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Chao Deng - One of the best experts on this subject based on the ideXlab platform.
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betahistine co treatment ameliorates dyslipidemia induced by chronic Olanzapine treatment in rats through modulation of hepatic ampkα srebp 1 and pparα dependent pathways
Pharmacological Research, 2015Co-Authors: Xuemei Liu, Chao Deng, Jiamei LianAbstract:Second-generation antipsychotics including Olanzapine are associated with weight gain, dyslipidemia and other metabolic disorders. Both animal and clinical studies have shown that co-treatment with betahistine (a histamine H1 receptor agonist/H3 receptor antagonist) is effective in controlling Olanzapine-induced weight gain. In the present study, we investigate whether co-treatment with betahistine is able to prevent dyslipidemia induced by chronic Olanzapine treatment and the underlying mechanisms. Female rats were orally administered with Olanzapine (1 mg/kg, t.i.d.) for 3.5 consecutive weeks and then a 2.5-week drug withdrawal. Then, rats were divided into 4 groups for 5 weeks treatment: (1) vehicle, (2) Olanzapine-only (1 mg/kg, t.i.d.), (3) betahistine-only (9.6 mg/kg, t.i.d.), and (4) Olanzapine and betahistine (O+B) co-treatment. After completing treatment, hepatic mRNA expression was measured by qRT-PCR, while the protein levels were detected by western blot. In our study, Olanzapine-only treatment significantly increased triglyceride accumulation and non-esterified fatty acids (NEFA), and upregulated mRNA expression of sterol regulatory element binding protein 1 (SREBP-1) and its target genes, while these alterations were ameliorated by O+B co-treatment. Hepatic AMP-activated protein kinase α (AMPKα) was activated in the O+B co-treatment group, with a significant reduction in nuclear SREBP-1 protein expression but an increased expression of peroxisome proliferator-activated receptor-α (PPARα) and its-responsive molecule(CPT1A), compared with Olanzapine-only treatment. In addition, Olanzapine significantly increased hepatic histamine H1 receptors, while O+B co-treatment significantly reversed them to normal levels. This study provided the first evidence that betahistine could act on hepatic H1 receptors via modulation of AMPKα-SREBP-1 and PPARα-dependent pathways to ameliorate Olanzapine-induced dyslipidemia in rats.
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chronic betahistine co treatment reverses Olanzapine s effects on dopamine d2 but not 5 ht2a 2c bindings in rat brains
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2015Co-Authors: Jiamei Lian, Nagesh B Pai, Xufeng Huang, Chao DengAbstract:Olanzapine is widely prescribed for treating schizophrenia and other mental disorders, although it leads to severe body weight gain/obesity. Chronic co-treatment with betahistine has been found to significantly decrease Olanzapine-induced weight gain; however, it is not clear whether this co-treatment affects the therapeutic effects of Olanzapine. This study investigated the effects of chronic treatment of Olanzapine and/or betahistine on the binding density of the serotonergic 5-HT2A (5-HT2AR) and 5-HT2C (5-HT2CR) receptors, 5-HT transporter (5-HTT), and dopaminergic D₂ receptors (D₂R) in the brain regions involved in antipsychotic efficacy, including the prefrontal cortex (PFC), cingulate cortex (Cg), nucleus accumbens (NAc), and caudate putamen (CPu). Rats were treated with Olanzapine (1 mg/kg, t.i.d.) or vehicle for 3.5 weeks, and then Olanzapine treatment was withdrawn for 19 days. From week 6, the two groups were divided into 4 groups (n=6) for 5 weeks' treatment: (1) Olanzapine-only (1 mg/kg, t.i.d.), (2) betahistine-only (9.6 mg/kg, t.i.d.), (3) Olanzapine and betahistine co-treatment (O+B), and (4) vehicle. Compared to the control, the Olanzapine-only treatment significantly decreased the bindings of 5-HT2AR, 5-HT2CR, and 5-HTT in the PFC, Cg, and NAc. Similar changes were observed in the rats receiving the O+B co-treatment. The Olanzapine-only treatment significantly increased the D₂R binding in the Cg, NAc, and CPu, while the betahistine-only treatment reduced D₂R binding. The co-treatment of betahistine reversed the D₂R bindings in the NAc and CPu that were increased by Olanzapine. Therefore, chronic O+B co-treatment has similar effects on serotonin transmission as the Olanzapine-only treatment, but reverses the D₂R that is up-regulated by chronic Olanzapine treatment. The co-treatment maintains the therapeutic effects of Olanzapine but decreases/prevents the excess weight gain.
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betahistine ameliorates Olanzapine induced weight gain through modulation of histaminergic npy and ampk pathways
Psychoneuroendocrinology, 2014Co-Authors: Chao Deng, Jiamei Lian, Xufeng HuangAbstract:Summary Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating Olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of Olanzapine and betahistine (O + B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing Olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O + B co-treatment significantly downregulated the H1R levels, compared to the Olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by Olanzapine, but it was significantly reversed by O + B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O + B co-treatment decreased the pAMPKα/AMPKα ratio, compared with Olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although Olanzapine administration decreased the POMC mRNA level, this level was not affected by O + B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse Olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.
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Olanzapine activated ampk signaling in the dorsal vagal complex is attenuated by histamine h1 receptor agonist in female rats
Endocrinology, 2014Co-Authors: Qingsheng Zhang, Chao Deng, Hongqin Wang, Xufeng HuangAbstract:Weight gain and its related metabolic disorders are major side effects associated with second generation antipsychotic drug treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of Olanzapine treatment (8, 16, and 36 d) on DVC AMPK signaling in Olanzapine-induced weight gain and whether these changes are associated with Olanzapine-induced H1 receptor antagonism. During the 8-day Olanzapine treatment, the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK (pAMPK) (activated AMPK) as well as its directly downstream phospho-acetyl-coenzyme A carboxylase was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36 d of Olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1 receptor protein expression was not significantly altered by Olanzapine, the pAMPK expression was significantly positively correlated with the H1 receptor level after the 8-, 16-, and 36-day Olanzapine treatments. Moreover, we showed that an H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the Olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in Olanzapine-induced obesity. Thus, Olanzapine-induced DVC AMPK activation may be at least partially related to Olanzapine's antagonistic effect on the H1 receptor.
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effects of Olanzapine and betahistine co treatment on serotonin transporter 5 ht2a and dopamine d2 receptor binding density
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2013Co-Authors: Jiamei Lian, Chao Deng, Nagesh B Pai, Xufeng HuangAbstract:Olanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing Olanzapine-induced weight gain/obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of Olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter (5-HTT) and D2R bindings in various brain regions involved in antipsychotic efficacy. Female Sprague Dawley rats were administered orally (t.i.d.) with either Olanzapine (1mg/kg), betahistine (2.7 mg/kg), Olanzapine plus betahistine (O+B), or vehicle (control) for 2 weeks. Quantitative autoradiography was used to detect the density of [(3)H]ketanserin, [(3)H]paroxetine and [(3)H]raclopride binding site to 5-HT2AR, 5-HTT and D2R. Compared to the controls, Olanzapine significantly decreased [(3)H]ketanserin bindings to 5-HT2AR in the prefrontal cortex, cingulate cortex, and nucleus accumbens. Similar changes in 5-HT2AR bindings in these nuclei were also observed in the O+B co-treatment group. Olanzapine also significantly decreased [(3)H]paroxetine binding to 5-HTT in the ventral tegmental area and substantia nigra, however, both Olanzapine only and O+B co-treatment did not affect [(3)H]raclopride binding to D2R. The results confirmed the important role of 5-HT2AR in the efficacy of Olanzapine, which is not influenced by the O+B co-treatment. Therefore, betahistine co-treatment would be an effective combination therapy to reduce Olanzapine-induced weight gain side-effects without affecting Olanzapine's actions on 5-HT2AR transmissions.
Mauricio Tohen - One of the best experts on this subject based on the ideXlab platform.
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Olanzapine monotherapy and Olanzapine combination therapy in the treatment of mania 12 week results from the european mania in bipolar longitudinal evaluation of medication emblem observational study
Journal of Affective Disorders, 2008Co-Authors: Mauricio Tohen, Eduard Vieta, Francesco Panicali, Iris Goetz, Catherine Reed, Merce ComesAbstract:Background To evaluate the 12-week outcomes (effectiveness, tolerability, and patterns of medication use) of Olanzapine (either in antimanic monotherapy or in combination with other antipsychotics, anticonvulsants, and/or lithium) in patients with bipolar mania or mixed mania. Method EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) is a 24-month prospective observational study of in- and outpatients with acute mania/mixed mania conducted in 14 European countries. Primary outcome measures included Clinical Global Impressions–Bipolar Disorder scale (overall, mania, and depression); 5-item Hamilton Depression Rating Scale; and Young Mania Rating Scale. Tolerability measures included a questionnaire to assess patients’ symptomatic complaints. Results Overall, 2004 patients received Olanzapine (Olanzapine monotherapy, n = 673; Olanzapine combination, n = 1331). Concomitant therapy with antidepressants and/or anxiolytics was possible in both groups. The countries significantly differed in the use of Olanzapine monotherapy versus Olanzapine combination (p < .0001). Baseline-to-endpoint changes on the CGI-BP subscales, YMRS, and HAMD-5 were significant within both treatment groups (p < .0001). Olanzapine monotherapy was generally better tolerated than Olanzapine combination, particularly with regard to sedation (12% vs 17%; p < .001), tremor (2% vs 5%; p < .001), and akathisia (3% vs 6%; p < .001). Discussion The acute-phase EMBLEM results suggest that in naturalistic settings, Olanzapine (both as monotherapy and combination) may be effective in treating patients with bipolar mania. The use of Olanzapine monotherapy or combination varies significantly across countries, but combination is generally the rule, rather than the exception.
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a 12 week double blind comparison of Olanzapine vs haloperidol in the treatment of acute mania
Archives of General Psychiatry, 2003Co-Authors: Robin Emsley, Mauricio Tohen, Eduard Vieta, Joseph F Goldberg, Ana Maria Gonzalezpinto Arrillaga, Jean M Azorin, Marie Christine Hardybayle, William Lawson, Fan ZhangAbstract:Background This randomized controlled trial compares the efficacy and safety of Olanzapine vs haloperidol, as well as the quality of life of patients taking these drugs, in patients with bipolar mania. Methods The design consisted of 2 successive, 6-week, double-blind periods and compared flexible dosing of Olanzapine (5-20 mg/d, n = 234) with haloperidol(3-15 mg/d, n = 219). Results Rates of remission (Young-Mania Rating Scale score of ≤12 and 21-item Hamilton Rating Scale for Depression score of ≤8 at week 6) were similar for Olanzapine- and haloperidol-treated patients (52.1% vs 46.1%, respectively; P = .15). For the subgroup of patients whose index episode did not include psychotic features, rates of remission were significantly greater for the Olanzapine group compared with the haloperidol group (56.7% vs 41.6%, P = .04). Relapse into an affective episode (mania and/or depression) occurred in 13.1% and 14.8% of Olanzapine- and haloperidol-treated patients, respectively ( P = .56). Switch to depression occurred significantly more rapidly with haloperidol than with Olanzapine when using survival analysis techniques ( P = .04), and significantly more haloperidol-treated patients experienced worsening of extrapyramidal symptoms, as indicated by several measures. Weight gain was significantly greater in the Olanzapine group compared with the haloperidol group (2.82 vs 0.02 kg, P Conclusions These data suggest that Olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania. However, haloperidol carries a higher rate of extrapyramidal symptoms, whereas Olanzapine is associated with weight gain.
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efficacy of Olanzapine and Olanzapine fluoxetine combination in the treatment of bipolar i depression
Archives of General Psychiatry, 2003Co-Authors: Mauricio Tohen, Eduard Vieta, Joseph R Calabrese, Terence A Ketter, Gary S Sachs, Charles L Bowden, Philip B Mitchell, Franca Centorrino, R C RisserAbstract:Background Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression. Objective To examine the use of Olanzapine and Olanzapine-fluoxetine combination in the treatment of bipolar I depression. Design Double-blind, 8-week, randomized controlled trial. Setting Eighty-four sites (inpatient and outpatient) in 13 countries. Patients A total of 833 randomized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20. Intervention Patients were randomly assigned to receive placebo (n = 377); Olanzapine, 5 to 20 mg/d (n = 370); or Olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86). Main Outcome Measure Changes in MADRS total scores using mixed-effects model repeated-measures analyses. Results During all 8 study weeks, the Olanzapine and Olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group ( P Conclusions Olanzapine is more effective than placebo, and combined Olanzapine-fluoxetine is more effective than Olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.
Jiamei Lian - One of the best experts on this subject based on the ideXlab platform.
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betahistine co treatment ameliorates dyslipidemia induced by chronic Olanzapine treatment in rats through modulation of hepatic ampkα srebp 1 and pparα dependent pathways
Pharmacological Research, 2015Co-Authors: Xuemei Liu, Chao Deng, Jiamei LianAbstract:Second-generation antipsychotics including Olanzapine are associated with weight gain, dyslipidemia and other metabolic disorders. Both animal and clinical studies have shown that co-treatment with betahistine (a histamine H1 receptor agonist/H3 receptor antagonist) is effective in controlling Olanzapine-induced weight gain. In the present study, we investigate whether co-treatment with betahistine is able to prevent dyslipidemia induced by chronic Olanzapine treatment and the underlying mechanisms. Female rats were orally administered with Olanzapine (1 mg/kg, t.i.d.) for 3.5 consecutive weeks and then a 2.5-week drug withdrawal. Then, rats were divided into 4 groups for 5 weeks treatment: (1) vehicle, (2) Olanzapine-only (1 mg/kg, t.i.d.), (3) betahistine-only (9.6 mg/kg, t.i.d.), and (4) Olanzapine and betahistine (O+B) co-treatment. After completing treatment, hepatic mRNA expression was measured by qRT-PCR, while the protein levels were detected by western blot. In our study, Olanzapine-only treatment significantly increased triglyceride accumulation and non-esterified fatty acids (NEFA), and upregulated mRNA expression of sterol regulatory element binding protein 1 (SREBP-1) and its target genes, while these alterations were ameliorated by O+B co-treatment. Hepatic AMP-activated protein kinase α (AMPKα) was activated in the O+B co-treatment group, with a significant reduction in nuclear SREBP-1 protein expression but an increased expression of peroxisome proliferator-activated receptor-α (PPARα) and its-responsive molecule(CPT1A), compared with Olanzapine-only treatment. In addition, Olanzapine significantly increased hepatic histamine H1 receptors, while O+B co-treatment significantly reversed them to normal levels. This study provided the first evidence that betahistine could act on hepatic H1 receptors via modulation of AMPKα-SREBP-1 and PPARα-dependent pathways to ameliorate Olanzapine-induced dyslipidemia in rats.
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chronic betahistine co treatment reverses Olanzapine s effects on dopamine d2 but not 5 ht2a 2c bindings in rat brains
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2015Co-Authors: Jiamei Lian, Nagesh B Pai, Xufeng Huang, Chao DengAbstract:Olanzapine is widely prescribed for treating schizophrenia and other mental disorders, although it leads to severe body weight gain/obesity. Chronic co-treatment with betahistine has been found to significantly decrease Olanzapine-induced weight gain; however, it is not clear whether this co-treatment affects the therapeutic effects of Olanzapine. This study investigated the effects of chronic treatment of Olanzapine and/or betahistine on the binding density of the serotonergic 5-HT2A (5-HT2AR) and 5-HT2C (5-HT2CR) receptors, 5-HT transporter (5-HTT), and dopaminergic D₂ receptors (D₂R) in the brain regions involved in antipsychotic efficacy, including the prefrontal cortex (PFC), cingulate cortex (Cg), nucleus accumbens (NAc), and caudate putamen (CPu). Rats were treated with Olanzapine (1 mg/kg, t.i.d.) or vehicle for 3.5 weeks, and then Olanzapine treatment was withdrawn for 19 days. From week 6, the two groups were divided into 4 groups (n=6) for 5 weeks' treatment: (1) Olanzapine-only (1 mg/kg, t.i.d.), (2) betahistine-only (9.6 mg/kg, t.i.d.), (3) Olanzapine and betahistine co-treatment (O+B), and (4) vehicle. Compared to the control, the Olanzapine-only treatment significantly decreased the bindings of 5-HT2AR, 5-HT2CR, and 5-HTT in the PFC, Cg, and NAc. Similar changes were observed in the rats receiving the O+B co-treatment. The Olanzapine-only treatment significantly increased the D₂R binding in the Cg, NAc, and CPu, while the betahistine-only treatment reduced D₂R binding. The co-treatment of betahistine reversed the D₂R bindings in the NAc and CPu that were increased by Olanzapine. Therefore, chronic O+B co-treatment has similar effects on serotonin transmission as the Olanzapine-only treatment, but reverses the D₂R that is up-regulated by chronic Olanzapine treatment. The co-treatment maintains the therapeutic effects of Olanzapine but decreases/prevents the excess weight gain.
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betahistine ameliorates Olanzapine induced weight gain through modulation of histaminergic npy and ampk pathways
Psychoneuroendocrinology, 2014Co-Authors: Chao Deng, Jiamei Lian, Xufeng HuangAbstract:Summary Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating Olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of Olanzapine and betahistine (O + B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing Olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O + B co-treatment significantly downregulated the H1R levels, compared to the Olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by Olanzapine, but it was significantly reversed by O + B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O + B co-treatment decreased the pAMPKα/AMPKα ratio, compared with Olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although Olanzapine administration decreased the POMC mRNA level, this level was not affected by O + B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse Olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.
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effects of Olanzapine and betahistine co treatment on serotonin transporter 5 ht2a and dopamine d2 receptor binding density
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2013Co-Authors: Jiamei Lian, Chao Deng, Nagesh B Pai, Xufeng HuangAbstract:Olanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing Olanzapine-induced weight gain/obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of Olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter (5-HTT) and D2R bindings in various brain regions involved in antipsychotic efficacy. Female Sprague Dawley rats were administered orally (t.i.d.) with either Olanzapine (1mg/kg), betahistine (2.7 mg/kg), Olanzapine plus betahistine (O+B), or vehicle (control) for 2 weeks. Quantitative autoradiography was used to detect the density of [(3)H]ketanserin, [(3)H]paroxetine and [(3)H]raclopride binding site to 5-HT2AR, 5-HTT and D2R. Compared to the controls, Olanzapine significantly decreased [(3)H]ketanserin bindings to 5-HT2AR in the prefrontal cortex, cingulate cortex, and nucleus accumbens. Similar changes in 5-HT2AR bindings in these nuclei were also observed in the O+B co-treatment group. Olanzapine also significantly decreased [(3)H]paroxetine binding to 5-HTT in the ventral tegmental area and substantia nigra, however, both Olanzapine only and O+B co-treatment did not affect [(3)H]raclopride binding to D2R. The results confirmed the important role of 5-HT2AR in the efficacy of Olanzapine, which is not influenced by the O+B co-treatment. Therefore, betahistine co-treatment would be an effective combination therapy to reduce Olanzapine-induced weight gain side-effects without affecting Olanzapine's actions on 5-HT2AR transmissions.
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reducing Olanzapine induced weight gain side effect by using betahistine a study in the rat model
Journal of Psychopharmacology, 2012Co-Authors: Chao Deng, Jiamei Lian, Nagesh B Pai, Xufeng HuangAbstract:Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug’s antagonistic affinity to histamine H1 receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H1 receptor agonist and H3 receptor antagonist) could reduce the body weight/obesity induced by Olanzapine. Female Sprague Dawley rats were treated orally with Olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with Olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of Olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole Olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings d...
Xufeng Huang - One of the best experts on this subject based on the ideXlab platform.
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chronic betahistine co treatment reverses Olanzapine s effects on dopamine d2 but not 5 ht2a 2c bindings in rat brains
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2015Co-Authors: Jiamei Lian, Nagesh B Pai, Xufeng Huang, Chao DengAbstract:Olanzapine is widely prescribed for treating schizophrenia and other mental disorders, although it leads to severe body weight gain/obesity. Chronic co-treatment with betahistine has been found to significantly decrease Olanzapine-induced weight gain; however, it is not clear whether this co-treatment affects the therapeutic effects of Olanzapine. This study investigated the effects of chronic treatment of Olanzapine and/or betahistine on the binding density of the serotonergic 5-HT2A (5-HT2AR) and 5-HT2C (5-HT2CR) receptors, 5-HT transporter (5-HTT), and dopaminergic D₂ receptors (D₂R) in the brain regions involved in antipsychotic efficacy, including the prefrontal cortex (PFC), cingulate cortex (Cg), nucleus accumbens (NAc), and caudate putamen (CPu). Rats were treated with Olanzapine (1 mg/kg, t.i.d.) or vehicle for 3.5 weeks, and then Olanzapine treatment was withdrawn for 19 days. From week 6, the two groups were divided into 4 groups (n=6) for 5 weeks' treatment: (1) Olanzapine-only (1 mg/kg, t.i.d.), (2) betahistine-only (9.6 mg/kg, t.i.d.), (3) Olanzapine and betahistine co-treatment (O+B), and (4) vehicle. Compared to the control, the Olanzapine-only treatment significantly decreased the bindings of 5-HT2AR, 5-HT2CR, and 5-HTT in the PFC, Cg, and NAc. Similar changes were observed in the rats receiving the O+B co-treatment. The Olanzapine-only treatment significantly increased the D₂R binding in the Cg, NAc, and CPu, while the betahistine-only treatment reduced D₂R binding. The co-treatment of betahistine reversed the D₂R bindings in the NAc and CPu that were increased by Olanzapine. Therefore, chronic O+B co-treatment has similar effects on serotonin transmission as the Olanzapine-only treatment, but reverses the D₂R that is up-regulated by chronic Olanzapine treatment. The co-treatment maintains the therapeutic effects of Olanzapine but decreases/prevents the excess weight gain.
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betahistine ameliorates Olanzapine induced weight gain through modulation of histaminergic npy and ampk pathways
Psychoneuroendocrinology, 2014Co-Authors: Chao Deng, Jiamei Lian, Xufeng HuangAbstract:Summary Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating Olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of Olanzapine and betahistine (O + B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing Olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O + B co-treatment significantly downregulated the H1R levels, compared to the Olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by Olanzapine, but it was significantly reversed by O + B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O + B co-treatment decreased the pAMPKα/AMPKα ratio, compared with Olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although Olanzapine administration decreased the POMC mRNA level, this level was not affected by O + B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse Olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.
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Olanzapine activated ampk signaling in the dorsal vagal complex is attenuated by histamine h1 receptor agonist in female rats
Endocrinology, 2014Co-Authors: Qingsheng Zhang, Chao Deng, Hongqin Wang, Xufeng HuangAbstract:Weight gain and its related metabolic disorders are major side effects associated with second generation antipsychotic drug treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of Olanzapine treatment (8, 16, and 36 d) on DVC AMPK signaling in Olanzapine-induced weight gain and whether these changes are associated with Olanzapine-induced H1 receptor antagonism. During the 8-day Olanzapine treatment, the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK (pAMPK) (activated AMPK) as well as its directly downstream phospho-acetyl-coenzyme A carboxylase was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36 d of Olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1 receptor protein expression was not significantly altered by Olanzapine, the pAMPK expression was significantly positively correlated with the H1 receptor level after the 8-, 16-, and 36-day Olanzapine treatments. Moreover, we showed that an H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the Olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in Olanzapine-induced obesity. Thus, Olanzapine-induced DVC AMPK activation may be at least partially related to Olanzapine's antagonistic effect on the H1 receptor.
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effects of Olanzapine and betahistine co treatment on serotonin transporter 5 ht2a and dopamine d2 receptor binding density
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2013Co-Authors: Jiamei Lian, Chao Deng, Nagesh B Pai, Xufeng HuangAbstract:Olanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing Olanzapine-induced weight gain/obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of Olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter (5-HTT) and D2R bindings in various brain regions involved in antipsychotic efficacy. Female Sprague Dawley rats were administered orally (t.i.d.) with either Olanzapine (1mg/kg), betahistine (2.7 mg/kg), Olanzapine plus betahistine (O+B), or vehicle (control) for 2 weeks. Quantitative autoradiography was used to detect the density of [(3)H]ketanserin, [(3)H]paroxetine and [(3)H]raclopride binding site to 5-HT2AR, 5-HTT and D2R. Compared to the controls, Olanzapine significantly decreased [(3)H]ketanserin bindings to 5-HT2AR in the prefrontal cortex, cingulate cortex, and nucleus accumbens. Similar changes in 5-HT2AR bindings in these nuclei were also observed in the O+B co-treatment group. Olanzapine also significantly decreased [(3)H]paroxetine binding to 5-HTT in the ventral tegmental area and substantia nigra, however, both Olanzapine only and O+B co-treatment did not affect [(3)H]raclopride binding to D2R. The results confirmed the important role of 5-HT2AR in the efficacy of Olanzapine, which is not influenced by the O+B co-treatment. Therefore, betahistine co-treatment would be an effective combination therapy to reduce Olanzapine-induced weight gain side-effects without affecting Olanzapine's actions on 5-HT2AR transmissions.
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reducing Olanzapine induced weight gain side effect by using betahistine a study in the rat model
Journal of Psychopharmacology, 2012Co-Authors: Chao Deng, Jiamei Lian, Nagesh B Pai, Xufeng HuangAbstract:Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug’s antagonistic affinity to histamine H1 receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H1 receptor agonist and H3 receptor antagonist) could reduce the body weight/obesity induced by Olanzapine. Female Sprague Dawley rats were treated orally with Olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with Olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of Olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole Olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings d...
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assessment of treatment algorithms including amantadine metformin and zonisamide for the prevention of weight gain with Olanzapine a randomized controlled open label study
The Journal of Clinical Psychiatry, 2012Co-Authors: Vicki Poole Hoffmann, Michael Case, Jennie G JacobsonAbstract:OBJECTIVE: This 22-week, open-label study, conducted between November 2006 and September 2008 in a community setting, was designed to determine if weight gain during Olanzapine treatment can be prevented or mitigated with adjunctive treatment algorithms that include amantadine, metformin, and zonisamide. METHOD: Outpatients with schizophrenia or schizoaffective disorder (DSM-IV-TR criteria) were randomly assigned to Olanzapine alone (n = 50), Olanzapine plus algorithm A (Olanzapine + A [amantadine 200 mg/d with possible switches to metformin 1,000-1,500 mg/d and then to zonisamide 100-400 mg/d; n = 76]), or Olanzapine plus algorithm B (Olanzapine + B [metformin 1,000-1,500 mg/d with possible switches to amantadine 200 mg/d and then to zonisamide 100-400 mg/d; n = 73]). Brief weight management education was provided at baseline. The primary outcome measure was comparison of mean weight gain between Olanzapine and pooled Olanzapine + A and Olanzapine + B results. RESULTS: Least squares mean ± SE weight gain was 2.76 ± 0.75 kg for Olanzapine, 2.40 ± 0.65 kg for Olanzapine + A, and 0.65 ± 0.63 kg for Olanzapine + B. Mean weight gain during Olanzapine treatment did not differ significantly from pooled results for Olanzapine + A and Olanzapine + B (P = .065). Participants treated with Olanzapine + B experienced significantly less mean weight gain than Olanzapine-treated participants (P = .036). CONCLUSIONS: Pooled treatment algorithm results were not significantly different from Olanzapine monotherapy in mitigating weight gain. However, participants who received treatment with metformin with possible progression to amantadine and then zonisamide had significantly less mean weight gain than participants treated with Olanzapine alone. Progression of some participants through the algorithm indicated that a single therapy solution may not be adequate for every patient. Patients treated with Olanzapine should receive regular weight monitoring. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00401973.
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Olanzapine fluoxetine combination in patients with treatment resistant depression rapid onset of therapeutic response and its predictive value for subsequent overall response in a pooled analysis of 5 studies
The Journal of Clinical Psychiatry, 2010Co-Authors: Michael Case, Scott J Burke, Madhukar H Trivedi, Michael E Thase, Todd M DurellAbstract:OBJECTIVE: To characterize response profiles of Olanzapine/fluoxetine combination therapy in treatment-resistant depression (TRD) and to investigate predictive relationships of early improvement with Olanzapine/fluoxetine combination for subsequent response/remission during the acute phase of treatment. METHOD: Results were pooled from 5 outpatient studies comparing oral Olanzapine/fluoxetine combination, fluoxetine, or Olanzapine for a maximum of 8 weeks in patients with TRD who had at least 1 historical antidepressant treatment failure during the current episode and who failed a prospective antidepressant therapy during the study lead-in period. Mean Montgomery-Asberg Depression Rating Scale (MADRS) total and core mood items scores from the 8-week evaluation period were compared across treatment groups. Positive and negative predictive values (PPVs, NPVs) were computed from Olanzapine/fluoxetine combination-treated patients demonstrating response and remission based on whether they demonstrated early improvement. RESULTS: Mean Olanzapine/fluoxetine combination MADRS score reductions were significantly greater than fluoxetine by week 0.5 and Olanzapine by week 1. Significantly more Olanzapine/fluoxetine combination patients demonstrated MADRS onset of response compared with fluoxetine and Olanzapine patients (P < .001 for both MADRS total and core mood items). In Olanzapine/fluoxetine combination patients, 38.1% exhibited MADRS total score response versus 26.9% of fluoxetine patients (P < .001) and 22.2% of Olanzapine patients (P < .001). NPVs for MADRS total and core mood items response and remission ranged from 85.7% to 92.1%; PPVs ranged from 29.9% to 45.1%. CONCLUSIONS: Olanzapine/fluoxetine combination is superior to fluoxetine and Olanzapine in producing early improvement in patients with TRD. The absence of early improvement is highly predictive for overall response failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00035321.
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a randomized double blind comparison of Olanzapine fluoxetine combination Olanzapine and fluoxetine in treatment resistant major depressive disorder
The Journal of Clinical Psychiatry, 2007Co-Authors: Michael E Thase, Michael Case, S. Corya, Olawale O. Osuntokun, David Henley, Todd M. Sanger, Susan B. Watson, Sanjay DubéAbstract:OBJECTIVE Two parallel, 8-week double-blind studies compared Olanzapine/fluoxetine combination, Olanzapine, and fluoxetine in outpatients with treatment-resistant depression (TRD). METHOD Treatment-resistant depression was defined as a documented history of current-episode antidepressant failure plus a prospective failure on fluoxetine. Following an 8-week fluoxetine lead-in, 605 nonresponders with DSM-IV major depressive disorder were randomly assigned to Olanzapine/fluoxetine combination, Olanzapine, or fluoxetine. The primary outcome measure was baseline-to-endpoint mean change on the Montgomery-Asberg Depression Rating Scale (MADRS). The study was conducted from April 2002 to May 2005. RESULTS After 8 weeks of double-blind treatment, Study 1 revealed no statistically significant therapy differences in MADRS mean change (Olanzapine/fluoxetine combination: -11.0, fluoxetine: -9.4, Olanzapine: -10.5). In Study 2, Olanzapine/fluoxetine combination demonstrated significantly greater MADRS improvement (-14.5) than fluoxetine (-8.6, p < .001) and Olanzapine (-7.0, p < .001). Pooled study results revealed significant differences for Olanzapine/ fluoxetine combination (-12.7) versus fluoxetine (-9.0, p < .001) and Olanzapine (-8.8, p < .001). Pooled remission rates were 27% for Olanzapine/ fluoxetine combination, 17% for fluoxetine, and 15% for Olanzapine. Adverse events were consistent with previous studies. Cholesterol mean change (mg/dL) was +15.1 for Olanzapine/ fluoxetine combination, +0.8 for fluoxetine, and +2.7 for Olanzapine. Mean weight change (kg) was +4.9 for Olanzapine/fluoxetine combination, +0.4 for fluoxetine, and +5.5 for Olanzapine. Nonfasting glucose mean change (mg/dL) was +11.4 for Olanzapine/fluoxetine combination, +4.9 for fluoxetine, and +9.9 for Olanzapine. CONCLUSION Patients with TRD (defined as treatment failure on 2 antidepressants) taking Olanzapine/fluoxetine combination demonstrated significantly greater improvement in depressive symptoms than patients taking Olanzapine or fluoxetine in 1 of 2 studies and in the pooled analysis. When considered within the context of all available evidence, Olanzapine/fluoxetine combination is an efficacious therapy for patients with TRD. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov identifier: NCT00035321.
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Olanzapine fluoxetine combination for treatment resistant depression a controlled study of ssri and nortriptyline resistance
The Journal of Clinical Psychiatry, 2005Co-Authors: Richard C Shelton, Michael Case, S. Corya, Douglas J Williamson, T M Sanger, Luann E Van Campen, Susan D Briggs, Gary D. TollefsonAbstract:BACKGROUND This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a pilot study of the Olanzapine/fluoxetine combination. METHOD The study was begun in August 1999. The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor (SSRI). Patients (N = 500) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were randomly assigned to 1 of 4 treatment groups: Olanzapine (6-12 mg/day) plus fluoxetine (25-50 mg/day) combination, Olanzapine (6-12 mg/day), fluoxetine (25-50 mg/day), or nortriptyline (25-175 mg/day). The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS At the 8-week study endpoint, MADRS total scores decreased by a mean 8.7 points from baseline (28.5) with the Olanzapine/fluoxetine combination, 7.0 points from baseline (28.4) with Olanzapine (p = .08), 8.5 points from baseline (28.4) with fluoxetine (p = .84), and 7.5 points from baseline (28.8) with nortriptyline (p = .30), with no significant differences among the therapies. The Olanzapine/fluoxetine combination was associated with significantly (p < or = .05) greater improvement (decrease) in MADRS scores than Olanzapine at weeks 2, 4, 6, and 7; than fluoxetine at weeks 2 through 5; and than nortriptyline at weeks 1 through 4. A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode (N = 314) revealed that the Olanzapine/fluoxetine combination group had a significantly (p = .005) greater decrease in MADRS scores than the Olanzapine group at endpoint. Safety data for the Olanzapine/fluoxetine combination were similar to those for its component monotherapies. CONCLUSIONS The Olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization.
