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.

Evaluating cognitive complaints in breast cancer survivors with the FACT-Cog and quantitative electroencephalography.

PURPOSE: Targeted methods for evaluating cognitive dysfunction in breast cancer survivors are needed to effectively address this important survivorship issue. To address this need, we examined the validity of a self-report instrument (The functional assessment of cancer therapy: cognitive function; FACT-Cog) regarding correspondence with neuropsychological performance versus depression and evaluated neurophysiological biomarkers of cognition and depressed mood in a sample of breast cancer survivors several years from diagnosis. METHODS: This is a cross-sectional study sample from the prospective observational Mind Body Study. Recruited participants were breast cancer survivors at least 3 years from cancer diagnosis who were part of a longitudinal cohort, and were without current psychiatric disorder or history of a neurological or cognitive disorder at baseline (after completion of primary cancer treatment). Exploratory analysis of the FACT-Cog and quantitative electroencephalography (qEEG) were conducted, with respect to their association with neuropsychological domain scores and depressive symptoms as measured by the Beck Depression Inventory, 2nd edition (BDI-II). RESULTS: Self-reported cognitive abilities and the impact of cognitive dysfunction on quality of life were associated with memory function in addition to depressive symptoms in our sample of breast cancer survivors. qEEG measures exhibit differential patterns of association with neuropsychological performance and mood. CONCLUSIONS: Our findings indicate that perceived cognitive abilities and the impact of cognitive difficulties on quality of life are valid indicators of objective cognitive function, independent of depressive symptoms. Neurophysiological correlates of cognitive function and depressive symptoms represent promising biomarkers of these behavioral difficulties in survivorship.

Can neurophysiologic measures serve as biomarkers for the efficacy of repetitive transcranial magnetic stimulation treatment of major depressive disorder?

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for Major Depressive Disorder (MDD). There are clinical data that support the efficacy of many different approaches to rTMS treatment, and it remains unclear what combination of stimulation parameters is optimal to relieve depressive symptoms. Because of the costs and complexity of studies that would be necessary to explore and compare the large number of combinations of rTMS treatment parameters, it would be useful to establish reliable surrogate biomarkers of treatment efficacy that could be used to compare different approaches to treatment. This study reviews the evidence that neurophysiologic measures of cortical excitability could be used as biomarkers for screening different rTMS treatment paradigms. It examines evidence that: (1) changes in excitability are related to the mechanism of action of rTMS; (2) rTMS has consistent effects on measures of excitability that could constitute reliable biomarkers; and (3) changes in excitability are related to the outcomes of rTMS treatment of MDD. An increasing body of evidence indicates that these neurophysiologic measures have the potential to serve as reliable biomarkers for screening different approaches to rTMS treatment of MDD.

Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression.

BACKGROUND: Pill-taking, expectations and therapeutic alliance may account for much of the benefit of medication and placebo treatment for major depressive disorder (MDD). Aims To examine the effects of medication, placebo and supportive care on treatment outcome, and the relationships of expectations and therapeutic alliance to improvement. METHOD: A total of 88 participants were randomised to 8 weeks of treatment with supportive care alone or combined with double-blind treatment with placebo or antidepressant medication. Expectations of medication effectiveness, general treatment effectiveness and therapeutic alliance were measured (trial registration at ClinicalTrials.gov: NCT00200902). RESULTS: Medication or placebo plus supportive care were not significantly different but had significantly better outcome than supportive care alone. Therapeutic alliance predicted response to medication and placebo; expectations of medication effectiveness at enrolment predicted only placebo response. CONCLUSIONS: Pill treatment yielded better outcome than supportive care alone. Medication expectations uniquely predicted placebo treatment outcome and were formed by time of enrolment, suggesting that they were shaped by prior experiences outside the clinical trial.

Predictive socioeconomic and clinical profiles of antidepressant response and remission.

BACKGROUND: There are many prognostic factors for treatment outcome in major depressive disorder (MDD). The predictive power of any single factor, however, is limited. We aimed to develop profiles of antidepressant response and remission based upon hierarchical combinations of baseline clinical and demographic factors. METHODS: Using data from Level 1 of the Sequenced Treatment Alternatives to Relieve Depression trial (STAR*D), in which 2,876 participants with MDD were treated with citalopram, a signal-detection analysis was performed to identify hierarchical predictive profiles for patients with different treatment outcome. An automated algorithm was used to determine the optimal predictive variables by evaluating sensitivity, specificity, positive and negative predictive value, and test efficiency. RESULTS: Hierarchical combinations of baseline clinical and demographic factors yielded profiles that significantly predicted treatment outcome. In contrast to an overall 47% response rate in STAR*D Level 1, response rates of profiled patient subgroups ranged from 31 to 63%. In contrast to an overall remission rate of 28%, identified subsets of patients had a 12 to 55% probability of remission. The predictors of antidepressant treatment outcome most commonly incorporated into profiles were related to socioeconomic status (e.g., income, education), whereas indicators of depressive symptom type and severity, as well as comorbid clinical conditions, were useful but less powerful predictors. CONCLUSIONS: Hierarchical profiles of demographic and clinical baseline variables categorized patients according to the likelihood they would benefit from a single antidepressant trial. Socioeconomic factors had greater predictive power than symptoms or other clinical factors, and profiles combining multiple factors were stronger predictors than individual factors alone.

Rostral anterior cingulate activity in major depressive disorder: state or trait marker of responsiveness to medication?

High rostral anterior cingulate cortex (rACC) activity has been shown to predict antidepressant treatment response; however, it is unclear whether this is a fixed versus variable marker of responsiveness. The authors measured rACC theta current density in 22 subjects 5 weeks before and again immediately before 5 weeks of blinded treatment with sertraline. Mixed-effects regression analysis found that the relationship between response and rACC activity depended significantly on the timing of the rACC assessment; rACC activity measured immediately before treatment was a significantly better predictor of response. rACC activity may constitute a variable "state" indicator of responsiveness to antidepressants.

Relative safety and quality of various dietary supplement products U.S. Service Members ask about.

CONTEXT: The purpose of this project was to determine types of dietary supplement products U.S. Service Members frequently ask about and identify risks associated with select products that consumers should be aware of when considering their use. METHODS: Forty-one dietary supplement products frequently asked about through the Operation Supplement Safety's (OPSS.org) Ask-the-Expert portal were selected. Product analysis was performed to verify whether select products were accurately labeled and to identify any risky ingredients contained in these products. Operation Supplement Safety Risk Assessment Scorecard criteria were additionally used as a screening tool to assess a product's relative safety potential. RESULTS: Among the select dietary supplements, 12 (29.3%) were marketed as pre-workout products; 14 (34.1%) for weight loss; four (9.8%) for male enhancement/testosterone boosters; and 11 (26.8%) as body building supplements. Eleven (26.8%) products had accurate labels; only eight of these had accurate labels plus no risky ingredients listed on the labels. Twenty-six (63.4%) products were misbranded; 10 (24.4%) were adulterated, and six (14.6%) were both misbranded and adulterated. Risky ingredients appeared on 23 (56%) of all product labels. Eight of these 23 products also had additional risky ingredients not listed on the labels but detected through analysis. According to the Scorecard based on label claims, 35 (85.4%) received a rating of "no-go/risky". CONCLUSIONS: U.S. Service Members and the public at large should be aware that dietary supplements may contain risky ingredients and know how to identify ingredients on the label to evaluate potential risk.

Rostral anterior cingulate cortex activity and early symptom improvement during treatment for major depressive disorder.

In treatment trials for major depressive disorder (MDD), early symptom improvement is predictive of eventual clinical response. Clinical response may also be predicted by elevated pretreatment theta (4-7Hz) current density in the rostral anterior cingulate (rACC) and medial orbitofrontal cortex (mOFC). We investigated the relationship between pretreatment EEG and early improvement in predicting clinical outcome in 72 MDD subjects across three placebo-controlled treatment trials. Subjects were randomized to receive fluoxetine, venlafaxine, or placebo. Theta current density in the rACC and mOFC was computed with Low-Resolution Brain Electromagnetic Tomography (LORETA). An analysis of covariance examining week-8 Hamilton Depression Rating Scale (HamD) percent change, showed a significant effect of week-2HamD percent change, and a significant three-way interaction of week-2HamD percent change×treatment×rACC. Medication subjects with robust early improvement showed almost no relationship between rACC theta current density and final clinical outcome. However, in subjects with little early improvement, rACC activity showed a strong relationship with clinical outcome. The model examining the mOFC showed a trend in the three-way interaction. A combination of pretreatment rACC activity and early symptom improvement may be useful for predicting treatment response.

Biomarkers to predict antidepressant response.

During the past several years, we have achieved a deeper understanding of the etiology/pathophysiology of major depressive disorder (MDD). However, this improved understanding has not translated to improved treatment outcome. Treatment often results in symptomatic improvement, but not full recovery. Clinical approaches are largely trial-and-error, and when the first treatment does not result in recovery for the patient, there is little proven scientific basis for choosing the next. One approach to enhancing treatment outcomes in MDD has been the use of standardized sequential treatment algorithms and measurement-based care. Such treatment algorithms stand in contrast to the personalized medicine approach, in which biomarkers would guide decision making. Incorporation of biomarker measurements into treatment algorithms could speed recovery from MDD by shortening or eliminating lengthy and ineffective trials. Recent research results suggest several classes of physiologic biomarkers may be useful for predicting response. These include brain structural or functional findings, as well as genomic, proteomic, and metabolomic measures. Recent data indicate that such measures, at baseline or early in the course of treatment, may constitute useful predictors of treatment outcome. Once such biomarkers are validated, they could form the basis of new paradigms for antidepressant treatment selection.

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.

Monoamine oxidase a and catechol-o-methyltransferase functional polymorphisms and the placebo response in major depressive disorder.

The placebo response shows pronounced interindividual variability. Placebos are postulated to act through central reward pathways that are modulated by monoamines. Because monoaminergic signaling is under strong genetic control, we hypothesized that common functional polymorphisms modulating monoaminergic tone would be related to degree of improvement during placebo treatment of subjects with major depressive disorder. We examined polymorphisms in genes encoding the catabolic enzymes catechol-O-methyltransferase and monoamine oxidase A. Subjects with monoamine oxidase A G/T polymorphisms (rs6323) coding for the highest activity form of the enzyme (G or G/G) had a significantly lower magnitude of placebo response than those with other genotypes. Subjects with ValMet catechol-O-methyltransferase polymorphisms coding for a lower-activity form of the enzyme (2 Met alleles) showed a statistical trend toward a lower magnitude of placebo response. These findings support the hypothesis that genetic polymorphisms modulating monoaminergic tone are related to degree of placebo responsiveness in major depressive disorder.

Midline and right frontal brain function as a physiologic biomarker of remission in major depression.

Prior investigations have reported that changes in the prefrontal electroencephalogram (EEG) precede symptom improvement from antidepressant medications, and could serve as a biomarker of treatment outcome in major depressive disorder (MDD). A new physiologically defined region of interest (ROI), overlying the midline and right frontal (MRF) cortical area, was examined here for a relationship between early decreases in theta-band cordance and remission. Subjects were 72 adults with unipolar MDD who had completed placebo-controlled antidepressant treatment trials, with 37 randomized to medication and 35 to placebo. We assessed changes in cordance and absolute and relative power in the MRF region at 48 h, 1 week, and 2 weeks after start of drug, as potential predictors of remission (final score on the 17-item Hamilton Depression Rating Scale of 5 or below. Out of 37 medication-treated subjects, 11 (30%) remitted versus 6 of 35 placebo subjects (17%). Change in MRF cordance 1 and 2 weeks after the beginning of treatment was significantly associated with remission in medication-treated subjects at 1 week, with receiver operating characteristic (ROC) analysis yielding 0.76 area under the curve. Decreases in MRF cordance at 1 week predicted remission with medication with 69% overall accuracy (90% sensitivity; 60% specificity). MRF cordance changes were not associated with remission with placebo. Absolute and relative power did not differentiate groups. These results suggest that remission may be predictable from physiologic measurements after 1 week of treatment, and that this region merits further investigation in the neurobiology of treatment response.

Brain functional changes and duloxetine treatment response in fibromyalgia: a pilot study.

OBJECTIVES: Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant medications may have efficacy in relieving pain associated with fibromyalgia syndrome (FMS), even in the absence of major depressive disorder (MDD). Current practice is to use a trial-and-error treatment strategy, often requiring 8-12 weeks to determine the effectiveness of a given pharmacological intervention. The ability to predict response to antidepressant medications would facilitate clinical management of FMS. Prior work in MDD has shown that the quantitative electroencephalographic (QEEG) cordance biomarker of brain functional changes early in the course of antidepressant treatment is related to later clinical response. We hypothesized that cordance might also predict response to antidepressant medications for symptoms of FMS. DESIGN: Twelve adults (9 females) meeting American College of Rheumatology criteria for FMS participated in a double-blind placebo-controlled treatment trial utilizing duloxetine 60 mg. QEEG cordance changes were examined over the first week of treatment. Primary clinical outcomes included change in average pain severity on the Brief Pain Inventory (BPI) and global improvement in pain on the Patient's Global Impressions of Improvement (PGI-I) scale at 12 weeks. RESULTS: Changes in left frontal QEEG cordance after the first week of duloxetine treatment significantly predicted BPI pain improvement (regression coefficient = 2.9, R(2) = 0.93, P = 0.008) and PGI-I global improvement (regression coefficient = 0.94, R(2) = 0.81, P = 0.04). CONCLUSIONS: This pilot study suggests that QEEG biomarkers may prove useful for predicting improvement in painful symptoms during SNRI treatment in FMS. Larger studies are needed to confirm this finding.

A new paradigm for the prediction of antidepressant treatment response.

Current treatment of Major Depressive Disorder utilizes a trial-and-error sequential treatment strategy that results in delays in achieving response and remission for a majority of patients. Protracted ineffective treatment prolongs patient suffering and increases health care costs. In addition, long and unsuccessful antidepressant trials may diminish patient expectations, reinforce negative cognitions, and condition patients not to respond during subsequent antidepressant trials, thus contributing to further treatment resistance. For these reasons, it is critical to identify reliable predictors of antidepressant treatment response that can be used to shorten or eliminate lengthy and ineffective trials. Research on possible endophenotypic as well as genomic predictors has not yet yielded reliable predictors. The most reliable predictors identified thus far are symptomatic and physiologic characteristics of patients that emerge early in the course of treatment. We propose here the term "response endophenotypes" (REs) to describe this class of predictors, defined as latent measurable symptomatic or neurobiologic responses of individual patients that emerge early in the course of treatment, and which carry strong predictive power for individual patient outcomes. Use of REs constitutes a new paradigm in which medication treatment trials that are likely to be ineffective could be stopped within 1 to 2 weeks and other medication more likely to be effective could be started. Data presented here suggest that early changes in symptoms, quantitative electroencephalography, and gene expression could be used to construct effective REs. We posit that this new paradigm could lead to earlier recovery from depressive illness and ultimately produce profound health and economic benefits.

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.

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.

Brain electrical source differences between depressed subjects and healthy controls.

Many brain regions show metabolic and perfusion abnormalities in major depressive disorder (MDD), including anterior cingulate and prefrontal cortices. Some of these same areas also show abnormal function with low resolution electromagnetic tomography (LORETA). However, LORETA results are not always consistent across studies, nor with findings from other imaging modalities. These discrepancies may be due, among other factors, to the sensitivity of EEG source localization to different electrode montages. Thirty-six channel EEG was collected from healthy controls and age- and gender-matched unmedicated subjects with MDD (n = 74). EEGs were analyzed with LORETA to assess resting state current density at each of 2,394 cortical voxels. For comparison to previous studies, LORETA was performed using all electrodes or with specific prefrontal electrodes removed. Voxel-by-voxel differences between the depressed and healthy groups were calculated using non-parametric statistics. MDD subjects showed significantly elevated current density in delta, theta, alpha, beta1, and beta2 frequency bands relative to controls in anterior cingulate and prefrontal cortices. Removal of certain prefrontal electrodes from input to LORETA decreased or eliminated significant differences between groups. LORETA detects differences in brain activity between MDD subjects and healthy controls that are consistent with previous findings using other imaging modalities. Inconsistent findings among LORETA studies, and between LORETA studies and those using other functional imaging techniques, may result from differences in electrode montages.