Repetitive transcranial magnetic stimulation for post-traumatic stress disorder in adults.

BACKGROUND: The estimated lifetime prevalence of post-traumatic stress disorder (PTSD) in adults worldwide has been estimated at 3.9%. PTSD appears to contribute to alterations in neuronal network connectivity patterns. Current pharmacological and psychotherapeutic treatments for PTSD are associated with inadequate symptom improvement and high dropout rates. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive therapy involving induction of electrical currents in cortical brain tissue, may be an important treatment option for PTSD to improve remission rates and for people who cannot tolerate existing treatments. OBJECTIVES: To assess the effects of repetitive transcranial magnetic stimulation (rTMS) on post-traumatic stress disorder (PTSD) in adults. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two clinical trials registers. We checked reference lists of relevant articles. The most recent search was January 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the efficacy and safety of rTMS versus sham rTMS for PTSD in adults from any treatment setting, including veterans. Eligible trials employed at least five rTMS treatment sessions with both active and sham conditions. We included trials with combination interventions, where a pharmacological agent or psychotherapy was combined with rTMS for both intervention and control groups. We included studies meeting the above criteria regardless of whether they reported any of our outcomes of interest. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias in accordance with Cochrane standards. Primary outcomes were PTSD severity immediately after treatment and serious adverse events during active treatment. Secondary outcomes were PTSD remission, PTSD response, PTSD severity at two follow-up time points after treatment, dropouts, and depression and anxiety severity immediately after treatment. MAIN RESULTS: We included 13 RCTs in the review (12 published; 1 unpublished dissertation), with 577 participants. Eight studies included stand-alone rTMS treatment, four combined rTMS with an evidence-based psychotherapeutic treatment, and one investigated rTMS as an adjunctive to treatment-as-usual. Five studies were conducted in the USA, and some predominantly included white, male veterans. Active rTMS probably makes little to no difference to PTSD severity immediately following treatment (standardized mean difference (SMD) -0.14, 95% confidence interval (CI) -0.54 to 0.27; 3 studies, 99 participants; moderate-certainty evidence). We downgraded the certainty of evidence by one level for imprecision (sample size insufficient to detect a difference of medium effect size). We deemed one study as having a low risk of bias and the remaining two as having 'some concerns' for risk of bias. A sensitivity analysis of change-from-baseline scores enabled inclusion of a greater number of studies (6 studies, 252 participants). This analysis yielded a similar outcome to our main analysis but also indicated significant heterogeneity in efficacy across studies, including two studies with a high risk of bias. Reported rates of serious adverse events were low, with seven reported (active rTMS: 6; sham rTMS: 1). The evidence is very uncertain about the effect of active rTMS on serious adverse events (odds ratio (OR) 5.26, 95% CI 0.26 to 107.81; 5 studies, 251 participants; very low-certainty evidence [Active rTMS: 23/1000, sham rTMS: 4/1000]). We downgraded the evidence by one level for risk of bias and two levels for imprecision. We rated four of five studies as having a high risk of bias, and the fifth as 'some concerns' for bias. We were unable to assess PTSD remission immediately after treatment as none of the included studies reported this outcome. AUTHORS' CONCLUSIONS: Based on moderate-certainty evidence, our review suggests that active rTMS probably makes little to no difference to PTSD severity immediately following treatment compared to sham stimulation. However, significant heterogeneity in efficacy was detected when we included a larger number of studies in sensitivity analysis. We observed considerable variety in participant and protocol characteristics across studies included in this review. For example, studies tended to be weighted towards inclusion of either male veterans or female civilians. Studies varied greatly in terms of the proportion of the sample with comorbid depression. Study protocols differed in treatment design and stimulation parameters (e.g. session number/duration, treatment course length, stimulation intensity/frequency, location of stimulation). These differences may affect efficacy, particularly when considering interactions with participant factors. Reported rates of serious adverse events were very low (< 1%) across active and sham conditions. It is uncertain whether rTMS increases the risk of serious adverse event occurrence, as our certainty of evidence was very low. Studies frequently lacked clear definitions for serious adverse events, as well as detail on tracking/assessment of data and information on the safety population. Increased reporting on these elements would likely aid the advancement of both research and clinical recommendations of rTMS for PTSD. Currently, there is insufficient evidence to meta-analyze PTSD remission, PTSD treatment response, and PTSD severity at different periods post-treatment. Further research into these outcomes could inform the clinical use of rTMS. Additionally, the relatively large contribution of data from trials that focused on white male veterans may limit the generalizability of our conclusions. This could be addressed by prioritizing recruitment of more diverse participant samples.

Development of infection prevention program standards for critical access hospitals.

Although critical access hospitals are small, the expected infection prevention activities remain extensive. Program standards, aligned with the Association for Professionals in Infection Control and Epidemiology infection prevention competency model domains, were developed and implemented in a midwestern health care system. Time estimates for completion of each activity were assigned and then extrapolated to offer guidance on necessary full-time equivalents for adequate staffing.

Magnesium-ibogaine therapy in veterans with traumatic brain injuries.

Traumatic brain injury (TBI) is a leading cause of disability. Sequelae can include functional impairments and psychiatric syndromes such as post-traumatic stress disorder (PTSD), depression and anxiety. Special Operations Forces (SOF) veterans (SOVs) may be at an elevated risk for these complications, leading some to seek underexplored treatment alternatives such as the oneirogen ibogaine, a plant-derived compound known to interact with multiple neurotransmitter systems that has been studied primarily as a treatment for substance use disorders. Ibogaine has been associated with instances of fatal cardiac arrhythmia, but coadministration of magnesium may mitigate this concern. In the present study, we report a prospective observational study of the Magnesium-Ibogaine: the Stanford Traumatic Injury to the CNS protocol (MISTIC), provided together with complementary treatment modalities, in 30 male SOVs with predominantly mild TBI. We assessed changes in the World Health Organization Disability Assessment Schedule from baseline to immediately (primary outcome) and 1 month (secondary outcome) after treatment. Additional secondary outcomes included changes in PTSD (Clinician-Administered PTSD Scale for DSM-5), depression (Montgomery-Åsberg Depression Rating Scale) and anxiety (Hamilton Anxiety Rating Scale). MISTIC resulted in significant improvements in functioning both immediately (Pcorrected < 0.001, Cohen's d = 0.74) and 1 month (Pcorrected < 0.001, d = 2.20) after treatment and in PTSD (Pcorrected < 0.001, d = 2.54), depression (Pcorrected < 0.001, d = 2.80) and anxiety (Pcorrected < 0.001, d = 2.13) at 1 month after treatment. There were no unexpected or serious adverse events. Controlled clinical trials to assess safety and efficacy are needed to validate these initial open-label findings. ClinicalTrials.gov registration: NCT04313712 .

Electrophysiological and behavioral effects of unilateral and bilateral rTMS; A randomized clinical trial on rumination and depression.

BACKGROUND: Rumination is significantly frequent in major depressive disorder (MDD). However, not a lot of studies have investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on rumination. METHODS: 61 participants with a minimum Hamilton Depression Rating Scale (HAM-D) score of 20 were randomly assigned to sham, bilateral stimulation (BS) or unilateral stimulation (US) groups. EEG, The Ruminative Response Scale (RRS), and HAM-D were administered before and after the 20 sessions of rTMS. Phase locked values (PLV) were calculated as a measure of connectivity. RESULTS: There was a significant decrease in HAM-D scores in both BS and US. In responders, BS and US differed significantly in RRS total scores, with greater reduction in BS. PLV significantly changed in the default mode network (DMN) in delta, theta, alpha, and beta in BS, in responders of which PLV decreased in the DMN in beta and gamma. Positive correlations between PLV and brooding in delta and theta, and negative correlations between PLV and reflection were found in theta, alpha, and beta. In US, connectivity in the DMN increased in beta, and PLV increased in theta and beta, and decreased in alpha and beta in its responders. Positive correlations between PLV and brooding in the delta and theta, as well as negative correlations between PLV and reflection in theta were observed in the DMN. CONCLUSION: US and BS resulted in different modulations in the DMN, however, both could alleviate both rumination and depression. Reductions in the beta and alpha frequency bands in the DMN can be considered as potential EEG-based markers of response to bilateral and unilateral rTMS, respectively.

Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial.

OBJECTIVE: Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression. METHODS: Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 4 weeks after treatment. RESULTS: At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group. CONCLUSIONS: SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

A Dissociation of the Acute Effects of Bupropion on Positive Emotional Processing and Reward Processing in Healthy Volunteers.

Background: Previous research indicates that antidepressants can restore the balance between negative and positive emotional processing early in treatment, indicating a role of this effect in later mood improvement. However, less is known about the effect of antidepressants on reward processing despite the potential relevance to the treatment of anhedonia. In this study, we investigated the effects of an acute dose of the atypical antidepressant (dual dopamine and noradrenaline reuptake inhibitor) bupropion on behavioral measures of emotional and reward processing in healthy volunteers. Methods: Forty healthy participants were randomly allocated to double-blind intervention with either an acute dose of bupropion or placebo prior to performing the Emotional Test Battery (ETB) and a probabilistic instrumental learning task. Results: Acute bupropion significantly increased the recognition of ambiguous faces as happy, decreased response bias toward sad faces and reduced attentional vigilance for fearful faces compared to placebo. Bupropion also reduced negative bias compared to placebo in the emotional recognition memory task (EMEM). There was no evidence that bupropion enhanced reward processing or learning. Instead, bupropion was associated with reduced likelihood to choose high-probability wins and increased score on a subjective measure of anhedonia. Conclusions: Whilst acute bupropion decreases negative and increases positive emotional processing, it has an adverse effect on reward processing. There seems to be a dissociation of the acute effects of bupropion on positive emotional processing and reward processing, which may have clinical implications for anhedonia early in treatment.

The role of mental imagery in mood amplification: An investigation across subclinical features of bipolar disorders.

Vivid emotional mental imagery has been identified across a range of mental disorders. In bipolar spectrum disorders - psychopathologies characterized by mood swings that alternate between depression and mania, and include irritability and mixed affect states - mental imagery has been proposed to drive instability in both 'positive' and 'negative' mood. That is, mental imagery can act as an "emotional amplifier". The current experimental study tested this hypothesis and investigated imagery characteristics associated with mood amplification using a spectrum approach to psychopathology. Young adults (N = 42) with low, medium and high scores on a measure of subclinical features of bipolar disorder (BD), i.e., hypomanic-like experiences such as overly 'positive' mood, excitement and hyperactivity, completed a mental imagery generation training task using positive picture-word cues. Results indicate that (1) mood amplification levels were dependent on self-reported hypomanic-like experiences. In particular, (2) engaging in positive mental imagery led to mood amplification of both positive and negative mood in those participants higher in hypomanic-like experiences. Further, (3) in participants scoring high for hypomanic-like experiences, greater vividness of mental imagery during the experimental task was associated with greater amplification of positive mood. Thus, for individuals with high levels of hypomanic-like experiences, the generation of emotional mental imagery may play a causal role in their mood changes. This finding has implications for understanding mechanisms driving mood amplification in bipolar spectrum disorders, such as targeting imagery vividness in therapeutic interventions.

Community managed alcohol programs in Canada: Overview of key dimensions and implementation.

INTRODUCTION AND AIMS: People with severe alcohol dependence and unstable housing are vulnerable to multiple harms related to drinking and homelessness. Managed Alcohol Programs (MAP) aim to reduce harms of severe alcohol use without expecting cessation of use. There is promising evidence that MAPs reduce acute and social harms associated with alcohol dependence. The aim of this paper is to describe MAPs in Canada including key dimensions and implementation issues. DESIGN AND METHODS: Thirteen Canadian MAPs were identified through the Canadian Managed Alcohol Program Study. Nine key informant interviews were conducted and analysed alongside program documents and reports to create individual case reports. Inductive content analysis and cross case comparisons were employed to identify six key dimensions of MAPs. RESULTS: Community based MAPs have a common goal of preserving dignity and reducing harms of drinking while increasing access to housing, health and social services. MAPs are offered as both residential and day programs with differences in six key dimensions including program goals and eligibility, food and accomodation, alcohol dispensing and administration, funding and money management, primary care services and clinical monitoring, and social and cultural connections. DISCUSSION AND CONCLUSIONS: MAPs consist of four pillars with the alcohol intervention provided alongside housing interventions, primary care services, social and cultural interventions. Availability of permanent housing and re-establishing social and cultural connections are central to recovery and healing goals of MAPs. Additional research regarding Indigenous and gendered approaches to program development as well as outcomes related to chronic harms and differences in alcohol management are needed.

No evidence for an acute placebo effect on emotional processing in healthy volunteers.

Placebo-controlled trials are the gold standard measure of efficacy in the development of new treatments for depression. However, the large placebo effects associated with standard measures of subjective symptoms reduce the sensitivity of such trials to detect antidepressant effects. There is a need to develop novel efficacy markers that are resistant to placebo effects. Measures of emotional processing, known to be sensitive to antidepressant treatment, may be such a marker, although the effect of an acute placebo treatment on these measures remains unclear. We assessed the influence of placebo on a validated battery of emotional processing tasks, the Emotional Test Battery (ETB), in healthy participants. Participants were informed they might receive the antidepressant drug bupropion, placebo or no treatment, with placebo effect being estimated as the difference between the placebo and no treatment groups. We found no significant difference between these groups on measures of emotional processing. There was also no effect of subjective treatment expectancy on performance in the tasks. This suggests that the ETB might be a useful tool for Phase I trials assessing novel antidepressant agents against placebo.

Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.

Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.