第二代抗精神病药对大鼠血糖、胰岛素和C肽分泌的影响

目的 了解第二代抗精神病药(氯氨平、奥氮平、喹硫平、阿立哌唑)对大鼠体重、空腹血糖、胰岛素和C肽分泌的影响.方法 25只雌性SD(Sprague Dawley,SD)大鼠随机均分成5组.分别给予氯氮平20 mg/(kg·d)、奥氮平5 mg/(kg·d)、喹硫平20 mg/(kg·d)、阿立哌唑5mg/(kg·d)和生理盐水灌胃,共28 d.在第1、7、14、28天分别剪尾采血,测体重及空腹血糖,于第28天测定空腹血浆胰岛素和C肽水平.结果 适应性喂养1周后,5组大鼠的空腹血糖和体重水平差异无统计学意义(P＞0.05).持续灌胃第14及28天,氯氮平、奥氮平和喹硫平组空腹血糖高于空白时照组(P＜0.05);持续灌胃28 d,氯氮平、奥氮平组的体重高于空白对照组(P＜0.05);与未加处理因素前(第1天)相比,氯氮平、奥氮平和喹硫平组体重和空腹血糖随时间的延长而增加(P＜0.05),而阿立哌哇组的变化无统计学意义(P＞0.05).持续灌胃第28天,氯氮平、奥氮平和喹硫平组空腹血浆胰岛素和C肽水平高于空白对照组(P＜0.05);而阿立哌唑组变化不明显(P＞0.05).结论 氯氮平、奥氮平、喹硫平可引起大鼠胰岛素抵抗和血糖代谢异常.     

Decreased levels of ghrelin, cortisol, and fasting blood sugar, but not n-octanoylated ghrelin, in Japanese schizophrenic inpatients treated with olanzapine

The mechanism by which chronic administration of olanzapine induces a marked weight gain in patients with schizophrenia remains unknown. We examined the influence of long-term treatment with olanzapine on plasma levels of hormones regulating food intake and energy homeostasis in schizophrenia. In this study, olanzapine was administered to 28 Japanese inpatients for 16 weeks after switching from typical antipsychotic drugs or risperidone. At endpoint, no significant changes in body weight or body mass index were found. There was a significant decrease in the plasma levels of ghrelin without any accompanying change in active, n-octanoylated ghrelin. Serum levels of leptin tended to be increased and a significant reduction in plasma cortisol levels was found. In addition, the levels of fasting blood sugar as well as free fatty acid were significantly decreased. Furthermore, we did not confirm any marked weight gain induced by chronic administration of olanzapine as previously reported. The reason for this discrepancy may be due to differences in subjects and treatment settings. Based on these findings, it is unlikely that the decrease in plasma ghrelin levels by chronic administration of olanzapine affects weight gain. Further studies examining the effect of chronic olanzapine administration on weight and energy homeostasis in inpatients are required.     

Evidence of an association of leptin serum levels and craving in alcohol dependence

Recent studies have described an association of leptin serum levels and craving in alcohol dependent patients. The aim of the present study was to investigate a large patients' sample using a power-based statistical analysis. We included 156 male and 33 female patients suffering from alcohol dependence admitted for detoxification treatment. Leptin serum levels were measured using a commercial ELISA kit. The Obsessive Compulsive Drinking Scale (OCDS) was used to assess alcohol craving at admission. For both genders Spearman's correlation revealed significant results. These findings could be confirmed using multiple linear regression models (males: r=1.881, t=4.338, p<0.001; females: r=6.160, t=5.793, p<0.001) with a power of 1.00. In contrast to previous results describing an association only in female patients, this power-based analysis shows that leptin is associated with alcohol craving in both genders.     

Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever

The second generation antipsychotics clozapine and olanzapine are known to cause weight gain. However, only clozapine is associated with drug-induced fever. Cytokines have been linked to the induction of both weight gain and drug-induced fever. We investigated these potential side effects of clozapine and olanzapine and studied their differential effects on cytokine secretion. Thirty patients suffering from schizophrenia, schizophreniform disorder or schizoaffective disorder were treated with either clozapine (mean modal dose: 266.7+/-77.9mg) or olanzapine (21.2+/-2.5mg) in a randomized, double-blind, 6-week study. Body mass index (BMI), tympanic temperature, and plasma levels of leptin and cytokines (tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 and 2 (sTNFR-1/2), soluble interleukin-2 receptors (sIL-2R), interleukin-6) were determined weekly. BMI, leptin and cytokines significantly increased over time, except interleukin-6 and sTNFR-1 in the olanzapine group. All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI. Five patients who received clozapine (33%) developed drug-induced fever (>/=38 degrees C). In these, interleukin-6 peak levels were significantly (p<0.01) higher than in those patients treated with clozapine who did not develop fever. In conclusion, increase of BMI appears to be related to clozapine's and olanzapine's similar effects on cytokine systems, whilst drug-induced fever appears to be related to clozapine's differential effects on interleukin-6.     

Ghrelin and leptin levels in patients with obsessive-compulsive disorder

To examine the importance of ghrelin and leptin in the pathogenesis of obsessive-compulsive disorder (OCD), we measured serum ghrelin and leptin levels, lipid profile and body mass index (BMI) in 43 patients with OCD and 20 healthy controls. The patients were divided into two subgroups according to whether DSM-IV OCD was accompanied with major depressive disorder (MDD) (OCD+MDD) or not (OCD-MDD). There was no statistically significant difference in ghrelin and leptin levels between groups. The OCD+MDD group had a trend of higher ghrelin levels and lower leptin levels than the OCD-MDD and control groups. There was a negative correlation between change in serum ghrelin and leptin levels only in the OCD+MDD group. Neither ghrelin nor leptin showed any correlation with severity of MDD and OCD. In conclusion, our results suggest that OCD is not associated with leptin or ghrelin levels. More comprehensive and detailed studies are needed to decipher the exact role of ghrelin and leptin in OCD.     

Clinical and polysomnographic predictors of severe obstructive sleep apnea in the South Indian population

Background:With the emergence of lifestyle diseases in epidemic proportions, obstructive sleep apnea (OSA) is being increasingly recognized in less developed countries as well.Aim:We sought to study the demographic, clinical, and polysomnographic (PSG) predictors of OSA severity in a cohort of South Indian patients.Results:There were 152 (119 males and 33 females) subjects with a mean age of 53.8 years and body mass index (BMI) of 29.31. Mean AHI was 36.2/h (range: 5.1-110) and 66 subjects had severe OSA. Around 12% had the presenting complaint as insomnia, mainly of sleep maintenance. Of the subjects, 35% had witnessed apneas and 67% had excessive daytime sleepiness (EDS); 40% of patients had ≥2 risk factors. PSG parameters showed short sleep onset latency with a high arousal index. Mean apnea duration was 24.92 s. We found that age >55 years, BMI >25 kg/m², witnessed apneas, EDS, hypertension, dyslipidemia, reduced slow wave sleep duration, mean apnea duration >20 s, and desaturation index >10/h correlated well with OSA severity while the arousal index, sleep latency and efficiency, and exposure to smoking and alcohol showed no association.Conclusions:Older subjects with witnessed apneas are likely to have more severe OSA. Even though overall sleep architecture was similar between the groups, severe OSA had shorter slow wave sleep, longer apneas, and higher nocturnal hypoxemia.     

The Joint Effects of Body Mass Index and MAOA Gene Polymorphism on Depressive Symptoms

The objective of the present study was to examine the joint effects of the body mass index and the MAOA gene polymorphism on depressive symptoms. In two independent Chinese samples, we measured adolescents'' depressive symptoms and body mass index and collected their DNA. The results indicated that the main effects of the MAOA gene polymorphism on depressive symptoms were significant. However, the main effects of body mass index and the interaction of the MAOA gene polymorphism and body mass index on depressive symptoms were not significant. By using Chinese adolescents, this study confirmed that the MAOA gene polymorphism directly influenced adolescents'' depressive symptoms.     

Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics

Accumulating evidence showed that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. Decreased BDNF levels have been found in the serum of schizophrenic patients with mixed results. In the present study, we assessed serum BDNF levels in a large group of 364 schizophrenic patients (157 on clozapine, 89 on risperidone and 118 on typical antipsychotics), compared to 323 healthy control subjects matched for age and gender. The schizophrenia symptomatology was assessed by the Positive and Negative Syndrome Scale (PANSS), and serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF levels were significantly lower in chronic patients with schizophrenia than in healthy control subjects (9.9 ± 2.0 ng/ml vs.11.9 ± 2.3 ng/ml, p < 0.0001). Lower BDNF levels were observed in patients treated with risperidone (9.3 ± 2.3 ng/ml) compared to those with clozapine (10.2 ± 2.0 ng/ml, p < 0.001) and typical antipsychotics (10.0 ± 2.1 ng/ml, p < 0.01). Furthermore, a stepwise multiple regression analysis identified types of antipsychotic drugs (beta = − 0.37, t = − 3.15, p = 0.001) and BDNF levels (beta = − 0.26, t = − 2.51, p = 0.014) as the influencing factor for the positive symptom subscore of PANSS. In addition, there was a sex difference in BDNF levels in patients with schizophrenia (9.7 ± 1.9 ng/ml for males vs.10.4 ± 2.1 ng/ml for female, p < 0.005), but not in normal controls. Our findings indicated decreased BDNF serum levels in chronic patients with schizophrenia, which may be related to clinical phenotypes, including gender, antipsychotic treatment and the severity of psychotic symptoms.     

第二代抗精神病药对慢性精神分裂症患者的治疗作用

目的：探讨第1代抗精神病药（FGA）联合与未联合第2代抗精神病药（SGA）对慢性精神分裂症患者临床疗效、认知功能及社会功能的影响。方法：74例慢性精神分裂症患者被随机分为联合组和对照组,联合组为FGA联合SGA,对照组则为持续应用FGA,治疗至少12周。采用简明精神病量表（BPRS）分别于治疗前后评估患者临床疗效,以探究性眼动检测来评估患者的认知功能,采用个人和社会功能量表（PSP）评估社会功能。结果：探究性眼动检测治疗前凝视点数联合组显著低于对照组（P〈0.05）;尽管经过联合SGA治疗后两组间凝视点数虽不存在差异（P〉0.05）,但联合组治疗前后的凝视点数增加值却显著好于对照组（P〈0.001）;反应性探索（RSS）评分在疗前、疗后两组间均差异无显著性。所有联合SGA患者在治疗后PSP评分均显著优于未联合用药组（P〈0.05或P〈0.001）;LSD分析提示：尤以联合利培酮或阿立哌唑对患者PSP评分改善最为显著（P均〈0.001）。结论：联合SGA对慢性精神分裂症患者疗效显著,尤其对患者认知和社会功能改善明显。     

Psychometric properties of the Spanish version of the Body Weight,Image and Self-Esteem Evaluation questionnaire in patients with severe mental disorders

Objective

Clinicians need brief and valid instruments to monitor the psychosocial impact of weight gain in persons with psychiatric disorders. We examined the psychometric properties of the Spanish version of the Body Weight, Image and Self-Esteem Evaluation (B-WISE) questionnaire in patients with severe mental disorders.

Method

The data come from a naturalistic, cross-sectional, validation study conducted at 6 centres in Spain. A total of 211 outpatients with severe mental disorders, 118 with schizophrenia and 93 with bipolar disorder, were evaluated using the B-WISE, the Visual Analogue Scale for Weight and Body Image, and the Clinical Global Impression–Severity (CGI-S). The body mass index was also obtained.

Results

The principal component analysis confirms 3 components explaining 50.93% of the variance. The Cronbach α values for B-WISE scales ranged between .55 and .73. Significant Pearson correlations were found between B-WISE total score and CGI-S (r = − 0.25; P < .001) and Visual Analogue Scale for Weight and Body Image (r = 0.47; P < .001). The B-WISE discriminates among patients with mild, moderate, and severe mental disorders according to CGI-S scores (F = 6.52; P < .005). Body mass index categorization significantly influenced total B-WISE scores (F = 3.586, P < .050). The B-WISE score corresponding to the 5th and 10th percentiles was 22.

Conclusions

We were able to demonstrate that the Spanish version of the B-WISE is a valid instrument for assessing psychosocial impact of weight gain in patients with severe mental disorders in daily clinical practice.     

Possible association between the -2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain

Antipsychotic-induced weight gain has important effects on treatment compliance and long-term health. Several reports have indicated that a -2548A/G single-nucleotide polymorphism (SNP) of the leptin gene is associated with antipsychotic-induced weight gain. We hypothesized that there is a similar relationship between the -2548A/G SNP and olanzapine-induced weight gain. A total of 74 Korean schizophrenic patients were examined. Their weight was measured before starting olanzapine and after long-term treatment lasting for at least 3 months. The weight gain was significantly higher for patients with the AG genotype than for those with the AA genotype (p=0.029). Analysis of covariance also showed the difference of weight gain was still significant when adjusted for sex and treatment duration (p=0.046). This finding supports the presence of a relationship between the -2548A/G SNP of the leptin gene and weight gain in Korean schizophrenic patients receiving olanzapine treatment.     

Sleep deficiency on school days in Icelandic youth,as assessed by wrist accelerometry

AimsThe purpose of this study was to objectively measure, with wrist-worn actigraphy, free-living sleeping patterns in Icelandic adolescents, and to compare sleep duration, sleep quality and clock times between school days (SchD) and non-school days (NSchD) and the association between sleep and body mass index (BMI).MethodsA cross-sectional study on 15.9-year-old (±0.3) adolescents from six schools in Reykjavík, Iceland, took place in the spring of 2015. Free-living sleep was measured on 301 subjects (122 boys and 179 girls) over seven days using wrist-worn actigraphy accelerometers. Total rest time (TRT), total sleep time (TST), sleep quality markers, and clock times for sleep were quantified and compared between SchD and NSchD and between the sexes, using paired and group t-tests as appropriate. Linear regression was used to assess the association between sleep parameters and BMI.ResultsOn SchD, TST was 6.2 ± 0.7 h, with sleep efficiency (SLE) of 87.9 ± 4.4% for the group. On NSchD, TST increased to 7.3 ± 1.1 h (p < 0.001), although SLE decreased to 87.4 ± 4.7% (p < 0.05). On SchD and NSchD, 67% and 93% had bed times after midnight, respectively, and on SchD 10.7% met sleep recommendations (8 h/night). There was no association between BMI and average sleep parameters.ConclusionThe majority of Icelandic adolescents did not get the recommended number of hours of sleep, especially on SchD. While TST increased on NSchD, many participants still did not achieve the recommendations. These findings provide information on the sleep patterns of adolescents and may serve as reference for development of policies and interventions to promote better sleep practices.     

Maprotiline induced weight gain in depressive disorder: changes in circulating ghrelin and adiponectin levels and insulin sensitivity

Agents such as clozapine, olanzapine and mirtazapine frequently trigger an increase in body weight. Though the mechanisms have not been thoroughly clarified, recent studies indicate a role for ghrelin in regulation of appetite and weight gain. We investigated the relation of maprotiline induced weight gain to serum ghrelin and adiponectin levels, as well as insulin resistance in lean subjects with depressive disorder. A total of 40 male lean subjects with depressive disorder were treated with maprotiline (150 mg/day) for 30-days. Clinical data, fasting plasma glucose, lipids, insulin levels, serum ghrelin and adiponectin concentrations were determined before and after treatment. Insulin resistance was estimated using the homeostasis model assessment (HOMA) formula. After 30 days of treatment with maprotiline, mean body mass index increased significantly. Blood ghrelin and insulin levels and HOMA indexes increased, and adiponectin concentration decreased (p<0.001, for all) after the treatment period. Changes in ghrelin levels correlated neither of the parameters tested; whereas decrease in plasma adiponectin was associated with an increase in BMI (r=-0.671, p<0.001). In conclusion, the results indicate that treatment of lean patients with depressive disorder with maprotiline results in an increase in serum ghrelin and reduction in adiponectin levels. Weight gain due to maprotiline treatment may be related to its negative effects on the metabolic variables.     

A prospective study of serum ghrelin levels in patients treated with clozapine

Summary. We investigated serum ghrelin levels (SGL) in 12 patients with schizophrenia over a 10-week period after initiation of clozapine treatment. In contrast to increments of body mass indices (BMI, kg/m²) and serum leptin levels (SLL), no significant change in SGL was detected. Inverse correlations between delta SGL and delta SLL did not reach statistical significance. Linear mixed model analysis could not detect effects of age, sex, BMI, SLL and serum clozapine levels on SGL. Our results do not support a causal involvement of ghrelin in clozapine-related weight gain.     

Screening for diabetes using monitoring guidance in schizophrenia patients treated with second-generation antipsychotics: a 1-year follow-up study

Second-generation antipsychotics (SGAs) tend to induce weight gain, dyslipidemia and diabetes mellitus. For those reasons, patients treated with SGAs should receive appropriate monitoring to avoid morbidity and mortality associated with cardiovascular disease. We conducted a one-year follow-up study using Japanese blood glucose monitoring guidance in schizophrenia patients treated with SGAs to evaluate the detection capability of the guidance in real clinical settings and to assess the importance of longitudinal monitoring. This retrospective cohort study included schizophrenia patients receiving at least one SGA, who were enrolled during June 2008-January 2009 at multiple sites and who had both baseline data and follow-up monitoring data at month 12. After one-year follow-up, the probable diabetes type (fasting blood glucose is higher than 125 mg/dL, casual blood glucose is higher than 179 mg/dL, or glycosylated hemoglobin (Hb_A1c) is greater than 6.4%) was detected in 30 (8%) of the patients, and the pre-diabetes type (fasting blood glucose is 110-125 mg/dL, or casual blood glucose is 140-179 mg/dL, or Hb_A1c is 6.0-6.4%) in 65 (17.4%) out of the total of 374 patients. During the follow-up period, 1.5% of patients had advanced from the normal (fasting blood glucose is less than 110 mg/dL, casual blood glucose is less than 140 mg/dL, or Hb_A1c is less than 6.0%) to probable diabetes type and 42.4% had progressed from the pre-diabetes to probable diabetes type. Predictive factors for worsening of the diabetic state were a family history of diabetes, and high serum total-cholesterol and triglyceride levels at baseline. Not only cross-sectional baseline screening but also longitudinal follow-up screening is important to detect glucose abnormalities in patients treated with SGAs.     

-759 C/T polymorphism of 5-HT2C receptor gene and early phase weight gain associated with antipsychotic drug treatment

5-HT2C receptor gene is viewed as an important candidate gene in pharmacogenetic studies of antipsychotic drug-induced weight gain. However, inconsistent results have been obtained in different populations. We investigated the association between the -759C/T polymorphism of the 5-HT2C receptor gene with early phase (after 4 weeks of treatment) weight gain induced by antipsychotic treatment in Korean schizophrenia patients. The study subjects were eighty-four in-patients receiving monotherapy with one of six antipsychotic drugs. Patients with the variant allele (-759T) were found to be less likely to have substantial (> 5%) weight gain (Fisher's exact test, p=0.030), and this association (t=1.91, df=75, p=0.030) was supported by the repeated measures analysis after controlling for possible confounding effects, i.e., age, sex, baseline BMI, and the type of antipsychotic medicine administered. The variant allele also appeared to have a protective effect against weight gain in a subgroup of patients receiving risperidone. These results support the involvement of the -759C/T polymorphism of the 5-HT2C receptor gene in antipsychotics-induced weight gain in the Korean population.     

Antidepressive effects of traditional and second generation antipsychotics: a review of the clinical data

For a long time,in the context of depressive symptoms in schizophrenia traditional neuroleptics were mostly discussed with respect to possible depressiogenic side effects, although some studies argued that they may also have certain antidepressive effects. However, this was not proven at that time in placebo-controlled studies. Placebo-controlled studies performed in recent years have shown that second generation antipsychotics have antidepressive effects which are significantly stronger than those of the traditional neuroleptics. In addition, it was demonstrated that this antidepressive effect can only partially be explained as being secondary to the improvement of positive and negative symptoms, and is apparently predominantly due to a direct (primary) effect on depressive symptoms. It is of special relevance in this context that the antidepressive effect of second generation antipsychotics was recently demonstrated in depression. The positive results from some studies in bipolar depression are especially impressive and underline the antidepressive potencies of novel antipsychotics beyond the spectrum of schizophrenia.     

The effects of the second generation antipsychotics and a typical neuroleptic on collagen-induced platelet aggregation in vitro

Objective. Antipsychotics are widely used in psychiatry, and consequently a lot of their side effects have been reported. One of them is cardiovascular disease leading to increased risk of stroke, thrombosis, pulmonary, embolism, in which hyperactivation of blood platelets is involved. The purpose of the present study was to examine the effects of the second generation antipsychotics (SGAs) such as clozapine, risperidone, and olanzapine, and a typical neuroleptic – haloperidol – on the one step of platelet activation–platelet aggregation induced by collagen in vitro. Blood was collected into buffered sodium citrate (3.8%) and centrifuged to get platelet-rich plasma (PRP). In PRP (2×10⁸ platelets/ml) obtained from healthy volunteers that was incubated with antipsychotics (clozapine, risperidone, olanzapine, haloperidol; 30 min) aggregation of blood platelets was measured using a Chrono-Log Lumi-aggregometer. Aggregation of platelets was measured after stimulation of platelets with 1 µl of collagen (2 µg/ml). Results. Clozapine, like haloperidol reduced platelet aggregation induced by collagen (inhibition of platelet aggregation reached about 20%) (P=1×10^?5 and P=0.003, respectively). Risperidone had also a weak antiaggregatory effect (P=0.05). Among tested antipsychotics only olanzapine had no effect on collagen-stimulated platelet aggregation (P>0.05). Conclusion. The obtained results indicate that the difference in action of tested drugs on platelet aggregation may dependent on the various chemical structures of these drugs. Clozapine, risperidone and haloperidol are structurally diverse, and they all significantly reduce platelet aggregability induced by collagen. On the other hand, a close structural analog of clozapine – olanzapine – did not inhibit platelet aggregation. However, mechanism of antipsychotics action on blood platelets is not clear. Moreover, it seems that clozapine, risperidone and haloperidol treatment due to antiaggregatory action may have even some antithrombotic effects.