Electroconvulsive Therapy Changes Immunological Markers in Patients With Major Depressive Disorder: A Scoping Review.

ABSTRACT: Major depressive disorder (MDD) is a highly prevalent and disabling condition. As such, understanding the causes of and treatment options for MDD is critical. Electroconvulsive therapy (ECT) remains the gold standard depression treatment, but the molecular mechanisms that underlie its effects are still largely unknown. One such explanation hinges on the immuno-inflammatory correlates of ECT treatment, given mounting evidence supporting the inflammatory hypothesis of depression. This review aims to provide an overview of the suggested immunomodulatory effects of ECT and the predictive value of immune biomarkers in relation to treatment outcomes and side effects. We conducted a preregistered, systematic literature search utilizing MEDLINE (PubMed), Embase (Elsevier), and PsycINFO (EBSCO) databases. We employed keywords related to MDD, ECT, gut microbiome, and the immune system. We only included human subjects research published between 1985 and January 13, 2021. Twenty-six unique studies were included in our analyses. Findings indicate a proinflammatory profile associated with MDD, with immune biomarkers exhibiting acute and chronic changes following ECT. Consistently, lower baseline interleukin 6 levels and higher C-reactive protein levels are correlated with a greater reduction in depressive symptoms following ECT. Furthermore, included studies emphasize the predictive value of peripheral immune changes, specifically interleukin 6 and tumor necrosis factor α, on cognitive outcomes following ECT. Given these results, further exploration of the potential roles of immunomodulatory effects on ECT treatment outcomes, as well as adverse cognitive side effects, is indicated.

Anxiety sensitivity and cannabis use motives among trauma-exposed young adult cannabis users.

BACKGROUND AND OBJECTIVES: Anxiety sensitivity, or fear of anxious arousal, may be an important risk factor for problematic cannabis use. Specifically, anxiety sensitivity may motivate cannabis use to cope with distress, particularly among trauma-exposed individuals. The current study tested associations among anxiety sensitivity, its subdomains, and cannabis use motives in a sample of trauma-exposed cannabis users. We hypothesized elevated anxiety sensitivity, particularly cognitive concerns, would be associated with increased maladaptive coping use motives, after covarying for the number of traumas and cannabis use quantity. METHOD: Hypotheses were tested in a cross-sectional study of trauma-exposed young adult cannabis users (N = 56) (Mage = 20.7 years, 59% women, 73% white). Participants completed self-report measures, and a clinical interview assessing cannabis use quantity. RESULTS: Multiple regression analyses indicated that elevated anxiety sensitivity was associated with increased cannabis use coping motives, after covarying for the number of traumas experienced and cannabis use quantity. Specifically, higher levels of anxiety sensitivity cognitive and social concerns were associated with coping motives for cannabis use. DISCUSSION AND CONCLUSIONS: Anxiety sensitivity, particularly concerns about cognitive dyscontrol and negative social evaluations of anxious arousal, may motivate cannabis use to cope with stress among trauma-exposed cannabis users. Future research should include prospective studies with diverse samples to replicate results and determine whether intervening on anxiety sensitivity could reduce maladaptive coping motives for cannabis use. SCIENTIFIC SIGNIFICANCE: The current study replicates prior research indicating anxiety sensitivity, particularly cognitive concerns, is associated with maladaptive cannabis use. Expanding on prior research, findings indicated anxiety sensitivity is associated with coping motives for cannabis use among trauma-exposed cannabis users.

Multimodal smoking cessation treatment combining repetitive transcranial magnetic stimulation, cognitive behavioral therapy, and nicotine replacement in veterans with posttraumatic stress disorder: A feasibility randomized controlled trial protocol.

Tobacco-related deaths remain the leading cause of preventable death in the United States. Veterans suffering from posttraumatic stress disorder (PTSD)-about 11% of those receiving care from the Department of Veterans Affairs (VA)-have triple the risk of developing tobacco use disorder (TUD). The most efficacious strategies being used at the VA for smoking cessation only result in a 23% abstinence rate, and veterans with PTSD only achieve a 4.5% abstinence rate. Therefore, there is a critical need to develop more effective treatments for smoking cessation. Recent studies suggest the insula is integrally involved in the neurocircuitry of TUD. Thus, we propose a feasibility phase II randomized controlled trial (RCT) to study a form of repetitive transcranial magnetic stimulation (rTMS) called intermittent theta burst stimulation (iTBS). iTBS has the advantage of allowing for a patterned form of stimulation delivery that we will administer at 90% of the subject's resting motor threshold (rMT) applied over a region in the right post-central gyrus most functionally connected to the right posterior insula. We hypothesize that by increasing functional connectivity between the right post-central gyrus and the right posterior insula, withdrawal symptoms and short-term smoking cessation outcomes will improve. Fifty eligible veterans with comorbid TUD and PTSD will be randomly assigned to active-iTBS + cognitive behavioral therapy (CBT) + nicotine replacement therapy (NRT) (n = 25) or sham-iTBS + CBT + NRT (n = 25). The primary outcome, feasibility, will be determined by achieving a recruitment of 50 participants and retention rate of 80%. The success of iTBS will be evaluated through self-reported nicotine use, cravings, withdrawal symptoms, and abstinence following quit date (confirmed by bioverification) along with evaluation for target engagement through neuroimaging changes, specifically connectivity differences between the insula and other regions of interest.

Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans.

Introduction: The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown. Methods: To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans. Results: Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR q-value <0.05), including cg13301722 on chromosome 7, which lies between the genes SLC4A2 and CDK5; cg04724646 in PDE3A; and cg04999352 in RARRES3. cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans. Discussion: Taken together, the present findings suggest that SLC4A2, CDK5, PDE3A, and RARRES3 may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples.

Multimodal smoking cessation treatment combining transcranial magnetic stimulation, cognitive behavioral therapy, and nicotine replacement therapy in veterans with posttraumatic stress disorder: A feasibility randomized controlled trial protocol.

Tobacco-related deaths exceed those resulting from homicides, suicides, motor vehicle accidence, alcohol consumption, illicit substance use, and acquired immunodeficiency syndrome (AIDS), combined. Amongst U.S. veterans, this trend is particularly concerning given that those suffering from posttraumatic stress disorder (PTSD)-about 11% of those receiving care from the Department of Veterans Affairs (VA)-have triple the risk of developing tobacco use disorder (TUD). The most efficacious strategies being used at the VA for smoking cessation only result in a 23% abstinence rate, and veterans with PTSD only achieve a 4.5% abstinence rate. Therefore, there is a critical need to develop more effective treatments for smoking cessation. Recent studies have revealed the insula as integrally involved in the neurocircuitry of TUD, specifically showing that individuals with brain lesions involving this region had drastically improved quit rates. Some of these studies show a probability of quitting up to 5 times greater compared to non-insula lesioned regions). Altered activity of the insula may be involved in the disruption of the salience network's (SN) connectivity to the executive control network (ECN), which compromises that patient's ability to switch between interoceptive states focused on cravings to executive and cognitive control. Thus, we propose a feasibility phase II randomized controlled trial (RCT) to study a patterned form of repetitive transcranial magnetic stimulation (rTMS), intermittent theta burst stimulation (iTBS), at 90% of the subject's resting motor threshold (rMT) applied over a region in the right post-central gyrus most functionally connected to the right posterior insula. We hypothesize that by increasing functional connectivity between the SN with the ECN to enhance executive control and by decreasing connectivity with the default mode network (DMN) to reduce interoceptive focus on withdrawal symptoms, we will improve smoking cessation outcomes. Fifty eligible veterans with comorbid TUD and PTSD will be randomly assigned to two conditions: active-iTBS + cognitive behavioral therapy (CBT) + nicotine replacement therapy (NRT) (n=25) or sham-iTBS + CBT + NRT (n=25). The primary outcome, feasibility, will be determined by achieving a recruitment of 50 participants and retention rate of 80%. The success of iTBS will be evaluated through self-reported nicotine use, cravings, withdrawal symptoms, and abstinence following quit date (confirmed by bioverification) along with evaluation for target engagement through neuroimaging changes, specifically connectivity differences between the insula and other regions of interest.

Attention-deficit/hyperactivity disorder and nonsuicidal self-injury among veterans with complex psychiatric presentations.

Prior research suggests a possible association between attention-deficit/hyperactivity disorder (ADHD) symptoms and nonsuicidal self-injury (NSSI) in veterans. However, this association has not yet been replicated. The present study sought to replicate and expand upon this association in a gender-balanced sample of veterans (N = 124), more than half of whom had a lifetime history of NSSI. Contrary to hypotheses, adult ADHD symptoms were not associated with NSSI history or disorder. Instead, our findings suggest that disorders characterized by negative affect may have greater utility for predicting NSSI versus those characterized by impulsivity. Further research in epidemiological samples is needed.

Contingency management and cognitive behavior therapy for smoking cessation among veterans with posttraumatic stress disorder: Design and methodology of a randomized clinical trial.

BACKGROUND: Smoking is a prevalent concern among Veterans, especially those with posttraumatic stress disorder (PTSD). Despite the availability of interventions for smoking cessation, these treatments have not been as effective among Veteran populations, particularly Veterans with PTSD. The present study seeks to describe the methods of a randomized clinical trial examining the efficacy of CPT-SMART, a multidimensional treatment combining cognitive processing therapy (CPT) for PTSD, smoking cessation counseling, pharmacotherapy, and contingency management (CM) compared to a yoked comparison group. METHODS: One hundred twenty Veterans with PTSD who smoke cigarettes will be enrolled. All participants will receive CPT in addition to counseling and pharmacotherapy for smoking cessation. Participants will be randomized to the CPT-SMART condition, which includes monetary reinforcement that is contingent on bioverification of smoking abstinence (i.e., contingency management), or a yoked comparison with monetary reinforcement matched to the participant to whom they are yoked. The primary outcome is bioverified smoking abstinence at the 6-month follow-up appointment. CONCLUSION: If shown efficacious, a combined PTSD and smoking treatment plus incentive-based approach for smoking could be implemented into specialty PTSD programs. The positive public health impact of reducing smoking among Veterans with PTSD could be enormous as it would prevent significant smoking-related morbidity and mortality.

Complementary/integrative healthcare utilization in US Gulf-War era veterans: Descriptive analyses based on deployment history, combat exposure, and Gulf War Illness.

Complementary and integrative health (CIH) approaches have gained empirical support and are increasingly being utilized among veterans to treat a myriad of conditions. A cluster of medically unexplained chronic symptoms including fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems, often referred to as Gulf War Illness (GWI) prominently affect US Gulf War era (GWE) veterans, yet little is known about CIH use within this population. Using data collected as part of a larger study (n = 1153), we examined the influence of demographic characteristics, military experiences, and symptom severity on CIH utilization, and utilization differences between GWE veterans with and without GWI. Over half of the sample (58.5%) used at least one CIH modality in the past six months. Women veterans, white veterans, and veterans with higher levels of education were more likely to use CIH. GWE veterans with a GWI diagnosis and higher GWI symptom severity were more likely to use at least one CIH treatment in the past six months. Over three quarters (82.7%) of veterans who endorsed using CIH to treat GWI symptoms reported that it was helpful for their symptoms. Almost three quarters (71.5%) of veterans indicated that they would use at least one CIH approach if it was available at VA. Results provide a deeper understanding of the likelihood and characteristics of veterans utilizing CIH to treat health and GWI symptoms and may inform expansion of CIH modalities for GWE veterans, particularly those with GWI.

Nonsuicidal self-injury in veterans: Prevalence, clinical characteristics, and gender differences from a national cohort.

Nonsuicidal self-injury (NSSI) is a robust predictor of suicidal thoughts and behaviors; however, while there are typically only small differences observed in the prevalence of NSSI between men and women, this condition has been largely overlooked and underestimated among men. Assessing NSSI methods more common in men may address misidentification as well as allow for more precise NSSI prevalence estimates. Survey data from a national sample of Gulf War I-Era veterans (N = 1063) was used to estimate the prevalence of NSSI and compare prevalence of NSSI methods between men and women veterans. Demographic and clinical correlates of NSSI engagement were also examined. The national lifetime prevalence rate of NSSI among Gulf War I-Era veterans was 22.40%, whereas the past year prevalence rate was 8.10%. In both men and women, wall/object punching was the most common NSSI method endorsed across the lifetime. Men had slightly higher overall NSSI prevalence rates compared with women. This study highlights the need to systematically assess NSSI, particularly among veterans, to better identify, and consequently treat, NSSI in men. This is the first available prevalence estimate of NSSI to include the assessment of wall/object punching in a national sample of adult veterans.

The Screen for Nonsuicidal Self-Injury: Development and initial validation among veterans with psychiatric disorders.

INTRODUCTION: Nonsuicidal self-injury (NSSI) is associated with significant impairment and is a robust predictor of suicidal ideation, attempts, and death by suicide; however, the present lack of a brief screening instrument for NSSI coupled with consistent underidentification of NSSI in male adults has led to concerning rates of missed identification of NSSI. METHODS: The Screen for Nonsuicidal Self-Injury (SNSI) is a brief, 10-item screen designed to identify individuals currently engaging in NSSI with an emphasis on behaviors more frequently endorsed by male adults. The present study examined the development and validation of the SNSI. RESULTS: In a sample of veterans (N = 124) with complex psychiatric presentations, SNSI scores demonstrated good internal consistency and strong construct validity with area under the curve (AUC) estimates of 0.85-0.93 for the identification of NSSI disorder. SNSI scores also demonstrated good convergent (rs 0.59-0.90) and external validity (rs = 0.25-0.42), and excellent predictive validity identifying future NSSI Suicide and Life-Threatening Behavior disorder (AUC = 0.88) and NSSI behaviors (AUC = 0.90). Importantly, SNSI performance was not affected by participants' race, sex assigned at birth, or age. CONCLUSION: The SNSI is an efficient screen to identify patients engaging in NSSI who are likely to benefit from more comprehensive assessment and treatment programs.

Experiential avoidance is associated with medical and mental health diagnoses in a national sample of deployed Gulf War veterans.

A substantial minority of deployed Gulf War veterans developed posttraumatic stress disorder (PTSD), depression, and several chronic illnesses. Although military combat and exposure to certain nuclear, biological, and chemical agents (NBCs) increase risk for post-deployment health problems, they do not fully explain many Gulf War veteran health diagnoses and are not viable treatment targets. Experiential avoidance (EA; one's unwillingness to remain in contact with unpleasant internal experiences) is a modifiable psychosocial risk factor associated with PTSD and depression in veterans as well as pain and gastrointestinal diseases in the general population. In this study, we recruited a national sample of deployed Gulf War veterans (N = 454) to test the hypothesis that greater EA would be significantly associated with higher lifetime odds of PTSD, depression, "Gulf War Illness" (GWI/CMI), and other chronic illnesses common in this veteran cohort. Participants completed a self-report battery assessing demographic, military-related, and health-related information. Multivariate analyses showed that after adjusting for age, sex, race, combat exposure, and NBC exposure, worse EA was associated with higher lifetime odds of PTSD, depression GWI/CMI, gastrointestinal problems, irritable bowel syndrome, arthritis, fibromyalgia, and chronic fatigue syndrome (ORs ranged 1.25 to 2.89; effect sizes ranged small to large), but not asthma or chronic obstructive pulmonary disease. Our findings suggest medical and mental health providers alike should assess for EA and potentially target EA as part of a comprehensive, biopsychosocial approach to improving Gulf War veterans' health and wellbeing. Study limitations and future research directions are also discussed.