title: Metabolic side-effects of the novel second-generation antipsychotic drugs asenapine and iloperidone: a comparison with olanzapine.
abstract: BACKGROUND
  The second generation antipsychotic (SGA) drugs are widely used in psychiatry due to their clinical efficacy and low incidence of neurological side-effects. However, many drugs in this class cause deleterious metabolic side-effects. Animal models accurately predict metabolic side-effects for SGAs with known clinical metabolic liability. We therefore used preclinical models to evaluate the metabolic side-effects of glucose intolerance and insulin resistance with the novel SGAs asenapine and iloperidone for the first time. Olanzapine was used as a comparator.
  
  
  METHODS
  Adults female rats were treated with asenapine (0.01, 0.05, 0.1, 0.5, 1.0 mg/kg), iloperidone (0.03, 0.5, 1.0, 5.0, 10.0 mg/kg) or olanzapine (0.1, 0.5, 1.5, 5.0, 10.0 mg/kg) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with asenapine (0.1 and 1.0 mg/kg), iloperidone (1.0 and 10 mg/kg) or olanzapine (1.5 and 15 mg/kg) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC).
  
  
  RESULTS
  Asenapine showed no metabolic effects at any dose in either test. Iloperidone caused large and significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with both doses in the HIEC. Olanzapine caused significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with the higher dose in the HIEC.
  
  
  CONCLUSIONS
  In preclinical models, asenapine shows negligible metabolic liability. By contrast, iloperidone exhibits substantial metabolic liability, comparable to olanzapine. These results emphasize the need for appropriate metabolic testing in patients treated with novel SGAs where current clinical data do not exist.
authors: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Heidi N
authors: HN
authors: Boyda
authors: Ric M
authors: RM
authors: Procyshyn
authors: Catherine C Y
authors: CC
authors: Pang
authors: Erin
authors: E
authors: Hawkes
authors: Daniel
authors: D
authors: Wong
authors: Chen Helen
authors: CH
authors: Jin
authors: William G
authors: WG
authors: Honer
authors: Alasdair M
authors: AM
authors: Barr
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects*; D001786:Blood Glucose / Q000187:drug effects; D003986:Dibenzocycloheptenes; D005215:Fasting / Q000097:blood / Q000378:metabolism; D005260:Female; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects*; D006946:Hyperinsulinism / Q000097:blood / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D007555:Isoxazoles / Q000009:adverse effects*; D008660:Metabolism / Q000187:drug effects*; D000077152:Olanzapine; D010880:Piperidines / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D001786:Blood Glucose; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; D007555:Isoxazoles; D010880:Piperidines; D001569:Benzodiazepines; C522667:asenapine; D000077152:Olanzapine; C081732:iloperidone