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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.

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.

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.

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.

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 Mescher–Garwood 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.

BackgroundRepetitive 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.MethodsMedications 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.ResultsUse 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).ConclusionsConcomitant 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.

ObjectiveTrigeminal 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.MethodSixty-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.ResultsADHD-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.ConclusionThis 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 informationTrigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov/; NCT02155608.

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/β-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.

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/β-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.

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.

Uterine cancer is the most common gynecologic malignancy in the United States, with endometrioid endometrial adenocarcinoma (EC) being the most common histologic sub-type. Considering the molecular classifications of EC, efforts have been made to identify additional biomarkers that can assist in diagnosis, prognosis, and individualized therapy. We sought to explore the relationship of Repressor Element 1 (RE1) silencing transcription factor (REST), which downregulates neuronal genes in non-neuronal tissue, along with matrix metalloproteinase-24 (MMP24) and EC. We analyzed the expression of REST and MMP24 in 31 cases of endometrial cancer and 16 controls. We then explored the baseline expression of REST and MMP24 in two EC cell lines (Ishikawa and HEC-1-A) compared to a benign cell line (t-HESC) and subsequently evaluated proliferation, migration, and invasion in the setting of loss of REST gene expression. REST and MMP24 expression were significantly lower in human EC samples compared to control samples. REST was highly expressed in EC cell lines, but decreasing REST gene expression increased proliferation (FC: 1.13X, p < 0.0001), migration (1.72X, p < 0.0001), and invasion (FC: 7.77X, p < 0.05) in Ishikawa cells, which are hallmarks of cancer progression and metastasis. These findings elicit a potential role for REST as a putative tumor suppressor in EC. [ABSTRACT FROM AUTHOR]

ObjectiveTo provide expert recommendations for the safe and effective application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD).ParticipantsParticipants included a group of 17 expert clinicians and researchers with expertise in the clinical application of rTMS, representing both the National Network of Depression Centers (NNDC) rTMS Task Group and the American Psychiatric Association Council on Research (APA CoR) Task Force on Novel Biomarkers and Treatments.EvidenceThe consensus statement is based on a review of extensive literature from 2 databases (OvidSP MEDLINE and PsycINFO) searched from 1990 through 2016. The search terms included variants of major depressive disorder and transcranial magnetic stimulation. The results were limited to articles written in English that focused on adult populations. Of the approximately 1,500 retrieved studies, a total of 118 publications were included in the consensus statement and were supplemented with expert opinion to achieve consensus recommendations on key issues surrounding the administration of rTMS for MDD in clinical practice settings.Consensus processIn cases in which the research evidence was equivocal or unclear, a consensus decision on how rTMS should be administered was reached by the authors of this article and is denoted in the article as "expert opinion."ConclusionsMultiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy. These consensus recommendations, developed by the NNDC rTMS Task Group and APA CoR Task Force on Novel Biomarkers and Treatments, provide comprehensive information for the safe and effective clinical application of rTMS in the treatment of MDD.

A major focus in development of novel therapies for Huntington's disease (HD) is identification of treatments that reduce the burden of mutant huntingtin (mHTT) protein in the brain. In order to identify and test the efficacy of such therapies, it is essential to have biomarkers that are sensitive to the effects of mHTT on brain function to determine whether the intervention has been effective at preventing toxicity in target brain systems before onset of clinical symptoms. Ideally, such biomarkers should have a plausible physiologic basis for detecting the effects of mHTT, be measureable both in preclinical models and human studies, be practical to measure serially in clinical trials, and be reliably measurable in HD gene expansion carriers (HDGECs), among other features. Quantitative electroencephalography (qEEG) fulfills many of these basic criteria of a "fit-for-purpose" biomarker. qEEG measures brain oscillatory activity that is regulated by the brain structures that are affected by mHTT in premanifest and early symptom individuals. The technology is practical to implement in the laboratory and is well tolerated by humans in clinical trials. The biomarkers are measureable across animal models and humans, with findings that appear to be detectable in HDGECs and translate across species. We review here the literature on recent developments in both preclinical and human studies of the use of qEEG biomarkers in HD, and the evidence for their usefulness as biomarkers to help guide development of novel mHTT lowering treatments.