Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

PURPOSE: The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS: Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS: In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Do early responders and treatment non-responders offer guidance to make CPT group a more effective treatment?

BACKGROUND: Treatment dropout has been problematic with evidence-based treatments for posttraumatic stress disorder (PTSD), including cognitive processing therapy (CPT). This study sought to evaluate whether CPT group contributed to symptom improvement among treatment completers and non-completers. METHODS: Sixty-one Iraq and Afghanistan combat Veterans self-selected CPT group or treatment as usual (TAU) forming a convenience sample. Defining treatment completion as attending at least nine sessions: 18 completed treatment, 20 dropped-out (DOs); 20 completed TAU, 3 lost to TAU follow-up. RESULTS: Multiple Regression revealed significant pre-post-treatment improvement, the Clinician-Administered PTSD Scale (CAPS-IV, F(5, 40.1) = 2.53, p = 0.0436). Reviewing DOs' last available PTSD Checklist-Military Version scores before leaving treatment, six achieved clinically significant improvement of >10 points; seven a clinically reliable change of 5-10 points. CONCLUSION: These findings highlight that CPT group may be effective at reducing trauma-related symptoms among treatment completers and dropouts and point to the utility of a clinical definition of good treatment end-state.

Nicotine Inhalation and Suicide: Clinical Correlates and Behavioral Mechanisms.

BACKGROUND AND OBJECTIVES: Extensive evidence links smoking and suicide independently of psychiatric diagnoses, but there are questions about the pathophysiology and specificity of this relationship. We examined characteristics of this linkage to identify potential transdiagnostic mechanisms in suicide and its prevention. METHODS: We reviewed literature that associated suicide with smoking and e-cigarettes, including the temporal sequence of smoking and suicide risk and their shared behavioral risk factors of sensitization and impulsivity. RESULTS: Smoking is associated with increased suicide across psychiatric diagnoses and in the general population, proportionately to the number of cigarettes smoked per day. Rapid nicotine uptake into the brain through inhalation of conventional cigarettes, electronic cigarettes (e-cigarette), or even second-hand smoke can facilitate long-term sensitization and short-term impulsivity. Both impair action regulation and predispose to negative affect, continued smoking, and suicidal behavior. Intermittent hypoxia, induced by cigarettes or e-cigarettes, synergistically promotes impulsivity and sensitization, exacerbating suicidality. Two other shared behavioral risks also develop negative urgency (combined impulsivity and negative affect) and cross-sensitization to stressors or to other addictive stimuli. Finally, early smoking onset, promoted by e-cigarettes in never-smokers, increases subsequent suicide risk. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Prevention or cessation of nicotine inhalation can strategically prevent suicidality and other potentially lethal behavior regardless of psychiatric diagnoses. Medications for reducing smoking and suicidality, especially in younger smokers, should consider the neurobehavioral mechanisms for acute impulsivity and longer-term sensitization, potentially modulated more effectively through glutamate antagonism rather than nicotine substitution. (Am J Addict 2021;30:316-329).

Measurement Properties of the MPAI-4 in Veterans With mTBI.

OBJECTIVES: To determine whether the measurement properties of the Mayo-Portland Adaptability Inventory Version 4 (MPAI-4) and its participation index (M2PI), which have been adopted as 2 outcome measures in the Veterans Health Administration (VHA) National Polytrauma Rehabilitation Systems of Care, are adequate in veterans with mild traumatic brain injury (mTBI). DESIGN: Cross-sectional. SETTING: Outpatient rehabilitation. PARTICIPANTS: Postdeployment veterans with blast-related mTBI (N=177). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Mayo-Portland Adaptability Inventory Version 4 (MPAI-4) and Community Integration Questionnaire (CIQ). RESULTS: The unidimensional factor structure of the MPAI-4 total and 3 index scores (abilities, adjustment, participation) were confirmed. Eight of the 30 items were removed for violating monotonicity (6 items) and exceeding Rasch infit (2 items). The rating scale was collapsed from 5 to 3 ratings because of structure issues. The remaining 22 MPAI-4 items demonstrated excellent item/person reliability (0.98/0.91) and separated person ability into 4 strata. Two of the MPAI-4 index scores (abilities and adjustment) had good measurement properties. The third index, M2PI, retained only 3 items that had adequate person reliability (0.75) but separated person ability into only 2 strata. A significant but fair association with the CIQ was demonstrated with the modified MPAI-4. CONCLUSIONS: The MPAI-4 has been validated in moderate to severe traumatic brain injury but required modification when used in active military personnel with mTBI. We also identified the need for modification of the MPAI-4 to support adequate psychometrics when measuring outcomes in veterans with mTBI. Additional validation of the M2PI is needed in veterans and active military personnel with mTBI, to determine whether the M2PI should continue to be used as an outcome measure in the VHA polytrauma rehabilitation systems.

Psychometric Properties of 2 Participation Measures in Veterans With Mild Traumatic Brain Injury.

OBJECTIVE: To compare the psychometric properties of 2 commonly used participation measures: the Community Reintegration of Service Members (CRIS) and the Participation Assessment with Recombined Tools-Objective (PART-O) in veterans with mild traumatic brain injury (mTBI). DESIGN: Data were collected from 2 cross-sectional observation studies conducted in 2 Veterans Affairs medical centers. SETTING: Questionnaires were completed in-person or by mail. PARTICIPANTS: Veterans with mTBI (N=201) were recruited from the Michael E. DeBakey Veterans Affairs Medical Center in Houston (n=94) and the Malcom Randall North Florida/South Georgia Veterans Health System (n=107). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: CRIS and PART-O. RESULTS: We conducted Rasch analysis on the PART-O and on 3 subscales of the CRIS (extent of participation, perceived limitation, and satisfaction). For PART-O, results showed PART-O has questionable unidimensionality. For both instruments, some rating categories were underused, and rating scales did not advance accordingly. Compared with PART-O, the CRIS was able to distinguish more categories of person's ability (>5 vs 2 for PART-O) and had better internal consistency as indicated by higher Cronbach α (.96-.98 vs .65 for PART-O). CONCLUSIONS: To capture participation unique to veterans with mTBI, CRIS has greater potential to detect a change in participation and is therefore recommended over PART-O. Rating scales of both instruments, however, need further refinement. We suggest future studies examine collapsed rating categories and use qualitative methods to redefine categories.

Factor Structure of the Community Reintegration of Service-Members (CRIS) in Veterans with Blast-Related Mild Traumatic Brain Injury.

Veterans with blast-related mild traumatic brain injury (mTBI) report difficulty engaging in life roles, also referred to as participation. Current measures are either global or lack comprehensive coverage of life roles and have not been validated in Veterans with mTBI. The Community Reintegration of Service-members instrument (CRIS) is a promising measure that was specifically developed for Veterans using a well-formulated conceptual framework and Rasch analysis. However, the CRIS has not been validated in Veterans with mTBI. Two data sets were combined for 191 Veterans with blast-related mTBI to conduct a confirmatory factor analysis of the CRIS. High residual and low loading items (33) were removed to improve the model fit. The remaining items demonstrated high correlation (0.87-0.89) between subscales and high test re-test (0.85 to 0.95). Mean scores were better for Veterans without Post Traumatic Stress Disorder (PTSD) or depression compared to Veterans with PTSD or depression. The refined CRIS offers a valid comprehensive measure of participation for Veterans with blast-related mTBI. Future directions include examining aspects of participation that may not be covered by the CRIS for Veterans with mTBI..

A Systematic Analysis of Treatment Effects on Depressive Symptom Severity by Level of Coercion.

Few studies examine the effect of interpersonal, regulatory or legal coercion on the treatment of depressive symptoms. This retrospective case-control study compared the recovery rates of 574 adults whose level of coercion was scored on a 0-3 scale from fully voluntary to severe coercion when admitted to the Menninger Clinic between 2009 and 2014. The change in Patient Health Questionnaire-9 (PHQ-9) scores (measuring depression severity) from admission to discharge served as the primary outcome measure. Level of coercion was not associated with a difference in rate of improvement in PHQ-9 score. Greater improvement in PHQ-9 scores was associated with (a) older age, (b) lack of a psychotic spectrum disorder diagnosis, (c) stronger working alliance with treatment team, and (d) less difficulty with emotional regulation [lower Difficulties in Emotion Regulation Scale (DERS) scores]. DERS scores were the most impactful factor. This study suggests that licensure boards can continue to mandate treatment despite concerns that coercion may decrease treatment effectiveness.

Association of Chronic Pain and Community Integration of Returning Veterans With and Without Traumatic Brain Injury.

OBJECTIVE: To evaluate the association between community integration and pain in veterans with and without mild blast-related traumatic brain injury (TBI). DESIGN AND PARTICIPANTS: A cross-sectional study of 198 Operation Enduring Freedom/Operation Iraqi Freedom veterans, 135 with mild TBI and 63 without TBI exposure. MAIN MEASURES: Community Integration Questionnaire (CIQ), Community Reintegration of Injured Service Members Instrument, Brief Pain Inventory. RESULTS: Pain interference was significantly associated with CIQ social integration (P = .037), and pain severity was significantly associated with CIQ home integration (P = .038) and CIQ social integration (P = .044). Pain interference and pain severity had a significant interaction as related to the CIQ total score (P = .046), CIQ job score (P = .034), and CIQ productivity score (P = .034). Pain interference (P = .042) and pain severity (P = .015) were associated with community participation, but not perceived limitations (P > .05) or satisfaction (P > .05) as measures by the Community Reintegration of Injured Service Members Instrument. There was a significant interaction between TBI status and pain severity (P = .021) with community participation. CONCLUSIONS: Chronic pain has a negative association with the community integration of returning veterans. Although TBI status was associated with overall community integration ratings, depression had a stronger association with impairments. These findings suggest, above and beyond the treatment of depression, the importance of effectively managing TBI-related pain to foster improved social functioning and to promote the psychological and social well-being of returning veterans.

US Veterans' Court Programs: An Inventory and Analysis of National Survey Data.

This study used data from a phone survey inventory of US veterans' courts to provide descriptive information on the current status of their various elements. To identify which items were most predictive of a court's percentage of subjects terminated from their program, a linear regression was performed. The following were associated with higher rates of termination from the veterans' court (VC) program: (a) programs that offered phase progression based on measurable goals, (b) programs that conduct frequent drug and alcohol testing, and (c) programs for which sanctions are more severe for failing immediate goals (sobriety) versus long-term ones (completion of training). The following were associated with lower rates of termination from the VC program: (a) programs in which later phases permit less stringent testing, (b) programs utilizing behavioral contracts, (c) programs utilizing brief incarcerations. This inventory provides nationwide empirical data that may be used in the development of veterans' courts.

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort.

Importance: Many psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans' health, such as suicide-related behaviors and substance use disorders (SUDs). Objective: To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP). Design, Setting, and Participants: A series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020. Exposures: PGSs for EXT, depression, schizophrenia, and suicide attempt. Main Outcomes and Measures: Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records. Results: Within the MVP (560 824 patients; mean [SD] age, 67.9 [14.3] years; 512 593 male [91.4%]), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio [OR], 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C. Conclusions and Relevance: Results of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population.

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort.

Background: Many psychiatric outcomes are thought to share a common etiological pathway reflecting behavioral disinhibition, generally referred to as externalizing disorders (EXT). Recent genome-wide association studies (GWAS) have demonstrated the overlap between EXT and important aspects of veterans' health, such as suicide-related behaviors, substance use disorders, and other medical conditions. Methods: We conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychiatric problems (depression, schizophrenia, and suicide attempt) in an ancestrally diverse cohort of U.S. veterans (N = 560,824), using diagnostic codes from electronic health records. We conducted ancestry-specific PheWASs of EXT PGS in the European, African, and Hispanic/Latin American ancestries. To determine if associations were driven by risk for other comorbid problems, we performed a conditional PheWAS, covarying for comorbid psychiatric problems (European ancestries only). Lastly, to adjust for unmeasured confounders we performed a within-family analysis of significant associations from the main PheWAS in full-siblings (N = 12,127, European ancestries only). Results: The EXT PGS was associated with 619 outcomes across all bodily systems, of which, 188 were independent of risk for comorbid problems of PGS. Effect sizes ranged from OR = 1.02 (95% CI = 1.01, 1.03) for overweight/obesity to OR = 1.44 (95% CI = 1.42, 1.47) for viral hepatitis C. Of the significant outcomes 73 (11.9%) and 26 (4.5%) were significant in the African and Hispanic/Latin American results, respectively. Within-family analyses uncovered robust associations between EXT and consequences of substance use disorders, including liver disease, chronic airway obstruction, and viral hepatitis C. Conclusion: Our results demonstrate a shared polygenic basis of EXT across populations of diverse ancestries and independent of risk for other psychiatric problems. The strongest associations with EXT were for diagnoses related to substance use disorders and their sequelae. Overall, we highlight the potential negative consequences of EXT for health and functioning in the US veteran population.

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Objective: Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies. Methods: In this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize specific loci. Results: Only 20% of veterans who self-reported SB had a corroborating ICD-9/10 code in their EHR; and among those who denied prior behaviors, more than 20% reported new-onset SB at follow-up. SB were associated with a range of psychiatric and non-psychiatric diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking, suicide attempt, and major depressive disorder were also associated with attempt and ideation. Conclusions: Among individuals with a diagnosed mental illness, a GWAS for SB did not yield any significant loci. Self-reported SB were strongly associated with clinical variables across several EHR domains. Overall, clinical and polygenic analyses point to sequelae of substance-use related behaviors and other psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in clinical settings, underscoring the value of regular screening based on direct, in-person assessments, especially among high-risk individuals.

Pharmacogenetics of Addiction Therapy.

Drug addiction is a serious relapsing disease that has high costs to society and to the individual addicts. Treatment of these addictions is still in its nascency, with only a few examples of successful therapies. Therapeutic response depends upon genetic, biological, social, and environmental components. A role for genetic makeup in the response to treatment has been shown for several addiction pharmacotherapies with response to treatment based on individual genetic makeup. In this chapter, we will discuss the role of genetics in pharmacotherapies, specifically for cocaine, alcohol, and opioid dependences. The continued elucidation of the role of genetics should aid in the development of new treatments and increase the efficacy of existing treatments.

Suicide Risk in a National VA Sample: Roles of Psychiatric Diagnosis, Behavior Regulation, Substance Use, and Smoking.

Background: Most suicides are first attempts that are difficult to predict, possibly reflecting impaired and unstable behavior regulation. We sought to identify characteristics specifically associated with severe suicidal behavior by comparing risk ratios (RRs) for severe suicidal attempts (ATTP) to RRs for suicidal ideation (SI) only in a transdiagnostic sample of Veterans, focusing on impulsive-aggressive or externalizing behavior (EB), substance use disorders (SUDs), and recurrent affective or psychotic disorders (ie, severe mental illness [SMI]).Methods: The VA Information and Computing Infrastructure (VINCI) Data Navigators provided aggregate phenotype counts and relevant ICD and clinic codes from about 350,000 Veterans in the US Department of Veterans Affairs national Million Veterans Program (MVP). Data were collected by MVP between 2011 and 2017, without relationship to the current work. Work on this report and related analyses took place from April 11, 2020, to October 6, 2021.Results: We compared 3 suicide risk groups: 1,269 Veterans with previous ATTP, 109,836 with SI only, and 242,872 without previous suicidality. Nearly three-fourths of ATTP Veterans did not have SMI diagnoses. RR for ATTP behavior was highest in Veterans with EB (25.4), followed by those with SUD (13.9); both RRs were greater than RRs for Veterans with schizophrenia (7.4) or bipolar disorder (7.8). ATTP RR was greater for smoking than for major depressive disorder (5.0 vs 3.5, respectively). RR for smoking, across clinical groups, was strongly related to RR for ATTP risk, but not for SI only.Discussion: ATTP suicidal behavior was more strongly associated with EB and SUD than with SMI. Suicide risk is associated with SUD or EB beyond SMI, so routine clinical encounters in primary care and emergency settings must recognize EB, SUD, and smoking as risks for severe suicidal behavior.

Methylation of the serotonin transporter gene moderates the depressive subjective effect of cocaine.

Genetic variation in the serotonin transporter (SLC6A4) has been shown to moderate the acute subjective effects of cocaine. Methylation of the SLC6A4 gene is associated with decreased transcription of the serotonin transporter, leading to increased serotonin in the synapse. In this study, methylation of the SLC6A4 gene was investigated in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N = 53) were intravenously administered cocaine (40 mg) and saline in a randomized order. The subjective effects of cocaine were self-reported using a visual analog scale starting prior to the administration of cocaine (-15 min) or saline and up to 20 min after infusion. Participants were evaluated for methylation of the SLC6A4 promoter region and 5-HTTLPR genotype. A series of ANCOVAs for SLC6A4 methylation (high/low) were run for each of ten subjective and three cardiovascular effects controlling for age, sex [utilizing the sex-determining region Y protein (SRY)], and population structure (determined from ancestry informative markers and STRUCTURE software). Participants with SLC6A4 hypermethylation reported greater subjective response to cocaine for 'depressed' relative to participants with SLC6A4 hypomethylation (experiment-wise p = 0.002). These findings indicate that SLC6A4 methylation moderates the 'depressed' subjective effect of cocaine in non-treatment-seeking cocaine-dependent participants.

Post-traumatic stress disorder and prediction of aggression in persons with dementia.

OBJECTIVE: This prospective cohort study evaluated the potential of increased aggression in patients with dementia who had a preexisting diagnosis of post-traumatic stress disorder (PTSD) compared with those without a diagnosis of PTSD. METHODS: Patients more than 60 years of age with newly diagnosed dementia between 2001 and 2004 were identified from the Michael E. DeBakey Veterans Affairs (VA) Medical Center in Houston, TX. Among these patients, we identified patients with a preexisting diagnosis of PTSD. The proportions of patients who became aggressive within 2 years of enrollment were compared in patients with and without PTSD. Fisher's exact tests were used to compare differences in the number of PTSD patients with and without aggression. RESULTS: A total of 215 patients were identified with newly diagnosed dementia. Ten were found to have a diagnosis of PTSD, and 205 did not. Eighty-four (41%) of the 205 were found to be aggressive. Among the 10 patients with a diagnosis of PTSD, 4 (40%) were aggressive. CONCLUSION: There was no evidence to support an increased risk of aggression in patients with a coexisting diagnosis of dementia and PTSD.

Apolipoprotein E DNA methylation and posttraumatic stress disorder are associated with plasma ApoE level: A preliminary study.

Mild traumatic brain injury (mTBI) occurred in 15-30% of Veterans returning from Iraq and Afghanistan. We examined whether DNA methylation of the apolipoprotein E (APOE) gene promoter region or plasma ApoE protein levels are altered in mTBI. APOE promoter region DNA methylation, APOE genotype, and plasma ApoE concentration were determined in 87 Veterans with or without mTBI who were recruited from 2010-2014. Plasma ApoE concentration was found to be associated with Posttraumatic Stress Disorder (PTSD) symptom severity ratings by hierarchical linear regression (p = .013) and ANCOVA (p = .007). Hierarchical linear regression revealed that plasma ApoE concentration was associated with APOE-ε4 genotype status (p=.022). Higher ApoE plasma levels were found in ε3/ε3 Veterans than in APOE-ε4 carriers (p = .031). Furthermore, plasma ApoE concentration was associated experiment-wise with DNA methylation at CpG sites -877 (p = .021), and -775 (p = .014). The interaction between APOE-ε4 genotype and having a PTSD diagnosis was associated with DNA methylation at CpG site -675 (p = .009).

An Investigation of Exposure Control Methods With Variable-Length CAT Using the Partial Credit Model.

The purpose of this simulation study was to investigate the effect of several different item exposure control procedures in computerized adaptive testing (CAT) with variable-length stopping rules using the partial credit model. Previous simulation studies on CAT exposure control methods with polytomous items rarely considered variable-length tests. The four exposure control techniques examined were the randomesque with a group of three items, randomesque with a group of six items, progressive-restricted standard error (PR-SE), and no exposure control. The two variable-length stopping rules included were the SE and predicted standard error reduction (PSER), along with three item pools of varied sizes (43, 86, and 172 items). Descriptive statistics on number of nonconvergent cases, measurement precision, testing burden, item overlap, item exposure, and pool utilization were calculated. Results revealed that the PSER stopping rule administered fewer items on average while maintaining measurement precision similar to the SE stopping rule across the different item pool sizes and exposure controls. The PR-SE exposure control procedure surpassed the randomesque methods by further reducing test overlap, maintaining maximum exposure rates at the target rate or lower, and utilizing all items from the pool with a minimal increase in number of items administered and nonconvergent cases.