• Olanzapine increased food intake and weight gain • No effect on fasting glucose or insulin • Olanzapine increased adipose tissue mass
Skrede et al. (2014) [44]	Female Sprague-Dawley rats	• Olanzapine; depot injection; 112 mg/kg; Once, Day 0 • Second injection 100 mg/kg Once, day 17 25 day total exposure	• Increased food intake, increased body weight • Decreased hypothalamic AMPKa1 at day 8
Skrede et al. (2017) [46]	• Female Sprague Dawley rats • Female OVX Sprague Dawley rats	Olanzapine; intramuscular; 100 mg/kg; Once; 8 days	• Increased food intake and body weight in WT rats • In OVX olanzapine did not potentiate increases in food intake, decreased body weight gain
B. Male Models
STUDY	MODEL	AP DOSE	EFFECT OF WEIGHT GAIN, FOOD INTAKE, ADIPOSITY METABOLISM
Ader et al. (2005) [47]	Male Dogs	• Olanzapine, oral; 15 mg/day • Risperidone; oral; 5 mg/day 21 days	• Olanzapine decreased fasting glucose and insulin compared to baseline • No significant body weight gain or food intake compared to placebo (olanzapine and risperidone) • Olanzapine significantly increased adiposity and decreased insulin sensitivity/decreased hepatic insulin sensitivity • Beta-cell insulin secretion/function failed during graded hyperglycemic test (olanzapine)
Albaugh et al. (2006) [33]	Male Wistar and Sprague-Dawley rats	Olanzapine; oral; 4–8 mg/kg 14 days	• No change in body weight or food intake
Albaugh et al. (2011) [48]	Male, SpragueDawley rats	Olanzapine; oral in food; ramped dosing 4 mg/kg-20 mg/kg 20 days	• Increased fat mass • Did no effect on body weight or food intake • Increased fasting glucose • Decreased glucose and insulin tolerance
Baptista et al. (1993) [49]	Male rats	• Olanzapine; mini-pumps; 5 mg/kg/day • Clozapine; mini pumps; 10 mg/kg/day 11 days	No effect on food intake or body weight in male rats
Cooper et al. (2007) [50]	Male Han Wistar rats	Olanzapine; I.P.; 1,2,4 mg/kg/day Twice daily 20 days	• Decreased body weight and no effect on food intake • Enhanced visceral adiposity and reduced lean muscle mass • No increase in plasma levels of insulin or glucose, decreased testosterone levels
Ferno et al. (2015) [51]	Male Sprague Dawley rats	• Olanzapine; depot injection; 100 mg/kg Once • Second injection 100 mg/kg Once, day 9 17 day total exposure	• Transient hyperphagia (~7 days) • Weight loss • Increased mesenteric WAT and liver weight • Decreased body weight compared to vehicle treated HFD-fed rats • Worsened adiposity compared to HFD fed rats
Houseknecht et al. (2007) [60]	Male Wistar Han rats	Clozapine; S.C.; 10 mg/kg; 5 days	• Increased insulin resistance (HIEC with 5th dose) • Changes in body weight not reported
Minet-Ringuet et al. (2006) [52]	Male Sprague-Dawley rats	• Olanzapine; oral with food; 0.01, 0.1, 0.5, 2 mg/kg; 6 weeks • Haloperidol; oral with food; 1 mg/kg; 3 weeks • Olanzapine; oral with food, 1 mg/kg; 3 weeks • Ziprasidone; oral with food; 10 mg/kg; 3 weeks	• Olanzapine (6 weeks): 0.5 mg/kg, 2 mg/kg increased body weight • Matched by increase in subcutaneous adipose tissue • Olanzapine (3 weeks) but not haloperidol or ziprasidone increased body weight and energy intake
Minet-Ringuet et al. (2006) [53]	Male Sprague-Dawley rats	• Haloperidol; oral in food; 1 mg/kg • Olanzapine; oral in food; 1 mg/kg. • Ziprasidone; oral in food; 10 mg/kg 6 Weeks	• No effect of treatment on body weight • Haloperidol and olanzapine increased adiposity (s.c. and retroperitoneal WAT) • Haloperidol increased retroperitoneal BAT • Olanzapine increased intrascapular BAT • No effect on cumulative caloric intake or food selection
Pouzet et al. (2003) [43]	Male Mol:Wistar Hannover rats	• Haloperidol; oral gavage; 0.08 and 0.31 mg/kg/day • Olanzapine; oral; 5.0 and 20 mg/kg/day 21 days	• Olanzapine (20 mg/kg) decreased body weight • All other groups had no effect on body weight • No effect of treatments on food intake
Smith et al. (2008) [54]	Male Sprague dawley rats	• Haloperidol; 0.25 mg/kg • Quetiapine;10 mg/kg • Clozapine;10 mg/kg 28 days	• Haloperidol and clozapine decreased body weight compared to vehicle treatment, no change in fat percentage • Quetiapine showed no difference in body weight, but 40% increase in fat pad mass
Smith et al. (2009) [55]	Male Sprague dawley rats (chow + HFD)	Clozapine (10 mg/kg), quetiapine (10 mg/kg) S.C.; 42 days	• Quetiapine alone increased adiposity, no additive effect with HFD • Clozapine alone decreased adiposity; no additive effect of HFD • both quetiapine and clozapine increased blood glucose levels 1-h post treatment at 42 days of treatment • worsened glucose tolerance via GTT, additive to HFD

AP: antipsychotic, OGTT: oral glucose tolerance test, HIEC: Hyperinsulinemic-euglycemic clamp, WAT: white adipose tissue, BAT: brown adipose tissue, HFD: high fat diet, GTT: glucose tolerance test.