Major Depressive Disorder (MDD): Potential Predictors of Vulnerability and Treatment ResponseAlbusaysi, Salwa (2019) Major Depressive Disorder (MDD): Potential Predictors of Vulnerability and Treatment Response. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractMajor Depressive Disorder (MDD): Potential Predictors of Vulnerability and Treatment Response Salwa Albusaysi, PharmD University of Pittsburgh, 2019 Major Depressive Disorder (MDD) is a common and disabling brain disorder affecting millions world-wide. Despite decades of research and advances in drug development, response to antidepressant treatment remains highly variable and less than optimal. Further investigation of the role of biomarkers, genes, pharmacokinetics, pharmacodynamics and neuroimaging are needed to elucidate the underlying pathophysiology of depression. Among the neurobiological hypotheses, the role of pro-inflammatory cytokines, neurotrophic factors and deficiency of monoamines are among the most supported. The research that comprises this dissertation aims to identify potential predictors of depression vulnerability and antidepressant treatment response. The first study investigated the relationship between the BDNF Val66Met polymorphism, serum BDNF levels, and the development of depressive symptoms in a clinical study of 149 patients receiving interferon-alpha (INF-α) therapy for treatment of Chronic Hepatitis C. Here we report an association between lower baseline BDNF levels and higher depressive symptoms during IFN-α treatment. The Met allele was associated with lower BDNF levels and higher suicidal ideation, sadness and worthlessness. In addition, IFN-α therapy further decreased BDNF serum levels. Collectively, these findings support the hypothesis that BDNF improves resiliency against developing a subset of cytokine-associated depressive symptoms. The second study in patients with MDD investigated variability in venlafaxine dose/drug concentrations and treatment response including clinical outcomes and alterations in brain functional connectivity. We observed a correlation between venlafaxine dose and drug concentration at late study time points; lower BMI and age over 65 years was associated with higher drug concentration. Higher concentration at week 1 was associated with low MADRS trajectory and there was a positive correlation between drug concentration and change in MADRS scores at week 12. Path analysis revealed indirect effect of dose on clinical outcomes which was mediated through drug concentration. These findings suggest that the efficacy and safety of venlafaxine treatment of patients with MDD may be optimized through dose titration based on therapeutic drug monitoring. Moreover, patient factors such as age and BMI should be taking into account during venlafaxine dose adjustment in the treatment of MDD. Share
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