Prospective testing of a neurophysiologic biomarker for treatment decisions in major depressive disorder: The PRISE-MD trial.

Management of Major Depressive Disorder (MDD) might be improved by a biomarker to predict whether a selected medication is likely to lead to remission. We previously reported on a quantitative electroencephalogram-based biomarker, the Antidepressant Treatment Response (ATR) index, that integrated recordings at baseline and after one week of treatment. The present study prospectively tested whether treatment directed by the biomarker increased the likelihood of remission; we hypothesized that continued treatment with a drug predicted to lead to remission (i.e., high ATR values) would be associated with better outcomes than if the drug was predicted not to lead to remission (i.e., low ATR values). We enrolled 180 adult outpatients with unipolar MDD from the community. After one week of escitalopram treatment to determine the biomarker, stratified randomization (high vs. low ATR) was used to assign subjects to either continued escitalopram or a switch to bupropion as a blinded control condition, for seven additional weeks. For the 73 evaluable subjects assigned to continued escitalopram treatment, the remission rate was significantly higher for those in whom ATR had predicted remission versus non-remission (60.4% vs. 30.0%, respectively, p = 0.01). Accuracy was enhanced by combining 1-week depressive symptom change with ATR (68.6% vs 28.9%). This prospective validation study supports further development of the ATR biomarker, alone or together with early symptom change, to improve care by identifying individuals unlikely to remit with their current treatment, and support the decision to change treatment after one week rather than after failing a full, prolonged course of medication.

EEG Spectral Features in Sleep of Autism Spectrum Disorders in Children with Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a multisystem disorder with increased prevalence of autism spectrum disorders (ASDs). This project aimed to characterize the autism phenotype of TSC and identify biomarkers of risk for ASD. Because abnormalities of EEG during sleep are tied to neurodevelopment in children, we compared electroencephalographic (EEG) measures during Stage II sleep in TSC children who either did (ASD+) or did not (ASD-) exhibit symptoms of ASD over 36-month follow up. Relative alpha band power was significantly elevated in the ASD+ group at 24 months of age with smaller differences at younger ages, suggesting this may arise from differences in brain development. These findings suggest that EEG features could enhance the detection of risk for ASD.

Hypnotic Discontinuation Using a Blinded (Masked) Tapering Approach: A Case Series.

Chronic use of hypnotic medications such as benzodiazepines is associated with adverse consequences including increased risk of falls. Efforts to help patients discontinue these medications have had varying levels of success. We developed a blinded (masked) tapering protocol to help patients taper off hypnotics. In this blinded protocol, patients consented to a drug taper but agreed to forego knowledge about the specific tapering schedule or the actual dose each night until the end of the taper. Blinded tapering aims to reduce negative expectancies for withdrawal effects that may impair a patient's successful discontinuation of hypnotics. In preparation for a randomized trial, we tested the feasibility of adding a blinded tapering component to current best evidence practice [supervised hypnotic taper combined with cognitive behavioral therapy for insomnia (CBTI)] in 5 adult patients recruited from an outpatient mental health practice in Oregon. A compounding pharmacy prepared the blinded capsules for each patient. During the gradual blinded taper, each participant completed CBTI. Measures collected included feasibility/process (e.g., recruitment barriers), hypnotic use, the Dysfunctional Beliefs and Attitudes about Sleep Scale, Insomnia Severity Index, Epworth Sleepiness Scale, and Patient Health Questionnaire-9 (depressive symptoms). The intervention was feasible, and participants reported high satisfaction with the protocol and willingness to follow the same treatment again. All five participants successfully discontinued their hypnotic medication use post-treatment. Dysfunctional beliefs/attitudes about sleep and insomnia severity improved. Blinded tapering is a promising new method for improving hypnotic discontinuation among patients treated with a combination of hypnotic tapering plus CBTI.

Time Course of Changes in Peripheral Blood Gene Expression During Medication Treatment for Major Depressive Disorder.

Changes in gene expression (GE) during antidepressant treatment may increase understanding of the action of antidepressant medications and serve as biomarkers of efficacy. GE changes in peripheral blood are desirable because they can be assessed easily on multiple occasions during treatment. We report here on GE changes in 68 individuals who were treated for 8 weeks with either escitalopram alone, or escitalopram followed by bupropion. GE changes were assessed after 1, 2, and 8 weeks of treatment, with significant changes observed in 156, 121, and 585 peripheral blood gene transcripts, respectively. Thirty-one transcript changes were shared between the 1- and 8-week time points (seven upregulated, 24 downregulated). Differences were detected between the escitalopram- and bupropion-treated subjects, although there was no significant association between GE changes and clinical outcome. A subset of 18 genes overlapped with those previously identified as differentially expressed in subjects with MDD compared with healthy control subjects. There was statistically significant overlap between genes differentially expressed in the current and previous studies, with 10 genes overlapping in at least two previous studies. There was no enrichment for genes overexpressed in nervous system cell types, but there was a trend toward enrichment for genes in the WNT/ß-catenin pathway in the anterior thalamus; three genes in this pathway showed differential expression in the present and in three previous studies. Our dataset and other similar studies will provide an important source of information about potential biomarkers of recovery and for potential dysregulation of GE in MDD.

Dorsolateral prefrontal γ-aminobutyric acid in patients with treatment-resistant depression after transcranial magnetic stimulation measured with magnetic resonance spectroscopy

Background: The therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of γ-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC). Methods: In 26 adults with TRD, we used Mescher­Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents. Results: Mean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment. Limitations: This study had an open-label design in a population receiving naturalistic treatment. Conclusion: Treatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression.

Concomitant medication use and clinical outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder.

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) is commonly administered to Major Depressive Disorder (MDD) patients taking psychotropic medications, yet the effects on treatment outcomes remain unknown. We explored how concomitant medication use relates to clinical response to a standard course of rTMS. METHODS: Medications were tabulated for 181 MDD patients who underwent a six-week rTMS treatment course. All patients received 10 Hz rTMS administered to left dorsolateral prefrontal cortex (DLPFC), with 1 Hz administered to right DLPFC in patients with inadequate response to and/or intolerance of left-sided stimulation. Primary outcomes were change in Inventory of Depressive Symptomatology Self Report (IDS-SR30) total score after 2, 4, and 6 weeks. RESULTS: Use of benzodiazepines was associated with less improvement at week 2, whereas use of psychostimulants was associated with greater improvement at week 2 and across 6 weeks. These effects were significant controlling for baseline variables including age, overall symptom severity, and severity of anxiety symptoms. Response rates at week 6 were lower in benzodiazepine users versus non-users (16.4% vs. 35.5%, p = 0.008), and higher in psychostimulant users versus non-users (39.2% vs. 22.0%, p = 0.02). CONCLUSIONS: Concomitant medication use may impact rTMS treatment outcome. While the differences reported here could be considered clinically significant, results were not corrected for multiple comparisons and findings should be replicated before clinicians incorporate the evidence into clinical practice. Prospective, hypothesis-based treatment studies will aid in determining causal relationships between medication treatments and outcome.

Changes in Functional Connectivity Predict Outcome of Repetitive Transcranial Magnetic Stimulation Treatment of Major Depressive Disorder.

Repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD) is associated with changes in brain functional connectivity (FC). These changes may be related to the mechanism of action of rTMS and explain the variability in clinical outcome. We examined changes in electroencephalographic FC during the first rTMS treatment in 109 subjects treated with 10 Hz stimulation to left dorsolateral prefrontal cortex. All subjects subsequently received 30 treatments and clinical response was defined as ≥40% improvement in the inventory of depressive symptomatology-30 SR score at treatment 30. Connectivity change was assessed with coherence, envelope correlation, and a novel measure, alpha spectral correlation (αSC). Machine learning was used to develop predictive models of outcome for each connectivity measure, which were compared with prediction based upon early clinical improvement. Significant connectivity changes were associated with clinical outcome (P < 0.001). Machine learning models based on αSC yielded the most accurate prediction (area under the curve, AUC = 0.83), and performance improved when combined with early clinical improvement measures (AUC = 0.91). The initial rTMS treatment session produced robust changes in FC, which were significant predictors of clinical outcome of a full course of treatment for MDD.

Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Trigeminal nerve stimulation (TNS), a minimal-risk noninvasive neuromodulation method, showed potential benefits for attention-deficit/hyperactivity disorder (ADHD) in an unblinded open study. The present blinded sham-controlled trial was conducted to assess the efficacy and safety of TNS for ADHD and potential changes in brain spectral power using resting-state quantitative electroencephalography. METHOD: Sixty-two children 8 to 12 years old, with full-scale IQ of at least 85 and Schedule for Affective Disorders and Schizophrenia-diagnosed ADHD, were randomized to 4 weeks of nightly treatment with active or sham TNS, followed by 1 week without intervention. Assessments included weekly clinician-administered ADHD Rating Scales (ADHD-RS) and Clinical Global Impression (CGI) scales and quantitative electroencephalography at baseline and week 4. RESULTS: ADHD-RS total scores showed significant group-by-time interactions (F1,228 = 8.12, p = .005; week 4 Cohen d = 0.5). CGI-Improvement scores also favored active treatment (χ21,168 = 8.75, p = .003; number needed to treat = 3). Resting-state quantitative electroencephalography showed increased spectral power in the right frontal and frontal midline frequency bands with active TNS. Neither group had clinically meaningful adverse events. CONCLUSION: This study demonstrates TNS efficacy for ADHD in a blinded sham-controlled trial, with estimated treatment effect size similar to non-stimulants. TNS is well tolerated and has minimal risk. Additional research should examine treatment response durability and potential impact on brain development with sustained use. CLINICAL TRIAL REGISTRATION INFORMATION: Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov/; NCT02155608.

Brain Activity and Clinical Outcomes in Adults With Depression Treated With Synchronized Transcranial Magnetic Stimulation: An Exploratory Study.

BACKGROUND: Synchronized transcranial magnetic stimulation (sTMS) imparts low-amplitude magnetic stimulation matched to each patient's individual alpha frequency. It may act through entrainment of brain oscillations. OBJECTIVES: To explore sTMS effects on neurophysiology with electroencephalography (EEG) in adults with major depressive disorder. METHODS: As an ancillary study to a clinical trial of sTMS, EEGs were recorded at baseline and at one and six weeks of treatment. Associations between EEG measures and clinical symptoms were examined. RESULTS: Absolute and relative power measures did not differ significantly between active and sham groups and did not change significantly over time. Changes occurring over six weeks in alpha current source density at anterior and central midline voxels were significantly correlated with changes in symptoms in subjects treated with active but not sham sTMS. CONCLUSION: Neurophysiologic measures suggest that active but not sham sTMS engages brain targets, and that target engagement is related to treatment outcome.

Predictors of response to synchronized transcranial magnetic stimulation for major depressive disorder.

BACKGROUND: Synchronized transcranial magnetic stimulation (sTMS) is a new modality to reduce symptoms of major depressive disorder (MDD). sTMS uses rotating neodymium magnets to deliver low-field stimulation matched to the individual alpha frequency (IAF). A previous multisite study showed that sTMS significantly reduced MDD symptoms in the per-protocol sample. To this end, we evaluated clinical features associated with optimal sTMS outcomes. METHODS: Using the per-protocol sample (n = 120) from the parent sham-controlled trial, we performed univariate and stepwise linear regression to identify predictors of response after 6 weeks of sTMS. A subsample (n = 83) that entered a 4-week open/active continuation phase also was examined. Candidate variables included age, sex, comorbid anxiety, number of failed antidepressants in the current depressive episode, MDD severity (17-item Hamilton Depression Rating Scale; HAMD17), anxiety symptom severity (HAMD17 anxiety/somatization factor), and IAF. RESULTS: We found that greater baseline depressive (p < 0.001) and anxiety (p < 0.001) symptom severity were associated with better response to active sTMS, whereas fewer failed antidepressant trials predicted superior response to sham (p < 0.001). MDD severity and antidepressant resistance predicted outcomes in open/active phase sTMS; lower IAF predicted poorer response in participants who received 10 weeks of active sTMS (p = 0.001). CONCLUSIONS: Participants with greater severity of depression and higher anxiety had superior responses to active sTMS, whereas treatment naïve individuals exhibited a greater response to sham. These results lend support to the primary efficacy findings, and support further investigation of sTMS as a therapeutic noninvasive brain stimulation modality.

Benefits and Harms of Cranial Electrical Stimulation for Chronic Painful Conditions, Depression, Anxiety, and Insomnia: A Systematic Review.

Background: Cranial electrical stimulation (CES) is increasingly popular as a treatment, yet its clinical benefit is unclear. Purpose: To review evidence about the benefits and harms of CES for adult patients with chronic painful conditions, depression, anxiety, and insomnia. Data Sources: Several databases from inception to 10 October 2017 without language restrictions and references from experts, prior reviews, and manufacturers. Study Selection: Randomized controlled trials of CES versus usual care or sham CES that reported pain, depression, anxiety, or sleep outcomes in any language. Data Extraction: Single-reviewer extraction checked by another; dual independent quality assessment; strength-of-evidence grading by the first author with subsequent group discussion. Data Synthesis: Twenty-eight articles from 26 randomized trials met eligibility criteria. The 2 trials that compared CES with usual care were small, and neither reported a statistically significant benefit in pain or anxiety outcomes for patients with fibromyalgia or anxiety, respectively. Fourteen trials with sham or placebo controls involving patients with painful conditions, such as headache, neuromuscular pain, or musculoskeletal pain, had conflicting results. Four trials done more than 40 years ago and 1 from 2014 provided low-strength evidence of a possible modest benefit compared with sham treatments in patients with anxiety and depression. Trials in patients with insomnia (n = 2), insomnia and anxiety (n = 1), or depression (n = 3) had inconclusive or conflicting results. Low-strength evidence suggested that CES does not cause serious side effects. Limitation: Most trials had small sample sizes and short durations; all had high risk of bias due to inadequate blinding. Conclusion: Evidence is insufficient that CES has clinically important effects on fibromyalgia, headache, neuromusculoskeletal pain, degenerative joint pain, depression, or insomnia; low-strength evidence suggests modest benefit in patients with anxiety and depression. Primary Funding Source: Veterans Affairs Quality Enhancement Research Initiative. (PROSPERO: CRD42016023951).