The First Steps on the Path Toward Genomic Predictors of Behavioral Therapy for Posttraumatic Stress Disorder

Abstract

Not everyone who has personally experienced, or has been exposed to, severe trauma develops posttraumatic stress disorder (PTSD). The risk-resilience equation is complex and, as we are becoming increasingly aware, includes both genetic predictors and environmental stressors, starting in early childhood. For example, as Binder and colleagues (1) first showed, FKBP5, a gene influencing activity of the hypothalamic-pituitaryadrenal axis, together with exposure to childhood trauma but not adult stressors, predicted the development of PTSD in a lowincome, urban African American sample. There is much to be understood about the etiology of PTSD and equally there is much to be learned about developing new treatment options and improving the rates of response to the current first-line treatment for PTSD: cognitive behavioral therapy (CBT). PTSD is thought to result from impaired fear extinction learning, i.e., the inability to suppress frightening or disturbing memories of a traumatic event (2). A key player in the formation of fear-related memories via the hippocampus, amygdala, and prefrontal cortex is brain-derived neurotrophic factor (BDNF) that, together with its receptor tyrosine kinase receptor B, is an important regulator of neuronal development, function, survival, and synaptic plasticity (2,3). Stress results in BDNF overexpression in the hippocampus, most likely a compensatory mechanism that appears to enhance fear extinction (2). However, some individuals have a compromised BDNF protective response to stress because they are Met allele carriers of the BDNF gene polymorphism Val66Met (rs6265) and have reduced secretion and neuroplastic effects of the BDNF protein (3). Even apparently healthy Met allele carriers have lower hippocampal volumes relative to Val/Val homozygotes (3). Notably, the Met allele has been associated with slower suppression of the learned fear response in mice and humans (4). It is clearly important to understand predictors for the disease for preventive purposes but also to determine treatment options. Are individuals who are more likely to develop PTSD more or less likely to respond to treatment? Can we tailor treatment options to PTSD subgroups based on genotype? We are beginning to make progress in delineating individualized responses to pharmacotherapies for behavioral disorders. For example, FKBP5 gene variation predicts speed of response to antidepressants (5) and the high activity variant of 5-HTTLPR, the promoter polymorphism in SLC6A4, the gene encoding the serotonin transporter, predicts greater responsiveness of PTSD symptoms to sertraline (6). Eventually, successful treatment of most behavioral disorders is