Atypical antipsychotics and diabetic ketoacidosis: a review
ABSTRACT RATIONALE: Atypical antipsychotics have been linked to weight gain and type 2 diabetes, but are also associated with diabetic ketoacidosis (DKA), which can occur more acutely and in the absence of weight gain. OBJECTIVES: Our aim was to review current case reports of DKA in the context of atypical antipsychotic treatment to better understand (a) the scope of the problem, (b) its relationship to different atypical agents, (c) risk factors, (d) long-term outcome, and (e) putative mechanisms of action. METHOD: Searches in PubMed/Medline, as well as the University of Toronto's Scholar Portal, were performed for all relevant articles/abstracts in English. RESULTS: Sixty reports, yielding 69 cases, affirm that DKA is a rare but serious risk with almost all atypical antipsychotics; however, liability seems to vary between agents, at least partially mirroring risk of weight gain. Mean age of onset was 36.9 years (range 12-80), with 68 % of cases occurring in males, and 41 % in individuals of African American or African Caribbean descent. Over one third of cases present with either no weight gain or weight loss, and 61 % of these require ongoing treatment for glycemic control. Death occurred in 7.25 % of cases. CONCLUSION: While the underlying mechanisms are not well understood, antipsychotic-related DKA can occur soon after treatment onset and in the absence of weight gain. Although rare, clinicians must remain vigilant given its acute onset and potential lethality.
- SourceAvailable from: link.springer.comPsychopharmacology 09/2013; 230(1). DOI:10.1007/s00213-013-3259-6 · 3.99 Impact Factor
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ABSTRACT: Although clozapine, olanzapine, and other atypical antipsychotic drugs (APDs) have fewer extrapyramidal side effects, they have serious metabolic side effects such as substantial weight gain, intra-abdominal obesity, and type 2 diabetes mellitus. Given that most patients with mental disorders face chronic, even life-long, treatment with APDs, the risks of weight gain/obesity and other metabolic symptoms are major considerations for APD maintenance treatment. This review focuses on the effects of APDs on weight gain, appetite, insulin resistance, and glucose dysregulation, and the relevant underlying mechanisms that may be help to prevent and treat metabolic side effects caused by APD therapy.Endocrinology and metabolism clinics of North America 09/2013; 42(3):545-63. DOI:10.1016/j.ecl.2013.05.006 · 2.86 Impact Factor
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ABSTRACT: Second generation antipsychotics (SGAs) are widely prescribed to treat various disorders, most notably schizophrenia and bipolar disorder; however, SGAs can cause abnormal glucose metabolism that can lead to insulin-resistance and type 2 diabetes mellitus side-effects by largely unknown mechanisms. This review explores the potential candidature of the acetylcholine (ACh) muscarinic M3 receptor (M3R) as a prime mechanistic and possible therapeutic target of interest in SGA-induced insulin dysregulation. Studies have identified that SGA binding affinity to the M3R is a predictor of diabetes risk; indeed, olanzapine and clozapine, SGAs with the highest clinical incidence of diabetes side-effects, are potent M3R antagonists. Pancreatic M3Rs regulate the glucose-stimulated cholinergic pathway of insulin secretion; their activation on β-cells stimulates insulin secretion, while M3R blockade decreases insulin secretion. Genetic modification of M3Rs causes robust alterations in insulin levels and glucose tolerance in mice. Olanzapine alters M3R density in discrete nuclei of the hypothalamus and caudal brainstem, regions that regulate glucose homeostasis and insulin secretion through vagal innervation of the pancreas. Furthermore, studies have demonstrated a dynamic sensitivity of hypothalamic and brainstem M3Rs to altered glucometabolic status of the body. Therefore, the M3R is in a prime position to influence glucose homeostasis through direct effects on pancreatic β-cells and by potentially altering signalling in the hypothalamus and brainstem. SGA-induced insulin dysregulation may be partly due to blockade of central and peripheral M3Rs, causing an initial disruption to insulin secretion and glucose homeostasis that can progressively lead to insulin resistance and diabetes during chronic treatment.CNS Drugs 10/2013; 27(12). DOI:10.1007/s40263-013-0115-5 · 4.38 Impact Factor