Background. Anxiety and mood disorders frequently occur following traumatic brain injury (TBI) and may influence cognitive and behavioral recovery. TBI involves both diffuse brain injury as well as frequent focal injuries to frontal and temporal structures, including the hippocampus and amygdala, areas that are associated with the neurobiology of anxiety. While there are anecdotal reports of response to selective serotonin reuptake inhibitors (SSRIs) in treating anxiety associated with TBI, no controlled trials have been conducted to establish SRSI efficacy in patients with anxiety following brain injury.

My major findings. I have been a co-principal investigator on two projects related to this proposed study: 1. An ancillary genetic study with a clinical effectiveness trial, Sequenced Treatment Alternatives to Relieve Depression (STAR*D), collected DNA from outpatients with non-psychotic major depressive disorder who received citalopram in the first treatment step in the trial. Participants were scored for treatment outcome and side effects. 2. An exploratory genetic study of individuals referred to the Walter Reed Army Medical Center and other collaborating military hospitals underwent a comprehensive TBI evaluation and were genotyped for polymorphisms in candidate genes involved in serotonin, dopamine, and glutamate neurotransmitter pathways. Comparison of mean differences among the genotype groups for several executive functioning measures was conducted. In the STAR*D study, a large population of patients with major depression (n = 4,000) treated with citalopram, we discovered and replicated an association of a reduction-of-function HTTLPR alleles to impaired SSRI treatment response. Furthermore, we found that side effects and treatment tolerability mediated this effect. We also identified a marker in the HTR2A serotonin receptor and a second marker in a glutamate receptor gene, GRIK4, that each predicted citalopram response in the same large patient cohort. In the TBI study, we determined that the e4 allele of the APOE gene (involved in neuronal plastic responses) predicted poorer memory performance while a variant of the naturally occurring Val158Met polymorphism of the catechol-O-methyltranseferase gene (COMT) gene, the Met 158 allele, which encodes an enzyme with reduced activity in metabolizing dopamine and norepinephrine, was associated with better performance on cognitive tests, supporting the idea that COMT Val158Met has a role in executive functioning, especially related to cognitive flexibility.

My aims and future plans. A goal of this study is to identify genetic components of behaviors following TBI. For example, decreased serotonin metabolism has been strongly implicated in controlling different behaviors in humans such as anxiety-related intolerance and impaired impulse control. In addition, because TBI results in the uncontrolled release of neurotransmitters, including glutamate and dopamine, both of these neurotransmitters are neurotoxic at high concentrations. Delineating the molecular mechanism of neurotoxicity acting through glutamate receptors (NMDA, NR1, NR2A-D; AMPA, GluR1-4) and dopamine receptors (D2) may provide sites of pharmacological intervention in protecting neurons from excitotoxic cell death. Envisioned is a randomized placebo controlled clinical trial of TBI patients treated with citalopram (estimated at 200 participants). Participants will be rated for improvement at weeks 3, 6, and 9 for possible dosage adjustment. Candidate genes and markers will be selected based on prior genetic linkage/association findings or neurobiological evidence from animal studies.

Relevance. The study is appropriate because a better understanding of the influence of genetic variation in response to treatment may aide in improving treatment regimens. It is likely that the future of patient care may rely on individualized therapies, where pre-treatment genotyping will be an essential part in the decision-making process to provide appropriate care and management of TBI patients.