Dong Feng Zhou

Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics

There is accumulating evidence of altered antioxidant enzyme activities and increased levels of lipid peroxidation in schizophrenia. Free radical-mediated abnormalities may contribute to specific aspects of schizophrenic symptomatology and complications of its treatment. However, few studies have evaluated both antioxidant enzymes and lipid peroxidation in the same schizophrenic patient groups treated with typical or atypical antipsychotics. Plasma malondialdehyde (MDA) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were analyzed using established procedures in 92 medicated schizophrenia including paranoid (n=34), disorganized (n=18) and residual subtypes (n=40), as well as in control subjects (n=50). The results showed that activities of SOD and GSH-Px were decreased but levels of MDA were elevated in patients with a chronic form of schizophrenia as compared with normal controls. SOD and GSH-Px activities were found to be significantly lower in paranoid and residual subtypes compared to both disorganized subtype and the control group. MDA levels were significantly higher in all subtypes compared to the control group. There were no significant differences in any parameters measured among all three subgroups treated with clozapine (n=44), risperidone (n=20) and typical antipsychotics (n=28). Additionally, a significantly higher MDA levels, but a significantly lower CAT activity was noted in female than male patients. These results suggest that oxidative stress may be implicated in the pathophysiology of all subtypes of schizophrenia, which may contribute to the increased membrane lipid peroxidation. Long-term treatments with typical and atypical antipsychotics may produce the similar effects on the antioxidant enzymes and lipid peroxidation.

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.

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.

Decreased BDNF in serum of patients with chronic schizophrenia on long-term treatment with antipsychotics

Accumulating evidence suggests BDNF as a molecule involved in the pathophysiology of schizophrenia. To examine the BDNF levels and the relationship between BDNF levels and psychopathology in patients with schizophrenia, 81 physically healthy patients with schizophrenia were compared with 45 age-, sex- matched normal controls. The psychopathology of patients were assessed by the Positive and Negative Syndrome Scale (PANSS). Serum BDNF levels were measured by sandwich ELISA. The results showed that BDNF-like immunoreactivity were significantly lower in medicated patients with chronic schizophrenia than in healthy control subjects. A significant negative correlation between BDNF-like immunoreactivity and PANSS negative subscore was observed. As compared with normal controls, there was a significant decrease in BDNF-like immunoreactivity in patients treated with both atypical and typical antipsychotics. However, no correlation between standardized drug doses and BDNF-like immunoreactivity was found. These findings suggest that serum BDNF levels in chronic schizophrenia under antipsychotic medication may be decreased. However, long-term effects of antipsychotics remain to be characterized.

BDNF Levels and Genotype are Associated with Antipsychotic-Induced Weight Gain in Patients with Chronic Schizophrenia

Recent evidence suggests that centrally released brain-derived neurotrophic factor (BDNF) modulates eating behavior and metabolism that is responsible for body weight fluctuation. BDNF also may play an important role in the therapeutic action of antipsychotic medications. We investigated whether the Val66Met polymorphism of the BDNF gene affected weight gain after long-term antipsychotic treatment in schizophrenia. The polymorphism was genotyped in 196 Chinese patients with schizophrenia on long-term antipsychotic medication. Serum BDNF was measured in all patients and 50 normal controls. Mean body mass index (BMI) change was evaluated retrospectively by means of clinical records. The results showed that there was a significant relationship between the three BDNF Val/Met genotypes and mean BMI gain, with genotype having a strong effect on BMI gain in male but not female patients. BDNF levels were significantly lower in patients than normal controls, and negatively correlated with BMI gain in female but not male patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment, and decreased BDNF levels may be associated with weight gain in females.

Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements

Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD). Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) plays a critical role in the maintenance of functional neurons. The present study was to examine plasma BDNF levels and the relationship among BDNF level, psychopathological and tardive dyskinesia symptoms in schizophrenic patients with TD. Eighty schizophrenic patients with TD were compared with 45 schizophrenic patients without TD, as well as with 45 age-, sex-matched normal controls. The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS). The psychopathology of patients was assessed by the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that the patients with TD had lower plasma BDNF levels than those without TD, and than that of normal controls. In the patients with TD, plasma BDNF levels was inversely correlated with AIMS total score, and with PANSS negative subscore. Female patients had significantly lower plasma BDNF levels than male TD patients. Our results suggest that decreased BDNF may play an important role in the pathophysiology of TD. There may be a relationship between decreased BDNF levels and dyskinetic movements associated with TD.

Elevated blood superoxide dismutase in neuroleptic-free schizophrenia: association with positive symptoms

Blood levels of superoxide dismutase (SOD), measured by radioimmunometric assay, were compared in 68 patients with chronic schizophrenia and 50 normal control subjects. Psychopathology in the patients was assessed with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS), and the Scale for the Assessment of Negative Symptoms. Blood SOD levels were significantly elevated in schizophrenia compared with control values. SOD levels showed a positive relationship with the BRPS and the SAPS total score in patients.

The Effect of Extract of Ginkgo Biloba Added to Haloperidol on Superoxide Dismutase in Inpatients With Chronic Schizophrenia

The purpose of the study was to evaluate the effect of the classic antipsychotic haloperidol plus extract of ginkgo biloba (EGb) on treatment-resistant chronic schizophrenia and on blood superoxide dismutase (SOD) levels. Eighty-two patients with chronic refractory schizophrenia were studied. Forty-three patients were treated with haloperidol plus extract of ginkgo biloba (group 1), and 39 received haloperidol plus placebo (group 2). SOD levels of these patients were measured before and after treatment and were compared with SOD levels of 30 healthy volunteers. Therapeutic efficiency was equated with a change in clinical rating scores assessed by standardized measurement tools that included the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms (SANS) over this period. Patients in group 1 improved significantly as demonstrated by scores from these two assessment instruments; those in group 2 improved significantly only as shown by scores on SANS. SOD levels before treatment in all patients were significantly higher than those in healthy controls; after treatment, the SOD level decreased significantly in group 1 but not in group 2. These results suggest that EGb may enhance the efficiency of the classic antipsychotic haloperidol in patients with schizophrenia, especially on their positive symptoms, and that EGb may work through an antioxidant effect that is involved in the therapeutic mechanism in patients with chronic refractory schizophrenia.

Association of clozapine-induced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population

Weight gain is a problem commonly encountered with antipsychotic treatment and has become more apparent with increasing use of the newer atypical antipsychotics. The adipocyte-derived hormone, leptin, has been associated with body weight and energy homeostasis, and abnormal regulation of leptin could play a role in weight gain induced by antipsychotics. We investigated whether a leptin gene promoter variant affected weight gain after long-term treatment with clozapine in chronic schizophrenia. Leptin G2548A polymorphism was genotyped in 102 Chinese Han inpatients with chronic schizophrenia treated with clozapine. Weight gains, expressed as change in body mass index (BMI), were monitored after long-term clozapine treatment. We found a significant relationship between the 3 leptin G/A genotypes and mean BMI gain (F2,99 = 3.35, P = 0.039, r2 = 0.09). Moreover, genotype had a strong effect on BMI gain in male (P = 0.004, r2 = 0.16), but not in female patients (P > 0.05). Thus, variation in the leptin gene may be a risk factor for weight gain in male patients with schizophrenia on long-term clozapine treatment.

Extract of Ginkgo biloba Treatment for Tardive Dyskinesia in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE Free radicals may be involved in the pathogenesis of tardive dyskinesia (TD). Extract of Ginkgo biloba (EGb) is a potent antioxidant possessing free radical-scavenging activities. The aim of the study was to evaluate the efficacy of EGb-761, a standardized extract given in capsule form, in treating TD in schizophrenia patients. METHOD Inpatients with DSM-IV-diagnosed schizophrenia and TD (n = 157) in a mainland China Veterans Affairs psychiatric hospital were randomly assigned to 12 weeks of treatment with either EGb-761, 240 mg/d (n = 78) or a placebo (n = 79) in a double-blind manner. Primary outcome measures were (1) change from baseline in the Abnormal Involuntary Movement Scale (AIMS) score and (2) proportion of patients with a ≥ 30% reduction in their AIMS total score at week 12. Secondary outcome measures included the Positive and Negative Syndrome Scale (PANSS) and cognitive performance as measured by the Continuous Performance Test-37 Version and the 3-card Stroop task. Patients were recruited for the study between December 2006 and May 2007. RESULTS Of the 157 patients who were randomly assigned, 152 (96.8%) completed the study. EGb-761 treatment significantly decreased the AIMS total score in patients with TD compared to those who were given a placebo (2.13 ± 1.75 vs -0.10 ± 1.69; P < .0001), with 40 (51.3%) and 4 (5.1%) patients achieving response in the EGb-761 and placebo treatment groups, respectively. There were no between-group differences in the PANSS total score or cognitive measures from baseline to week 12. CONCLUSIONS EGb-761 appears to be an effective treatment for reducing the symptoms of TD in schizophrenia patients, and improvement may be mediated through the well-known antioxidant activity of this extract. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00672373.