Antipsychotic Medication and Oxidative Cell Stress

Lepping, Peter; Delieu, John; Mellor, Richard; Williams, John; Hudson, Peter; Hunter-Lavin, Claire

doi:10.4088/jcp.09r05268yel

Cited by 47 publications

(29 citation statements)

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“…Such chronic inflammation increases the expression of circulating inflammatory factors. Atypical antipsychotics have been reported to be both protective against inflammation, as well as causative [51]. However, these studies have been performed on different cell types, under different conditions, and have not been systematically conducted.…”

Section: Discussionmentioning

confidence: 99%

Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells

et al. 2013

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BackgroundMetabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. Clozapine, an atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for the development of clozapine-related DIMS. In this study, the effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined.Methodology/Principal FindingsCultured mouse myoblasts (C2C12), adipocytes (3T3-L1), hepatocytes (FL-83B), and monocytes (RAW 264.7) were treated with 0, 25, 50 and 75 µM clozapine for 24 hours. The mitochondrial selective probe TMRM was used to assess membrane potential and morphology. ATP levels from cell lysates were determined by bioluminescence assay. Cytokine levels in cell supernatants were assessed using a multiplex array. Clozapine was found to alter mitochondria morphology, membrane potential, and volume, and reduce ATP levels in all cell lines. Clozapine also significantly induced the production of proinflammatory cytokines IL-6, GM-CSF and IL12-p70, and this response was particularly robust in the monocyte cell line.Conclusions/SignificanceClozapine damages mitochondria and promotes inflammation in insulin responsive cells and obesity-associated cell types. These phenomena are closely associated with changes observed in human and animal studies of MetS, obesity, insulin resistance, and diabetes. Therefore, the use of clozapine in DIMS may be an important and relevant tool for investigating cellular and molecular changes associated with the development of these diseases in the general population.

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Section: Discussionmentioning

confidence: 99%

Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells

et al. 2013

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“…On the other hand, neuroprotective properties of antipsychotics are considered to be questionable and need further confirmation in humans [87][88][89].…”

Section: Possible Mechanisms Underlying the Impact Of Antipsychotics mentioning

confidence: 97%

Proton Magnetic Resonance Spectroscopy Changes After Antipsychotic Treatment

Szulc¹,

Galińska-Skok²,

Waszkiewicz³

et al. 2013

Current Medicinal Chemistry

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Proton magnetic resonance spectroscopy ((1)H MRS) enables the observation of brain function in vivo. Several brain metabolites can be measured by the means of (1)H MRS: N-acetylaspartate (NAA), choline containing compounds (Cho), myo-inositol (mI) and glutamate (Glu), glutamine (Gln) and GABA (together as Glx complex or separately). (1)H MRS measures have been found to be abnormal in psychotic disorders such as schizophrenia. Here we specifically review the influence exerted by antipsychotic drugs on brain metabolism, as detected by (1)H MRS. We systematically reviewed the available literature and uncovered 27 studies, 16 before-after treatment and 11 cross-sectional. Most of them addressed the effects of antipsychotics in schizophrenia and mainly focusing on NAA alterations. Follow up studies indicated antipsychotic drugs may act by increasing NAA levels in selected brain areas (the frontal lobe and thalamus), especially during the short-time observation. This phenomenon seems to vanish after longer observation. Other studies indicated that glutamate measures are decreasing along with the duration of the disease, suggesting both a neurodegenerative process present in schizophrenic brain as well as an influence of antipsychotics. The above results were reviewed according to the most recent theories in the field accounting for the impact of antipsychotics (1)HMRS measures.

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“…Furthermore, our aging population increases the need to consider cardiovascular problems that may arise as side effects of these medications. A systematic review has also shown that it remains unclear whether antipsychotics increase or reduce cell stress, and claims of neuroprotective properties of antipsychotics seem premature 12. Furthermore, there is the issue of tardive dyskinesia, which has caused significant problems for psychiatric patients in the past.…”

Section: Current Issues In Treating Schizophrenia and Bipolar Disordermentioning

confidence: 99%

Paliperidone extended-release: does it have a place in antipsychotic therapy?

Gahr¹,

Kölle²,

Schönfeldt‐Lecuona³

et al. 2011

DDDT

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Paliperidone (9-hydroxy-risperidone), the active metabolite of risperidone, was approved for treating schizophrenia worldwide in 2006 as paliperidone extended-release (PER), and became the first second-generation antipsychotic specifically licensed for treating schizoaffective disorder in 2009. However, at the same time, its comparatively high cost gave rise to concerns about the cost-effectiveness of PER as compared with its precursor, risperidone. This paper reviews the existing knowledge of the pharmacology, kinetics, efficacy, tolerability, and fields of application of PER, and compares PER with risperidone in order to determine whether it has a place in antipsychotic therapy. An independent assessment of all relevant publications on PER published until July 2010 was undertaken. PER has a unique pharmacological profile, including single dosing, predominantly renal excretion, low drug–drug interaction risk, and differs from risperidone in terms of mode of action and pharmacokinetics. High-level evidence suggests that PER is efficacious and safe in schizophrenia, schizoaffective disorder, and acute manic episodes. There is a striking lack of published head-to-head comparisons between PER and risperidone, irrespective of indication. Low-level evidence shows a lower risk for hyperprolactinemia and higher patient satisfaction with PER than with risperidone. PER adds to the still limited arsenal of second-generation antipsychotics. In the absence of direct comparisons with risperidone, it remains difficult to come to a final verdict on the potential additional therapeutic benefits of PER which would justify its substantially higher costs as compared with risperidone. However, in terms of pharmacology, the available evidence cautiously suggests a place for PER in modern antipsychotic therapy.

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Antipsychotic Medication and Oxidative Cell Stress

Abstract: It remains unclear whether antipsychotics increase or reduce cell stress. Claims of neuroprotective properties of antipsychotics seem premature.

Cited by 47 publications

References 0 publications

Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells

Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells

Proton Magnetic Resonance Spectroscopy Changes After Antipsychotic Treatment

Paliperidone extended-release: does it have a place in antipsychotic therapy?

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