Michelle Abrams

Executive dysfunction predicts nonresponse to fluoxetine in major depression.

BACKGROUND Functional brain imaging studies of major depression have consistently revealed hypometabolism or hypoperfusion in specific regions of the prefrontal cortex and basal ganglia. Studies of cognitive functioning in major depression have suggested that some but not all subjects exhibit cognitive deficits that are consistent with frontal-subcortical dysfunction, although the reasons for this heterogeneity are unclear. In this study, we explored this heterogeneity among depressed subjects by examining the relationship between cognitive functioning and treatment outcome. METHOD Subjects with major depression were administered a complete neuropsychological test battery prior to treatment with fluoxetine. RESULTS There were no significant differences between responders and nonresponders to fluoxetine in terms of age, educational achievement, number of past episodes of depression, and estimated premorbid IQ. However, nonresponders performed significantly worse than responders on several pretreatment measures of executive functioning, after controlling for baseline group differences in depression severity. LIMITATIONS The results are based on a small sample of primarily female subjects, resulting in low statistical power and less generalizability to samples of male subjects with depression. CONCLUSIONS The findings suggest that subtle prefrontal dysfunction in subjects with major depression may be predictive of poor response with particular medications. Assessment of the executive functions may play a particular role in pretreatment identification of subjects likely to respond to specific medications.

Yoga as a Complementary Treatment of Depression: Effects of Traits and Moods on Treatment Outcome

Preliminary findings support the potential of yoga as a complementary treatment of depressed patients who are taking anti-depressant medications but who are only in partial remission. The purpose of this article is to present further data on the intervention, focusing on individual differences in psychological, emotional and biological processes affecting treatment outcome. Twenty-seven women and 10 men were enrolled in the study, of whom 17 completed the intervention and pre- and post-intervention assessment data. The intervention consisted of 20 classes led by senior Iyengar yoga teachers, in three courses of 20 yoga classes each. All participants were diagnosed with unipolar major depression in partial remission. Psychological and biological characteristics were assessed pre- and post-intervention, and participants rated their mood states before and after each class. Significant reductions were shown for depression, anger, anxiety, neurotic symptoms and low frequency heart rate variability in the 17 completers. Eleven out of these completers achieved remission levels post-intervention. Participants who remitted differed from the non-remitters at intake on several traits and on physiological measures indicative of a greater capacity for emotional regulation. Moods improved from before to after the yoga classes. Yoga appears to be a promising intervention for depression; it is cost-effective and easy to implement. It produces many beneficial emotional, psychological and biological effects, as supported by observations in this study. The physiological methods are especially useful as they provide objective markers of the processes and effectiveness of treatment. These observations may help guide further clinical application of yoga in depression and other mental health disorders, and future research on the processes and mechanisms.

Early changes in prefrontal activity characterize clinical responders to antidepressants.

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. Fifty-one adults with unipolar depression completed treatment trials using either fluoxetine or venlafaxine vs. placebo. Data were recorded at baseline and after 48 h 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 h and 1 week. Clinical differences did not emerge until after four 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.

Neurophysiologic predictors of treatment response to fluoxetine in major depression

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.

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.

Cognitive, behavioral, and autonomic correlates of mind wandering and perseverative cognition in major depression

Autonomic dysregulation has been hypothesized to play a role in the relationships between psychopathology and cardiovascular risk. An important transdiagnostic factor that has been associated with autonomic dysfunction is perseverative cognition (PC), mainly present in Major Depressive Disorder (MDD) in the form of rumination. As the ability to adaptively let our mind wander without ruminating is critical to mental health, this study aimed to examine the autonomic concomitants of functional vs. dysfunctional intrusive thoughts in MDD. Ambulatory heart rate (HR) and variability (HRV) of 18 MDD subjects and 18 healthy controls were recorded for 24 h. Approximately every 30 min during waking hours subjects reported their ongoing thoughts and moods using electronic diaries. Random regression models were performed. Compared to controls, MDD subjects were more often caught during episodes of PC. In both groups, PC required more effort to be inhibited and interfered more with ongoing activities compared to mind wandering (MW) (ps < 0.0001). This cognitive rigidity was mirrored by autonomic inflexibility, as PC was characterized by lower HRV (p < 0.0001) compared to MW. A worse mood was reported by MDD patients compared to controls, independently of their ongoing cognitive process. Controls, however, showed the highest mood worsening during PC compared to being on task and MW. HRV during rumination correlated with self-reported somatic symptoms on the same day and several dispositional traits. MDD subjects showed lower HRV during sleep, which correlated with hopelessness rumination. Results show that PC is associated with autonomic dysfunctions in both healthy and MDD subjects. Understanding when spontaneous thought is adaptive and when it is not may clarify its role in the etiology of mood disorders, shedding light on the still unexplained association between psychopathology, chronic stress, and risk for health.

Altered cerebral energy utilization in late life depression

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.

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.

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.

Brain functional changes (QEEG cordance) and worsening suicidal ideation and mood symptoms during antidepressant treatment

Hunter AM, Leuchter AF, Cook IA, Abrams M. Brain functional changes (QEEG cordance) and worsening suicidal ideation and mood symptoms during antidepressant treatment.