Gary H. Wynn

Pharmacokinetic Drug Interactions of Synthetic Opiate Analgesics

Earlier reviews have covered pharmacokinetic drug interactions of natural and semi-synthetic opioid analgesics. This review will focus on the pharmacokinetic drug-drug interactions of methadone, propoxyphene, levomethadyl, meperidine, other phenylpiperidines (such as fentanyl), pentazocine, diphenoxylate, loperimide, and tramadol. The authors present an extensive review of the current literature. These drugs, with a few exceptions, are, at least partially, if not primarily, metabolized by the cytochrome P450 isoenzyme system (CYP) 3A4, and the action/interaction of these enzymes can have an effect on outcome. Therefore, these drugs are likely to produce drug-drug interactions when the CYP3A4 system is inhibited or induced. Knowledge of these drug-drug interactions is important because such interactions may decrease drug efficacy or result in adverse effects.

The Basolateral Amygdala γ-Aminobutyric Acidergic System in Health and Disease

The brain comprises an excitatory/inhibitory neuronal network that maintains a finely tuned balance of activity critical for normal functioning. Excitatory activity in the basolateral amygdala (BLA), a brain region that plays a central role in emotion and motivational processing, is tightly regulated by a relatively small population of γ‐aminobutyric acid (GABA) inhibitory neurons. Disruption in GABAergic inhibition in the BLA can occur when there is a loss of local GABAergic interneurons, an alteration in GABAA receptor activation, or a dysregulation of mechanisms that modulate BLA GABAergic inhibition. Disruptions in GABAergic control of the BLA emerge during development, in aging populations, or after trauma, ultimately resulting in hyperexcitability. BLA hyperexcitability manifests behaviorally as an increase in anxiety, emotional dysregulation, or development of seizure activity. This Review discusses the anatomy, development, and physiology of the GABAergic system in the BLA and circuits that modulate GABAergic inhibition, including the dopaminergic, serotonergic, noradrenergic, and cholinergic systems. We highlight how alterations in various neurotransmitter receptors, including the acid‐sensing ion channel 1a, cannabinoid receptor 1, and glutamate receptor subtypes, expressed on BLA interneurons, modulate GABAergic transmission and how defects of these systems affect inhibitory tonus within the BLA. Finally, we discuss alterations in the BLA GABAergic system in neurodevelopmental (autism/fragile X syndrome) and neurodegenerative (Alzheimers disease) diseases and after the development of epilepsy, anxiety, and traumatic brain injury. A more complete understanding of the intrinsic excitatory/inhibitory circuit balance of the amygdala and how imbalances in inhibitory control contribute to excessive BLA excitability will guide the development of novel therapeutic approaches in neuropsychiatric diseases.

Risk Factors, Methods, and Timing of Suicide Attempts Among US Army Soldiers

IMPORTANCE Suicide attempts in the US Army have risen in the past decade. Understanding the association between suicide attempts and deployment, as well as method and timing of suicide attempts, can assist in developing interventions. OBJECTIVE To examine suicide attempt risk factors, methods, and timing among soldiers currently deployed, previously deployed, and never deployed at the time this study was conducted. DESIGN, SETTING, AND PARTICIPANTS This longitudinal, retrospective cohort study of Regular Army-enlisted soldiers on active duty from 2004 through 2009 used individual-level person-month records to examine risk factors (sociodemographic, service related, and mental health), method, and time of suicide attempt by deployment status (never, currently, and previously deployed). Administrative data for the month before each of 9650 incident suicide attempts and an equal-probability sample of 153 528 control person-months for other soldiers were analyzed using a discrete-time survival framework. MAIN OUTCOMES AND MEASURES Suicide attempts and career, mental health, and demographic predictors were obtained from administrative and medical records. RESULTS Of the 9650 enlisted soldiers who attempted suicide, 86.3% were male, 68.4% were younger than 30 years, 59.8% were non-Hispanic white, 76.5% were high school educated, and 54.7% were currently married. The 40.4% of enlisted soldiers who had never been deployed (n = 12 421 294 person-months) accounted for 61.1% of enlisted soldiers who attempted suicide (n = 5894 cases). Risk among those never deployed was highest in the second month of service (103 per 100 000 person-months). Risk among soldiers on their first deployment was highest in the sixth month of deployment (25 per 100 000 person-months). For those previously deployed, risk was highest at 5 months after return (40 per 100 000 person-months). Currently and previously deployed soldiers were more likely to attempt suicide with a firearm than those never deployed (currently deployed: OR, 4.0; 95% CI, 2.9-5.6; previously deployed: OR, 2.7; 95% CI, 1.8-3.9). Across deployment status, suicide attempts were more likely among soldiers who were women (currently deployed: OR, 3.4; 95% CI, 3.0-4.0; previously deployed: OR, 1.5; 95% CI, 1.4-1.7; and never deployed: OR, 2.4; 95% CI, 2.3-2.6), in their first 2 years of service (currently deployed: OR, 1.9; 95% CI, 1.5-2.3; previously deployed: OR, 2.2; 95% CI, 1.9-2.7; and never deployed: OR, 3.1; 95% CI, 2.7-3.6), and had a recently received a mental health diagnosis in the previous month (currently deployed: OR, 29.8; 95% CI, 25.0-35.5; previously deployed: OR, 22.2; 95% CI, 20.1-24.4; and never deployed: OR, 15.0; 95% CI, 14.2-16.0). Among soldiers with 1 previous deployment, odds of a suicide attempt were higher for those who screened positive for depression or posttraumatic stress disorder after return from deployment and particularly at follow-up screening, about 4 to 6 months after deployment (depression: OR, 1.4; 95% CI, 1.1-1.9; posttraumatic stress disorder: OR, 2.4; 95% CI, 2.1-2.8). CONCLUSIONS AND RELEVANCE Identifying the timing and risk factors for suicide attempt in soldiers requires consideration of environmental context, individual characteristics, and mental health. These factors can inform prevention efforts.

Complementary and Alternative Medicine Approaches in the Treatment of PTSD

Complementary and alternative medicine is a diverse set of practices and treatments that has seen a significant increase among Americans over the past decade. These approaches have been applied to a myriad of medical and mental health disorders with varying levels of efficacy. Recent years have seen an increased interest in the use of complementary and alternative medicine to address the growing numbers of individuals suffering from post-traumatic stress disorder and other trauma-related disorders. These approaches include pharmacologic and non-pharmacologic modalities. This article will review some of the most widely used non-pharmacologic complementary and alternative medicine practices used to treat post-traumatic stress disorder such as recreational therapy, animal-assisted therapy, yoga, and acupuncture as well as alternative delivery methods for psychotherapy.

Risk of Suicide Attempt Among Soldiers in Army Units With a History of Suicide Attempts

Importance Mental health of soldiers is adversely affected by the death and injury of other unit members, but whether risk of suicide attempt is influenced by previous suicide attempts in a soldier’s unit is unknown. Objective To examine whether a soldier’s risk of suicide attempt is influenced by previous suicide attempts in that soldier’s unit. Design, Setting, and Participants Using administrative data from the Army Study to Assess Risk and Resilience in Servicemembers (STARRS), this study identified person-month records for all active-duty, regular US Army, enlisted soldiers who attempted suicide from January 1, 2004, through December 31, 2009 (n = 9650), and an equal-probability sample of control person-months (n = 153 528). Data analysis was performed from August 8, 2016, to April 10, 2017. Main Outcomes and Measures Logistic regression analyses examined the number of past-year suicide attempts in a soldier’s unit as a predictor of subsequent suicide attempt, controlling for sociodemographic features, service-related characteristics, prior mental health diagnosis, and other unit variables, including suicide-, combat-, and unintentional injury–related unit deaths. The study also examined whether the influence of previous unit suicide attempts varied by military occupational specialty (MOS) and unit size. Results Of the final analytic sample of 9512 enlisted soldiers who attempted suicide and 151 526 control person-months, most were male (86.4%), 29 years or younger (68.4%), younger than 21 years when entering the army (62.2%), white (59.8%), high school educated (76.6%), and currently married (54.8%). In adjusted models, soldiers were more likely to attempt suicide if 1 or more suicide attempts occurred in their unit during the past year (odds ratios [ORs], 1.4-2.3; P < .001), with odds increasing as the number of unit attempts increased. The odds of suicide attempt among soldiers in a unit with 5 or more past-year attempts was more than twice that of soldiers in a unit with no previous attempts (OR, 2.3; 95% CI, 2.1-2.6). The association of previous unit suicide attempts with subsequent risk was significant whether soldiers had a combat arms MOS or other MOS (ORs, 1.4-2.3; P < .001) and regardless of unit size, with the highest risk among those in smaller units (1-40 soldiers) (ORs, 2.1-5.9; P < .001). The population-attributable risk proportion for 1 or more unit suicide attempts in the past year indicated that, if this risk could be reduced to no unit attempts, 18.2% of attempts would not occur. Conclusions and Relevance Risk of suicide attempt among soldiers increased as the number of past-year suicide attempts within their unit increased for combat arms and other MOSs and for units of any size but particularly for smaller units. Units with a history of suicide attempts may be important targets for preventive interventions.

Genome-wide analysis of insomnia disorder

Insomnia is a worldwide problem with substantial deleterious health effects. Twin studies have shown a heritable basis for various sleep-related traits, including insomnia, but robust genetic risk variants have just recently begun to be identified. We conducted genome-wide association studies (GWAS) of soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). GWAS were carried out separately for each ancestral group (EUR, AFR, LAT) using logistic regression for each of the STARRS component studies (including 3,237 cases and 14,414 controls), and then meta-analysis was conducted across studies and ancestral groups. Heritability (SNP-based) for lifetime insomnia disorder was significant (h2g = 0.115, p = 1.78 × 10−4 in EUR). A meta-analysis including three ancestral groups and three study cohorts revealed a genome-wide significant locus on Chr 7 (q11.22) (top SNP rs186736700, OR = 0.607, p = 4.88 × 10−9) and a genome-wide significant gene-based association (p = 7.61 × 10−7) in EUR for RFX3 on Chr 9. Polygenic risk for sleeplessness/insomnia severity in UK Biobank was significantly positively associated with likelihood of insomnia disorder in STARRS. Genetic contributions to insomnia disorder in STARRS were significantly positively correlated with major depressive disorder (rg = 0.44, se = 0.22, p = 0.047) and type 2 diabetes (rg = 0.43, se = 0.20, p = 0.037), and negatively with morningness chronotype (rg = −0.34, se = 0.17, p = 0.039) and subjective well being (rg = -0.59, se = 0.23, p = 0.009) in external datasets. Insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease.

Documented family violence and risk of suicide attempt among U.S. Army soldiers

Suicide attempt (SA) rates in the U.S. Army increased substantially during the wars in Afghanistan and Iraq. This study examined associations of family violence (FV) history with SA risk among soldiers. Using administrative data from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS), we identified person-month records of active duty, Regular Army, enlisted soldiers with medically documented SAs from 2004 to 2009 (n = 9650) and a sample of control person-months (n = 153,528). Logistic regression analyses examined associations of FV with SA, adjusting for socio-demographics, service-related characteristics, and prior mental health diagnosis. Odds of SA were higher in soldiers with a FV history and increased as the number of FV events increased. Soldiers experiencing past-month FV were almost five times as likely to attempt suicide as those with no FV history. Odds of SA were elevated for both perpetrators and those who were exclusively victims. Male perpetrators had higher odds of SA than male victims, whereas female perpetrators and female victims did not differ in SA risk. A discrete-time hazard function indicated that SA risk was highest in the initial months following the first FV event. FV is an important consideration in understanding risk of SA among soldiers.

PTSD symptom severity and sensitivity to blood, injury, and mutilation in U.S. army special operations soldiers

Sensitivity to blood, injury, and mutilation (SBIM) may increase risk for posttraumatic stress disorder (PTSD), given that traumatic events often involve actual or perceived threat of bodily harm to oneself and/or others, including exposure to blood and other mutilation-related stimuli. A self-report questionnaire was administered to male, active duty, U.S. Army Special Operations Command soldiers who had deployed to Iraq and Afghanistan (n =694 males). We first used exploratory factor analysis to examine whether the 30-item Mutilation Questionnaire (Klorman et al., 1974) comprised a unitary measure of SBIM, finding that 10 of the items form a cohesive SBIM factor. Summed, those 10 SBIM items had a significant bivariate correlation with PTSD symptom severity. In a multiple regression analysis that included demographic characteristics and lifetime trauma exposure, SBIM was positively associated with PTSD symptom severity. Other significant multivariate predictors were high lifetime trauma exposure and junior enlisted rank. When trait neuroticism was added to the model to test the robustness of these findings, the association of SBIM with PTSD symptom severity remained significant. The results suggest that SBIM may be a risk factor for PTSD in male soldiers. Further research is warranted to improve measurement and understanding of SBIM.

Associations of Time-Related Deployment Variables With Risk of Suicide Attempt Among Soldiers: Results From the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS)

Importance There has been limited systematic examination of whether risk of suicide attempt (SA) among US Army soldiers is associated with time-related deployment variables, such as time in service before first deployment, duration of first deployment, and dwell time (DT) (ie, length of time between deployments). Objective To examine the associations of time-related deployment variables with subsequent SA among soldiers who had deployed twice. Design, Setting, and Participants Using administrative data from January 1, 2004, through December 31, 2009, this longitudinal, retrospective cohort study identified person-month records of active-duty Regular Army enlisted soldiers who had served continuously in the US Army for at least 2 years and deployed exactly twice. The dates of analysis were March 1 to December 1, 2017. There were 593 soldiers with a medically documented SA during or after their second deployment. An equal-probability sample of control person-months was selected from other soldiers with exactly 2 deployments (n = 19 034). Logistic regression analyses examined the associations of time in service before first deployment, duration of first deployment, and DT with subsequent SA. Main Outcomes and Measures Suicide attempts during or after second deployment were identified using US Department of Defense Suicide Event Report records and International Classification of Diseases, Ninth Revision, Clinical Modification E950 to E958 diagnostic codes. Independent variables were constructed from US Army personnel records. Results Among 593 SA cases, most were male (513 [86.5%]), white non-Hispanic (392 [66.1%]), at least high school educated (477 [80.4%]), currently married (398 [67.1%]), and younger than 21 years when they entered the US Army (384 [64.8%]). In multivariable models adjusting for sociodemographics, service-related characteristics, and previous mental health diagnosis, odds of SA during or after second deployment were higher among soldiers whose first deployment occurred within the first 12 months of service vs after 12 months (odds ratio, 2.0; 95% CI, 1.6-2.4) and among those with a DT of 6 months or less vs longer than 6 months (odds ratio, 1.6; 95% CI, 1.2-2.0). Duration of first deployment was not associated with subsequent SA. Analysis of 2-way interactions indicated that the associations of early deployment and DT with SA risk were not modified by other characteristics. Multivariable population-attributable risk proportions were 14.2% for deployment within the first 12 months of service and 4.0% for DT of 6 months or less. Conclusions and Relevance Time in service before first deployment and DT are modifiable risk factors for SA risk among soldiers.

Risk Factors Associated With Attempted Suicide Among US Army Soldiers Without a History of Mental Health Diagnosis

Importance The US Army suicide attempt rate increased sharply during the wars in Afghanistan and Iraq. Although soldiers with a prior mental health diagnosis (MH-Dx) are known to be at risk, little is known about risk among those with no history of diagnosis. Objective To examine risk factors for suicide attempt among soldiers without a previous MH-Dx. Design, Setting, and Participants In this retrospective longitudinal cohort study using administrative data from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS), person-month records were identified for all active-duty Regular Army enlisted soldiers who had a medically documented suicide attempt from January 1, 2004, through December 31, 2009 (n = 9650), and an equal-probability sample of control person-months (n = 153 528). Data analysis in our study was from September 16, 2017, to June 6, 2018. In a stratified sample, it was examined whether risk factors for suicide attempt varied by history of MH-Dx. Main Outcomes and Measures Suicide attempts were identified using Department of Defense Suicide Event Report records and International Classification of Diseases, Ninth Revision, Clinical Modification E95 × diagnostic codes. Mental health diagnoses and related codes, as well as sociodemographic, service-related, physical health care, injury, subjection to crime, crime perpetration, and family violence variables, were constructed from Army personnel, medical, legal, and family services records. Results Among 9650 enlisted soldiers with a documented suicide attempt (74.8% male), 3507 (36.3%) did not have a previous MH-Dx. Among soldiers with no previous diagnosis, the highest adjusted odds of suicide attempt were for the following: female sex (odds ratio [OR], 2.6; 95% CI, 2.4-2.8), less than high school education (OR, 1.9; 95% CI, 1.8-2.0), first year of service (OR, 6.0; 95% CI, 4.7-7.7), previously deployed (OR, 2.4; 95% CI, 2.1-2.8), promotion delayed 2 months or less (OR, 2.1; 95% CI, 1.7-2.6), past-year demotion (OR, 1.6; 95% CI, 1.3-1.8), 8 or more outpatient physical health care visits in the past 2 months (OR, 3.3; 95% CI, 2.9-3.8), past-month injury-related outpatient (OR, 3.0; 95% CI, 2.8-3.3) and inpatient (OR, 3.8; 95% CI, 2.3-6.3) health care visits, previous combat injury (OR, 1.6; 95% CI, 1.0-2.4), subjection to minor violent crime (OR, 1.6; 95% CI, 1.1-2.4), major violent crime perpetration (OR, 2.0; 95% CI, 1.3-3.0), and family violence (OR, 2.9; 95% CI, 1.9-4.4). Most of these variables were also associated with suicide attempts among soldiers with a previous MH-Dx, although the strength of associations differed. Conclusions and Relevance Suicide attempt risk among soldiers with unrecognized mental health problems is a significant and important challenge. Administrative records from personnel, medical, legal, and family services systems can assist in identifying soldiers at risk.