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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atypical antipsychotics offer significant improvements over older, conventional antipsychotic agents. However, recently the newer agents have been linked to medical morbidity including hyperglycaemia, diabetes mellitus, bodyweight gain and abnormal lipid levels. Even more concerning, because of a significant risk of death, there have been numerous case reports of patients treated with clozapine or olanzapine developing diabetic ketoacidosis shortly after initiation of the drug. Much of the information concerning the medical morbidity of diabetes mellitus is based on case reports, retrospective chart reviews, naturalistic studies and cross-sectional studies. While definitive studies have yet to be reported, mounting evidence suggests that the atypical antipsychotic agents, particularly clozapine and olanzapine, may significantly impair glucose metabolism and increase the risk of diabetes in patients with schizophrenia. Diabetic ketoacidosis, although it appears to be uncommon, is of great concern secondary to the risk of death. Patients treated with atypical antipsychotic agents should be routinely screened for diabetes and other metabolic abnormalities including raised lipid levels. Patients with risk factors for diabetes should be monitored more closely. Reports and clinical experience suggest that in a case of atypical antipsychotic-associated diabetes or diabetic ketoacidosis, discontinuation of the antipsychotic agent may result in complete resolution of the hyperglycaemia and diabetes.
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PMID:Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? 1182 99

Since the introduction of chlorpromazine in the 1950s, antipsychotics have been used for the treatment of schizophrenia. The phenothiazines were followed by the butyrophenones, particularly haloperidol. With all the movement disorder side effects of these medications (extrapyramidal syndrome, akathisia, tardive dyskinesia), the pharmaceutical industry has gradually released atypical antipsychotics. This class includes clozapine (released in the USA in 1990), risperidone (1994), olanzapine (1996), quetiapine (1998) and ziprasidone (2001). However, the rate of diabetes mellitus in patients with schizophrenia appeared to increase with the availability of this class of medications. In reviewing rate and degree of changes in weight, glucose control and lipid levels induced by typical and atypical antipsychotics, it was found that in contrast to case reports, there is a dearth of retrospective, open and controlled studies. However, in studies as early as 1964, significant weight increases were found to be associated with use of chlorpromazine. While the phenothiazines may have some effect on patients with chemical diabetes, there is little evidence of the typical antipsychotics producing diabetes mellitus de novo, or worsening diabetes that is already been discovered. Ziprasidone appears to be the antipsychotic with the most beneficial combination of effects: no weight gain, no change in glucose utilisation and reductions in cholesterol and serum triglycerides (TGs).
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PMID:Antipsychotic medication: effects on regulation of glucose and lipids. 1182

Approximately 16 million people in the United States have diabetes, and the World Health Organization has estimated that the worldwide prevalence of diabetes will more than double from 1995 to 2025. Type 2 diabetes, the most common form of diabetes, may be 2 to 4 times more prevalent in patients with severe mental disorders. Within the psychiatric community, there is a great deal of concern about diabetes as a potential side effect of antipsychotic agents. An important population to remember in the context of treatment-emergent hyperglycemia is the 20 million people with impaired glucose tolerance (IGT) (fasting plasma glucose > 110 mg/dL and < 126 mg/dL or 2-hour postload glucose > 140 mg/dL and < 200 mg/dL according to the American Diabetes Association). This prediabetic condition has a 5% to 10% annual risk of converting to diabetes. One hypothesis for antipsychotic treatment-emergent diabetes during double-blind, randomized, controlled trials is that people who develop diabetes soon after the initiation of drug therapy for schizophrenia may have had undiagnosed IGT or diabetes before they started treatment. The emergence of diabetes in clinical practice may be due to an observation effect, but because the incidence of diabetes is greater in people with severe mental illnesses, it is crucial for psychiatrists to be aware of national guidelines for the diagnosis and treatment of type 2 diabetes.
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PMID:Metabolic side effects of antipsychotics: focus on hyperglycemia and diabetes. 1191 75

The atypical antipsychotic, clozapine, exerts superior efficacy in therapy-resistant schizophrenia, but unfortunately induces agranulocytosis with an incidence of 0.8 - 1 %. In this study, we investigated the cellular uptake of clozapine into human promyelocytic leukaemia HL-60 cells using HPLC with electrochemical detection. On incubation with 1.25 to 40 microM clozapine for 30 min, a saturable, energy- and temperature-dependent uptake process takes place (K m = 18.8 microM, k cat = 1.36 nmol/5 min/mg protein at 37 degrees C). This suggests membrane passage of clozapine by a carrier mechanism. 10 microM Indatraline, an inhibitor of dopamine, noradrenaline and serotonin (5-HT) reuptake, but not the selective 5-HT reuptake inhibitor fluvoxamine, markedly reduced the transport of clozapine by 62 %, whereas addition of 10 mM glucose to the incubation medium increased intracellular clozapine concentrations by 28 %. Since cyclosporine A, vinblastine or verapamil up to a final concentration of 10 microM did not alter the intracellular accumulation of clozapine, an involvement of P-glycoprotein seems to be unlikely. In summary, clozapine uptake into HL-60 cells meets criteria of an active unidirectional transport. Its molecular correlates remain to be established.
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PMID:Uptake of clozapine into HL-60 promyelocytic leukaemia cells. 1210 52

Atypical antipsychotic drugs, such as clozapine, show many differences in their actions as compared to typical antipsychotic drugs, such as haloperidol. In particular, the neuroanatomical substrates responsible for the superior therapeutic profile of clozapine are unknown. In order to identify regions of the CNS which are affected either differentially or in parallel by clozapine and haloperidol, we have used 2-deoxyglucose autoradiography to monitor local cerebral glucose utilisation (LCGU), in parallel with in situ hybridisation to monitor the expression of five immediate-early genes (c-fos, fos B, fra 1, fra 2 and zif 268). Clozapine (20 mg/kg i.p.) caused a reduction in LCGU in many areas of the psychosis-related corticolimbothalamic and Papez circuits, such as the anterior cingulate and retrosplenial cortices and the mammillary body. Haloperidol (1 mg/kg i.p.) showed less ability to modulate LCGU in these regions. Clozapine also increased immediate-early gene expression in these limbic circuits, although the pattern of induction was different for each gene, and also differed from the pattern of effects on LCGU. The only region which displayed similar effects with both antipsychotics was the anteroventral thalamus, with LCGU and c-fos mRNA expression being altered similarly by both drugs. This further supports the hypothesis of the thalamus being a common site of antipsychotic action. Since the Papez circuit has been implicated in emotive learning, and to be involved in mediating the negative symptoms associated with schizophrenia, the greater action of clozapine on regions within this circuit may also provide clues to the atypical antipsychotic's superior efficacy against negative symptoms. This is one of the first studies which provides a direct comparison of regional activity as assessed by LCGU and by a panel of IEGs. The results emphasise the necessity of monitoring a number of different parameters of regional activity in order to identity the neuroanatomical substrate for actions of a drug in the CNS.
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PMID:Induction of differential patterns of local cerebral glucose metabolism and immediate-early genes by acute clozapine and haloperidol. 1224 69

We examined the effects of long-term clozapine treatment, concurrent treatment with beta-adrenergic antagonists, and clozapine-induced weight gain on serum glucose and lipid measures. Fifty subjects met the DSM-III-R criteria for schizophrenia or schizoaffective disorder, participated in a 10-week, double-blind comparison of haloperidol and clozapine and a 1-year, open-label clozapine trial, and had available serum glucose and lipid levels. Weight and glucose, and lipid laboratory values were measured at the baseline and throughout the double-blind and year-long study. There were significant increases in serum triglyceride, total cholesterol, and glucose levels during the course of clozapine treatment. There were no significant changes in high-density lipoprotein (HDL) or low-density lipoprotein (LDL). Propranolol and atenolol had additive effects on changes in the total cholesterol and triglycerides, with propranolol having the most pronounced effects. Propranolol and atenolol had no significant effect on the serum glucose levels. There were significant correlations between the triglyceride and HDL level changes and clozapine-associated weight gain during the study. There were no significant correlations between the change in serum total cholesterol, LDL, or glucose and weight gain. Clozapine therapy has adverse effects on glucose and lipid homeostasis, with clozapine-induced changes in serum glucose likely due to the inherent pharmacological properties of clozapine. Concurrent beta-adrenergic receptor antagonist treatment may have an additive effect on serum lipids, and clozapine-associated weight gain also plays a modest role in triglyceride increases.
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PMID:Serum glucose and lipid changes during the course of clozapine treatment: the effect of concurrent beta-adrenergic antagonist treatment. 1241 42

Impairments of glucose and mitochondrial function are important causes of brain dysfunction and therefore of brain disease. Abnormalities have been found in association with disease of the nervous system in most of the components of glucose/mitochondrial metabolism. In many, molecular genetic abnormalities have been defined. Brain glucose oxidation is abnormal in common diseases of the nervous system, including Alzheimer disease and other dementias, Parkinson disease, delirium, probably schizophrenia and other psychoses, and of course cerebrovascular disease. Defects in a single component and even a single mutation can be associated with different clinical phenotypes. The same clinical phenotype can result from different genotypes. The complex relationship between biological abnormality in brain glucose utilization and clinical disorder is similar to that in other disorders that have been intensively studied at the genetic level. Genes for components of the pathways of brain glucose oxidation are good candidate genes for disease of the brain. Preliminary data support the proposal that treatments to normalize abnormalities in brain glucose oxidation may benefit many patients with common brain diseases.
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PMID:Glucose/mitochondria in neurological conditions. 1242 Mar 64

Aripiprazole (Abilitat, Bristol-Myers Squibb) is the most recent addition to the new class of atypical antipsychotic medications, following the release of clozapine, risperidone, olanzapine, quetiapine and ziprasidone. Aripiprazole exhibits typical antagonism at dopamine (D2) receptors in the mesolimbic pathway, as well as having unique partial agonist activity at D2 receptors in the mesocortical pathway. As exemplified by other atypical antipsychotics, it displays strong 5-HT(2a) receptor antagonism and is similar to ziprasidone in also having agonistic activity at the 5-HT(1a) receptor. Among the atypical antipsychotics, aripiprazole displays the lowest affinity for alpha(1)adrenergic (alpha(1)), histamine (H1) and muscarinic (M1) receptors. This combination of effects may be responsible for its efficacy in positive and negative symptoms of schizophrenia and in bipolar disorder. Similarly, this profile may be the reason for the low rates of reported side effects observed. This includes general adverse events, a low incidence of reported weight gain and a low liability for inducing movement disorders. Other early data suggest that aripiprazole may induce reductions in plasma prolactin, as well as in plasma glucose and lipid profiles. Finally, results also support the proposition that aripiprazole may lead to reductions in corrected QT interval and have minimal drug interactions.
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PMID:Aripiprazole: profile on efficacy and safety. 1247 74

The D2 dopamine receptor (DRD2) has been one of the most extensively investigated gene in neuropsychiatric disorders. After the first association of the TaqI A DRD2 minor (A1) allele with severe alcoholism in 1990, a large number of international studies have followed. A meta-analysis of these studies of Caucasians showed a significantly higher DRD2 A1 allelic frequency and prevalence in alcoholics when compared to controls. Variants of the DRD2 gene have also been associated with other addictive disorders including cocaine, nicotine and opioid dependence and obesity. It is hypothesized that the DRD2 is a reinforcement or reward gene. The DRD2 gene has also been implicated in schizophrenia, posttraumatic stress disorder, movement disorders and migraine. Phenotypic differences have been associated with DRD2 variants. These include reduced D2 dopamine receptor numbers and diminished glucose metabolism in brains of subjects who carry the DRD2 A1 allele. In addition, pleiotropic effects of DRD2 variants have been observed in neurophysiologic, neuropsychologic, stress response, personality and treatment outcome characteristics. The involvement of the DRD2 gene in certain neuropsychiatric disorders opens up the potential of a targeted pharmacogenomic approach to the treatment of these disorders.
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PMID:D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. 1249 24

This paper compares the metabolic changes associated with risperidone treatment in schizophrenia to those induced by haloperidol, as a representative typical neuroleptic. A group of 11 schizophrenic patients of recent onset underwent two [18F] fluoro-desoxi-glucose (FDG)-positron emission tomography (PET) scans at rest: the first one at the moment of the diagnosis, after a minimal treatment with haloperidol followed by wash-out, and the second one after 6 months on risperidone. The study also included 34 patients on chronic haloperidol for comparison. PET images were analyzed using Statistical Parametric Mapping (SPM'99) methods. The only change after treatment with risperidone with respect to the baseline was a slight increase in activity in the primary visual area and the right insula. Patients on chronic haloperidol showed increased activity in the motor cortex and cerebellum, as compared to both minimally treated and risperidone-treated patients. The pattern of metabolic changes induced by risperidone appears to be different from that produced by typical antipsychotics.
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PMID:Cerebral metabolism and risperidone treatment in schizophrenia. 1250 32


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