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Biomedical subjects

John W Newcomer

Publications and source records attributed to John W Newcomer.

At least 19 recordsLinked to original sources
PubMed2006

The metabolic effects of antipsychotic medications.

OBJECTIVES: To review current evidence for the hypothesis that treatment with antipsychotic medications may be associated with increased risks for weight gain, insulin resistance, hyperglycemia, dyslipidemia, and type 2 diabetes mellitus (T2DM) and to examine the relation of adiposity to medical risk. METHODS: We identified relevant publications through a search of MEDLINE from the years 1975 to 2006, using the following primary search parameters: "diabetes or hyperglycemia or glucose or insulin or lipids" and "antipsychotic." Meeting abstracts and earlier nonindexed articles were also reviewed. We summarized key studies in this emerging literature, including case reports, observational studies, retrospective database analyses, and controlled experimental studies. RESULTS: Treatment with different antipsychotic medications is associated with variable effects on body weight, ranging from modest increases (for example, less than 2 kg) experienced with amisulpride, ziprasidone, and aripiprazole to larger increases during treatment with agents such as olanzapine and clozapine (for example, 4 to 10 kg). Substantial evidence indicates that increases in adiposity are associated with decreases in insulin sensitivity in individuals both with and without psychiatric disease. The effects of increasing adiposity, as well as other effects, may contribute to increases in plasma glucose and lipids observed during treatment with certain antipsychotics. CONCLUSION: Treatment with certain antipsychotic medications is associated with metabolic adverse events that can increase the risk for metabolic syndrome and related conditions such as prediabetes, T2DM, and cardiovascular disease.

Antipsychotic Agents↗
PubMed2006

Medical risk in patients with bipolar disorder and schizophrenia.

Patients with schizophrenia and bipolar disorder are vulnerable to developing key modifiable risk factors for cardiovascular disease, such as obesity, smoking, hypertension, dyslipidemia, and type 2 diabetes mellitus. In addition, mood stabilizers, anticonvulsants, and antipsychotic medications, which are commonly used to treat schizophrenia and bipolar disorder, have been linked to risk for adverse metabolic changes in patients. This article reviews the current literature on the prevalence of medical risk factors in the general population as well as in those patients with schizophrenia or bipolar disorder and discusses treatment strategies and lifestyle changes that patients can make in order to reduce their risks for certain diseases.

Anticonvulsants↗
PubMed2006

Medical risk in patients with bipolar disorder and schizophrenia.

Patients with schizophrenia and bipolar disorder are vulnerable to developing key modifiable risk factors for cardiovascular disease, such as obesity, smoking, hypertension, dyslipidemia, and type 2 diabetes mellitus. In addition, mood stabilizers, anticonvulsants, and antipsychotic medications, which are commonly used to treat schizophrenia and bipolar disorder, have been linked to risk for adverse metabolic changes in patients. This review reports the prevalence of medical risk factors in the general population as well as in those patients with schizophrenia or bipolar disorder and discusses treatment strategies and lifestyle changes that patients can make in order to reduce their risks for certain diseases.

Antipsychotic Agents↗
PubMed2005

From clinical research to clinical practice: a 4-year review of ziprasidone.

Ziprasidone is a second-generation antipsychotic that received Food and Drug Administration approval in February 2001. It has a unique receptor profile that includes high-affinity antagonist activity at dopamine D2 receptors, inverse agonist activity at serotonin (5-HT)2A receptors, agonist activity at 5-HTlA receptors, and a relatively high affinity for the serotonin and norepinephrine transporters. The 5-HTIA affinity, together with the inhibitory effect on mono-amine reuptake, may underlie the hypothesized beneficial effects on comorbid affective and cognitive abnormalities in schizophrenia and schizoaffective disorder. The short-term efficacy of ziprasidone for core positive symptoms of schizophrenia appears to be comparable to other conventional and atypical antipsychotics. The short-term efficacy of ziprasidone in acute mania has been established based on two 3-week, double-blind, placebo-controlled trials.Open-label treatment for up to 52 weeks confirms the sustained efficacy and safety of ziprasidone in bipolar disorder. Maintenance studies in schizophrenia and schizoaffective disorder indicate that long-term ziprasidone therapy is effective in preventing relapse, while maintaining cognitive and psychosocial benefits. The safety database suggests that the overall cardiovascular and cerebrovascular risk associated with ziprasidone is lower than with other atypicals, with notably lower risk of drug-related increases in weight, glucose, or lipids. The data also suggest a modestly increased risk of QTc prolongation that is not dose related or linked to torsades de pointes. Switching to ziprasidone from other atypicals appears to improve both clinical symptoms and metabolic parameters, though more studies are needed to fully characterize these benefits. This monograph summarizes the efficacy, tolerability, and safety of oral ziprasidone in the treatment of schizophrenia, schizoaffective disorder, and bipolar mania.

Antipsychotic Agents↗
PubMed2005

Plasma leptin and adiposity during antipsychotic treatment of schizophrenia.

Alterations in plasma leptin have been reported in schizophrenia patients treated with antipsychotics, suggesting the hypothesis that impairments in leptin secretion or signaling might play a role in antipsychotic-induced weight gain. Plasma leptin was measured in 72 schizophrenia patients chronically treated with olanzapine (n=27), risperidone (n=24) or typical antipsychotics (n=21) and 124 healthy adult control subjects. ANCOVA was used to test effects of adiposity (body mass index kg/m2; BMI), subject group (treated patients vs untreated controls), and treatment group (specific medication groups and untreated controls) on plasma leptin concentrations. Additional analyses were performed in a subset of patients and controls individually matched for BMI to further assess group differences in plasma leptin independent of adiposity. BMI strongly predicted plasma leptin concentrations in the overall sample. In addition, a significant three-way interaction between BMI, subject group, and gender was observed. In the individually BMI-matched sample, modestly reduced plasma leptin levels (effect size 0.4 SD) were observed in treated patients in comparison to the BMI-matched healthy controls, with both groups including males and females. However, no differences in plasma leptin levels were observed in the matched sample when separately comparing male patients vs untreated male controls and female patients vs untreated female controls. Plasma leptin in chronically treated patients with schizophrenia is strongly predicted by adiposity, similar to untreated healthy individuals despite adequate power to detect a difference. The results argue against a role for defective leptin secretion or sensitivity in the weight gain induced by antipsychotic medications.

Adipose Tissue↗
PubMed2005

Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review.

Increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical) antipsychotics have raised concerns about a possible association between these metabolic effects and treatment with these medications. This comprehensive literature review considers the evidence for and against an association between glucose or lipid dysregulation and eight separate second-generation antipsychotics currently available in the US and/or Europe, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone and aripiprazole. This review also includes an assessment of the potential contributory role of treatment-induced weight gain in conferring risk for hyperglycaemia and dyslipidaemia during treatment with different antipsychotic medications. Substantial evidence from a variety of human populations, including some recent confirmatory evidence in treated psychiatric patients, indicates that increased adiposity is associated with a variety of adverse physiological effects, including decreases in insulin sensitivity and changes in plasma glucose and lipid levels. Comparison of mean weight changes and relative percentages of patients experiencing specific levels of weight increase from controlled, randomised clinical trials indicates that weight gain liability varies significantly across the different second generation antipsychotic agents. Clozapine and olanzapine treatment are associated with the greatest risk of clinically significant weight gain, with other agents producing relatively lower levels of risk. Risperidone, quetiapine, amisulpride and zotepine generally show low to moderate levels of mean weight gain and a modest risk of clinically significant increases in weight. Ziprasidone and aripiprazole treatment are generally associated with minimal mean weight gain and the lowest risk of more significant increases. Published studies including uncontrolled observations, large retrospective database analyses and controlled experimental studies, including randomised clinical trials, indicate that the different second-generation antipsychotics are associated with differing effects on glucose and lipid metabolism. These studies offer generally consistent evidence that clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidaemia. Inconsistent results, and a generally smaller effect in studies where an effect is reported, suggest limited if any increased risk for treatment-induced diabetes mellitus and dyslipidaemia during risperidone treatment, despite a comparable volume of published data. A similarly smaller and inconsistent signal suggests limited if any increased risk of diabetes or dyslipidaemia during quetiapine treatment, but this is based on less published data than is available for risperidone. The absence of retrospective database studies, and little or no relevant published data from clinical trials, makes it difficult to draw conclusions concerning risk for zotepine or amisulpride, although amisulpride appears to have less risk of treatment-emergent dyslipidaemia in comparison to olanzapine. With increasing data from clinical trials but little or no currently published data from large retrospective database analyses, there is no evidence at this time to suggest that ziprasidone and aripiprazole treatment are associated with an increase in risk for diabetes, dyslipidaemia or other adverse effects on glucose or lipid metabolism. In general, the rank order of risk observed for the second-generation antipsychotic medications suggests that the differing weight gain liability of atypical agents contributes to the differing relative risk of insulin resistance, dyslipidaemia and hyperglycaemia. This would be consistent with effects observed in nonpsychiatric samples, where risk for adverse metabolic changes tends to increase with increasing adiposity. From this perspective, a possible increase in risk would be predicted to occur in association with any treatment that produces increases in weight and adiposity. However, case reports tentatively suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes that occur during treatment. Pending further testing from preclinical and clinical studies, limited controlled studies support the hypothesis that clozapine and olanzapine may have a direct effect on glucose regulation independent of adiposity. The results of studies in this area are relevant to primary and secondary prevention efforts that aim to address the multiple factors that contribute to increased prevalence of type 2 diabetes mellitus and cardiovascular disease in populations that are often treated with second-generation antipsychotic medications.

Animals↗
PubMed2005

Metabolic and endocrine disturbances in psychiatric disorders: a multidisciplinary approach to appropriate atypical antipsychotic utilization.

Patients with psychiatric disorders have an increased rate of cardiovascular morbidity and mortality compared with the general population. Metabolic issues such as weight gain, dyslipidemia, diabetes mellitus, diabetic ketoacidosis,and pancreatitis have been reported with the use of antipsychotic agents. Although atypical antipsychotics have not been linked directly to the development of metabolic syndrome, these medications have been shown to increase risk factors that can lead to metabolic and endocrine disturbances. Therefore, clinicians should provide ongoing monitoring for patients who are being treated for psychiatric disorders with these agents. According to the 2004 Consensus Report on Antipsychotics, screening measures should include baseline and follow-up monitoring of personal/family histories, weight (body mass index), waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile.

Antipsychotic Agents↗
PubMed2004

Effects of dexamethasone on declarative memory function in posttraumatic stress disorder.

Alterations in the hypothalamic-pituitary-adrenal (HPA) axis and hippocampal-based memory have been associated with posttraumatic stress disorder (PTSD), and the administration of exogenous glucocorticoids has been shown to result in a transient verbal declarative memory impairment in healthy human subjects. The purpose of this study was to assess the effects of the glucocorticoid dexamethasone on verbal declarative memory function in patients with PTSD. Forty-two men and women with (n=14) and without (n=28) PTSD received placebo or dexamethasone (1 and 2 mg on two successive days) in a double-blind, randomized fashion. Declarative memory was assessed with paragraph recall at baseline (day 1) and day 3. There was a significant interaction between diagnosis and drug (dexamethasone vs. placebo) on paragraph recall related to a relative detrimental effect of dexamethasone on memory function in healthy subjects, but not those with PTSD. These findings are consistent with an altered sensitivity of declarative memory function in PTSD to regulation by glucocorticoids, possibly explainable by alterations in glucocorticoid receptors in the hippocampus or other brain regions mediating declarative memory.

Adult↗
PubMed2004

Effects of glucocorticoids on declarative memory function in major depression.

BACKGROUND: Major depression has been associated with hypercortisolemia in a subset of patients with depression. Administration of exogenous cortisol and other glucocorticoids to healthy human subjects has been observed to result in a transient impairment in verbal declarative memory function. The purpose of this study was to assess the effects of the glucocorticoid, dexamethasone, on verbal declarative memory function in patients with untreated unipolar major depressive disorder (MDD). METHODS: Fifty two men and women with (n = 28) and without (n = 24) MDD received placebo or dexamethasone (1 mg and 2 mg on 2 successive days) in a double-blind, randomized fashion. Declarative memory was assessed with paragraph recall at baseline (day 1) and day 3. RESULTS: There was a significant interaction between diagnosis and drug (dexamethasone vs. placebo) on paragraph recall. In the healthy subjects, memory improved from baseline to day 3 with placebo and was unchanged with dexamethasone, whereas in MDD patients memory function showed a pattern of decreasing with placebo and improving with dexamethasone from baseline to day 3. CONCLUSIONS: These findings are consistent with an altered sensitivity of declarative memory function in MDD to regulation by glucocorticoids. Possible explanations of the findings include alterations in glucocorticoid receptors in the hippocampus or other brain regions mediating declarative memory, or differential sensitivity to dexamethasone-induced reductions in cortisol, in patients with MDD.

Adolescent↗
PubMed2004

Metabolic risk during antipsychotic treatment.

BACKGROUND: Compared with the general population, individuals with schizophrenia demonstrate an increased prevalence of obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD). Increased adiposity is associated with decreases in insulin sensitivity, leading to an increased risk of hyperglycemia and hyperlipidemia. Antipsychotic medications can increase adiposity, and a range of evidence from case reports, observational studies, retrospective database analyses, and controlled experimental studies (including randomized clinical trials) suggests that treatment with antipsychotic medications may be associated with an increased risk for insulin resistance, hyperglycemia, dyslipidemia, and T2DM. OBJECTIVE: This article reviews current evidence for the hypothesis that treatment with antipsychotic medications may be associated with increased risks for weight gain, insulin resistance, hyperglycemia, dyslipidemia, and T2DM, and examines the relationship of adiposity to medical risk. METHODS: Relevant publications were identified through a search of MEDLINE from 1975 to the present using the primary search parameters "diabetes or hyperglycemia or glucose or insulin or lipids" and "antipsychotic." Meeting abstracts and earlier nonindexed articles concerning antipsychotic-associated weight gain and metabolic disturbance were also reviewed. Key studies in this emerging literature were summarized, including case reports, observational studies, retrospective database analyses, and controlled experimental studies. RESULTS: Individual antipsychotic medications are associated with different degrees of treatment-induced increases in body weight and adiposity, ranging from modest effects (<2 kg) with amisulpride, ziprasidone, and aripiprazole to clinically significant increases with olanzapine (4-10 kg). In addition to strong evidence concerning the effect of adiposity on insulin sensitivity in nonpsychiatric populations, increased adiposity in patients with schizophrenia has been associated with decreases in insulin sensitivity; this and other effects may contribute to increases in plasma glucose concentrations and lipid levels. CONCLUSION: Metabolic changes in psychiatric patients who receive antipsychotic agents can contribute to the development of the metabolic syndrome and increase the risk for T2DM and CVD.

Antipsychotic Agents↗
PubMed2004

The Atypical Antipsychotic Therapy and Metabolic Issues National Survey: practice patterns and knowledge of psychiatrists.

A nationwide survey in 2003 of 300 randomly selected psychiatrists who routinely treat schizophrenia with atypical antipsychotic therapy was conducted to ascertain practice patterns and attitudes regarding metabolic disturbances during atypical antipsychotic therapy with an emphasis on how these perceptions impact therapeutic decision making. Psychiatrists generally believe that some atypical antipsychotic drugs are associated with metabolic disturbances and that atypical antipsychotics differ in their risk for metabolic disturbances. A majority of respondents (82%) believed that patients with schizophrenia-even those not receiving atypical antipsychotic therapy-are at greater risk for metabolic abnormalities than the general population. A majority of respondents recognized weight gain and diabetes mellitus (59% and 51%, respectively) as potential metabolic complications of atypical antipsychotic therapy, while only some recognized dyslipidemia and certain acute metabolic decompensations like diabetic ketoacidosis (22% and 2%, respectively). Large minorities of respondents (48% and 43%) indicated a willingness to risk weight gain and/or diabetes for the benefits of atypical antipsychotics, possibly because metabolic issues were regarded as long-term issues. However, large majorities also stated that they considered metabolic issues when selecting atypical antipsychotic therapy for some or all of their patients (90%), and that emergence of metabolic dysfunction prompted them to change atypical antipsychotic treatment regimens (85%). Additional efforts at continuing education and communication regarding metabolic outcomes associated with atypical antipsychotic therapy, as well as critical reviews in this area, may help clarify atypical antipsychotic treatment risks and benefits. The results from the survey indicate that psychiatrists are aware of and concerned about metabolic risks and how they differ across the atypical antipsychotic class. The impact of additional data and educational efforts in this area, such as a recently published consensus statement from the American Diabetes Association and other organizations, remains to be assessed.

Antipsychotic Agents↗
PubMed2004

Atypical antipsychotics and metabolic dysregulation: evaluating the risk/benefit equation and improving the standard of care.

Atypical antipsychotics are a major advance in the management of schizophrenia. The reevaluation of widely held risk/benefit assessments of the various atypical antipsychotics provides an opportunity to improve treatment patterns. The best available clinical trial evidence indicates that efficacy among the atypical antipsychotics (at equivalent doses) is very similar, but safety and tolerability profiles differ significantly. Atypical antipsychotics differ markedly in their potential to cause metabolic disturbances, including obesity, diabetes, dyslipidemia, and the metabolic syndrome; clozapine and olanzapine carry the greatest risks, atypical antipsychotics like risperidone and quetiapine have lower risks, and newer agents like ziprasidone and aripiprazole are associated with minimal metabolic risks. Results from the Atypical Antipsychotic Therapy and Metabolic Issues (AtAMI) survey define important opportunities for improving medical and psychiatric outcomes during atypical antipsychotic therapy. (See accompanying article by Newcomer et al) Additional educational and research efforts are required to increase understanding of common conditions such as the metabolic syndrome, increase awareness of uncommon but serious events like diabetic ketoacidosis, and pancreatitis, and identify appropriate strategies for monitoring the risks/benefits of atypical antipsychotic therapy. As clinicians refine practice patterns regarding the atypical antipsychotics, they may require additional knowledge and resources to fully incorporate risk/benefit considerations and optimize long-term psychiatric and medical outcomes.

Antipsychotic Agents↗
PubMed2004

Abnormalities of glucose metabolism associated with atypical antipsychotic drugs.

The introduction of atypical antipsychotic drugs has provided a clear benefit for many schizophrenia patients, with less risk for the extrapyramidal side effects associated with conventional antipsychotics. However, some antipsychotics are associated with an increased risk of adverse metabolic outcomes, including weight gain, dyslipidemia, and hyperglycemia. Increases in adiposity and disturbances in glucose and lipid metabolism represent a serious health risk in a patient that may be predisposed to these metabolic conditions. The increased risk for diabetes with certain antipsychotics may be associated with the risk of treatment-induced weight gain. However, other mechanisms, including effects on central neurotransmitters and direct effects on glucose metabolism, may contribute to the development of disordered glucose metabolism. The purpose of this article is to review the association between antipsychotic medications and obesity, insulin resistance, and diabetes, including the mechanisms through which these changes might be effected.

Antipsychotic Agents↗
PubMed2003

Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype.

In previous studies, adults with Alzheimer's disease (AD) showed memory enhancement when plasma insulin levels were raised to 85 microU/ml, whereas normal adults' memory was unchanged. Degree of memory enhancement was also related to apolipoprotein E (apoE) genotype status for AD patients. Response differences between normal and AD groups could reflect dose-response differences for insulin. To examine this question, 22 adults with AD and 15 normal adults received five doses of insulin on separate days in counterbalanced order, resulting in five plasma insulin levels (10, 25, 35, 85 and 135 microU/ml), while plasma glucose levels of ~100 mg/dl were maintained. Cognitive performance and plasma APP levels were measured after 120 min of infusion. Relative to baseline, AD patients who were not apoE- epsilon 4 homozygotes had improved memory at higher insulin levels of 35 and 85 microuU/ml, whereas normal adults and AD patients who were epsilon 4 homozygotes showed improved memory at insulin levels of 25 microU/ml. Normal adults' memory was also improved at insulin levels of 85 microU/ml. Plasma APP was lowered for adults with AD without the epsilon 4 allele at higher levels (85 microU/ml) than for normal adults and epsilon 4 homozygotes, who showed decreased APP at the 35 microU/ml level. AD patients with a single epsilon 4 allele showed a different pattern of insulin effects on APP than did other subjects. In general, few effects of insulin were seen at the highest dose for any subject group. These results support a role for insulin in normal memory and APP modulation that follows a curvilinear response pattern, and suggest that AD patients who are not epsilon 4 homozygotes have reduced sensitivity to insulin that may interfere with such modulation.

Aged↗
PubMed2002

Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia.

BACKGROUND: Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Glucoregulatory abnormalities have also been associated with the use of antipsychotic medications themselves. While antipsychotics may increase adiposity, which can decrease insulin sensitivity, disease- and medication-related differences in glucose regulation might also occur independent of differences in adiposity. METHODS: Modified oral glucose tolerance tests were performed in schizophrenic patients (n = 48) receiving clozapine, olanzapine, risperidone, or typical antipsychotics, and untreated healthy control subjects (n = 31), excluding subjects with diabetes and matching groups for adiposity and age. Plasma was sampled at 0 (fasting), 15, 45, and 75 minutes after glucose load. RESULTS: Significant time x treatment group interactions were detected for plasma glucose (F(12,222) = 4.89, P<.001) and insulin (F(12,171) = 2.10, P =.02) levels, with significant effects of treatment group on plasma glucose level at all time points. Olanzapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at all time points, in comparison with patients receiving typical antipsychotics as well as untreated healthy control subjects. Clozapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at fasting and 75 minutes after load, again in comparison with patients receiving typical antipsychotics and untreated control subjects. Risperidone-treated patients had elevations in fasting and postload glucose levels, but only in comparison with untreated healthy control subjects. No differences in mean plasma glucose level were detected when comparing risperidone-treated vs typical antipsychotic-treated patients and when comparing typical antipsychotic-treated patients vs untreated control subjects. CONCLUSION: Antipsychotic treatment of nondiabetic patients with schizophrenia can be associated with adverse effects on glucose regulation, which can vary in severity independent of adiposity and potentially increase long-term cardiovascular risk.

Adult↗