National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

Distinct predictors of short- versus long-term depression outcomes following electroconvulsive therapy.

Patients and clinicians considering electroconvulsive therapy (ECT) for treatment-resistant depression are faced with limited information about the likely long-term outcomes, and the individual characteristics that predict those outcomes. We aimed to identify sociodemographic and clinical predictors of acute ECT response and subsequent long-term depression severity. This prospective longitudinal study followed adult patients at a single academic ECT center. Among 114 participants, 105 completed an index ECT series and 70 were classified as acute ECT responders. Over a 2-year follow-up period, 82 subjects provided data on depression severity (Patient Health Questionnaire; PHQ-9). Better acute ECT response was predicted by less medication resistance, shorter index episode, and psychotic features (p < 0.05). PHQ-9 scores during the two-year follow-up period improved from baseline at all time points (p < 0.000001) but individual scores varied widely. Lower long-term PHQ-9 scores were predicted by better acute therapeutic response to ECT (p = 0.004) but not by ECT adverse effects (p > 0.05). Married status and greater baseline clinician-rated severity were not associated with acute ECT response but those variables did predict lower PHQ-9 scores longitudinally (p < 0.001), independent of other baseline features, initial ECT response, or intensity of ongoing treatment. These findings confirm previously identified predictors of short-term ECT response and demonstrate that distinct individual characteristics predict long-term depression outcomes. An individual's social context appears to strongly influence long-term but not short-term outcomes, suggesting a potential target for post-ECT therapeutic interventions.

Long-term quality of life in treatment-resistant depression after electroconvulsive therapy.

BACKGROUND: Electroconvulsive therapy (ECT) is highly effective for treatment-resistant depression (TRD), and previous studies have demonstrated short-term improvements in quality of life (QoL) after ECT.  However, long-term QoL after ECT has not been studied, and the baseline patient characteristics that predict long-term QoL remain unknown. METHODS: Seventy-nine subjects with unipolar or bipolar TRD were enrolled in this prospective longitudinal observational study. Physical, psychological, social, and environmental QoL domains were measured with the abbreviated World Health Organization Quality of Life scale (WHOQOL-BREF) at baseline and every 6 months for up to 2 years after ECT.  Baseline sociodemographic and clinical features were tested for association with long-term QoL. RESULTS: Long-term follow-up data were available from 49 participants.  Relative to baseline, average psychological and physical QoL improved during the follow-up period (Hedges' effect size: 0.27-0.83).  About 40-50% of individuals experienced clinically meaningful improvement.  Subjects with better initial antidepressant response with ECT reported better QoL over the subsequent two years.  Long-term QoL improved most among individuals who were married, those without disability status, and those with psychotic features or shorter depressive episodes at baseline. LIMITATIONS: Participants were from a single US academic center and mainly of European ancestry, so findings may not generalize to other settings or ethnicities.  The observational design does not allow causal inferences. CONCLUSIONS: Long-term psychological and physical QoL outcomes vary widely after ECT. Individuals with the best outcomes are those who respond well to ECT initially, married people, and those with a less chronic course of illness.

Electroconvulsive Therapy for Bipolar Depression in Older Adults.

OBJECTIVES: Electroconvulsive therapy (ECT) is a well-established treatment for mood disorders in younger adults and has been consistently shown to be safe and effective in unipolar depression in older adults. However, data on this treatment in older adults with bipolar disorder are limited. In this retrospective study, we report outcomes from all cases of older adults with bipolar depression who received ECT from a large academic institution over a 7-year period. METHODS: We retrospectively identified all patients 65 years and older with bipolar depression who were treated with ECT over a 7-year period. Patients receiving ECT for an episode of bipolar depression were included in the study based on chart review and availability of documented outcome measures. Primary outcomes were changes in Montreal Cognitive Assessment and Clinical Global Impressions scores. RESULTS: We identified 34 patients meeting inclusion criteria. Collectively, patients had statistically significant improvement in Montreal Cognitive Assessment scores and reductions in Clinical Global Impressions severity scores after treatment. Pre- and posttreatment Montgomery-Asberg Depression Rating Scale scores were also available for a subset of 20 patients and demonstrated a similarly significant reduction in severity with treatment. There were no serious adverse effects of treatment, and no patients discontinued treatment. CONCLUSIONS: Electroconvulsive therapy was well tolerated and effective in treating bipolar depression in older adults. Importantly, these findings challenge commonly held worries about cognitive decline in older adults receiving ECT. It should be a regular consideration for management of this challenging illness in a population that may otherwise not respond to pharmacotherapy.

ElectroConvulsive therapy Cognitive Assessment (ECCA) tool: A new instrument to monitor cognitive function in patients undergoing ECT.

BACKGROUND: Electroconvulsive therapy (ECT) is a well-established treatment for severe depression but may result in adverse cognitive effects. Available cognitive screening instruments are nonspecific to the cognitive deficits associated with ECT. An ECT-cognitive assessment tool which can be easily administered was developed and validated in a clinical setting. METHODS: One hundred and thirty-six participants were enrolled. The ElectroConvulsive therapy Cognitive Assessment (ECCA) and the Montreal Cognitive Assessment (MoCA) were administered prospectively to 55 participants with major depressive disorder (MDD) undergoing ECT at three time points: pre-treatment, before the sixth treatment and one-week post-treatment. The psychometric properties of the total and domain scores were evaluated at all three time points. Forty demographically comparable participants with MDD who did not receive ECT, and 41 healthy, age-matched controls were evaluated at a single time point. RESULTS: ECCA and MoCA scores were not statistically different at baseline. Prior to the sixth and final ECT session, total ECCA scores were significantly lower than the MoCA total scores. The ECCA domains of subjective memory, informant-assessed memory, attention, autobiographical memory and delayed verbal recall were significantly lower post-ECT compared to pre-ECT. LIMITATIONS: The ECCA was compared only to the MoCA rather than to a more comprehensive neuropsychological testing. This limitation reflected the real-life clinical burden of performing full neuropsychological testing at three time points during the treatment course. CONCLUSIONS: The ECCA is a brief, reliable, bedside cognitive screening assessment tool that may be useful to monitor cognitive function in patients treated with ECT. The test can be downloaded from fuquacenter.org/ecca.

Electroconvulsive Therapy for Neuroleptic Malignant Syndrome: A Case Series.

OBJECTIVES: Neuroleptic malignant syndrome (NMS) is an uncommon condition associated with significant morbidity and mortality. Data on treatment interventions are limited. In this case series, we sought to describe all NMS cases requiring ECT from a large academic institution over a nearly 2-decade period. METHODS: We retrospectively identified all patients with NMS who were treated with ECT over a 17-year period. Patients were included in the study based on chart review using the International Consensus Diagnostic Criteria for NMS. Data were collected related to clinical findings, treatment course, and response to ECT. RESULTS: We identified 15 patients meeting the inclusion criteria. Most patients had neurocognitive or schizophrenia spectrum disorders and developed NMS after exposure to multiple antipsychotic drugs. All patients received bitemporal ECT after failed pharmacotherapy for NMS. Electroconvulsive therapy was well tolerated and resulted in a remission rate of 73.3% (n = 11). Patients showed early initial response to ECT (mean of 4.2 treatments), but an average of 17.7 treatments was necessary to minimize recurrence of catatonic signs. One patient died after interruption of the index course of ECT because of severe infection, and another was discharged to hospice care after limited response. These cases highlight the lethality of NMS and its complications despite aggressive treatment measures. CONCLUSIONS: Bitemporal ECT was well tolerated and effective in treating NMS refractory to pharmacotherapy. We suggest that ECT be considered early in cases of NMS that are refractory to pharmacological interventions, especially if the underlying condition is also responsive to ECT.

Segregation of salience network predicts treatment response of depression to repetitive transcranial magnetic stimulation.

BACKGROUND: The present study tested the hypothesis that network segregation, a graph theoretic measure of functional organization of the brain, is correlated with treatment response in patients with major depressive disorder (MDD) undergoing repetitive transcranial magnetic stimulation (rTMS). METHODS: Network segregation, calculated from resting state functional magnetic resonance imaging scans, was measured in 32 patients with MDD who entered a sham-controlled, double-blinded, randomized trial of rTMS to the left dorsolateral prefrontal cortex, and a cohort of 20 healthy controls (HCs). Half of the MDD patients received sham treatment in the blinded phase, followed by active rTMS in the open-label phase. The analyses focused on segregation of the following networks: default mode (DMN), salience (SN), fronto-parietal (FPN), cingulo-opercular (CON), and memory retrieval (MRN). RESULTS: There was no differential change in network segregation comparing sham to active treatment. However, in the combined group of patients who completed active rTMS treatment (in the blinded plus open-label phases), higher baseline segregation of SN significantly predicted more symptom improvement after rTMS. Compared to HCs at baseline, MDD patients showed decreased segregation in DMN, and trend-level decreases in SN and MRN. CONCLUSION: The results highlight the importance of network segregation in MDD, particularly in the SN, where more normal baseline segregation of SN may predict better treatment response to rTMS in depression.

Quality of life across domains among individuals with treatment-resistant depression.

BACKGROUND: Treatment-resistant depression affects millions of people worldwide and is a leading cause of disability and suicide. Studies of treatment-resistant depression outcomes have traditionally focused on depressive symptoms and functional impairment. Quality of life (QoL) has not been well described. We aimed to measure QoL in individuals with treatment-resistant depression and to determine how QoL was related to traditional measures of symptoms and social functioning. METHODS: We used a reliable, cross-culturally validated questionnaire, the abbreviated World Health Organization Quality of Life scale (WHOQOL-BREF), to prospectively measure QoL in 79 patients with treatment-resistant depression who were referred for electroconvulsive therapy at a United States tertiary-care medical center. QoL was characterized in four domains: physical, psychological, social, and environmental. QoL domains were examined for association with demographic variables, patient-reported depressive symptoms, functional impairment, and childhood adversity, as well as clinician-rated scales. RESULTS: Relative to published international norms, mean QoL scores were low in physical (standardized score, z = -2.0), psychological (z = -2.6), and social (z = -1.0) domains, but not in the environmental domain (z = 0.2). After controlling for age and income, patient-rated depressive symptoms correlated with physical (Pearson correlation, r = -0.26) and psychological (r = -0.43) QoL, whereas adverse childhood experiences correlated with environmental QoL (r = -0.33). Patient-rated functional impairment correlated modestly with all domains (r = -0.25 to -0.39). Surprisingly, QoL correlated very weakly with clinician-rated measures. These modest associations of QoL with other clinical scales were confirmed in multiple regression analyses. LIMITATIONS: We used a single QoL instrument, which did not allow us to directly compare the WHOQOL-BREF scale with other commonly used instruments. Our sample was recruited from a single academic medical center in the Midwest region of the United States and was largely Caucasian. These factors may limit generalizability to other settings and ethnicities. CONCLUSION: Among individuals with treatment-resistant depression, QoL is lowest in the psychological and physical domains. QoL is only modestly correlated with patient-rated symptoms and functioning, and even more weakly correlated with clinician-rated scales, indicating that measures of symptoms and functioning cannot serve as QoL proxies. QoL should be assessed when caring for patients with treatment-resistant depression. When developing novel biological, psychological, and social interventions for treatment-resistant depression, QoL should be targeted as a distinct clinical outcome.

Cost-effectiveness of Electroconvulsive Therapy vs Pharmacotherapy/Psychotherapy for Treatment-Resistant Depression in the United States.

Importance: Electroconvulsive therapy (ECT) is a highly effective treatment for depression but is infrequently used owing to stigma, uncertainty about indications, adverse effects, and perceived high cost. Objective: To assess the cost-effectiveness of ECT compared with pharmacotherapy/psychotherapy for treatment-resistant major depressive disorder in the United States. Design, Setting, and Participants: A decision analytic model integrating data on clinical efficacy, costs, and quality-of-life effects of ECT compared with pharmacotherapy/psychotherapy was used to simulate depression treatment during a 4-year horizon from a US health care sector perspective. Model input data were drawn from multiple meta-analyses, randomized trials, and observational studies of patients with depression. Where possible, data sources were restricted to US-based studies of nonpsychotic major depression. Data were analyzed between June 2017 and January 2018. Interventions: Six alternative strategies for incorporating ECT into depression treatment (after failure of 0-5 lines of pharmacotherapy/psychotherapy) compared with no ECT. Main Outcomes and Measures: Remission, response, and nonresponse of depression; quality-adjusted life-years; costs in 2013 US dollars; and incremental cost-effectiveness ratios. Strategies with incremental cost-effectiveness ratios of $100 000 per quality-adjusted life-year or less were designated cost-effective. Results: Based on the Sequenced Treatment Alternatives to Relieve Depression trial, we simulated a population with a mean (SD) age of 40.7 (13.2) years, and 62.2% women. Over 4 years, ECT was projected to reduce time with uncontrolled depression from 50% of life-years to 33% to 37% of life-years, with greater improvements when ECT is offered earlier. Mean health care costs were increased by $7300 to $12 000, with greater incremental costs when ECT was offered earlier. In the base case, third-line ECT was cost-effective, with an ICER of $54 000 per quality-adjusted life-year. Third-line ECT remained cost-effective in a range of univariate, scenario, and probabilistic sensitivity analyses. Incorporating all input data uncertainty, we estimate a 74% to 78% likelihood that at least 1 of the ECT strategies is cost-effective and a 56% to 58% likelihood that third-line ECT is the optimal strategy. Conclusions and Relevance: For US patients with treatment-resistant depression, ECT may be an effective and cost-effective treatment option. Although many factors influence the decision to proceed with ECT, these data suggest that, from a health-economic standpoint, ECT should be considered after failure of 2 or more lines of pharmacotherapy/psychotherapy.

Cortisol trajectory, melancholia, and response to electroconvulsive therapy.

While biomarkers have been used to define pathophysiological types and to optimize treatment in many areas of medicine, in psychiatry such biomarkers remain elusive. Based on previously described abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function in severe forms of depression, we hypothesized that the temporal trajectory of basal cortisol levels would vary among individuals with depression due to heterogeneity in pathophysiology, and that cortisol trajectories that reflect elevated or increasing HPA activity would predict better response to electroconvulsive therapy (ECT). To test that hypothesis, we sampled scalp hair from 39 subjects with treatment-resistant depression just before ECT. Cortisol trajectory over the 12 weeks preceding ECT was reconstructed from cortisol concentrations in sequential hair segments. Cortisol trajectories varied widely between individuals, and exploratory analyses of clinical features revealed associations with melancholia and global severity. ECT non-responders showed a decreasing trajectory (mean change -25%, 95%-CI = [-1%,-43%]) during the 8 weeks preceding ECT (group-by-time interaction, p = 0.004). The association between cortisol trajectory and subsequent ECT response was independent of clinical features. A classification algorithm showed that cortisol trajectory predicted ECT response with 80% accuracy, suggesting that this biomarker might be developed into a clinically useful test for ECT-responsive depression. In conclusion, cortisol trajectory mapped onto symptoms of melancholia and independently predicted response to ECT in this severely depressed sample. These findings deserve to be replicated in a larger sample. Cortisol trajectory holds promise as a reliable, noninvasive, inexpensive biomarker for psychiatric disorders.

Changes in brain connectivity during a sham-controlled, transcranial magnetic stimulation trial for depression.

BACKGROUND: The subgenual anterior cingulate cortex (sgACC) has been implicated in major depressive disorder (MDD), and this study evaluated sgACC connectivity before and after repetitive transcranial magnetic stimulation (rTMS) treatment. METHODS: Thirty-two MDD patients entered a sham-controlled, double-blinded, randomized trial of rTMS to the left dorsolateral prefrontal cortex (dlFPC). Subjects underwent resting state functional magnetic resonance imaging before and after 20 sessions of high frequency rTMS. Seed voxels identified the affective network (AN; sgACC, amygdala), default mode network (DMN; posterior cingulate cortex [PCC]), and fronto-parietal network (FPN; dlPFC stimulation site). RESULTS: There was no significant effect of active rTMS over sham on the primary outcome measure (Montgomery-Asberg Depression Scale rating), with both groups improving over time, and no specific effect of rTMS (sham vs active) on connectivity. However, among patients who showed significant improvement, sgACC connectivity decreased for sham (to AN, trend to DMN) and active rTMS responders (to AN, DMN, FPN), but not in non-responders, who tended to maintain connectivity. Including subjects who started with sham but then received open-label active treatment, baseline connectivity from the PCC to the anterior insula was greater in non-responders compared to responders (n = 27, excluding 5 sham responders). LIMITATIONS: The sample size was small; the stimulation target was non-standard, and the lack of a significant clinical effect of rTMS limits conclusions about negative findings. CONCLUSIONS: sgACC connectivity reduces along with depressive symptoms, not specific to rTMS therapy. Altered connectivity of DMN with anterior insula may reflect a type of patient less likely to respond to an intervention.

Use of Expert Consultation in a Complex Case of Neuroleptic Malignant Syndrome Requiring Electroconvulsive Therapy.

Our team at Emory University Hospital contacted experts at the National Network of Depression Centers (NNDC) for clinical guidance concerning a patient with schizophrenia hospitalized in the intensive care unit with a complex case of prolonged delirium secondary to neuroleptic malignant syndrome (NMS). Through the NNDC, leading psychiatrists across the United States with expertise in electroconvulsive therapy (ECT) provided us with treatment strategies based on experience in our area of concern. This report describes our use of ECT to treat severe NMS in this patient with schizophrenia, utilizing the recommendations made by the NNDC's ECT experts concerning electrode position, number and frequency of treatments, and selection of anesthetic induction agents. This case report highlights the utility of expert consultation in the treatment of rare diseases and provides guidance on how to treat NMS in the intensive care unit setting.

Response of depression to electroconvulsive therapy: a meta-analysis of clinical predictors.

OBJECTIVE: Roughly one-third of individuals with depression do not respond to electroconvulsive therapy (ECT). Reliable predictors of ECT response would be useful for patient selection, but have not been demonstrated definitively. We used meta-analysis to measure effect sizes for a series of clinical predictors of ECT response in depression. DATA SOURCES: PubMed was searched systematically to identify studies published after 1980 that tested at least 1 clinical predictor of response to ECT. STUDY SELECTION: Of 51 studies identified, 32 were compatible with meta-analysis. DATA EXTRACTION: The weighted mean odds ratio (OR) or standardized mean difference (SMD) was computed for each of 10 clinical predictors, based on dichotomous outcomes (responder vs nonresponder). Statistical analyses examined robustness, bias, and heterogeneity. RESULTS: Shorter depressive episode duration predicted higher ECT response rate (SMD = -0.37, 7 studies, 702 subjects, P = 4 × 10(-6)). History of medication failure in the current episode was also a robust predictor: response rates were 58% and 70%, respectively, for those with and without medication failure (OR = 0.56, 11 studies, 1,175 subjects, P = 1 × 10(-5)). Greater age and psychotic features were weakly associated with higher ECT response rates, but heterogeneity was notable. Bipolar diagnosis, sex, age at onset, and number of previous episodes were not significant predictors. Analyses of symptom severity and melancholic features were inconclusive due to study heterogeneity. CONCLUSIONS: Longer depressive episodes and medication failure at baseline are robust predictors of poor response to ECT, with effect sizes that are modest but clinically relevant. Patient characteristics used traditionally such as age, psychosis, and melancholic features are less likely to be clinically useful. More robust clinical and biological predictors are needed for management of depressed patients considering ECT.

Electroconvulsive therapy device classification: response to FDA advisory panel hearing and recommendations.

Electroconvulsive therapy (ECT) is a safe and highly effective treatment for management of acute episodes of a variety of serious mental disorders, particularly for major depressive episodes that are resistant to multiple interventions with treatment alternatives. As such, the National Network of Depression Centers (NNDC), a consortium of major academic centers with interest and expertise in this area, believes there is an important public health need for ECT to remain available for clinical use. As with all medical devices, ECT is regulated by the US Food and Drug Administration (FDA), which is presently involved in formulating a proposed rule as to how such devices should be classified. Since such classification may have substantial effects on the availability of ECT to patients for whom it is clinically indicated, the NNDC has reviewed the information provided by the FDA to its Advisory Panel, as well as the subsequent deliberations of the Panel itself at a January 2011 public hearing. This review indicates that the FDA may have substantially underestimated the efficacy of ECT as a means to produce large clinical improvements for individuals suffering from severe major depressive disorders and that such an underestimate likely affected the Panel's willingness to recommend reclassification of ECT devices to a less restrictive category. In addition, the NNDC's review generates support for a variety of methods by which the safety of ECT can be ensured, which is an essential requirement for such reclassification.

Auditory memory decrements, without dissimulation, among patients with major depressive disorder.

Questions have been raised about whether poor performance on memory tasks by individuals with major depressive disorder (MDD) might be the result of poor or variable effort or disease-related disruption of neural circuits supporting memory functions. The present study examined performance on a measure of task engagement and on an auditory memory task among 45 patients with MDD (M age = 47.82, SD = 19.55) relative to 32 healthy controls (HC; M age = 51.03, SD = 22.09). One-hundred percent of HC and MDD volunteers performed above the threshold for adequate effort on a formal measure of task engagement. The MDD subjects performed significantly more poorly than the HC subjects on an auditory learning and memory test. The present results suggest that auditory memory difficulties do occur among those with MDD and that decrements in performance in this group may be related to factors other than lack of effort.

Onset of catatonia at puberty: electroconvulsive therapy response in two autistic adolescents.

Catatonia is a syndrome of motor and behavioral disturbance. It is a poorly understood condition, which is underrecognized and may go untreated despite intensive medical workup and numerous unsuccessful medication trials. However, with treatments known to be effective, such as benzodiazepines and/or electroconvulsive therapy, patients may return to their baseline functioning. Autism and catatonia have been previously reported together. We report 2 patients with autism and mental retardation who developed catatonic symptoms at the onset of puberty. Both patients experienced persistent symptoms over several years and presented with a history of motor disturbance, functional decline, and episodic aggression. Both patients were treated with electroconvulsive therapy resulting in a positive response and functional improvement. Catatonia may persist as a chronic condition, lasting over several months or years, if not recognized and treated.

Transcranial magnetic stimulation in the acute treatment of major depressive disorder: clinical response in an open-label extension trial.

BACKGROUND: This report describes the results of an open-label extension study of active trans-cranial magnetic stimulation (TMS) in medication-resistant patients with major depressive disorder who did not benefit from an initial course of therapy in a previously reported 6-week, randomized controlled study of active versus sham TMS. METHOD: Patients with DSM-IV-defined major depressive disorder were actively enrolled in the study from February 2004 through September 2005 and treated with left prefrontal TMS administered 5 times per week at 10 pulses per second, at 120% of motor threshold, for a total of 3000 pulses/session. The primary outcome was the baseline to endpoint change score on the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: In those patients who received sham in the preceding randomized controlled trial (N = 85), the mean reduction in MADRS scores after 6 weeks of open-label active TMS was -17.0 (95% CI = -14.0 to -19.9). Further, at 6 weeks, 36 (42.4%) of these patients achieved response on the MADRS, and 17 patients (20.0%) remitted (MADRS score < 10). For those patients who received and did not respond to active TMS in the preceding randomized controlled trial (N = 73), the mean reduction in MADRS scores was -12.5 (95% CI = -9.7 to -15.4), and response and remission rates were 26.0% and 11.0%, respectively, after 6 weeks of additional open-label TMS treatment. CONCLUSIONS: This open-label study provides further evidence that TMS is a safe and effective treatment of major depressive disorder. Furthermore, continued active TMS provided additional benefit to some patients who failed to respond to 4 weeks of treatment, suggesting that longer courses of treatment may confer additional therapeutic benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00104611.