Atsuko Ikenouchi-Sugita

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.

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.

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

Serum levels of brain‐derived neurotrophic factor in comorbidity of depression and alcohol dependence

Alcohol dependence is often comorbid with depression. The purpose of the present study was to compare serum brain‐derived neurotrophic factor (BDNF) levels between depressive patients with and without alcohol dependence. Our subjects were 16 inpatients (M/F: 13/3, age: 48 ± 8 years) at our university hospital who met the DSM‐IV‐TR criteria for both major depressive disorder and alcohol dependence and whose Hamilton Rating Scale for Depression (HAM‐D) scores were at least 15. Twenty sex‐ and age‐matched depressive patients and 20 healthy subjects were also examined. Serum BDNF levels in the depressive patients with (9.0 ± 4.3 ng/ml) and without (9.8 ± 5.2 ng/ml) alcohol dependence were significantly lower than those in the healthy subjects (21.1 ± 7.0 ng/ml); however, no significant difference was found in the serum BDNF levels of depressive patients with and without alcohol dependence. Eight of the 16 (50%) depressive patients suffering from both depression and alcohol dependence responded to 8 weeks of treatment with antidepressant drugs which significantly increased their serum BDNF levels. These results suggest that the serum BDNF level is a useful biological marker for depression in patients with alcohol dependence. Copyright

Aripiprazole altered plasma levels of brain-derived neurotrophic factor and catecholamine metabolites in first-episode untreated Japanese schizophrenia patients.

We investigated the effects of aripiprazole on plasma levels of brain‐derived neurotrophic factor (BDNF) and catecholamine metabolites in first‐episode untreated schizophrenia patients.

Predictive factors for responding to sertraline treatment: views from plasma catecholamine metabolites and serotonin transporter polymorphism

In the present study, we investigated the effects of sertraline on plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and serum brain-derived neurotrophic factor (BDNF) levels in 59 depressed patients treated with sertraline. We also examined the relationship between the dynamics of the catecholamine metabolites, BDNF, serotonin transporter-linked polymorphic region (5-HTTLPR) gene polymorphism (long and short alleles), and the clinical response to sertraline. The extent of clinical improvement was evaluated using the 17-item Hamilton Rating Scale for Depression (Ham-D) before and 8 weeks after treatment with sertraline. Responders were defined as showing at least a 50% decrease in the Ham-D score. Baseline plasma HVA levels of responders to sertraline treatment were significantly lower than those of non-responders (p = 0.02). In addition, a positive correlation was identified between changes in plasma HVA levels and the rate of response to sertraline treatment (p = 0.001). A trend toward higher baseline serum BDNF levels was found in responders compared with non-responders (p = 0.095). In addition, serum BDNF levels were slightly increased (not significant) in responders (p = 0.058), but not in non-responders. Responders had a higher short-allele genotype frequency in the 5-HTTLPR for the promoter region than did non-responders (p = 0.037). These results suggest that pre-treatment plasma HVA levels and the 5-HTTLPR genotype for the promoter might be associated with a response to sertraline.

Effects of antidepressants on plasma metabolites of nitric oxide in major depressive disorder: comparison between milnacipran and paroxetine.

Depression is a risk factor for coronary heart disease (CHD). It has been demonstrated that there is a potential role of nitric oxide (NO) in the relationship between depression and CHD risk as well as an effect of antidepressants on NO production. This study included 40 in- or outpatients in our university hospital who met the DSM-IV-TR criteria for major depressive disorder (M/F: 15/25, age: 47+/-19 years) and 30 age- and sex-matched healthy controls (M/F: 10/20, age: 45+/-15 years), and also examined the effects of the antidepressants on the plasma NOx levels in depressed patients. The baseline plasma NOx levels were significantly lower in the whole depressed group than in the control group (p<0.01). Treatment with milnacipran, but not paroxetine, significantly increased the plasma NOx levels by 4 and 8 weeks. These results suggest that decreased plasma NOx levels might be partially associated with the pathophysiology of depression, and that treatment with milnacipran, a serotonin noradrenaline reuptake inhibitor, might increase those levels in depressed patients.