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ABSTRACT: There has been a surge of interest in biomarkers that can rapidly predict or assess response to psychiatric treatment, as the current standard practice of extended therapeutic trials is often dissatisfying to both clinicians and patients. Electroencephalographic (EEG) biomarkers in particular have been proposed as an inexpensive yet rapid way of determining whether a patient is responding to an intervention, usually before subjective mood improvement occurs. However, even the most well-reported EEG algorithms have not been subjected to independent replication, limiting their clinical generalizability. It is also unclear whether those biomarkers can generalize beyond their original study population, e.g. to patients undergoing somatic treatments for depression. We report here analysis of EEG data from the pivotal OPT-TMS study of transcranial magnetic stimulation (rTMS) for major depressive disorder. In this dataset, previously reported biomarkers of medication response showed no significant correlation with eventual response to rTMS treatment. Furthermore, EEG power in multiple bands measured at baseline and throughout the treatment course did not correlate with or predict either binary (response/nonresponse) or continuous (Hamilton Rating Scale for Depression) outcome measures. While somewhat limited by technical difficulties in data collection, these analyses are adequately powered to detect clinically relevant biomarkers. We believe this highlights a need for wider-scale independent replication of previous EEG biomarkers, both in pharmacotherapy and neuromodulation.
Brain Stimulation 05/2013; · 3.76 Impact Factor
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William M McDonald,
Valerie Durkalski,
Edward R Ball,
Paul E Holtzheimer,
Martina Pavlicova,
Sarah H Lisanby,
David Avery,
Berry S Anderson,
Ziad Nahas, Paul Zarkowski,
Harold A Sackeim,
Mark S George
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ABSTRACT: To assess the efficacy of increasing the number of fast left repetitive transcranial magnetic stimulations (rTMS) (10 Hz @ 120% of motor threshold (MT) over the left dorsolateral prefrontal cortex (DLPFC)) needed to achieve remission in treatment-resistant depression (TRD). And, to determine if patients who do not remit to fast left will remit using slow right rTMS (1 Hz @ 120% MT over the right DLPFC).
Patients were part of a multicenter sham-controlled trial investigating the efficacy of fast left rTMS. Patients who failed to meet minimal response criteria in the sham-controlled study could enroll in this open fast left rTMS study for an additional 3-6 weeks. Patients who failed to remit to fast left could switch to slow right rTMS for up to 4 additional weeks. The final outcome measure was remission, defined as a HAM-D score of <3 or 2 consecutive HAM-D scores less than 10.
Forty-three of 141 (30.5%) patients who enrolled in the open phase study eventually met criteria for remission. Patients who remitted during fast left treatment received a mean of 26 active treatments (90,000 pulses). Twenty-six percent of patients who failed fast left remitted during slow right treatment.
The total number of rTMS stimulations needed to achieve remission in TRD may be higher than is used in most studies. TRD patients who do not respond to fast left rTMS may remit to slow right rTMS or additional rTMS stimulations.
Depression and Anxiety 09/2011; 28(11):973-80. · 4.18 Impact Factor
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Mark S George,
Sarah H Lisanby,
David Avery,
William M McDonald,
Valerie Durkalski,
Martina Pavlicova,
Berry Anderson,
Ziad Nahas,
Peter Bulow, Paul Zarkowski,
Paul E Holtzheimer,
Theresa Schwartz,
Harold A Sackeim
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ABSTRACT: Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been studied as a potential treatment for depression, but previous work had mixed outcomes and did not adequately mask sham conditions.
To test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder.
Prospective, multisite, randomized, active sham-controlled (1:1 randomization), duration-adaptive design with 3 weeks of daily weekday treatment (fixed-dose phase) followed by continued blinded treatment for up to another 3 weeks in improvers.
Four US university hospital clinics.
Approximately 860 outpatients were screened, yielding 199 antidepressant drug-free patients with unipolar nonpsychotic major depressive disorder.
We delivered rTMS to the left prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations.
In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode.
Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90% sham and 86% active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1% active rTMS and 5.1% sham) (P = .02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.32-13.24). The number needed to treat was 12. Most remitters had low antidepressant treatment resistance. Almost 30% of patients remitted in the open-label follow-up (30.2% originally active and 29.6% sham).
Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham.
clinicaltrials.gov Identifier: NCT00149838.
Archives of general psychiatry 05/2010; 67(5):507-16. · 12.26 Impact Factor
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ABSTRACT: The resting motor threshold (rMT) is an important factor in the selection of treatment intensity for patients receiving repetitive transcranial magnetic stimulation (rTMS). In many clinical studies to date, due to concerns about potential drift, the rMT has been routinely re-measured weekly or every fifth session.
Our aim is to investigate whether ongoing treatment with rTMS affects the rMT, the degree of change, and whether frequent remeasurement is needed.
Clinical data were drawn from 50 medication free patients receiving treatment for major depression with rTMS in a large U.S. NIH-sponsored multisite study. Four measurements of rMT were obtained including before and after the double blind phase, followed by weekly measurements during the open phase. Active treatment consisted of 75 four second trains of 10Hz stimulation applied over 37.5 minutes with the coil over the left DLPFC at 120% rMT.
For the group as a whole, there was no significant change in the rMT during a minimum of 2 weeks of treatment with prefrontal rTMS (p=0.911, one way ANOVA). The average within-subject coefficient of variation was 6.58%. On average the last rMT was 2.45% less than the baseline rMT (range 32.3% increase, 40.6% decrease).
Daily left prefrontal rTMS over several weeks as delivered in this trial does not cause systematic changes in rMT. While most subjects had <10% variance in rMT over time, 5 subjects had changes of approximately 20% from baseline, raising dosing and safety issues if undetected. We recommend that clinical trials of rTMS have periodic retesting of rMT, especially if the dose is at or near the edge of the TMS safety tables.
Brain Stimulation 07/2009; 2(3):163-7. · 3.76 Impact Factor
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Paul Zarkowski
American Journal of Psychiatry 10/2008; 165(9):1126. · 12.54 Impact Factor
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ABSTRACT: Previous studies of repetitive transcranial magnetic stimulation suggest a hemispheric imbalance in patients with major depression. These studies report an antidepressant effect by activation of the left prefrontal cortex or inhibition of the right prefrontal cortex. The aim of this study is to investigate interhemispheric differences in cortical excitability in a large sample of patients with major depression.
The resting motor threshold (RMT) was measured on 91 patients with treatment-resistant major depression. We controlled for current medication use, gender, age, handedness, and study site.
There was no significant difference between the left RMT (55.96 [10.356]) and the right (57.74 [11.359]) (P = 0.131, Wilcoxon matched-pairs test). A multivariate analysis found no significant association between depression scores and right or left RMT. After adjusting for important cofactors, benzodiazepine use was found to be a significant predictor of left RMT (P = 0.017, linear regression) and right RMT (P = 0.007, linear regression).
Our results do not support the existence of an interhemispheric imbalance of cortical excitability in depressed patients. Benzodiazepine use was found to raise both the left and right RMT.
The journal of ECT 07/2008; 25(1):39-43. · 1.19 Impact Factor
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ABSTRACT: Our objective is to study the link between hotel registration and suicide. Clark County, which contains Las Vegas, drew our interest because of its extremely large number of hotel rooms. Case files of suicide from the Clark County Coroner were reviewed for years 2003-2005. The suicide rate of local residents registering in local hotels was 271/100,000. This is greater than the suicide rate in the general population of Clark County, 16.6/100,000, P<0.0001, Poisson distribution. Hotel guests from outside Clark County had a reduced rate of suicide, 4.6/100,000, P<0.0001. Residents of Clark County registering in local hotels have an increased suicide risk that is statistically significant. Possible explanations for the results are provided.
Social Psychiatry and Psychiatric Epidemiology 02/2008; 43(1):25-7. · 2.70 Impact Factor
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ABSTRACT: Malingering is easy to define, difficult to detect, and very costly for any health care system. The structured interview of reported symptoms (SIRS) was constructed using rational strategies to detect malingering in patients endorsing psychotic symptoms. This study validated the SIRS using evoked potentials. Nineteen patients meeting DSM-IV criteria for schizophrenia and 15 healthy controls completed an oddball and paired click protocol. Severity of psychotic symptoms was documented using the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. The patient group was divided by probability of malingering according to the SIRS. Patients with a high probability of malingering had significantly greater P3 amplitude (P = 0.006, t-test) and more P50 suppression (P = 0.044, t-test) than patients with a low probability of malingering. No significant difference in P3 amplitude or P50 suppression was found between the patients with a high probability of malingering and the healthy controls. This study provides empirical support for the validity of the SIRS with evidence that is independent of patient report.
Journal of Clinical Neurophysiology 11/2007; 24(5):413-8. · 1.45 Impact Factor
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ABSTRACT: The objective of our research was to quantify the increased risk of suicide associated with registering in local hotels/motels. Medical examiner case files of suicide in King County, Washington, were reviewed for years 2002-2004. The incidence of suicide in local residents registering in local hotels/motels was 223/100,000 which is significantly greater than the incidence of suicide in the general population of King County (11.7/100,000 p < 0.0001). Hotel/motel guests from outside Washington had a significantly reduced incidence of suicide (3.9/100,000 p = 0.002). The study results suggest that there is an increased risk of suicide in local residents who register in local hotel rooms.
Suicide and Life-Threatening Behavior 11/2006; 36(5):578-81. · 1.33 Impact Factor
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ABSTRACT: This study aims to investigate excessive tearfulness as a sign to help determine the etiology of depressive symptoms.
Clinicians were instructed to document the occurrence of excessive tearfulness in all patients seen in the Psychiatric Emergency Service. Excessive tearfulness was defined as crying to the severity that at least 1 tear drops off the face. A comparison group was formed from the general population of the Psychiatric Emergency Service.
Excessive tearfulness was documented in 36 different patients. The prevalence of the sign in the general population was 1.9%. Patients with excessive tearfulness were more likely to have cocaine in their urine (P < .0001, chi(2) test), receive a substance-related primary diagnosis (P < .0001, chi(2) test), and be admitted for psychiatric hospitalization (P < .001 chi(2) test). Patients with excessive tearfulness had significantly shorter voluntary hospital stays (P < .05, t test).
Excessive tearfulness could be a useful clinical sign of cocaine-induced depression.
Comprehensive Psychiatry 48(3):252-6. · 2.26 Impact Factor
