Elsevier

Psychiatry Research

Volume 110, Issue 3, 31 July 2002, Pages 249-257
Psychiatry Research

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

https://doi.org/10.1016/S0165-1781(02)00127-0Get rights and content

Abstract

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.

Introduction

Impaired brain development is often implicated in the etiology of schizophrenia (Kerwin and Murray, 1992, Marenco and Weinberger, 2000). Recent evidence indicates that abnormal signaling of cytokines and growth factors influences neuronal differentiation and synaptic plasticity to perturb brain development and function (Nawa et al., 2000). Gene manipulation studies in mice indicate that neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), are important for normal development of the central nervous system (Croll et al., 1999, Xu et al., 2000). Accordingly, impairments in their signaling may be implicated in various psychiatric diseases such as schizophrenia, mood disorder and autism (Altar, 1999, Nawa et al., 2000, Chen et al., 2001, Vaidya and Duman, 2001, Nelson et al., 2001). For example, BDNF levels are elevated and, conversely, BDNF receptor (TrkB) expression is down-regulated in the corticolimbic system of patients with schizophrenia (Takahashi et al., 2000). Animal experiments revealed the opposite effects of haloperidol on BDNF and TrkB levels in the brain, indicating that these changes likely cannot be ascribed to treatment with antipsychotic drugs (Angelucci et al., 2000). Moreover, the latest studies have revealed a strong link between BDNF signals and dopaminergic function in the brain (Batchelor et al., 2000, Guillin et al., 2001). Together, these findings suggest that neurotrophic abnormality might be associated with schizophrenic pathology or etiology.

High levels of BDNF and TrkB are expressed in the brain and in various peripheral tissues including muscle and blood cells in humans (Shibayama and Koizumi, 1996, Radka et al., 1996). Assuming that regulation of BDNF expression, release or signaling is profoundly affected by schizophrenia, it is possible that a similar abnormality in BDNF also occurs in other peripheral tissues. In the present investigation, we measured BDNF protein levels in human blood and serum and examined the production and release of this neurotrophic factor in the periphery in schizophrenic patients.

Section snippets

Subjects and procedure

Human blood was collected from two independent pairs of groups: 35 normal healthy volunteers who had no history of psychiatric or neurologic disorders and 34 chronic patients with schizophrenia (Group I), as well as 27 volunteers and 34 schizophrenic patients (Group II), after they had provided written informed consent (see details in Table 1). All of the experiments were performed with the authorization of Niigata University Ethics Committee. A part of the whole blood was collected into tubes

Results

Serum BDNF levels were measured using sandwich EIA. Most of the BDNF values did not fit to a standard distribution curve and were therefore subjected to non-parametric analyses. The authenticity of this assay was confirmed previously; its cross-reactivity against other neurotrophins is less than 0.2% (Nawa et al., 1995). Serum was collected from both chronic schizophrenic patients (n=34) and age-matched healthy volunteers (n=35; Table 1). Serum BDNF levels in healthy human volunteers were very

Discussion

Using a two-site EIA, we demonstrated that human serum BDNF levels in schizophrenic patients are significantly reduced to 55% of control levels. BDNF levels in the whole blood are not reduced. Almost all schizophrenic patients were treated with typical antipsychotics, but the BDNF reduction in serum is not likely to be due to their chronic treatment, because patients’ serum BDNF levels do not correlate with their daily doses of antipsychotics. Animal experiments also support this explanation.

Acknowledgments

We thank Ms Higuchi for technical assistance and volunteers who provided us with control blood. This work was supported by the Japanese Society for the Promotion of Science (RFTF-96L00203, 13GS0014) and Special Coordination Funds for Promoting Science and Technology, Target-Oriented Brain Science Program (MECSST, Japan).

References (41)

  • D Tardito et al.

    Abnormal levels of cAMP-dependent protein kinase regulatory subunits in platelets from schizophrenic patients

    Neuropsychopharmacology

    (2000)
  • J.K Yao et al.

    Increased turnover of platelet phosphatidylinositol in schizophrenia

    Prostaglandins, Leukotrienes and Essential Fatty Acids

    (1992)
  • J.K Yao et al.

    Decreased serotonergic responsivity in platelets of drug-free patients with schizophrenia

    Psychiatry Research

    (1996)
  • B Xu et al.

    Cortical degeneration in the absence of neurotrophin signaling: dendritic retraction and neuronal loss after removal of the receptor TrkB

    Neuron

    (2000)
  • R Alitalo et al.

    Induction of platelet-derived growth factor gene expression during megakaryoblastic and monocytic differentiation of human leukemia cell lines

    The EMBO Journal

    (1987)
  • C.A Altar

    Neurotrophins and depression

    Trends in Pharmacological Science

    (1999)
  • American Psychiatric Association, 1997. Practice guideline for the treatment of patients with schizophrenia. III....
  • F Angelucci et al.

    Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration

    Journal of Neuroscience Research

    (2000)
  • P.E Batchelor et al.

    Inhibition of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression reduces dopaminergic sprouting in the injured striatum

    European Journal of Neuroscience

    (2000)
  • J Ben-Ezra et al.

    Megakaryocyte synthesis is the source of epidermal growth factor in human platelets

    American Journal of Pathology

    (1990)
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