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1.  Nonfatal Suicidal Behaviors in U.S. Army Administrative Records, 2004–2009: Results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) 
Psychiatry  2015;78(1):1-21.
Although the U.S. Army suicide rate is known to have risen sharply over the past decade, information about medically documented, nonfatal suicidal behaviors is far more limited. Here we examine trends and sociodemographic correlates of suicide attempts, suspicious injuries, and suicide ideation among regular Army soldiers.
Data come from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) Historical Administrative Data Study (HADS), which integrates administrative records for all soldiers on active duty during the years 2004 through 2009 (n = 1.66 million).
We identified 21,740 unique regular Army soldiers with a nonfatal suicidal event documented at some point during the HADS study period. There were substantial increases in the annual incidence rates of suicide attempts (179–400/100,000 person-years) and suicide ideation (557–830/100,000 person-years), but not suspicious injuries. Using hierarchical classification rules to identify the first instance of each soldier's most severe behavior, we found increased risk of all outcomes among those who were female, non-Hispanic White, never married, lower-ranking enlisted, less educated, and of younger age when entering Army service. These sociodemographic associations significantly differed across outcomes, despite some patterns that appear similar.
Results provide a broad overview of nonfatal suicidal trends in the U.S. Army during 2004 through 2009 and demonstrate that integration of multiple administrative data systems enriches analysis of the predictors of such events.
PMCID: PMC4503376  PMID: 26168022
2.  Thirty-Day Prevalence of DSM-IV Mental Disorders Among Nondeployed Soldiers in the US Army 
JAMA psychiatry  2014;71(5):504-513.
Although high rates of current mental disorder are known to exist in the US Army, little is known about the proportions of these disorders that had onsets prior to enlistment.
To estimate the proportions of 30-day DSM-IV mental disorders among nondeployed US Army personnel with first onsets prior to enlistment and the extent which role impairments associated with 30-day disorders differ depending on whether the disorders had pre-vs post-enlistment onsets.
A representative sample of 5428 soldiers participating in the Army Study to Assess Risk and Resilience in Servicemembers completed self-administered questionnaires and consented to linkage of questionnaire responses with administrative records.
Thirty-day DSM-IV internalizing (major depressive, bipolar, generalized anxiety, panic, and posttraumatic stress) and externalizing (attention-deficit/ hyperactivity, intermittent explosive, alcohol/drug) disorders were assessed with validated self-report scales. Age at onset was assessed retrospectively. Role impairment was assessed with a modified Sheehan Disability Scale.
A total of 25.1% of respondents met criteria for any 30-day disorder (15.0% internalizing; 18.4% externalizing) and 11.1% for multiple disorders. A total of 76.6% of cases reported pre-enlistment age at onset of at least one 30-day disorder (49.6% internalizing; 81.7% externalizing). Also, 12.8% of respondents reported severe role impairment. Controlling for sociodemographic and Army career correlates, which were broadly consistent with other studies, 30-day disorders with pre-enlistment (χ82=131.8, P < .001) and post-enlistment (χ72=123.8, P < .001) ages at onset both significantly predicted severe role impairment, although pre-enlistment disorders were more consistent powerful predictors (7 of 8 disorders significant; odds ratios, 1.6–11.4) than post-enlistment disorders (5 of 7 disorders significant; odds ratios, 1.5–7.7). Population-attributable risk proportions of severe role impairment were 21.7% for pre-enlistment disorders, 24.3% for post-enlistment disorders, and 43.4% for all disorders.
Interventions to limit accession or increase resilience of new soldiers with pre-enlistment mental disorders might reduce prevalence and impairments of mental disorders in the US Army.
PMCID: PMC4057988  PMID: 24590120
3.  Suicidal ideation and risk factors in primary care patients with anxiety disorders 
Psychiatry research  2013;209(1):60-65.
The presence of an anxiety disorder is associated with greater frequency of suicidal thoughts and behaviors. Given the high personal and societal costs of suicidal behaviors, suicide prevention is a priority. Understanding factors present within individuals with anxiety disorders that increase suicide risk may inform prevention efforts. The aims of the present study were to examine the prevalence of suicidal ideation and behaviors, as well as factors associated with suicide risk in patients with anxiety disorders in primary care. Data from a large scale randomized controlled study were analyzed to assess prevalence of suicidal thoughts and behaviors, as well as factors associated with suicide risk. Results revealed that suicidal ideation and behaviors were relatively common in this group. When examining mental and physical health factors jointly, presence of depression, mental health-related impairment, and social support each uniquely accounted for variance in suicide risk score. Methodological limitations include cross-sectional data collection and lack of information on comorbid personality disorders. Moreover, patients included were from a clinical trial with exclusion criteria that may limit generalizability. Results highlight the complex determinants of suicidal behavior and the need for more nuanced suicide assessment in this population, including evaluation of comorbidity and general functioning.
PMCID: PMC3745797  PMID: 23608160
suicidality; depression; functional impairment; PTSD; GAD; Social anxiety; panic disorder
4.  Response bias, weighting adjustments, and design effects in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) 
The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi-component epidemiological and neurobiological study designed to generate actionable recommendations to reduce U.S. Army suicides and increase knowledge about determinants of suicidality. Three Army STARRS component studies are large-scale surveys: one of new soldiers prior to beginning Basic Combat Training (BCT; n=50,765 completed self-administered questionnaires); another of other soldiers exclusive of those in BCT (n=35,372); and a third of three Brigade Combat Teams about to deploy to Afghanistan who are being followed multiple times after returning from deployment (n= 9,421). Although the response rates in these surveys are quite good (72.0-90.8%), questions can be raised about sample biases in estimating prevalence of mental disorders and suicidality, the main outcomes of the surveys based on evidence that people in the general population with mental disorders are under-represented in community surveys. This paper presents the results of analyses designed to determine whether such bias exists in the Army STARRS surveys and, if so, to develop weights to correct for these biases. Data are also presented on sample inefficiencies introduced by weighting and sample clustering and on analyses of the trade-off between bias and efficiency in weight trimming.
PMCID: PMC3992816  PMID: 24318218
Suicide; mental disorders; U.S. Army; epidemiologic research design; design effects; sample bias; sample weights; survey design efficiency; survey sampling
5.  Age differences in treatment response to a collaborative care intervention for anxiety disorders*† 
Some data suggest that older adults with anxiety disorders do not respond as well to treatment as do younger adults.
We examined age differences in outcomes from the Coordinated Anxiety Learning and Management (CALM) study, an effectiveness trial comparing usual care to a computer-assisted collaborative care intervention for primary care patients with panic disorder, generalised anxiety disorder, post-traumatic stress disorder (PTSD), and/or social anxiety disorder. This is the first study to examine the efficacy of a collaborative care intervention in a sample that included both younger and older adults with anxiety disorders. We hypothesised that older adults would show a poorer response to the intervention than younger adults.
We examined findings for the overall sample, as well as within each diagnostic category ( identifier: NCT00347269).
The CALM intervention was more effective than usual care among younger adults overall and for those with generalised anxiety disorder, panic disorder and social anxiety disorder. Among older adults, the intervention was effective overall and for those with social anxiety disorder and PTSD but not for those with panic disorder or generalised anxiety disorder. The effects of the intervention also appeared to erode by the 18-month follow-up, and there were no significant effects on remission among the older adults.
These results are consistent with the findings of other investigators suggesting that medications and psychotherapy for anxiety disorders may not be as effective for older individuals as they are for younger people.
PMCID: PMC3696879  PMID: 23580378
6.  Evaluation of the factor structure and psychometric properties of the brief symptom inventory—18 with homebound older adults 
Homebound older adults are at high risk for depression and anxiety. Systematic screening may increase identification of these difficulties and facilitate service usage. The purpose of this study was to investigate the factor structure, internal consistency, and concurrent validity of the Brief Symptom Inventory—18 (BSI-18) for use as a screening instrument for depression and anxiety with homebound older adults and to examine if the BSI-18 could be shortened further and exhibit comparable psychometric properties.
A sample of 142 older adults receiving in-home aging services completed interviews that included the BSI-18 and the depression and anxiety modules of the structured clinical interview for DSM-IV.
Confirmatory factor analysis showed that the theorized three-factor, second-order model of the BSI-18 fit the data well (S-B X2 = 136.17; p = 0.36). The depression and anxiety subscales exhibited high internal consistency (α >0.81), whereas the somatic subscale exhibited lower internal consistency (α = 0.69). Receiver operator curve (ROC) analyses suggest that the BSI-18 depression and anxiety subscales were able to predict those with DSM-IV diagnoses (Depression AUC = 0.89 p <0.001; Anxiety AUC = 0.80, p <0.001). The ROC results suggested adapting a cut score of T = 50 to achieve optimal sensitivity and specificity. The short three-item depression scale exhibited comparable psychometric properties to the full scale, while the three-item somatic and anxiety scales exhibited lower internal consistency and sensitivity.
These findings provide initial evidence that the BSI-18 is valid for use with homebound older adults.
PMCID: PMC4070299  PMID: 20013879
measures; homebound; older adults; psychometrics; anxiety; depression
7.  Changes in self-efficacy and outcome-expectancy as predictors of anxiety outcomes from the CALM study 
Depression and anxiety  2014;31(8):678-689.
While self-efficacy (SE) and outcome-expectancy (OE) have been well researched as predictors of outcome, few studies have investigated changes in these variables across treatments. We evaluated changes in OE and SE throughout treatment as predictors of outcomes in a large sample with panic disorder, generalized anxiety disorder, social anxiety disorder, or post-traumatic stress disorder. We hypothesized that increases in SE and OE would predict reductions in anxiety and depression as well as improvement in functioning.
Participants (mean age = 43.3, SD=13.2, 71.1% female, 55.5% white) were recruited from primary care centers throughout the US and were randomized to receive either Coordinated Anxiety Learning and Management (CALM) treatment, comprised of cognitive-behavioral therapy, psychotropic medication, or both, or to usual care. SE and OE ratings were collected at each session for participants in the CALM treatment (n=482) and were entered into a structural equation model as predictors of changes in Brief Symptom Inventory, Anxiety Sensitivity Index, Patient Health Questionnaire, and Sheehan Disability Scale outcomes at 6, 12, and 18 months after baseline.
The best fitting models predict symptom levels from OE and SE and not vice versa. The slopes and intercept of OE significantly predicted change in each outcome variable except PHQ-8. The slope and intercept of SE significantly predicted change in each outcome variable.
Over and above absolute level, increases in SE and OE were significant predictors of decreases in symptoms and increases in functioning. Implications for treatment are discussed, as well as future directions of research.
PMCID: PMC4244230  PMID: 24619599
Self-efficacy; outcome-expectancy; anxiety; cognitive behavioral therapy; primary care
8.  An examination of the bidirectional relationship between functioning and symptom levels in patients with anxiety disorders in the CALM study 
Psychological medicine  2014;45(3):647-661.
Patients with anxiety disorders suffer marked functional impairment in their activities of daily living. Many studies have documented that improvements in anxiety symptom severity predict functioning improvements. However, no studies have investigated how improvements in functioning simultaneously predict symptom reduction. We hypothesized that symptom levels at a given time point will predict functioning at the subsequent time point, and simultaneously that functioning at a given time point will predict symptom levels at a subsequent time point.
Patients were recruited from primary care centers for the Coordinated Anxiety Learning and Management (CALM) study and were randomized to receive either computer-assisted cognitive-behavioral therapy and/or medication management (ITV) or usual care (UC). A cross-lagged panel design examined the relationship between functional impairment and anxiety and depression symptom severity at baseline, 6, 12, and 18 month follow-up assessments.
Prospective prediction of functioning from symptoms and symptoms from functioning were both important in modeling these associations. Anxiety and depression predicted functioning as strongly as functioning predicted anxiety and depression. There were some differences in these associations between UC and ITV. Where differences emerged, the UC group was best modeled with prospective paths predicting functioning from symptoms, whereas symptoms and functioning were both important predictors in the ITV group.
Treatment outcome is best captured by measures of functional impairment as well as symptom severity. Implications for treatment are discussed, as well as future directions of research.
PMCID: PMC4383724  PMID: 25272965
9.  Treatment Engagement and Response to CBT among Latinos with Anxiety Disorders in Primary Care 
In the current study, we compare measures of treatment outcome and engagement for Latino and non-Latino White patients receiving a cognitive-behavioral therapy (CBT) program delivered in primary care.
Participants were 18–65 years old and recruited from 17 clinics at four different sites to participate in a randomized controlled trial for anxiety disorders, which compared the CALM intervention (consisting of CBT, medication, or both) to usual care. Of those participants who were randomized to the intervention arm and selected CBT (either alone or in combination with medication), 85 were Latino and 251 were non-Latino White; the majority of the Latino participants received the CBT intervention in English (n = 77). Blinded assessments of clinical improvement and functioning were administered at baseline, and at 6, 12, and 18 months after baseline. Measures of engagement, including attendance, homework adherence, understanding of CBT principles, and commitment to treatment were assessed weekly during the CBT intervention.
Findings from propensity weighted linear and logistic regression models revealed no statistically significant differences between Latinos and non-Latino Whites on symptom measures of clinical improvement and functioning at almost all time points. There were significant differences on two of seven engagement outcomes, namely number of sessions attended and patients’ understanding of CBT principles.
These findings suggest that CBT can be an effective treatment approach for Latinos who are primarily English speaking and likely more acculturated, although continued attention should be directed toward engaging Latinos in such interventions.
PMCID: PMC4303048  PMID: 24660674
anxiety; Latinos; primary care; engagement; treatment
10.  Age, Period, and Cohort Effects in Psychological Distress in the United States and Canada 
American Journal of Epidemiology  2014;179(10):1216-1227.
Although treatment utilization for depression and anxiety symptoms has increased substantially in the United States and elsewhere, it remains unclear whether the underlying population distribution of psychological distress is changing over time. We estimated age, period, and cohort effects using data from 2 countries over more than 20 years, including National Health Interview Surveys from 1997 to 2010 (n = 447,058) and Canadian Community Health Surveys from 2000 to 2007 (n = 125,306). Psychological distress was measured with the Kessler Psychological Distress Scale. By period, both countries showed the highest levels of psychological distress in 2001 and the lowest levels in 2007. By age, psychological distress was highest in adolescence and during the late 40s and early 50s. By cohort, Canadian Community Health Survey results indicated a decreasing cohort effect among those born in 1922–1925 through 1935–1939 (β = −0.36, 95% confidence interval: −0.45, −0.27) and then a continuously increasing cohort effect during the remainder of the 20th century through 1989–1992 (β = 0.49, 95% confidence interval: 0.38, 0.61). The National Health Interview Survey data captured earlier-born cohorts and indicated an increased cohort effect for the earliest born (for 1912–1914, β = 0.44, 95% confidence interval: 0.26, 0.61). In sum, individuals in the oldest and more recently born birth cohorts have higher mean psychological distress symptoms compared with those born in midcentury, underscoring the importance of a broad, population-level lens for conceptualizing mental health.
PMCID: PMC4010185  PMID: 24692432
age-period-cohort effects; anxiety; Canada; Canadian Community Health Surveys; depression; National Health Interview Surveys; psychological distress; United States
11.  Influence of RGS2 on Sertraline Treatment for Social Anxiety Disorder 
Neuropsychopharmacology  2014;39(6):1340-1346.
Only a minority of patients with social anxiety disorder (SAD) has a robust therapeutic response to evidence-based serotonin reuptake inhibitor (SSRI) treatment. To help improve the personalized medicine approach to psychiatric care, we evaluated several candidate genetic predictors of SSRI response in SAD. At the start of a randomized controlled trial (NCT00282828), 346 patients with SAD at three sites received protocol-driven, open-label treatment with sertraline, up to 200. mg/d over 10 weeks. Efficacy was determined using a continuous measure of outcome (Liebowitz Social Anxiety Scale (LSAS)) and dichotomous indicators of response (LSAS ⩽50) and remission (LSAS ⩽30). Predictors of efficacy were examined in multivariate regression models that included eight polymorphic variants in four candidate genes (four in RGS2, two in HTR2A, one in SLC6A2, and one in SLC6A4). Adjusting for genetic ancestral cluster and non-genetic predictors of response, all four single-nucleotide polymorphisms (SNPs) in RGS2 predicted change in LSAS over time, at study-wise significance (p=0.00833), with the minor allele associated with less improvement over time. After adjusting for genetic ancestral cluster and non-genetic predictors of remission, two of the four RGS2 SNPs predicted likelihood of remission at or just below study-wise significance (p=0.025): rs4606 (AOR=0.49 (95% CI=0.27–0.90), p=0.022) and rs1819741 (AOR=0.50 (95% CI=0.28–0.92), p=0.027). Variation in RGS2, a gene previously shown to be associated with social anxiety phenotypes and serotonergic neurotransmission, may be a biomarker of the likelihood of substantially benefiting from sertraline among patients with SAD.
PMCID: PMC3988537  PMID: 24154666
clinical pharmacology; clinical trials; Mood; anxiety; Stress Disorders; Pharmacogenetics; Pharmacogenomics; Psychopharmacology; selective serotonin reuptake inhibitor; social anxiety disorder; social anxiety disorder; selective serotonin reuptake inhibitor; genetics; pharmacotherapy
12.  Prevalence and Correlates of Suicidal Behavior Among Soldiers 
JAMA psychiatry  2014;71(5):514-522.
The suicide rate among US Army soldiers has increased substantially in recent years.
To estimate the lifetime prevalence and sociodemographic, Army career, and psychiatric predictors of suicidal behaviors among nondeployed US Army soldiers.
A representative cross-sectional survey of 5428 nondeployed soldiers participating in a group self-administered survey.
Lifetime suicidal ideation, suicide plans, and suicide attempts.
The lifetime prevalence estimates of suicidal ideation, suicide plans, and suicide attempts are 13.9%, 5.3%, and 2.4%. Most reported cases (47.0%–58.2%) had pre-enlistment onsets. Pre-enlistment onset rates were lower than in a prior national civilian survey (with imputed/simulated age at enlistment), whereas post-enlistment onsets of ideation and plans were higher, and post-enlistment first attempts were equivalent to civilian rates. Most reported onsets of plans and attempts among ideators (58.3%–63.3%) occur within the year of onset of ideation. Post-enlistment attempts are positively related to being a woman (with an odds ratio [OR] of 3.3 [95% CI, 1.5–7.5]), lower rank (OR = 5.8 [95% CI, 1.8–18.1]), and previously deployed (OR = 2.4–3.7) and are negatively related to being unmarried (OR = 0.1–0.8) and assigned to Special Operations Command (OR = 0.0 [95% CI, 0.0–0.0]). Five mental disorders predict post-enlistment first suicide attempts in multivariate analysis: pre-enlistment panic disorder (OR = 0.1 [95% CI, 0.0–0.8]), pre-enlistment posttraumatic stress disorder (OR = 0.1 [95% CI, 0.0–0.7]), post-enlistment depression (OR = 3.8 [95% CI, 1.2–11.6]), and both pre- and post-enlistment intermittent explosive disorder (OR = 3.7–3.8). Four of these 5 ORs (posttraumatic stress disorder is the exception) predict ideation, whereas only post-enlistment intermittent explosive disorder predicts attempts among ideators. The population-attributable risk proportions of lifetime mental disorders predicting post-enlistment suicide attempts are 31.3% for pre-enlistment onset disorders, 41.2% for post-enlistment onset disorders, and 59.9% for all disorders.
The fact that approximately one-third of post-enlistment suicide attempts are associated with pre-enlistment mental disorders suggests that pre-enlistment mental disorders might be targets for early screening and intervention. The possibility of higher fatality rates among Army suicide attempts than among civilian suicide attempts highlights the potential importance of means control (ie, restricting access to lethal means [such as firearms]) as a suicide prevention strategy.
PMCID: PMC4100464  PMID: 24590178
13.  Predictors of Suicide and Accident Death in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) 
JAMA psychiatry  2014;71(5):493-503.
The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multicomponent study designed to generate actionable recommendations to reduce Army suicides and increase knowledge of risk and resilience factors for suicidality.
To present data on prevalence, trends, and basic sociodemographic and Army experience correlates of suicides and accident deaths among active duty Regular Army soldiers between January 1, 2004, and December 31, 2009, and thereby establish a foundation for future Army STARRS investigations.
Analysis of trends and predictors of suicide and accident deaths using Army and Department of Defense administrative data systems. Participants were all members of the US Regular Army serving at any time between 2004 and 2009.
Death by suicide or accident during active Army service.
The suicide rate rose between 2004 and 2009 among never deployed and currently and previously deployed Regular Army soldiers. The accident death rate fell sharply among currently deployed soldiers, remained constant among the previously deployed, and trended upward among the never deployed. Increased suicide risk was associated with being a man (or a woman during deployment), white race/ethnicity, junior enlisted rank, recent demotion, and current or previous deployment. Sociodemographic and Army experience predictors were generally similar for suicides and accident deaths. Time trends in these predictors and in the Army’s increased use of accession waivers (which relaxed some qualifications for new soldiers) do not explain the rise in Army suicides.
Predictors of Army suicides were largely similar to those reported elsewhere for civilians, although some predictors distinct to Army service emerged that deserve more in-depth analysis. The existence of a time trend in suicide risk among never-deployed soldiers argues indirectly against the view that exposure to combat-related trauma is the exclusive cause of the increase in Army suicides.
PMCID: PMC4124912  PMID: 24590048
14.  Single-Subject Anxiety Treatment Outcome Prediction using Functional Neuroimaging 
Neuropsychopharmacology  2014;39(5):1254-1261.
The possibility of individualized treatment prediction has profound implications for the development of personalized interventions for patients with anxiety disorders. Here we utilize random forest classification and pre-treatment functional magnetic resonance imaging (fMRI) data from individuals with generalized anxiety disorder (GAD) and panic disorder (PD) to generate individual subject treatment outcome predictions. Before cognitive behavioral therapy (CBT), 48 adults (25 GAD and 23 PD) reduced (via cognitive reappraisal) or maintained their emotional responses to negative images during fMRI scanning. CBT responder status was predicted using activations from 70 anatomically defined regions. The final random forest model included 10 predictors contributing most to classification accuracy. A similar analysis was conducted using the clinical and demographic variables. Activations in the hippocampus during maintenance and anterior insula, superior temporal, supramarginal, and superior frontal gyri during reappraisal were among the best predictors, with greater activation in responders than non-responders. The final fMRI-based model yielded 79% accuracy, with good sensitivity (0.86), specificity (0.68), and positive and negative likelihood ratios (2.73, 0.20). Clinical and demographic variables yielded poorer accuracy (69%), sensitivity (0.79), specificity (0.53), and likelihood ratios (1.67, 0.39). This is the first use of random forest models to predict treatment outcome from pre-treatment neuroimaging data in psychiatry. Together, random forest models and fMRI can provide single-subject predictions with good test characteristics. Moreover, activation patterns are consistent with the notion that greater activation in cortico-limbic circuitry predicts better CBT response in GAD and PD.
PMCID: PMC3957121  PMID: 24270731
Anxiety disorders; Biological Psychiatry; Emotion regulation; fMRI; Imaging; Clinical or Preclinical; Mood/Anxiety/Stress Disorders; Prediction; Psychiatry & Behavioral Sciences; Random forest; anxiety disorders; prediction; fMRI; random forest; emotion regulation; cognitive behavioral therapy
15.  Neural functional and structural correlates of childhood maltreatment in women with intimate-partner violence-related posttraumatic stress disorder 
Psychiatry research  2012;211(2):93-103.
Childhood maltreatment (CM) is a strong risk factor for development of posttraumatic stress disorder (PTSD) upon adult exposure to extreme adverse events. However, the neural underpinnings of this relationship are not well understood. Here, we test the hypothesis that severity of CM history is positively correlated with emotion-processing limbic and prefrontal brain activation/connectivity and negatively correlated with prefrontal gray matter volumes in women with PTSD due to intimate-partner violence (IPV-PTSD). Thirty-three women with IPV-PTSD underwent structural and functional magnetic resonance imaging while completing a facial emotion processing task. Multivariate regressions examined the relationship of CM to patterns of activation, connectivity, and gray matter volumes. CM severity was: a) positively correlated with ventral ACC activation while processing angry faces; b) negatively correlated with dorsal ACC and insula activation while processing fear and angry faces, arising from positive correlations with the shape-matching baseline; c) positively correlated with limbic-prefrontal connectivity while processing fear faces but negatively correlated with amygdalo-insular connectivity while processing fear and angry; and d) negatively correlated with prefrontal gray matter volumes. These results suggest CM exposure may account for variability in limbic/prefrontal brain function and prefrontal structure in adulthood PTSD and offer one potential mechanism through which CM confers risk to future development of PTSD.
PMCID: PMC3570713  PMID: 23154098
early life stress; anxiety; imaging; trauma; abuse; neglect
16.  Prefrontal Dysfunction during Emotion Regulation in Generalized Anxiety and Panic Disorder 
Psychological medicine  2012;43(7):1475-1486.
The mechanisms that contribute to emotion dysregulation in anxiety disorders are not well understood. Two common disorders, Generalized Anxiety Disorder (GAD) and Panic Disorder (PD), were examined to test the hypothesis that both disorders are characterized by hypo-activation in prefrontal cortex (PFC) during emotion regulation. A competing hypothesis that GAD in particular is characterized by PFC hyper-activation during emotion regulation (reflecting overactive top-down control) also was evaluated.
Twenty-two medication-free Healthy Control (HC), 23 GAD, and 18 PD participants underwent functional magnetic resonance imaging (fMRI) during a task that required them to reappraise (i.e., reduce) or maintain emotional responses to negative images.
GAD participants reported the least reappraisal use in daily life, and reappraisal use was inversely associated with anxiety severity and functional impairment in these participants. During fMRI, HC demonstrated greater activation during both reappraisal and maintenance than either GAD or PD (who did not differ) in brain areas important for emotion regulation (e.g., dorsolateral and dorsomedial PFC). Furthermore, across all anxious participants, activation during reappraisal in dorsolateral and dorsomedial PFC was inversely associated with anxiety severity and functional impairment.
Emotion dysregulation in GAD and PD may be the consequence of PFC hypo-activation during emotion regulation, consistent with insufficient top-down control. The relationship between PFC hypo-activation and functional impairment suggests that the failure to engage PFC during emotion regulation may be part of the critical transition from dispositionally high anxiety to an anxiety disorder.
PMCID: PMC4308620  PMID: 23111120
17.  Imbalance of Approach and Avoidance: The Yin and Yang of Anxiety Disorders 
Biological psychiatry  2009;66(12):1072-1074.
PMCID: PMC2825567  PMID: 19944792
18.  The effect of pregabalin on sensorimotor gating in ‘low’ gating humans and mice 
Neuropharmacology  2012;63(3):480-485.
Pregabalin, an anticonvulsant and anxiolytic compound that binds to α2-δ auxiliary subunit Types 1 and 2 of voltage-gated calcium channels, has been shown to reduce excitatory neurotransmission partially through modulation of glutamatergic signaling. Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating impacted by disruption of the glutamatergic system and is reduced in schizophrenia patients. Dysregulation of the glutamatergic system has also been implicated in the pathophysiology of schizophrenia. Here we tested the hypothesis that pregabalin may ameliorate PPI in a model of deficient gating in humans and mice. In study 1, 14 healthy human subjects participated in a within subjects, cross-over study with placebo, 50 mg or 200 mg pregabalin treatment prior to undergoing a PPI task. In study 2, 24 C57BL/6 mice underwent a similar procedure with vehicle, 30 and 100 mg/kg dose treatments. In both studies, subjects were assigned to a “Low” or “High” gating group using a median split procedure based on their PPI performance during placebo/vehicle. Drug effects were then examined across these groups. In humans, pregabalin treatment significantly increased PPI performance in the “low gating” group. In mice, pregabalin treatment significantly increased PPI in the low gating group but reduced PPI in the high gating group. Across species, pregabalin treatment improves PPI in subjects with low gating. These data support further exploration of pregabalin as a potential treatment for disorders characterized by sensorimotor gating deficits and glutamatergic hypersignaling, such as schizophrenia.
PMCID: PMC3572212  PMID: 22575075
Schizophrenia; Pre-pulse inhibition; Glutamate; Pregabalin; Startle; Sensorimotor gating
19.  Pharmacotherapy of PTSD: Premises, Principles, and Priorities 
Brain research  2009;1293:24-39.
Post-traumatic stress disorder (PTSD) is a prevalent anxiety disorder that results in multiple disabling symptoms. Research into the underlying neurobiology has implicated dysregulation in multiple neurotransmitter systems including norepinephrine, serotonin, and glutamate as well as the hypothalamic-pituitary axis. Understanding how these biological systems interact with each other and how they may affect key neural structures, such as the amygdala, hippocampus, and prefrontal cortex, to produce post-traumatic symptoms is critical for the development of effective pharmacological treatments. We briefly discuss the proposed biological dysfunctions underlying PTSD and how agents that target these dysfunctions may be utilized in PTSD. We then provide a review of the different pharmacological agents that have been investigated in PTSD. These drugs include: antidepressants, anti-adrenergic agents, anticonvulsants, benzodiazepines, atypical antipsychotics, and novel agents.
PMCID: PMC2748176  PMID: 19332035
20.  Recent Findings in Social Phobia among Children and Adolescents 
Childhood social phobia (SP) is common and associated with varying forms of impairment. The cause of social anxiety disorder is often complex, involving both genetic and environmental factors. Shyness in young children may be a possible precursor to social anxiety later in life, although not the sole antecedent. Current assessment of childhood social anxiety includes psychometrically sound self report and clinician administered measures either specifically targeting SP disorder or including the construct as a subscale of a broader measure. The type of measure that is used most often depends on the purpose of the assessment, the setting, time constraints, and required training. Extant data support the efficacy of both psychosocial and pharmacological interventions, with response rates ranging from 50–80%. Further research is needed to clarify the developmental stages of SP, the psychometric properties of brief measures, as well as the efficacy of combined interventions.
PMCID: PMC2925835  PMID: 19728571
21.  Genetic Variation in 5HTTLPR is Associated with Emotional Resilience 
Emotional resilience can be defined as the ability to maintain healthy and stable levels of psychological functioning in the wake of stress and trauma. Although genes that contribute to psychopathology (often in interaction with environmental stressors) are being detected with increasing consistency, genes that influence resilience to stress have been less studied. In this study, 423 undergraduate college students completed a psychometrically sound 10-item self-report measure of resilience (CDRISC-10) and provided blood for DNA. Linear and logistic regression analyses were used to model relationships between the serotonin transporter promoter polymorphism (5HTTLPR) and CDRISC-10 scores and categories, respectively. CDRISC–10 scores were normally distributed (mean 26.17 SD 5.88 [range 5 – 40]). In models adjusting for ancestry proportion scores (to mitigate confounding by population stratification) and other covariates, each copy of the “s” allele of 5HTTLPR was associated with ~1-point lower CDRISC-10 score. Each copy of the “s” allele was associated with increased (adjusted OR = 1.53, 95% CI 1.06-2.21, p = 0.024) odds of being in the low resilient category (> 1 SD below the mean), compared to being homozygous for the “l” allele. These findings suggest that variation in 5HTTLPR is associated with individual differences in emotional resilience, defined as an individual's ability to withstand and bounce back from stress. This relationship may explain the frequently observed interaction between 5HTTLPR and life stressors in predicting adverse mental health outcomes (e.g., depressive symptoms). Replication is needed, in concert with identification of other genes that influence emotional resilience and related phenotypes.
PMCID: PMC2885845  PMID: 19152387
emotional resilience; stress; depression; 5HTTLPR; serotonin; gene
22.  Design of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) 
The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi-component epidemiological and neurobiological study designed to generate actionable evidence-based recommendations to reduce U.S. Army suicides and increase basic knowledge about the determinants of suicidality. This report presents an overview of the designs of the six component Army STARRS studies. These include: an integrated study of historical administrative data systems (HADS) designed to provide data on significant administrative predictors of suicides among the more than 1.6 million soldiers on active duty in 2004–2009; retrospective case-control studies of suicide attempts and fatalities; separate large-scale cross-sectional studies of new soldiers (i.e., those just beginning Basic Combat Training [BCT], who completed self-administered questionnaires [SAQ] and neurocognitive tests and provided blood samples) and soldiers exclusive of those in BCT (who completed SAQs); a pre-post deployment study of soldiers in three Brigade Combat Teams about to deploy to Afghanistan (who completed SAQs and provided blood samples) followed multiple times after returning from deployment; and a platform for following up Army STARRS participants who have returned to civilian life. DoD/Army administrative data records are linked with SAQ data to examine prospective associations between self-reports and subsequent suicidality. The presentation closes with a discussion of the methodological advantages of cross-component coordination.
PMCID: PMC3992857  PMID: 24318217
Suicide; mental disorders; U.S. Army; epidemiologic research design; design effects; sample bias; sample weights; survey design efficiency; survey sampling
23.  Field procedures in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) 
The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi-component epidemiological and neurobiological study of unprecedented size and complexity designed to generate actionable evidence-based recommendations to reduce U.S. Army suicides and increase basic knowledge about determinants of suicidality by carrying out coordinated component studies. A number of major logistical challenges were faced in implementing these studies. The current report presents an overview of the approaches taken to meet these challenges, with a special focus on the field procedures used to implement the component studies. As detailed in the paper, these challenges were addressed at the onset of the initiative by establishing an Executive Committee, a Data Coordination Center (the Survey Research Center [SRC] at the University of Michigan), and study-specific design and analysis teams that worked with staff on instrumentation and field procedures. SRC staff, in turn, worked with the Office of the Deputy Under Secretary of the Army (ODUSA) and local Army Points of Contact (POCs) to address logistical issues and facilitate data collection. These structures, coupled with careful fieldworker training, supervision, and piloting contributed to the major Army STARRS data collection efforts having higher response rates than previous large-scale studies of comparable military samples.
PMCID: PMC3992884  PMID: 24038395
Suicide; mental disorders; U.S. Army; epidemiologic research design; design effects; sample bias; sample weights; survey design efficiency; survey sampling
24.  Clinical reappraisal of the Composite International Diagnostic Interview Screening Scales (CIDI-SC) in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) 
A clinical reappraisal study was carried out in conjunction with the Army STARRS All-Army Study (AAS) to evaluate concordance of DSM-IV diagnoses based on the Composite International Diagnostic Interview screening scales (CIDI-SC) and PTSD Checklist (PCL) with diagnoses based on independent clinical reappraisal interviews (Structured Clinical Interview for DSM-IV [SCID]). Diagnoses included: lifetime mania/hypomania, panic disorder, and intermittent explosive disorder; 6-month adult attention-deficit/hyperactivity disorder; and 30-day major depressive episode, generalized anxiety disorder, PTSD, and substance (alcohol or drug) use disorder (abuse or dependence). The sample (n=460) was weighted for over-sampling CIDI-SC/PCL screened positives. Diagnostic thresholds were set to equalize false positives and false negatives. Good individual-level concordance was found between CIDI-SC/PCL and SCID diagnoses at these thresholds (AUC = .69–.79). AUC was considerably higher for continuous than dichotomous screening scale scores (AUC = .80–.90), arguing for substantive analyses using not only dichotomous case designations but also continuous measures of predicted probabilities of clinical diagnoses.
PMCID: PMC4027964  PMID: 24318219
Composite International Diagnostic Interview (CIDI); CIDI Screening Scales (CIDI-SC); diagnostic concordance; PTSD Checklist (PCL); screening scales; validity
25.  Trajectories of Change in Anxiety Severity and Impairment During and After Treatment with Evidence-Based Treatment for Multiple Anxiety Disorders in Primary Care 
Depression and anxiety  2013;30(11):1099-1106.
Coordinated Anxiety Learning and Management (CALM) is a model for delivering evidence-based treatment for anxiety disorders in primary care. Compared to usual care, CALM produced greater improvement in anxiety symptoms. However, mean estimates can obscure heterogeneity in treatment response. This study aimed to identify (1) clusters of participants with similar patterns of change in anxiety severity and impairment (trajectory groups); and (2) characteristics that predict trajectory group membership.
The CALM randomized controlled effectiveness trial was conducted in 17 primary care clinics in 4 US cities in 2006–2009. 1,004 English- or Spanish-speaking patients age 18–75 with panic, generalized anxiety, social anxiety, and/or posttraumatic stress disorder participated. The Overall Anxiety Severity and Impairment Scale was administered repeatedly to 482 participants randomized to CALM treatment. Group-based trajectory modeling was applied to identify trajectory groups and multinomial logit to predict trajectory group membership.
Two predicted trajectories, representing about two-thirds of participants, were below the cut-off for clinically significant anxiety a couple of months after treatment initiation. The predicted trajectory for the majority of remaining participants was below by nine months. A small group of participants did not show consistent improvement. Being sicker at baseline, not working, and reporting less social support were associated with less favorable trajectories.
There is heterogeneity in patient response to anxiety treatment. Adverse circumstances appear to hamper treatment response. To what extent anxiety symptoms improve insufficiently because adverse patient circumstances contribute to suboptimal treatment delivery, suboptimal treatment adherence, or suboptimal treatment response requires further investigation.
Clinical Trial Registration Identifier: NCT00347269
PMCID: PMC3902647  PMID: 23801589
Anxiety/anxiety disorders; CBT/cognitive behavior therapy; primary care; treatment; life events/stress

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