State-dependent increase in the levels of neurotrophin-3 and neurotrophin-4/5 in patients with bipolar disorder: A meta-analysis

https://doi.org/10.1016/j.jpsychires.2016.05.009Get rights and content

Highlights

  • Meta-analysis was performed to examine blood NT-3 and NT-4/5 levels in bipolar disorder.

  • NT-3 and NT-4/5 levels are increased in patients with bipolar disorder.

  • These levels are increased only in patients in depressed state, but not in manic or euthymic state.

  • Illness duration of patients was associated with the change of NT-3 and NT-4/5.

Abstract

Bipolar disorder (BD) is one of the most serious psychiatric disorders in the world, but its pathophysiology is still unclear. Regulation of neurotrophic factors have been thought to play a role in this process. There have been inconsistent findings regarding the differences in blood neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) between patients with BD and healthy controls (HCs). The aim of the current meta-analysis is to examine the changes in the levels of NT-3 and NT-4/5 in BD patients at different affective states. Eight articles (including 465 BD patients and 353 HCs) were included in the analysis, and their results were pooled by using a random effects model. We found the levels of both NT-3 (p = 0.0046) and NT-4/5 (p = 0.0003) were significantly increased in BD patients, compared to HCs. Through subgroup analysis, this increase persisted only in patients in depressed state (p = 0.0038 for NT-3 and p = 0.0001 for NT-4/5), but not in manic or euthymic state. In addition, we found the differences in NT-3 and NT-4/5 were significantly associated with the duration of illness, but not by the mean age or female proportion. Our results suggest a state-dependent increase in NT-3 and NT-4/5 levels in patients with BD. Further studies are needed to examine dynamic changes of these neurotrophins in BD patients along the disease course.

Introduction

Bipolar disorder (BD) is one of the common psychiatric diseases and can lead to serious consequences, including higher risk of medical comorbidities (Zhang et al., 2013), substance abuse (Evans et al., 2004), suicide (Takebayashi et al., 2010), and heavy economic burden (He et al., 2014). Although the etiology of BD is not well understood (Muneer, 2016), altered activity of neurotrophins (NTs) have been believed to play a role in the pathophysiology of BD (Pfaffenseller et al., 2013). The NT family, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), have been shown to play various roles in the development of nervous system (Liu et al., 2014). Most previous studies have focused on BDNF when examining NTs in patients with BD (Wang et al., 2014). A prior meta-analytic study has shown that blood BDNF level was reduced in manic or depressed state of BD, but not in euthymic state (Lin, 2009).

Compared to BDNF, NT-3 was less studied in psychiatric research. NT-3 is expressed in the hippocampus, which is the key structure of emotion modulation and memory formation (Shimazu et al., 2006). It can stimulate and control neurogenesis through the activation of tyrosine kinase NT receptor C (trkC) (Pae et al., 2008), which facilitates synaptic plasticity and increases the number of synaptic sites in the hippocampus (Je et al., 2006). In addition, NT-3 plays an important role in the survival of specific neurons in the brain, such as noradrenergic neurons (Arenas and Persson, 1994) and the progenitor cells in the hippocampus (Shimazu et al., 2006). NT-3 has been demonstrated to be associated with the regulation of serotonin and noradrenaline, to be involved in the treatment effect of mood stabilizers (Pae et al., 2008), and to interact with and compensate for the alteration of other neurotrophic factors in neuropsychiatric illnesses, including BDNF (Agerman and Ernfors, 2003, Schutte et al., 2000).

NT-4/5, as a member of the neurotrophin family, has some properties which differ from those of NT-3. NT-3 mainly acts on trkC, while NT-4/5 acts mainly on trkB and p75NTR, which can influence neurite outgrowth (Runge et al., 2012) or induce cell apoptosis and modify the selectivity and affinity of binding of specific NT (Dawbarn and Allen, 2003), respectively. In some aspects, NT-4/5 acts in a manner similar to BDNF, but has a more potent effect than BDNF, such as having a better protective effect on striatal dopaminergic neurons, which are believed to be one of the key neurons in the pathophysiology of BD (Sauer et al., 1995).

In the past decade, a few studies have examined alteration of NT-3 and/or NT-4/5 in patients with BD, but had discrepant results. Some studies have found that peripheral NT-3 and/or NT-4/5 levels are significantly higher in patients with BD than in HCs (Fernandes et al., 2010, Kapczinski et al., 2011, Loch et al., 2015, Walz et al., 2007, Walz et al., 2009). Another report has demonstrated an opposite result (Otsuki et al., 2008), and some studies have revealed no difference (Aydemir et al., 2014, Barbosa et al., 2014, Munkholm et al., 2014). The inconsistency might be due to differences in study design, precise psychiatric diagnoses, mood states of BD, age of the subjects, gender distribution, usage of different psychotropic agents, severity of disease, or different sample sources (plasma or serum).

The aims of the current meta-analysis are (1) to compare the differences in peripheral NT-3 and NT-4/5 between patients with BD and HCs and (2) to examine the potential variables that influence the difference.

Section snippets

Literature search and inclusion process

We set the target as those observational studies or related trials related to the NT levels in patients with BD. Literature search was performed by three of the authors (Tseng PT, Tu KY, and Wang HY) through the PubMed and Scopus databases for all articles available by February 21st, 2016. They used the keywords for the search: “(neurotrophin-3 OR neurotrophin-4/5) AND (bipolar disorder OR depress OR mania OR euthymia)”. There was no special limitation in language. These authors screened the

Studies included in the current meta-analysis

Seventy-six articles were initially found through database and manual searches (see Fig. 1). After excluding review articles (n = 24) and non-human studies (n = 35), a total of 17 articles were selected for detailed eligibility screening based on inclusion criteria. Nine of the 17 articles were excluded because they did not provide NT-3 or NT-4/5 blood protein levels in BD patients and HCs (Anisman and Hayley, 2012, Fakhri et al., 2014, Gronli et al., 2009, Otsuki et al., 2008, Rybakowski

Discussion

In this meta-analysis, we found significantly higher peripheral NT-3 and NT-4/5 levels in patients with BD than in HC. The significantly increased levels persisted when we focused on the comparison between BD patients in depressed state and HCs, but this increase turned out to be insignificant when we focused on patients in manic or euthymic state. To our knowledge, this is the first meta-analysis discussing the changes in peripheral NT-3 and NT-4/5 levels at different mood states of BD.

Conclusion

The results of our meta-analysis suggest a state-dependent increase in the blood levels of NT-3 and NT-4/5 in patients with BD. Further larger-scale, well-controlled studies are needed to investigate the changes in these NT levels along the disease course, the correlation of NT levels between CNS and peripheral environments, and the generalization to other ethnicities.

Funding body agreements and policies

The authors declare no biomedical financial interests.

Author contribution

Tseng PT and Lin PY designed the study and wrote down the research protocol. Tseng PT, Tu KY, and Wang HY performed the literature search and study selection. Tseng PT conducted the statistical analysis and generated the figures. Tseng PT, Chen YW, and Tu KY wrote the initial draft. Chen YW, Wang HY, Chung W, Wu CK, Hsu SP, Kuo HC, and Lin PY interpreted the statistical results and added critical comments. Tseng PT and Lin PY critically revised and completed the manuscript. All authors approved

Conflict of interest

The authors declare no biomedical conflicts of interest.

Role of funding source

The study received no research funding.

Acknowledgements

None.

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