Effects of risperidone and haloperidol on superoxide dismutase and nitric oxide in schizophrenia.

Oxidative stress may be involved in the pathophysiology of schizophrenia. No double-blind study has compared the effects of typical and atypical antipsychotics on both antioxidant enzyme activity and nitric oxide (NO) levels in schizophrenic patients. Seventy-eight inpatients with chronic schizophrenia were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol using a double-blind design. Clinical efficacy was determined using the Positive and Negative Syndrome Scale. Blood superoxide dismutase (SOD) and plasma NO levels were measured in patients and 30 normal controls. Our results showed that following a 2-week washout period, levels of SOD and NO were significantly increased in patients with schizophrenia compared to normal controls. Both risperidone and haloperidol equivalently reduced the elevated blood SOD levels in schizophrenia, but neither medication reduced the elevated plasma NO levels in schizophrenia. Low blood SOD levels at baseline predicted greater symptom improvement during treatment, and greater change in SOD was correlated with greater symptom improvement. These results suggest that both typical and atypical antipsychotic drugs may at least partially normalize abnormal free radical metabolism in schizophrenia, and some free radical parameters at baseline may predict antipsychotic responses of schizophrenic patients.

Perceived barriers to mental health treatment in metropolitan China.

OBJECTIVES: This community-based study examined perceived barriers to the initiation of mental health treatment among individuals with anxiety, mood, and alcohol use disorders. METHODS: Face-to-face interviews were conducted with 5,201 respondents in Beijing and Shanghai using the World Mental Health Composite International Diagnostic Interview. Perceived barriers to initiating treatment from various health practitioners were examined among 211 individuals who met criteria for 12-month DSM-IV disorders and did not receive treatment. RESULTS: Most respondents (92%) with DSM-IV disorders perceived a low need for treatment. Among respondents who perceived a need, 47% reported structural barriers and 83% reported attitudinal barriers. Respondents who had severe mental disorders and perceived a need reported more structural barriers (72%) than attitudinal barriers (65%). Lack of knowledge about service availability was the most common structural barrier. CONCLUSIONS: Future studies should examine the reasons for perceived low need for treatment and other treatment barriers among people with mental disorders.

Individual and societal impact on earnings associated with serious mental illness in metropolitan China.

To evaluate individual-level and societal-level losses of income associated with serious mental illness in metropolitan China, a multi-stage probability survey was administered to adults aged 18-70 years in Beijing and Shanghai. We used data to estimate individual-level expected earnings from a model that included information about the respondents' education level, marital status, age, and gender. Expected earnings were compared to observed earnings among respondents with mental illness and serious disability. The result shows that the 12-month prevalence of such serious mental illness was 0.6%. Its impact on earnings was significant in the total sample and was higher for males (76% of gender-specific expected salary was lost) than for females (32%). When projected to societal level, the annual impact was estimated to be 466 million Renminbi (RMB 8.27=USD 1), less than 0.2% of the gross domestic product (GDP) of the two cities. Serious mental illness was associated with a substantial decrease in individual-level earnings, but the burden that resulted from societal-level loss of earnings was not large enough to help drive mental health policy and programs in China.

Impaired role functioning and treatment rates for mental disorders and chronic physical disorders in metropolitan China.

OBJECTIVES: To compare impairments in role functioning and treatment rate of mental disorders and chronic physical disorders in the general population of metropolitan China. METHOD: Face-to-face household interviews of 5201 people aged 18 to 70 years in Beijing and Shanghai were conducted from November 2001 to February 2002, using a multistage household probability sampling method. The World Mental Health version of the Composite International Diagnostic Interview (WMH-CIDI) was used for assessing sociodemographic characteristics, diagnoses, and treatment. The Sheehan Disability Scale (SDS) was used to measure disorder-specific role impairment. RESULTS: Respondents generally attributed greater impairment to mental disorders than to chronic physical disorders, although there were some variations among specific disorders. This general pattern was supported by within-person comparison of impairment associated with a mental disorder versus any chronic physical disorder. Depression, generalized anxiety disorder, and specific phobia were the most impairing mental disorders. Diabetes, headaches, and asthma were the most impairing physical disorders. Comorbid mental and physical disorders were associated with more severe impairment. A much lower percentage of respondents with mental disorders (3.0%) than chronic physical disorders (42.8%) received treatment in the previous 12 months. CONCLUSION: Common mental disorders were associated with greater impairment than chronic physical disorders but were markedly undertreated. They warrant prioritization in the allocation of healthcare resources in China.

Associations of cohort and socio-demographic correlates with transitions from alcohol use to disorders and remission in metropolitan China.

AIMS: To examine socio-demographic associations of transitions from alcohol use to disorders and of remission from disorders in metropolitan China. DESIGN AND SETTING: Face-to-face interviewing by trained lay-interviewers on a multi-staged, clustered sample from the general population of Beijing and Shanghai, China. PARTICIPANTS: A total of 5201 adults aged 18-70 years and with household registration. MEASUREMENTS: World Mental Health version of Composite International Diagnostic Interview. FINDINGS: Lifetime prevalence estimates for alcohol use, regular use (at least 12 drinks in a year), DSM-IV abuse and dependence with abuse were 65.4%, 39.5% (60.4% of ever-drinkers), 4.6% (11.6% of regular users) and 0.9% (20.4% of lifetime alcohol abusers), respectively. These estimates were higher among respondents from the recent cohort; 64.3% and 36.9% respondents with a history of lifetime abuse and dependence respectively had remitted. The number of socio-demographic associations for the onset of each transitional stage decreased from alcohol use to alcohol dependence. Onset of ever-use was more common in respondents who were male, 18-50 years of age, with middle education level and never married, but less common among the previously married and students. First onset of regular use among those with ever-use was more common in respondents who were male, less than 50 years of age and never married, but less common in students. Being male and less than 50 years of age was associated with more alcohol abusers among regular users. CONCLUSION: This study was the first to reveal in a Chinese population that qualitatively different risk factors might operate during the different stages of progression from alcohol use to disorders. Further research is needed to clarify the mechanisms underlying these differences in order to guide prevention programmes.

[The establishment of an animal model of gut-brain interaction in irritable bowel syndrome for the evaluation of visceral sensation, motility and psychological behavior.].

OBJECTIVE: To develop a gut-brain interaction animal model of IBS which combines multiple factors including behavior, visceral sensation and motility. METHODS: Setting up a multifactor interactional animal model (chronic acute combining stress model, CACS) based on a chronic unpredictable mild stress model of depression (CUMS) while combined with wrap restraint stress (WRS), changes of some indexes were recorded including motility (granules of defecating, time of defecating), visceral sensitivity (spontaneous contraction of abdominal striated muscles) and behavior/mind (sucrose consumption, body weight). G protein subunits were measured by Western blot in both hippocampus and prefrontal cortex simultaneously. RESULTS: (1) Compared with the state before stress given, defecating granules increased, defecating time of glassie from rectum shorten, number of abdominal contraction increased, and sucrose consumption decreased in CACS, however, neither significant change was found on defecating behavior in CUMS nor on sucrose consumption in WRS;(2) Compared with the control group, some G protein submits expression decreased in both CACS and CUMS (P < 0.05), while no significant changes of any G protein subunits were found in WRS. CONCLUSION: The CACS animal model was a new, brain-gut interaction model, which can mimic part of human symptoms of IBS very well.

Association of SNPs and haplotypes in APOL1, 2 and 4 with schizophrenia.

Prior work found the APOL1, 2 and 4 genes, located on chromosome 22q12.3-q13.1, to be upregulated in brains of schizophrenic patients. We performed a family-based association study using 130 SNPs tagging the APOL gene family (APOL1-6). The subjects were 112 African-American (AA), 114 European-American (EA), 109 Chinese (Ch) and 42 Japanese (Jp) families with schizophrenia (377 families, 1161 genotyped members and 647 genotyped affected in total). Seven SNPs had p-values<0.05 in the APOL1, 2 and 4 regions for the AA, EA and combined (AA and EA) samples. In the AA sample, two SNPs, rs9610449 and rs6000200 showed low p-values; and a haplotype which comprised these two SNPs yielded a p-value of 0.00029 using the global test (GT) and the allele specific test (AST). The two SNPs and the haplotype were associated with risk for schizophrenia in African-Americans. In the combined (AA and EA) sample, two SNPs, rs2003813 and rs2157249 showed low p-values; and a three SNP haplotype including these two SNPs was significant using the GT (p=0.0013) and the AST (p=0.000090). The association of this haplotype with schizophrenia was significant for the entire (AA, EA, Ch and Jp) sample using the GT (p=0.00054) and the AST (p=0.00011). Although our study is not definitive, it suggests that the APOL genes should be more extensively studied in schizophrenia.

Lifetime prevalence and inter-cohort variation in DSM-IV disorders in metropolitan China.

BACKGROUND: This is the first study to examine variation across cohorts in lifetime risk of DSM-IV mental disorders in metropolitan China. METHOD: Face-to-face household interviews of 2633 adults in Beijing and 2568 adults in Shanghai were conducted from November 2001 to February 2002 using a multi-stage household probability sampling method. The Chinese World Mental Health (WMH) Survey Initiative version of the WHO Composite International Diagnostic Interview (WMH-CIDI) was used for assessment. RESULTS: Lifetime prevalence of any disorder was 13.2%. Alcohol abuse (4.7%), major depressive disorder (3.5%), and specific phobia (2.6%) were the most common disorders. The median age of onset was later for mood (43 years) than anxiety (17 years) and substance use (25 years) disorders. Compared to observed lifetime prevalence, the projected lifetime risk as of age 75 years increased by 106% for major depressive disorder (7.2%), and was uniformly higher for all disorders. Relative odds of any lifetime disorder were 4.7 in the most recent cohorts (ages 18-34) compared to the eldest cohorts (ages > or =65). CONCLUSIONS: The findings of this cross-sectional study tally with the view that rapid socioeconomic changes may bring about increasing incidence of mental disorders in China. However, prospective longitudinal studies are needed to confirm if the increase is real. Because of the huge size of the Chinese population, any increase in projected lifetime risk of mental disorders represents an enormous increase in the number of affected individuals.

Twelve-month prevalence, severity, and unmet need for treatment of mental disorders in metropolitan China.

BACKGROUND: Psychiatric epidemiological surveys in China have repeatedly found much lower prevalence estimates than in most other parts of the world. METHOD: Face-to-face household interviews of 5201 subjects (2633 in Beijing and 2568 in Shanghai respectively) were conducted from November 2001 to February 2002 using a multistage household probability sampling method. A Chinese version of the World Health Organization Composite International Diagnostic Interview (CIDI) was used for assessment. RESULTS: Twelve-month prevalence of any DSM-IV mental disorder in metropolitan China is estimated to be 7.0%, with major depressive disorder (2.0%), specific phobia (1.9%), and intermittent explosive disorder (1.7%) the most common disorders. Of these, 13.9% are classified as serious, 32.6% moderate, and 53.5% mild. Only 3.4% of respondents with any disorder sought treatment within the previous 12 months. CONCLUSIONS: Although the general pattern of disorders, risk factors, and unmet need for treatment are similar to those in other countries, a low prevalence of mental disorders is found in metropolitan China. Resolving methodological problems that cause downward bias in estimates, such as stigma-related under-reporting and diagnostic incongruity with a somatopsychic mode of symptom presentation may lead to more accurate and probably higher prevalence estimates in future epidemiological studies. As a low prevalence still translates into an enormous number of people in China, measures are urgently needed to address the huge unmet need for treatment of mental disorders.

Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics.

The bilateral communication between the immune and neuroendocrine systems plays an essential role in modulating the adequate response of the hypothalamic-pituitary-adrenal (HPA) axis to the stimulatory influence of cytokines and stress-related mediators. Growing evidence suggests that neuro-immune-endocrine crosstalk may be impaired in schizophrenia. We determined the relationship between cortisol, cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6), and symptoms in schizophrenia during treatment with typical and atypical antipsychotic drugs. Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients. SCH were randomly assigned to 12-week treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol using a double-blind design. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS). Serum cortisol and IL-2 levels were assayed by radioimmunometric assay, and serum IL-6 levels by quantitative enzyme-linked immunosorbent assay. Following a 2-week washout period, serum levels of cortisol, IL-2, and IL-6 were increased in patients with schizophrenia compared to HC. Elevations in cortisol were associated with increase in both IL-2 and IL-6 in SCH. Moreover, elevations in cortisol were associated with negative symptoms and IL-2 with positive symptoms. In all, 12 weeks of risperidone treatment significantly decreased elevated cortisol and improved negative symptoms, but produced similar effects on IL-2 and IL-6 as well as on positive symptoms compared to haloperidol. The improvement of negative symptoms was related to the change in cortisol. Our results suggest that the imbalance in the HPA axis and cytokine system in patients with SCH is implicated in clinical symptoms, and is improved with atypical antipsychotic treatment.

Prolactin levels in male schizophrenic patients treated with risperidone and haloperidol: a double-blind and randomized study.

RATIONALE: There are few data from systematic, double-blind clinical trials that have compared the effect of the typical and the atypical antipsychotics on serum prolactin (PRL) levels in patients with schizophrenia. OBJECTIVES: The goal of this study was to compare the effect of risperidone and haloperidol on serum PRL and investigate the relationship between serum PRL levels and clinical response in patients with schizophrenia. METHODS: Seventy-eight inpatients with a diagnosis of schizophrenia (according to DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol after a 2-week washout period, using a randomized, double-blind design. Clinical efficacy was determined using the positive and negative syndrome scale (PANSS). Their serum PRL was assayed by means of radioimmunometric assay (RIA) between pre-treatment and post-treatment, and compared with 30 sex-matched and age-matched normal subjects. RESULTS: Both risperidone and haloperidol treatment significantly increased serum PRL levels in drug-free chronic schizophrenia patients (both P<0.001). Hyperprolactinemia induced by risperidone 6 mg/kg was comparable to levels produced by haloperidol 20 mg/day. Considering dose-adjusted serum PRL levels, risperidone treatment induced a significant elevation of PRL levels compared with haloperidol treatment at the haloperidol equivalent (P<0.001). Change in PRL levels at pre-treatment and post-treatment were related to positive symptom improvement seen in the risperidone group (r=0.51, P=0.016), but not in the haloperidol group (P>0.05). Female patients showed both a higher baseline and post-treatment PRL level and a greater increase in PRL than men (all P<0.05). CONCLUSIONS: Risperidone is associated with a robust effect on prolactin secretion in contrast to the conventional antipsychotic haloperidol. Prolactin monitoring during risperidone treatment should be performed.

Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia.

BACKGROUND: Many studies have indicated that immune cytokines may be involved in the pathophysiology of schizophrenia. Recently, there have been reports that typical and atypical antipsychotic drugs may influence the levels of cytokines or cytokine receptors. The aim of this study was to compare the effect of typical and atypical antipsychotic drugs on serum interleukin-2 (IL-2), interleukin-6 (IL-6), and interleukin-8 (IL-8) and to investigate the relationship between the changes in cytokines and the therapeutic outcome in schizophrenia. METHOD: From April 1996 to August 1997, seventy-eight inpatients with a diagnosis of chronic schizophrenia (DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol. Clinical efficacy was determined using the Positive and Negative Syndrome Scale. Serum IL-2 was assayed by radioimmunometric assay, and serum IL-6 and IL-8 concentrations were measured by quantitative enzyme-linked immunosorbent assay in patients and 30 sex- and age-matched normal subjects. RESULTS: Both risperidone and haloperidol reduced the elevated serum IL-2 concentrations in schizophrenia, and no significant difference was noted in the reduction of serum IL-2 concentrations between risperidone and haloperidol treatment. Neither risperidone nor haloperidol showed significant influence on the higher serum IL-6 or IL-8 concentrations in schizophrenia. Correlations between serum IL-2 or IL-8 concentrations at baseline and the therapeutic outcome were observed, demonstrating that patients presenting with low concentrations of serum IL-2 or IL-8 at baseline showed greater improvement and patients presenting with higher serum IL-2 or IL-8 concentrations at baseline showed less improvement after treatment. CONCLUSIONS: Both typical and atypical anti-psychotic drugs may at least partially normalize abnormal immune alterations in schizophrenia. Some immune parameters at baseline may be useful for predicting the neuroleptic response of schizophrenic patients.

Mutation screening and association study of the beta-adrenergic receptor kinase 2 gene in schizophrenia families.

Chromosome 22q12 is one of the most promising regions for harboring a risk gene for schizophrenia. We have reported significant linkage of intermediate phenotypes for schizophrenia with markers within or near the beta-adrenergic receptor kinase 2 (ADRBK2, or GRK3) gene, which is highly expressed in dopaminergic pathways in the central nervous system, and mediates homologous desensitization for a variety of neurotransmitters and hormones through phosphorylation of G protein-coupled receptors (GPCRs). A polymorphism in the promoter region of the ADRBK2 was reported to be associated with bipolar disorder. We screened the putative promoter region, and all 21 exonic and flanking intronic regions of the ADRBK2 gene for mutations in 48 schizophrenia probands (including 16 Japanese and 32 Chinese patients), and evaluated the detected polymorphisms and those reported in the JSNP database for associations with schizophrenia in 113 family trios of schizophrenia probands. Four single nucleotide variants in the 5'-UTR/promoter region, and 16 rare variants in exonic and flanking regions, were identified. Among them, the Cys208Ser variant was the only non-synonymous mutation. Cys208Ser was found in one family without cosegregation between the variant and schizophrenia. Moreover, allelic, genotypic and haplotypic analyses provided no evidence for association between alleles at these polymorphisms and schizophrenia. The present study indicates that the ADRBK2 gene is unlikely to contribute strongly to schizophrenia susceptibility in this set of families.

Family-based association study of the NOTCH4 gene in schizophrenia using Japanese and Chinese samples.

BACKGROUND: A family based association study in a British sample found the NOTCH4 gene to be associated with schizophrenia; however, all six replication studies failed to confirm the finding. METHODS: We performed a family based association study of NOTCH4 and schizophrenia in 123 trios (16 Japanese and 107 Chinese). In addition to the original study's polymorphisms, we examined four new single nucleotide polymorphisms (SNPs)--SNPs_A, B, C and D--around SNP1 of the original study. We genotyped all samples for SNPs_A-D and for SNP1 and (CTG)n of the original study. RESULTS: We found no significant associations between NOTCH4 and schizophrenia or its subtypes for all polymorphisms, regardless of gender. The finding remained negative when the Chinese sample was analyzed separately. Exploratory analyses suggested that SNP_A may be associated with early-onset schizophrenia and that SNP1 may be associated with schizophrenia characterized by numerous negative symptoms. CONCLUSIONS: NOTCH4 is not a significant susceptibility gene for schizophrenia when clinical heterogeneity is ignored; however, NOTCH4 may be associated with early-onset schizophrenia or schizophrenia with many negative symptoms, but these findings should be interpreted cautiously.

Family-based association study of markers on chromosome 22 in schizophrenia using African-American, European-American, and Chinese families.

Several studies suggest that loci at chromosome 22q11.2-q13 might be linked to susceptibility to schizophrenia. Here we performed family-based association studies on chromosome 22q using 12 DNA microsatellite markers in African-American, European-American, and Chinese pedigrees. The marker D22S683 showed significant linkage and association with schizophrenia in not only the European-American sample but also in a combined sample (European-American and Chinese samples). Notably, D22S683 is located nearby and between D22S278 and D22S283, which have shown linkage and association to schizophrenia in prior reports. However, we found no significant association for the African-American sample. In conclusion, our data provide further support for the idea that the region around D22S683 contains a susceptibility gene for schizophrenia.

The effect of risperidone treatment on superoxide dismutase in schizophrenia.

Some reports have shown that schizophrenia is accompanied by the abnormal metabolism of free radicals. The purpose of this study was to investigate the effect of the atypical antipsychotic drug risperidone on blood superoxide dismutase (SOD), a critical enzyme in the detoxification of superoxide radicals, and to explore the relationship between changes in SOD and the therapeutic outcome. Forty-one inpatients with diagnosed schizophrenia (DSM-III-R) were assigned to 12 weeks of treatment with risperidone at a fixed dosage of 6 mg/d after a 2-week washout period. Clinical efficacy was determined with the Positive and Negative Syndrome Scale (PANSS). Blood SOD was assayed by radioimmunoassay (RIA) in schizophrenic patients before and after the 12-week treatment, and the values were compared with those of 50 age-, sex-, and smoking-matched subjects without schizophrenia. Risperidone treatment significantly decreased the initially high blood SOD levels in schizophrenia. There was a significantly positive relationship between the change in SOD at pretreatment and posttreatment and the reduction in the PANSS negative subscore. These findings suggest that risperidone treatment significantly decreased the blood SOD levels of schizophrenic patients, a change which may be associated with the diminishment of symptoms. The limitations of this study are the measurement of SOD levels by RIA rather than biochemical assay; the 2-week washout, which may not be adequate; and the measurement of only SOD enzyme and not the other antioxidant enzymes.

Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology.

Cytokines have been one of the recent focal points of immunological research in schizophrenia. The present study was to assess the serum levels of some of interleukins in schizophrenia and their relationships with the psychopathological parameters. Seventy physically healthy Chinese patients, who met DSM-III-R criteria for schizophrenia and who were drug-free for at least 2 weeks, were compared with 30 age- and sex-matched Chinese normal controls. The psychopathology of schizophrenia was assessed by the Positive and Negative Syndrome Scale (PANSS). Serum levels of IL-6 and IL-8 were measured by sandwich enzyme-linked immunosorbent assay (ELISA), and serum IL-2 level was assayed by radioimmunometric assay (RIA). Serum levels of IL-2, IL-6 and IL-8 were significantly elevated in patients with a chronic form of schizophrenia (all p<0.05). There was a significant inverse relationship between IL-2 level and the PANSS positive subscale P (r=-0.31, p=0.006) and a significant positive correlation between IL-8 level and PANSS negative subscale N (r=0.25, p=0.036) in schizophrenic patients. In control subjects, a significant and positive relationship between serum IL-2 and IL-6 (r=0.513, p=0.004) was noted, whereas, there was a significant and negative relationship between IL-2 and IL-8 in schizophrenic patients (r=-0.28, p=0.02). Our data confirms and supports the view that immune disturbance is involved in schizophrenia, which is compatible with the possibility that Chinese schizophrenic patients have an ongoing autoimmune process. This immune disturbance is related to the subgroup of schizophrenic patients with characteristic clinical variables. The dysfunction of interaction or inter-adjustment between different cytokines may exist in schizophrenic patients.

Risperidone-induced increase in serum prolactin is correlated with positive symptom improvement in chronic schizophrenia.

The elevation in serum prolactin (PRL) concentration in schizophrenic patients treated with typical antipsychotic drugs is well documented. Recently, increased prolactin levels have been reported in patients taking risperidone. The purpose of this study was to explore the effect of the atypical antipsychotic drug risperidone on serum prolactin, and to investigate the relationship between the change in PRL and the therapeutic outcome. In this study, 30 male inpatients with a diagnosis of chronic schizophrenia (DSM-III-R) were assigned to 12 weeks of treatment with risperidone after a 2-week washout period. The risperidone dose was fixed at 6 mg/day. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS). Serum PRL was assayed in serum by radioimmunometric assay in schizophrenic patients before and after 12-week treatment, as compared to 30 age-matched normal male subjects. The results showed that risperidone treatment significantly increased the serum PRL. A significant and positive relationship between the change in PRL at pre- and post-treatment and the reduction rate of PANSS positive subscore was observed. Risperidone treatment significantly increased the serum PRL levels of schizophrenic patients. There was a close relationship between the improvement in positive symptoms and the change of serum PRL level before and after risperidone treatment. The serum PRL levels at baseline could be used to predict the responses of schizophrenic patients to risperidone.