Hikaru Hori

Effects of paroxetine or milnacipran on serum brain-derived neurotrophic factor in depressed patients

Brain-derived neurotrophic factor (BDNF) is an important member of the neurotrophin family of growth factors, abundant in the brain and periphery. Researchers have reported that serum BDNF levels in drug-free depressed patients are lower than those of healthy controls, and have proposed that these low levels might reflect a failure of neuronal plasticity in depression. In the present study, we investigated the effects of paroxetine, an SSRI, and milnacipran, an SNRI, on serum BDNF levels in depressed patients. Serum levels of BDNF were measured by ELISA before, 4 weeks, and 8 weeks after the start of treatment with antidepressants. Forty-two patients were randomly administered paroxetine (21 cases) or milnacipran (21 cases). A negative correlation was found between serum BDNF levels and baseline Ham-D scores. The response and remission rates for each drug were not significantly different. Serum BDNF levels in responders were significantly increased 2.6- and 1.8-fold 8 weeks after treatment with paroxetine or milnacipran, respectively. These results suggest that both drugs improve the depressive state by increasing BDNF levels.

Higher plasma interleukin-6 (IL-6) level is associated with SSRI- or SNRI-refractory depression

In the present study, we compared plasma levels of interleukin-6 (IL-6), tumor necrosis factor-alpha(TNFalpha), and brain-derived neurotrophic factor (BDNF) among selective serotonin reuptake inhibitor (SSRI)- or serotonin noradrenaline reuptake inhibitor (SNRI)-responsive depressed patients (n=31), SSRI- or SNRI-refractory depressed patients (n=20), and healthy controls (n=30). The plasma levels of IL-6 and TNF-alpha were significantly higher in depressed patients than in healthy controls. Treatment with antidepressants significantly reduced plasma levels of IL-6 and TNF-alpha. In addition, the plasma IL-6 level, but not the plasma TNF-alpha level, was higher in SSRI-refractory than SSRI-responsive depressed patients, and higher in SNRI-refractory than SNRI-responsive depressed patients. On the other hand, the plasma BDNF level was significantly lower in depressed patients than in healthy controls, whereas no difference was found in plasma BDNF levels between SSRI-responsive and -refractory depressed patients or between SNRI-responsive and -refractory depressed patients. These results suggest that higher plasma IL-6 activity is associated with the refractoriness of depression, and plasma IL-6 levels might be a predictor for response to SSRIs or SNRI.

Stress at work alters serum brain-derived neurotrophic factor (BDNF) levels and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in healthy volunteers: BDNF and MHPG as possible biological markers of mental stress?

There is growing evidence that blood levels of brain-derived neurotrophic factor (BDNF) and catecholamine, and cytokines are related to not only to depressive, suicidal, and anxious states but also to depression-associated personality traits. Psychological job stress is well known to lead to symptoms of depression and anxiety. In the present study, we examined effects of psychological job stress on serum levels of BDNF and plasma levels of catecholamine metabolites, and cytokines in healthy volunteers (n=106, male/female=42/64, age=36+/-12 yr) working in a hospital setting. The values (mean+/-SD) of scores for stress items in the Stress and Arousal Check List (s-SACL), plasma MHPG levels, and, serum BDNF levels in all participants were 7.2+/-3.3, 5.2+/-3.4 ng/mL, and 23.3+/-14.7 ng/mL, respectively. A negative correlation was found between scores for s-SACL and serum BDNF levels (rho=-0.211, p=0.022). A positive correlation was also found between scores on the s-SACL and plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) (rho=0.416, p=0.01), but not homovanillic acid (HVA). No relationship was found between s-SACL scores and plasma levels of interleukin-6 (IL-6) or tumor necrosis factor alpha (TNFalpha). These results suggest that serum BDNF levels and plasma MHPG levels might be biological markers reflective of psychological job stress in hospital employees.

Efficacy of electroconvulsive therapy is associated with changing blood levels of homovanillic acid and brain-derived neurotrophic factor (BDNF) in refractory depressed patients: a pilot study.

Electroconvulsive therapy (ECT) is effective for patients with antidepressant medication-resistant depression. However, the mechanisms of ECTs effectiveness for treating depression are not fully understood. We therefore investigated ECTs effects on blood levels of brain-derived neurotrophic factor (BDNF), catecholamine metabolites, and nitric oxide (NO) in 18 treatment-refractory depressed patients. Serum BDNF levels increased significantly following ECT in responders to ECT (before ECT: 8.0+/-9.7 ng/mL; five weeks after start of ECT: 15.1+/-11.1 ng/mL), whereas BDNF levels in non-responders were unchanged (before ECT: 11.5+/-11.0 ng/mL; five weeks after start of ECT: 9.4+/-7.5 ng/mL). Furthermore, the plasma HVA levels, but not MHPG levels, were significantly reduced after ECT (before ECT: 8.5+/-1.9 ng/mL; five weeks after start of ECT: 5.8+/-2.2 ng/mL). This latter finding occurred in parallel with the improvement of depressive symptoms in all patients. These results suggest that the mechanisms underlying ECTs effect on refractory depression may be related to dopaminergic neurons and BDNF.

Treatment with risperidone for 4 weeks increased plasma 3-methoxy-4-hydroxypnenylglycol (MHPG) levels, but did not alter plasma brain-derived neurotrophic factor (BDNF) levels in schizophrenic patients

In the present study, we investigated the effects of risperidone treatment for 4 weeks on plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and brain-derived neurotrophic factor (BDNF) in 89 schizophrenic patients. We also compared the plasma levels of BDNF and MHPG between the schizophrenic group and 103 sex-and age-matched normal controls. In addition, we investigated the effects of two SNPs of the noradrenaline transporter (NAT) gene on plasma levels of MHPG, BDNF, and clinical improvement. The mean dose of risperidone was 3.8+/-1.4 mg/day. We demonstrated that treatment with risperidone increased plasma MHPG levels, and this increase was associated with an improvement of the negative symptoms of schizophrenia. In contrast, plasma BDNF did not change after 4 weeks of risperidone treatment, and the two SNPs in NAT did not influence the response to risperidone treatment or plasma MHPG and BDNF levels. These results suggest that the enhancement of noradrenergic neurons by risperidone, which occurs independently of the two SNPs of NAT, plays a role in the clinical efficacy of the drug.

Gray and white matter volumetric and diffusion tensor imaging (DTI) analyses in the early stage of first-episode schizophrenia.

PURPOSE To determine whether statistical analyses of quantitative MR imaging data, including morphological changes, mean diffusivity (MD), and fractional anisotropy (FA), could provide useful biomarkers in early stage of first-episode schizophrenia. MATERIALS AND METHODS Twenty-three patients, who met all the criteria in the DSM-IV-TR category for schizophrenia excluding the duration of the disease (less than 6 months of follow-up), were examined by MR imaging during the initial consultation. Nineteen of the 23 patients were finally diagnosed to have schizophrenia after a 6-month follow-up, and they were included in this study as having been in the early stage of first-episode schizophrenia. Nineteen healthy volunteers also underwent MR imaging as age-matched controls. Three-dimensional spoiled gradient recalled acquisition with steady state (3D-SPGR) and diffusion tensor imaging (DTI) were performed at 3T. Image processing for voxel-based morphometry, a fully automatic technique for a computational analysis of differences in regional brain volume throughout the entire brain, was conducted using the Statistical Parametric Mapping 5 software package (SPM5). The 3D-SPGR images in the native space were bias-corrected; spatially normalized; segmented into gray matter, white matter, and cerebrospinal fluid images; and intensity-modulated using SPM5. A voxel-based analysis was conducted using both the MD and FA maps computed from DTI. The customized MD and FA template specific to this study was created from all participants. Thereafter, all the MD and FA maps in the native space were transformed onto the stereotactic space by registering each of the images to the customized MD and FA template. The two groups were compared using SPM5. Age and sex were treated as confounding covariates. RESULTS The patients demonstrated a significant increase in the MD of the left parahippocampal gyrus, left insula, and right anterior cingulate gyrus in comparison to the control subjects (FDR corrected p<0.05). No significant difference was observed in the correlation between the gray/white matter volume and FA. CONCLUSION These findings suggest that structural abnormalities in the brain are present during the early stage of first-episode schizophrenia and MD might therefore be a sensitive marker for the detection of these abnormalities.

Adding a low dose atypical antipsychotic drug to an antidepressant induced a rapid increase of plasma brain-derived neurotrophic factor levels in patients with treatment-resistant depression.

Only two-thirds of depressive patients respond to antidepressant treatment. Recently, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we examined the effects of various atypical antipsychotic drugs as adjuvant to antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants and mood stabilizers, on plasma BDNF levels in refractory depressed patients. Forty-five patients who met the DSM-IV criteria for major depressive disorder (n=31) or bipolar disorder (10 with bipolar I, 4 with bipolar II) were enrolled in the study. Twenty-one were male and 24 were female, and their ages ranged from 28 to 71 (mean+/-SD=49+/-12) years. Plasma BDNF levels were measured using a sandwich ELISA. The plasma BDNF levels in responders (those showing a decline in HAM-D scores of 50% or more) were significantly increased 4weeks after the administration of each atypical antipsychotic drug, while the levels in non-responders were not changed. Furthermore, there was a significant correlation between the changes in HAM-D scores and the changes in plasma BDNF levels. These results suggest that adding an atypical antipsychotic drug to ongoing treatment with an antidepressant or mood stabilizer is useful and well-tolerated for refractory depressed patients, and the efficacy of atypical antipsychotics as an adjuvant might involve an increase of plasma BDNF levels.

Different patterns of longitudinal changes in plasma levels of catecholamine metabolites and brain-derived neurotrophic factor after administration of atypical antipsychotics in first episode untreated schizophrenic patients.

In the present study, we longitudinally investigated the effects of risperidone, olanzapine, and aripiprazole on plasma levels of catecholamine metabolites and brain-derived neurotrophic factor (BDNF) in first-episode unmedicated schizophrenic patients. The subjects were 59 Japanese schizophrenic patients (35 males and 24 females; age range: 18–46 years; mean±SD: 25±16 years). The patients were treated with risperidone (n=32) in a dose range of 2–6 mg/day (mean±SD=3.4±1.9), olanzapine (n=18) in a dose range of 5–20 mg/day (mean±SD=12.1±5.8), or aripiprazole (n=9) in a dose range of 12–30 mg/day (mean±SD=22.8±10.1). All three drugs significantly decreased plasma homovanillic acid (HVA) levels within 8 weeks, although aripiprazole transiently raised this level before 8 weeks. All three drugs also significantly increased plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels within 8 weeks. On the other hand, none of them altered plasma BDNF levels. These results indicate that risperidone, olanzapine, and aripiprazole affect catecholaminergic systems in the brain, that the effects of aripiprazole on the dopaminergic systems seem to slightly different than those of risperidone and olanzapine, and that these atypical antipsychotic drugs might not alter BDNF levels, at least within 8 weeks of treatment.

six-month treatment with atypical antipsychotic drugs decreased frontal-lobe levels of glutamate plus glutamine in early-stage first-episode schizophrenia

Objective To study the effects of treatment with atypical antipsychotic drugs on brain levels of glutamate plus glutamine in early-stage first-episode schizophrenia. Participants Sixteen patients (eight males, eight females; aged 30 ± 11 years) completed the study. Methods We used administered 6 months of atypical antipsychotic drugs and used proton magnetic resonance spectroscopy to evaluate the results. Results We found that the administration of atypical antipsychotic drugs for 6 months decreased the glutamate plus glutamine/creatine ratio in the frontal lobe. These results suggest that the administration of atypical antipsychotic drugs for at least 6 months decreased glutamatergic neurotransmissions in the frontal lobe in early-stage first-episode schizophrenia, but there was no difference in frontal-lobe levels between patients and control subjects before administration. Conclusion Taking these findings into account, the glutamatergic and GABAergic neurons are implicated in early-stage first-episode schizophrenia, but in complex ways.

Association between plasma nitric oxide metabolites levels and negative symptoms of schizophrenia: a pilot study

Nitric oxide (NO) is involved in pathophysiology of psychiatric disorders such as depression and schizophrenia. We hypothesize that plasma levels of NO and its metabolites (NOx) are decreased in patients with schizophrenia. To examine the hypothesis, we compared plasma NOx levels between 30 schizophrenic patients (M/F: 18/12, age: 38 ± 15 years) and age‐ and sex‐matched 30 healthy controls (M/F: 18/12, age: 41 ± 19 years), and we also examined the effects of risperidone on plasma NOx levels in schizophrenic patients. The baseline plasma NOx levels were significantly lower in the schizophrenia group (1.85 ± 0.70 µM) than those in control group (3.37 ± 2.27 µM). A significantly negative correlation was found between plasma NOx levels and PANSS‐N scores before risperidone administration (ρ = −0.385, p = 0.0416). Treatment with risperidone significantly increased the plasma NOx levels by 8 weeks (before; 1.85 ± 0.70 µM, after; 2.25 ± 1.00 µM, p = 0.0491). These results suggest that NO might be one of the candidates factors which are associated with the pathophysiology of negative symptoms of schizophrenia. Copyright