The relationship between neurotrophins and bipolar disorder.

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The relationship between neurotrophins and bipolar disorder Expert Rev. Neurother. 14(1), 51–65 (2014)

Renrong Wu*1, Jinbo Fan2,3, Jingping Zhao1, Joseph R Calabrese2 and Keming Gao*2 1 Institute of Mental Health of Second Xiangya Hospital, South Central University, Changsha 410011, Hunan, P.R. China 2 Mood & Anxiety Clinic in the Mood Disorders Program of Department Psychiatry, University Hospitals Case Medical Center/Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA 3 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA *Author(s) for correspondence: [email protected] [email protected]

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Relationship between neurotrophins, especially brain-derived neurotrophic factor (BDNF) and bipolar disorder (BPD) has been widely investigated, but results have been inconsistent. BDNF polymorphism may be associated with the susceptibility to subtype BPD such as rapid cycling BPD or early onset BPD. Met allele carriers of Val66Met of BDNF gene had smaller gray matter (GM) in both patients and healthy controls, but bipolar patients carrying Met allele had better response to lithium treatment. Decreased serum/plasma BDNF levels were observed at different mood states. BDNF may interact with other systems to execute its neuroprotective effects. Overall data suggest that neurotrophins may be involved in the pathogenesis of BPD and treatment response, but the magnitude of their role needs further investigation with large sample size studies. KEYWORDS: bipolar disorder • brain-derived neurotrophic factor • cognitive performance • genetic association study • major depressive disorder • neuroimaging • neurotrophins • pharmacogenetic • schizophrenia • serum chemistry

Bipolar disorders (BPD) are chronic, recurrent, debilitating disorders and cause significant burden to patients, their families and society. The lifetime prevalence of bipolar I disorder was estimated to be approximately 1% in the USA, but the prevalence of bipolar spectrum disorders was approximately 4.5% [1]. In other countries, a lower prevalence of BPD was reported [2]. In the USA, direct and indirect costs were estimated to be US$ 45 billion in 1991 [3], which translated into about US$ 71 billion in 2008. There have been a number of drugs approved for the acute mania [4], but only a limited number of drugs were used for the acute bipolar depression and maintenance treatment [5,6]. There is an urgent need to understand the pathophysiology of BPD in order to develop more effective treatments for BPD. Neurotrophins include NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NTF-3), neurotrophin-4/5 (NTF-4/5) and neurotrophin-6 (NTF-6). Neurotrophins play an important role in neurodevelopment, neuronal survival and activity-dependent neuronal plasticity. Mature neurotrophin proteins interact with two well-characterized types of cell surface receptors, tyrosine kinase (Trk)

10.1586/14737175.2014.863709

receptors and the p75 neurotrophic receptor (p75NTR), but the pathways activated by neurotrophins binding to Trk receptors are related to the neurodevelopment and synaptic plasticity [7]. Animal studies have also shown that BDNF is implicated in adapting to stress exposure. A short-term and long-term decrease in BDNF levels in the hippocampus was associated with depressive states in animal models. Antidepressant treatments including ECT can induce the expression of neurotrophins and synaptic changes [8]. Neuroplasticity has been hypothesized as a model for mood disorders. For this reason, among these neurotrophins, BDNF has been extensively studied in different psychiatric disorders. In this review, the role of neurotrophins in BPD is reviewed with a focus on BDNF. Relationship between BDNF & BPD Genetic association studies General susceptibility to BPD

Family, twin and adoption studies have shown that BPD is a highly inheritable disease [9]. A systematic review of genetic studies of BPD is beyond the scope of this review, but a brief review of studies between BDNF gene and

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Wu, Fan, Zhao, Calabrese & Gao

BPD will help us to understand the genetic complexity of BPD. BDNF gene (OMIM: 113505) is located in chromosome 11p14.1 region which has been implicated in BPD by linkage studies [10]. Position 196 in exon 5 of the BDNF gene contains a G to A transition (dbSNP: rs6265) that results in an amino acid substitution (valine to methionine) at codon 66 in the precursor BDNF peptide sequence [11]. In a previous family-based association study of candidate genes in BPD, Sklar and colleagues genotyped 90 singlenucleotide polymorphisms (SNPs) in 76 candidate genes of 136 parent-proband trios and found that SNPs of BDNF gene and the a subunit of the voltage-dependent calcium channel gene (CACNA1C) were associated with an increased risk for BPD [12]. In the initial screening set of SNPs, only two SNPs were associated with BPD. One was the Val66Met polymorphism in BDNF gene and another was a silent C/T polymorphism in CACNA1C gene. The association of Val66Met of BDNF gene, but not the SNP of CACNA1C gene, with BPD was replicated in a separated combined sample of 334 parentproband trios as in the original sample although the difference did not reach statistical significance (p = 0.066). Re-sequencing the BDNF gene identified 44 additional SNPs. Genotyping eight of these SNPs found that three additional SNPs were associated with BPD, but these results were not replicated in an independent sample of 189 trios [12]. Another family-based association study also found that the Val66Met SNP of the BDNF gene was significantly associated with the susceptibility to BPD [13]. Following these two reports, a large number of genetic studies between BDNF gene polymorphisms and BPD have been published. Most of them have specifically focused on the functional Val66Met polymorphism and have yielded conflicting results. Among them, several independent family-based studies and case-control studies have reported significant associations between BDNF polymorphisms and BPD [14–21], while other studies failed to detect any association among them [22–29]. A previous meta-analysis based on fourteen association studies published up to May 2007, including 4248 cases, 7080 control subjects and 858 nuclear families, revealed a moderate but nominally significant association between the Val allele of Val66Met SNP of the DBNF gene and BPD (random-effects pooled OR [odds ratio]: 1.13, p = 0.004) [30]. This observation supports the hypothesis that the BDNF gene Val66Met variation is a moderate risk factor for BPD susceptibility. In addition to the widely studied Val66Met polymorphism, several other polymorphisms within the BDNF gene have also been examined. For example, a previous study examined 10 SNPs across BDNF gene in a sample of 1749 Caucasian Americans from 250 multiplex bipolar families and found that significant associations (p < 0.05) existed between several SNPs and BPD [18]. The strength of associations between SNPs and BPD depended on the definition of the phenotype and the unaffected. During the initial analysis, the previously reported Val66Met SNP (rs6265) was not significantly associated with BPD, although, there was a trend of over-transmission of the 52

common Val allele when using the broadest phenotype definition for BPD. Interestingly, when the researchers used the same phenotypic definition as a previous study [12], there was a significant association between Val66Met SNP and the narrowest phenotype definition of BPD, which was consistent with the finding of the previous study [12]. Taken together, polymorphisms in BDNF gene may be involved in the pathogenesis of BPD, but there is no compelling evidence supporting that BDNF gene plays an important role in the susceptibility to BPD. The inconsistent findings from these genetic association studies could be due to different definitions of phenotypes and controls, ethnic heterogeneities or sample sizes. Further large-scale studies with same definitions of phenotypes and controls in homogenous ethnic groups are warranted to elucidate the relevance of BDNF gene variations as a risk factor for BPD (or diagnostic subtypes) susceptibility. Rapid cycling & non-rapid cycling BPD

A previous large-scale case-control study with over 3000 individuals from the UK did not find any significant association between the Val66Met polymorphism of BDNF gene and the susceptibility to BPD [28]. However, in a subset of 131 individuals with lifetime rapid cycling (RC) course, the frequency of Val allele increased significantly compared to the controls with an OR of 1.74 (95% CI: 1.19–2.56). Re-analysis of a previous family-based study also found an association between increased Val allele frequency and RC BPD [28]. Similarly, a family-based association study found that four SNPs of the BDNF gene including the Val66Met polymorphism were significantly associated with BPD [17], but when the patients was divided into bipolar I and II subgroups, only the Val66Met polymorphism was still significantly associated with either subgroup of BPD with overly transmitted Val allele compared to Met allele. The ratio of Val versus Met transmission was 80:52 in bipolar I and 34:18 in bipolar II disorder, respectively. When the data were further analyzed by using RC versus non-RC BPD, all four SNPs showing significant associations in the whole sample were significantly associated with RC patients with larger effect sizes. In contrast, among non-RC patients, there was no significant association between those four SNPs and susceptibility to BPD [17]. An independent familybased study also found a significant association between a SNP rs7127507 in BDNF gene and RC subtype in a sample of 1749 Caucasian Americans from 250 multiplex bipolar families [18]. Seemingly, the Val66Met and other SNPs of the BDNF gene are associated with the susceptibility for RC BPD. It remains unclear that how these genetic variants affect the course and/or the treatment response of patients with RC BPD. Early onset or child & adolescent BPD

The studies of BDNF gene and BPD in children and adolescents have also been inconsistent. A previous study in children and early adolescents with BPD from 53 complete and independent trios found that BDNF Val66 allele was preferentially Expert Rev. Neurother. 14(1), (2014)


The relationship between neurotrophins & bipolar disorder

transmitted [14]. The association between BDNF genotype and an early onset of BPD is supported by a study of 184 patients and 214 healthy controls from Korea [31]. The Val/Val carriers was associated with an earlier onset of BPD (25.57 ± 8.35 years old) compared to Val/Met carriers (30.42 ± 12.91 years old) and Met/Met carriers (32.45 ± 13.46 years old). However, there was no significant difference between bipolar patients and healthy controls in BDNF genotypes and allele frequencies [31]. Earlier onset of BPD with Val/Val compared to Val/Met genotype was also observed in other studies [32,33]. In contrast, a group of adults with a history of childhood onset mood disorders did not have significant difference in BDNF Val66Met alleles compared to healthy controls, but had a significant association with a dinucleotide repeat (GT) polymorphism of BDNF [34]. Similarly, an association study of neurotrophic tyrosine kinase receptor 2 (NTRK2) polymorphism and childhood-onset mood disorders did not find evidence for allelic or genotypic association of three polymorphisms of NTRK2 with childhood-onset mood disorders including bipolar I and II disorder [35]. These studies also had the similar problems as the general genetic association studies. There were no unified criteria for early onset versus late onset BPD. The studied populations were heterogeneous. In order to produce robust results, futures studies should adopt the same criteria for early and late onset BPD. Executive & cognitive function

Cognitive performance has been used as an endophenotype for bipolar genetic studies. An early study of the BNDF Val66Met polymorphism on cognitive performance in BPD found that the performance in all domains of Wisconsin Card Sorting Test (WCST) was significantly better in subjects with Val/Val genotype than with Val/Met genotype [32]. A following study of BDNF polymorphism on cognitive performance in patients with BPD (n = 111) and schizophrenia (n = 129) found that bipolar patients with Val/Val genotype had significantly better results on three of five domains of the WCST, but there was no association between BDNF polymorphism and the results of N-back test [36]. In contrast, there was no significant association between BDNF Val66Met polymorphism and the results of WCST in schizophrenia. However, patients with schizophrenia and Val/Val genotype had a higher percentage of correct reactions in the N-back test than those with remaining genotypes. Better performance on auditory verbal learning test and the Rey Complex Figure Test (RCFT) was also observed in Val/Val genotype than Met carries in patients with euthymic BPD. Individuals with Val/Met or Met/Met genotype performed significantly worse than individuals with Val/Val on measurements of susceptibility to proactive interference [37]. In addition, BDNF Met carriers of patients with bipolar I disorder or schizophrenia, and healthy controls had a numerical, but non-significantly reduced performance in the verbal learning memory test [38]. www.expert-reviews.com

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These data suggest that Val/Val homozygous carriers performed better than Met carriers on cognitive tests, but Val/Val carriers had significantly higher percentage of non-perseverative errors. There was no other significant association between (BDNF) genotype frequency and other WCST domains [39]. Moreover, a study in children and adolescents with BPD did not find any significant association of the Val/Val, Val/Met and Met/Met genotypes with any WCST scores [40]. Cognitive deficits have been observed in both pediatric and adult patients with BPD [41,42]. The deficits consist of different domains including attention, working memory, executive functions, verbal fluency, visual memory, motor speed and visualperceptual skills. However, the magnitude of differences in these domains between patients with BPD and healthy controls varies significantly [41]. More importantly, some of these deficits may be the presentations of general psychopathology of different psychiatric disorders, not specific to BPD. Comorbidities including attention deficit hyperactivity disorder in BPD are common [1,43]. Clearly, bipolar specific cognitive deficits should be defined before they can be used as an endophenotype for genetic studies. Otherwise, the results from different studies will be difficult to be interpreted and reconciled. BPD with comorbidity

Comorbidity in BPD is the rule rather than an exception [1,43]. Focusing on a specific comorbid condition may produce positive and robust findings. In a study of 160 bipolar patients and 160 healthy controls, SNPs of BDNF gene including rs49233463, rs6265 (Val66Met), rs2049045 and rs7103411 were genotyped. There was no genotypic, allelic or haplotype differences between patients and healthy controls, but the rs4923463 (G/G) genotype was significantly associated with alcoholism, smoking and violent suicide attempt. The G-G haplotype (rs4923463-rs2049045) and the G-T haplotype (rs4923463-rs7103411) were significantly more frequent in the group of patients with alcoholism compared with the group without alcoholism [44]. BDNF gene expression

Gene expression is a key step for a gene executing its function. Even if there is no significant difference between patients with BPD and healthy controls in BDNF gene, BDNF gene can still be involved in the pathogenesis of BPD through regulating gene expression by other genetic and/or environment factors. However, BDNF gene has 5’ exons preceded by 5 different promoters which drive tissue-specific expression of BDNF regulated by neuronal activity [45]. It is important to keep this in mind when comparing the results of BDNF expression from different tissues. In a study, comparing depressed patients during a drug-free period and healthy controls, there was a decrease in BDNF gene expression in the lymphocytes and platelets of adults and pediatric depressed patients relative to healthy controls [46]. In the pediatric BPD, the mRNA levels of BDNF in lymphocytes and protein levels of BDNF in platelets were significantly lower 53


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compared to healthy controls [47]. After 8-week treatment, the decreased mRNA levels of BDNF returned to comparable levels as healthy controls. At the DNA level, there is a report that patients with bipolar II, but not those with bipolar I, had a significant BDNF gene expression downregulation in blood mononuclear cells compared to healthy controls [48]. Using human brains to study gene expression can provide a snapshot of neuronal activity shortly before death. Disease specific marker(s) may be well preserved and reliably detected. However, state-dependent marker(s) will be difficult to be captured. A study in patients with BPD or major depressive disorder (MDD) showed that there were reductions in (pro)BDNF in all layers of the right, but not the left, hippocampus with no change in the dentate gyrus in patients with MDD [49]. The pattern was similar, but less marked in patients with BPD. In addition, patients with BPD had bilateral reductions in p75NTR protein in hippocampus, but not in dentate gyrus. There was no change in TrkB density in either MDD or BPD. These data suggest that BPD and MDD may share impairment in (pro)BDNF expression, but BPD may have impairments of both (pro)BDNF and p75NTR. Decreased BDNF gene expression in dorsolateral prefrontal cortex was also observed in patients with BPD or schizophrenia [50]. A significant decrease (33%) in BDNF mRNA in CA4 of hippocampus was also observed in BPD compared to controls [51]. TrkB-TK + mRNA levels were significantly present in the layer II of the entorhinal cortex of patients with BPD (28%) or MDD (21%) than the controls [51]. In addition, patients with BPD as well as those with schizophrenia or MDD had reduced TrkB immunoreactivity in the molecular and granule-cell layers of cerebellum compared to healthy controls, but only the reduction in BPD remained statistical significant after Turkey-Kramer post-hoc analyses [52]. However, the BDNF immunoreactivity in all three disease groups was not statistically significant compared to the controls. On the other hand, a family-based association study of Val66Met polymorphism in 312 bipolar nuclear families did not find any significant difference in the ratio of Val/Met specific mRNA expression between bipolar patients and healthy controls in either the brains or B lymphoblasts [53]. A recent systematic review of state-dependent alterations of gene expression in BPD found that only BDNF was investigated with three different studies with a total of 64 patients and 50 controls, but there was no significant difference in BDNF expression between patients with BPD and control individuals [54]. Neuroimaging studies Magnetic resonance imaging

Results from post-mortem studies suggested that the reduced BDNF gene expression in patient with BPD might be involved in the morphological changes in brain regions. In a small study of patients with BPD (n = 20) and healthy controls (n = 18), hippocampus volumes were significant smaller in BPD compared to the controls; and the presence of Met allele of Val66Met polymorphism was associated with smaller hippocampus 54

volumes in both patients and healthy controls [55]. Among all participants, those with BPD and BDNF Met allele had the smallest hippocampus volumes. 3D mapping identified these decreases as most prominent in left anterior hippocampus. A larger study in 42 patients with BPD and 42 healthy controls found that the left and right anterior cingulate gray matter (GM) volumes had a significant interaction between genotype and diagnosis [56]. The anterior cingulate was significantly smaller in the Val/Met carriers compared to the Val/Val carriers with BPD. Within-group comparisons revealed that the Val/Met carriers had smaller GM volumes of the dorsolateral prefrontal cortex compared to the Val/Val carriers with BPD, and healthy controls. The Val/Met healthy controls had smaller GM volumes of the left hippocampus compared to Val/Val healthy controls. Significant smaller hippocampal volumes were also observed in patients with MDD compared to healthy controls [57]. Patients and healthy controls with BDNF Met allele had significantly smaller hippocampal volumes compared to subjects with homozygous Val allele of BDNF. Healthy subjects with BDNF Met carriers also had smaller parahippocampal volumes and a smaller right amygdala compared to Val/Val homozygotes [58]. The whole-brain analysis showed that the thalamus, fusiformus gyrus and several parts of the frontal gyrus were smaller in 66Met allele carriers compared to Val/Val homozygotes. The finding of smaller hippocampus of Met carriers in healthy controls raises a question that how specific is the effect of Met allele on hippocampus and other brain regions in patients with psychiatric disorders. In contrast, the largest study of BDNF Va66Met polymorphism and brain morphology including 166 bipolar patients and 64 healthy controls did not find an association between BDNF polymorphism and brain morphology [59]. There were more than 10 regions showing significant decreases in total and regional GM in BPD compared to healthy controls, more pronounced in the inferior and posterior parts of the brain, along with a concomitant increase in total CSF, particularly in the lateral ventricles. However, there was no significant difference in white matter or GM of other regions, as previously reported, such as hippocampus and anterior cingulate. There was also no significant difference in brain morphology between BDNF Val66 homozygotes and Met66 carriers. Similarly, a MRI study in patients with schizophrenia or bipolar I disorder and healthy controls showed that BDNF genotype did not affect hippocampal volumes [38]. A recent meta-analysis of 16 voxel-based morphology studies in BPD found that patients with BPD had reduced GM in a single cluster encompassing the right ventral prefrontal cortex, insula, temporal cortex and claustrum compared to healthy controls [60]. The widespread study heterogeneity was also observed through the brain, but the difference in the cluster between patients and the controls remained significant after the extraneous voxels had been removed. Clearly, more studies are needed to determine the specific effect of BDNF gene on brain morphology in BPD. In addition, an updated review found Expert Rev. Neurother. 14(1), (2014)



that medication appeared to influence the results of many structural neuroimaging studies [61]. Future studies on BDNF gene and brain morphology should take medication effect into consideration. A longitudinal study also supports an unspecific effect of BDNF Met allele on neurodevelopment and neuroplasticity across the spectrum of psychiatric disorders and healthy subjects [62]. The changes in gyrification over a 4-year period in patients with BPD (n = 18) and healthy controls (n = 18) revealed that prefrontal, ventral and dorsal gyrification decreased significantly with time in both groups, but the rate of decrease did not differ significantly between two groups. Within the bipolar group, individuals with one or more BDNF Met alleles showed greater losses in gyrification index. Another 4-year longitudinal study of patients with bipolar I disorder also showed that BDNF Met carriers (n = 6) had significantly greater temporal lobe reductions than non-Met carriers (n = 14) [63]. Magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) can measure neuronal activity through measuring changes in neurotransmitters and their metabolites. A study using MRS to measure the metabolism in the left dorsolateral prefrontal cortex of BPD and healthy controls in relation to the BDNF Val66Met polymorphism found that Met carrier of bipolar patients had lower phosphocreatine + creatine (PCr+Cr) levels than Val/Val bipolar patients [64]. However, Val/Val bipolar patients had higher PCr+Cr levels than Val/Val healthy controls. In contrast, in a mixed group of patients with schizophrenia (n = 66) or BPD (n = 45), and healthy controls (n = 47) [38], MRS in hippocampus and other brain regions found that BDNF genotype had significant effect on metabolic markers in the left hippocampus, but not in the left dorsolateral prefrontal cortex or the left posterior frontomedian cortex. Homozygous carries of the Met allele exhibited significantly lower N-acetyl aspartate/creatine (NAA/Cr) and glutamate + glutamine/Cr (Glu + Gln/Cr metabolic ratios compared with Val/Val homozygotes. The means of NAA/Cr and Glu + Gln/Cr ratios of the heterozygous Val/Met group were in between the two homozygous groups. There was no significant difference between Met carriers and Val/Val homozygotes in the MRS ratios. There was also no significant interaction effect of diagnosis (bipolar, schizophrenia or healthy controls) with BDNF on the MRS ratios, suggesting that these changes were independent of psychiatric diagnoses. The results from aforementioned studies suggest that BDNF Met carriers had decreased GM and metabolic activities in different brain regions of patients with BPD, schizophrenia or MDD, and healthy subjects. However, a study in healthy subjects found that BDNF Met carriers had increased absolute NAA concentration in the anterior cingulate cortex and decreased creatine-phosphocreatine concentration in the hippocampus [65]. Undoubtedly, the effect of the BDNF Met allele on the brain metabolism in patients with BPD or healthy controls also need further investigation. www.expert-reviews.com

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Serum/plasma BDNF levels at different mood states

Although it was initially proposed that BDNF overactivity might be implicated in the manic state [66], as shown in TABLE 1, the majority of studies have shown that serum/plasma levels of BDNF in unmedicated and medicated bipolar patients during manic state, depressed or euthymic state was lower than healthy controls or MDD [67–74]. Meanwhile, treatment-naı¨ve patients with MDD also had decreased serum BDNF levels relative to healthy controls [75]. The BDNF levels were negatively correlated to the severity of depression and recovered to normal levels after successful antidepressant treatment. These data do not support that BDNF has discriminative effect to differentiate BPD from MDD, as initially proposed [70]. Significantly increased plasma BDNF levels during mania (n = 34) or euthymia (n = 19) relative to healthy controls (n = 38) have also been reported in patients with long-term BPD, especially in those with 10 or >10 years of illness [76] as well as in euthymic bipolar patients with cognitive dysfunctions [77]. However, a following study did not find significant association between increased BDNF levels and the length of bipolar illness in a group of patients with long-term bipolar illness of 23.4 years although both patients in mania or remission had increased BDNF levels relative to healthy controls [78]. Apparently, decreased BDNF levels could be a statedependent biomarker for BPD [79,80], but overall data suggest that decreased serum/plasma BDNF levels could be a statedependent (mania and depression vs euthymia), stage-dependent (early vs later) or disease-specific (bipolar vs unipolar) biomarker (TABLE 1). Cognitive function & serum/plasma BDNF levels

In a study comparing serum BDNF levels of patients with bipolar I disorder (n = 50) and healthy controls (n = 50) and their cognitive function, there was no significant difference found between patients and controls in serum BDNF levels although patients performed significantly worse on 11 of 16 neurocognitive tests as compared to the controls. However, there were significant positive association between serum BDNF levels and a test of verbal fluency in both patients and controls [72]. Poorer executive function and increased BDNF levels relative to healthy controls were observed in euthymic bipolar patients, but executive function was correlated with age and Mini Mental Status Examination, but not with BDNF [77]. Similarly, there were significant differences in sub-items of the facial memory test and the WCST between patients and healthy controls, but the overall deficits in cognition in bipolar patients were not significantly correlated with the BDNF levels [71]. The relationship between BDNF plasma levels and cognitive function has also been studied in bipolar patients on prophylactic lithium treatment [81]. Excellent lithium responder performed better on all neuropsychological tests, and had higher plasma BDNF levels than the remaining lithium patients with partial or non-response, but there was no significant difference 55

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Table 1. Summary of serum/plasma levels of brain-derived neurotrophic factor in patients with bipolar disorder at different phase of illness compared to the controls. Study (year)

Patients

Depressive state

Manic state

Euthymic state

Comparison group

MachadoVieira et al. (2007)

30 BPI mania and drug-free 30 healthy controls

n/a

Decrease

n/a

HC

[67]

de Oliveira et al. (2009)

22 mania or depression and drug free 22 BPI patients medicated 22 healthy controls

Decrease Decrease

Decrease Decrease

n/a

HC HC

[68]

Cunha et al. (2006)

32 21 32 32

Decrease

Decrease

n/a

HC and euthymia

[69]

Fernandes et al. (2009)

40 BPI depressed 10 current MDD 30 healthy controls

Decrease

n/a

n/a

HC and MDD

[70]

Chou et al. (2012)

23 BPI euthymic 30 healthy controls

n/a

n/a

NS

HC

[71]

Dias et al. (2009)

65 BPI euthymic 50 healthy controls

n/a

n/a

NS

HC

[72]

Huang et al. (2012)

26 BPI mania 56 healthy controls

n/a

NS

n/a

HC

[73]

Monteleone et al. (2008)†

24 17 11 11 22

Barbosa et al. (2010)‡

BPI euthymic medicated BPI depressed medicated BPI mania medicated healthy controls

euthymic MDD euthymic BP I euthymic BP II current MDD healthy control

Decrease Decrease

Ref.

†

[74]

HC HC

n/a n/a

n/a n/a

34 BPI mania 19 BPI euthymia 38 healthy controls

n/a n/a

n/a n/a

Increase Increase

HC HC

[76]

Barbosa et al. (2010)

25 BPI euthymic with cognitive deficit 25 healthy controls

n/a

n/a

Increase

HC

[77]

Barbosa et al. (2013)

87 BPI with long-term illness (48 in mania; 39 in remission) 58 healthy control

n/a

Increase

Increase

HC

[78]

†

Patients with euthymic MDD or current MDD had lower levels of BDNF compared to healthy controls. There were no significant differences among the patients. Increase in BDNF levels was correlated the duration of illness with a longer duration and a higher level of BDNF. BPI: Bipolar I disorder; BPII: Bipolar II disorder; HC: Healthy controls; MDD: Major depressive disorder; n/a: Not available; NS: Not statistically significant. ‡

in BDNF levels between patients and healthy controls. Excellent lithium responders may constitute a specific subgroup of bipolar patients so that long-term lithium administration can produce complete normality in cognitive function and plasma BDNF concentration. The other finding supports this assumption including that euthymic bipolar patients who did not respond to lithium treatment had decreased serum BDNF levels [82]. Serum/plasma BDNF levels before & after treatment

Decreased BDNF levels during acute mania were normalized after treatment [83]. Acute treatment with lithium monotherapy in bipolar mania also increased plasma BDNF levels compared 56

to pre-treatment, but there was no significant association between BDNF levels and changes in manic symptom severity [84]. In 141 euthymic bipolar patients who were on long-term treatment with lithium, as a group, bipolar patients had lower BDNF levels compared to healthy controls [82]. After dividing patients into excellent lithium response group, partial response group and non-response group, only patients in the non-response group had significantly lower levels of BDNF compared to the controls. On the contrary, decreased BDNF levels (36%) were observed in the transformed lymphoblasts of patients with lithium-response relative to matched controls; and there was 55% lower in patients with lithium-response relative to their Expert Rev. Neurother. 14(1), (2014)



unaffected relatives [85]. One more recent study in patients with mania who were treated with mood stabilizer for 4 weeks did not find significant changes in serum BDNF or TrkB protein levels [73]. The relationship between BDNF levels and pharmacological treatments has also been explored with other agents. In a study of risperidone treatment for both acute manic and depressive episodes in BPD (n = 18), the administration of risperidone did not alter plasma BDNF levels [86]. Quetiapine extended release treatment produced increasing BDNF levels with time in bipolar patients with a depressive episode, but a decrease in BDNF levels with time in those with a manic/mixed episode [87]. Adjunctive atypical antipsychotics to antidepressants and/or mood stabilizers in treatment-resistant BPD or MDD for 4 weeks increased the plasma BDNF levels in responders (those showing a decline in HAM-D scores of 50% or more), but not the levels in non-responders. There was a significant correlation between the changes in HAM-D scores and the changes in plasma BDNF levels [88]. However, the serum BDNF levels were not associated with response to the electroconvulsive therapy in treatment-resistant depression [89]. In summary, these data suggest that the change in BDNF serum/plasma levels may not only depends on treatment and treatment response, but also depends on the state of the illness being treated. In addition, a study of serum and plasma BDNF levels in abstinent alcoholics and social drinkers found that there were significant higher serum BDNF levels in alcoholics than in social drinkers, but there was no significant difference between alcoholics and social drinkers in plasma BDNF levels [90]. These findings highlight the importance of measuring serum and/or plasma BDNF levels in future studies. Interactions between BDNF & HPA-axis

In a high risk study of healthy monozygotic and dizygotic twins with (high-risk) and without (low-risk) a co-twin history of affective disorder, the familial predisposition to MDD and BPD was not associated with any specific genotype patterns of the BDNF Val66Met polymorphism [91]. However, the combination of having a high familial risk of affective disorder and the Met allele was associated with a higher whole blood BDNF and a higher evening cortisol level, suggesting that the presence of a specific genotype alone may not be enough to enhance the risk of developing an affective disorder. It also suggests that, individuals at a high risk for affective disorders who also carry a Met allele of the BDNF gene may present with an increased stress response and an increased risk for a mood disorder. The interactions between BDNF genotype and environment were observed in a study of stressful life events and BDNF Val/ 66Met polymorphism in BPD (n = 487) and healthy controls (n = 598) [92]. Both Val/Met-Met/Met genotypes and stressful life events were significantly associated with the worst depressive episode of BPD. The effects of stressful life events on the worst depressive episodes were significantly moderated by BDNF genotypes. Similarly, in a mixed group drug-free depressed patients with MDD or BPD, homozygous carriers of www.expert-reviews.com

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Met/Met genotype showed a significant higher HPA-axis activity during a dexamethasone/corticotrophin releasing hormone test than patients carrying Val/Val or Val/Met genotype [93]. In contrast, a study of BDNF Val66Met genotypes and early life stress effect on bipolar course of patients with a spectrum of bipolar disorders found that BDNF Met carrier with history of childhood sexual abuse had higher (21%) illness severity a year prior to the study and an earlier onset of bipolar illness (14.6 ± 5.7 vs 22.8 ± 7.9 years old) than those without a childhood sexual abuse. However, regression analysis did not find significant interaction between BDNF genotypes and childhood sexual abuse [94]. These preliminary findings suggest that BDNF gene may interact with environment to affect the onset and/or severity of bipolar illness, suggesting that the interaction between the BDNF gene and the timing of adverse life vents is worthy of exploration in order to prevent or delay the onset of BPD. Interaction between BDNF & monoamine system

The role of monoamine system in BPD remains unclear [95,96]. The interaction between BDNF and monoamine system was explored in a study including 447 patients with BPD and 370 controls. Three common polymorphisms of BDNF including Val66Met and serotonin-transporter-linked polymorphic region (5-HTTLPR) were genotyped. There was an association between Val66Met and BPD and a correlation between the number of G196 alleles and short alleles of 5-HTTLPR and the severity of suicidal behavior in BPD. However, there was no significant interaction between these two markers [97]. In contrast, a study of the catechol-O-methyltransferase (COMT) and BDNF polymorphism in bipolar II disorder with (n = 117) or without (n = 314) comorbid anxiety disorder and healthy controls (n = 340) showed a significant interaction effect of the COMT and the BDNF polymorphisms [98]. The Val/Val genotype of BDNF and the Val/Met and Met/Met genotypes of COMT Val158Met polymorphism was observed to discriminate patients with bipolar II without AD from the controls. The interaction between BDNF and dopamine D2 receptor polymorphisms was also studied in patients with BPD (208 of bipolar I and 329 of bipolar II) and healthy controls (n = 255) [99]. Significant interaction effect of the Val/Val genotype of BDNF Val66Met polymorphism and A1/A2 genotype of the dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) Taq1A polymorphism was only observed in bipolar II patients. Similarly, significant interaction between BDNF Val66Met Val/Val genotype and both DRD3 Ser9Gly Ser/Ser and Ser/Gly genotypes were found only in bipolar II disorder [100]. A SPECT study of serotonin transporter (SERT) in patients with bipolar I disorder found that SERT availability in both midbrain and striatal regions were decreased in bipolar patients compared to healthy controls, but there was no significant difference in serum BDNF levels between two groups. There was also no significant correlation between SERT availability and serum BDNF levels [71]. 57

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Interaction between BDNF & proinflammatory markers

Inflammatory process may also be involved in BPD [101]. Patients with reactive depression (n = 13), MDD (n = 18) or bipolar depression (n = 10) had lower serum BDNF levels, but had significantly higher levels of TNF-a than healthy controls (n = 21). There was no significant difference between subtypes of depression in BDNF, adiponectin, high sensitivity C-reactive protein (shCRP), TNF-a and IL-6. There was also no significant association between BDNF and adiponectin, shCRP, TNF-a and IL-6 in any depressed subject [102]. In bipolar adolescents, BDNF and IL-6 were not significantly associated with manic or depressive symptom severity. In contrast, hsCRP was positively associated with hypomanic/ manic symptoms, but not depressive symptoms [103]. More importantly, not all patients with high manic symptoms severity had high hsCRP. BNDF levels were negatively associated with IL-6, but not with hsCRP. The BDNF levels and inflammatory markers have also been compared in patients with early or late stage of BPD and controls [104]. BDNF was decreased only in those in the late stage of illness and negatively correlated with the length of illness. In contrast, IL-10, IL-6 and TNF-a were increased in the early stage of illness compared to controls; and IL-6 and TNF-a continued significantly higher than the controls at late stage of BD. Within bipolar patients, there was significant decrease in BDNF and IL-6 in the late stage of illness compared to those in the early stage. Inversely, TNF-a showed a significant increase at late stage of illness. Although the involvement of inflammatory markers in psychiatric disorders, especially in mood disorders, has attracted the attention of researchers in recent years, the big challenge for studying peripheral chemicals in psychiatric disorders is how to translate the peripheral changes into the function of the brain. Even if there is a robust interaction or association between serum/plasma BDNF and inflammatory markers, it will be naı¨ve to believe that a similar relationship between them exists in the brain. Unless the technology allows us to measure these chemicals simultaneously in the brain, their relationship(s) in the brain will never be established. Pharmacogenetic studies

Lithium has been the most commonly used drug for pharmacogenetic studies in BPD. An early study of the association between prophylactic lithium response and BDNF gene Val66Met polymorphism found that there was a trend for a higher incidence of Met allele in excellent lithium responders than in lithium non-responders [105]. Genotyping four SNPs within the BDNF gene and three SNPs within the NTRK2 gene by the same group of researchers found that SNP rs988748 and Val66Met polymorphism of BDNF gene were associated with a degree of prophylactic lithium response, but there was no significant association between lithium response and polymorphisms of NTRK2 gene [106]. However, a study in Japanese patients with BPD and treated with lithium for 1 year did not find any significant difference 58

in genotypic or allelic frequency of BDNF gene between retrospectively determined lithium responders and lithium nonresponders [107]. Similarly, in a study from Brazil including134 bipolar I patients who were treated with lithium for at least 2 years, genotyping five variants within BDNF gene and other genes did not find significant association between these polymorphisms and lithium response [108]. A study from China found that the Met allele of BDNF Val66Met polymorphism had opposite effect on the treatment response in bipolar I and II subtypes. In bipolar I disorder, the response scores in the Val/Val genotype group were significantly lower than that in the Met allele carriers. In bipolar II disorder, the response scores in the Val/Val genotype group were significantly higher than that in the Met allele carriers [19]. The importance of gene-gene interaction on treatment response is highlighted by the different effects of Val66Met of BDNF and 5HTTLPR genotypes on lithium response [109]. Patients with s/s or s/l genotype of 5HTTLPR and Val/Val genotype of BDNF gene were significantly more frequently observed in non-responders than in excellent responders or partial responders. In the s/s or s/l plus Val/Val genotype group, 19% were excellent responders and 37% were non-responders. In the s/s or s/l plus Val/Met or Met/Met genotype group, 40% were excellent responders and 3% were non-responders. The results from these pharmacogenetic studies between the BDNF gene, especially Val66Met polymorphism, and treatment response to lithium have been inconsistent. A recent systematic review of pharmacogenetics in BPD showed that three out of eight lithium and BDNF studies did not find an association between BDNF polymorphism and lithium response [110]. In contrast, two out of three lithium and NTRK gene studies did not find any genotype associated with lithium response. Overall, Val/Val genotype of BDNF was associated with poor lithium response and Val/Met and Met/Met genotypes were associated with good lithium response, especially in bipolar I disorder [110]. Currently, a study (Clinicaltrials.gov Identifier: NCT01272531) funded by the National Institute of Mental Health in the USA is investigating pharmacogenomics of mood stabilizer response in BPD (PGBD). In this study, patients with bipolar I disorder are prospectively determined if they respond to lithium or valproate monotherapy in acute and stabilization phase of 12 weeks in total. For those who are stabilized over a 3-month acute treatment period and 1-month observation period, a follow-up would be done in every 2 months for 2 years. The primary outcome measure of the study is the time to a relapse of a mood episode. A total of 880 patients will be recruited. The estimated completion date is in the January of 2016. Involvement of BDNF in the mechanism of mood stabilizers

Traditional mood stabilizers include lithium and some anticonvulsants such as valproate and carbamazepine. Newer mood stabilizers include anticonvulsant, lamotrigine and newer atypical antipsychotics [4]. Lithium and valproate have been used as representatives of mood stabilizers in preclinical studies although Expert Rev. Neurother. 14(1), (2014)



their efficacy in the acute treatment of bipolar depression has never been established [5]. Lithium and valproate have been extensively studied in preclinical settings [111–114]. At the molecular level, the effect of lithium and valproate appeared to be unspecific and multiple. In a microarray gene expression study, 4474 of 39,000 genes showed changed mRNA expression in response to lithium; and 1027 of 4474 genes was significantly changed [115]. Increased BDNF mRNA was among the significantly changed genes. The inhibition of GSK-3 and upregulation of BDNF has been speculated as the main mechanism of lithium and valproate for their neuroprotective effects [111]. Lithium and valproate have striking functional similarities, but clear differences in the biological process [113]. Valproate, but not lithium network was highly enriched for nodes associated with the nuclear lumen functional cluster, cell cycle, nucleotide excision repair and DNA replication. Meanwhile, lithium and valproate sharing network nodes are highly associated with apoptosis cluster and neurotrophic signaling. BDNF was among the 25 molecules regulated by lithium and reported by at least two studies. Similarly, BDNF was among the 47 molecules regulated by valproate and reported by at least two studies. Lamotrigine, an anticonvulsant, also affects BDNF expression in animal models of depression. Sub-chronic twice daily (b.i.d.) injections of 30 mg/kg lamotrigine robustly decreased escape failures in animals with learned helplessness symptoms [116]. Sub-chronic lamotrigine treatment also upregulated frontal and hippocampal BDNF in both naı¨ve and stressed animals; and restored the stress-induced downregulation of BDNF expression. The antidepressant effect of lamotrigine was blocked by an inhibitor of BDNF receptor, TrkB [117]. Olanzapine, an atypical antipsychotic with mood stabilizing property, had a similar, but less robust effect as lithium on regulating gene expression in the animal brains [118]. These data suggest that mood stabilizers and antipsychotics may target different genes and molecular pathways to execute their mood stabilizing function, but there are overlaps and divergences among their targets. In order to understand the genetic marker(s) of each psychotropic agent, pharmacogenetic studies should focus on one medication at a time. The PGBD is an example of this design.

Review

kinase genes, which includes TrkA (NTRK1), TrkB (NTRK2) and TrkC (NTRK3). TrkC is the receptor for NTF-3 and preferentially expressed in the brain, but does not bind to NGF or BDNF. An association study of 603 families with 723 affected children and adolescents who had an onset of the first mood episode by 15-years-old found that five of 18 genotyped markers in NTRK3 gene were significantly associated with childhoodonset mood disorder. The common haplotype with three of five significant markers was over transmitted to affected offspring [121]. In contrast, a study of a dinucleotide repeat polymorphism in the NTF-3 gene from Japan did not find a significant association between patients with BPD (n = 88) and their healthy controls (n = 98) [122]. Patients with BPD did not have altered NTF-3 mRNA expression in the peripheral blood cells although patients with current MDD, but not in remission, had reduced NTF-3 mRNAs expression [123]. Serum NTF-3 levels were increased in manic and depressed patients compared euthymic state and healthy controls [124]. Increased serum NTF-3 levels compared to healthy controls were observed in both drug-free and medicated manic and depressed patients [125]. However, the NTF-3 levels did not significantly differ between drug-free and medicated patients. There was no significant difference between manic and depressed patients in NTF-3 levels. Relationship between NGF & BPD

An early study did not find an association between NGF gene and BPD [12]. However, a more recent study genotyped 94 SNPs with the region of chromosome 3p22.3 found that there was a SNP encoding a subunit of the integrin, a membrane glycoprotein receptor for neurotrophins including NGF and BDNF associated with an increased risk for BPD [126]. Reduced NTF-3 mRNAs, but not NGF or NTF-4, in patients with current MDD were reported [123]. Unaltered mRNA expression of NGF was also observed in patients with BPD. Compare to healthy controls, patients with BPD had decreased NGF levels. Patients with mania had lower levels of NGF than euthymic patients and healthy control. NGF levels were negatively correlated with the severity of mania [127]. Relationship between NTF-4/5 & BPD

The 5HTTLPR polymorphism may be involved in antidepressant-induced manic switch [95,96]. However, two small studies of the genetic variants within BDNF gene and antidepressant-induced mania found no significant difference in allelic or genotypic frequencies between patients with antidepressant-induced mania and those without it [9,120].

There is only one study focused on NTF-4/5 in BPD. The serum NTF-4/5 levels were significantly higher in bipolar I patients (n = 154) than healthy controls (n = 30). The NTF-4/ 5 levels were increased in mania, depression and euthymia, but there were no significant differences among the patients in different mood states [128]. However, the mRNAs expression of NTF-4/5 was not altered in patients with current MDD or BPD [123].

Relationship between NTF-3 & BPD

Expert commentary

The genetic studies of NTF-3 in BPD have focused on the gene for neurotrophic tyrosine kinase receptor 3 (NTRK3). The NTRK3 is a member of the TRK family of tyrosine protein

Genetic association studies

Involvement of BDNF in antidepressant-induced manic switch


The challenges for genetic studies at least include study sample size, study population and phenotype selection. Since national 59


Review


and international collaborations have taken place, large sample studies are easily achievable. However, finding a homogenous sample of participants is still a big challenge. A population genetic study of the BDNF gene found that there were substantial variations in BDNF coding region SNP allele and haplotype frequencies between 58 global populations [129]. The Met allele of Val66Met ranged from 0–72% frequency across populations. Meanwhile, haplotype diversity of the BDNF allele among the global populations was also observed. Clearly, unless all study participants are from the same ethnic origin, the confounding effect from different ethnic groups is unavoidable. Similarly, selecting a homogenous bipolar phenotype and healthy control group is also important and challenging. According to DSM-IV and DSM-5 diagnostic criteria for bipolar phenotype, BPDs are classified as bipolar I, bipolar II and bipolar disorder (not other specified or other specified types). However, ‘pure’ BPD is relatively rare [1,41]. Unlikely, bipolar patients with different phenotypes and different comorbidities share the same genetic variants. The different findings with different definitions of phenotypes and controls highlight the importance of selecting phenotype and controls in genetic studies [18]. The finding from the comorbidity genetic study suggests that selecting patients based on comorbidity may yield robust results [42].

the inconsistent findings pose a question of how specific are the changes in serum/plasma levels of neurotrophins in BPD. The current available data do not support the use of serum/ plasma BDNF levels as a biomarker to differentiate bipolar from unipolar depression. There are not enough data to support the use of BDNF as a biomarker to predict the treatment and/or prognostic outcome for patients with BPD. Obviously, the current data are limited by small sample sizes, from a small group of researchers and measuring different polls of BDNF, serum or plasma. Large studies from different researchers, measuring both serum and plasma BDNF levels, using ‘standard’ treatment regimen, and following longitudinally are needed to elucidate the potential role of serum/plasma neurotrophins in the diagnosis, treatment response and progress of BPD. From the pathophysiological point of view, the importance of measuring serum/plasma levels is to determine how the change in the blood reflects the changes in the brain. Measuring changes in neurotrophins in the cerebral spinal fluid may help to understand the correlation between changes in the blood and changes in the brain. However, the invasive nature of lumbar puncture will limit this approach. Combining neuroimaging technology and serum/plasma measures may shed light on the correlation between brain function and changes in peripheral neurotrophins.

Pharmacogenetic studies

In addition to sample size, study population and study phenotype, the definition and criteria for response and the selection of investigated drugs are also important. So far, pharmacogenetic studies are limited due to small sample sizes, the use of different treatments and/or retrospective determination of treatment responses. Lithium and valproate are two most studied mood stabilizers in preclinical settings [111,113]. The finding of lithium and valproate shared striking functional similarities, but clear differences in the biological process suggest that these two drugs should be studies separately. The PGBD is studying lithium and valproate separately. The results from this study may shed light on the relationship between neurotrophins and response to lithium or valproate treatment. More importantly, Met allele carriers had better response to lithium than Val homozygotes although genetic association studies showed that Val allele over transmitted in patients with BDP compared to healthy controls and Met allele carriers has smaller brain regions and poorer cognitive performance than Val homozygotes. This opposite direction of Met allele in response to treatment and structural changes and cognitive performance raise the possibility that a SNP may have differential effect on neurodevelopment, neurological function and response to psychotropic medications. Serum/plasma levels of neurotrophins

The data of the serum/plasma levels of neurotrophins, especially BDNF levels, in different phase of bipolar disorder suggested that the levels of neurotrophins can be used as phasespecific, stage-specific or disease-specific marker(s). However, 60

Five-year view

Although the results from genetic association studies have been inconsistent, the plausible functional involvement of neurotrophins in neuroplasticity will keep the investigation of genetic polymorphism of neurotrophins, especially BDNF gene in BPD to continue. The results from associated studies are essential to help us understand the susceptibility to BPD, but will not help us to understand the function of genes. More studies with the combination of genetic and neuroimaging technology such as functional MRI will be available in next 5 year. Similarly, pharmacogenetic studies like the PGBD will provide information on genetic polymorphism and treatment response even if neurotrophin genes are not involved in the pathogenesis of BPD. Like genetic association studies, results from pharmacogenetic studies without neuroimaging data will limit the interpretation on the changes in the brain even if there is a response to treatment. More recent studies using PET to investigate the neural correlates of ketamine and mood stabilizer on serotonin type 1A receptor binding in bipolar depression [130,131], suggest that the combination of pharmacogenetic and neuroimaging technique is essential to help us understand the mechanisms of psychotropic agents including neurotrophins from genetic, molecular, neuronal and circuitry levels. However, the requirement of synthesizing radiotracers for PET will limit the use of this technique. Research in serum/plasma levels of neurotrophins in BPD and other psychiatric disorders will also continue because it is relatively easy to carry out with low cost. If the findings are robust, the implementation of clinical applications becomes Expert Rev. Neurother. 14(1), (2014)



easy. Interaction between neurotrophins and other factors including inflammatory markers will be investigated more extensively. More importantly, the polymorphisms of neurotrophins and the inflammatory markers should be taken into consideration when measuring peripheral changes of these chemicals. Moreover, studying the relationship between serum/ plasma level neurotrophins and brain function will provide a link between the brain and the blood. Financial & competing interests disclosure

JR Calabrese has received grant support, lecture honoraria or has participated in advisory boards with Abbott, AstraZeneca, Bristol-Myers Squibb/

Review

Otsuka, Cephalon, Dainippon, Sumitomo, Forest, France Foundation, GlaxoSmithKline, Janssen, Johnson and Johnson, Lilly, Lundbeck, Merck, Neurosearch, OrthoMcNeil, Pfizer, Repligen, Sanofi, Schering-Plough, Servier, Solvay, Synosia, Supernus Pharmaceuticals, Takeda and Wyeth. K Gao has received grant supports from Astrazeneca, The Brain and Behavior Research Foundation and The Cleveland Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Preclinical studies suggest that neurotrophins are essential for neurodevelopment, neuronal survival and neuroplasticity, but their functions in bipolar disorder (BPD) remain unknown. • Brain-derived neurotrophic factor is the most studied neurotrophin in BPD , but results from genetic association studies, pharmacogenetic studies and serum/plasma level studies have been inconsistent. • BDNF gene polymorphism, especially Val66Met may be associated with an increased risk for subtypes of BPD such as rapid cycling RC BPD. • Met allele of BDNF gene was associated with smaller brain regions compared to Val homozygotes in both patients and healthy controls. • Pharmacogenetic studies suggest that Met allele carriers may have better response to lithium than Val allele homozygotes. • Serum/plasma levels of neurotrophins may be a disease marker (bipolar vs major depressive disorder), a state marker (depressive and mania vs euthymia) or a stage marker (early stage vs late stage), but large sample studies are needed to clarify the roles of neurotrophins in these different conditions. • Cognitive deficits in BPD have been used as an endophenotype of BPD. There is no convincing evidence supporting an association between any genotype and cognitive performance although the Met carriers had worse performance than Val homozygotes. • There are some data which suggest that neurotrophins may interact with other system such as HPA-axis, neurotransmitters such as serotonins or inflammatory markers such as IL-6, but the data have also been inconsistent. • Brain-derived neurotrophic factor may be involved in the intracellular pathways of psychotropic medications, especially lithium and valproate.

Papers of special note have been highlighted as: • of interest •• of considerable interest 1

2

3

4

Merikangas KR, Akiskal HS, Angst J et al. Lifetime and 12-month prevalence ofbipolar spectrum disorder in the national comorbidity survey replication. Arch. Gen. Psychiatry 64(5), 543–552 (2007).

5

6

Merikangas KR, Jin R, He JP et al. Prevalence and Correlates of Bipolar Spectrum Disorder in the World Mental Health Survey Initiative. Arch. Gen. Psychiatry 68(3), 241–251 (2011). Wyatt RJ, Henter I. An economic evaluation of manic-depressive illness–1991. Soc. Psychiatry Psychiatr. Epidemiol. 30(5), 213–219 (1995). Gao K, Kemp DE, Wu R et al. Mood Stabilizers. In: Psychiatry (4th Edition). Tasman A, Liberman J, Kay J, First M,


Curr. Med. Chem. - Central Nervous System Agents 5, 26–41 (2005).

Riba M (Eds). John Wiley and Sons, Ltd., West Sussex, UK (In Press).

References

7

Gao K, Wu R, Grunze H et al. Phamarcological treatment of acute bipolar depression. In: Bipolar Disorder: Mellinium Upate.Yildiz A, Nemeroff C, Ruiz P (Eds), Oxford University Press, New York, USA (In Press). Gao K, Kemp DE, Calabrese JR. Pharmacological treatment of the maintenance phase of bipolar depression: focus on relapse prevention studies and the impact of design on generalizability.In: Milestones in Drug Therapy, Bipolar Depression: Molecular Neurobiology, Clinical Diagnosis and Pharmacotherapy. Zarate CA, Manji HK (Ed.), Spinger, Birkhauser Vertag, Switzerland, 159–178 (2009). Longo FM, Xie Y, Massa SM. Neurophin small molecule mimetics: candidate therapeutic agents for neurological disorders.

8

Duman RS. Novel therapeutic approaches beyond the serotonin receptor. Biol. Psychiatry 44(5), 324–35 (1998).

9

Craddock N, Jones I. Genetics of bipolar disorder. J. Med. Genet. 36(8), 585–594 (1999).

10

Craddock N, Lendon C, Cichon S et al. Chromosome Workshop: Chromosomes 11, 14, and 15. Am. J. Med. Genet. 88(3), 244–254 (1999).

11

Cargill M, Altshuler D, Ireland J et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22(3), 231–238 (1999).

12

Sklar P, Gabriel SB, McInnis MG et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus.

61

Review


Brain-derived neutrophic factor. Mol. Psychiatry 7(6), 579–593 (2002). 13


14

15

16

Neves-Pereira M, Mundo E, Muglia P et al. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: Evidence from a family-based association study. Am. J. Hum. Genet. 71(3), 651–655 (2002). Geller B, Badner JA, Tillman R et al. Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am. J. Psychiatry 161(9), 1698–1700 (2004). Kremeyer B, Herzberg I, Garcia J et al. Transmission distortion of BDNF variants to bipolar disorder type I patients from a South American population isolate. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B(5), 435–439 (2006). Lohoff FW, Sander T, Ferraro TN et al. Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 139B(1), 51–53 (2005).

17

Muller DJ, De Luca V, Sicard T et al. Brain-derived neurotrophic factor (BDNF) gene and rapid-cycling bipolar disorder Family-based association study. Br. J. Psychiatry 189, 317–323 (2006).

18

Liu LX, Foroud T, Xuei XL et al. Evidence of association between brain-derived neurotrophic factor gene and bipolar disorder. Psychiatr. Genet. 18(6), 267–274 (2008).

19

Wang Z, Li Z, Chen J et al. Association of BDNF gene polymorphism with bipolar disorders in Han Chinese Population. Genes Brain Behav. 11(5), 524–528 (2012).

20

21

22

62

Ivanova MA, Christova TN, Asan TS et al. Evidence of an association between bipolar disorder and rs16917237 in the BDNF gene in a Bulgarian sample. Psychiatr. Genet. 23(3), 141–142 (2013). Xu J, Liu Y, Wang P et al. Positive association between the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder in the Han Chinese Population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B(1), 275–279 (2010). Nakata K, Ujike H, Sakai A et al. Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neurosci. Lett. 337(1), 17–20 (2003).

23

Hong CJ, Huo SJ, Yen FC et al. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 48(4), 186–189 (2003).

34

Strauss J, Barr CL, George CJ et al. Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder. Am. J. Med. Gene.t B Neuropsychiatr. Genet. 131B(1), 16–19 (2004).

35

Adams JH, Wigg KG, King N et al. Association study of neurotrophic tyrosine kinase receptor type 2 (NTRK2) and childhood-onset mood disorders. Am. J. Med. Genet. B Neuropsychiat.r Genet. 132B(1), 90–95 (2005).

36

Rybakowski JK, Borkowska A, Skibinska M et al. Illness-specific association of val66met BDNF polymorphism with performance on Wisconsin Card Sorting Test in bipolar mood disorder. Mol. Psychiatry 11(2), 122–124 (2006).

37

Moreira L, Neves FS, Romano-Silva MA et al. BDNF and episodic memory in patients with bipolar disorder. Rev. Bras. Psiquiatr. 33(1), 96–97 (2011).

38

Gruber O, Hasan A, Scherk H et al. Association of the brain-derived neurotrophic factor val66met polymorphism with magnetic resonance spectroscopic markers in the human hippocampus: in vivo evidence for effects on the glutamate system. Eur. Arch. Psychiatry Clin. Neurosci. 262(1), 23–31 (2012).

39

Tramontina JF, Yates D, Magalhaes PVD et al. Brain-derived neurotrophic factor gene val66met polymorphism and executive functioning in patients with bipolar disorder. Rev. Bras. Psiquiatr. 31(2), 136–140 (2009).

40

Fan J, Sklar P. Genetics of bipolar disorder: focus on BDNF Val66Met polymorphism. Novartis Foundation symposium 289, 60–72 (2008).

Zeni CP, Tramontina S, Zeni TA et al. The Val66Met polymorphism at the BDNF gene does not influence Wisconsin Card Sorting Test results in children and adolescents with bipolar disorder. Rev. Bras. Psiquiatr. 35(1), 44–50 (2013).

41

Min HJ, Cho HS, Kim SJ et al. Association of the brain-derived neurotrophic factor gene and clinical features of bipolar disorder in Korea. Clin. Psychopharmacol. Neurosci. 10(3), 163–167 (2012).

Joseph MF, Frazier TW, Youngstrom EA et al. A quantitative and qualitative review of neurocognitive performance in pediatric bipolar disorder. J. Child Adolesc. Psychopharmacol. 18(6), 595–605 (2008).

42

Vo¨hringer PA, Barroilhet SA, Amerio A et al. Cognitive impairment in bipolar disorder and schizophrenia: a systematic review. Front. Psychiatry 4, 87 (2013).

43

Gao K, Wang Z, Chen J et al. Should an assessment of Axis I comorbidity be included in the initial diagnostic assessment of mood disorders? Role of QIDS-16-SR total score in predicting number of Axis I

24

Neves-Pereira M, Cheung J, Pasdar A et al. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol. Psychiatry 10(2), 208–212 (2005).

25

Oswald P, Del-Favero J, Massat I et al. Non-replication of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: A Belgian patient-control study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 129B(1), 34–35 (2004).

26

Skibinska M, Hauser J, Czerski PM et al. Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder. World J. Biol. Psychiatry 5(4), 215–220 (2004).

27

Craddock N, Forty L. Genetics of affective (mood) disorders. Eur. J. Hum. Genet. 14(6), 660–668 (2006).

28

Green EK, Raybould R, MacGregor S et al. Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder - Case-control study of over 3000 individuals from the UK. Br. J. Psychiatry 188, 21–25 (2006).

•

A large case-controlled genetic assoicatiion study of BDNF gene in bipolar disorder found BDNF was associated with rapid cycling course, but no bipolar disorder overall.

29

30

31

32

33

and bipolar disorder with early age of onset in mainland China. Neurosci.Lett. 433(2), 98–102 (2008).

Ye CY, Xu YQ, Hu H et al. [An association study of brain-derived neurotrophic factor gene polymorphism in bipolar disorders]. Zhonghua yi xue za zhi 89(27), 1897–1901 (2009).

Rybakowski JK, Borkowska A, Czerski PM et al. Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. Bipolar Disord. 5(6), 468–472 (2003). Tang J, Xiao L, Shu C et al. Association of the brain-derived neurotrophic factor gene

Expert Rev. Neurother. 14(1), (2014)


comorbidity. J. Affect. Disord. 148(2–3), 256–264 (2013). 44


45

46

47

48

49

50

51

Neves FS, Malloy-Diniz L, Romano-Silva MA et al. The role of BDNF genetic polymorphisms in bipolar disorder with psychiatric comorbidities. J. Affect. Disord. 131(1–3), 307–311 (2011). Koppel I, Aid-Pavlidis T, Jaanson K et al. Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice. BMC Neurosci. 10, 68 (2009).

in bipolar disorder: a systematic review. Bipolar Disord. 14(7), 684–696 (2012). •

A good review on gene expression in bipolar disorder.

55

Chepenik LG, Fredericks C, Papademetris X et al. Effects of the brain-derived neurotrophic growth factor Val66Met variation on hippocampus morphology in bipolar disorder. Neuropsychopharmacology 34(4), 944–951 (2009).

56

Pandey GN, Dwivedi Y. Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects. Prog. Neuropsychopharmacol Biol. Psychiatry 34(6), 1161–1161 (2010). Pandey GN, Rizavi HS, Dwivedi Y et al. Brain-derived neurotrophic factor gene expression in pediatric bipolar disorder: effects of treatment and clinical response. J. Am. Acad. Child Adolesc. Psychiatry 47(9), 1077–1085 (2008). D’Addario C, Dell’Osso B, Palazzo MC et al. Selective DNA Methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology 37(7), 1647–1655 (2012).

57

58

Matsuo K, Walss-Bass C, Nery FG et al. Neuronal correlates of brain-derived neurotrophic factor Val66Met polymorphism and morphometric abnormalities in bipolar disorder. Neuropsychopharmacology 34(8), 1904–1913 (2009). Frodl T, Schuele C, Schmitt G et al. Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch. Gen. Psychiatry 64(4), 410–416 (2007). Montag C, Weber B, Fliessbach K et al. The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: incremental support for a genetic risk factor for depression. Psychol. Med. 39(11), 1831–1839 (2009).

Dunham JS, Deakin JFW, Miyajima F et al. Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains. J. Psychiatr. Res. 43(14), 1175–1184 (2009).

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Pillai A. Decreased expression of sprouty2 in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder: A positive correlation with BDNF expression. Biol. Psychiatry 63(7), 107s (2008).

This study provides evidence that Met allele of BDNF Val66Met polymorphism is associated with smaller brain volume in different brain regions even in healthy subjects.

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Teh CA, Lee TS, Kuchibhatla M et al. Bipolar disorder, brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and brain morphology. PloS ONE 7(7), e38469 (2012).

Thompson Ray M, Weickert CS, Wyatt E et al. Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. J. Psychiatry Neurosci. 36(3), 195–203 (2011).

52

Soontornniyomkij B, Everall IP, Chana G et al. Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder. J. Affect. Disord. 133(3), 646–654 (2011).

53

De Luca V, Strauss J, Semeralul M et al. Analysis of BDNF Val66Met allele-specific mRNA levels in bipolar disorder. Neurosci. Lett. 441(2), 229–232 (2008).

54

Munkholm K, Vinberg M, Berk M et al. State-related alterations of gene expression


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Selvaraj S, Arnone D, Job D et al. Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies. Bipolar Disord. 14(2), 135–145 (2012). Hafeman DM, Chang KD, Garrett AS et al. Effects of medication on neuroimaging findings in bipolar disorder: an updated review. Bipolar Disord. 14(4), 375–410 (2012). Mirakhur A, Moorhead TW, Stanfield AC et al. Changes in gyrification over 4 years in bipolar disorder and their association with the brain-derived neurotrophic factor valine (66) methionine variant. Biol. Psychiatry 66(3), 293–297 (2009). McIntosh AM, Moorhead TW, McKirdy J et al. Temporal grey matter reductions in

Review

bipolar disorder are associated with the BDNF Val66Met polymorphism. Mol. Psychiatry 12(10), 902–903 (2007). 64

Frey BN, Walss-Bass C, Stanley JA et al. Brain-derived neurotrophic factor val66met polymorphism affects prefrontal energy metabolism in bipolar disorder. Neuroreport 18(15), 1567–1570 (2007).

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Gallinat J, Schubert F, Bruhl R et al. Met carriers of BDNF Val66Met genotype show increased N-acetylaspartate concentration in the anterior cingulate cortex. Neuroimage 49(1), 767–771 (2010).

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Tsai SJ. Is mania caused by overactivity of central brain-derived neurotrophic factor? Med. Hypotheses 62(1), 19–22 (2004).

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Machado-Vieira R, Dietrich MO, Leke R et al. Decreased plasma brain derived neurotrophic factor levels in unmedicated bipolar patients during manic episode. Biol. Psychiatry 61(2), 142–144 (2007).

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de Oliveira GS, Cereser KM, Fernandes BS et al. Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients. J. Psychiatr. Res. 43(14), 1171–1174 (2009).

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Cunha AB, Frey BN, Andreazza AC et al. Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci. Lett. 398(3), 215–219 (2006).

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Fernandes BS, Gama CS, Kauer-Sant’ Anna M et al. Serum brain-derived neurotrophic factor in bipolar and unipolar depression: a potential adjunctive tool for differential diagnosis. J. Psychiatr. Res. 43(15), 1200–1204 (2009).

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Chou YH, Wang SJ, Lirng JF et al. Impaired cognition in bipolar I disorder: the roles of the serotonin transporter and brain-derived neurotrophic factor. J. Affect. Disord. 143(1–3), 131–137 (2012).

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Dias VV, Brissos S, Frey BN et al. Cognitive function and serum levels of brain-derived neurotrophic factor in patients with bipolar disorder. Bipolar Disord. 11(6), 663–671 (2009).

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Huang TL, Hung YY, Lee CT et al. Serum protein levels of brain-derived neurotrophic factor and tropomyosin-related kinase B in bipolar disorder: effects of mood stabilizers. Neuropsychobiology 65(2), 65–69 (2012).

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Monteleone P, Serritella C, Martiadis V et al. Decreased levels of serum brain-derived neurotrophic factor in both depressed and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders. Bipolar Disord. 10(1), 95–100 (2008).

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Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: An historical overview and future directions. Psychiatry Clin. Neurosci. 64(4), 341–357 (2010).

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Barbosa IG, Huguet RB, Mendonca VA et al. Increased plasma levels of brain-derived neurotrophic factor in patients with long-term bipolar disorder. Neurosci. Lett. 475(2), 95–98 (2010).

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Barbosa IG, Rocha NP, Huguet RB et al. Executive dysfunction in euthymic bipolar disorder patients and its association with plasma biomarkers. J. Affect. Disord. 137(1–3), 151–155 (2012).

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Barbosa IG, Rocha NP, de Miranda AS et al. Increased BDNF levels in long-term bipolar disorder patients. Rev. Bras. Psiquiatr. 35(1), 67–69 (2013).

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Lin PY. State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study. Neurosci. Lett. 466(3), 139–143 (2009).

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Fernandes BS, Gama CS, Cereser KM et al. Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J. Psychiatr. Res. 45(8), 995–1004 (2011).

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Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int. J. Neuropsychophamcol. 13(5), 617–622 (2010).

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Suwalska A, Sobieska M, Rybakowski JK. Serum brain-derived neurotrophic factor in euthymic bipolar patients on prophylactic lithium therapy. Neuropsychobiology 62(4), 229–234 (2010).

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Tramontina JF, Andreazza AC, Kauer-Sant’ Anna M et al. Brain-derived neurotrophic factor serum levels before and after treatment for acute mania. Neurosci. Lett. 452(2), 111–113 (2009).

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de Sousa RT, van de Bilt MT, Diniz BS et al. Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: a preliminary 4-week study. Neurosci. Lett. 494(1), 54–56 (2011).

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Tseng M, Alda M, Xu L et al. BDNF protein levels are decreased in transformed lymphoblasts from lithium-responsive patients with bipolar disorder. J. Psychiatry Neurosci. 33(5), 449–453 (2008). Yoshimura R,Nakano Y, Hori H et al. Effect of risperidone on plasma catecholamine metabolites and brain-derived neurotrophic factor in patients with bipolar

disorders. Hum. Psychopharmacol. 21(7), 433–438 (2006). 87

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Grande I, Kapczinski F, Stertz L et al. Peripheral brain-derived neurotrophic factor changes along treatment with extended release quetiapine during acute mood episodes: An open-label trial in drug-free patients with bipolar disorder. J. Psychiatr. Res. 46(11), 1511–1514 (2012). Yoshimura R, Ikenouchi-Sugita A, Hori H et al. Adding a low dose atypical antipsychotic drug to an antidepressant induced a rapid increase of plasma brain-derived neurotrophic factor levels in patients with treatment-resistant depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 34(2), 308–312 (2010).

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Fernandes B, Gama CS, Massuda R et al. Serum brain-derived neurotrophic factor (BDNF) is not associated with response to electroconvulsive therapy (ECT): a pilot study in drug resistant depressed patients. Neurosci. Lett. 453(3), 195–198 (2009).

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D’Sa C, Dileone RJ, Anderson GM et al. Serum and plasma brain-derived neurotrophic factor (BDNF) in abstinent alcoholics and social drinkers. Alcohol 46(3), 253–259 (2012).

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Vinberg M, Trajkovska V, Bennike B et al. The BDNF Val66Met polymorphism: relation to familiar risk of affective disorder, BDNF levels and salivary cortisol. Bipolar Disord. 11, 12–13 (2009).

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This study prevides preliminary data supporting that a genetic variant alone may not confer an increased risk for a mood disorder, but the interactions with other risk variants and/or the environment may be the key for developing a mood disorder.

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Hosang GM, Uher R, Keers R et al. Stressful life events and the brain-derived neurotrophic factor gene in bipolar disorder. J. Affect. Disord. 125(1–3), 345–349 (2010).

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A good example of the impact of the gene and eviroment interaction on the severity of depression in bipolar disorder.

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Schule C, Zill P, Baghai TC et al. Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients. Psychoneuroendocrinology 31(8), 1019–1025 (2006).

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Miller S, Hallmayer J, Wang PW et al. Brain-derived neurotrophic factor val66met genotype and early life stress effects upon bipolar course. J. Psychiatr. Res. 47(2), 252–258 (2013). Chen J, Fang Y, Kemp DE et al. Switching to Hypomania and Mania: Differential

Neurochemical, Neuropsychological, and Pharmacologic Triggers and Their Mechanisms. Curr. Psychiatry Rep. 12(6), 512–521 (2010). 96

Wu R, Gao K, Calabrese JR et al. Treatment Induced Mood Instability: Treatment – Emergent Affective Switches and Cycle Acceleration. In: Bipolar Disorder: Millennium Update. Yildiz A, Nemeroff C, Ruiz P (Eds), Oxford University Press, New York, USA, in press

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Vincze I, Perroud N, Buresi C et al. Association between brain-derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter gene. Bipolar Disord.10(5), 580–587 (2008).

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Lee S-Y, Chen S-L, Wang Y-S et al. COMT and BDNF interacted in bipolar II disorder not comorbid with anxiety disorder. Behav. Brain Res. 237(0), 243–248 (2013).

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Data from this study suggest that interactions between neurotrophins such as BDNF and monoamine system may be required to differentiate subgroups of patients with bipolar disorders.

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Huang CC, Chang YH, Lee SY et al. The interaction between BDNF and DRD2 in bipolar II disorder but not in bipolar I disorder. Am. J Med. Genet. B Neuropsychiatr. Genet. 2159B(5), 501–507 (2012).

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Lee SY, Lu RB. Interaction of the DRD3 and BDNF gene variants in subtype bipolar disorder. Bipolar Disord. 14, 96–96 (2012).

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Goldstein BI, Kemp DE, Soczynska JK et al. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J. Clin. Psychiatry 70(8), 1078–1090 (2009).

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Su SC, Sun MT, Wen MJ et al. Brain-derived neurotrophic factor, adiponectin, and proinflammatory markers in various subtypes of depression in young men. Int. J. Psychiatry Med. 42(3), 211–226 (2011).

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Goldstein BI, Collinger KA, Lotrich F et al. Preliminary findings regarding proinflammatory markers and brain-derived neurotrophic factor among adolescents with bipolar spectrum disorders. J. Child Adolesc. Psychopharmacol. 21(5), 479–484 (2011).

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Kauer-Sant’Anna M, Kapczinski F, Andreazza AC et al. Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage

Expert Rev. Neurother. 14(1), (2014)


bipolar disorder. Int. J. Neuropsychopharmacol. 12(4), 447–458 (2009). 105


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Dmitrzak-Weglarz M, Rybakowski JK, Suwalska A et al. Association studies of the BDNF and the NTRK2 gene polymorphisms with prophylactic lithium response in bipolar patients. Pharmacogenomics 9(11), 1595–1603 (2008). Masui T, Hashimoto R, Kusumi I et al. Lithium response and Val66Met polymorphism of the brain-derived neurotrophic factor gene in Japanese patients with bipolar disorder. Psychiatr. Genet. 16(2), 49–50 (2006).

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Michelon L, Meira-Lima I, Cordeiro Q et al. Association study of the INPP1, 5HTT, BDNF, AP-2beta and GSK-3beta GENE variants and restrospectively scored response to lithium prophylaxis in bipolar disorder. Neurosci. Lett. 403(3), 288–293 (2006).

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Rybakowski JK, Suwalska A, Skibinska M et al. Response to lithium prophylaxis: Interaction between serotonin transporter and BDNF genes. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B(6), 820–823 (2007). This study provide preliminary data supporting that the combination of genetic markers from different systems may be essential for treatment response to a pharmacological agent. Future pharmacogenetic studies should focus on multple genetic markers from didfferent sysmtems in order to find the ‘best’ predictor(s) of treatment response.

A good reveiw of pharmacogenetic studies in bipolar disorder.

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Chiu C-T, Chuang D-M. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol. Ther. 128(2), 281–304 (2010) Machado-Vieira R, Manji HK, Zarate CA. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying


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Feng Y, Vetro A, Kiss E et al. Association of the neurotrophic tyrosine kinase receptor 3 (NTRK3) gene and childhood-onset mood disorders. Am. J. Psychiatry 165(5), 610–616 (2008).

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Tadokoro K, Hashimoto R, Tatsumi M et al. Analysis of enhancer activity of a dinucleotide repeat polymorphism in the neurotrophin-3 gene and its association with bipolar disorder. Neuropsychobiology 50(3), 206–210 (2004).

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Otsuki K, Uchida S, Watanuki T et al. Altered expression of neurotrophic factors in patients with major depression. J. Psychiatr. Res. 42(14), 1145–1153 (2008).

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Walz JC, Andreazza AC, Frey BN et al. Serum neurotrophin-3 is increased during manic and depressive episodes in bipolar disorder. Neurosci. Lett. 415(1), 87–89 (2007).

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This study showed the unsepcific effect of lithium on gene expression, which may cause difficulty of finding sepecfic genetic marker(s) for lithium response.

Fernandes BS, Gama CS, Walz JC et al. Increased neurotrophin-3 in drug-free subjects with bipolar disorder during manic and depressive episodes. J. Psychiatr. Res. 44(9), 561–565 (2010).

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Li N, He X, Qi X et al. The mood stabilizer lamotrigine produces antidepressant behavioral effects in rats: role of brain-derived neurotrophic factor. J. Psychopharmacol. 24(12), 1772–1778 (2010).

Secolin R, Banzato CE, Mella LF et al. Refinement of chromosome 3p22.3 region and identification of a susceptibility gene for bipolar affective disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B(2), 163–168 (2013).

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Barbosa IG, Huguet RB, Neves FS et al. Impaired nerve growth factor homeostasis in patients with bipolar disorder. World J. Biol. Psychiatry 12(3), 228–232 (2011).

128

Walz JC, Magalhaes PV, Giglio LM et al. Increased serum neurotrophin-4/5 levels in bipolar disorder. J. Psychiatr. Res. 43(7), 721–723 (2009).

129

Petryshen TL, Sabeti PC, Aldinger KA et al. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol. Psychiatry 15(8), 810–815 (2010).

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Nugent AC, Diazgranados N, Carlson PJ et al. Neural correlates of rapid antidepressant response to ketamine in bipolar disorder. Bipolar Disord. doi:10.1111/bdi.12118 (2013) (Epub ahead of print).

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Nugent AC, Carlson PJ, Bain EE, et al. Mood stabilizer treatment increases serotonin type 1A receptor binding in bipolar depression. J. Psychopharmacol. 27(10), 894–902 (2013).

Gupta A, Schulze TG, Nagarajan V et al. Interaction networks of lithium and valproate molecular targets reveal a striking enrichment of apoptosis functional clusters and neurotrophin signaling. Pharmacogenomics J. 12(4), 328–341 (2012).

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A good review on molecular targets of lithium and valproate.

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Malhi GS, Tanious M, Das P et al. Potential mechanisms of action of lithium in bipolar disorder current understanding. CNS Drugs 27(2), 135–153 (2013).

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McQuillin A, Rizig M, Gurling HM. A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder. Pharmacogenet. Genomics 17(8), 605–617 (2007).

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Severino G, Squassina A, Costa M et al. Pharmacogenomics of bipolar disorder. Pharmacogenomics 14(6), 655–674 (2013).

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Rybakowski JK, Suwalska A, Skibinska M et al. Prophylactic lithium response and polymorphism of the brain-derived neurotrophic factor gene. Pharmacopsychiatry 38(4), 166–170 (2005).

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hypothesis. Bipolar Disord. 11, 92–109 (2009).

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Review

Li N, He X, Zhang Y et al. Brain-derived neurotrophic factor signalling mediates antidepressant effects of lamotrigine. Int. J. Neuropsychopharmacol. 14(8), 1091–1098 (2011). Hammonds MD, Shim SS. Effects of 4-week treatment with lithium and olanzapine on levels of brain-derived neurotrophic factor, B-cell CLL/lymphoma 2 and phosphorylated cyclic adenosine monophosphate response element-binding protein in the sub-regions of the hippocampus. Basic Clin. Pharmacol. Toxicol. 105(2), 113–119 (2009). Zai G, Mundo E, Strauss J et al. Brain-derived neurotrophic factor (BDNF) gene not associated with antidepressant-induced mania. Bipolar Disord. 9(5), 521–525 (2007). de Aguiar Ferreira A, Neves FS, Pimenta GJ et al. The role of genetic variation of BDNF gene in antidepressant-induced mania in bipolar disorder. Psychiatry Res. 180(1), 54–56 (2010).

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The role of neurotrophins in bipolar disorder.

The relationship between borderline personality disorder and bipolar disorder.

The relationship between bipolar disorder and biological rhythms.

The Relationship between Cognitive Decline and Psychopathology in Patients with Schizophrenia and Bipolar Disorder.

The relationship between affective state and the rhythmicity of activity in bipolar disorder.

The serotonin transporter genotype modulates the relationship between early stress and adult suicidality in bipolar disorder.

Relationship between personality disorder functioning styles and the emotional states in bipolar I and II disorders.

The Relationship between Impulsivity and Quality of Life in Euthymic Patients with Bipolar Disorder.

Correction: the relationship between bipolar disorder and cannabis use in daily life: an experience sampling study.

The relationship between self-reported borderline personality features and prospective illness course in bipolar disorder.

The relationship between interleukin-1 receptor antagonist and cognitive function in older adults with bipolar disorder.

Genetic relationships between schizophrenia, bipolar disorder, and schizoaffective disorder.

The Relationship Between Educational Years and Phonemic Verbal Fluency (PVF) and Semantic Verbal Fluency (SVF) Tasks in Spanish Patients Diagnosed With Schizophrenia, Bipolar Disorder, and Psychotic Bipolar Disorder.

Relationship between adjunctive medications for anxiety and time spent ill in patients with bipolar disorder.

Longitudinal associations between interpersonal relationship functioning and mood episode severity in youth with bipolar disorder.

Relationship between affective temperaments and aggression in euthymic patients with bipolar mood disorder and major depressive disorder.

Comparing clinical responses and the biomarkers of BDNF and cytokines between subthreshold bipolar disorder and bipolar II disorder.

Verbal memory as a mediator in the relationship between subthreshold depressive symptoms and functional outcome in bipolar disorder.

Screening for bipolar disorder: confusion between case-finding and screening.

Association between GSK3β gene and increased impulsivity in bipolar disorder.

Lurasidone and bipolar disorder.

The relationship between social class and mental disorder.

Bipolar disorder.

hyperactivity disorder.