The main findings in the present study were that any correlations were not observed between serum BDNF, proBDNF, or plasma MHPG and the PANSS scores in the 68 chronic schizophrenia patients. No difference was found in the serum proBDNF between the two groups. Plasma levels of MHPG and the serum BDNF levels were significantly lower in the chronic schizophrenia patients compared to the healthy controls.

We reported in a preliminary study that plasma MHPG concentrations in patients with schizophrenia were lower than those in healthy subjects. The findings of the present study reconfirmed our preliminary results, especially the findings in the chronic schizophrenia patients. It is possible that noradrenergic activity decreases in chronic schizophrenia [14–16]. In addition, clozapine and risperidone treatment increased plasma noradrenaline levels. Taking these findings together, it appears that the hypo-activity of noradrenergic neurons may exist in chronic schizophrenia patients and atypical antipsychotic drugs may enhance noradrenergic functions. However, our present revealed no correlations between the plasma levels of MHPG or serum BDNF and any scores on the PANSS. One point at any situations of the patients and/or antipsychotic medications might explain the present results.

Chen et al. [17] reported that the application of noradrenaline in embryonic hippocampal neurons increased the serum levels of BDNF and phosphorylated tropomyosin receptor kinase (TrkB), and that these increases were prevented by extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase inhibitors (PI-3K). They also showed that noradrenaline-induced increases in phospho-ERK2 and PI-3K were each suppressed by a PI-3K and mitogen-activated protein kinase inhibitor, respectively. In addition, the phosphorylation of cAMP-response element-binding protein (CREB) was also increased by noradrenaline and was reduced to baseline levels by MAPK and PI-3K inhibitors. In addition, both the MAPK and PI-3K inhibitors suppressed the phosphorylation of both TrkB and CREB. Taking all of these results into account, it appears that the noradrenaline-evoked BDNF expression leads a cyclic pathway, reminiscent of a positive feedback loop.

The results of another study elucidated an in vitro model of the intracellular signaling mechanisms activated by noradrenaline—via ligand G-protein-coupled receptor-to-BDNF-receptor tyrosine kinases transactivation — that is putatively thought to occur in vivo as a result of excitatory neural activity [18]. Astrocytes as an active part of the tripartite synapse can respond to the synoptically released neurotransmitters. BDNF is produced by astrocytes and neurons. Monoamines are able to potently and transiently increase BDNF cellular contents [19]. Taken together, these findings indicate a deficiency of noradrenaline brought to reduced BDNF levels in chronic schizophrenia; however, we observed no correlation between the plasma levels of MHPG and serum BDNF, which may be plausible that the noradrenaline function does not directly influence the BDNF level. In other words, it is possible that key molecules that regulate the balance between noradrenaline and BDNF might exist. We also observed that although treatment with an atypical antipsychotic drug increased plasma MHPG levels, it did not alter plasma BDNF levels [1, 2, 20].

The serum proBDNF level in chronic schizophrenia remains unknown. Yamamoto et al. [21] reported that matrix metalloproteinase-9, which plays a role in the conversion of proBDNF to mature BDNF, was significantly increased in patients with schizophrenia.

In addition, noradrenergic functions and BDNF were not related to the GAF scores of the present patients with chronic schizophrenia, indicating that both of the noradrenergic functions do not reflect the social activities of the chronic schizophrenia patients.

The present study has several limitations. This was a cross-sectional study, and all of the chronic schizophrenia patients were being treated with several medications; i.e., antipsychotics, mood stabilizers, and benzodiazepines. Thus, the medications might have influenced the results. Exercise, stress exposure, menstrual cycle, body mass index, and dietary composition also influenced the data. Finally, we did not check for the functional imaging of brain areas, where BDNF is concentrated.

In conclusion, any correlations were not found between serum BDNF, proBDNF, or plasma MHPG and the PANSS scores in the 68 chronic schizophrenia patients. We also reconfirmed that serum BDNF and plasma MHPG levels were significantly reduced in the 68 chronic schizophrenia patients compared to healthy controls.