Development and cross-validation of a veterans mental health risk factor screen.

BACKGROUND: VA primary care patients are routinely screened for current symptoms of PTSD, depression, and alcohol disorders, but many who screen positive do not engage in care. In addition to stigma about mental disorders and a high value on autonomy, some veterans may not seek care because of uncertainty about whether they need treatment to recover. A screen for mental health risk could provide an alternative motivation for patients to engage in care. METHOD: Data from samples of veterans and traumatic injury survivors were analyzed to identify mental health risk factors that are characteristics of individuals or stressors or of post-trauma, post-deployment, or post-military service resources, experiences, or responses. Twelve risk factors were strongly related to PTSD (r > .50): current PTSD, depression, dissociation, negative thinking, and emotional lability symptoms, life stress, relationship stress, social constraints, and deployment experiences of a difficult environment, concerns about life and family, perceived threat, and moral injury. Items assessing each of these risk factors were selected and their validity to prospectively predict PTSD and/or depression 6 months later was assessed in a new sample of 232 VA primary care patients. RESULTS: Twelve items assessing dissociation, emotional lability, life stress, and moral injury correctly classified 86% of those who later had elevated PTSD and/or depression symptoms (sensitivity) and 75% of those whose later symptoms were not elevated (specificity). Performance was also very good for 110 veterans who identified as members of ethnic/racial minorities. CONCLUSIONS: Mental health status was prospectively predicted in VA primary care patients with high accuracy using a screen that is brief, easy to administer, score, and interpret, and fits well into VA's integrated primary care. When care is readily accessible, appealing to veterans, and not perceived as stigmatizing, information about mental health risk may result in higher rates of engagement than information about current mental disorder status.

Amygdala and Insula Connectivity Changes Following Psychotherapy for Posttraumatic Stress Disorder: A Randomized Clinical Trial.

BACKGROUND: Exposure-based psychotherapy is a first-line treatment for posttraumatic stress disorder (PTSD), but its mechanisms are poorly understood. Functional brain connectivity is a promising metric for identifying treatment mechanisms and biosignatures of therapeutic response. To this end, we assessed amygdala and insula treatment-related connectivity changes and their relationship to PTSD symptom improvements. METHODS: Individuals with a primary PTSD diagnosis (N = 66) participated in a randomized clinical trial of prolonged exposure therapy (n = 36) versus treatment waiting list (n = 30). Task-free functional magnetic resonance imaging was completed prior to randomization and 1 month following cessation of treatment/waiting list. Whole-brain blood oxygenation level-dependent responses were acquired. Intrinsic connectivity was assessed by subregion in the amygdala and insula, limbic structures key to the disorder pathophysiology. Dynamic causal modeling assessed evidence for effective connectivity changes in select nodes informed by intrinsic connectivity findings. RESULTS: The amygdala and insula displayed widespread patterns of primarily subregion-uniform intrinsic connectivity change, including increased connectivity between the amygdala and insula; increased connectivity of both regions with the ventral prefrontal cortex and frontopolar and sensory cortices; and decreased connectivity of both regions with the left frontoparietal nodes of the executive control network. Larger decreases in amygdala-frontal connectivity and insula-parietal connectivity were associated with larger PTSD symptom reductions. Dynamic causal modeling evidence suggested that treatment decreased left frontal inhibition of the left amygdala, and larger decreases were associated with larger symptom reductions. CONCLUSIONS: PTSD psychotherapy adaptively attenuates functional interactions between frontoparietal and limbic brain circuitry at rest, which may reflect a potential mechanism or biosignature of recovery.

Rethinking Violence Prevention in Rural and Underserved Communities: How Veteran Peer Support Groups Help Participants Deal with Sequelae from Violent Traumatic Experiences.

PURPOSE: Access to mental health care and programs that address violence prevention can be a challenge for veterans residing in rural and underserved areas. A growing number of trauma-affected veterans are now returning to rural areas upon completion of military service. The Palo Alto VA Health Care System has piloted a program known as the Peer Support Program (PSP) where certified peer support specialists hold group sessions for their fellow veterans in remote, community-based outpatient clinics. METHODS: A total of 29 peer-support group participants and 1 certified peer specialist were interviewed. Semistructured interviews began with open-ended questions regarding participant firsthand experiences with the support group setting. These were followed by direct questions that addressed the role of the PSP, expectations for the PSP, as well as benefits and limitations of the program. We performed a domain analysis using the Spradley ethnographic method on 325 pages of compiled narrative data focusing on violence-related themes. FINDINGS: Four key themes emerged, including: 1) Violence in Military Training Not Acceptable in Civilian Life, 2) Peer Support Creates the Trust to Speak Freely, 3) Skills Are Taught to Defuse Violence, and 4) The Veteran Peer Support Specialist Relationship Is Multi-Dimensional. CONCLUSIONS: These emergent themes illustrate how trauma-focused assistance rendered by peer support specialists as part of an interdisciplinary mental health team can be implemented to benefit trauma-affected individuals and their communities in the prevention of future violence.

Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder.

A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.

Peer support in an outpatient program for veterans with posttraumatic stress disorder: Translating participant experiences into a recovery model.

Veterans returning from recent conflicts present with increased rates of posttraumatic stress disorder (PTSD), and veterans from prior service eras continue to seek trauma-based services. Peer support for veterans with PTSD has the potential to resolve ongoing challenges in access and engagement in mental health care. Assessing the value of peer support services requires a thorough understanding of the expected role and the empirical mechanisms of peer support participation in PTSD recovery. To better understand these mechanisms, this study interviewed 29 veteran participants from an established peer support program (PSP), located in the Central Valley of the Veterans Affairs (VA) Palo Alto Health Care System (VAPAHCS) in Northern California. A domain analysis of narrative transcripts generated 34 codes through a grounded theory method. Codes were organized into the following thematic categories: the perceived role of the PSP, supportive experiences of the PSP, global gains from the PSP, and limitations to PSP and further mental health engagement. These results were synthesized into a theoretical model that identifies improved functioning and reduced distress as the expected outcomes of PSP-mediated recovery and illustrates the continuum from in-group experiences to these outcomes. Our results suggest that PSP-mediated recovery is defined as acceptance of PTSD into daily life and identity, rather than resolution of symptoms. This conceptualization has implications for peer support provider training, PSP integration into health care settings, and future outcome analyses on the effectiveness of PSPs. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Selective Effects of Psychotherapy on Frontopolar Cortical Function in PTSD.

OBJECTIVE: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but a comprehensive, emotion-focused perspective on how psychotherapy affects brain function is lacking. The authors assessed changes in brain function after prolonged exposure therapy across three emotional reactivity and regulation paradigms. METHOD: Individuals with PTSD underwent functional MRI (fMRI) at rest and while completing three tasks assessing emotional reactivity and regulation. Individuals were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30) and underwent a second scan approximately 4 weeks after the last treatment session or a comparable waiting period, respectively. RESULTS: Treatment-specific changes were observed only during cognitive reappraisal of negative images. Psychotherapy increased lateral frontopolar cortex activity and connectivity with the ventromedial prefrontal cortex/ventral striatum. Greater increases in frontopolar activation were associated with improvement in hyperarousal symptoms and psychological well-being. The frontopolar cortex also displayed a greater variety of temporal resting-state signal pattern changes after treatment. Concurrent transcranial magnetic stimulation and fMRI in healthy participants demonstrated that the lateral frontopolar cortex exerts downstream influence on the ventromedial prefrontal cortex/ventral striatum. CONCLUSIONS: Changes in frontopolar function during deliberate regulation of negative affect is one key mechanism of adaptive psychotherapeutic change in PTSD. Given that frontopolar connectivity with ventromedial regions during emotion regulation is enhanced by psychotherapy and that the frontopolar cortex exerts downstream influence on ventromedial regions in healthy individuals, these findings inform a novel conceptualization of how psychotherapy works, and they identify a promising target for stimulation-based therapeutics.

PTSD Psychotherapy Outcome Predicted by Brain Activation During Emotional Reactivity and Regulation.

OBJECTIVE: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but many patients do not respond. Brain functions governing treatment outcome are not well characterized. The authors examined brain systems relevant to emotional reactivity and regulation, constructs that are thought to be central to PTSD and exposure therapy effects, to identify the functional traits of individuals most likely to benefit from treatment. METHOD: Individuals with PTSD underwent functional MRI (fMRI) while completing three tasks assessing emotional reactivity and regulation. Participants were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30). A random subset of the prolonged exposure group (N=17) underwent single-pulse transcranial magnetic stimulation (TMS) concurrent with fMRI to examine whether predictive activation patterns reflect causal influence within circuits. Linear mixed-effects modeling in line with the intent-to-treat principle was used to examine how baseline brain function moderated the effect of treatment on PTSD symptoms. RESULTS: At baseline, individuals with larger treatment-related symptom reductions (compared with the waiting list condition) demonstrated 1) greater dorsal prefrontal activation and 2) less left amygdala activation, both during emotion reactivity; 3) better inhibition of the left amygdala induced by single TMS pulses to the right dorsolateral prefrontal cortex; and 4) greater ventromedial prefrontal/ventral striatal activation during emotional conflict regulation. Reappraisal-related activation was not a significant moderator of the treatment effect. CONCLUSIONS: Capacity to benefit from prolonged exposure in PTSD is gated by the degree to which prefrontal resources are spontaneously engaged when superficially processing threat and adaptively mitigating emotional interference, but not when deliberately reducing negative emotionality.

An RCT of Effects of Telephone Care Management on Treatment Adherence and Clinical Outcomes Among Veterans With PTSD.

OBJECTIVE: This study assessed whether adding telephone care management to usual outpatient mental health care improved treatment attendance, medication compliance, and clinical outcomes of veterans with posttraumatic stress disorder (PTSD). METHODS: In a multisite randomized controlled trial, 358 veterans were assigned to either usual outpatient mental health treatment (N=165) or usual care plus twice-a-month telephone care management (TCM) and support in the first three months of treatment (N=193). Treatment utilization and medication refills were determined from U.S. Department of Veterans Affairs administrative data. PTSD, depression, quality of life, aggressive behavior, and substance use were assessed with self-report questionnaires at intake, four months, and 12 months. RESULTS: Telephone care managers reached 95% of TCM participants (N=182), completing an average 5.1 of 6.0 planned telephone calls. During the three-month intervention period, TCM participants completed 43% more mental health visits (M±SD=5.9±6.8) than did those in usual care (4.1±4.2) (incident rate ratio=1.36, χ2=6.56, df=1, p<.01). Treatment visits in the nine-month follow-up period and medication refills did not differ by condition. Only 9% of participants were scheduled to receive evidence-based psychotherapy. Slopes of improvement in PTSD, depression, alcohol misuse, drug problems, aggressive behavior, and quality of life did not differ by condition or treatment attendance. CONCLUSIONS: TCM improved PTSD patients' treatment attendance but not their outcomes. TCM can enhance treatment engagement, but outcomes depend on the effectiveness of the treatments that patients receive.

Participatory System Dynamics Modeling: Increasing Stakeholder Engagement and Precision to Improve Implementation Planning in Systems.

Implementation planning typically incorporates stakeholder input. Quality improvement efforts provide data-based feedback regarding progress. Participatory system dynamics modeling (PSD) triangulates stakeholder expertise, data and simulation of implementation plans prior to attempting change. Frontline staff in one VA outpatient mental health system used PSD to examine policy and procedural "mechanisms" they believe underlie local capacity to implement evidence-based psychotherapies (EBPs) for PTSD and depression. We piloted the PSD process, simulating implementation plans to improve EBP reach. Findings indicate PSD is a feasible, useful strategy for building stakeholder consensus, and may save time and effort as compared to trial-and-error EBP implementation planning.

Psychotic-like experiences, symptom expression, and cognitive performance in combat veterans with posttraumatic stress disorder.

Apparent psychotic symptoms are often associated with posttraumatic stress disorder (PTSD), but these symptoms are poorly understood. In a sample of 30 male Vietnam combat veterans with severe and chronic PTSD, we conducted detailed assessments of psychotic symptom endorsement, insight, symptom severity, neurocognitive function, and feigning. Two thirds of the subjects endorsed a psychotic item but did not believe that the experiences were real. Those endorsing psychotic items were higher in PTSD severity, general psychopathology, and dissociation but not depression, functional health, cognitive function, or feigned effort. Severity of psychotic symptoms correlated with dissociation, combat exposure, and attention but not PTSD, depression, or functional health. Those endorsing psychotic items scored higher on a screen but not on a detailed structured interview for malingering. Endorsement of psychotic experiences by combat veterans with PTSD do not seem to reflect psychotic symptoms or outright malingering.

Hypothalamic-pituitary-adrenal axis physiology and cognitive control of behavior in stress inoculated monkeys.

Monkeys exposed to stress inoculation protocols early in life subsequently exhibit diminished neurobiological responses to moderate psychological stressors and enhanced cognitive control of behavior during juvenile development compared to non-inoculated monkeys. The present experiments extended these findings and revealed that stress inoculated monkeys: (a) mount neurobiological responses equivalent to non-inoculated monkeys when the stressor is of sufficient intensity, and (b) continue to exhibit enhanced cognitive control as young adults compared to non-inoculated monkeys. These results suggest that stress inoculation protocols alter the appraisal of and response to moderate stressors as less threatening and permanently enhance cognitive control, at least through early adulthood. These data therefore support the notion that the stress inoculation phenotype reflects stress resilience rather than stress pathology.

A randomized, double-blind, placebo-controlled trial of augmentation topiramate for chronic combat-related posttraumatic stress disorder.

BACKGROUND: Topiramate, a novel anticonvulsant, has been reported to rapidly reduce symptoms of posttraumatic stress disorder (PTSD) in an open-label trial. The present study was designed as a test of topiramate's efficacy as adjunctive therapy in a 7-week, randomized, double-blind, placebo-controlled trial. METHODS: Forty male veterans with PTSD in a residential treatment program were randomized to flexible-dose topiramate or placebo augmentation. The primary outcome measures were PTSD symptom severity and global symptom improvement. RESULTS: Baseline Clinician-Administered PTSD Scale scores were 62.1 +/- 13.9 for placebo and 61.0 +/- 22.2 for topiramate. There was a high dropout rate from the study (55% topiramate; 25% placebo), with 40% of topiramate and 10% of placebo dropping because of adverse events (AEs). No significant treatment effects of topiramate versus placebo were observed for the primary treatment outcomes. Subjects reporting central nervous system-related AEs and with higher baseline severity of depression were more likely to discontinue because of AEs. CONCLUSIONS: Primary outcome measures failed to demonstrate a significant effect for topiramate over placebo; however, high dropout rate in the treatment group prohibits definitive conclusions about the efficacy of topiramate in this population.

Early life stress and novelty seeking behavior in adolescent monkeys.

Recent evidence suggests that early exposure to mild stress promotes the development of novelty seeking behavior. Here we test this hypothesis in squirrel monkeys and investigate whether novelty seeking behavior is associated with differences in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the dopamine metabolite homovanillic acid (HVA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the neuropeptide corticotrophin-releasing factor (CRF). Monkeys were randomized early in life to either mild intermittent stress (IS) or no stress (NS) conditions, and subsequently presented with opportunities to interact with a familiar or novel object in a test box that was connected to each monkey's home cage. To further minimize the potentially stressful nature of the test situation, monkeys were acclimated to the test procedures prior to study initiation. Post-test plasma levels of cortisol in IS and NS monkeys did not differ significantly from baseline levels measured in undisturbed conditions. During testing, more IS than NS monkeys voluntarily left the home cage, and IS monkeys spent more time in the test box compared to NS monkeys. More IS than NS monkeys engaged in object exploration in the test box, and IS monkeys preferred to interact with the novel vs. familiar object. Novelty seeking was not associated with differences in 5HIAA, HVA, MHPG, or CRF, but correlated with differences in object exploration observed in a different test situation at an earlier age. These trait-like differences in novelty seeking appear to reflect mild early stress-induced adaptations that enhance curiosity and resilience.

No improvement of posttraumatic stress disorder symptoms with guanfacine treatment.

OBJECTIVE: The authors report an 8-week, double-blind, randomized controlled trial of guanfacine versus placebo for posttraumatic stress disorder (PTSD). METHOD: Veterans with chronic PTSD who were medication-free or receiving stable pharmacotherapy were randomly assigned to guanfacine (N=29) versus placebo (N=34). RESULTS: Guanfacine had no effect on PTSD symptoms, subjective sleep quality, or general mood disturbances. Guanfacine was associated with a number of side effects. CONCLUSIONS: These results do not support the use of alpha 2 agonists in veterans with chronic PTSD.

Monoamine oxidase and catechol-o-methyltransferase enzyme activity and gene expression in response to sustained glucocorticoids.

We previously reported changes in DA neurochemical estimates after sustained corticosterone (CORT) administration or adrenalectomy (ADX) that are consistent with glucocorticoid-induced inhibition of DA metabolism. The present investigation measured monoamine oxidase type A (MAO-A), type B (MAO-B) and catechol-o-methyltransferase (COMT) activity by enzymatic assay and levels of gene expression by real-time quantitative polymerase chain reaction (rt-PCR) in tissues from sham, ADX, or ADX+CORT-replaced Lewis rats. One week of ADX had no significant effect on either enzyme activity or gene expression for any of the three enzymes examined in the medial prefrontal cortex, striatum, or liver. One week of CORT administration (100mg-21 day release pellet) in ADX rats produced statistically significant decreases in MAO-A enzyme activity and MAO-B gene expression in the liver but no significant changes for any of the three enzymes in either activity or gene expression in the medial prefrontal cortex or striatum. The results do not support inhibition of DA metabolism as a mechanism by which glucocorticoids influence DA-mediated behaviors.

Basal and dexamethasone suppressed salivary cortisol concentrations in a community sample of patients with posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with lower concentrations of cortisol and enhanced suppression of cortisol by dexamethasone, although discrepancies exist among reports. The objective of the study was to determine the pattern of cortisol responses in patients seeking treatment for PTSD resulting from a variety of traumatic experiences and to test whether cortisol responses are significantly related to childhood trauma, severity of symptoms, or length of time since trauma. METHODS: Salivary cortisol was measured at 8 AM, 4 PM, and 10 PM on 2 consecutive days before and after a 10 PM dose of .5 mg dexamethasone in 17 psychotropic medication and substance-free subjects with PTSD and 17 matched control subjects. RESULTS: Repeated-measures analysis of variance (ANOVA) of the baseline salivary cortisol concentrations demonstrated a significant effect for group with higher concentrations in the PTSD group but no significant differences in responses to dexamethasone. The presence of childhood abuse did not significantly affect salivary cortisol concentrations, and there was no correlation between predexamethasone cortisol and either the severity of PTSD symptoms or the time since the index trauma. CONCLUSIONS: Neither low basal concentrations nor enhanced suppression of cortisol are consistent markers of a PTSD diagnosis.

Mesotelencephalic dopamine neurochemical responses to glucocorticoid administration and adrenalectomy in Fischer 344 and Lewis rats.

The effects of alterations in peripheral corticosterone levels on multiple dopamine neurochemical estimates were examined in inbred Fischer and Lewis inbred rat strains. 2x2 ANOVA's (treatment x strain) showed a main effect for treatment (1 week CORT versus placebo) on the concentrations of the dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid in the medial prefrontal cortex, with lower levels after treatment, but no significant treatment versus strain interaction. There was no effect of CORT treatment on DA metabolites in the nucleus accumbens shell or dorsal striatum. DOPA accumulation in any terminal region examined and tyrosine hydroxylase protein content in the ventral tegmental area were also not affected by 1 week of corticosterone in either strain. One week after adrenalectomy, homovanillic acid but not dihydroxyphenylacetic acid concentrations were significantly increased in the medial prefrontal cortex, dorsal striatum, and nucleus accumbens shell in the Lewis but not the Fischer strain, with a significant treatment x strain interaction only in the dorsal striatum. Based on these findings, the effect of adrenalectomy on DOPA accumulation and extracellular DA concentrations was examined in the Lewis strain only. Adrenalectomy produced a decrease in DOPA accumulation in the dorsal striatum with no significant change in the other regions. Adrenalectomy did not alter estimates of extracellular dopamine concentrations determined by in vivo no net flux microdialysis but did significantly increase in vivo dopamine recovery in the dorsal striatum. The findings indicate a pattern of changes in neurochemical measurements consistent with a small magnitude inhibition of basal dopamine metabolism, but not with a change neuronal activity, release or reuptake.