Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses

Melkersson, Kristina; Dahl, Marja­‐Liisa

doi:10.1007/s00213-003-1529-4

Cited by 96 publications

(75 citation statements)

References 40 publications

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“…In contrast, SGAs' leptin effects (Monteleone et al, 2002;Melkersson and Dahl, 2003;Ebenbichler et al, 2005;Murashita et al, 2005;Sporn et al, 2005;Theisen et al, 2005) seem to be entirely attributable to increased adiposity (Haupt et al, 2005;Sporn et al, 2005). In a cross-sectional study of plasma leptin and adiposity in schizophrenic patients treated with olanzapine (N ¼ 27), risperidone (N ¼ 24), or a typical antipsychotic (N ¼ 21), and in 124 healthy controls, BMI correlated with leptin levels in the entire sample.…”

Section: Putative Mechanisms Of Sgas-induced Weight Gainmentioning

confidence: 98%

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

138

142

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Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies. INTRODUCTIONObesity has reached pandemic proportions and it is rapidly surpassing smoking as a number one killer in the industrialized world (Sturm, 2002;Skidmore and Yarnell, 2004). Its annual cost to the American society is staggering, and is estimated to be around $117 billion owing to related illnesses and loss of productivity (National Institute of Diabetes and Digestive and Kidney Diseases, 2005).In schizophrenia, obesity is twice as prevalent as in the general public, afflicting over half this patient population (Allison et al, 1999a;Dixon et al, 2000; American Diabetes Association, 2004;Marder et al, 2004;Wirshing, 2004). Besides negative psychosocial impacts (distorted selfesteem and societal stigmatization) and medications noncompliance, schizophrenics appear to be particularly susceptible to the detrimental medical sequelae of obesity such as the 'Metabolic Syndrome', which is a cluster of cardiovascular risk factors, including abdominal adiposity, insulin resistance, impaired, glucose tolerance, dyslipidemia, and hypertension (McKee et al, 1986;Mukherjee et al, 1996;Brown et al, 2000;Haupt and Newcomer, 2002;Ryan and Thakore, 2002;Ryan et al, 2003;Holt et al, 2004;Kohen, 2004;Marder et al, 2004;Lieberman et al, 2005).Excessive body weight gain (BWG) could be attributed to a constellation of endocrine, molecular, genetic, demographic, and lifestyle-related factors. Provided that a common tra...

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Section: Putative Mechanisms Of Sgas-induced Weight Gainmentioning

confidence: 98%

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

Neuropsychopharmacol

138

142

View full text Add to dashboard Cite

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“…2014). The most common adverse effects of these compounds include GI manifestations, drowsiness, extrapyramidal symptoms, cardiac effects, elevation of liver enzymes, and obesity, which can be associated with insulin resistance and fatty liver (Melkersson and Dahl 2003; Begriche et al. 2011; De Fazio et al.…”

Section: Introductionmentioning

confidence: 99%

“…2013). However, the pathophysiological significance of this effect remains unclear since this drug classically induces hyperinsulinemia, even in the absence of weight gain (Melkersson and Dahl 2003; Teff et al. 2013).…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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“…The increased prevalence of type 2 diabetes and abnormalities in glucose regulation in schizophrenia after clozapine treatment have been reported. [8][9][10][11] However, levels of insulin and insulin sensitivity in schizophrenia treated with clozapine appear to be controversial: two studies report higher insulin levels and blunted insulin sensitivity 12,13 while another reports no changes in insulin levels and insulin resistance. 14 Significant elevations in triglyceride levels have also been reported in association with clozapine treatment.…”

Section: Introductionmentioning

confidence: 99%

Glucose–insulin homeostasis, lipid profiles and GH-IGF-IGFBP axis in clozapine-treated schizophrenic obesity versus non-psychiatric obesity

Huang

Liou

et al. 2007

Int J Obes

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Objective: Obese patients with schizophrenia being treated with clozapine and non-psychiatric obese are often assumed to share the same physiological changes in obesity. The aim of this study was to identify possible metabolic and hormonal differences between non-psychiatric obese subjects (OB) and obese patients with schizophrenia being treated with clozapine (OSC). Subjects: Fifty-one normal healthy subjects (Nor, body mass index (BMI):23.270.3), 50 OB (BMI:31.770.7) and 71 OSC (BMI:30.470.5). Measurements: Anthropometric, metabolic and hormonal parameters were determined by anthropometry, enzyme autoanalyzer, immunoassay and enzyme-linked immunosorbent assay. Results: Triglyceride, total cholesterol divided by high-density lipoprotein (HDL) cholesterol (TC/HDL) and leptin levels were significantly higher whereas the HDL and the molar ratio of insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein (IGFBP)-3 levels were significantly lower in both OB and OSC groups than those in the Nor group. Compared to normal subjects, insulin and homeostasis model assessment (HOMA) index levels were significantly higher in OSC, and, in OSC, insulin sensitivity and insulin-like growth factor (IGF)-1 were significantly lower. Although the anthropometric parameters in the OB and OSC groups were similar, in the OSC group the waist-to-hip ratio (WHR), insulin levels and HOMA index were significantly higher, while insulin sensitivity, cholesterol, low-density lipoprotein (LDL) cholesterol, TC/HDL, LDL/HDL, IGF-1 and IGF-1/IGFBP-3 molar ratio were lower, than those of the OB group. Conclusion: Insulin homeostasis and lipid profiles in clozapine-treated schizophrenic obesity were different from those in nonpsychiatric obesity with similar anthropometric parameters, body weight and BMI. Among the three groups, the highest fasting insulin, the lowest insulin sensitivity and the highest HOMA index occurred in the OSC group. The OSC group was characterized by impaired glucose-insulin homeostasis, abnormal lipid profiles and hormonal changes in the GH-IGF-IGFBP axis and in leptin.

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Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses

Cited by 96 publications

References 40 publications

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Role of endoplasmic reticulum stress in drug‐induced toxicity

Glucose–insulin homeostasis, lipid profiles and GH-IGF-IGFBP axis in clozapine-treated schizophrenic obesity versus non-psychiatric obesity

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