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, risperi-done, 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.

Second-Generation (Atypical) Antipsychotics and Metabolic Effects: A Comprehensive Literature Review.

Appropriate prescribing in elderly people: how well can it be measured and optimised?

Oxidative stress has been implicated in the pathogenesis of diverse disease states, and may be a common pathogenic mechanism underlying many major psychiatric disorders, as the brain has comparatively greater vulnerability to oxidative damage This review aims to examine the current evidence for the role of oxidative stress in psychiatric disorders, and its academic and clinical implications A literature search was conducted using the Medline, Pubmed, PsycINFO, CINAHL PLUS, BIOSIS Previews, and Cochrane databases, with a time-frame extending to September 2007 The broadest data for oxidative stress mechanisms have been derived from studies conducted in schizophrenia, where evidence is available from different areas of oxidative research, including oxidative marker assays, psychopharmacology studies, and clinical trials of antioxidants For bipolar disorder and depression, a solid foundation for oxidative stress hypotheses has been provided by biochemical, genetic, pharmacological, preclinical therapeutic studies and one clinical trial Oxidative pathophysiology in anxiety disorders is strongly supported by animal models, and also by human biochemical data Pilot studies have suggested efficacy of N-acetylcysteine in cocaine dependence, while early evidence is accumulating for oxidative mechanisms in autism and attention deficit hyperactivity disorder In conclusion, multi-dimensional data support the role of oxidative stress in diverse psychiatric disorders These data not only suggest that oxidative mechanisms may form unifying common pathogenic pathways in psychiatric disorders, but also introduce new targets for the development of therapeutic interventions

/pdf/oxidative-stress-in-psychiatric-disorders-evidence-base-and-2pe1tb4wua.pdf

Oxidative stress in psychiatric disorders : evidence base and therapeutic implications

Objective: The development of both type I and type II diabetes after initiation of some atypical neuroleptics has been reported, primarily in studies involving small series of patients. This study used administrative data from a large national sample of patients with a diagnosis of schizophrenia to compare the prevalence of diabetes mellitus in patients receiving prescriptions for atypical and typical neuroleptics. Method: All outpatients with schizophrenia treated with typical and atypical neuroleptics over 4 months in 1999 in the Veterans Health Administration of the Department of Veterans Affairs (VA) were included in this study. Patients treated with atypical neuroleptics were those who received prescriptions for clozapine, olanzapine, risperidone, or quetiapine. Patients with a diagnosis of diabetes were also identified by using ICD-9 codes in VA administrative databases. The prevalence of diabetes mellitus across age groups and among patients receiving prescriptions for different atypical neuroleptics was examined with multiple logistic regression. Results: A total of 38,632 patients were included in the study: 15,984 (41.4%) received typical neuroleptics and 22,648 (58.6%) received any atypical neuroleptic (1,207 [5.3%] received clozapine; 10,970 [48.4%], olanzapine; 955 [4.2%], quetiapine; and 9,903 [43.7%], risperidone; 387 patients received prescriptions for more than one atypical neuroleptic). When the effects of age were controlled, patients who received atypical neuroleptics were 9% more likely to have diabetes than those who received typical neuroleptics, and the prevalence of diabetes was significantly increased for patients who received clozapine, olanzapine, and quetiapine, but not risperidone. However, for patients less than 40 years old, all of the atypical neuroleptics were associated with a significantly increased prevalence of diabetes. Conclusions: In this large group of patients with schizophrenia, receipt of a prescription for atypical neuroleptics was significantly associated with diabetes mellitus.

http://psychrights.org/research/digest/nlps/seroquel/seroquelmedicalstudies/gen. cause resp. ex 44.pdf

Association of Diabetes Mellitus With Use of Atypical Neuroleptics in the Treatment of Schizophrenia

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.

/pdf/statin-adverse-effects-a-review-of-the-literature-and-5byfkzyay5.pdf

Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

/pdf/hyperglycemia-associated-with-olanzapine-22ajmfm90g.pdf

Hyperglycemia associated with olanzapine.

OBJECTIVE:To evaluate the reliability of a medication appropriateness index (MAI) modified for elderly outpatients in a non-Veterans Affairs setting.DESIGN:Reliability study.SETTING:General community.PARTICIPANTS:Ten community-dwelling elderly (> 65 y) taking five or more regularly scheduled medications and participating in a university-based health service intervention study.MAIN OUTCOME MEASURES:Interrater reliability of MAI ratings of 65 medications made by two clinical pharmacists for individual items and for an overall summed score was calculated by use of κ statistics and intraclass correlation coefficient.RESULTS:The interrater agreement for each of the individual MAI items was high for both appropriate and inappropriate ratings and ranged from 80% to 100% (overall κ = 0.64). Overall agreement for the summed score was good (intraclass correlation = 0.80).CONCLUSIONS:The modified MAI is a reliable instrument for evaluation of medication appropriateness in a non-Veterans Affairs, ambulatory, elderly ...

Reliability of a Modified Medication Appropriateness Index in Ambulatory Older Persons

The disproportionate use of medications, combined with age-related pharmacokinetic and pharmacodynamic changes, places older adults at high risk for medication related problems (MRPs). MRPs demonstrate significant morbidity, mortality and economic impact among healthcare systems. The negative outcomes associated with MRPs emphasise the need for more careful and thorough assessments of drug therapy among older adults. In the 1990s a number of methods and instruments were developed to assist in the assessment of medication appropriateness. These tools may be categorised by criteria as: implicit, explicit or one utilising a combination of implicit and explicit criteria. This article reviews these available tools and outlines the advantages and disadvantages of each. In conclusion, those instruments considered to be comprised of both implicit and explicit criteria offer a more thorough assessment of medication appropriateness.

Assessing medication appropriateness in the elderly: a review of available measures.

OBJECTIVE:To review the efficacy of vitamin E in the treatment of tardive dyskinesia (TD).DATA SOURCES:Published articles and abstracts in English were identified from January 1986 to March 1999 by MEDLINE and International Pharmaceutical Abstracts searches using the terms vitamin E, α-tocopherol, and tardive dyskinesia. Additional articles were identified from the references of the retrieved articles and cross- referencing selected articles.DATA EXTRACTION:All clinical trials evaluating the use of vitamin E in human subjects with TD were reviewed. Selected articles also included those considered to be helpful in providing a basic introduction to TD pathophysiology and management.DATA SYNTHESIS:TD occurs in approximately 20% of patients treated with neuroleptics. The resulting dyskinesias can be irreversible and are often psychologically and physically debilitating. Recent research suggests that TD may be a result of neuronal damage inflicted by free radicals generated from increased neurotransmitter turn...

Vitamin E in the Treatment of Tardive Dyskinesia

ObjectiveTo describe two elderly patients with dementia and severe nighttime wandering in whom Zolpidem restored normal sleep patterns.Case SummariesA 90-year-old African-American woman (case 1) and an 87-year-old African-American man (case 2) presented with nighttime wandering associated with the progression of Alzheimerlike dementia. Both patients had previously not responded to bedtime regimens of benzodiazepines, trazodone (an antidepressant used for its sedative properties), and neuroleptics. Both patients averaged 2–3 hours of sleep each night. Low-dose Zolpidem (5 mg hs) was initiated with only partial response. The dosage was titrated in 5-mg increments until the optimum dosage was reached for case 1 (15 mg hs) and case 2 (10 mg hs). These dosages have proven to be effective over a period of 3 months, with both patients averaging 7–8 hours of sleep each night with no apparent adverse effects.DiscussionDementia produces inversion of the circadian sleep/ wake cycle, leading to daytime sedation and n...

Penny S. Shelton

Papers

Hyperglycemia associated with olanzapine.

Reliability of a Modified Medication Appropriateness Index in Ambulatory Older Persons

Assessing medication appropriateness in the elderly: a review of available measures.

Vitamin E in the Treatment of Tardive Dyskinesia

Zolpidem for dementia-related insomnia and nighttime wandering.