Hiroki Koizumi

Decreased levels of serum brain-derived neurotrophic factor in female patients with eating disorders

BACKGROUND Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays a role in the regulation of eating behavior. Because of its role in eating behavior, which is especially relevant to eating disorders, BDNF is an attractive candidate for investigation of potential biological markers of eating disorders such as bulimia nervosa (BN) and anorexia nervosa (AN). METHODS We enrolled 18 female patients with BN, 12 female patients with AN, and 21 age-matched female normal control subjects in this study. Eating-related psychopathology and depressive symptoms were evaluated using the Bulimic Investigatory Test, Edinburgh (BITE) and the Hamilton Depression Rating Scale (HDRS). Serum BDNF levels were measured by a sandwich enzyme-linked immunosorbent assay. RESULTS Serum levels of BDNF in the patients with AN or BN were significantly (p<.0001) decreased compared with those of normal control subjects, and serum BDNF levels in the patients with AN were significantly (p=.027) lower than those in patients with BN. A significant positive correlation (r=.378, p=.006) between serum BDNF levels and body mass index in all of the subjects was detected. Furthermore, there was a significant positive correlation (r=.435, p=.015) between the BITE symptom scale score and HDRS in these patients. CONCLUSIONS The present study suggests that BDNF may play a role in the pathophysiology of eating disorders.

Association between the brain-derived neurotrophic factor 196G/A polymorphism and eating disorders.

Several lines of evidence suggest that genetic factors might contribute to the pathogenesis of eating disorders and that brain‐derived neurotrophic factor (BDNF) plays a role in the pathophysiology of eating disorders. To investigate the role of the BDNF gene in the susceptibility to eating disorders, we analyzed the BDNF 196G/A gene polymorphism in female patients with eating disorders and female normal controls. The difference in the genotype frequency between patients (n = 198) and normal controls (n = 222) was statistically significant (P = 0.029). Interestingly, a significant (P = 0.015) difference in the genotype frequency between normal controls and bulimia nervosa patients (n = 101) with binge‐purging type was detected. This study suggests that the BDNF 196G/A gene polymorphism might be associated with a susceptibility to eating disorders.© 2003 Wiley‐Liss, Inc.

Serum brain-derived neurotrophic factor (BDNF) levels in patients with panic disorder: as a biological predictor of response to group cognitive behavioral therapy.

Little is known about biological predictors of treatment response in panic disorder. Our previous studies show that the brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of major depressive disorders and eating disorders. Assuming that BDNF may be implicated in the putative common etiologies of depression and anxiety, the authors examined serum BDNF levels of the patients with panic disorder, and its correlation with therapeutic response to group cognitive behavioral therapy (CBT). Group CBT (10 consecutive 1 h weekly sessions) was administered to the patients with panic disorder after consulting the panic outpatient special service. Before treatment, serum concentrations of BDNF and total cholesterol were measured. After treatment, we defined response to therapy as a 40% reduction from baseline on Panic Disorder Severity Scale (PDSS) score as described by [Barlow, D.H., Gorman, J.M., Shear, M.K., Woods, S.W., 2000. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. JAMA. 283, 2529-2536]. There were 26 good responders and 16 poor responders. 31 age- and sex-matched healthy normal control subjects were also recruited in this study. The serum BDNF levels of the patients with poor response (25.9 ng/ml [S.D. 8.7]) were significantly lower than those of the patients with good response (33.7 ng/ml [S.D. 7.5]). However, there were no significant differences in both groups of the patients, compared to the normal controls (29.1 ng/ml [S.D. 7.1]). No significant differences of other variables including total cholesterol levels before treatment were detected between good responders and poor responders. These results suggested that BDNF might contribute to therapeutic response of panic disorder. A potential link between an increased risk of secondary depression and BDNF remains to be investigated in the future.

Possible role of d-serine in the pathophysiology of Alzheimer's disease

Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site on the N-methyl-D-aspartate (NMDA) receptor that has been implicated in the pathophysiology of Alzheimers disease (AD). The purpose of the study was to determine whether serum levels of D- and L-serine in patients with AD are altered as compared with normal controls. Serum levels of D- and L-serine in patients of AD and age- and gender-matched normal controls were determined using a high-performance liquid chromatography (HPLC). Serum levels of D-serine in the patients with AD were slightly (z=-1.77, p=0.078) lower than those of normal controls. In contrast, serum levels of L-serine in the patients were slightly (z=-1.73, p=0.083) higher than those of controls. In addition, the percentage (%) of D-serine in the total (L+D) serine in the patients was significantly (z=-2.36, p=0.018) lower than that of controls. The present study suggests that the reduced activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine may play a role in the pathophysiology of AD.

No association of the brain-derived neurotrophic factor (BDNF) gene polymorphisms with panic disorder

Several lines of evidence suggest that genetic factors might contribute to susceptibility to panic disorder. Our previous studies show that the brain-derived neurotrophic factor (BDNF) may play a role in the pathophysiology of major depressive disorders and eating disorders. Assuming that BDNF may be implicated in the putative common pathophysiology of depression and anxiety, we analyzed the association of two BDNF gene single nucleotide polymorphisms (SNPs), 132C > T (formerly named C270T) in the noncoding region of exon V and 196G > A (val66met) in the coding region of exon XIIIA, with panic disorder. In this study, 109 patients with panic disorder diagnosed according to the DSM-IV criteria, and 178 control subjects were recruited. There were no significant differences in the frequency of the genotype or allele in these two SNPs between patients and controls [132C > T in exon V: genotype, p = 1.0, allele, p = 0.59; 196G > A (val66met) in exon XIIIA: genotype, p = 0.77, allele, p = 0.78]. Furthermore, no significant associations of agoraphobia with the two SNPs were detected. This study suggests that the BDNF gene polymorphisms are not associated with panic disorder in our Japanese population.

Dietary restriction changes behaviours in brain-derived neurotrophic factor heterozygous mice: role of serotonergic system

Accumulating evidence has suggested that brain‐derived neurotrophic factor (BDNF) plays a role in eating behaviours, and that BDNF‐heterozygous (+/–) mice exhibit abnormal behaviours (e.g. obesity, anxiety and aggression). The present study was undertaken to determine whether or not dietary restriction (DR) alters the behaviours in BDNF+/– mice, as DR has been shown to exert a number of beneficial effects on the brain. Eight‐week‐old male wild‐type (+/+) and BDNF+/– mice were divided into two groups, ad libitum (AL) diet group and DR group, for 16 weeks. After carrying out a behavioural evaluation, we determined the BDNF mRNA levels, as well as mRNA levels for subtypes (5‐HT1A, 5‐HT1B, 5‐HT2A and 5‐HT2C) of the 5‐HT receptor and 5‐HT transporter (5‐HTT), protein levels of BDNF and concentrations of 5‐HT and 5‐HIAA in the hypothalamus, hippocampus and frontal cortex. DR significantly ameliorated behaviours including obesity, anxiety and aggression in BDNF+/– mice. The concentrations of 5‐HT and 5‐HIAA in the frontal cortex, and 5‐HT in the hippocampus, of BDNF+/– mice were significantly lower than those of wild‐type mice. Interestingly, DR significantly increased the levels of 5‐HT and 5‐HIAA in the frontal cortex of BDNF+/– mice. These findings suggest that DR may alter the behaviours in BDNF+/– mice, and that the 5‐HT system may be implicated in the beneficial effects of DR on these behaviours.

No changes in serum ghrelin levels in female patients with bulimia nervosa

It has been reported that fasting plasma ghrelin levels may play a role in the pathophysiology of eating disorders. In this study, the authors examined whether serum levels of ghrelin were altered in the patients with bulimia nervosa (BN). We enrolled 18 female patients with BN, and 21 age-matched female controls for this study. Eating-related psychopathology, depressive symptoms were evaluated by using the Bulimic Investigatory Test, Edinburgh (BITE) and the 17-item Hamilton Depression Rating Scale (HDRS). Serum levels of ghrelin were measured by Ghrelin enzyme immunoassay kit. There were no significant differences in serum ghrelin levels between the patients with BN and normal controls. Furthermore, the authors did not found correlation between serum ghrelin levels and clinical parameters in the patients with BN. Our study suggests that serum ghrelin levels in the patients with BN were indistinguishable from normal controls. Therefore, it is unlikely that ghrelin plays a role in the pathophysiology of BN.

Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers

Several lines of evidence suggest that increased generation of auto‐oxidized dopamine (DA) o‐quinone is associated with the neurotoxicity of methamphetamine (MAP) in the brain, and that, as a cellular defenses against DA‐derived quinines, glutathione S‐transferase (GST) detoxifies auto‐oxidized DA o‐quinone in the brain. Glutathione S‐transferase M1 (GSTM1) of the mu‐class of GSTs catalyzes reaction between glutathione and catecholamine o‐quinones under physiological conditions. This study was undertaken to investigate the role of the GSTM1 gene deletion polymorphism in the neuropathology of MAP abuse. One hundred fifty‐seven MAP abusers and 200 healthy comparison subjects were tested for a genetic polymorphism of GSTM1. The difference in the frequency of deletion (D)/non‐deletion (N) alleles between the female abusers and female controls was close to statistical significance (P = 0.071), although there was no statistical difference (P = 0.651) between male abusers and male controls. Furthermore, the number of female abusers with deletion alleles was significantly (P = 0.007, odds ratio: 2.77, 95% CI 1.30–5.89) higher than that of male abusers with deletion alleles. These findings suggest that GSTM1 gene deletion may contribute to a vulnerability to MAP abuse in female subjects, but not in male subjects.

Lack of association between angiotensin I-converting enzyme insertion/deletion gene functional polymorphism and panic disorder in humans.

Family and twin studies have indicated that genes influence susceptibility to panic disorder, but the genes involved remain unknown. The neuropeptide angiotensin II has been found to be involved in anxiety and regulation of respiration which are important in the pathophysiology of panic attacks. Assuming that angiotensins may be candidate genes in panic disorder, we analyzed the association between panic disorder and angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) gene functional polymorphism. We recruited 101 patients with panic disorder diagnosed according to DSM-IV criteria, and 184 control subjects in the study. No significant differences in the frequency of the genotype or allele in the polymorphism between patient and control groups were found (genotype, chi(2)=0.56, d.f.=2, P=0.77; allele, chi(2)=0.074, d.f.=1, P=0.78). This study suggests that the ACE I/D gene polymorphism is not directly associated with panic disorder in our Japanese patient group.

An open trial of outpatient group therapy for bulimic disorders : Combination program of cognitive behavioral therapy with assertive training and self-esteem enhancement

Abstract  The purposes of this study were to examine the therapeutic efficacy of combined group cognitive behavioral therapy (CGCBT) and to explore the characteristics of the patients who failed to complete it. Our group cognitive behavioral therapy combined with assertiveness training for alexithymia and self‐esteem enhancement therapy were attended over a 10‐week period. Twenty‐five participants were enrolled in the study. The clinical symptoms were assessed before and after treatment, using rating scales including the Eating Disorder Inventory‐2, the Bulimic Investigatory Test, Edinburgh, the Toronto Alexithymia Scale, the Rosenberg Self‐Esteem Scale, and Global Assessment of Functioning. Sixteen participants (64%) completed the CGCBT program. Completion of the CGCBT resulted in significant improvements in reducing binge‐eating behavior and improving social functioning. Eight patients (32%) significantly improved using the Clinical Global Impression Change (CGI‐C). Stepwise logistic regression analysis of the results indicated that a lower age (P = 0.04) and psychiatric comorbidity (P = 0.06) were predictors of dropout from the CGCBT program. Our CGCBT program is a promising first‐line treatment for bulimic outpatients. Lower age and the presence of comorbidity had effects on dropout rates.