The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophrenia

Antipsychotic drugs can regulate transcription of some genes, including those involved in regulation of hypothalamic-pituitary-adrenal (HPA) axis, whose activity is frequently disturbed in schizophrenic patients. However, molecular mechanism of antipsychotic drug action on the corticotropin-releasing hormone (CRH) gene activity has not been investigated so far. This study was undertaken to examine the influence of conventional and atypical antipsychotic drugs on the CRH gene promoter activity in differentiated Neuro-2A cell cultures stably transfected with a human CRH promoter fragment linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It has been found that chlorpromazine (0.1-5.0 mM), haloperidol (0.5-5.0 mM), clozapine (1.0-5.0 mM), thioridazine (1.0-5.0 mM), promazine (5.0 and 10 mM), risperidone (5.0 and 10.0 mM), and raclopride (only at the highest used concentrations, ie 30 and 100 mM) present in culture medium for 5 days inhibited the CRH-CAT activity. Sulpiride and remoxipride had no effect. Since CRH gene activity is most potently enhanced by cAMP/protein kinase A pathway, the effect of antipsychotics on the forskolin-induced CRH-CAT activity was determined. Chlorpromazine (1.0-5.0 mM), haloperidol (1.0-5.0 mM), clozapine (1.0-5.0 mM), thioridazine (3.0 and 5.0 mM), and raclopride (30 and 100 mM), but not promazine, sulpiride, risperidone, and remoxipride, inhibited the forskolin-stimulated CRH gene promoter activity. A possible involvement of protein kinases in chlorpromazine and clozapine inhibitory action on CRH activity was also investigated. It was found that wortmannin (0.01 and 0.02 mM), an inhibitor of phosphatidylinositol 3-kinase (PI3-K), significantly attenuated the inhibitory effect of chlorpromazine and clozapine on CRH gene promoter activity. In line with these results, a Western blot study showed that these drugs increased phospho-Ser-473 Akt level, had no effect on total Akt, and decreased glycogen synthase kinase-3b level. Additionally, we found that clozapine decreased protein kinase C (PKC) level and that its action on CRH activity was attenuated by PKC activator (TPA, 0.1 mM). The obtained results indicate that inhibition of CRH gene promoter activity by some antipsychotic drugs may be a molecular mechanism responsible for their inhibitory action on HPA axis activity. Clozapine and chlorpromazine action on CRH activity operates mainly through activation of the PI3-K/Akt pathway. Moreover, PKC-mediated pathway seems to be involved in clozapine action on CRH gene activity.

Section: Discussionmentioning

confidence: 40%

Section: Introductionmentioning

confidence: 99%

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

Basta‐Kaim

Budziszewska

Jaworska-Feil

et al. 2005

“…Previous studies have found raised cortisol and ACTH levels in patients with first-episode schizophrenia (Ryan et al, 2003(Ryan et al, , 2004aSachar et al, 1970), together with increased intra-abdominal fat (Ryan et al, 2004a) and impaired glucose tolerance (Ryan et al, 2003), thus suggesting that these endocrine abnormalities could have important metabolic consequences (Dinan, 2004). Studies of patients in the acute relapse phase of a psychotic disorder (with florid symptoms, newly hospitalized or unmedicated) have also found elevated cortisol levels that correlate with the severity of psychotic and arousal symptoms (Lammers et al, 1995;Tandon et al, 1991;Walder et al, 2000), nonsuppression of cortisol secretion by dexamethasone in the dexamethasone suppression test and in the dexamethasone/CRH test (Coryell and Tsuang, 1992;Herz et al, 1985;Lammers et al, 1995), and elevated levels of CRH in the cerebrospinal fluid (Banki et al, 1987).…”

Section: Discussionmentioning

confidence: 97%

“…Both old (Sachar et al, 1970) and recent studies (Ryan et al, 2003(Ryan et al, , 2004a have demonstrated hyperactivity of the main hormonal stress system, the hypothalamic-pituitary-adrenal (HPA) axis, in subjects experiencing their first psychotic episode. In turn, HPA axis hyperactivityFin major depressionFhas been linked to an increased volume of the pituitary gland (Axelson et al, 1992;Krishnan et al, 1991;MacMaster and Kusumakar, 2004).…”

Section: Introductionmentioning

confidence: 99%

Increased Pituitary Volume in Antipsychotic-Free and Antipsychotic-Treated Patients of the Æsop First-Onset Psychosis Study

Pariante

Dazzan

Danese

et al. 2005

142

Subjects at their first psychotic episode show an enlarged volume of the pituitary gland, but whether this is due to hypothalamicpituitary-adrenal (HPA) axis hyperactivity, or to stimulation of the prolactin-secreting cells by antipsychotic treatment, is unclear. We measured pituitary volume, using 1.5-mm, coronal, 1.5 T, high-resolution MRI images, in 78 patients at the first psychotic episode and 78 age-and gender-matched healthy controls. In all, 18 patients were antipsychotic-free (12 of these were antipsychotic-naïve), 26 were receiving atypical antipsychotics, and 33 were receiving typical antipsychotics. As hypothesized, patients had a larger pituitary volume than controls ( þ 22%, po0.001). When divided by antipsychotic treatment, and compared to controls, the pituitary volume was 15% larger in antipsychotic-free patients (p ¼ 0.028), 17% larger in patients receiving atypicals (p ¼ 0.01), and 30% larger in patients receiving typicals (po0.001). Patients receiving typicals not only had the largest pituitary volume compared to controls but also showed a trend for a larger pituitary volume compared to the other patients grouped together ( þ 11%, p ¼ 0.08). When divided by diagnosis, and compared to controls, the pituitary volume was 24% larger in patients with schizophrenia/schizophreniform disorder (n ¼ 40, po0.001), 19% larger in depressed patients (n ¼ 13, p ¼ 0.022), 16% larger in bipolar patients (n ¼ 16, p ¼ 0.037), and 12% larger in those with other psychoses (n ¼ 9, p ¼ 0.2). In conclusion, the first-episode of a psychotic disorder is associated with a larger pituitary independently of the presence of antipsychotic treatment, and this could be due to activation of the HPA axis. Typical antipsychotics exert an additional enlarging effect on pituitary volume, likely to be related to activation of prolactin-secreting cells. This activation of the hormonal stress response could participate to the important metabolic abnormalities observed in patients with psychosis.

“…The basic mechanisms behind these metabolic irregularities have not been fully elucidated, but it appears that antipsychotic medications could play an important role (Newcomer, 2005). Moreover, high rates of obesity and type II diabetes mellitus, observed in drug-naive/free patients (Mukherjee et al, 1996;Allison et al, 1999a;Thakore et al, 2002;Ryan et al, 2003Ryan et al, , 2004 before Kohen, 2004) and after the advent of antipsychotics and in nonschizophrenic blood relatives (Dynes, 1969;Mukherjee et al, 1989;Cheta et al, 1990;Martins et al, 2001;Lamberti et al, 2004), were potentially attributed to genetic factors (Stone et al, 2004), illness neurobiology (Thakore, 2005) and to unhealthy lifestyle (Brown et al, 1999). The interpretability of the preneuroleptic era data (reviewed in Kohen, 2004) is, however, limited by flaws in epidemiological methodology including lack of evaluation of and adjustments for adiposity, lifestyle, and anthropometric measures together with inconsistent diagnostic criteria for schizophrenia and glucose/insulin abnormalities Newcomer, 2005).…”

mentioning

confidence: 99%

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

Elman

Borsook

Lukas

2006

131

138

Obesity is highly prevalent among patients with schizophrenia and is associated with detrimental health consequences. Although excessive consumption of fast food and pharmacotherapy with such second-generation antipsychotic agents (SGAs) as clozapine and olanzapine has been implicated in the schizophrenia/obesity comorbidity, the pathophysiology of this link remains unclear. Here, we propose a mechanism based on brain reward function, a relevant etiologic factor in both schizophrenia and overeating. A comprehensive literature search on neurobiology of schizophrenia and of eating behavior was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) energy homeostasis, (2) food reward and hedonics, (3) reward function in schizophrenia, and (4) metabolic effects of the SGAs. A mesolimbic hyperdopaminergic state may render motivational/incentive reward system insensitive to low salience/palatability food. This, together with poor cognitive control from hypofunctional prefrontal cortex and enhanced hedonic impact of food, owing to exaggerated opioidergic drive (clinically manifested as pain insensitivity), may underlie unhealthy eating habits in patients with schizophrenia. Treatment with SGAs purportedly improves dopamine-mediated reward aspects, but at the cost of increased appetite and worsened or at least not improved opiodergic capacity. These effects can further deteriorate eating patterns. Pathophysiological and therapeutic implications of these insights need further validation via prospective clinical trials and neuroimaging studies. INTRODUCTIONObesity has reached pandemic proportions and it is rapidly surpassing smoking as a number one killer in the industrialized world (Sturm, 2002;Skidmore and Yarnell, 2004). Its annual cost to the American society is staggering, and is estimated to be around $117 billion owing to related illnesses and loss of productivity (National Institute of Diabetes and Digestive and Kidney Diseases, 2005).In schizophrenia, obesity is twice as prevalent as in the general public, afflicting over half this patient population (Allison et al, 1999a;Dixon et al, 2000; American Diabetes Association, 2004;Marder et al, 2004;Wirshing, 2004). Besides negative psychosocial impacts (distorted selfesteem and societal stigmatization) and medications noncompliance, schizophrenics appear to be particularly susceptible to the detrimental medical sequelae of obesity such as the 'Metabolic Syndrome', which is a cluster of cardiovascular risk factors, including abdominal adiposity, insulin resistance, impaired, glucose tolerance, dyslipidemia, and hypertension (McKee et al, 1986;Mukherjee et al, 1996;Brown et al, 2000;Haupt and Newcomer, 2002;Ryan and Thakore, 2002;Ryan et al, 2003;Holt et al, 2004;Kohen, 2004;Marder et al, 2004;Lieberman et al, 2005).Excessive body weight gain (BWG) could be attributed to a constellation of endocrine, molecular, genetic, demographic, and lifestyle-related factors. Provided that a common tra...