Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics

Several lines of evidence suggest that central brain-derived neurotrophic factor (BDNF) modulates food intake, metabolism, and increases in body weight. Reports have also shown that serum BDNF is altered in schizophrenic patients treated with antipsychotics. This study aimed to determine if there was a relationship between BDNF and antipsychotic-induced weight gain in patients with chronic schizophrenia. Serum BDNF was measured in 124 schizophrenia patients chronically treated with clozapine (n = 57), risperidone (n = 23) or typical antipsychotics (n = 44) and 50 healthy control subjects. To further assess group differences in serum BDNF, additional analyses were performed in a subset of patients and controls individually matched for body mass index (BMI). BDNF levels were lower in patients with schizophrenia than normal controls. However, this difference was not present when controlling for current BMI. In the individually BMI-matched sample, no differences in serum BDNF levels were observed in schizophrenic patients compared to BMI-matched healthy controls. BDNF levels negatively correlated with BMI gain in female but not in male patients when gender was considered. Antipsychotic class exerted differential effects over BDNF levels and BMI gain. Our findings suggest that decreased BDNF levels may be associated with weight gain in female schizophrenic patients on long-term antipsychotic treatment.     

The association of fetal and childhood growth with risk of schizophrenia. Cohort study of 720,000 Swedish men and women

Previous studies have shown that endogenous brain levels of kynurenic acid (KYNA), a glutamate receptor antagonist, are elevated in patients with schizophrenia. Here we analyse KYNA in the cerebrospinal fluid (CSF) from a large cohort, including male healthy controls (n = 49) and male patients with schizophrenia (n = 90). We found that male patients with schizophrenia had significantly higher levels of CSF KYNA compared to healthy male controls (1.45 nM ± 0.10 vs. 1.06 nM ± 0.06 in the control group). Furthermore, when the patients with schizophrenia were divided into subgroups we found that CSF KYNA levels were significantly elevated in drug-naïve, first episode patients (1.53 nM ± 0.19, n = 37) and in patients undergoing treatment with antipsychotic drugs (1.53 nM ± 0.17, n = 34) compared to healthy male controls. No elevated CSF KYNA levels were detected in drug-free patients with schizophrenia, i.e. patients previously undergoing antipsychotic medications but drug-free at time of sampling (1.16 nM ± 0.10, n = 19). Present results confirm that CSF KYNA concentration is elevated in patients with schizophrenia and are consistent with the hypothesis that KYNA contributes to the pathophysiology of the disease.     

Plasma cortisol-dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder

Hypercortisolaemia is a feature of many severe psychiatric illnesses and has been suggested to be both a causal and exacerbating factor of clinical symptoms and neurocognitive impairment. The adrenal steroid dehydroepiandrosterone (DHEA) has antiglucocorticoid properties that may have regulatory effects on glucocorticoid action in the brain. However, there is a paucity of data on these steroids and their ratio in schizophrenia and bipolar disorder. We therefore sought to assess cortisol and DHEA levels and the cortisol-DHEA ratio in patients with schizophrenia (n = 20) and bipolar disorder (n = 20), on stable medication for a minimum of 6 weeks, and healthy age- and sex-matched control subjects (n = 20). Steroid levels were measured from plasma samples collected at 30 min intervals from 1:00 p.m. to 4:00 p.m. Cortisol levels were found to be significantly elevated in both patient groups compared with controls. DHEA levels were elevated in schizophrenic patients compared with bipolar patients and controls, but there was no evidence of a difference in the cortisol-DHEA ratio of the groups. These data suggest that afternoon hypercortisolaemia is evident in symptomatic bipolar and schizophrenic patients compared to controls. However, an elevation in DHEA levels may represent a specific endocrine marker in schizophrenia.     

Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia

Neurotrophic factors (NFs) play a pivotal role in the development of the central nervous system. They are thus also suspected of being involved in the etiology of schizophrenia. Previous studies reported a decreased level of serum brain-derived neurotrophic factor (BDNF) in schizophrenia, whereas the association of epidermal growth factor (EGF) with this illness remains controversial. Using a two-site enzyme immunoassay, we conducted the simultaneous measurement of serum BDNF and EGF levels in a group of patients with chronic schizophrenia (N = 74) and a group of normal controls matched in age, body mass index, smoking habit and sex (N = 87). We found that, compared to normal controls, patients with chronic schizophrenia exhibited lower serum levels of both BDNF and EGF across all ages examined (21–59 years). The serum levels of BDNF and EGF were negatively correlated in the controls (r = − 0.387, P = 0.0002) but not in the patients. Clinical parameters such as duration of illness and psychiatric rating scale also showed no robust correlations with the NF levels. Collectively, these results suggest that pervasive, abnormal signaling of NFs underlies the pathophysiology of chronic schizophrenia.     

Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics

Neurotrophic factors regulate neuronal development and synaptic plasticity, possibly playing a role in the pathophysiology of schizophrenia and other psychiatric disorders. Decreased brain-derived neurotrophic factor (BDNF) levels have been found in brains and in the serum of schizophrenic patients, but results are inconsistent. Also, clozapine may upregulate brain BDNF expression. In the present study, we assessed serum BDNF immunoreactivity in 44 schizophrenic patients (20 on clozapine and 24 on typical antipsychotics) and in 25 healthy volunteers. Serum BDNF levels were measured using an enzyme immunoassay. Healthy controls showed significantly higher levels of BDNF compared to the whole group of schizophrenic patients (p<0.001) as well as to the subgroups on typical antipsychotics and clozapine (p<0.001). Serum BDNF values for controls were 168.8+/-26.3pg/ml, for the clozapine group were 125.4+/-44.5pg/ml and for the group on typicals were 101.3+/-51.6pg/ml. BDNF values from patients on clozapine were non-significantly higher than values from patients on typical antipsychotics (p=0.09). Serum BDNF was strongly and positively correlated with clozapine dose (r=0.643; p=0.002) but not with other demographic characteristics. These results reinforce previous findings of reduced serum BDNF levels in schizophrenic patients and suggest a differential effect of clozapine compared to typical antipsychotics on such levels.     

Effects of acute metabolic stress on the dopaminergic and pituitary-adrenal axis activity in patients with schizophrenia, their unaffected siblings and controls

A genetically mediated abnormal sensitivity to stress is thought to play a role in the onset, exacerbation and relapse of schizophrenia. In a double blind, placebo-controlled crossover study, peak increases in plasma ACTH (ΔACTH) and homovanillic-acid, a dopamine metabolite, (ΔHVA) following exposure to a metabolic stressor(2DG) were studied in unaffected siblings of patients with schizophrenia (n = 15), their patient relatives (n = 15) and healthy controls (n = 14). Siblings showed a stress response (both ΔACTH and ΔHVA) that was significantly greater compared to controls and significantly less pronounced compared to patients. The results suggest that the genetic risk for schizophrenia may be characterized by an enhanced sensitivity to stress.     

Serum brain-derived neurotrophic factor response to aerobic exercise in multiple sclerosis

Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-1, support brain health through protective, regenerative and adaptive neural processes. In this study, we investigated whether exercise and exercise training would alter circulating BDNF and IGF-1 in people with multiple sclerosis (MS) and matched controls. Twenty-two volunteers (MS (n = 11) and controls (n = 11)) matched in age, weight, body fatness and aerobic capacity (VO_2peak) completed the study. Subjects cycled at 60% of VO_2peak, three times per week for 8 weeks. Serum was analyzed for BDNF and IGF-1 at rest and BDNF after a standardized exercise bout at weeks 0, 4 and 8. Resting BDNF levels were lower in MS compared to controls at week 0 (p = 0.03) and only tended to be lower at week 8 (p = 0.07). BDNF increased at week 4 in MS subjects (p = 0.04) and returned to baseline at week 8. With acute exercise, BDNF decreased in both groups during the 3-hour post-exercise recovery period. Resting IGF-1 concentration was not significantly different between groups before or after training. Our study provides preliminary evidence that exercise may influence BDNF regulation in humans. Further research is needed to elucidate the impact of exercise on neurotrophin production, secretion and target tissue responses in humans.     

Gender differences in prolactin elevation induced by olanzapine in Japanese drug-naïve schizophrenic patients

We investigated the effect of gender on plasma prolactin levels in 20 Japanese drug-naïve schizophrenic patients [10 male, 10 female, aged 25.4 ± 10.3 (mean ± S.D.), range = 12–46 years] treated with olanzapine. Plasma prolactin levels were measured at baseline, and weeks 3 and 8 after starting titration of olanzapine. Comparisons of plasma prolactin levels between baseline and week 3, and between baseline and week 8 were made by repeated analysis of variance (ANOVA) and paired t-test. Two-way ANOVA showed a significant difference in olanzapine-induced prolactin changes between male and female patients (P = 0.037). In male patients (n = 10), the plasma concentration of prolactin at week 3 was significantly higher than at baseline (P = 0.016), but there was no significant difference between the plasma concentration of prolactin at week 8 and at baseline or week 3 (P = 0.191). In female patients (n = 10), there was a significant change of prolactin between baseline and week 3 (P = 0.005), and between baseline and week 8 (P = 0.047). Our results indicate the possibility of gender differences in prolactin elevation induced by olanzapine in Japanese drug-naïve schizophrenic patients. These gender-based findings may be helpful for clinicians when deciding the frequency of follow-up visits once a patient starts olanzapine therapy.     

Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients

Neurotrophic factors regulate neuronal development as well as synaptic plasticity, and their impairment is often implicated as a cause of schizophrenia. Among various neurotrophic molecules, brain-derived neurotrophic factor (BDNF) levels have been found to be increased in the corticolimbic regions of patients’ brains. In the present study, we assessed peripheral BDNF levels in whole blood as well as in the serum of two independent groups of schizophrenic patients (n=34 in each group) and healthy volunteers (n=35 and n=27, respectively). BDNF protein levels in fresh serum and blood of the patients and volunteers were measured using a two-site enzyme immunoassay and correlated with the number and decay of platelets. In addition to the studies of patients and volunteers, neuroleptic effects on BDNF levels were assessed by administering haloperidol to adult rats for 2 weeks or 5 months. The major findings were as follows: BDNF levels were significantly reduced in the serum of schizophrenic patients (P<0.005, Mann–Whitney U-test) but not in their whole blood. Antipsychotic dose did not correlate with serum BDNF levels. Moreover, chronic administration of haloperidol failed to decrease serum BDNF levels in adult rats. Abnormal levels of BDNF are evident not only in the brain of schizophrenic patients, but also in their peripheral blood. The BDNF reduction in serum but not in whole blood suggests a potential deficit in neurotrophic factor release in patients with schizophrenia.     

Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse,who were treated with typical or atypical antipsychotics

Brain-derived neurotrophic factor signals and dopaminergic function in the brain are strongly associated, and research on BDNF in schizophrenia may enhance our insights on the pathophysiological mechanisms of this disease. In the present study we aimed to investigate the possible association between serum BDNF levels and schizophrenic relapses and the possible differential effects of treatment with typical and atypical antipsychotics on serum BDNF levels in the same group of patients. We measured serum BDNF levels in 47 patients with schizophrenia during a relapse and again 6 weeks after administration of antipsychotic treatment (14 on risperidone, 18 on haloperidol, 10 on olanzapine and five on amisulpride) and in 44 healthy volunteers. Patients with schizophrenia showed reduced serum BDNF levels in relation to healthy volunteers at study entry. No significant differences were revealed in BDNF serum levels after 6 weeks of antipsychotic treatment in the patients compared to their own levels at study entry. However, serum BDNF was significantly increased in the subgroup receiving olanzapine compared to the other antipsychotics. Our findings may indicate a differential effect of olanzapine on BDNF levels compared to haloperidol, risperidone, and amisulpride.     

Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia

Brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations of serum BDNF levels with the cognition and clinical characteristics in patients with schizophrenia. Sixty-three patients with schizophrenia and 52 age- and sex-matched healthy controls were examined with neuropsychological tests. Serum BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in serum BDNF levels between normal controls and patients with schizophrenia. Serum BDNF levels of normal controls showed negative correlations with verbal working memory, but this was not the case with schizophrenic patients. Meanwhile, serum BDNF levels of schizophrenic patients showed positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels are related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia.     

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.     

Cognitive function and serum levels of brain-derived neurotrophic factor in patients with bipolar disorder

Objectives:  Brain-derived neurotrophic factor (BDNF) is an important contributor to the pathophysiology of bipolar disorder (BD), and abnormalities in the BDNF-signaling system may be implicated in the cognitive decline observed in BD patients. We aimed to investigate serum BDNF levels in BD patients and its relation to neurocognitive function.
Methods:  We measured serum BDNF levels using an enzyme-linked immunosorbent assay method in 65 euthymic type I BD patients and 50 healthy controls, and administered a neuropsychological test battery to assess attention and mental control, perceptual-motor skills, executive functions, verbal fluency and abstraction, visuospatial attention, and memory.
Results:  We found no significant differences regarding serum BDNF levels in BD patients and healthy controls. We found significant positive associations between serum BDNF levels and illness duration, and manic and depressive episodes in female BD patients only. Serum BDNF levels were lower in patients medicated with antipsychotics and/or lithium, whereas patients on valproate and/or antidepressants showed higher serum BDNF levels. Patients performed significantly worse on 11 out of 16 neurocognitive tests as compared to controls. We found a significant positive association between serum BDNF levels and a test of verbal fluency in both BD patients and controls.
Conclusions:  Present results support the hypothesis that BDNF normalizes with mood stabilization and pharmacological treatment. Our findings in young and physically healthy patients with short illness duration and few mood episodes may explain the lack of association between serum BDNF levels and neurocognitive performance, even though cognitive performance in patients was overall significantly worse as compared to healthy controls.     

Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment

Brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the etiology of schizophrenia. There is a line of evidence that disruption of neurotrophins could play a role in the etiology of schizophrenia, and antipsychotics show their effect by altering levels of neurotrophins. The aim of this study was to evaluate the effect of antipsychotics on serum BDNF levels and their relationship with the symptoms in patients with schizophrenia. Twenty-two schizophrenia patients were enrolled in the study. The control group consisted of 22 age- and sex-matched physically and mentally healthy volunteers (7 male, 15 female). Serum BDNF levels and the positive and negative syndrome scale (PANSS) scores were recorded at baseline and after 6 weeks of treatment. Serum BDNF levels were also recorded in the control group. Schizophrenia patients who failed to meet 30% improvement in PANSS score were excluded from the study. The baseline serum BDNF levels of schizophrenia patients were lower than those of controls (t = 4.56; df = 21; p < 0.001). There was no correlation between serum BDNF levels and PANSS scores in patients with schizophrenia (p > 0.05). Although PANSS (for positive symptoms p < 0.001, for negative symptoms p < 0.001) and general psychopathology (t = 20.9; df = 22; p < 0.001) scores improved significantly after 6 weeks of antipsychotic treatment; there was no change in BDNF levels in patients' serum (p > 0.05). Our results support the view that BDNF would be associated with schizophrenia. However, we could not conclude that treatment with antipsychotics alters serum BDNF levels in patients with schizophrenia.     

血清瘦素与抗精神病药源性肥胖及糖尿病的相关性研究

目的　调查和探讨长期使用抗精神病药患者血瘦素水平及其与服用抗精神病药后体重 增加、肥胖及糖尿病之间的关系。方法　对符合入组标准的308例长期服用抗精神病药的精神分裂症 患者分为对照组、肥胖组、糖耐量减低组及糖尿病组,比较血清瘦素水平、胰岛素抵抗指数、血清甘油三 酯及总胆固醇水平。结果　(1)肥胖组、糖耐量减低组及糖尿病组患者的血清瘦素水平、胰岛素抵抗指 数、血清甘油三酯及总胆固醇水平均显著高于对照组(P<0.05)。(2)长期应用抗精神病药患者血瘦 素水平与体重指数、简易胰岛素抵抗指数、空腹血糖、血甘油三酯及胆固醇均呈极显著正相关(P<0.01 ～0.0001),而与餐后2h血糖水平及用药时间无相关性。结论　长期应用抗精神病药患者血瘦素水 平在肥胖、糖耐量降低及糖尿病患者中显著升高,且与体重指数、简易胰岛素抵抗指数、空腹血糖水平等 均呈显著正相关,提示高血清瘦素水平是长期应用抗精神病药所致的代谢紊乱综合征的重要指征之一。     

No association between global leukocyte DNA methylation and homocysteine levels in schizophrenia patients

Meta-analysis recently suggested that a 5 μM increase in homocysteine is associated with a 70% higher risk for schizophrenia. Elevated homocysteine is reported to alter macromolecule methylation. We studied whether elevated plasma homocysteine levels in schizophrenia are associated with altered leukocyte global DNA methylation. DNA was extracted from peripheral blood leukocytes of 28 schizophrenia patients vs. 26 matched healthy controls. Percent of global genome DNA methylation was measured using the cytosine-extension method. Homocysteine levels were higher in schizophrenia patients than in controls. No difference in global DNA methylation between schizophrenia patients and control subjects was found (74.0% ± 14.8 vs. 69.4 ± 22.0, p = 0.31). A significant interaction between diagnosis and smoking on DNA methylation was obtained (F = 6.8, df = 1,47, p = 0.032). Although leukocytes may be a useful cell model to evaluate epigenetic changes such as global DNA methylation in brain, future studies should compare global DNA methylation in peripheral tissue vs. brain in laboratory animals.     

Pituitary volume in neuroleptic-naïve schizophrenia: a structural MRI study

Abnormalities in the hypothalamic–pituitary–adrenal axis (HPA) have been implicated in psychosis. To our knowledge, no prior study has measured pituitary volume in a neuroleptic-naïve schizophrenic population. Herein, we present data exploring the volumetric differences in a sample of antipsychotic-naïve patients with a DSM-IV diagnosis of schizophrenia versus appropriately matched healthy controls.

Pituitary volumes were measured in 51 patients with schizophrenia (36 males, 15 females, mean age ± S.D.: 25.2 ± 7.4 years) and 55 healthy controls (30 males, 25 females; mean age ± S.D.: 25.2 ± 6.6 years) Measurements were conducted on 1.5 mm thick T1-weighted coronal images from a 1.5T scanner by two trained raters. Patients with schizophrenia had significantly smaller pituitary volumes than healthy control subjects (mean volume ± S.D. = 0.58 ± 0.14 cm³ and 0.66 ± 0.17 cm³ respectively; ANCOVA (using intracranial volume, gender and age as covariates), F = 6.81, df = 1, 101; p = 0.01). These findings provide new evidence of a smaller pituitary volume in neuroleptic-naïve patients with schizophrenia. The observed alterations in pituitary volume are consistent with neuroendocrine studies that have reported abnormalities in the HPA axis in psychosis. Similar volume reductions have been seen in other neuropsychiatric populations and may cut across diagnostic boundaries.     

Pituitary volume in teenagers with first-presentation borderline personality disorder

This study used magnetic resonance imaging to examine pituitary gland volume (PGV) in teenage patients with a first presentation of borderline personality disorder (BPD). No difference in PGV was observed between healthy controls (n = 20) and the total BPD cohort (n = 20). However, within the BPD cohort, those exposed to childhood trauma (n = 9) tended to have smaller pituitaries (− 18%) than those with no history of childhood trauma (n = 10). These preliminary findings suggest that exposure to childhood trauma, rather than BPD, per se, might be associated with reduced PGV, possibly reflecting hypothalamic–pituitary–adrenal axis dysfunction.     

A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study

Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT_2C) plays a key role in control of appetite and satiety. A 5-HT_2C Cys23Ser substitution, coded for by a single nucleotide polymorphism (Cys23Ser) within the 5-HT_2C gene, has been shown to influence 5-HT_2C function. We hypothesized that Cys23Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys23Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p = 0.044) and Cys23Ser was associated with weight (p = 0.039), body mass index (BMI; p = 0.038), and seasonal appetite change (p = 0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys23Ser was associated with minimum lifetime BMI (p = 0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys23Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys23Ser in the behavioral regulation of body weight.