two genetic variants continued to be significant factors in the ANCOVA analysis, which included age and education as covariates. The model also remained significant in a follow-up analysis in which participants who identified as AfricanAmerican (N515) were excluded. Carriers of the 5HTTLPR-S’ allele had increased PTSD symptoms compared to individuals homozygous for the L’ allele (IES mean score: L’L’547.3 6 5.3, S559.8 6 4.1). For DISC1, individuals homozygous for the T allele had increased PTSD symptoms compared to A carriers (A545.3 6 2.8, TT561.9 6 7.2). In ANCOVA analysis of symptom sub-factors, 5-HTTLPR and DISC1 selectively influenced intrusion and hypervigilance symptoms, but did not affect avoidance symptoms. PTSD symptom severity (total IES scores) increased by an average of 40% with each risk genotype (none538.4, one5 54.5, two565.6). These data support prior observations of 5-HTTLPR effects on PTSD symptoms in military veterans1,2. Although 5-HTTLPR has been identified as a potential contributor to PTSD susceptibility in civilian-based populations, its effect may be less robust in those populations, due to lower overall level of trauma exposure3. The effects of 5-HTTLPR on PTSD in military veterans after deployment to a war zone may be more robust because of a universal and constant exposure to threat, military training, and/or separation from family and home social support. In addition to 5-HTTLPR, genetic variation in DISC1, a gene associated with susceptibility to multiple mental disorders, was found to contribute to PTSD symptom severity. Possessing both DISC1 and 5-HTTLPR risk genotypes resulted in a 1.7fold increase in PTSD symptoms. Although this is the first report of DISC1 S704C TT allele as a risk factor for PTSD, the finding is not surprising, considering that this allele has been identified as a risk factor for major depression4. DISC1 variants interfere with a protein complex important for organelle transport and in tethering of mitochondria, interfering with dendritic development and reducing densities of dendritic spines in the frontal cortex, paralleling our recent report of spine density reductions in the frontal cortex in PTSD5-7.
This study was powered to screen for candidate genes with relatively large effect sizes on PTSD symptoms in combat veterans, which may be different from sets of genes affecting PTSD in civilian populations. Study of the serotonin system in PTSD is motivated in large part by the therapeutic utility of serotonin uptake inhibitors to treat symptoms of PTSD. Our data provide additional impetus for continued study of this system in PTSD pharmacotherapy. In addition, antipsychotics such as risperidone have been shown to reverse DISC1-related behavioral deficits and pathophysiology in animal models, suggesting the possibility that such agents could be re-examined for use as alternative pharmacotherapies for PTSD8,9. Keith A. Young1-3, Sandra B. Morissette4, Robert Jamroz1, Eric C. Meyer1-3, Matthew S. Stanford5, Li Wan3, Nathan A. Kimbrel6-8 1
Central Texas Veterans Health Care System, Temple, TX, USA; 2Department of Veterans Affairs VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, USA; 3Department of Psychiatry and Behavioral Science, Texas A&M Health Science Center, Temple, TX, USA; 4University of Texas at San Antonio, San Antonio, TX, USA; 5Hope and Healing Center & Institute, Houston, TX, USA; 6Durham Veterans Affairs Medical Center, Durham, NC, USA; 7VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center, Durham, NC, USA; 8Duke University Medical Center, Durham, NC, USA This work was supported with resources and use of facilities at the Central Texas Veterans Health Care System, Temple, TX. The views expressed here are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs (VA) or the US government. N.A. Kimbrel was supported by a Career Development Award (IK2 CX000525) from the Clinical Science Research and Development Service of the VA Office of Research and Development. S.B. Morissette was supported by a Merit Award (RX00030404A1) from the VA Rehabilitation, Research and Development section. 1. 2. 3. 4. 5. 6. 7. 8. 9.
Telch MJ, Beevers CG, Rosenfield D et al. World Psychiatry 2015;14:198-206. Kimbrel NA, Morissette SB, Meyer EC et al. Anxiety Stress Coping 2014;14: 1-24. Gressier F, Calati R, Balestri M et al. J Trauma Stress 2013;26:645-53. Hashimoto R, Numakawa T, Ohnishi T et al. Hum Mol Genet 2006;15: 3024-33. Norkett R, Modi S, Birsa N et al. Biol Chem 2016;291:613-29. Lee FH, Fadel MP, Preston-Maher K et al. J Neurosci 2011;31:3197-206. Young K, Thompson P, Cruz D et al. Neurobiol Stress 2015;2:67-72. Vaisburd S, Shemer Z, Yeheskel A et al. Sci Rep 2015;5:16300. Petty F, Brannan S, Davis L et al. Int Clin Psychopharmacol 2001;16:1-7.
DOI:10.1002/wps.20359
Cardiovascular risk and incidence of depression in young and older adults: evidence from the SUN cohort study Cardiovascular disease (CVD) and depression are two leading causes of disability worldwide1 and frequently co-occur. A higher load of cardiovascular risk factors without the presence of CVD may imply a higher risk of depression. To assess this hypothesis we evaluated the relationship between the predicted absolute cardiovascular risk and the subsequent observed incidence of depression. In a cohort of university graduates, the Seguimiento Universidad de Navarra (SUN) Project2, we followed 16,739 participants (mean age: 38 years), initially free of depression and CVD, up to 14 years (mean follow-up 9 years).
110
Cardiovascular risk was estimated using a logistic regression model in which the incidence of CVD (myocardial infarction, stroke, and death from cardiovascular causes) during followup was the dependent variable, and age (linear and quadratic terms), sex, body mass index (linear and quadratic terms), smoking (never, current, former), type 2 diabetes, hypertension, hypercholesterolemia and hypertriglyceridemia were the independent variables. Once we had obtained the predicted probabilities of CVD (theoretically ranging from 0 to 100%), we categorized these estimated probabilities into sex-specific
World Psychiatry 16:1 - February 2017
quintiles. We assessed incident depression through the selfreport of a medical diagnosis during follow-up. This definition had been previously validated3. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) of depression across sex-specific quintiles of predicted CVD risk. Models were adjusted for age, adherence to the Mediterranean dietary pattern (low/moderate/high), physical activity (quintiles), total energy intake (quintiles), menopause due to natural causes (yes/no), living alone (yes/no), employment status (employed, unemployed, retired), marital status (married or not), and personality traits (competitiveness, relaxation, dependence). Over 151,125 person-years of follow-up, we identified 927 incident cases of depression. A higher predicted cardiovascular risk at baseline was significantly associated with higher risk of depression. Young adult participants (
This study was powered to screen for candidate genes with relatively large effect sizes on PTSD symptoms in combat veterans, which may be different from sets of genes affecting PTSD in civilian populations. Study of the serotonin system in PTSD is motivated in large part by the therapeutic utility of serotonin uptake inhibitors to treat symptoms of PTSD. Our data provide additional impetus for continued study of this system in PTSD pharmacotherapy. In addition, antipsychotics such as risperidone have been shown to reverse DISC1-related behavioral deficits and pathophysiology in animal models, suggesting the possibility that such agents could be re-examined for use as alternative pharmacotherapies for PTSD8,9. Keith A. Young1-3, Sandra B. Morissette4, Robert Jamroz1, Eric C. Meyer1-3, Matthew S. Stanford5, Li Wan3, Nathan A. Kimbrel6-8 1
Central Texas Veterans Health Care System, Temple, TX, USA; 2Department of Veterans Affairs VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, USA; 3Department of Psychiatry and Behavioral Science, Texas A&M Health Science Center, Temple, TX, USA; 4University of Texas at San Antonio, San Antonio, TX, USA; 5Hope and Healing Center & Institute, Houston, TX, USA; 6Durham Veterans Affairs Medical Center, Durham, NC, USA; 7VA Mid-Atlantic Mental Illness Research, Education, and Clinical Center, Durham, NC, USA; 8Duke University Medical Center, Durham, NC, USA This work was supported with resources and use of facilities at the Central Texas Veterans Health Care System, Temple, TX. The views expressed here are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs (VA) or the US government. N.A. Kimbrel was supported by a Career Development Award (IK2 CX000525) from the Clinical Science Research and Development Service of the VA Office of Research and Development. S.B. Morissette was supported by a Merit Award (RX00030404A1) from the VA Rehabilitation, Research and Development section. 1. 2. 3. 4. 5. 6. 7. 8. 9.
Telch MJ, Beevers CG, Rosenfield D et al. World Psychiatry 2015;14:198-206. Kimbrel NA, Morissette SB, Meyer EC et al. Anxiety Stress Coping 2014;14: 1-24. Gressier F, Calati R, Balestri M et al. J Trauma Stress 2013;26:645-53. Hashimoto R, Numakawa T, Ohnishi T et al. Hum Mol Genet 2006;15: 3024-33. Norkett R, Modi S, Birsa N et al. Biol Chem 2016;291:613-29. Lee FH, Fadel MP, Preston-Maher K et al. J Neurosci 2011;31:3197-206. Young K, Thompson P, Cruz D et al. Neurobiol Stress 2015;2:67-72. Vaisburd S, Shemer Z, Yeheskel A et al. Sci Rep 2015;5:16300. Petty F, Brannan S, Davis L et al. Int Clin Psychopharmacol 2001;16:1-7.
DOI:10.1002/wps.20359
Cardiovascular risk and incidence of depression in young and older adults: evidence from the SUN cohort study Cardiovascular disease (CVD) and depression are two leading causes of disability worldwide1 and frequently co-occur. A higher load of cardiovascular risk factors without the presence of CVD may imply a higher risk of depression. To assess this hypothesis we evaluated the relationship between the predicted absolute cardiovascular risk and the subsequent observed incidence of depression. In a cohort of university graduates, the Seguimiento Universidad de Navarra (SUN) Project2, we followed 16,739 participants (mean age: 38 years), initially free of depression and CVD, up to 14 years (mean follow-up 9 years).
110
Cardiovascular risk was estimated using a logistic regression model in which the incidence of CVD (myocardial infarction, stroke, and death from cardiovascular causes) during followup was the dependent variable, and age (linear and quadratic terms), sex, body mass index (linear and quadratic terms), smoking (never, current, former), type 2 diabetes, hypertension, hypercholesterolemia and hypertriglyceridemia were the independent variables. Once we had obtained the predicted probabilities of CVD (theoretically ranging from 0 to 100%), we categorized these estimated probabilities into sex-specific
World Psychiatry 16:1 - February 2017
quintiles. We assessed incident depression through the selfreport of a medical diagnosis during follow-up. This definition had been previously validated3. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) of depression across sex-specific quintiles of predicted CVD risk. Models were adjusted for age, adherence to the Mediterranean dietary pattern (low/moderate/high), physical activity (quintiles), total energy intake (quintiles), menopause due to natural causes (yes/no), living alone (yes/no), employment status (employed, unemployed, retired), marital status (married or not), and personality traits (competitiveness, relaxation, dependence). Over 151,125 person-years of follow-up, we identified 927 incident cases of depression. A higher predicted cardiovascular risk at baseline was significantly associated with higher risk of depression. Young adult participants (
