Pharmacogenetics and Pharmacotherapy of Military Personnel Suffering from Post-traumatic Stress Disorder

Abstract

Background: Posttraumatic stress disorder (PTSD) is a severe problem among soldiers with combating experience difficult to treat. The pathogenesis is still not fully understood at the psychological level. Therefore, genetic research became a focus of interest. The identification of single nucleotide polymorphisms (SNPs) may help to predict, which persons are at high risk to develop PTSD as a starting point to develop novel targeted drugs for treatment.

Methods: We conducted a systematic review on SNPs in genes related to PTSD pathology and development of targeted pharmacological treatment options based on PubMed database searches. We focused on clinical trials with military personnel.

Results: SNPs in 22 human genes have been linked to PTSD. These genes encode proteins acting as neurotransmitters and receptors, downstream signal transducers and metabolizing enzymes. Pharmacological inhibitors may serve as drug candidates for PTSD treatment, e.g. β2 adrenoreceptor antagonists, dopamine antagonists, partial dopamine D2 receptor agonists, dopamine β hydroxylase inhibitors, fatty acid amid hydrolase antagonists, glucocorticoid receptor agonists, tropomyosin receptor kinase B agonists, selective serotonin reuptake inhibitors, catechol-O-methyltransferase inhibitors, gamma-amino butyric acid receptor agonists, glutamate receptor inhibitors, monoaminoxidase B inhibitors, N-methyl-d-aspartate receptor antagonists.

Conclusion: The combination of genetic and pharmacological research may lead to novel targetbased drug developments with improved specificity and efficacy to treat PTSD. Specific SNPs may be identified as reliable biomarkers to assess individual disease risk. Focusing on soldiers suffering from PTSD will not only help to improve treatment options for this specific group, but for all PTSD patients and the general population.

Keywords: DNA; gene-environment interactions; genetics; mental diseases; pharmacology; single nucleotide polymorphisms.

Fig. (1)

(a) Localization of hippocampus in brain, (b) two hippocampal synapses, c) pharmacological targets and signaling cascades contributing to PTSD vulnerability.

Fig. (2)

Schematic representation of the BDNF gene with exons (black 1-2) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (3)

Inverted U-shaped kinetics of dopamine function. Relation between Val¹⁵⁸Met genotype, dopamine level and function of the prefrontal cortex [73].

Fig. (4)

Schematic representation of the COMT gene [80] with exons (black 1-6) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (5)

Schematic representation of the DRD2 gene [85] with exons (black 1-7) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases

Fig. (6)

Schematic representation of the DRD3 gene with exons (black 1-8) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (7)

Schematic representation of the SLC6A4 gene [37] with exons (black 1-15) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel.

Fig. (8)

Schematic representation of the NR3C1 gene with exons (black 1-9) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (9)

Schematic representation of the CRHR2 gene with exons (black 1-13) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (10)

Schematic representation of the ADCY8 gene with exons (black 1-17) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (11)

Schematic representation of the ADRB2 gene with exon (black) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases, UTR Untranslated region.

Fig. (12)

Schematic representation of the ANK3 gene with exons (black 1-44) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (13)

Schematic representation of the APOE gene with exons (black 1-4) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (14)

Schematic representation of the DBH gene with exons (black 1-12) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. *Association with PTSD in general, #Association with PTSD among military personnel, $Association with other diseases.

Fig. (15)

Schematic representation of the DPP6 gene with exons (black 1-27) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (16)

Schematic representation of the SLC1A1 gene with exons (black 1-12) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (17)

Schematic representation of the FAAH gene with exons (black 1-15) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (18)

Schematic representation of the FKBP5 gene with exons (black 1-12) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (19)

Schematic representation of the GABRB3 gene with exons (black 1-9) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (20)

Schematic representation of the MAOB gene with exons (black 1-15) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (21)

Schematic representation of the NOS1AP gene with exons (black 1-10) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (22)

Schematic representation of the PRKCA gene with exons (black 1-9) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases, UTR Untranslated region.

Fig. (23)

Schematic representation of the PRTFDC1 gene with exons (black 1-9) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases.

Fig. (24)

Schematic representation of the RORA gene with exons (black 1-11) and introns (grey). Localization of representative SNPs in the gene is marked with bolts. * Association with PTSD in general, # Association with PTSD among military personnel, $ Association with other diseases, UTR Untranslated region.