Effectiveness of Prefrontal Transcranial Magnetic Stimulation for Depression in Older US Military Veterans.

OBJECTIVE: While typical aging is associated with decreased cortical volume, major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) likely exacerbates this process. Cerebral atrophy leads to increased coil-to-cortex distance and when using transcranial magnetic stimulation (TMS), potentially reducing effectiveness in older adults. METHODS: Data from a large-scale quality improvement project was used. Included veterans eligible for TMS and completed TMS treatment. Age was assessed as a predictive factor of depression outcomes after TMS treatment among veterans. Secondary analyses examined the impact of age on 1) MDD response and remission and 2) MDD change within MDD-only verses comorbid MDD and PTSD groups. RESULTS: The entire sample included 471 veterans. Primary analysis revealed age as a negative predictor of depression outcomes (p = 0.019). Secondary analyses found age to be a significant predictor of remission (p = 0.004), but not clinical response. Age was not a predictive factor in depression outcomes between those with MDD-only compared to MDD+PTSD. CONCLUSIONS: Increased age predicts greater MDD symptom reduction after TMS. Although age did not predict response rates, it did predict increased rates of remission in veterans. Age did not differentially predict depression outcomes between those with or without PTSD. The sample size was sufficient to discern a difference in efficaciousness, and limitations were those inherent to registry studies in veterans. This data indicates that TMS can be an important treatment option for older individuals.

Predictive modeling of initiation and delayed mental health contact for depression.

BACKGROUND: Depression is prevalent among Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) Veterans, yet rates of Veteran mental health care utilization remain modest. The current study examined: factors in electronic health records (EHR) associated with lack of treatment initiation and treatment delay; the accuracy of regression and machine learning models to predict initiation of treatment. METHODS: We obtained data from the VA Corporate Data Warehouse (CDW). EHR data were extracted for 127,423 Veterans who deployed to Iraq/Afghanistan after 9/11 with a positive depression screen and a first depression diagnosis between 2001 and 2021. We also obtained 12-month pre-diagnosis and post-diagnosis patient data. Retrospective cohort analysis was employed to test if predictors can reliably differentiate patients who initiated, delayed, or received no mental health treatment associated with their depression diagnosis. RESULTS: 108,457 Veterans with depression, initiated depression-related care (55,492 Veterans delayed treatment beyond one month). Those who were male, without VA disability benefits, with a mild depression diagnosis, and had a history of psychotherapy were less likely to initiate treatment. Among those who initiated care, those with single and mild depression episodes at baseline, with either PTSD or who lacked comorbidities were more likely to delay treatment for depression. A history of mental health treatment, of an anxiety disorder, and a positive depression screen were each related to faster treatment initiation. Classification of patients was modest (ROC AUC = 0.59 95%CI = 0.586-0.602; machine learning F-measure = 0.46). CONCLUSIONS: Having VA disability benefits was the strongest predictor of treatment initiation after a depression diagnosis and a history of mental health treatment was the strongest predictor of delayed initiation of treatment. The complexity of the relationship between VA benefits and history of mental health care with treatment initiation after a depression diagnosis is further discussed. Modest classification accuracy with currently known predictors suggests the need to identify additional predictors of successful depression management.

Diffuse optical tomography for mapping cerebral hemodynamics and functional connectivity in delirium.

INTRODUCTION: Delirium is associated with mortality and new onset dementia, yet the underlying pathophysiology remains poorly understood. Development of imaging biomarkers has been difficult given the challenging nature of imaging delirious patients. Diffuse optical tomography (DOT) offers a promising approach for investigating delirium given its portability and three-dimensional capabilities. METHODS: Twenty-five delirious and matched non-delirious patients (n = 50) were examined using DOT, comparing cerebral oxygenation and functional connectivity in the prefrontal cortex during and after an episode of delirium. RESULTS: Total hemoglobin values were significantly decreased in the delirium group, even after delirium resolution. Functional connectivity between the dorsolateral prefrontal cortex and dorsomedial prefrontal cortex was strengthened post-resolution compared to during an episode; however, this relationship was still significantly weaker compared to controls. DISCUSSION: These findings highlight DOT's potential as an imaging biomarker to measure impaired cerebral oxygenation and functional dysconnectivity during and after delirium. Future studies should focus on the role of cerebral oxygenation in delirium pathogenesis and exploring the etiological link between delirium and dementias. HIGHLIGHTS: We developed a portable diffuse optical tomography (DOT) system for bedside three-dimensional functional neuroimaging to study delirium in the hospital. We implemented a novel DOT task-focused seed-based correlation analysis. DOT revealed decreased cerebral oxygenation and functional connectivity strength in the delirium group, even after resolution of delirium.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

An accelerated course of TMS using intermittent theta burst for veterans with major depressive disorder: A case series.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a neuro-modulation technique for treatment-resistant major depressive disorder (MDD). Standard TMS protocols for MDD involve once-daily treatment for 6 to 9 weeks. We report a case series of an accelerated TMS protocol for outpatient MDD treatment. METHODS: From July 2020 through January 2021, patients deemed appropriate candidates for TMS treatment were offered an accelerated TMS protocol consisting of intermittent theta burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex, localized by the Beam F3 method, and consisting of 5 treatments daily for 5 days. Assessment scales were obtained as part of standard clinical care. RESULTS: A total of 19 veterans received the accelerated protocol and 17 completed treatment. Statistically significant mean reductions from baseline to end of treatment were observed across all assessment scales. Remission and response rates, as defined by changes in Montgomery-Åsberg Depression Rating Scale scores, were 47.1% and 64.7%, respectively. Treatments were well tolerated without unexpected or serious adverse events. CONCLUSIONS: This case series details the safety and efficacy of an accelerated iTBS TMS protocol consisting of 25 treatments over 5 days. Improved depressive symptoms were observed, with remission and response rates similar to standard TMS protocols of daily TMS for ≥6 weeks.

Auditory N2 Correlates of Treatment Response in Posttraumatic Stress Disorder.

Emotional processing and cognitive control are implicated as being dysfunctional in posttraumatic stress disorder (PTSD) and targeted in cognitive processing therapy (CPT), a trauma-focused treatment for PTSD. The N2 event-related potential has been interpreted in the context of emotional processing and cognitive control. In this analysis of secondary outcome measures from a randomized controlled trial, we investigated the latency and amplitude changes of the N2 in responses to task-relevant target tones and task-irrelevant distractor sounds (e.g., a trauma-related gunshot and a trauma-unrelated lion's roar) and the associations between these responses and PTSD symptom changes. United States military veterans (N = 60) diagnosed with combat-related PTSD were randomized to either active or sham repetitive transcranial magnetic stimulation (rTMS) and received a CPT intervention that included a written trauma account element (CPT+A). Participants were tested before and 6 months after protocol completion. Reduction in N2 amplitude to the gunshot stimulus was correlated with reductions in reexperiencing, |r| = .445, and hyperarousal measures, |r| = .364. In addition, in both groups, the latency of the N2 event-related potential to the distractors became longer with treatment and the N2 latency to the task-relevant stimulus became shorter, ηp 2  = .064, both of which are consistent with improved cognitive control. There were no between-group differences in N2 amplitude and latency. Normalized N2 latencies, reduced N2 amplitude to threatening distractors, and the correlation between N2 amplitude reduction and PTSD symptom reduction reflect improved cognitive control, consistent with the CPT+A objective of addressing patients' abilities to respond more appropriately to trauma triggers.

Identifying response and predictive biomarkers for Transcranial magnetic stimulation outcomes: protocol and rationale for a mechanistic study of functional neuroimaging and behavioral biomarkers in veterans with Pharmacoresistant depression.

BACKGROUND: Although repetitive transcranial magnetic stimulation ('TMS') is becoming a gold standard treatment for pharmacoresistant depression, we lack neural target biomarkers for identifying who is most likely to respond to TMS and why. To address this gap in knowledge we evaluate neural targets defined by activation and functional connectivity of the dorsolateral prefrontal cortex-anchored cognitive control circuit, regions of the default mode network and attention circuit, and interactions with the subgenual anterior cingulate. We evaluate whether these targets and interactions between them change in a dose-dependent manner, whether changes in these neural targets correspond to changes in cognitive behavioral performance, and whether baseline and early change in neural target and cognitive behavioral performance predict subsequent symptom severity, suicidality, and quality of life outcomes. This study is designed as a pragmatic, mechanistic trial partnering with the National Clinical TMS Program of the Veteran's Health Administration. METHODS: Target enrollment consists of 100 veterans with pharmacoresistant Major Depressive Disorder (MDD). All veterans will receive a clinical course of TMS and will be assessed at 'baseline' pre-TMS commencement, 'first week' after initiation of TMS (targeting five sessions) and 'post-treatment' at the completion of TMS (targeting 30 sessions). Veterans will be assessed using functional magnetic resonance imaging (fMRI), a cognitive behavioral performance battery, and established questionnaires. Multivariate linear mixed models will be used to assess whether neural targets change with TMS as a function of dose (Aim 1), whether extent and change of neural target relates to and predicts extent of behavioral performance (Aim 3), and whether extent of neural target change predicts improvement in symptom severity, suicidality, and quality of life (Aim 3). For all three aims, we will also assess the contribution of baseline moderators such as biological sex and age. DISCUSSION: To our knowledge, our study will be the first pragmatic, mechanistic observational trial to use fMRI imaging and cognitive-behavioral performance as biomarkers of TMS treatment response in pharmacoresistant MDD. The results of this trial will allow providers to select suitable candidates for TMS treatment and better predict treatment response by assessing circuit connectivity and cognitive-behavioral performance at baseline and during early treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663481 , December 5th, 2020, retrospectively registered. The first veteran was enrolled October 30th, 2020.

Clinical repetitive transcranial magnetic stimulation for veterans with major depressive disorder.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is a relatively new treatment modality for patients with major depressive disorder (MDD). Numerous studies have demonstrated the efficacy of TMS for MDD in the general population. However, there is limited information regarding clinical outcomes among veterans receiving TMS for MDD. METHODS: The clinical outcome and characteristics of all veterans with MDD who were treated with TMS as outpatients at the James A. Haley Veterans' Hospital from October 2013 to December 2016 were assessed. RESULTS: Among 40 patients who received TMS, there was a significant improvement of depressive symptoms using the Quick Inventory of Depressive Symptomatology-Self-Report (45% response, 20% remission) and the Montgomery-Åsberg Depression Rating Scale (61.9% response, 42.9% remission). In addition to significant improvement in depressive symptoms, self-report of anxiety symptoms and function significantly improved. TMS was generally well tolerated, with only a small percentage of patients discontinuing treatment due to side effects. No seizures or persistent adverse effects were observed or reported. CONCLUSIONS: TMS is an effective and well-tolerated option for MDD in a veteran population with significant treatment resistance and multiple comorbidities.

Factors Impacting Functional Status in Veterans of Recent Conflicts With PTSD.

Veterans with posttraumatic stress disorder (PTSD) underwent a systematic evaluation to determine which factors were associated with the degree of functional status. Demographic information, self-report scales, and symptom ratings performed by trained evaluators were investigated in multiple regression models to determine their contribution to functional status. Ninety-six participants were included in the model assessing degree of functional status. Depressive symptoms, a depressive disorder diagnosis, and to a lesser extent, the Clinician-Administered PTSD Scale were selected in the final model that best predicted the degree of functional status. Depressive symptoms significantly affect the function of veterans with PTSD.

Depressive Symptoms Before, During, and After Delirium: A Literature Review.

BACKGROUND: Delirium and depression are often thought of as mutually exclusive conditions. However, several studies cite depression as a risk factor for delirium whereas others note that patients with delirium often manifest depressive symptoms. Whether these depressive symptoms persist after delirium resolves remains unclear. OBJECTIVES: This article reviews published studies that have investigated the relationship between depression and delirium. METHODS: Literature searches on PubMed, CINAHL, Cochrane Library, and PsycInfo were conducted using search criteria "delirium" AND "depress⁎" as keywords or MeSH terms. RESULTS: Of 722 search results, 10 prospective cohort studies were identified for inclusion. These studies were categorized regarding the time of assessment for depressive symptoms. Included studies varied greatly (regarding their index population, their methods of assessment, and their timing of assessments). Of the studies, 3 involved patients undergoing hip fracture repair. They demonstrated more severe depressive symptoms both during delirium and after delirium ended. Conversely, the other studies did not find any statistically significant correlations between the 2 conditions. CONCLUSIONS: The literature suggests a correlation between depression and delirium in patients with hip fracture. Whether other specific populations have higher comorbidity is unclear. Unfortunately, studies varied widely in their methods, precluding a meta-analysis. Nonetheless, our review provides a foundation for future research.

Sleep as a predictor of improved response to transcranial magnetic stimulation for depression (SPIRiTeD).

BACKGROUND: Transcranial magnetic stimulation (TMS) is an evidence-based approach to treatment- resistant Major Depressive Disorder (TRD). Sleep dysfunction is associated with poor outcomes in TRD, however, the impacts of sleep dysfunction on TMS treatment has yet to be defined. This study examined the association between sleep dysfunction and improvement in depression symptoms with TMS treatment for TRD. METHODS: A retrospective observational cohort study was conducted examining all Veterans receiving TMS treatments through the "VA TMS Clinical Pilot Program" over a three-year period. The Patient Health Questionnaire (PHQ-9) sleep item was utilized to assess sleep dysfunction. The association between sleep dysfunction improvements during TMS treatment with depression outcomes was analyzed. RESULTS: 94.3 % (N = 778) of Veterans reported baseline sleep dysfunction. Chi-square analysis demonstrated higher rates of depression remission at the completion of TMS treatment for those with sleep improvement at weeks 1, 3 and 6 (all p < .001). ANOVA comparing sleep improvements and end of treatment PHQ-8 score (modified to remove sleep item) found a statistically significant difference in mean improvements of depression scores at all 3 time points. LIMITATIONS: Limitations include those that are inherent to retrospective studies, as well as limitations in using the PHQ-9 sleep item as the primary means to assess sleep dysfunction. CONCLUSION: This study reports on the largest sample size to date examining the relationship between sleep dysfunction and TMS treatment outcomes for MDD, and found that improvement in sleep dysfunction was associated with greater reductions in end of treatment depression symptoms including higher depression remission rates.

The Relationship of Anxious Arousal With Treatment of Dysphoria Using Virtual Reality Mindfulness and 2 Accelerated Transcranial Magnetic Stimulation Protocols.

Objective: This secondary analysis investigated the relationship of anxious arousal, as measured by the Tension Anxiety subscale of the Profile of Mood States (TA-POMS), to treatment outcome across diagnoses for each phase of the study. Sequential treatment phases of virtual reality (VR) mindfulness followed by left dorsolateral prefrontal cortex (dlPFC) accelerated transcranial magnetic stimulation (accel-TMS) and then dorsomedial prefrontal cortex (dmPFC) accel-TMS were used to treat dysphoria across diagnoses in an open trial from September 2021 to August 2023.Methods: The change in the TA-POMS subscale was compared to the percent change in primary clinician scale scores using a bivariate analysis. Baseline TA-POMS subscales were compared to treatment response using linear regression models to assess anxious arousal's impact on treatment outcome for the 3 phases. Significance was defined as P < .05, 2-tailed.Results: Twenty-three participants were enrolled in VR mindfulness, 19 in left dlPFC accel-TMS, and 12 in dmPFC accel TMS. Although the change in TA-POMS scores did not significantly correlate with the percent change in primary clinician scale ratings for the VR phase, they did for both the dlPFC (P = .041) and the dmPFC (P = .003) accel-TMS treatment phases. Importantly, baseline anxious arousal levels as measured by TA-POMS were not predictive of treatment outcome in any treatment phase.Conclusion: The outcome of accel-TMS treatment was not adversely affected by anxious arousal and similarly improved along with primary rating scales.Trial Registration: ClinicalTrials.gov identifier: NCT05061745.

Mental health treatment utilization patterns among 108,457 Afghanistan and Iraq veterans with depression.

People with depression often underutilize mental health care. This study was conceived as a first step toward a clinical decision support tool that helps identify patients who are at higher risk of underutilizing care. The primary goals were to (a) describe treatment utilization patterns, early termination, and return to care; (b) identify factors associated with early termination of treatment; and (c) evaluate the accuracy of regression models to predict early termination. These goals were evaluated in a retrospective cohort analysis of 108,457 U.S. veterans who received care from the Veterans Health Administration between 2001 and 2021. Our final sample was 16.5% female with an average age of 34.5. Veterans were included if they had a depression diagnosis, a positive depression screen, and received general health care services at least a year before and after their depression diagnosis. Using treatment quality guidelines, the threshold for treatment underutilization was defined as receiving fewer than four psychotherapy sessions or less than 84 days of antidepressants. Over one fifth of veterans (21.6%) received less than the minimally recommended care for depression. The odds of underutilizing treatment increased with lack of Veterans Administration benefits, male gender, racial/ethnic minority status, and having received mental health treatment in the past (adjusted OR > 1.1). Posttraumatic stress disorder comorbidity correlated with increased depression treatment utilization (adjusted OR < .9). Models with demographic and clinical information from medical records performed modestly in classifying patients who underutilized depression treatment (area under the curve = 0.595, 95% CI [0.588, 0.603]). Most veterans in this cohort received at least the minimum recommended treatment for depression. To improve the prediction of underutilization, patient factors associated with treatment underutilization likely need to be supplemented by additional clinical information. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A Retrospective Analysis of Guanfacine for the Pharmacological Management of Delirium.

Background Delirium is a syndrome of acute brain failure that represents a change from an individual's baseline cognitive functioning characterized by deficits in attention and multiple aspects of cognition that fluctuate in severity over time. The symptomatic management of delirium's behavioral manifestations remains difficult. The alpha-2 agonists, dexmedetomidine and clonidine, are efficacious, but their potential cardiovascular adverse effects limit their utilization. Guanfacine is an oral alpha-2 agonist with a lower potential for such adverse outcomes; however, its use in delirium has not been studied. Methods A retrospective descriptive analysis of guanfacine for managing hyperactive or mixed delirium at Tampa General Hospital from January 2020 to October 2020 was conducted. The primary outcome was the time reduction in acute sedative administration. Secondary outcomes included renewed participation in physical therapy or occupational therapy (PT/OT), decreased opioid use, and an incidence of cardiovascular adverse effects. Results One hundred forty-nine patients were identified as having received guanfacine for managing delirium during the study period. All experienced a reduction in acute sedative use after the initiation of guanfacine. In 93 patients receiving PT/OT and no longer participating due to behavioral agitation, 74% had a documented renewal of services within four days. Of 112 patients on opioids, 70% experienced a 25% reduction in opioid administration within four days. No patients experienced consecutive episodes of hypotension that required a change in their clinical care. Two patients experienced a single episode of consecutive bradycardia that led to the discontinuation of guanfacine.  Conclusions Based on our retrospective study, guanfacine is a well-tolerated medication for the management of delirium. Even in medically and critically ill patients, cardiovascular adverse events were rare with guanfacine. Patients treated with guanfacine experienced decreased acute sedative use for behavioral agitation. Additionally, patients treated with guanfacine received fewer opioids and were better able to participate in PT/OT. Future studies with prospective, randomized, placebo-controlled designs are warranted to evaluate this promising intervention for delirium further.

P3a amplitude to trauma-related stimuli reduced after successful trauma-focused PTSD treatment.

An elevated P3a amplitude to trauma-related stimuli is strongly associated with posttraumatic stress disorder (PTSD), yet little is known about whether this response to trauma-related stimuli is affected by treatment that decreases PTSD symptoms. As an analysis of secondary outcome measures from a randomized controlled trial, we investigated the latency and amplitude changes of the P3a in responses in a three-condition oddball visual task that included trauma-related (combat scenes) and trauma-unrelated (threatening animals) distractors. Fifty-five U.S. veterans diagnosed with combat-related PTSD were randomized to receive either active or sham repetitive transcranial magnetic stimulation (rTMS). All received cognitive processing therapy, CPT+A, which requires a written account of the index trauma. They were tested before and 6 months after protocol completion. P3a amplitude and response time decreases were driven largely by the changes in the responses to the trauma-related stimuli, and this decrease correlated to the decrease in PTSD symptoms. The amplitude changes were greater in those who received rTMS + CPT than in those who received sham rTMS + CPT, suggesting that rTMS plays beneficial role in reducing arousal and threat bias, which may allow for more effective engagement in trauma-focused PTSD treatment.

Neural correlates of successful response inhibition in unmedicated patients with late-life depression.

OBJECTIVE: Accumulating evidence implicates a strong association between abnormal frontostriatal-limbic brain circuits, executive dysfunction, and late-life depression (LLD). The stop signal task (SST) was designed by Rubia et al. for use with functional magnetic resonance imaging (fMRI) to identify the neural correlates of motor response inhibition, a well-characterized executive function. In this study, we compared brain activation between a group of unmedicated participants with LLD and an unmedicated healthy cohort during SST performance. METHODS: Participants 55-85 years of age were screened, clinically evaluated, and entered into either the LLD (n = 15) or healthy comparison group (n = 13). Both groups underwent neuroimaging while performing the SST under similar conditions. The brain circuitry of successful motor inhibition was evaluated by contrasting the condition of correctly inhibiting responses with the condition of correctly responding to Go signals. Differential areas of brain activation between the LLD and comparison groups were determined with FMRIB Software Library. RESULTS: Despite comparable SST performance measures, LLD participants demonstrated greater blood oxygen level dependent activation relative to the comparison group in predominantly left-lateralized frontostriatal-limbic circuitry that included the bilateral superior frontal cortices and left-hemispheric orbitofrontal gyri, insular cortex, cingulate cortex, caudate, and putamen. Conversely, the healthy comparison group did not exhibit any areas of greater activation than the LLD group. CONCLUSION: Unmedicated participants with LLD activate additional areas within frontostriatal-limbic brain circuitry when performing the SST at a level comparable to a healthy cohort.

Neuromodulation as an Augmenting Strategy for Behavioral Therapies for Anxiety and PTSD: a Narrative Review.

Purpose of Review: Post-traumatic stress disorder (PTSD) is a prevalent problem. Despite current treatments, symptoms may persist, and neuromodulation therapies show great potential. A growing body of research suggests that transcranial magnetic stimulation (TMS) is effective as a standalone treatment for PTSD, with recent research demonstrating promising use when combined synergistically with behavioral treatments. In this review, we survey this literature including data suggesting mechanisms involved in anxiety and PTSD that may be targeted by neurostimulation. Recent Findings: Evidence suggests the mechanism of action for TMS that contributes to behavioral change may be enhanced neural plasticity via increased functionality of prefrontal and subcortical/limbic structures and associated networks. Some research has demonstrated a behavioral change in PTSD and anxiety due to enhanced extinction learning or improved ability to think flexibly and reduce ruminative tendencies. Growing evidence suggests TMS may be best used as a therapeutic adjunct, at least acutely, for extinction-based exposure therapies in patients by accelerating therapy response. Summary: While TMS has shown promise as a standalone intervention, augmentation with psychotherapy is one avenue of interest. Non-responders to current EBPs might particularly benefit from this sort of targeted approach, and it may shorten treatment length, which would help the successful completion of a course of therapy.

Systematic review of preservation TMS that includes continuation, maintenance, relapse-prevention, and rescue TMS.

BACKGROUND: A dearth of evidence-based information exists to guide the delivery of transcranial magnetic stimulation (TMS) after a successful acute course of treatment for Major Depressive Disorder. METHODS: To provide guidance for clinicians, existing literature focused on "preservation TMS" was systematically reviewed and synthesized. Preservation TMS was defined as TMS used to sustain a clinical response after a successful acute course of treatment and included reports using the terms maintenance, continuation, relapse prevention, or rescue TMS. The review protocol was registered on Open Science Framework and reported following PRISMA guidelines. Data were abstracted by two authors and discrepancies were resolved by a third author. Primary outcome measures focused on clinical efficacy. The evaluated studies were graded using the Levels of Evidence criteria published by the Oxford Centre for Evidence-Based Medicine. RESULTS: The search included 536 abstracts and 16 additional papers, from which 63 full articles were screened. Data were abstracted from 30 qualifying sources (N=1,494) including 4 randomized controlled trials (one sham controlled), 14 open trials, and 12 case series. Overall, the quality of existing literature was low regarding efficacy but provided clear support for effectiveness and safety across a range of preservation TMS protocols based on mostly uncontrolled studies. CONCLUSIONS: Existing literature suggests that preservation TMS protocols significantly vary and are mostly supported by open trials and case series. Due to a lack of effective alternatives, preservation TMS will likely be required for certain patients who respond to acute TMS therapy. More studies of preservation TMS are critically needed.