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.

Changes in brain function during administration of venlafaxine or placebo to normal subjects.

Previous research has demonstrated neurophysiologic effects of antidepressants in depressed subjects. We evaluated neurophysiologic effects of venlafaxine in normal subjects. Healthy adults (n=32) received a 1-week placebo lead-in followed by 4 weeks randomized double-blind treatment with venlafaxine IR 150 mg. (n = 17) or placebo (n = 15). Brain function was examined using quantitative electroencephalographic (QEEG) power and theta cordance. Normal subjects receiving venlafaxine showed a decrease in theta-band cordance in the midline-and-right-frontal (MRF) region at 48 hours and at 1 week after randomization. Decreases in relative power also were seen in the MRF region; there were no significant changes in absolute power. These changes were significantly different from those in subjects receiving placebo. Changes in MRF cordance accurately identified treatment condition at 48 hours in 81.3% of subjects, and relative power from this region identified 60.7% of subjects. In conclusion, cordance may detect the pharmacological effects of antidepressant medication in normal subjects. Future studies should examine other classes of medication, as well as antidepressants with other mechanisms of action, to determine if cordance detects antidepressant medication effects in general in normal subjects.

Influence of age, gender, health status, and depression on quantitative EEG.

Quantitative electroencephalography (QEEG) has shown increasing utility in assessing brain function in clinical research studies of depression. QEEG findings may be influenced by a variety of factors other than the presence of depression, including age, gender, depression severity, and physical health status. Many of these factors have not been systematically evaluated. We therefore examined QEEG measures in 104 subjects with depression and normal controls to determine the influence of these factors. We examined QEEG power as well as cordance, a QEEG measure that has a stronger association with cerebral perfusion than conventional QEEG measures. Prefrontal cordance in the theta band has been associated with the pathophysiology of depression and response to treatment. We found that prefrontal cordance and relative power in the theta band were unaffected by age, gender, severity of depression, and health status, while prefrontal absolute power was higher in women than men. All of these measures were different from global measures of absolute and relative power, which were influenced by age, gender, and health status. These findings suggest that prefrontal cordance in depressed patients is not significantly affected by factors of age, gender, severity of depression, or physical illness. Global measures of power, and to a lesser extent prefrontal absolute power, must be interpreted with regard to confounding factors of age, gender, physical illness, and severity of depression.

Changes in prefrontal activity characterize clinical response in SSRI nonresponders: a pilot study.

Previous studies in unipolar depression have shown that early decreases in prefrontal values of the QEEG cordance measure identified responders to pharmacotherapy. These studies have all examined individuals who were drug-free prior to the first physiologic assessment, yet in the clinical management of treatment resistant depression (TRD), many patients undergo changes in treatment without a drug-free interval between treatments. Here, we investigated whether cordance decreases were associated with response in Stage I TRD subjects without wash-out between treatment trials. Awake EEGs were recorded from 12 adults with unipolar depression. Subjects were receiving naturalistic treatment, had failed SSRI monotherapy, and were starting a new treatment prescribed by their treating psychiatrists. EEG data were recorded before starting the new treatment and after approximately 1 week. Six of the 12 subjects responded to treatment after 8--10 weeks. Five of the six responders showed an early cordance decreases, compared with two of the six nonresponders (accurate characterization in 75% of the cases). Consistent with previous treatment trials, decreases in prefrontal cordance differentiated responders from nonresponders in this setting as well. These findings suggest that cordance biomarkers may be a useful tool in effectiveness trials that parallel clinical practices in SSRI nonresponders, and may not require a wash-out period between treatments.

Neurophysiologic correlates of side effects in normal subjects randomized to venlafaxine or placebo.

Adverse events reported in the context of medication administration may be due to pharmacodynamic and/or nonpharmacodynamic effects (eg, nocebo phenomena). Neurophysiological substrates of side effects may be examined in placebo-controlled antidepressant treatment trials. We explored the relationship between side effects and regional neurophysiologic changes in normal subjects receiving a 1-week placebo lead-in followed by 4 weeks randomized treatment with placebo (n = 15) or venlafaxine IR (n = 17). Quantitative electroencephalographic (QEEG) cordance measures were obtained before and during treatment, and side effects were assessed weekly using semistructured interviews. Side effect burden, characterized as the mean number of side effects per postrandomization visit, correlated significantly with neurophysiologic changes in the antidepressant group but not the placebo group. Medication group side effects were negatively correlated with changes in prefrontal cordance at end of placebo lead-in (r = -0.67, p < 0.003), at 2 weeks (r = -0.77, p < 0.002), and at 4 weeks (r = -0.77, p < 0.004) post randomization. After controlling for the prefrontal change at the end of placebo lead-in, postrandomization brain changes did not further explain side effect burden. Changes in prefrontal brain function associated with later antidepressant side effects were observed during placebo lead-in-prior to the administration of medication. Prefrontal brain function during brief placebo administration may help explain susceptibility to the development of antidepressant side effects. Results of these exploratory hypothesis-generating analyses should be considered tentative until replicated.