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1.  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.
doi:10.1016/j.psychres.2013.03.017
PMCID: PMC3745797  PMID: 23608160
suicidality; depression; functional impairment; PTSD; GAD; Social anxiety; panic disorder
2.  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.
doi:10.1002/mpr.1399
PMCID: PMC3992816  PMID: 24318218
Suicide; mental disorders; U.S. Army; epidemiologic research design; design effects; sample bias; sample weights; survey design efficiency; survey sampling
3.  Age differences in treatment response to a collaborative care intervention for anxiety disorders*† 
Background
Some data suggest that older adults with anxiety disorders do not respond as well to treatment as do younger adults.
Aims
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.
Method
We examined findings for the overall sample, as well as within each diagnostic category (clinicaltrials.gov identifier: NCT00347269).
Results
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.
Conclusions
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.
doi:10.1192/bjp.bp.112.118547
PMCID: PMC3696879  PMID: 23580378
4.  Evaluation of the factor structure and psychometric properties of the brief symptom inventory—18 with homebound older adults 
Objective
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.
Methods
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.
Results
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.
Conclusions
These findings provide initial evidence that the BSI-18 is valid for use with homebound older adults.
doi:10.1002/gps.2377
PMCID: PMC4070299  PMID: 20013879
measures; homebound; older adults; psychometrics; anxiety; depression
5.  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.
doi:10.1016/j.pscychresns.2012.08.006
PMCID: PMC3570713  PMID: 23154098
early life stress; anxiety; imaging; trauma; abuse; neglect
6.  Prefrontal Dysfunction during Emotion Regulation in Generalized Anxiety and Panic Disorder 
Psychological medicine  2012;43(7):1475-1486.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1017/S0033291712002383
PMCID: PMC4308620  PMID: 23111120
7.  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.
doi:10.1016/j.neuropharm.2012.04.018
PMCID: PMC3572212  PMID: 22575075
Schizophrenia; Pre-pulse inhibition; Glutamate; Pregabalin; Startle; Sensorimotor gating
8.  Imbalance of Approach and Avoidance: The Yin and Yang of Anxiety Disorders 
Biological psychiatry  2009;66(12):1072-1074.
doi:10.1016/j.biopsych.2009.09.023
PMCID: PMC2825567  PMID: 19944792
9.  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.
doi:10.1002/mpr.1401
PMCID: PMC3992857  PMID: 24318217
Suicide; mental disorders; U.S. Army; epidemiologic research design; design effects; sample bias; sample weights; survey design efficiency; survey sampling
10.  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.
doi:10.1002/mpr.1400
PMCID: PMC3992884  PMID: 24038395
Suicide; mental disorders; U.S. Army; epidemiologic research design; design effects; sample bias; sample weights; survey design efficiency; survey sampling
11.  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.
doi:10.1002/mpr.1398
PMCID: PMC4027964  PMID: 24318219
Composite International Diagnostic Interview (CIDI); CIDI Screening Scales (CIDI-SC); diagnostic concordance; PTSD Checklist (PCL); screening scales; validity
12.  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.
doi:10.1016/j.brainres.2009.03.037
PMCID: PMC2748176  PMID: 19332035
13.  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
14.  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.
doi:10.1002/ajmg.b.30916
PMCID: PMC2885845  PMID: 19152387
emotional resilience; stress; depression; 5HTTLPR; serotonin; gene
15.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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
clinicaltrials.gov Identifier: NCT00347269
doi:10.1002/da.22149
PMCID: PMC3902647  PMID: 23801589
Anxiety/anxiety disorders; CBT/cognitive behavior therapy; primary care; treatment; life events/stress
16.  Comorbidity of Borderline Personality Disorder and Posttraumatic Stress Disorder in the U.S. Population 
Journal of psychiatric research  2010;44(16):1190-1198.
While placed on different axes of the DSM classification system, borderline personality disorder (BPD) and posttraumatic stress disorder (PTSD) have important relationships with trauma, and overlap between these disorders has long been recognized. The current study is the first to examine comorbidity of PTSD and BPD in a large nationally representative sample using a reliable and valid method of assessing Axis I and II mental disorders. Data came from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Wave II (N=34,653; response rate 70.2%). Multiple regression models were used to examine differences in psychopathology, traumatic events and health-related quality of life across individuals with PTSD alone (n=1820), BPD alone (n=1290) and those with comorbid PTSD-BPD (n=643). The lifetime prevalence of PTSD and BPD were 6.6% and 5.9%, respectively. Of individuals with BPD, 30.2% were also diagnosed with PTSD, whereas 24.2% of individuals with PTSD were also diagnosed with BPD. Individuals with comorbid PTSD-BPD had a poorer quality of life, more comorbidity with other Axis I conditions, increased odds of a lifetime suicide attempt, and a higher prevalence of repeated childhood traumatic events than individuals with either condition alone. These results show that PTSD and BPD have a high degree of lifetime co-occurrence but are not entirely overlapping. Their concurrence is associated with poorer functioning compared to either diagnosis alone, emphasizing the clinical utility of diagnosing both conditions. Future research should explore the determinants of having either or both diagnoses with an aim toward improved identification, prevention, and intervention.
doi:10.1016/j.jpsychires.2010.04.016
PMCID: PMC4209725  PMID: 20537660
posttraumatic stress disorder; borderline personality disorder; comorbidity; epidemiology; suicide attempt
17.  Effects of Medical Comorbidity on Anxiety Treatment Outcomes in Primary Care 
Psychosomatic medicine  2013;75(8):713-720.
Objective
To evaluate the effects of medical comorbidity on anxiety treatment outcomes.
Methods
Data were analyzed from 1,004 primary care patients enrolled in a trial of a collaborative care intervention for anxiety. Linear mixed models accounting for baseline characteristics were used to evaluate effects of overall medical comorbidity [2 or more chronic medical conditions (CMCs) vs. fewer than 2 CMCs] and specific CMCs (migraine, asthma, and gastrointestinal disease) on anxiety treatment outcomes at 6, 12, and 18 months.
Results
At baseline, patients with two or more CMCs (n = 582; 58.0%) reported more severe anxiety symptoms [10.5 (95% CI = 10.1 to 10.9) vs. 9.5 (95% CI = 9.0 to 10.0); p = .003) and anxiety-related disability [17.6 (95% CI = 17.0 to 18.2) vs. 16.0 (95% CI = 15.3 to 16.7); p = .001). However, their clinical improvement was comparable to those with one or zero CMCs (predicted Δ in anxiety symptoms = −3.9 vs. −4.1 at 6 months, −4.6 vs. − 4.4 at 12 months, −4.9 vs. −5.0 at 18 months; predicted Δ in anxiety-related disability = −6.4 vs. −6.9 at 6 months, −6.9 vs. −7.3 at 12 months, −7.3 vs. −7.5 at 18 months). The only specific CMC with a detrimental effect was migraine, which was associated less improvement in anxiety symptoms at 18 months (predicted Δ = −4.1 vs. −5.3).
Conclusions
Effectiveness of the anxiety intervention was not significantly affected by presence of multiple CMCs; however, migraine sufferers displayed less improvement at long-term follow up.
Clinical Trials Registration
www.clinicaltrials.gov Identifier: NCT00347269
doi:10.1097/PSY.0b013e31829def54
PMCID: PMC3797868  PMID: 23886736
anxiety; medical illness; asthma; migraine; primary care; randomized controlled trial
18.  The Effects of a MAP2K5 MicroRNA Target Site SNP on Risk for Anxiety and Depressive Disorders 
Functional variants that contribute to genomewide association study (GWAS) signals are difficult to identify. MicroRNAs could contribute to some of these gene-trait relationships. We compiled a set of GWAS trait gene SNPs that were predicted to affect microRNA regulation of mRNA. Trait associations were tested in a sample of 6725 European-American (EA) and African-American (AA) subjects that were interviewed using the polydiagnostic SSADDA to diagnose major psychiatric disorders. A predicted miR-330-3p target site SNP (rs41305272) in mitogen-activated protein kinase kinase 5 (MAP2K5) mRNA was in LD (d’=1.0, r2=0.02) with a reported GWAS-identified variant for restless legs syndrome (RLS), a disorder frequently comorbid with anxiety and depression, possibly because of a shared pathophysiology. We examined the SNP’s association with mood and anxiety-related disorders. Rs41305272 was associated with agoraphobia (Ag) in EAs (odds ratio[OR]=1.95, p=0.007; 195 cases) and AAs (OR=3.2, p=0.03; 148 cases) and major depressive disorder (MDD) in AAs (OR=2.64, p=0.01; 427 cases), but not EAs (465 cases). Rs41305272*T carrier frequency was correlated with the number of anxiety and depressive disorders diagnosed per subject. RLS was not evaluated in our subjects. Predicted miR-330-3p target genes were enriched in pathways relevant to psychiatric disorders. These findings suggest that microRNA target site information may be useful in the analysis of GWAS signals for complex traits. MiR-330-3p and MAP2K5 are potentially important contributors to mood and anxiety-related traits. With support from additional studies, these findings could add to the large number of risk genes identified through association to medical disorders that have primary psychiatric effects.
doi:10.1002/ajmg.b.32219
PMCID: PMC4174417  PMID: 24436253
restless legs syndrome; depression; miR-330; MEK5; GWAS
19.  EFFECTS OF PAIN AND PRESCRIPTION OPIOID USE ON OUTCOMES IN A COLLABORATIVE CARE INTERVENTION FOR ANXIETY 
The Clinical journal of pain  2013;29(9):800-806.
Objective
To determine the effects of pain and opioid pain medication use on clinical and functional outcomes in 1004 primary care patients with an anxiety disorder randomized to receive the CALM collaborative care intervention (CBT and/or medication) versus usual care.
Methods
1004 patients with PD, GAD, SAD, or PTSD were randomized to CALM or usual care. Outcomes at 6, 12, and 18 months were compared in patients with and without moderate pain interference (for the entire anxiety disorder group and then just those with comorbid major depression) and in patients taking and not taking opioid medication (entire group, just those with comorbid major depression, and just those with moderate pain interference).
Results
Patients with pain interference and patients taking opioid pain medication were more anxious (BSI anxiety subscale) and disabled (Sheehan Disability) at baseline, improved over time at similar rates, but at 18 months had lower response and remission rates. There was no moderating effect on the intervention. In patients with comorbid major depression, patients using opioid medications showed a trend for less disability improvement over time, and in patients with pain, patients using opioids showed less sustained anxiety response at 18 months.
Conclusions
Anxious patients with pain benefit as much as those without pain from CBT and medication treatment. Among patients with pain, however, there is some evidence of a reduced anxiety treatment response in those taking opioid medication, which should be further studied.
doi:10.1097/AJP.0b013e318278d475
PMCID: PMC3644331  PMID: 23370069
pain; prescription opioid use; anxiety; depression; primary care; randomized controlled trial
20.  Perceived Social Support Mediates Anxiety and Depressive Symptom Changes Following Primary Care Intervention 
Depression and anxiety  2013;31(5):436-442.
Background
The current study tested whether perceived social support serves as a mediator of anxiety and depressive symptom change following evidence-based anxiety treatment in the primary care setting. Gender, age, and race were tested as moderators.
Methods
Data were obtained from 1004 adult patients (age M=43, SD=13; 71% female; 56% White, 20% Hispanic, 12% Black) who participated in a randomized effectiveness trial (CALM Study) comparing evidence-based intervention (cognitive-behavioral therapy and/or psychopharmacology) to usual care in the primary care setting. Patients were assessed with a battery of questionnaires at baseline, as well as at 6-, 12-, and 18-months following baseline. Measures utilized in the mediation analyses included the Abbreviated Medical Outcomes (MOS) Social Support Survey, the Brief Symptom Index (BSI) – Somatic and Anxiety subscales, and the Patient Health Questionnaire (PHQ-9).
Results
There was a mediating effect over time of perceived social support on symptom change following treatment, with stronger effects for 18-month depression than anxiety. None of the mediating pathways were moderated by gender, age, or race.
Conclusions
Perceived social support may be central to anxiety and depressive symptom changes over time with evidence-based intervention in the primary care setting. These findings possibly have important implications for development of anxiety interventions.
doi:10.1002/da.22216
PMCID: PMC4136523  PMID: 24338947
anxiety; depression; social support; primary care; intervention studies
21.  Age Differences in Treatment Response to a Collaborative Care Intervention for Anxiety Disorders 
Background
Some data suggest that older adults with anxiety disorders do not respond as well to treatment as do younger adults.
Aims
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, generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and/or social anxiety disorder (SAD). This study represents the first investigation to examine the efficacy of a collaborative care intervention in a sample that included both younger and older adults with anxiety disorders. We hypothesized that older adults would show a poorer response to the intervention than younger adults.
Methods
We examined findings for the overall sample, as well as within each diagnostic category.
Results
The CALM intervention was more effective than usual care among younger adults overall and for those with GAD, panic disorder, and SAD. Among elderly patients, the intervention was effective overall and for those with SAD and PTSD but not for those with panic disorder or GAD. 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.
Conclusions
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.
doi:10.1192/bjp.bp.112.118547
PMCID: PMC3696879  PMID: 23580378
Aged; Elderly; Geriatric; Cognitive-behavioral; Pharmacotherapy; Computer; Treatment
22.  The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) 
Psychiatry  2014;77(2):107-119.
Importance/Objective
Although the suicide rate in the U.S. Army has traditionally been below age-gender matched civilian rates, it has climbed steadily since the beginning of the Iraq and Afghanistan conflicts and since 2008 has exceeded the demographically matched civilian rate. The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multicomponent epidemiological and neurobiological study designed to generate actionable evidence-based recommendations to reduce Army suicides and increase knowledge about risk and resilience factors for suicidality and its psychopathological correlates. This paper presents an overview of the Army STARRS component study designs and of recent findings.
Design/Setting/Participants/Intervention
Army STARRS includes six main component studies: (1) the Historical Administrative Data Study (HADS) of Army and Department of Defense (DoD) administrative data systems (including records of suicidal behaviors) for all soldiers on active duty 2004–2009 aimed at finding administrative record predictors of suicides; (2) retrospective case-control studies of fatal and nonfatal suicidal behaviors (each planned to have n = 150 cases and n = 300 controls); (3) a study of new soldiers (n = 50,765 completed surveys) assessed just before beginning basic combat training (BCT) with self-administered questionnaires (SAQ), neurocognitive tests, and blood samples; (4) a cross-sectional study of approximately 35,000 (completed SAQs) soldiers representative of all other (i.e., exclusive of BCT) active duty soldiers; (5) a pre-post deployment study (with blood samples) of soldiers in brigade combat teams about to deploy to Afghanistan (n = 9,421 completed baseline surveys), with sub-samples assessed again one, three, and nine months after returning from deployment; and (6) a pilot study to follow-up SAQ respondents transitioning to civilian life. Army/DoD administrative data are being linked prospectively to the large-scale survey samples to examine predictors of subsequent suicidality and related mental health outcomes.
Main outcome measures
Measures (self-report and administratively recorded) of suicidal behaviors and their psychopathological correlates.
Results
Component study cooperation rates are comparatively high. Sample biases are relatively small. Inefficiencies introduced into parameter estimates by using nonresponse adjustment weights and time-space clustering are small. Initial findings show that the suicide death rate, which rose over 2004–2009, increased for those deployed, those never deployed, and those previously deployed. Analyses of administrative records show that those deployed or previously deployed were at greater suicide risk. Receiving a waiver to enter the Army was not associated with increased risk. However, being demoted in the past two years was associated with increased risk. Time in current deployment, length of time since return from most recent deployment, total number of deployments, and time interval between most recent deployments (known as dwell time) were not associated with suicide risk. Initial analyses of survey data show that 13.9% of currently active non-deployed regular Army soldiers considered suicide at some point in their lifetime, while 5.3% had made a suicide plan, and 2.4% had attempted suicide. Importantly, 47–60% of these outcomes first occurred prior to enlistment. Prior mental disorders, in particular major depression and intermittent explosive disorder, were the strongest predictors of these self-reported suicidal behaviors. Most onsets of plans-attempts among ideators (58.3–63.3%) occurred within the year of onset of ideation. About 25.1% of non-deployed U.S. Army personnel met 30-day criteria for a DSM-IV anxiety, mood, disruptive behavior, or substance disorder (15.0% an internalizing disorder; 18.4% an externalizing disorder) and 11.1% for multiple disorders. Importantly, three-fourths of these disorders had pre-enlistment onsets.
Conclusions
Integration across component studies creates strengths going well beyond those in conventional applications of the same individual study designs. These design features create a strong methodological foundation from which Army STARRS can pursue its substantive research goals. The early findings reported here illustrate the importance of the study and its approach as a model of studying rare events particularly of national security concern. Continuing analyses of the data will inform suicide prevention for the U.S. Army.
doi:10.1521/psyc.2014.77.2.107
PMCID: PMC4075436  PMID: 24865195
23.  Medical conditions and depressive, anxiety, and somatic symptoms in older adults with and without generalized anxiety disorder 
Aging & mental health  2010;14(6):764-768.
Objective
The objective of this study was to examine medical illness and anxiety, depressive, and somatic symptoms in older medical patients with generalized anxiety disorder (GAD).
Method
A case-control study was designed and conducted in the University of California, San Diego (UCSD) Geriatrics Clinics. A total of fifty-four older medical patients with GAD and 54 matched controls participated.
Measurements
The measurements used for this study include: Brief Symptom Inventory – 18, Mini International Neuropsychiatric Interview, and the Anxiety Disorders Interview Schedule.
Results
Older medical patients with GAD reported higher levels of somatic symptoms, anxiety, and depression than other older adults, as well as higher rates of diabetes and gastrointestinal conditions. In a multivariate model that included somatic symptoms, medical conditions, and depressive and anxiety symptoms, anxiety symptoms were the only significant predictors of GAD.
Conclusion
These results suggest first, that older medical patients with GAD do not primarily express distress as somatic symptoms; second, that anxiety symptoms in geriatric patients should not be discounted as a byproduct of medical illness or depression; and third, that older adults with diabetes and gastrointestinal conditions may benefit from screening for anxiety.
doi:10.1080/13607861003713240
PMCID: PMC4066633  PMID: 20635235
elderly; somatization; depression
24.  Use of Complementary and Alternative Medicine in a Large Sample of Anxiety Patients 
Psychosomatics  2012;53(3):266-272.
Objective
To examine a large sample of patients with anxiety and the association between types of complementary and alternative treatments that were used, demographic variables, diagnostic categories, and treatment outcomes.
Method
Cross-sectional and longitudinal survey during the Coordinated Anxiety Learning and Management (CALM) study that assessed this intervention against the Usual Care in a sample of patients with anxiety recruited from primary care. Interviewer-administered questionnaires via a centralized telephone survey by blinded assessment raters. The interviews were done at baseline, 6, 12, and 18 months of the study. A total of 1004 adults ages 18–75 who met DSM-IV criteria for Generalized Anxiety Disorder (GAD), Panic Disorder, Social Anxiety Disorder, or Post-Traumatic Stress Disorder. We assessed medication/herbal use, the use of any alternative therapies, and combined Complementary and Alternative Medicine (CAM) use.
Results
We found an extensive (43%) use of a variety of CAM treatments that is consistent with previous study results in populations with anxiety. Only a few significant demographic or interventional characteristics of CAM users were found. Users most often had a diagnosis of GAD, were older, more educated, and had two or more chronic medical conditions. CAM users who had a 50% or more drop in anxiety scores over 18 months were less likely to report continued use of alternative therapies.
Conclusions
The study confirms the importance of awareness of CAM use in this population for possible interference with traditional first-line treatments of these disorders, but also for finding the best integrative use for patients who require multiple treatment modalities.
doi:10.1016/j.psym.2011.11.009
PMCID: PMC4014348  PMID: 22304968
25.  Anxiety treatment improves physical functioning with oblique scoring of the SF-12 Short Form Health Survey☆ 
General hospital psychiatry  2013;35(3):291-296.
Objective
No studies have found a positive effect of anxiety treatment on physical functioning, but recent investigations of the 12-item Short Form Health Questionnaire (SF-12), which is frequently used to assess physical functioning, have suggested that orthogonal scoring of the summary measure may distort representations of physical health. The current study reanalyzes whether anxiety treatment improves physical functioning using oblique scoring in the Coordinated Anxiety Learning and Management (CALM) randomized clinical trial for the treatment of anxiety disorders. Replication was tested in reanalysis of data from the earlier Collaborative Care for Anxiety and Panic (CCAP) randomized clinical trial for the treatment of panic disorder.
Method
The CALM study included 1004 primary care patients with panic, social anxiety, generalized anxiety or posttraumatic stress disorders. Patients received usual care (UC) or an evidence-based intervention (cognitive behavioral therapy, psychotropic medication or both; ITV). Physical functioning (SF-12v2) was assessed at baseline and at 6, 12 and 18 months. Oblique and orthogonal scoring methods for the physical functioning aggregate measure from SF-12 scale items were compared.
Results
In CALM, physical functioning improved to a greater degree in ITV than UC for oblique but not orthogonal scoring. Findings were replicated in the CCAP data.
Conclusions
Evidence-based treatment for anxiety disorders in primary care improves physical functioning when measured using oblique scoring of the SF-12. Due to this scoring issue, effects of mental health treatment on physical functioning may have been understated.
doi:10.1016/j.genhosppsych.2012.12.004
PMCID: PMC3747957  PMID: 23332608
Short Form Health Survey; Anxiety; Measurement; Physical functioning; Physical health; Health psychology

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