A four-year naturalistic prospective study of cardiometabolic disease in antipsychotic-treated patients.

The relationship between antipsychotic use and cardiovascular morbidity and mortality is controversial. There is a lack of long-term prospective studies investigating changes in cardiometabolic risk in patients treated with antipsychotic drugs. We report data from a 4-year prospective study. Patients (89) underwent detailed metabolic and cardiovascular risk assessment at 4-years which included anthropometric assessment, blood pressure, lipid profile, and an oral glucose tolerance test. We used the homeostatic model assessment to determine insulin resistance, and calculated 10-year cardiovascular risk scores. Mean age of subjects was 44.7 (± 11.5) years, and 52% were male. The prevalence of type 2 diabetes was 8%, and 38.4% fulfilled diagnostic criteria for the metabolic syndrome. With the exception of increased central adiposity over the 4-year follow-up period (p < 0.001), other cardiometabolic parameters were generally unchanged. There was a high prevalence of dyslipidaemia, but only 16.9% were prescribed lipid-lowering treatment. Commencing lipid-lowering therapy was associated with a reduction in cardiovascular risk score (OR 7.9, 95% CI = 1.3 to 48.7; p = 0.02). Patients established on longer-term antipsychotic treatment show less dramatic metabolic changes than those occurring in the early stages of treatment, but have a high burden of cardiovascular risk. Lipid-lowering therapy is associated with a significant reduction in cardiovascular risk.

Olanzapine-induced hyperglycaemic coma and neuroleptic malignant syndrome: case report and review of literature.

Although the relationship between antipsychotic medication, particularly second-generation antipsychotics (SGAs), and metabolic disturbance is increasingly accepted, there is an important, but little recognised, potential interaction between this and the other important serious adverse effect of neuroleptic malignant syndrome (NMS). We report a case of a 35-year old female who developed new onset type II diabetes mellitus with hyperosmolar hyperglycaemic coma and acute renal failure following treatment with a SGA for a first manic episode. The history is strongly suggestive of concurrent NMS. This case raises important questions about non-ketotic, hyperosmolar diabetic coma with antipsychotics, the possible association between hyperglycaemia and hyperthermia, and the direction of causality in this, the recognition of either syndrome when they co-exist and management issues in such patients. These questions are considered in the context of currently available literature.

Antiglucocorticoid treatments for mood disorders.

BACKGROUND: Antiglucocorticoids may have antidepressant effects and have been reported to be efficacious in the treatment of severe psychiatric disorders. The efficacy and safety of antiglucocorticoid treatments for mood disorders is the subject of this systematic review. OBJECTIVES: To compare the efficacy and safety of antiglucocorticoid agents in the treatment of mood episodes (manic, mixed affective or depressive) with placebo or alternative drug treatment in mood disorders. SEARCH STRATEGY: CCDANCTR-Studies and CCDANCTR-References were searched on 11-9-2007. Additional searches of electronic databases were conducted in December 2006. Conference proceedings were searched. Experts and pharmaceutical companies were contacted. SELECTION CRITERIA: Randomised controlled trials comparing antiglucocorticoid drugs in the treatment of mood episodes with placebo or alternative drug treatment in mood disorders were selected. DATA COLLECTION AND ANALYSIS: Data were extracted and the methodological quality of each study was assessed independently by two review authors. Meta-analyses were performed using Review Manager software. Relative risk (RR) with 95% confidence intervals (CI) were calculated for dichotomous outcomes. For continuous data, weighted mean differences (WMD) were calculated. MAIN RESULTS: Nine studies met criteria for inclusion. A number of drugs were examined, including mifepristone [RU-486], ketoconazole, metyrapone and DHEA. Three trials were in patients with psychotic major depression (pMDD), five trials in non-psychotic major depression and one trial in bipolar disorder. When examining all trials together across all affective episodes, there was no significant difference in the overall proportion of patients responding to antiglucocorticoid treatment over placebo, although the mean change in HAM-D scores indicated a significant difference in favour of treatment (WMD -4.54, 95%CI -6.78 to -2.29). Of the five trials in non-psychotic depression (unipolar or bipolar), there was a significant difference favouring treatment (HAM-D 50% reduction: RR 0.72, 95%CI 0.56 to 0.91). In pMDD, there was no evidence of an overall antidepressant effect (HAM-D 50% reduction: RR 0.98, 95%CI 0.79 to 1.22) or an effect on overall psychopathology (BPRS 30% reduction: RR 0.96, 95%CI 0.76 to 1.22). In these subtypes, the mean change in HAM-D indicated a significant difference in favour of treatment. AUTHORS' CONCLUSIONS: The use of antiglucocorticoids in the treatment of mood disorders is at the proof-of-concept stage. Considerable methodological differences exist between studies with respect to the compounds used and the patient cohorts studied. Results in some diagnostic subtypes are promising and warrant further investigation to establish the clinical utility of these drugs in the treatment of mood disorders.

A prospective study of glycaemic status in anti-psychotic-treated patients.

Anti-psychotic drugs, particularly the second generation, or ;atypical' agents, have been implicated in the development of metabolic dysfunction such as diabetes mellitus. There is a paucity of longitudinal data on the natural history of glucose homeostasis in anti-psychotic-treated patients, and there are no universally accepted strategies for managing worsening glycaemic control in this population. Notwithstanding, several guidelines recommend switching to a ;lower risk' agent if patients develop worsening glycaemic control during anti-psychotic treatment. We prospectively followed a cohort of 106 anti-psychotic-treated patients from across the diagnostic spectrum, and investigated changes in glycaemic status. Between baseline and follow-up assessment (mean follow-up time, 599.3 [SD+/-235.4] days glycaemic status was unchanged in 78 (86.7%) patients; 5 (5.6%) reverted from impaired fasting glucose (IFG) to normoglycaemia in the absence of any pharmacological or lifestyle intervention and all were taking a ;high risk' drug (clozapine or olanzapine). These preliminary data suggest that progression to overt diabetes mellitus is not inevitable in patients who develop IFG during anti-psychotic treatment. Switching to another agent simply on the basis of the development of IFG may not offer any advantage, especially if the mental state is stable.

Minimising metabolic and cardiovascular risk in schizophrenia: diabetes, obesity and dyslipidaemia.

People with schizophrenia are at greater risk of obesity, Type 2 diabetes, dyslipidaemia and hypertension than the general population. This results in an increased incidence of cardiovascular disease (CVD) and reduced life expectancy, over and above that imposed by their mental illness through suicide. Several levels of evidence from data linkage analyses to clinical trials demonstrate that treatment-related metabolic disturbances are commonplace in this patient group, and that the use of certain second-generation antipsychotics may compound the risk of developing the metabolic syndrome and CVD. In addition, smoking, poor diet, reduced physical activity and alcohol or drug abuse are prevalent in people with schizophrenia and contribute to the overall CVD risk. Management and minimization of metabolic risk factors are pertinent when providing optimal care to patients with schizophrenia. This review recommends a framework for the assessment, monitoring and management of patients with schizophrenia in the UK clinical setting.

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs.

AIMS/HYPOTHESIS: Intraportal infusion of serotonin (5-hydroxytryptamine, 5-HT) or inhibitors of its cellular uptake stimulate hepatic glucose uptake in vivo by either direct or indirect mechanisms. The aims of this study were to determine the direct effects of 5-HT in hepatocytes and to test the hypothesis that atypical antipsychotic drugs that predispose to type 2 diabetes counter-regulate the effects of 5-HT. MATERIALS AND METHODS: Rat hepatocytes were studied in short-term primary culture. RESULTS: Serotonin (5-HT) stimulated glycogen synthesis at nanomolar concentrations but inhibited it at micromolar concentrations. The stimulatory effect was mimicked by alpha-methyl-5-HT, a mixed 5-HT1/5-HT2 receptor agonist, whereas the inhibition was counteracted by a 5-HT2B/2C receptor antagonist. alpha-Methyl-5-HT stimulated glycogen synthesis additively with insulin, but unlike insulin, did not stimulate glucose phosphorylation and glycolysis, nor did it cause Akt (protein kinase B) phosphorylation. Stimulation of glycogen synthesis by alpha-methyl-5-HT correlated with depletion of phosphorylase a. This effect could not be explained by elevated levels of glucose 6-phosphate, which causes inactivation of phosphorylase, but was explained, at least in part, by decreased phosphorylase kinase activity in situ. The antipsychotic drugs clozapine and olanzapine, which bind to 5-HT receptors, counteracted the effect of alpha-methyl-5-HT on phosphorylase inactivation. CONCLUSIONS/INTERPRETATION: This study provides evidence for both stimulation and inhibition of glycogen synthesis in hepatocytes by serotonergic mechanisms. The former effects are associated with the inactivation of phosphorylase and are counteracted by atypical antipsychotic drugs that cause hepatic insulin resistance. Antagonism of hepatic serotonergic mechanisms may be a component of the hepatic dysregulation caused by antipsychotic drugs that predispose to type 2 diabetes.

Hypothalamic-pituitary-adrenal axis and bipolar disorder.

There is robust evidence demonstrating abnormalities of the HPA axis in bipolar disorder. Hypercortisolism may be central to the pathogenesis of depressive symptoms and cognitive deficits, which may in turn result from neurocytotoxic effects of raised cortisol levels. Manic episodes may be preceded by increased ACTH and cortisol levels, leading to cognitive problems and functional impairments. Identification and effective treatment of mood and cognitive symptoms of mood disorders are clinical goals, but currently available treatments may fall short of this ideal. Manipulation of the HPA axis has been shown to have therapeutic effects in preclinical and clinical studies, and recent data suggest that direct antagonism of GRs maybe a future therapeutic strategy in the treatment of mood disorders.

Prevalence of obesity, glucose homeostasis disorders and metabolic syndrome in psychiatric patients taking typical or atypical antipsychotic drugs: a cross-sectional study.

AIMS/HYPOTHESIS: Atypical antipsychotic drugs may be associated with obesity and other components of the metabolic syndrome, but this relationship is controversial. We investigated the hypothesis that atypical antipsychotics are associated with a greater degree of metabolic dysfunction than typical agents. METHODS: Metabolic parameters were measured in 103 diagnostically heterogeneous psychiatric out-patients. Patients had been taking typical or atypical antipsychotic drugs for a minimum of six months. RESULTS: Sixty-nine patients were taking atypical agents, 20 typical agents and 14 a combination. Mean values (+/-SD) for the whole group were: age 43.8 years (11.4); BMI 29.1 kg/m(2) (5.1); W:H ratio 0.88 (0.09). Metabolic parameters, including beta cell function and insulin sensitivity, measured by HOMA, did not differ with regard to the prescribed antipsychotic drug. Six patients had undiagnosed diabetes, six patients had impaired fasting glucose, and eight fulfilled criteria for the metabolic syndrome, all of whom were taking atypical agents (p=0.07 vs typical agents). Subgroup analyses of those taking atypical agents revealed differences in BMI (mean, +/-SD) between olanzapine (27.3 kg/m(2)+/-5.1) and quetiapine (31.9 kg/m(2)+/-5.1), p=0.01, and HbA(1c) (olanzapine, 5.1%+/-0.6 vs quetiapine, 5.6%+/-0.6; p=0.03). Other atypical agents were intermediate with regard to these parameters. CONCLUSIONS: Obesity, dyslipidaemia and abnormalities of glucose homeostasis are prevalent in this group. Patients taking atypical agents showed a trend towards abnormalities of glucose homeostasis. Prospective studies are needed to explore the precise relationship between antipsychotic drugs, glucose homeostasis, obesity and the metabolic syndrome.

Labour ward midwives' perceptions of stress.

This exploratory study set out to examine labour ward midwives' perceptions of stress. It utilized a combination of two self-report questionnaires, one devised by McGrath et al. and the GHQ12. Additional qualitative data were collected by asking midwives to produce narratives about recent stressful events. A convenience sample of the 43 midwives formed the study population and a response rate of 77% was achieved. Quantitative data were analysed using descriptive statistics and qualitative narratives were explored for content analysis. Midwives in this study demonstrated their awareness of stress in their working and personal lives and many took active steps to redress the negative effects with exercise, hobbies and talking with colleagues. However, the study revealed that 78% of the midwives indicated that having insufficient time to perform their duties was very stressful, paralleled by their perceived inability to influence work-based decisions. The study revealed that both medical and midwifery colleagues frustrated their endeavours to change an unsatisfactory condition. The GHQ12 revealed 30% of the midwives had scores above the threshold level of 2 indicating psychiatric morbidity and this is of major concern. The narratives revealed that lack of communication between the professionals about decision making was a major source of stress and as a result of this study efforts to improve multidisciplinary communication through the development of journal clubs and planned social activities is under consideration by the unit. Overall, the findings from this study highlight stress as a potential, occupational health problem in the working lives of some labour ward midwives.

Lack of association of angiotensin II type 1 receptor gene polymorphism with diabetic nephropathy in insulin-dependent diabetes mellitus.

Several observations suggest that inherited factors are influential in the development of nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). Genetic components of the renin angiotensin system are possible candidate genes. The aim of this study was to determine the role of the hypertension associated angiotensin II type 1 receptor (AT1R) gene A1166C polymorphism in susceptibility to nephropathy in IDDM. We examined 264 Caucasoid patients with IDDM and overt nephropathy (as defined by persistent proteinuria in the absence of other causes, hypertension and retinopathy), 136 IDDM patients with long duration of diabetes and no nephropathy (LDNN group), 200 recently diagnosed IDDM patients (Sporadic Diabetic group), and 212 non-diabetic subjects. The AT1R gene polymorphism was assessed using the polymerase chain reaction and restriction isotyping. Genotype frequencies did not differ significantly between the sporadic diabetic group and the nephropathy group (p = 0.245), nor between the long duration non-nephropathy group and the nephropathy group (p = 0.250). Allele frequencies were not significantly different between the three groups (p = 0.753). We conclude that there is no significant association between the hypertension associated AT1R gene polymorphism and diabetic nephropathy in patients with IDDM in the UK.

Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM.

Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.

Renal function in long-duration type I diabetes.

OBJECTIVE: The development of persistent proteinuria is reported to be uncommon after 30 years of type I diabetes, and the significance of microalbuminuria in patients with long-duration diabetes is unclear. We therefore undertook to study, in detail, renal function in patients with long-duration type I diabetes. RESEARCH DESIGN AND METHODS: We measured albumin excretion rate (AER), glomerular filtration rate (GFR), and serum creatinine in 140 patients with > or = 30 years of type I diabetes. We also assessed patients for other micro- macrovascular complications of diabetes together with factors implicated in the development of diabetic renal disease. RESULTS: Of the patients, 23% had microalbuminuria (AER 20-200 micrograms/min and/or urinary albumin-to-creatinine ratio [ACR] > 2.5 mg/mmol [men] or > 3.5 mg/mmol [women] and dipstick negative for proteinuria), 4% had overt nephropathy (AER > 200 micrograms/min or persistent dipstick positive proteinuria), and 73% were normoalbuminuric (AER < 20 micrograms/min or ACR < 2.5 mg/mmol [men], < 3.5 mg/mmol [women]). Patients with microalbuminuria had lower GFR (81.5 +/- 30.2 vs. 96.0 +/- 20.3 ml.min-1.1.73 m-2; P = 0.06) and higher serum creatinine (104 +/- 32 vs. 92 +/- 16 mumol/l; P = 0.06) than those patients with normoalbuminuria. Both serum creatinine (P < 0.05) and tobacco consumption (P = 0.01) were significantly and independently related to elevated albumin excretion. CONCLUSIONS: A substantial proportion of these patients have microalbuminuria and evidence of impaired renal function, suggesting that progression to end-stage renal failure may still be inevitable. Clinicians should continue to monitor renal function in these patients. The relationship between tobacco consumption and nephropathy also makes clear the need to reduce cigarette smoking in the diabetic population.