Baseline and Treatment-Emergent EEG Biomarkers of Antidepressant Medication Response Do Not Predict Response to Repetitive Transcranial Magnetic Stimulation

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.     

Response to Antidepressant Treatment in a Community Mental Health Center

This study examines anti-depressant response after 6 months of treatment in 75 depressed patients in a community mental health clinic. Symptomatic and functional outcome measures were administered. A pharmacotherapy algorithm was followed.Many patients presented with chronic depressive disorders complicated by psychosocial problems and co-morbidity with substance use and other psychiatric and medical conditions. Level of functioning was seriously impaired. Attrition rate after 6 months was high (49%). Response rate after 6 months of treatment was 24%. Conclusions: Research studies cannot predict the response potential in the real world because of numerous complicating factors in the presentation and treatment of depression in the community.     

Black and White Patients Response to Antidepressant Treatment for Major Depression

Differences in response to psychopharmacologic agents according to race has so far primarily focused on investigations related to the response of Asian-American patients to neuroleptics and lithium. In this article, we present evidence which depicts that black patients need lower doses of tricyclic antidepressants (TCAs) than white patients to attain a similar response in the treatment of major depression. Likewise, we also advance that black patients might need lower doses of selective serotonin re-uptake inhibitor antidepressants (SSRIs) than white patients to attain a similar response in the treatment of major depression. Further studies are suggested to confirm these findings.     

Cardiac Biomarkers Predict Large Vessel Occlusion in Patients with Ischemic Stroke

Background and PurposeCardiac biomarkers may help identify stroke mechanisms and may aid in improving stroke prevention strategies. There is limited data on the association between these biomarkers and acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). We hypothesized that cardiac biomarkers (cardiac troponin and left atrial diameter [LAD]) would be associated with the presence of LVO.MethodsData were abstracted from a single center prospective AIS database over 18 months and included all patients with AIS with CT angiography of the head and neck. The presence of LVO was defined as proximal LVO of the internal carotid artery terminus, middle cerebral artery (M1 or proximal M2), or basilar artery. Univariate analyses and predefined multivariable models were performed to determine the association between cardiac biomarkers (positive troponin [troponin ≥0.1 ng/mL] and LAD on transthoracic echocardiogram) and LVO adjusting for demographic factors (age and sex), risk factors (hypertension, diabetes, hyperlipidemia, history of stroke, congestive heart failure, coronary heart disease, and smoking), and atrial fibrillation (AF).ResultsWe identified 1234 patients admitted with AIS; 886 patients (71.8%) had vascular imaging to detect LVO. Of those with imaging available, 374 patients (42.2%) had LVO and 207 patients (23.4%) underwent thrombectomy. There was an association between positive troponin and LVO after adjusting for age, sex and other risk factors (adjusted OR 1.69 [1.08-2.63], P = .022) and this association persisted after including AF in the model (adjusted OR 1.60 [1.02-2.53], P = 0.043). There was an association between LAD and LVO after adjusting for age, sex, and risk factors (adjusted OR per mm 1.03 [1.01-1.05], P = 0.013) but this association was not present when AF was added to the model (adjusted OR 1.01 [0.99-1.04], P = .346). Sensitivity analyses using thrombectomy as an outcome yielded similar findings.ConclusionsCardiac biomarkers, particularly serum troponin levels, are associated with acute LVO in patients with ischemic stroke. Prospective studies are ongoing to confirm this association and to test whether anticoagulation reduces the risk of recurrent embolism in this patient population.     

Assessing past treatment history: test-retest reliability of the Treatment Response to Antidepressant Questionnaire

A reliable and valid instrument has yet to be developed that elicits antidepressant treatment history via patient interview. The goal of the present study was to establish the test-retest reliability of the Treatment Response to Antidepressant Questionnaire (TRAQ). The TRAQ is a semistructured interview that was designed to collect systematically information regarding previous antidepressant treatment, adequacy of trials, and nature of response. Fifty subjects who sought outpatient treatment as part of the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project participated in the study. Patients were interviewed initially by a psychologist, who administered the TRAQ. An average of 5 to 6 days later, a psychiatrist who was blind to the results of the initial evaluation readministered the TRAQ to each of these patients. Reliability of recall of antidepressant trials, trial adequacy, and nature of response were evaluated using the kappa statistic. The mean duration of the TRAQ interviews was 3.30 minutes (SD=2.03 minutes). The reliability of recall of antidepressant trials ranged from 0.81 to 0.95, with an overall kappa of 0.91. The kappa for trial adequacy, depending on the definition used, ranged from 0.72 to 0.84. The kappa for determining positive versus negative response was 0.72. Thus, the test-retest reliability of the TRAQ was found to be in the good to excellent range for each of the principal outcome measures. The TRAQ can be administered by non-MDs as a reliable measure for collecting standardized information regarding antidepressant treatment history via patient interview.     

REM Sleep Components Predict the Response to Initial Treatment of Infantile Spasms

PURPOSE: The phasic inhibition index (PII) is the rate of the simultaneous occurrence of rapid eye movement bursts (RBs) and phasic chin muscle activity (PCMA) during rapid eye movement sleep (REMS). PII is low insofar as physiologically occurring REM-related phasic inhibition acts on chin muscles. Previously we found that PII was significantly higher in patients with infantile spasms (ISs) who had a recurrence of convulsions than in patients with ISs who exhibited no recurrence. We aimed to predict the response of patients with ISs to conventional anticonvulsants (AEDs) by means of REMS components including PII, expecting to facilitate avoidance of potentially hazardous hormonal therapy. METHODS: REMS, recorded before the beginning of any medication, was retrospectively examined in 15 patients with ISs. The patients were classified into two groups according to the response to initial treatment with conventional AEDs. Conventional AEDs were enough to control the spasms in six good responders (GRs), whereas further hormonal therapy was required in nine poor responders (PRs) to control the spasms. RESULTS: The amount of REMS was significantly lower in patients with ISs than in controls. GRs had less REMS than did PRs, although no significant difference was observed. Although the frequencies of RB and PCMA showed no significant differences among GRs, PRs, and controls, the average PII value in PRs (12.6+/-3.4; mean+/-SD) was significantly (p < 0.001) higher than that in GRs (6.1+/-1.7). CONCLUSIONS: PII is a useful parameter for differentiating GRs from PRs.     

Brain-Specific Serum Biomarkers Predict Neurological Morbidity in Diagnostically Diverse Pediatric Intensive Care Unit Patients

Background

Unexpected neurological morbidity in Pediatric Intensive Care Units (PICUs) remains high and is difficult to detect proactively. Brain-specific biomarkers represent a novel approach for early detection of neurological injury. We sought to determine whether serum concentrations of neuron-specific enolase (NSE), myelin basic protein (MBP), and S100B, specific for neurons, oligodendrocytes, and glia, respectively, were predictive of neurological morbidity in critically ill children.

Methods

Serum was prospectively collected on days 1–7 from diagnostically diverse PICU patients (n = 103). Unfavorable neurological outcome at hospital discharge was defined as Pediatric Cerebral Performance Category (PCPC) score of 3–6 with a deterioration from baseline. NSE, MBP, and S100B concentrations were measured by enzyme-linked immunosorbent assay.

Results

Peak biomarker levels were greater in patients with unfavorable versus favorable neurological outcome [NSE 39.4 ± 44.1 vs. 12.2 ± 22.9 ng/ml (P = 0.005), MBP 9.1 ± 11.5 vs. 0.6 ± 1.3 ng/ml (P = 0.003), S100B 130 ± 232 vs. 34 ± 70 pg/ml (P = 0.04), respectively; mean ± SD]. Peak levels were each independently associated with unfavorable neurological outcome when controlling for presence of primary neurologic admission diagnosis and poor baseline PCPC using logistic regression analysis (NSE, P = 0.04; MBP, P = 0.004; S100B, P = 0.04), and had the following receiver operating characteristics: NSE 0.75 (0.58, 0.92), MBP 0.81 (0.66, 0.94), and S100B 0.80 (0.67, 0.93) (area under the curve [95% confidence intervals]).

Conclusions

Prospectively collected brain-specific serum biomarkers predict unfavorable neurological outcome in critically ill children. Serum biomarkers used in conjunction with clinical data could be used to generate models predicting early detection of neurological injury, allowing for more timely diagnostic and therapeutic interventions, potentially reducing neurological morbidity in the PICU.

     

CLOCK may Predict the Response to Fluvoxamine Treatment in Japanese Major Depressive Disorder Patients

Recent studies have shown that selective serotonin reuptake inhibitors (SSRIs) have circadian properties, suggesting that the antidepressive action of SSRIs may also be attributable to circadian mechanisms. Another study reported an association between clock gene (CLOCK) and improvements in insomnia symptoms from SSRIs treatment. Therefore, we examined the association between CLOCK and the efficacy of fluvoxamine treatment in 121 patients with Japanese major depressive disorder (MDD). The MDD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a therapeutic response as a decrease of more than a 50% in baseline SIGH-D within 8 weeks, and clinical remission as a SIGH-D score of less than seven at 8 weeks. We selected three tagging SNPs in CLOCK for the subsequent statistical association analysis. We detected a significant association between rs3736544, a synonymous polymorphism in exon 20, and the fluvoxamine therapeutic response in MDD in the allele/genotype-wise analyses. In addition, remission with fluvoxamine was also significantly associated with rs3736544. These associations remained significant after Bonferroni correction. Moreover, haplotype analysis findings supported these significant associations, which appeared to be due mainly to rs3736544, in the fluvoxamine therapeutic remission. Our results indicate that CLOCK genotype may be a predictor of fluvoxamine treatment response in Japanese MDD. However, our sample size was small, and a replication study using larger samples may be required for conclusive results. Taro Kishi and Tsuyoshi Kitajima contributed equally to this work.     

Augmentation Strategies for Inadequate Antidepressant Response: A Review of Placebo-Controlled Studies

Uncontrolled trials of strategies directed at inadequate antidepressant response are prone to falsely positive results. Most of those studies which have used placebo control have assessed augmentation and the addition of lithium to tricyclic antidepressants or serotonin reuptake inhibitors has so far received the most support. A smaller literature shows promise for augmentation with triiodothyronine, pindolol and dehydroepiandrosterone.