Publications by authors named "Scott T Aaronson"

31 Publications

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

J Affect Disord 2022 Jan 17;296:79-88. Epub 2021 Sep 17.

Department of Behavioral Sciences and Social Medicine, Florida State University College of Medicine, Florida State University, 1115 W. Call Street, Tallahassee, FL 32306, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jad.2021.09.040DOI Listing
January 2022

Vagus Nerve Stimulation in Patients Receiving Maintenance Therapy With Electroconvulsive Therapy: A Series of 10 Cases.

J ECT 2021 Jun;37(2):84-87

From the Department of Clinical Research, Sheppard Pratt Health System, Baltimore, MD.

Objectives: Electroconvulsive therapy (ECT) is a mainstay in both acute and long-term management of difficult-to-treat depression. However, frequent acute courses of ECT or prolonged maintenance ECT treatment may increase adverse-effect burden and/or reduce patient acceptability. Therefore, we investigated the effectiveness of adjunctive vagus nerve stimulation (VNS) therapy as an alternative strategy for long-term maintenance treatment in ECT-responsive patients.

Methods: This retrospective chart review identified maintenance ECT patients with unipolar (n = 5) and bipolar depression (n = 5) from 2 large hospital systems who had a history of ECT response, but the patients had significant residual incapacitating symptoms or increasing concerns regarding the burden associated with ECT and opted to receive adjunctive VNS therapy. The patients were followed for 2 years after VNS implantation. Response and remission were defined as Clinical Global Impression-Severity scale scores of ≤2 and 1, respectively, obtained at 1- and 2-year postimplantation compared with just before VNS implantation.

Results: One-year postimplantation, 6 of 10 had responded of which 5 met remission criteria. All 10 patients benefited from adjunctive VNS therapy with either fewer hospitalizations and/or ECT sessions. Seven of 10 stopped maintenance ECT by the end of year 1; an additional patient stopped maintenance ECT by year 2. No patients required an acute course of ECT during the 2-year follow-up. There was a statistically significant reduction (P < 0.0001) in mean (SD) Clinical Global Impression-Severity scale scores between baseline (5.4 [0.51]) and the 1-year postimplantation (2.1 [1.37]) time points, and between baseline and the 2-year postimplantation (2.3 [1.16]) time points, whereas no difference existed between the 1- and 2-year postimplantation time points.

Conclusions: Vagus nerve stimulation therapy may be a useful maintenance strategy in patients with difficult-to-treat depression receiving maintenance ECT.
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http://dx.doi.org/10.1097/YCT.0000000000000724DOI Listing
June 2021

A retrospective analysis of bipolar depression treated with transcranial magnetic stimulation.

Brain Behav 2020 12 10;10(12):e01805. Epub 2020 Nov 10.

Clinical Research, Sheppard Pratt Health System, Baltimore, Maryland, USA.

Introduction: Treatment options are limited for patients with bipolar depression. Antidepressants added to mood stabilizers even carry risks of precipitating mixed/manic episodes. Transcranial magnetic stimulation (TMS) may provide a safe and effective option for these patients.

Methods: Database analysis of the TMS Service at Sheppard Pratt Health System identified patients with bipolar disorder type I (BD1) or II (BD2) in a pure depressive phase at initiation of TMS. Records were reviewed for response and remission rates based on MADRS scores, time to effect, and adverse events, notably treatment-emergent affective switching. All had failed at least two prior treatments for depression, were currently on at least one mood stabilizer and off antidepressants. Stimulation parameters targeted left dorsolateral prefrontal cortex: 120% motor threshold, 10 pulses per second (pps) × 4s, intertrain interval (ITI) 26s, 75 trains (37.5 min/session) for 3,000 pps total, 5 sessions/week for 30 total treatments, or until remission criteria were met.

Results: A total of 44 patients with BD were identified, representing 15% of the total TMS population. 77% of those who completed a course of TMS met response criteria, and 41% of subjects who completed at least 25 treatments met remission criteria. Subjects with BD1 were more likely to respond, remit, or suffer an adverse event than those with BD2. No patient met clinical criteria for a manic/mixed episode, but four (10%) discontinued due to concerns of activation.

Conclusions: TMS is effective in the bipolar depressed population where episode focused intervention can be specifically offered. Risk of psychomotor agitation must be closely monitored.
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http://dx.doi.org/10.1002/brb3.1805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749511PMC
December 2020

Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: a double-blind, randomized, sham-controlled trial.

Neuropsychopharmacology 2021 01 12;46(2):462-469. Epub 2020 Sep 12.

Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA.

Treatment-resistant depression (TRD) is prevalent and associated with a substantial psychosocial burden and mortality. There are few prior studies of interventions for TRD in adolescents. This was the largest study to date examining the feasibility, safety, and efficacy of 10-Hz transcranial magnetic stimulation (TMS) for adolescents with TRD. Adolescents with TRD (aged 12-21 years) were enrolled in a randomized, sham-controlled trial of TMS across 13 sites. Treatment resistance was defined as an antidepressant treatment record level of 1 to 4 in a current episode of depression. Intention-to-treat patients (n = 103) included those randomly assigned to active NeuroStar TMS monotherapy (n = 48) or sham TMS (n = 55) for 30 daily treatments over 6 weeks. The primary outcome measure was change in the Hamilton Depression Rating Scale (HAM-D-24) score. After 6 weeks of blinded treatment, improvement in the least-squares mean (SE) HAM-D-24 scores were similar between the active (-11.1 [2.03]) and sham groups (-10.6 [2.00]; P = 0.8; difference [95% CI], - 0.5 [-4.2 to 3.3]). Response rates were 41.7% in the active group and 36.4% in the sham group (P = 0.6). Remission rates were 29.2% in the active group and 29.0% in the sham group (P = 0.95). There were no new tolerability or safety signals in adolescents. Although TMS treatment produced a clinically meaningful change in depressive symptom severity, this did not differ from sham treatment. Future studies should focus on strategies to reduce the placebo response and examine the optimal dosing of TMS for adolescents with TRD.
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http://dx.doi.org/10.1038/s41386-020-00829-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852515PMC
January 2021

Clinical outcomes in a large registry of patients with major depressive disorder treated with Transcranial Magnetic Stimulation.

J Affect Disord 2020 12 7;277:65-74. Epub 2020 Aug 7.

Nashville NeuroCare Therapy, Franklin, TN, USA.

Background: Randomized clinical trials have demonstrated that Transcranial Magnetic Stimulation (TMS) is an effective treatment for episodes of major depressive disorder (MDD). However, characterization of outcomes in routine clinical practice is needed, as well as identification of patient- and treatment-related outcome predictors. This study documented patient-rated (PHQ-9) and clinician-rated (CGI-S) clinical outcomes in the NeuroStar® Advanced Therapy System Clinical Outcomes Registry.

Methods: Registry data were collected at 103 practice sites. Of 7759 participants, 5010 patients were included in an intent-to-treat (ITT) sample, defined as a primary MDD diagnosis, age ≥ 18, and completion of the PHQ-9 before TMS and with at least one PHQ-9 assessment after baseline. Completers (N = 3,814) were responders or had received ≥ 20 sessions and had an end of acute treatment PHQ-9 assessment. CGI-S ratings were obtained in smaller samples.

Results: In the total ITT and Completer samples, response (58-83%) and remission (28-62%) rates were notably high across self-report and clinician-administered assessments. Female patients and those treated with a larger number of pulses per session had superior clinical outcomes.

Limitations: Site participation in the registry was voluntary and treatment was open label.

Conclusions: The extent of clinical benefit reported by patients and clinicians following TMS in routine practice compares favorably with alternative interventions for treatment-resistant depression. Strong efficacy and the low side effect and medical risk profile suggest that TMS be evaluated as a first-line treatment for MDD. The findings derive from the largest registry of clinical outcomes in MDD for any treatment.
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http://dx.doi.org/10.1016/j.jad.2020.08.005DOI Listing
December 2020

A prospective, multi-center randomized, controlled, blinded trial of vagus nerve stimulation for difficult to treat depression: A novel design for a novel treatment.

Contemp Clin Trials 2020 08 19;95:106066. Epub 2020 Jun 19.

Duke-NUS Medical School, Singapore; Duke University, Durham, NC, USA; Texas Tech University, Permian Basin, TX, USA.

Few treatment options exist for patients with difficult-to-treat depression (DTD). One potentially efficacious treatment is vagus nerve stimulation (VNS): chronic stimulation of the vagus nerve using an implanted stimulator. Given a series of recent VNS clinical studies, including a large, five-year naturalistic investigation, the Center for Medicare and Medicaid Services (CMS) reconsidered the previous non coverage determination and announced coverage for patients participating in a "coverage with evidence" trial. This study, entitled, A PRospective, Multi-cEnter, Randomized Controlled Blinded Trial DemOnstrating the Safety and Effectiveness of VNS Therapy® System as AdjunctivE Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression (RECOVER), includes DTD patients with at least four unsuccessful antidepressant treatments in the current episode and will randomize both unipolar and bipolar DTD participants, each up to 500 evaluable enrollees. Predetermined interim analyses will define the necessary sample size. All participants will be implanted with VNS devices: half receive active stimulation during year one, and half receive delayed stimulation after year one. Participants will be followed for 5 years. This RCT is unique for DTD studies: 1) large sample size and long study duration (one year of controlled comparison); 2) use of a percent time in response as the primary outcome measure, given the chronic illness and its fluctuating course (vis-à-vis meeting a response criteria at a single time point); 3) inclusion of diverse measures of VNS impact on function, including quality of life, degree of disability, health status, and suicidality.
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http://dx.doi.org/10.1016/j.cct.2020.106066DOI Listing
August 2020

A prospective, multi-center randomized, controlled, blinded trial of vagus nerve stimulation for difficult to treat depression: A novel design for a novel treatment.

Contemp Clin Trials 2020 08 19;95:106066. Epub 2020 Jun 19.

Duke-NUS Medical School, Singapore; Duke University, Durham, NC, USA; Texas Tech University, Permian Basin, TX, USA.

Few treatment options exist for patients with difficult-to-treat depression (DTD). One potentially efficacious treatment is vagus nerve stimulation (VNS): chronic stimulation of the vagus nerve using an implanted stimulator. Given a series of recent VNS clinical studies, including a large, five-year naturalistic investigation, the Center for Medicare and Medicaid Services (CMS) reconsidered the previous non coverage determination and announced coverage for patients participating in a "coverage with evidence" trial. This study, entitled, A PRospective, Multi-cEnter, Randomized Controlled Blinded Trial DemOnstrating the Safety and Effectiveness of VNS Therapy® System as AdjunctivE Therapy Versus a No Stimulation Control in Subjects With Treatment-Resistant Depression (RECOVER), includes DTD patients with at least four unsuccessful antidepressant treatments in the current episode and will randomize both unipolar and bipolar DTD participants, each up to 500 evaluable enrollees. Predetermined interim analyses will define the necessary sample size. All participants will be implanted with VNS devices: half receive active stimulation during year one, and half receive delayed stimulation after year one. Participants will be followed for 5 years. This RCT is unique for DTD studies: 1) large sample size and long study duration (one year of controlled comparison); 2) use of a percent time in response as the primary outcome measure, given the chronic illness and its fluctuating course (vis-à-vis meeting a response criteria at a single time point); 3) inclusion of diverse measures of VNS impact on function, including quality of life, degree of disability, health status, and suicidality.
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http://dx.doi.org/10.1016/j.cct.2020.106066DOI Listing
August 2020

Treatment-Resistant Depression in Adolescents: Clinical Features and Measurement of Treatment Resistance.

J Child Adolesc Psychopharmacol 2020 05 21;30(4):261-266. Epub 2020 Apr 21.

Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.

To describe the clinical characteristics of adolescents with antidepressant treatment-resistant major depressive disorder (MDD) and to examine the utility of the Antidepressant Treatment Record (ATR) in categorizing treatment resistance in this population. Adolescents with treatment-resistant MDD enrolled in an interventional study underwent a baseline evaluation with the ATR, Children's Depression Rating Scale-Revised (CDRS-R), and Clinical Global Impressions-Severity (CGI-S) scales. Demographic and clinical characteristics were examined with regard to ATR-defined level of resistance (level 1 to ≥3) using analysis of variance and χ tests. In adolescents with treatment-resistant MDD ( = 97), aged 12-21 years, most were female (65%), white (89%), and had recurrent illness (78%). Patients were severely ill (median CGI-S score of 5), had a mean CDRS-R score of 63 ± 10, and 17.5% had been hospitalized for depression-related symptoms. Fifty-two patients were classified as ATR 1, whereas 32 were classified as ATR level 2 and 13 patients as ≥3, respectively. For increasing ATR-defined levels, illness duration increased from 12.0 (range: 1.5-31.9) to 14.8 (range: 1.8-31.7) to 19.5 (range: 2.5-36.2) months and the likelihood of treatment with serotonin norepinephrine reuptake inhibitors (SNRIs) and dopamine norepinephrine reuptake inhibitors (DNRIs) similarly increased ( = 0.006 for both SNRIs and DNRIs) as did the likelihood of treatment with mixed dopamine serotonin receptor antagonists (χ = 17,  < 0.001). This study underscores the morbidity and chronicity of treatment-resistant MDD in adolescents. The present characterization of related clinical features describes the use of nonselective serotonin reuptake inhibitors in adolescents with treatment-resistant depression and raises the possibility that those with the greatest medication treatment resistance are less likely to have had recurrent episodes. The study also demonstrates the utility of the ATR in categorizing treatment resistance in adolescents with MDD.
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http://dx.doi.org/10.1089/cap.2020.0008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640745PMC
May 2020

Neurocognitive effects of transcranial direct current stimulation (tDCS) in unipolar and bipolar depression: Findings from an international randomized controlled trial.

Depress Anxiety 2020 03 16;37(3):261-272. Epub 2020 Jan 16.

Black Dog Institute, Sydney, Australia.

Objective: Transcranial direct current stimulation (tDCS) has been found to have antidepressant effects and may have beneficial neurocognitive effects. However, prior research has produced an unclear understanding of the neurocognitive effects of repeated exposure to tDCS. The study's aim was to determine the neurocognitive effects following tDCS treatment in participants with unipolar or bipolar depression.

Method: The study was a triple-masked, randomized, controlled clinical trial across six international academic medical centers. Participants were randomized to high dose (2.5 mA for 30 min) or low dose (0.034 mA, for 30 min) tDCS for 20 sessions over 4 weeks, followed by an optional 4 weeks of open-label high dose treatment. The tDCS anode was centered over the left dorsolateral prefrontal cortex at F3 (10/20 EEG system) and the cathode over F8. Participants completed clinical and neurocognitive assessments before and after tDCS. Genotype (BDNF Val66Met and catechol-o-methyltransferase [COMT] Val158Met polymorphisms) were explored as potential moderators of neurocognitive effects.

Results: The study randomized 130 participants. Across the participants, tDCS treatment (high and low dose) resulted in improvements in verbal learning and recall, selective attention, information processing speed, and working memory, which were independent of mood effects. Similar improvements were observed in the subsample of participants with bipolar disorder. There was no observed significant effect of tDCS dose. However, BDNF Val66Met and COMT Val158Met polymorphisms interacted with tDCS dose and affected verbal memory and verbal fluency outcomes, respectively.

Conclusions: These findings suggest that tDCS could have positive neurocognitive effects in unipolar and bipolar depression. Thus, tDCS stimulation parameters may interact with interindividual differences in BDNF and COMT polymorphisms to affect neurocognitive outcomes, which warrants further investigation.
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http://dx.doi.org/10.1002/da.22988DOI Listing
March 2020

The assessment of resistance to antidepressant treatment: Rationale for the Antidepressant Treatment History Form: Short Form (ATHF-SF).

J Psychiatr Res 2019 06 22;113:125-136. Epub 2019 Mar 22.

Duke-NUS Medical School, Singapore; Duke University, Durham, NC, USA; Texas Tech University, Permian Basin, TX, USA.

There is considerable diversity in how treatment-resistant depression (TRD) is defined. However, every definition incorporates the concept that patients with TRD have not benefited sufficiently from one or more adequate trials of antidepressant treatment. This review examines the issues fundamental to the systematic evaluation of antidepressant treatment adequacy and resistance. These issues include the domains of interventions deemed effective in treatment of major depressive episodes (e.g., pharmacotherapy, brain stimulation, and psychotherapy), the subgroups of patients for whom distinct adequacy criteria are needed (e.g., bipolar vs. unipolar depression, psychotic vs. nonpsychotic depression), whether trials should be rated dichotomously as adequate or inadequate or on a potency continuum, whether combination and augmentation strategies require specific consideration, and the criteria used to evaluate the adequacy of treatment delivery (e.g., dose, duration), trial adherence, and clinical outcome. This review also presents the Antidepressant Treatment History Form: Short-Form (ATHF-SF), a completely revised version of an earlier instrument, and details how these fundamental issues were addressed in the ATHF-SF.
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http://dx.doi.org/10.1016/j.jpsychires.2019.03.021DOI Listing
June 2019

The Evolving Concept of a Therapeutic Community.

Psychiatry 2019 14;82(1):24-26. Epub 2019 Mar 14.

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http://dx.doi.org/10.1080/00332747.2019.1565557DOI Listing
April 2019

Durability of symptomatic responses obtained with adjunctive vagus nerve stimulation in treatment-resistant depression.

Neuropsychiatr Dis Treat 2019 13;15:457-468. Epub 2019 Feb 13.

Department of Psychiatry and Behavioral Sciences, National University of Singapore, Singapore.

Objective: To compare the durations of response achieved with adjunctive vagus nerve stimulation (VNS + TAU) vs treatment as usual (TAU) alone in treatment-resistant depression (TRD) over a 5-year period in the TRD registry.

Materials And Methods: Data from 271 participants on TAU and 328 participants on VNS + TAU were analyzed. Response was defined as ≥50% decrease in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score at postbaseline visit and was considered retained until the decrease was <40%. MADRS was obtained quarterly in year 1 and biannually thereafter. Time-to-events were estimated using Kaplan-Meier method and compared using log-rank test. HR was estimated using Cox proportion hazard model.

Results: In the VNS + TAU arm, 62.5% (205/328) of participants had a first response over 5 years compared with 39.9% (108/271) in TAU. The time to first response was significantly shorter for VNS + TAU than for TAU (<0.01). For responders in the first year, median time to relapse from first response was 10.1 months (Q1=4.2, Q3=31.5) for VNS + TAU vs 7.3 months (Q1=3.1, Q3=17.6) for TAU (<0.01). HR=0.6 (95% CI: 0.4, 0.9) revealed a significantly lower chance for relapse in VNS + TAU. Probability of retaining first response for a year was 0.39 (0.27, 0.51) for TAU and 0.47 (0.38, 0.56) for VNS + TAU. Timing of the onset of the response did not impact the durability of the response.

Conclusion: VNS therapy added to TAU in severe TRD leads to rapid onset and higher likelihood of response, and a greater durability of the response as compared to TAU alone.
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http://dx.doi.org/10.2147/NDT.S196665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387594PMC
February 2019

Difficult-to-treat depression: A clinical and research roadmap for when remission is elusive.

Aust N Z J Psychiatry 2019 02 31;53(2):109-118. Epub 2018 Oct 31.

6 University Psychiatric Centre, University of Leuven, Leuven, Belgium.

Objectives: The report considers the pros and cons of the most commonly used conceptual model that forms the basis for most clinical practice guidelines for depression. This model promotes the attainment of sustained symptom remission as the treatment goal based on its well-established prognostic and functional importance. Sustained remission is very unlikely, however, after multiple treatment attempts. Our current model propels many clinicians to continue to change or add treatments despite little chance for remission or full functional restoration and despite the increasing risk of more adverse events from polypharmacy. An alternative 'difficult-to-treat depression' model is presented and considered. It accepts that the treatment aims for some depressed patients may shift to optimal symptom control rather than remission. When difficult-to-treat depression is suspected, the many treatable causes of persistent depression must be assessed and addressed (given the importance of remission when attainable) before difficult-to-treat depression can be ascribed. The clinical and research implications of the difficult-to-treat depression model are discussed.

Conclusion: Suspected difficult-to-treat depression provides a practical basis for considering when to conduct a comprehensive evaluation. Once difficult-to-treat depression is confirmed, treatment may better focus on optimal disease management (symptom control and functional improvement).
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http://dx.doi.org/10.1177/0004867418808585DOI Listing
February 2019

Pre-treatment attentional processing speed and antidepressant response to transcranial direct current stimulation: Results from an international randomized controlled trial.

Brain Stimul 2018 Nov - Dec;11(6):1282-1290. Epub 2018 Aug 23.

School of Psychiatry, University of New South Wales, Sydney, NSW, Australia; Black Dog Institute, Sydney, NSW, Australia; St George Hospital, Sydney, NSW, Australia.

Background: Transcranial direct current stimulation (tDCS) has promising antidepressant effects, however, clinical trials have shown variable efficacy. Pre-treatment neurocognitive functioning has previously been identified as an inter-individual predictor of tDCS antidepressant efficacy.

Objective: In this international multicentre, sham-controlled study, we investigated this relationship while also assessing the influence of clinical and genotype (BDNF Val66Met and COMT Val158Met polymorphisms) factors as predictors of response to active tDCS.

Methods: The study was a triple-masked, parallel, randomized, controlled design across 6 international academic medical centers. Participants were randomized to active (2.5 mA) or sham (34 μA) tDCS for 30 min each session for 20 sessions. The anode was centered over the left dorsolateral prefrontal cortex at F3 (10/20 EEG system) and the cathode over the lateral right frontal area at F8.

Results: Better pre-treatment attentional processing speed on the Ruff 2 & 7 Selective Attention Test (Total Speed: β = 0.25, p < .05) and concurrent antidepressant medication use (β = 0.31, p < .05) predicted antidepressant efficacy with active tDCS. Genotype differences in the BDNF Val66Metand COMT Val158Met polymorphisms were not associated with antidepressant effects. Secondary analyses revealed that only participants in the highest performing Ruff 2 & 7 Total Speed group at pre-treatment in both active and sham tDCS conditions showed significantly greater antidepressant response compared to those with lower performance at both the 2 and 4 week treatment time points (p < .05).

Conclusions: These results suggest that high pre-treatment attentional processing speed may be relevant for identifying participants more likely to show better tDCS antidepressant response to both high (2.5 mA) and very low (34 μA) current intensity stimulation.

Clinical Trials Registration: www.clinicaltrials.gov, NCT01562184.
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http://dx.doi.org/10.1016/j.brs.2018.08.011DOI Listing
May 2019

Chronic Vagus Nerve Stimulation Significantly Improves Quality of Life in Treatment-Resistant Major Depression.

J Clin Psychiatry 2018 08 21;79(5). Epub 2018 Aug 21.

Duke-National University of Singapore, Singapore.

Objective: To compare quality-of-life (QOL) change associated with treatment as usual (TAU, any antidepressant treatment) versus adjunctive vagus nerve stimulation treatment (VNS + TAU) in a population of patients with treatment-resistant depression (TRD) for 5 years.

Methods: Self-reported QOL assessments, using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF), were gathered in a multicenter, longitudinal registry (January 2006-May 2015) comparing the antidepressant efficacy of VNS + TAU versus TAU in TRD. All depressed patients (N = 599), with either unipolar or bipolar depression, met DSM-IV-TR major depressive episode criteria and failed at least 4 adequate antidepressant trials. The Montgomery-Asberg Depression Rating Scale (MADRS) was administered by blinded raters. Q-LES-Q-SF scores in the treatment arms were compared via linear regression; linear regression was employed to compare QOL differences with percent decrease in MADRS. A subanalysis comparing Q-LES-Q-SF functional domain change was performed.

Results: 328 VNS + TAU and 271 TAU patients with TRD were compared. On average, VNS + TAU demonstrated a significant, comparative QOL advantage over TAU (as demonstrated via non-overlapping 95% confidence bands) that began at 3 months and was sustained through 5 years and was reinforced using a clinical global improvement measure. Patients receiving VNS + TAU, but not TAU alone, demonstrated a clinically meaningful QOL improvement (34% MADRS decrease) well below the classically defined antidepressant response (50% MADRS decrease). Exploratory post hoc subanalysis demonstrated that VNS + TAU had a significant advantage in multiple Q-LES-Q domains.

Conclusion: Compared to TAU, adjunctive VNS significantly improved QOL in TRD, and this QOL advantage was sustained. Further, TRD patients treated with VNS experienced clinically meaningful QOL improvements even with depression symptom reduction less than the conventional 50% reduction used to ascribe "response."
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http://dx.doi.org/10.4088/JCP.18m12178DOI Listing
August 2018

Neuromodulation.

Psychiatr Clin North Am 2018 09 17;41(3):xiii-xvi. Epub 2018 Jul 17.

Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Psychiatric Neuromodulation, Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, 830 Chalkstone Avenue, Providence, RI 02908, USA. Electronic address:

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http://dx.doi.org/10.1016/j.psc.2018.06.001DOI Listing
September 2018

Vagus Nerve Stimulation: Changing the Paradigm for Chronic Severe Depression?

Psychiatr Clin North Am 2018 09;41(3):409-418

Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8134, St Louis, MO 63110, USA.

Vagus nerve stimulation (VNS) has been studied for its effect on treatment-resistant depression. Open-label studies have shown a significant positive effect in an especially treatment-resistant depressive population. Insurance company support for VNS has been limited but may be reviewed given recent positive open-label data. Coming developments in novel external ways to stimulate the vagus nerve may revive interest in this area. This article reviews the clinical development of VNS starting with the first recognition of its potential for treating depression, parses the results of several large clinical trials, and suggests a future path for optimal clinical development and use.
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http://dx.doi.org/10.1016/j.psc.2018.05.001DOI Listing
September 2018

Neurocognitive Effects of Repetitive Transcranial Magnetic Stimulation With a 2-Coil Device in Treatment-Resistant Major Depressive Disorder.

J ECT 2018 Dec;34(4):258-265

Brown Department of Psychiatry and Human Behavior, Butler Hospital, Providence, RI.

Background: Neurocognitive dysfunction is an understudied and undertreated aspect of psychiatric research and treatment. There is emerging evidence to suggest that repetitive transcranial magnetic stimulation (rTMS) may possess neurocognition-enhancing capabilities.

Methods: This study examined the neurocognitive data from a randomized, double-blind, sham-controlled trial of an investigational 2-coil rTMS device in antidepressant treatment or treatment-intolerant major depressive disorder patients. This device has the potential to stimulate deeper areas of the brain than the Food and Drug Administration-approved TMS devices, which primarily stimulate cortical brain areas and may therefore have different neurocognitive adverse effects. Patients received 20 daily rTMS treatments (10-Hz stimulation; either active or sham) with coil centers positioned over the left dorsolateral prefrontal cortex and dorsomedial prefrontal cortex. Neurocognitive safety was evaluated at baseline and within 72 hours of final treatment session with a computerized battery assessing aspects of attention and memory in 84 participants.

Results: There were no observed negative neurocognitive effects of the 2-coil rTMS device. A significant effect of active rTMS was observed on the quality of episodic memory. There were no observed effects for attention or working memory. Baseline quality of episodic memory predicted depression treatment response and remission, in that lower baseline episodic memory was associated with greater likelihood of depression response/remission. This was observed in logistic regression analyses controlling for treatment and baseline depressive symptoms.

Conclusions: The 2-coil rTMS device is a cognitively safe treatment for treatment-resistant depression that may possess episodic memory-enhancing capabilities. Furthermore, baseline episodic memory may reflect an important predictor of subsequent depression treatment response/remission to rTMS.
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http://dx.doi.org/10.1097/YCT.0000000000000494DOI Listing
December 2018

rTMS with a two-coil array: Safety and efficacy for treatment resistant major depressive disorder.

Brain Stimul 2017 Sep - Oct;10(5):926-933. Epub 2017 Jun 9.

Rio Grande Neurosciences, Inc. (Formerly Cervel Neurotech, Inc.), 600 Central SE, Ste 221, Albequerque, NM 87102, United States; Stanford University, Department of Psychiatry and Behavioral Sciences, 401 Quarry Road, Stanford, CA 94305-5717, United States; Stanford University Department of Neurosurgery, 213 Quarry Road, Palo Alto, CA 94304-5979, United States. Electronic address:

Background: Therapeutic repetitive Transcranial Magnetic Stimulation (rTMS) has emerged as a standard of care for individuals with major depressive disorder (MDD) who do not benefit from, or are unable to tolerate, antidepressant pharmacotherapy. Depth of stimulation is limited with currently approved figure-eight coils and larger coils capable of deeper penetration may be associated with loss of stimulation focality and undesired recruitment of motor cortex. A second generation 2-coil array rTMS system was designed to target converging brain pathways for potentially deeper prefrontal cortex stimulation.

Methods: A randomized, double-blind, sham-controlled trial examined the safety and efficacy of an investigational 2-coil rTMS device. Antidepressant treatment-resistant or treatment-intolerant MDD patients (n = 92) received 20 daily rTMS treatments with coil centers positioned over left dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC). 10 Hz stimulation (maximum summated power for both coils ≤ 120% motor threshold) was delivered. Primary efficacy endpoint was change in HAMD-24 score from baseline to the conclusion of treatments.

Results: Data from n = 75 (per-protocol sample) showed significantly greater improvement (mean HAMD-24 change) over time for the active (n = 38) versus sham (n = 37) group after 20 sessions (F = 7.174; p = 0.008) and also at the one-month follow-up (F = 6.748; p = 0.010). Response rates were 55.3% (active) versus 32.4% (sham) (p = 0.063); remission rates were 26.3% versus 18.9% (p > 0.05). Other secondary outcomes were generally supportive.

Conclusions: The results confirmed safety and acute efficacy of the 2-coil rTMS device. Despite modest sample size, primary outcome was clinically and statistically significant, and the effect size was comparable with those reported for regulatory trials with FDA-cleared devices.
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April 2018

rTMS with a two-coil array: Safety and efficacy for treatment resistant major depressive disorder.

Brain Stimul 2017 Sep - Oct;10(5):926-933. Epub 2017 Jun 9.

Rio Grande Neurosciences, Inc. (Formerly Cervel Neurotech, Inc.), 600 Central SE, Ste 221, Albequerque, NM 87102, United States; Stanford University, Department of Psychiatry and Behavioral Sciences, 401 Quarry Road, Stanford, CA 94305-5717, United States; Stanford University Department of Neurosurgery, 213 Quarry Road, Palo Alto, CA 94304-5979, United States. Electronic address:

Background: Therapeutic repetitive Transcranial Magnetic Stimulation (rTMS) has emerged as a standard of care for individuals with major depressive disorder (MDD) who do not benefit from, or are unable to tolerate, antidepressant pharmacotherapy. Depth of stimulation is limited with currently approved figure-eight coils and larger coils capable of deeper penetration may be associated with loss of stimulation focality and undesired recruitment of motor cortex. A second generation 2-coil array rTMS system was designed to target converging brain pathways for potentially deeper prefrontal cortex stimulation.

Methods: A randomized, double-blind, sham-controlled trial examined the safety and efficacy of an investigational 2-coil rTMS device. Antidepressant treatment-resistant or treatment-intolerant MDD patients (n = 92) received 20 daily rTMS treatments with coil centers positioned over left dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC). 10 Hz stimulation (maximum summated power for both coils ≤ 120% motor threshold) was delivered. Primary efficacy endpoint was change in HAMD-24 score from baseline to the conclusion of treatments.

Results: Data from n = 75 (per-protocol sample) showed significantly greater improvement (mean HAMD-24 change) over time for the active (n = 38) versus sham (n = 37) group after 20 sessions (F = 7.174; p = 0.008) and also at the one-month follow-up (F = 6.748; p = 0.010). Response rates were 55.3% (active) versus 32.4% (sham) (p = 0.063); remission rates were 26.3% versus 18.9% (p > 0.05). Other secondary outcomes were generally supportive.

Conclusions: The results confirmed safety and acute efficacy of the 2-coil rTMS device. Despite modest sample size, primary outcome was clinically and statistically significant, and the effect size was comparable with those reported for regulatory trials with FDA-cleared devices.
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April 2018

Can Medication Free, Treatment-Resistant, Depressed Patients Who Initially Respond to TMS Be Maintained Off Medications? A Prospective, 12-Month Multisite Randomized Pilot Study.

Brain Stimul 2016 Mar-Apr;9(2):251-7. Epub 2015 Nov 25.

Medical University of South Carolina, Charleston, SC, USA; Ralph H. Johnson VA Medical Center, Charleston, SC, USA.

Background: Repetitive transcranial magnetic stimulation (TMS) is efficacious for acute treatment of resistant major depressive disorder (MDD), but there is little information on maintenance TMS after acute response.

Objective/hypothesis: This pilot feasibility study investigated 12-month outcomes comparing two maintenance TMS approaches--a scheduled, single TMS session delivered monthly (SCH) vs. observation only (OBS).

Methods: Antidepressant-free patients with unipolar, non-psychotic, treatment-resistant MDD participated in a randomized, open-label, multisite trial. Patients meeting protocol-defined criteria for improvement after six weeks of acute TMS were randomized to SCH or OBS regimens. TMS reintroduction was available for symptomatic worsening; all patients remained antidepressant-free during the trial.

Results: Sixty-seven patients enrolled in the acute phase, and 49 (73%) met randomization criteria. Groups were matched, although more patients in the SCH group had failed ≥ 2 antidepressants (p = .035). There were no significant group differences on any outcome measure. SCH patients had nonsignificantly longer time to first TMS reintroduction, 91 ± 66 days, vs. OBS, 77 ± 52 days; OBS patients were nonsignificantly more likely to need reintroduction (odds ratio = 1.21, 95% CI .38-3.89). Reintroduction lasted 14.3 ± 17.8 days (SCH) and 16.9 ± 18.9 days (OBS); 14/18 (78%) SCH and 17/27 (63%) OBS responded to reintroduction. Sixteen patients (32.7%) completed all 53 weeks of the study.

Conclusions: Maintaining treatment-resistant depressed patients off medications with periodic TMS appears feasible in some cases. There was no statistical advantage of SCH vs. OBS, although SCH was associated with a nonsignificantly longer time to relapse. Those who initially respond to TMS have a strong chance of re-responding if relapse occurs.
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http://dx.doi.org/10.1016/j.brs.2015.11.007DOI Listing
February 2017

Efficacy and Safety of Low-field Synchronized Transcranial Magnetic Stimulation (sTMS) for Treatment of Major Depression.

Brain Stimul 2015 Jul-Aug;8(4):787-94. Epub 2015 May 22.

Department of Psychiatry, Medical University of South Carolina, and the Ralph H. Johnson VA Medical Center, Charleston, SC, USA.

Background: Transcranial Magnetic Stimulation (TMS) customarily uses high-field electromagnets to achieve therapeutic efficacy in Major Depressive Disorder (MDD). Low-field magnetic stimulation also may be useful for treatment of MDD, with fewer treatment-emergent adverse events.

Objective/hypothesis: To examine efficacy, safety, and tolerability of low-field magnetic stimulation synchronized to an individual's alpha frequency (IAF) (synchronized TMS, or sTMS) for treatment of MDD.

Methods: Six-week double-blind sham-controlled treatment trial of a novel device that used three rotating neodymium magnets to deliver sTMS treatment. IAF was determined from a single-channel EEG prior to first treatment. Subjects had baseline 17-item Hamilton Depression Rating Scale (HamD17) ≥ 17.

Results: 202 subjects comprised the intent-to-treat (ITT) sample, and 120 subjects completed treatment per-protocol (PP). There was no difference in efficacy between active and sham in the ITT sample. Subjects in the PP sample (N = 59), however, had significantly greater mean decrease in HamD17 than sham (N = 60) (-9.00 vs. -6.56, P = 0.033). PP subjects with a history of poor response or intolerance to medication showed greater improvement with sTMS than did treatment-naïve subjects (-8.58 vs. -4.25, P = 0.017). Efficacy in the PP sample reflects exclusion of subjects who received fewer than 80% of scheduled treatments or were inadvertently treated at the incorrect IAF; these subgroups failed to separate from sham. There was no difference in adverse events between sTMS and sham, and no serious adverse events attributable to sTMS.

Conclusions: Results suggest that sTMS may be effective, safe, and well tolerated for treating MDD when administered as intended.
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http://dx.doi.org/10.1016/j.brs.2015.05.005DOI Listing
February 2016

A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up period.

J Clin Psychiatry 2014 Dec;75(12):1394-401

7525 SE 24th St, Ste 400, Center for Anxiety and Depression, Mercer Island, WA 98040

Objective: Transcranial magnetic stimulation (TMS) is an effective and safe acute treatment for patients not benefiting from antidepressant pharmacotherapy. Few studies have examined its longer term durability. This study assessed the long-term effectiveness of TMS in naturalistic clinical practice settings following acute treatment.

Method: Adult patients with a primary diagnosis of unipolar, nonpsychotic major depressive disorder (DSM-IV clinical criteria), who did not benefit from antidepressant medication, received TMS treatment in 42 clinical practices. Two hundred fifty-seven patients completed a course of acute TMS treatment and consented to follow-up over 52 weeks. Assessments were obtained at 3, 6, 9, and 12 months. The study was conducted between March 2010 and August 2012.

Results: Compared with pre-TMS baseline, there was a statistically significant reduction in mean total scores on the Clinical Global Impressions-Severity of Illness scale (primary outcome), 9-Item Patient Health Questionnaire, and Inventory of Depressive Symptoms-Self Report (IDS-SR) at the end of acute treatment (all P < .0001), which was sustained throughout follow-up (all P < .0001). The proportion of patients who achieved remission at the conclusion of acute treatment remained similar at conclusion of the long-term follow-up. Among 120 patients who met IDS-SR response or remission criteria at the end of acute treatment, 75 (62.5%) continued to meet response criteria throughout long-term follow-up. After the first month, when the majority of acute TMS tapering was completed, 93 patients (36.2%) received reintroduction of TMS. In this group, the mean (SD) number of TMS treatment days was 16.2 (21.1).

Conclusions: TMS demonstrates a statistically and clinically meaningful durability of acute benefit over 12 months of follow-up. This was observed under a pragmatic regimen of continuation antidepressant medication and access to TMS retreatment for symptom recurrence.

Trial Registration: ClinicalTrials.gov identifier: NCT01114477.
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http://dx.doi.org/10.4088/JCP.13m08977DOI Listing
December 2014

Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia.

Schizophr Res 2014 Aug 28;157(1-3):84-9. Epub 2014 May 28.

Sheppard Pratt Health System, Baltimore, MD, USA; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. As a group, while people with schizophrenia have moderate cognitive impairment, it is the best predictor of long-term outcome. Unfortunately, there are no approved medications for cognitive impairment in this population. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimer's dementia. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathophysiology of cognitive symptoms in schizophrenia and hence memantine may positively impact cognition. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current. This results in an increased signal transmission; therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding. The combination of galantamine and memantine may be particularly effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone. In the future, multitarget-directed ligands may play a role in the treatment of complex diseases like schizophrenia.
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http://dx.doi.org/10.1016/j.schres.2014.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099270PMC
August 2014

Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of quality of life outcome measures in clinical practice.

CNS Spectr 2013 Dec 30;18(6):322-32. Epub 2013 Jul 30.

1 Psychiatric Clinical Research Center and Transcranial Magnetic Stimulation Center, Rush University, Chicago, Illinois, USA.

Background: Transcranial magnetic stimulation (TMS) is an effective and safe therapy for major depressive disorder (MDD). This study assessed quality of life (QOL) and functional status outcomes for depressed patients after an acute course of TMS.

Methods: Forty-two, U.S.-based, clinical TMS practice sites treated 307 outpatients with a primary diagnosis of MDD and persistent symptoms despite prior adequate antidepressant pharmacotherapy. Treatment parameters were based on individual clinical considerations and followed the labeled procedures for use of the approved TMS device. Patient self-reported QOL outcomes included change in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the EuroQol 5-Dimensions (EQ-5D) ratings from baseline to end of the acute treatment phase.

Results: Statistically significant improvement in functional status on a broad range of mental health and physical health domains was observed on the SF-36 following acute TMS treatment. Similarly, statistically significant improvement in patient-reported QOL was observed on all domains of the EQ-5D and on the General Health Perception and Health Index scores. Improvement on these measures was observed across the entire range of baseline depression symptom severity.

Conclusion: These data confirm that TMS is effective in the acute treatment of MDD in routine clinical practice settings. This symptom benefit is accompanied by statistically and clinically meaningful improvements in patient-reported QOL and functional status outcomes.
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http://dx.doi.org/10.1017/S1092852913000357DOI Listing
December 2013

Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects.

Brain Stimul 2013 Jul 23;6(4):631-40. Epub 2012 Oct 23.

Sheppard Pratt Health System, Clinical Research Programs, 6501 N. Charles Street, Baltimore, MD 21285, USA.

Background: Major depressive disorder is a prevalent, disabling, and often chronic or recurrent psychiatric condition. About 35% of patients fail to respond to conventional treatment approaches and are considered to have treatment-resistant depression (TRD).

Objective: We compared the safety and effectiveness of different stimulation levels of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of TRD.

Methods: In a multicenter, double blind study, 331 patients with TRD were randomized to one of three dose groups: LOW (0.25 mA current, 130 μs pulse width), MEDIUM (0.5-1.0 mA, 250 μs), or HIGH (1.25-1.5 mA, 250 μs). A highly treatment-resistant population (>97% had failed to respond to ≥6 previous treatments) was enrolled. Response and adverse effects were assessed for 22 weeks (end of acute phase), after which output current could be increased, if clinically warranted. Assessments then continued until Week 50 (end of long-term phase).

Results: VNS therapy was well tolerated. During the acute phase, all groups showed statistically significant improvement on the primary efficacy endpoint (change in Inventory of Depressive Symptomatology-Clinician Administered Version [IDS-C]), but not for any between-treatment group comparisons. In the long-term phase, mean change in IDS-C scores showed continued improvement. Post-hoc analyses demonstrated a statistically significant correlation between total charge delivered per day and decreasing depressive symptoms; and analysis of acute phase responders demonstrated significantly greater durability of response at MEDIUM and HIGH doses than at the LOW dose.

Conclusions: TRD patients who received adjunctive VNS showed significant improvement at study endpoint compared with baseline, and the effect was durable over 1 year. Higher electrical dose parameters were associated with response durability.
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http://dx.doi.org/10.1016/j.brs.2012.09.013DOI Listing
July 2013

Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice.

Depress Anxiety 2012 Jul 11;29(7):587-96. Epub 2012 Jun 11.

Butler Hospital/Brown Department of Psychiatry, 345 Blackstone Boulevard, Providence, RI 02906, USA.

Background: Few studies have examined the effectiveness of transcranial magnetic stimulation (TMS) in real-world clinical practice settings.

Methods: Forty-two US-based clinical TMS practice sites treated 307 outpatients with Major Depressive Disorder (MDD), and persistent symptoms despite antidepressant pharmacotherapy. Treatment was based on the labeled procedures of the approved TMS device. Assessments were performed at baseline, week 2, at the point of maximal acute benefit, and at week 6 when the acute course extended beyond 6 weeks. The primary outcome was change in the Clinician Global Impressions-Severity of Illness from baseline to end of acute phase. Secondary outcomes were change in continuous and categorical outcomes on self-report depression scales (9-Item Patient Health Questionnaire [PHQ-9], and Inventory of Depressive Symptoms-Self Report [IDS-SR]).

Results: Patients had a mean ± SD age of 48.6 ± 14.2 years and 66.8% were female. Patients received an average of 2.5 (± 2.4) antidepressant treatments of adequate dose and duration without satisfactory improvement in this episode. There was a significant change in CGI-S from baseline to end of treatment (-1.9 ± 1.4, P < .0001). Clinician-assessed response rate (CGI-S) was 58.0% and remission rate was 37.1%. Patient-reported response rate ranged from 56.4 to 41.5% and remission rate ranged from 28.7 to 26.5%, (PHQ-9 and IDS-SR, respectively).

Conclusion: Outcomes demonstrated response and adherence rates similar to research populations. These data indicate that TMS is an effective treatment for those unable to benefit from initial antidepressant medication.
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http://dx.doi.org/10.1002/da.21969DOI Listing
July 2012

Olanzapine versus divalproex versus placebo in the treatment of mild to moderate mania: a randomized, 12-week, double-blind study.

J Clin Psychiatry 2008 Nov 7;69(11):1776-89. Epub 2008 Oct 7.

Lilly Research Laboratories, 450 South Madison Ave., Indianapolis, IN 46225, USA.

Objective: To evaluate the efficacy and safety of olanzapine, divalproex, and placebo in a randomized, double-blind trial in mild to moderate mania (DSM-IV-TR criteria).

Method: The study was conducted from October 2004 to December 2006. A total of 521 patients from private practices, hospitals, and university clinics were randomly assigned to olanzapine (5-20 mg/day), divalproex (500-2500 mg/day), or placebo for 3 weeks; those completing continued with a 9-week double-blind extension. Efficacy (mean change in Young Mania Rating Scale [YMRS] total score was the primary outcome) and safety were assessed.

Results: After 3 weeks of treatment, olanzapine-treated (N = 215) and placebo-treated (N = 105) patients significantly differed in YMRS baseline-to-endpoint total score change (p = .034; least squares [LS] mean: -9.4 and -7.4, respectively). Such changes were not significantly different between olanzapine vs. divalproex (N = 201) or divalproex vs. placebo. After 12 weeks of treatment, olanzapine- and divalproex-treated patients significantly differed in YMRS baseline-to-endpoint changes (p = .004; LS mean: -13.3 and -10.7, respectively). Of observed cases, 35.4% (35/99; 3 weeks) to 57.1% (28/49; 12 weeks) had valproate plasma concentrations lower than the recommended valproate therapeutic range, but these patients' YMRS scores were lower than those of patients with valproate concentrations above/within range. Compared with divalproex, after 12 weeks, olanzapine-treated patients had significant increases in weight (p < .001) and in glucose (p < .001), triglyceride (p = .003), cholesterol (p = .024), uric acid (p = .027), and prolactin (p < .001) levels. Divalproex-treated patients had significant decreases in leukocytes (p = .044) and platelets (p < .001) compared with olanzapine after 12 weeks of treatment. The incidence of potentially clinically significant weight gain (>/= 7% from baseline) was higher with olanzapine than with divalproex (3-week: p = .064, 6.4% vs. 2.7%; 12-week: p = .002, 18.8% vs. 8.5%; respectively).

Conclusion: Olanzapine was significantly more efficacious than placebo but not divalproex at 3 weeks and significantly more efficacious than divalproex at 12 weeks. Olanzapine-treated patients had significantly greater increases in weight and in glucose, cholesterol, triglyceride, uric acid, and prolactin levels than divalproex-treated patients.

Trial Registration: clinicaltrials.gov Identifier: NCT00094549.
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http://dx.doi.org/10.4088/jcp.v69n1113DOI Listing
November 2008
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