Changes in Brain-Derived Neurotrophic Factor Following Treatment with Mifepristone in Bipolar Disorder and Schizophrenia
School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, Leazes Wing (Psychiatry), Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK. Australian and New Zealand Journal of Psychiatry
(Impact Factor: 3.41).
05/2007; 41(4):321-6. DOI: 10.1080/00048670701213211
Brain-derived neurotrophic factor (BDNF) is stress-responsive and has been implicated in a number of disparate neuropsychiatric disorders. Glucocorticoid antagonists have been shown to have beneficial effects on mood and cognitive function in bipolar disorder but not in schizophrenia. The aim of the present study was to investigate BDNF levels in patients with bipolar disorder and schizophrenia before and after treatment with the glucocorticoid receptor antagonist mifepristone.
Peripheral BDNF levels were measured in patients with bipolar disorder (n=20), schizophrenia (n=20) and 14 matched healthy controls following 7 days of adjunctive mifepristone (600 mg day(-1)) treatment in a double-blind, placebo-controlled crossover design study.
Baseline BDNF values were similar in both patient groups and in healthy controls. Following treatment with mifepristone, cortisol levels were significantly increased and BDNF levels decreased in both schizophrenia and bipolar disorder. A significant correlation existed between change in cortisol level and change in BDNF levels following mifepristone treatment in schizophrenia, but not in bipolar disorder.
Differing BDNF responses to increasing cortisol levels between patients with schizophrenia and with bipolar disorder may reflect underlying pathophysiological mechanisms.
Available from: Isabelle Esther Bauer
- "A potential explanation for the abnormal HPA axis activity is that pro-inflammatory cytokines disrupt the glucocorticoid function and lead to glucocorticoid resistance, characterized by cortisol and CRF hypersecretion . In turn, glucocorticoid resistance initiates pro-inflammatory mechanisms and reduces peripheral BDNF levels (Pace et al., 2007; Mackin et al., 2007). Both glucocorticoid resistance and inflammation have been associated with depressed mood and cognitive difficulties (Pace et al., 2007). "
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Recent studies have pointed to neuroinflammation, oxidative stress and neurotrophic factors as key mediators in the pathophysiology of mood disorders. Little is however known about the cascade of biological episodes underlying the cognitive deficits observed during the acute and euthymic phases of bipolar disorder (BD). The aim of this review is to assess the potential association between cognitive impairment and biomarkers of inflammation, oxidative stress and neurotrophic activity in BD.
Scopus (all databases), Pubmed and Ovid Medline were systematically searched with no language or year restrictions, up to November 2013, for human studies that collected both inflammatory markers and cognitive data in BD. Selected search terms were bipolar disorder, depression, mania, psychosis, inflammatory, cognitive and neurotrophic.
Ten human studies satisfied the criteria for consideration. The findings showed that high levels of peripheral inflammatory-cytokine, oxidative stress and reduced brain derived neurotrophic factor (BDNF) levels were associated with poor cognitive performance. The BDNF val66met polymorphism is a potential vulnerability factor for cognitive impairment in BD.
Current data provide preliminary evidence of a link between the cognitive decline observed in BD and mechanisms of neuroinflammation and neuroprotection. The identification of BD specific inflammatory markers and polymorphisms in inflammatory response genes may be of assistance for therapeutic intervention.
Available from: Hans Ågren
- "One study also found decreased levels of BDNF during euthymia (Monteleone et al., 2008). However, these findings were not replicated in other reports (Dias et al., 2009; Huang et al., 2012; Kauer-Sant'Anna et al., 2009; Mackin et al., 2007). Meta-analyses (Fernandes et al., 2011; Huang et al., 2012; Lin, 2009) have concluded serum levels of BDNF to be significantly lower in patients with bipolar disorder, and BDNF levels were normalized after recovery from depression (Hashimoto, 2010). "
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Early detection and diagnosis of bipolar disorder can be difficult. Tools are needed to help clinicians detect bipolar disorder earlier, which would ameliorate the prognosis.
ELISA kits that distinguish between mature brain derived neurotrophic factor (BDNF) and proBDNF, we compared serum levels of mature BDNF, proBDNF, and matrix metalloproteinase-9 (MMP-9) in two independent cohorts (Sahlgrenska cohort and Karolinska cohort) of mood-stabilized bipolar patients and healthy controls. The total sample size in both cohorts consisted of 263 (48+215) bipolar patients and 155 (43+112) healthy controls.
Levels of mature BDNF and the ratio mature BDNF/proBDNF were significantly higher in patients than in controls. Serum levels of proBDNF were significantly lower in patients compared to controls. Serum levels of MMP-9 did not differ between the groups but MMP-9 correlated positively and significantly with mature BDNF.
Mature BDNF, proBDNF, the ratio of mature BDNF/proBDNF and interactions with MMP-9 explained the diagnostic dichotomy in both cohorts with high significance, using multivariate logistic ANCOVA (gender, age, and BMI were covaried out). The model explained 41% of the diagnostic variance in the Sahlgrenska cohort (p<0.0001) and 15% in the Karolinska cohort (p<0.0001). In both cohorts, the equations provided good power for diagnostic classification. The diagnostic sensitivity was 89% in the Sahlgrenska and 74% in the Karolinska cohort, and specificity 77% and 64%, respectively.
The study is cross-sectional with no longitudinal follow up. The cohorts are relatively small with no medication-free patients. There are no “ill patient controls”.
Abnormalities in the conversion of proBDNF to mature BDNF may be associated with pathogenesis of bipolar disorder. Clinical use of these biomarkers may provide opportunities for earlier detection and correct treatment.
Available from: Clarissa Severino Gama
- "The major limitation of this study remains the analysis of BDNF changes after treatment for a depressive episode. This analysis was only able to include two studies that had negative results (Mackin et al., 2007; Yoshimura et al., 2006). It must be acknowledged that the pharmacological treatments used in these studies 4, risperidone and mifepristone, are not used to treat bipolar depression, and this may have been responsible for this negative result. "
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) plays a central role in synaptic plasticity and neurogenesis. Bipolar disorder (BD) is among the most disabling of all psychiatric disorders and is associated with poor outcomes. Some studies suggest that BDNF levels decrease during mood states and remain normal during euthymia, but other studies have contradicted this paradigm. Therefore, the aim of this study was to perform a meta-analysis of all studies that measured peripheral BDNF levels in adults with BD. We conducted a systematic review using electronic databases. Inclusion criteria were studies that measured BDNF in plasma or serum in vivo in adult patients with BD. The resulting studies were compiled to measure the effect sizes (ESs) of the differences in BDNF levels between BD patients in different mood states and controls. Thirteen studies were included with a total of 1113 subjects. The BDNF levels were decreased in both mania and depression when compared to controls (ES -0.81, 95% CI -1.11 to -0.52, p < 0.0001 and ES -0.97, 95% CI -1.79 to -0.51, p = 0.02, respectively). The BDNF levels were not different in euthymia when compared to controls (ES -0.20, 95% CI -0.61 to 0.21, p = 0.33). Meta-regression analyses in euthymia showed that age (p < 0.0001) and length of illness (p = 0.04) influenced the variation in ES. There was also an increase in BDNF levels following the treatment for acute mania (ES -0.63, 95% CI -1.11 to -0.15, p = 0.01). In conclusion, BDNF levels are consistently reduced during manic and depressive episodes and recover after treatment for acute mania. In euthymia, BDNF decreases with age and length of illness. These data suggest that peripheral BDNF could be used as a biomarker of mood states and disease progression for BD.
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