Elsevier

Journal of Psychiatric Research

Volume 106, November 2018, Pages 43-53
Journal of Psychiatric Research

The neurobiological hypothesis of neurotrophins in the pathophysiology of schizophrenia: A meta-analysis

https://doi.org/10.1016/j.jpsychires.2018.09.007Get rights and content

Highlights

  • Neurotrophins are associated with the pathophysiology of schizophrenia.

  • Patients with schizophrenia have decreased levels of neurotrophins.

  • Peripheral levels of neurotrophins contribute to the neurobiological hypothesis of schizophrenia.

Abstract

Background

Schizophrenia is associated with patterns of aberrant neurobiological circuitry. The disease complexity is mirrored by multiple biological interactions known to contribute to the disease pathology. One potential contributor is the family of neurotrophins which are proteins involved in multiple functional processes in the nervous system, with crucial roles in neurodevelopment, synaptogenesis and neuroplasticity. With these roles in mind, abnormal neurotrophin profiles have been hypothesized to contribute to the pathology of schizophrenia.

Methods

We performed a systematic review and a meta-analysis to scrutinize the neurobiological hypothesis of neurotrophins in schizophrenia, examining the correlation between peripheral levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5) associated with schizophrenia.

Results

Fifty-two studies were reviewed and twenty-two studies were included in this meta-analysis. Using a random effects model, we confirmed that decreased levels of neurotrophins (BDNF, NGF and NT-4/5) were associated with schizophrenia (Hedges's g = −0.846; SE = 0.058; 95% confidence interval: −0.960 to −0.733; Z-value = −14.632; p-value = 0.000). Subgroup analysis indicated that neurotrophin levels are significantly decreased in both medicated and drug-näive patients. Meta-regression of continuous variables such as mean age, duration of illness and PANSS total score did not show significant effects (p > 0.05) in relation to neurotrophins levels.

Discussion

We confirm that decreased peripheral neurotrophin levels are significantly associated with schizophrenia, thereby confirming the neurobiological hypothesis of neurotrophins in schizophrenia. Low levels of neurotrophins in peripheral blood of patients with schizophrenia may explain, in part, the pathophysiology of schizophrenia.

Introduction

Schizophrenia is a major psychiatric disorder. Over time, intensifying efforts have been made to determine the neurobiological origins of the disease (Birnbaum and Weinberger, 2017). However the pathogenesis of schizophrenia remains only partially understood owing to likely multiple origins linked to metabolic, auto-immunological, genetic and environmental factors, abnormalities in neurotransmission and in brain structures (Dhindsa and Goldstein, 2016; Rodrigues-Amorim et al., 2018; Syvälahti, 1994; van Kesteren et al., 2017). Symptoms of the disease appear in young adults, and are associated with early neurodevelopment anomalies, with clinical prodromal results of acute psychosis (positive and negative symptoms) and cognitive impairment (Birnbaum and Weinberger, 2017; Rodrigues-Amorim et al., 2017; Tamminga and Medoff, 2000). In recent decades, efforts have been made to understand the genetic basis of schizophrenia (for example, Dhindsa and Goldstein, 2016). Additionally, anatomical changes in brain structures, neurochemical alterations, immune system disturbances and epigenetic mechanisms have also been reported (Agartz et al., 2006; Auta et al., 2013; Dong et al., 2015).

More recently, efforts to establish biological markers for schizophrenia have intensified (for example; Martinez-Cengotitabengoa et al., 2016). However, due to the high heterogeneity of clinical features of schizophrenia, the search for new biomarkers as predictors, therapeutic indicators and/or diagnostics of schizophrenia is necessarily a multifaceted process (Rodrigues-Amorim et al., 2017). One potential biomarker is the Neurotrophin family of proteins. Neurotrophins are regulators of neuronal activity during development and in the maintenance of the mature nervous system, and as such, they form potential candidates to contribute to the physiopathology of schizophrenia (Gratacòs et al., 2007). They are structurally related proteins (extracellular ligands) and include brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5) (Gratacòs et al., 2007; Shoval and Weizman, 2005; Skaper, 2012). These proteins are synthetized as endogenous pro-neurotrophin precursors which undergo enzymatic cleavage process to convert them into mature (active) neurotrophins (Perkovic et al., 2017; Sun et al., 2013). Neurotrophins have crucial roles in neuronal survival, differentiation, the development of circuitry and synaptic plasticity (Rizos et al., 2014). Moreover, neurotrophins are key regulators of monoaminergic, cholinergic and GABAergic systems (Ajami et al., 2014). Due to the widespread and complex functions of the neurotrophins, it is not surprising that dysfunction of the neurotrophic system has been associated with schizophrenia (Rizos et al., 2014). For example, neurotrophins contribute to the critical process of dendritic maturation during neurodevelopment. Abnormalities in dendritic formation are associated with structural aberrations consistent with schizophrenia (e.g. ventricular enlargement and decreased brain volume) (Bellon et al., 2011). BDNF is the most abundant neurotrophin in the brain and is involved in synaptogenesis, axon and dendritic plasticity, growth processes, cell resilience and apoptosis (Nieto et al., 2013; Sun et al., 2016). It also promotes the activity and maintenance of dopaminergic, serotoninergic, cholinergic and GABAergic neurons (Ikeda et al., 2008). There are reports describing low levels of BDNF in the prefrontal cortex (PFC) and cerebrospinal fluid (CSF) in patients with schizophrenia (Issa et al., 2010). Similarly, NGF plays an important role in neuroplasticity, and specifically in the projection and maintenance of cholinergic neurons in the CNS (Ajami et al., 2014; Xiong et al., 2010). A meta-analysis of patients with schizophrenia demonstrated that NGF levels are decreased in peripheral blood indicating that at least this member of the neurotrophin family has an abnormal profile in schizophrenia (Qin et al., 2017). With a similar structure to BDNF and NGF, but with high expression levels in early (fetal) development, that then reduce in the adult, neurotrophin-3 (NT-3) is a key protein implicated in early neurodevelopment (Shoval and Weizman, 2005). Serum levels of NT-3 in schizophrenia have been recorded in several studies, again suggesting that abnormal levels of this neurotrophin could be contributing to disturbances in neural development and plasticity (Durany et al., 2001). Decreased levels of NT-3 have also been reported in the cerebral cortex of patients with schizophrenia when compared with non-psychotic controls (Perkovic et al., 2017). Finally, neurotrophin-4/5 (NT-4/5) is expressed in muscle, where it is known to promote survival of sensory and motor neurons (Gu et al., 2015). It also contributes to the differentiation of motoneurons from basal forebrain neurons (Shoval and Weizman, 2005).

There is now an accumulating body of literature implicating various neurotrophins in schizophrenia. In an effort to test the validity of these reports, and to draw wider conclusions, we performed a systematic review and meta-analysis of recent literature linking peripheral neurotrophin levels with schizophrenia. This approach therefore seeks to test the neurobiological hypothesis that peripheral neurotrophins contribute, in part, to the pathophysiology of schizophrenia.

Section snippets

Methodology

A systematic review of the literature and meta-analysis was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations (Liberati et al., 2009; Moher et al., 2009).

Electronic database searches

Electronic searches generated 3041 reports from PubMed, Medline, PsychINFO and Web of Science. Applying the defined limits and discarding all duplicates; 204 studies remained. The full-text of these 204 studies was assessed, and 152 reports were excluded on the basis of failing to meet preliminary appraisal criteria. Following this, 52 articles remained for further consideration (supplementary table 1). The purpose of this review is to identify the role of neurotrophins in schizophrenia, based

Discussion

Following the systematic review and meta-analysis of 22 case-control studies, comprising 1475 patients with schizophrenia and 1250 healthy controls, we confirmed a significant relationship between neurotrophin levels and the pathophysiology of schizophrenia. In general, neurotrophins are identified as growth factors with roles in neuronal activity, development and survival in both the peripheral and central nervous system (CNS) (Sahay et al., 2017). They are synthetized in the brain and at

Limitations

A number of limitations have been identified in this systematic review and meta-analysis. The inclusion criteria excluded all studies that were not published in English. As such, a potentially significant body of research may have been missed. In our subgroup analysis investigating the effect of antipsychotic use we did not consider potential confounders such as the type or dose of antipsychotics and any other medications such as antidepressants or benzodiazepines were not considered as

Conclusion

Neurotrophins are small proteins essential to neuronal survival and differentiation, synaptogenesis and dendritic growth, being crucial not only during neuronal development but also in adult stages, especially in synaptic and neuroplasticity. Despite displaying moderate heterogeneity, meta-analysis of the 22 included studies supports the neurobiological hypothesis of neurotrophins in schizophrenia. This meta-analysis confirmed decreased levels of peripheral neurotrophins in both näive and

Conflicts of interest

The authors declare no conflict of interest.

Funding

CS is supported by the Fundación Tatiana Pérez de Guzman el Bueno and Rede Galega de Investigación en Demencias IN607C-2017/02, GAIN, Xunta de Galicia, JMO is supported by ISCIII P16/00405, RCAB is funded by FEDER, a Ramón& Cajal grant (RYC-2014-15246) and the Galicia Innovation Agency - GAIN grant (IN607D-2016/003).

References (100)

  • T. Huang et al.

    Associations between brain-derived neurotrophic factor G196A gene polymorphism and clinical phenotypes in schizophrenia patients

    J. Psychiatr. Res.

    (2006)
  • T.L. Huang et al.

    Associations between serum brain-derived neurotrophic factor levels and clinical phenotypes in schizophrenia patients

    J. Psychiatr. Res.

    (2006)
  • Y. Ikeda et al.

    Low serum levels of brain-derived neurotrophic factor and epidermal growth factor in patients with chronic schizophrenia

    Schizophr. Res.

    (2008)
  • G. Issa et al.

    An inverse relationship between cortisol and BDNF levels in schizophrenia: data from human postmortem and animal studies

    Neurobiol. Dis.

    (2010)
  • R.D. Jindal et al.

    Decreased BDNF in patients with antipsychotic naïve first episode schizophrenia

    Schizophr. Res.

    (2010)
  • A. Kale et al.

    Reduced cerebrospinal fluid and plasma nerve growth factor in drug-naïve psychotic patients

    Schizophr. Res.

    (2009)
  • H. jae Kim et al.

    Increase of circulating BDNF levels and its relation to improvement of physical fitness following 12 weeks of combined exercise in chronic patients with schizophrenia: a pilot study

    Psychiatr. Res.

    (2014)
  • F.C. Kuo et al.

    Lifestyle modification and behavior therapy effectively reduce body weight and increase serum level of brain-derived neurotrophic factor in obese non-diabetic patients with schizophrenia

    Psychiatr. Res.

    (2013)
  • J. Li et al.

    Increased serum brain-derived neurotrophic factor levels following electroconvulsive therapy or antipsychotic treatment in patients with schizophrenia

    Eur. Psychiatr.

    (2016)
  • A.A. Loch et al.

    Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium

    Prog. Neuro Psychopharmacol. Biol. Psychiatr.

    (2015)
  • Y. Mizuno et al.

    Clinical and biological correlates of resilience in patients with schizophrenia and bipolar disorder: a cross-sectional study

    Schizophr. Res.

    (2016)
  • T. Niitsu et al.

    A positive correlation between serum levels of mature brain-derived neurotrophic factor and negative symptoms in schizophrenia

    Psychiatr. Res.

    (2014)
  • T. Niitsu et al.

    Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia

    Prog. Neuro Psychopharmacol. Biol. Psychiatr.

    (2011)
  • T. Niitsu et al.

    Association between serum levels of glial cell-line derived neurotrophic factor and attention deficits in schizophrenia

    Neurosci. Lett.

    (2014)
  • V. Parikh et al.

    Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome

    Schizophr. Res.

    (2003)
  • H. Persson

    Neurotrophin production in the brain

    Semin. Neurosci.

    (1993)
  • Ş. Pirildar et al.

    Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment

    Prog. Neuro Psychopharmacol. Biol. Psychiatr.

    (2004)
  • S. Rao et al.

    Peripheral blood nerve growth factor levels in major psychiatric disorders

    J. Psychiatr. Res.

    (2017)
  • E.N. Rizos et al.

    Association of serum BDNF levels with hippocampal volumes in first psychotic episode drug-naive schizophrenic patients

    Schizophr. Res.

    (2011)
  • E.N. Rizos et al.

    Investigation of serum BDNF levels in drug-naive patients with schizophrenia

    Prog. Neuro Psychopharmacol. Biol. Psychiatr.

    (2008)
  • D. Rodrigues-Amorim et al.

    Schizophrenia: a review of potential biomarkers

    J. Psychiatr. Res.

    (2017)
  • A.S. Sahay et al.

    Neurotrophins: role in placental growth and development

  • X. Song et al.

    Serum levels of BDNF, folate and homocysteine: in relation to hippocampal volume and psychopathology in drug naïve, first episode schizophrenia

    Schizophr. Res.

    (2014)
  • X. Song et al.

    Decreased cortical thickness in drug naïve first episode schizophrenia: in relation to serum levels of BDNF

    J. Psychiatr. Res.

    (2015)
  • M. Sotiropoulou et al.

    BDNF serum concentrations in first psychotic episode drug-naïve schizophrenic patients: associations with personality and BDNF Val66Met polymorphism

    Life Sci.

    (2013)
  • Z.L. Sun et al.

    Serum brain-derived neurotrophic factor levels associate with cognitive improvement in patients with schizophrenia treated with electroacupuncture

    Psychiatr. Res.

    (2016)
  • Y.L. Tan et al.

    Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements

    Schizophr. Res.

    (2005)
  • C. Theleritis et al.

    Brain derived neurotropic factor (BDNF) is associated with childhood abuse but not cognitive domains in first episode psychosis

    Schizophr. Res.

    (2014)
  • K. Toyooka et al.

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

    Psychiatr. Res.

    (2002)
  • P. Xiong et al.

    Reduced NGF serum levels and abnormal P300 event-related potential in first episode schizophrenia

    Schizophr. Res.

    (2010)
  • M.H. Xiu et al.

    Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics

    Prog. Neuro Psychopharmacol. Biol. Psychiatr.

    (2009)
  • H. Yamamori et al.

    Plasma levels of mature brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) in treatment-resistant schizophrenia treated with clozapine

    Neurosci. Lett.

    (2013)
  • R. Yoshimura et al.

    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

    Prog. Neuro Psychopharmacol. Biol. Psychiatr.

    (2007)
  • R. Zakharyan et al.

    Brain-derived neurotrophic factor blood levels are decreased in schizophrenia patients and associate with rs6265 genotypes

    Clin. Biochem.

    (2014)
  • X.Y. Zhang et al.

    The interplay between BDNF and oxidative stress in chronic schizophrenia

    Psychoneuroendocrinology

    (2015)
  • X.Y. Zhang et al.

    Gender difference in association of cognition with BDNF in chronic schizophrenia

    Psychoneuroendocrinology

    (2014)
  • X.Y. Zhang et al.

    Interaction of BDNF with cytokines in chronic schizophrenia

    Brain Behav. Immun.

    (2016)
  • X.Y. Zhang et al.

    Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics

    J. Psychiatr. Res.

    (2007)
  • A. Zugman et al.

    Serum brain-derived neurotrophic factor and cortical thickness are differently related in patients with schizophrenia and controls

    Psychiatry Res. Neuroimaging.

    (2015)
  • I. Agartz et al.

    BDNF gene variants and brain morphology in schizophrenia

    Am. J. Med. Genet. Part B Neuropsychiatr. Genet.

    (2006)
  • Cited by (43)

    • Biological hypotheses, risk factors, and biomarkers of schizophrenia

      2023, Progress in Neuro-Psychopharmacology and Biological Psychiatry
      Citation Excerpt :

      According to this hypothesis neurotrophins (mainly brain-derived neurotrophic factor (BDNF), nerve growth factor, and neurotrophin-3) are involved in the pathophysiology of schizophrenia, and alterations in the expression of neurotrophins could be responsible for disturbed neurodevelopment and neuroplasticity associated with schizophrenia (Durany et al., 2001). The hypothesis is supported both by changes in neurotrophin concentrations in the periphery in schizophrenia (Ajami et al., 2014; Rodrigues-Amorim et al., 2018) and by a significant association between the BDNF gene Val66Met polymorphism and schizophrenia (Kheirollahi et al., 2016). The hypothesis that inhibitory cortical circuits are involved in the development of schizophrenia was formulated based on the observation that impairment of some cognitive functions in schizophrenia are associated with decreased GABA synthesis in a subpopulation of parvalbumin-expressing inhibitory GABA neurons located in the dorsolateral prefrontal cortex (Lewis et al., 2005).

    • The role of BDNF and NGF plasma levels in first-episode schizophrenia: A longitudinal study

      2022, European Neuropsychopharmacology
      Citation Excerpt :

      BDNF and NGF are the two most prominent and extensively studied members of the neurotrophin family. Although clinical data has not always been consistent, several meta-analyses have demonstrated a reduction of BDNF and NGF in plasma or serum of schizophrenia patients when compared with healthy controls (Fernandes et al., 2015; Qin et al., 2017; Rodrigues-Amorim et al., 2018). Therefore, these proteins have been considered potential schizophrenia biomarkers and potential players in the neuroprogression process involved in schizophrenia and other neuropsychiatric disorders.

    View all citing articles on Scopus
    View full text