BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity.

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF(Val/Val)) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF(Met/Met)). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF(Met/Met) mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF(Met/Met) mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.

Phenotypic differences between pregnancy-onset and postpartum-onset major depressive disorder.

OBJECTIVE: To compare clinical features of major depression that begins during pregnancy to clinical features of postpartum-onset depression. The hormonal environments of pregnancy and postpartum periods are quite different and therefore may promote distinct subtypes of major depression. METHOD: Data were collected from medical records of 229 women who were evaluated in an academic medical center reproductive psychiatry clinic. All patients evaluated between 2005 and 2010 who were pregnant or in the first year postpartum and received a DSM-IV diagnosis of major depressive disorder were included. Comparisons between the pregnancy-onset and postpartum-onset subjects included demographics, psychiatric diagnostic history, psychosocial stressors, reproductive history, and current episode symptoms. Time of onset within trimesters of pregnancy and within the postpartum year as well as the effects of discontinuation of antidepressant medication were also examined. RESULTS: Women with major depressive episodes that began during pregnancy had higher rates of prior episodes of postpartum and nonperinatal major depression (both P values < .001). Major depression that began during pregnancy was also more commonly associated with psychosocial stressors. Obsessive-compulsive symptoms and psychotic symptoms were more common in postpartum-onset depression. These findings were also evident in the subgroup of 176 subjects who did not discontinue antidepressant medication during the year prior to development of perinatal depression. The onset of 94% of postpartum major depressive episodes occured within the first 4 months postpartum. Episodes of major depression during pregnancy were more likely to develop in the first trimester for women who discontinued antidepressant medication within the past year; otherwise, depression onset was more evenly distributed across trimesters. CONCLUSIONS: Women with a history of perinatal and nonperinatal major depression are more likely to relapse during pregnancy than postpartum, a finding that points to the need for closely monitoring these women for depression during pregnancy. In addition, these findings of differences in risk factors and clinical features suggest that postpartum-onset major depression may have a pathophysiology distinct from major depression that begins during pregnancy. Time of onset of perinatal depression should be considered in the design of genetic and treatment studies.