PhD Student, University of Ottawa
Antipsychotic drugs are prescribed to treat serious psychotic disorders. Atypical antipsychotics (AAPs), second-generation drugs, are dopamine antagonists acting on dopamine receptors. They offer many advantages over their predecessors: they enhance cognitive function in patients who adhere to the prescribed treatment; they also result in fewer extrapyramidal symptoms, rendering them more desirable from a clinical point of view.
Evidence from case studies supports a possible association between the use of prescribed atypical antipsychotic drugs and hyperglycemic diabetic complications, namely Diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HSS). DKA and HSS are serious diabetic complications that occur mainly in patients living with type 1 diabetes mellitus and type 2 diabetes mellitus, respectively. Both conditions are associated with a high level of morbidity and mortality, as well as high health care costs.
This research project will focus on the patterns of use, and the safety and efficacy profiles of prescribed AAP drugs to treat psychotic disorders, which may result in adverse hyperglycemic diabetic complications. The Cerner HealthFacts TM Data warehouse is a United States-based database that contains electronic health records (EHR) from 500 United States medical facilities since the year 2000 for 50 million patients. HealthFacts is a time-stamped EHR, which provides access to patient demographics, characteristics of the treating center, prescribed and dispensed medications, and medical diagnosis and procedures.
A quantitative analysis of trends in the use of prescribed AAP drugs in patients with psychotic disorders will provide information on the hyperglycaemic risks associated with their uses in certain populations. A nested case-control study will be used for that purpose.
The prescribed use of atypical antipsychotic drugs to treat psychotic disorders could potentially lead to the development of DKA and HSS, and even mortality. Existing co-morbidities and risk factors may contribute to this association.
Abstract: As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT(2A) and 5-HT(2C) serotonin receptors, H(1)-histamine receptors, alpha(1)- and alpha(2)-adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H(1)-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman rho=-0.72; p<0.01), as were affinities for alpha(1A) adrenergic (rho=-0.54; p<0.05), 5-HT(2C) (rho=-0.49; p<0.05) and 5-HT(6) receptors (rho=-0.54; p<0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H(1), alpha(2A), alpha(2B), 5-HT(2A), 5-HT(2C), and 5-HT(6) receptors were most highly correlated with the first principal component, and affinities for the D(2), 5-HT(1A), and 5-HT(7) receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H(1) and alpha(1A) receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H(1)-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H(1)-histamine receptor antagonists are known to induce weight gain with chronic use, and because H(1)-histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H(1)-histamine receptors.
Pub.: 12 Mar '03, Pinned: 01 Aug '17
Abstract: The authors report a case with life-threatening hyperglycemia and acidosis in a patient with no previous diabetic history following treatment with olanzapine. A 35-year-old woman with a history of bipolar affective disorder treated with olanzapine presented with severe diabetic ketoacidosis. She had no prior history of diabetes or risk factors for diabetes. Glycosylated hemoglobin (HbA1c) on admission blood sample suggested that long-term glycemic control had been poor. The authors postulate that treatment with olanzapine precipitated hyperglycemia, an elevated creatine kinase level, and a high amylase level. A concurrent urinary tract infection precipitated an episode of sepsis, which combined to precipitate life-threatening diabetic ketoacidosis. During her stay in the intensive treatment unit and subsequently in the medical ward, her blood glucose concentration was intensively monitored. She remains on insulin therapy, and her antipsychotic medication was changed to risperidone. Newer atypical antipsychotic drugs such as olanzapine have been introduced with the benefit of fewer extrapyramidal side effects. A number of these have reported metabolic side effects of uncertain etiology such as diabetic ketoacidosis and elevated creatine kinase. The authors believe that the diabetic ketoacidosis occurred in this patient, who had no previous history of diabetes mellitus. Blood glucose should be monitored in patients taking olanzapine, especially in those patients with risk factors for diabetes mellitus.
Pub.: 30 Jan '07, Pinned: 01 Aug '17
Abstract: Data from 191 post-mortem cases where post-mortem blood beta-hydroxybutyrate (βHB) and acetone concentrations and vitreous humor glucose concentrations (where available) had been measured were retrospectively investigated to determine the markers required to identify and distinguish between Alcoholic Ketoacidosis (AKA), Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS). Blood βHB concentrations above 250 μg/mL were considered significant and it was shown to be the preferred marker of ketoacidosis. All cases with significant βHB detected also had acetone present (greater than 2mg/dL) demonstrating that acetone can be used as a marker to identify ketoacidosis and can be used to indicate when βHB measurement is necessary. Vitreous humor glucose concentrations above 6.9 mmol/L were considered high and indicative of hyperglycemia prior to death. Vitreous humor glucose concentrations can be used to distinguish between DKA and ketoacidosis from other causes and to identify deaths due to HHS. The data showed that ketoacidosis can occur without a history of alcoholism or diabetes. Many diabetics are undiagnosed for many years. Therefore, DKA or HHS should be considered in sudden or unexplained deaths and glucose should be routinely measured especially in cases with risk factors for diabetes including obesity, old age, a history of mental health problems or treatment with atypical antipsychotic drugs including clozapine, olanzapine, quetiapine and risperidone.
Pub.: 16 Aug '11, Pinned: 01 Aug '17
Abstract: Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of treatment with some atypical antipsychotic drugs in children and youth. Because drug-associated DKA is rare, large automated health outcomes databases may be a valuable data source for conducting pharmacoepidemiologic studies of DKA associated with exposure to individual antipsychotic drugs. However, no validated computer case definition of DKA exists. We sought to assess the positive predictive value (PPV) of a computer case definition to detect incident cases of DKA, using automated records of Tennessee Medicaid as the data source and medical record confirmation as a "gold standard."The computer case definition of DKA was developed from a retrospective cohort study of antipsychotic-related type 2 diabetes mellitus (1996-2007) in Tennessee Medicaid enrollees, aged 6-24 years. Thirty potential cases with any DKA diagnosis (ICD-9 250.1, ICD-10 E1x.1) were identified from inpatient encounter claims. Medical records were reviewed to determine if they met the clinical definition of DKA.Of 30 potential cases, 27 (90%) were successfully abstracted and adjudicated. Of these, 24 cases were confirmed by medical record review (PPV 88.9%, 95% CI 71.9 to 96.1%). Three non-confirmed cases presented acutely with severe hyperglycemia, but had no evidence of acidosis.Diabetic ketoacidosis in children and youth can be identified in a computerized Medicaid database using our case definition, which could be useful for automated database studies in which drug-associated DKA is the outcome of interest.
Pub.: 25 Nov '11, Pinned: 01 Aug '17
Abstract: Determination of the incidence rate of diabetic ketoacidosis (DKA) in type 2 diabetes mellitus (T2DM) is urgent, in response to the safety issue with use of the glucose lowering drugs, sodium-glucose cotransporter-2 inhibitors, and DKA.We extracted data of adult patients with T2DM from a medical claims database in Japan, which included 1 million individuals. The study period was 2005-2013, before the era of sodium-glucose cotransporter-2 inhibitors. The inclusion criteria were patients with a diagnosis of T2DM who had at least 1 prescription for a glucose-lowering drug. We further examined the number of DKA-related admissions and medication use prior to admission. Calculation of DKA incidence was on a patient-years basis, with 95% confidence interval using a Poisson distribution.Of 36,674 adult patients with T2DM, we identified 74 cases admitted for DKA, with an estimated DKA incidence of 0.48/1000 (95% confidence interval, 0.38-0.60/1000) patient-years. Of these 74 cases, approximately two-thirds of patients had no past or recent history of glucose-lowering drug use before admission for DKA.This study estimated that the incidence of DKA was 0.48/1000 patient-years in Japan, similar to previous studies. We also found that underuse of glucose-lowering medication was common among patients hospitalized for DKA. KEY POINTS The population-based incidence of DKA in T2DM is largely unknown. In Japan, the estimated DKA incidence was 0.48/1000 (95% CI, 0.38-0.60/1000) patient-years. Drug-induced DKA is an emerging research area, and our results can be applied to evaluating the risk of DKA.
Pub.: 29 Jul '17, Pinned: 01 Aug '17