The neurobiological hypothesis of neurotrophins in the pathophysiology of schizophrenia: A meta-analysis
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).
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2022, European NeuropsychopharmacologyCitation 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.