Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

Mediators of Ethnic Differences in Dropout Rates From a Randomized Controlled Treatment Trial Among Latinx and Non-Latinx White Primary Care Patients With Anxiety Disorders.

ABSTRACT: Disparities in treatment engagement and adherence based on ethnicity have been widely recognized but are inadequately understood. Few studies have examined treatment dropout among Latinx and non-Latinx White (NLW) individuals. Using Andersen's Behavioral Model of Health Service Use (A behavioral model of families' use of health services. 1968; J Health Soc Behav. 1995; 36:1-10) as a framework, we examine whether pretreatment variables (categorized as predisposing, enabling, and need factors) mediate the relationship between ethnicity and premature dropout in a sample of Latinx and NLW primary care patients with anxiety disorders who participated in a randomized controlled trial (RCT) of cognitive behavioral therapy. Data from a total of 353 primary care patients were examined; 96 Latinx and 257 NLW patients participated. Results indicated that Latinx patients dropped out of treatment more often than NLW patients, resulting in roughly 58% of Latinx patients failing to complete treatment compared with 42% of NLW, and approximately 29% of Latinx patients dropping out before engaging in modules related to cognitive restructuring or exposure, relative to 11% of NLW patients. Mediation analyses suggest that social support and somatization partially explained the relationship between ethnicity and treatment dropout, highlighting the importance of these variables in understanding treatment disparities.

Age Differences in Death and Suicidal Ideation in Anxious Primary Care Patients.

OBJECTIVES: The objective of this study was to examine age differences in the likelihood of endorsing of death and suicidal ideation in primary care patients with anxiety disorders. METHOD: Participants were drawn from the Coordinated Anxiety Learning and Management (CALM) Study, an effectiveness trial for primary care patients with panic disorder (PD), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and/or social anxiety disorder (SAD). RESULTS: Approximately one third of older adults with anxiety disorders reported feeling like they were better off dead. Older adults with PD and SAD were more likely to endorse suicidal ideation lasting at least more than half the prior week compared with younger adults with these disorders. Older adults with SAD endorsed higher rates of suicidal ideation compared with older adults with other anxiety disorders. Multivariate analyses revealed the importance of physical health, social support, and comorbid MDD in this association. CONCLUSIONS: Suicidal ideation is common in anxious, older, primary care patients and is particularly prevalent in socially anxious older adults. Findings speak to the importance of physical health, social functioning, and MDD in this association. CLINICAL IMPLICATIONS: When working with anxious older adults it is important to conduct a thorough suicide risk assessment and teach skills to cope with death and suicidal ideation-related thoughts.

Improving outcomes for patients with medication-resistant anxiety: effects of collaborative care with cognitive behavioral therapy.

BACKGROUND: Many patients with anxiety disorders remain symptomatic after receiving evidence-based treatment, yet research on treatment-resistant anxiety is limited. We evaluated effects of cognitive behavioral therapy (CBT) on outcomes of patients with medication-resistant anxiety disorders using data from the Coordinated Anxiety Learning and Management (CALM) trial. METHODS: Primary care patients who met study entry criteria (including DSM-IV diagnosis of generalized anxiety disorder, panic disorder, posttraumatic stress disorder, or social anxiety disorder) despite ongoing pharmacotherapy of appropriate type, dose, and duration were classified as medication resistant (n = 227). Logistic regression was used to estimate effects of CALM's CBT program (CALM-CBT; chosen by 104 of 117 medication-resistant patients randomized to CALM) versus usual care (UC; n = 110) on response [≥ 50% reduction of 12-item Brief Symptom Inventory (BSI-12) anxiety and somatic symptom score] and remission (BSI-12 < 6) at 6, 12, and 18 months. Within-group analyses examined outcomes by treatment choice (CBT vs. CBT plus medication management) and CBT dose. RESULTS: Approximately 58% of medication-resistant CALM-CBT patients responded and 46% remitted during the study. Relative to UC, CALM-CBT was associated with greater response at 6 months (AOR = 3.78, 95% CI 2.02-7.07) and 12 months (AOR = 2.49, 95% CI 1.36-4.58) and remission at 6, 12, and 18 months (AORs = 2.44 to 3.18). Patients in CBT plus medication management fared no better than those in CBT only. Some evidence suggested higher CBT dose produced better outcomes. CONCLUSIONS: CBT can improve outcomes for patients whose anxiety symptoms are resistant to standard pharmacotherapy.

Perceived social support mediates anxiety and depressive symptom changes following primary care intervention.

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 (coordinated anxiety learning and management [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.

Changes in self-efficacy and outcome expectancy as predictors of anxiety outcomes from the CALM study.

BACKGROUND: Although self-efficacy (SE) and outcome expectancy (OE) have been well researched as predictors of outcome, few studies have investigated changes in these variables across treatments. We evaluated changes in OE and SE throughout treatment as predictors of outcomes in a large sample with panic disorder, generalized anxiety disorder, social anxiety disorder, or posttraumatic stress disorder. We hypothesized that increases in SE and OE would predict reductions in anxiety and depression as well as improvement in functioning. METHODS: Participants (mean age = 43.3 years, SD = 13.2, 71.1% female, 55.5% white) were recruited from primary care centers throughout the United States and were randomized to receive either Coordinated Anxiety Learning and Management (CALM) treatment - composed of cognitive behavioral therapy, psychotropic medication, or both - or usual care. SE and OE ratings were collected at each session for participants in the CALM treatment (n = 482) and were entered into a structural equation model as predictors of changes in Brief Symptom Inventory, Anxiety Sensitivity Index, Patient Health Questionnaire (PHQ), and Sheehan Disability Scale outcomes at 6, 12, and 18 months after baseline. RESULTS: The best-fitting models predict symptom levels from OE and SE and not vice versa. The slopes and intercept of OE significantly predicted change in each outcome variable except PHQ-8. The slope and intercept of SE significantly predicted change in each outcome variable. CONCLUSION: Over and above absolute level, increases in SE and OE were significant predictors of decreases in symptoms and increases in functioning. Implications for treatment are discussed, as well as future directions of research.

Low-intensity focused ultrasound pulsation device used during magnetic resonance imaging: evaluation of magnetic resonance imaging-related heating at 3 Tesla/128 MHz.

OBJECTIVE: The objective of this study was to determine magnetic resonance imaging (MRI)-related heating for a low-intensity focused ultrasound pulsation (LIFUP) device used during MRI performed at 3 T/128 MHz. MATERIALS AND METHODS: A special phantom was constructed to mimic the thermal properties of the human brain, and a piece of human temporal bone (skull) was embedded on top. Four fluoroptic thermometry probes, placed above and below the skull, were used to measure temperature changes during MRI (3 T/128 MHz; scanner-reported head average specific absorption rate 1.1-2 W/kg) with and without concurrent LIFUP sonication. LIFUP sonication was applied using a focused ultrasound device (BXPulsar 1001, Brainsonix, Inc., Los Angeles, CA, USA) at a derated spatial-peak temporal-average intensity of 3870 mW/cm(2) . RESULTS: MRI performed at relatively high specific absorption rate (SAR) caused a slight elevation in temperature (≤0.6°C). Concurrent use of MRI at a medium-strength SAR and LIFUP sonication resulted in maximum temperature rise of 3.1°C after 8 min of continuous use. CONCLUSIONS: Under the specific conditions utilized for this investigation, LIFUP sonication does not appear to present significant heating risks when used concurrently with MRI. This information has important implications for the use of the LIFUP sonication in human subjects undergoing MRI at 3 T/128 MHz.

Reciprocal and Indirect Effects Among Intervention, Perceived Social Support, and Anxiety Sensitivity Within a Randomized Controlled Trial for Anxiety Disorders.

Social support may facilitate adaptive reappraisal of stressors, including somatic symptoms. Anxiety sensitivity refers to negative beliefs about somatic symptoms of anxiety, which may influence one's perception of social support. Evidence-based treatment may impact these associations. The current longitudinal study evaluated reciprocal relationships between perceived social support and anxiety sensitivity, and explored indirect intervention effects, in a randomized controlled trial for anxiety disorders that compared cognitive behavioral therapy with or without medications (CALM) to usual care. Data collected over 18 months from 940 primary care patients were examined in random intercept cross-lagged panel models. There were significant reciprocal associations between perceived social support increases and anxiety sensitivity decreases over time. There were significant indirect effects from intervention to perceived social support increases through anxiety sensitivity decreases and from intervention to anxiety sensitivity decreases through perceived social support increases. These data suggest that, relative to usual care, CALM predicted changes in one construct, which predicted subsequent changes in the other. Secondary analyses revealed an influence of anxiety and depressive symptoms on reciprocal associations and indirect effects. Findings suggest that future treatments could specifically address perceived social support to enhance reappraisal of somatic symptoms, and vice versa.

Effects of medical comorbidity on anxiety treatment outcomes in primary care.

OBJECTIVE: To evaluate the effects of medical comorbidity on anxiety treatment outcomes. METHODS: Data were analyzed from 1004 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 the effects of overall medical comorbidity (two or more chronic medical conditions [CMCs] versus fewer than two 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% confidence interval {CI} = 10.1-10.9] versus 9.5 [95% CI = 9.0-10.0], p = .003) and anxiety-related disability (17.6 [95% CI = 17.0-18.2] versus 16.0 [95% CI = 15.3-16.7], p = .001). However, their clinical improvement was comparable to that of patients with one or zero CMCs (predicted change in anxiety symptoms = -3.9 versus -4.1 at 6 months, -4.6 versus -4.4 at 12 months, -4.9 versus -5.0 at 18 months; predicted change in anxiety-related disability = -6.4 versus -6.9 at 6 months, -6.9 versus -7.3 at 12 months, -7.3 versus -7.5 at 18 months). The only specific CMC with a detrimental effect was migraine, which was associated with less improvement in anxiety symptoms at 18 months (predicted change = -4.1 versus -5.3). CONCLUSIONS: Effectiveness of the anxiety intervention was not significantly affected by the presence of multiple CMCs; however, patients with migraine displayed less improvement at long-term follow-up. Trial Registration ClinicalTrials.com Identifier: NCT00347269.

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.

CBT competence in novice therapists improves anxiety outcomes.

OBJECTIVE: This study explores the relationships between therapist variables (cognitive behavioral therapy [CBT] competence, and CBT adherence) and clinical outcomes of computer-assisted CBT for anxiety disorders delivered by novice therapists in a primary care setting. METHODS: Participants were recruited for a randomized controlled trial of evidence-based treatment, including computer-assisted CBT, versus treatment as usual. Therapists (anxiety clinical specialists; ACSs) were nonexpert clinicians, many of whom had no prior experience in delivering psychotherapy (and in particular, very little experience with CBT). Trained raters reviewed randomly selected treatment sessions from 176 participants and rated therapists on measures of CBT competence and CBT adherence. Patients were assessed at baseline and at 6-, 12-, and 18-month follow-ups on measures of anxiety, depression, and functioning, and an average Reliable Change Index was calculated as a composite measure of outcome. CBT competence and CBT adherence were entered as predictors of outcome, after controlling for baseline covariates. RESULTS: Higher CBT competence was associated with better clinical outcomes whereas CBT adherence was not. Also, CBT competence was inversely correlated with years of clinical experience and trended (not significantly, though) down as the study progressed. CBT adherence was inversely correlated with therapist tenure in the study. CONCLUSIONS: Therapist competence was related to improved clinical outcomes when CBT for anxiety disorders was delivered by novice clinicians with technology assistance. The results highlight the value of the initial training for novice therapists as well as booster training to limit declines in therapist adherence.

Current diagnosis and treatment of anxiety disorders.

Anxiety disorders are the most prevalent mental health conditions. Although they are less visible than schizophrenia, depression, and bipolar disorder, they can be just as disabling. The diagnoses of anxiety disorders are being continuously revised. Both dimensional and structural diagnoses have been used in clinical treatment and research, and both methods have been proposed for the new classification in the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-5). However, each of these approaches has limitations. More recently, the emphasis in diagnosis has focused on neuroimaging and genetic research. This approach is based partly on the need for a more comprehensive understanding of how biology, stress, and genetics interact to shape the symptoms of anxiety. Anxiety disorders can be effectively treated with psychopharmacological and cognitive-behavioral interventions. These inter ventions have different symptom targets; thus, logical combinations of these strategies need to be further studied in order to improve future outcomes. New developments are forthcoming in the field of alternative strategies for managing anxiety and for treatment-resistant cases. Additional treatment enhancements should include the development of algorithms that can be easily used in primary care and with greater focus on managing functional impairment in patients with anxiety.

Microbiome in Anxiety and Other Psychiatric Disorders.

Initial studies suggested that the fluctuations in the quantity, variety, and composition of the gut microbiota can significantly affect disease processes. This change in the gut microbiota causing negative health benefits was coined dysbiosis. Initial research focused on gastrointestinal illnesses. However, the gut microbiome was found to affect more than just gastrointestinal diseases. Numerous studies have proven that the gut microbiome can influence neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis.

Functional MRI Lateralization [M1] of dlPFC and Implications for Transcranial Magnetic Stimulation (TMS) Targeting.

The present study investigates a potential method of optimizing effective strategies for the functional lateralization of the dorsolateral prefrontal cortex (dlPFC) while in a scanner. Effective hemisphere lateralization of the dlPFC is crucial for lowering the functional risks connected to specific interventions (such as neurosurgery and transcranial magnetic stimulation (TMS), as well as increasing the effectiveness of a given intervention by figuring out the optimal location. This task combines elements of creative problem solving, executive decision making based on an internal rule set, and working memory. A retrospective analysis was performed on a total of 58 unique participants (34 males, 24 females, Mage = 42.93 years, SDage = 16.38). Of these participants, 47 were classified as right-handed, 7 were classified as left-handed, and 4 were classified as ambidextrous, according to the Edinburgh Handedness Inventory. The imaging data were qualitatively judged by two trained, blinded investigators (neurologist and neuropsychologist) for dominant handedness (primary motor cortex) and dominant dorsolateral prefrontal cortex (dlPFC). The results demonstrated that 21.4% of right-handed individuals showed a dominant dlPFC localized to the right hemisphere rather than the assumed left, and 16.7% of left-handers were dominant in their left hemisphere. The task completed in the scanner might be an efficient method for localizing a potential dlPFC target for the purpose of brain stimulation (e.g., TMS), though further study replications are needed to extend and validate these findings.

Pursuing personalized medicine for depression by targeting the lateral or medial prefrontal cortex with Deep TMS.

BACKGROUNDMajor depressive disorder (MDD) can benefit from novel interventions and personalization. Deep transcranial magnetic stimulation (Deep TMS) targeting the lateral prefrontal cortex (LPFC) using the H1 coil was FDA cleared for treatment of MDD. However, recent preliminary data indicate that targeting the medial prefrontal cortex (MPFC) using the H7 coil might induce outcomes that are as good or even better. Here, we explored whether Deep TMS targeting the MPFC is noninferior to targeting the LPFC and whether electrophysiological or clinical markers for patient selection can be identified.METHODSThe present prospective, multicenter, randomized study enrolled 169 patients with MDD for whom antidepressants failed in the current episode. Patients were randomized to receive 24 Deep TMS sessions over 6 weeks, using either the H1 coil or the H7 coil. The primary efficacy endpoint was the change from baseline to week 6 in Hamilton Depression Rating Scale scores.RESULTSClinical efficacy and safety profiles were similar and not significantly different between groups, with response rates of 60.9% for the H1 coil and 64.2% for the H7 coil. Moreover, brain activity measured by EEG during the first treatment session correlated with clinical outcomes in a coil-specific manner, and a cluster of baseline clinical symptoms was found to potentially distinguish between patients who can benefit from each Deep TMS target.CONCLUSIONThis study provides a treatment option for MDD, using the H7 coil, and initial guidance to differentiate between patients likely to respond to LPFC versus MPFC stimulation targets, which require further validation studies.TRIAL REGISTRATIONClinicalTrials.gov NCT03012724.FUNDINGBrainsWay Ltd.

Use of complementary and alternative medicine in a large sample of anxiety patients.

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.

A prototype stimulator system for noninvasive Low Intensity Focused Ultrasound delivery.

A prototype Low Intensity Focused Ultrasound (LIFU) stimulator system was developed to evaluate non-invasive neuromodulation in a large animal model. We conducted a feasibility study on a Göttingen minipig, demonstrating reversible, targeted transcranial neuromodulation. The hypothalamus of the minipig was repeatedly stimulated with LIFU which evoked temporally correlated increases in both heart rate and blood pressure.

Noninvasive Delivery of Biologicals to the Brain.

In the past, psychotherapy and neuropharmacological approaches have been the most common treatments for disordered thoughts, moods, and behaviors. One new path of brain therapeutics is in the deployment of noninvasive approaches designed to reprogram brain function at the cellular level. Treatment at the cellular level may be considered for a wide array of disorders, ranging from mood disorders to neurodegenerative disorders. Brain-targeted biological therapy may provide minimally invasive and accurate delivery of treatment. The present article discusses the hurdles and advances that characterize the pathway to this goal.

Current State of Potential Mechanisms Supporting Low Intensity Focused Ultrasound for Neuromodulation.

Low intensity focused ultrasound (LIFU) has been gaining traction as a non-invasive neuromodulation technology due to its superior spatial specificity relative to transcranial electrical/magnetic stimulation. Despite a growing literature of LIFU-induced behavioral modifications, the mechanisms of action supporting LIFU's parameter-dependent excitatory and suppressive effects are not fully understood. This review provides a comprehensive introduction to the underlying mechanics of both acoustic energy and neuronal membranes, defining the primary variables for a subsequent review of the field's proposed mechanisms supporting LIFU's neuromodulatory effects. An exhaustive review of the empirical literature was also conducted and studies were grouped based on the sonication parameters used and behavioral effects observed, with the goal of linking empirical findings to the proposed theoretical mechanisms and evaluating which model best fits the existing data. A neuronal intramembrane cavitation excitation model, which accounts for differential effects as a function of cell-type, emerged as a possible explanation for the range of excitatory effects found in the literature. The suppressive and other findings need additional theoretical mechanisms and these theoretical mechanisms need to have established relationships to sonication parameters.

Sonication of the Anterior Thalamus With MRI-Guided Transcranial Focused Ultrasound (tFUS) Alters Pain Thresholds in Healthy Adults: A Double-Blind, Sham-Controlled Study.

(Appeared originally in Brain Stimulation 2020; 13:1805-1812) Reprinted with permission from Elsevier.