The relationship between neurotrophins and bipolar disorder

Abstract

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

Financial & competing interests disclosure

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