Abstract: 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 8Ð10 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.

Abstract: 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.

Abstract: RATIONALE: High placebo response rates are a confound in treatment trials for major depressive disorder (MDD). A method for prospective identification of placebo responders could enhance the efficiency of clinical trials. OBJECTIVE: The objective was to identify the neurophysiological, symptomatic, and cognitive characteristics of subjects who were likely to respond to placebo in clinical trials for MDD. METHODS: Fifty-one subjects with MDD were treated in clinical trials with either fluoxetine (n=24) or venlafaxine (n=27) versus placebo. All subjects underwent pretreatment assessment with quantitative electroencephalographic (QEEG) power and cordance, as well as symptom ratings and neuropsychological testing. After a 1-week single-blind placebo lead-in, subjects were randomized to double-blind placebo controlled treatment with a medication or placebo. At the end of 8 weeks, the blind was broken and treatment response assessed. Response was defined by a final Hamilton Depression Rating Scale score of ≤ 10. RESULTS: Of the medication-treated and placebo-treated subjects, 52% (13/25) and 38% (10/26) responded. Placebo responders had lower pretreatment frontocentral cordance in the theta frequency band than all other subjects (P < 0.006) and medication responders in particular ( P < 0.004). Placebo responders also had faster cognitive processing time, as assessed by neuropsychological testing, and lower reporting of late insomnia ( P < 0.03). Exploratory examination of a multiple variable model for predicting placebo response was conducted using logistic regression, in which these three pretreatment measures accurately identified 97.6% of eventual placebo responders. CONCLUSIONS: These findings suggest that combined clinical, neurophysiological, and cognitive assessments of prospective subjects for clinical trials may be useful for identifying MDD subjects who are likely to show robust response to placebo. Prospective validation of these results in a larger, independent sample of subjects is necessary to establish the reliability and usefulness of this method for prospective identification of placebo responders.

Abstract: OBJECTIVE: To evaluate the association between treatment expectations and response in a 9-week, single-blind experimental antidepressant treatment study. METHOD: Twenty-five adult subjects meeting DSM-IV criteria for major depressive disorder with Hamilton Rating Scale for Depression (HAM-D) scores of ≥ 17 completed a treatment trial using the experimental antidepressant reboxetine. Following a 1-week placebo lead-in, subjects received single-blind treatment for 8 weeks with reboxetine 8 to 10 mg/day. During the screening visit, subjects were asked to self-rate their expectations of the effectiveness of the study medication. Forced-choice responses were "not at all effective," "somewhat effective," or "very effective." Response to treatment was defined as a final HAM-D score of ≤ 10 at the end of the 9-week trial. Data were collected from October 1999 to July 2001. RESULTS: Subjects with a higher pretreatment expectation of medication effectiveness had a greater likelihood of response. Of the subjects who reported an expectation that the medication would be very effective, 90.0% (N = 9) responded to treatment, while only 33.3% (N = 5) of those who reported expecting medication to be somewhat effective responded to treatment (chi(2) = 7.819, p < .005). There was no association between the level of depression severity, duration of current episode, number of prior episodes, or basic demographic factors and treatment outcome. CONCLUSIONS: These findings indicate that individuals with high baseline expectations of improvement demonstrate a significantly higher level of response to reboxetine than those with lower expectations of improvement with treatment. The data in this study suggest that a subject's expectation of efficacy is associated with the outcome of experimental antidepressant treatment.

Abstract: OBJECTIVES: Recent brain imaging studies have provided evidence that brain function assessed prior to treatment of depression may be associated with eventual treatment response. The present study tested the hypothesis that brain activity in midline apical quantitative EEG (QEEG) electrodes would be associated with therapeutic response to electroconvulsive therapy (ECT). METHODS: Ten treatment-refractory patients with unipolar or bipolar depression received a Hamilton Rating Scale for Depression (Ham-D) at baseline, during, and following ECT treatment. Resting, eyes-closed, 35-lead QEEG recordings were done 1 day before the initial ECT treatment. Data were analyzed using QEEG power and cordance. RESULTS: The mean of the theta-band pretreatment cordance from the central brain region was strongly associated with percentage decrease in Ham-D score over the course of treatment (r = 0.80, P = 0.005). QEEG cordance from other brain regions and power from all brain regions did not show an association with clinical improvement. CONCLUSIONS: Depressed subjects with higher pretreatment central cordance appear to be more likely to experience therapeutic benefits of ECT. The location of central electrodes over the cingulate cortex may indicate that pretreatment cingulate activity is associated with response to ECT.

Abstract: Psychiatric disorders are characterized by diverse clinical manifestations that include deficits in cognition, perception, mood and arousal. These complex processes are not mediated by any specific brain region but require the coordinated activity of several areas that are anatomically connected. Impairments in these neural circuits may therefore be expected to result in an attenuation of the functions regulated by them. The white matter provides the structural and physiological substrate of neural circuits in the central nervous system. We propose that injury to the white matter, from diverse biological sources, may compromise neural connectivity by associated axonal injury or impaired conductivity. Either mechanism could result in clusters of signs and symptoms that are currently recognized as psychiatric disorders. The role of white matter impairment in the pathophysiology of psychiatric illness is under-appreciated in the neurosciences. Focused translational research aimed at identifying the links between white matter compromise and specific behaviors are necessary for a more thorough understanding of the etiology of mental illness to emerge.

Abstract: Previous studies have shown that changes in brain function precede clinical response to antidepressant medications. Here we examined quantitative EEG (QEEG) absolute and relative power and a new measure, cordance, for detecting regional changes associated with treatment response. 51 adults with unipolar depression completed treatment trials using either fluoxetine or venlafaxine vs placebo. Data were recorded at baseline and after 48 hours and 1 week on drug or placebo. Baseline and change from baseline values were examined for specific brain regions in four subject groups (medication and placebo responders and nonresponders). No regional baseline QEEG differences were found among the groups; there also were no significant changes in theta power over time. In contrast, medication responders uniquely showed significant decreases in prefrontal cordance at 48 hours and 1 week. Clinical differences did not emerge until after 4 weeks. Subjects with greater changes in cordance had the most complete 8-week responses. These findings implicate the prefrontal region in mediating response to antidepressant medications. Cordance may have clinical applicability as a leading indicator of individual response.

Abstract: Objective: It has been proposed that the 50-75% of the efficacy of antidepressant medication represents the "placebo effect," since many depressed patients improve when treated either with medication or placebo. This study examined brain function in depressed subjects receiving either active medication or placebo, and sought to determine whether quantitative electroencephalography (QEEG) could detect differences in brain function between medication and placebo responders. Both QEEG power and cordance, a new measure that reflects cerebral perfusion and is sensitive to the effect of antidepressant medication, were examined.
Method: Fifty one subjects with major depression were enrolled in one of two independent, nine-week, double-blind placebo-controlled studies in which either fluoxetine (n = 24) or venlafaxine (n = 27) was the active medication. Serial QEEG recordings were performed during the course of treatment. After 9 weeks, the blind was broken and subjects were classified as medication responders, placebo responders, medication nonresponders, or placebo nonresponders.
Results: No significant pretreatment differences in clinical or QEEG measures were found among the four outcome groups. Placebo responders, however, showed a significant increase in prefrontal cordance starting early in treatment that was not seen in medication responders (who showed decreased cordance) or in placebo nonresponders or medication nonresponders subjects (who showed no significant change). There was no significant change in QEEG power during treatment.
Conclusion: These findings suggest that "effective" placebo treatment induces changes in brain function that are distinct from those associated with antidepressant medication. If these results are confirmed, cordance may be useful for differentiating between medication and placebo responders.

Abstract: A continuing challenge in the treatment of depression is how to determine whether an effective drug has been selected for a particular patient, given that individuals will respond to some antidepressants but not others. The factors that contribute to response for each person have been examined from a variety of perspectives, both psychological and physiological. Advances in neuroimaging and in quantitative electroencephalography (QEEG) have made it possible to examine features of brain activity that are associated with response. A new QEEG measure, cordance, is correlated with regional cortical perfusion, and has been used with retrospective and prospective studies to evaluate specific findings that are predictive of clinical response in major depression. We present here a series of depressed subjects treated with antidepressants of different classes; decreases in prefrontal activity were seen as early as 48 hours into treatment in responders and were absent in nonresponders. These findings suggest a role for the prefrontal region in mediating response to medications with different mechanisms of action and raise the possibility of using new QEEG measures to identify changes in brain activity that are predictive of clinical outcome from antidepressant treatment.

Abstract: Treatment with antidepressants is marked by heterogeneity of response; predicting individual response to any given agent remains problematic. Neuroimaging studies suggest that response is accompanied by physiologic changes in cerebral energy utilization, but have not provided useful markers at pretreatment baseline. Using quantitative EEG (QEEG) techniques, we investigated pretreatment neurophysiologic features to identify responders and non-responders to fluoxetine. In a double-masked study, 24 adult subjects with current major depression of the unipolar type were studied over 8 weeks while receiving fluoxetine (20 mg QD) or placebo. Neurophysiology was assessed with QEEG cordance, a measure reflecting cerebral energy utilization. Response was determined with rating scales and clinical interview. Subjects were divided into discordant and concordant groups based upon the number of electrodes exhibiting discordance. The concordant group had a more robust response than the discordant group, judged by lower final Hamilton Depression (HAM-D) mean score (8.0+/-7.5 vs. 19.6+/-4.7, P = 0.01) and final Beck Depression Inventory (BDI) mean score (14.0+/-9.4 vs. 27.8+/-3.7, P = 0.015), and by faster reduction in symptoms (HAM-D: 14.0+/-5.0 vs. 23.8+/-4.1, P = 0.004 at 1 week). Groups did not differ on pretreatment clinical or historical features. Response to placebo was not predicted by this physiologic measure. We conclude that cordance distinguishes depressed adults who will respond to treatment with fluoxetine from those who will not. This measure detects a propensity to respond to fluoxetine and may indicate a more general responsiveness to antidepressants.

Abstract: BACKGROUND: Global and regional changes in cerebral energy utilization are reported to characterize late life depression.
METHODS: Twenty seven subjects with late life depression (9 prior to starting medication, 18 after starting) and 27 matched controls were evaluated with cordance, a quantitative EEG measure that reflects cerebral energy utilization.
RESULTS: Global and focal (anterior and centrotemporal) differences were present in theta-band cordance between unmedicated depressed and control subjects. Depressed subjects receiving treatment had cordance patterns similar to controls.
CONCLUSIONS: The presence of both diffuse and focal disturbances in energy utilization prior to initiating treatment indicates that cordance detects altered cerebral physiology in depressed patients, and that this measure may also be sensitive to treatment interventions.