Faculty Bibliography

BACKGROUND: We assessed the efficacy of low-dose aripiprazole added to antidepressant therapy (ADT) in major depressive disorder (MDD) patients with inadequate response to prior ADT. METHODS: As per the sequential parallel comparison design, 225 MDD subjects were randomized to adjunctive treatment with aripiprazole 2 mg/day or placebo across two 30-day phases, with a 2:3:3 randomization ratio to drug/drug (aripiprazole 2 mg/day in phase 1; 5 mg/day in phase 2), placebo/placebo (placebo in both phases), and placebo/drug (placebo in phase 1; aripiprazole 2 mg/day in phase 2). Eligible subjects were patients whose MDD was independently deemed 'valid' with SAFER criteria. Subjects had been receiving ADT for >/=8 weeks, and had inadequate response to >/=1 and <4 adequate ADTs in the current episode, as defined by the Antidepressant Treatment Response Questionnaire. RESULTS: The pooled, weighted response difference between aripiprazole 2 mg/day and placebo in the two phases was 5.6% (p = 0.18; NS). The aripiprazole 2 mg/day-placebo difference on the Montgomery-Asberg Depression Rating Scale pooled across the two phases was -1.51 (p = 0.065; NS). Other secondary endpoint analyses showed nonsignificant pooled differences favoring aripiprazole over placebo. Of the 225 randomized subjects in phase 1, 2 dropped out in both arms, while in phase 2, of 138 phase 1 placebo nonresponders, 9 dropped out on aripiprazole and 5 on placebo. There were only minimal differences in adverse event rates between treatments, except for constipation, weight gain, and dry mouth, more common on aripiprazole. CONCLUSIONS: This study provides clear support for the tolerability of low-dose aripiprazole as an ADT-augmenting agent, with marginal efficacy.

Major depressive disorder (MDD) is a disabling medical condition associated with significant morbidity, mortality and public health costs. However, neurocircuitry abnormalities underlying depression remain incompletely understood and consequently current treatment options are unfortunately limited in efficacy. Recent research has begun to focus specifically on cognitive aspects of depression and potential neurobiological correlates. Two fundamental types of cognitive dysfunction observed in MDD are cognitive biases, which include distorted information processing or attentional allocation toward negative stimuli, and cognitive deficits, which include impairments in attention, short-term memory and executive functioning. In this article, we present a selective review of current research findings in these domains and examine neuroimaging research that is beginning to characterize the neurocircuitry underlying these biases and deficits. We propose that deficient cognitive functioning, attention biases and the sustained negative affect characteristic of MDD can be understood as arising in part from dysfunctional prefrontal-subcortical circuitry and related disturbances in the cognitive control of emotion. Finally, we highlight potential new pharmacological and non-pharmacological therapeutic strategies for MDD based on an evolving mechanistic understanding of the disorder

OBJECTIVE: Little is known about the relevance of lesion in neural circuits reported to be associated with major depressive disorder. We investigated the association between lesion stroke size in the limbic-cortical-striatal-pallidal-thalamic (LCSPT) circuit and incidence of major depressive episode (MDE). METHODS: We enrolled 68 patients with first-ever ischemic stroke and no history of major depressive disorder. Neurological and psychiatric examinations were performed at three time-points. We diagnosed major depressive episode, following DSM-IV criteria. Lesion location and volume were determined with magnetic resonance imaging, using a semi-automated method based on the Brodmann Cytoarchitectonic Atlas. RESULTS: Twenty-one patients (31%) experienced major depressive episode. Larger lesions in the left cortical regions of the LCSPT circuit (3,760 vs. 660 mm3; P = 0.004) were associated with higher incidence of MDE. Secondary analyses revealed that major depressive episode was associated with larger lesions in areas of the medial prefrontal cortex including the ventral (BA24) and dorsal anterior cingulate cortex (BA32) and subgenual cortex (BA25); and also the subiculum (BA28/36) and amygdala (BA34). CONCLUSIONS: Our findings indicate that depression due to stroke is aetiologically related to the disruption of the left LCSPT circuit and support the relevance of the medial prefrontal cortex dysfunction in the pathophysiology of depression.

Recent meta-analyses point to the relatively low efficacy of commonly used antidepressant medications. Selecting the most effective medications for depressed subjects having failed previous treatments is especially difficult. There is a clear need for objective biomarkers that could assist and optimize such treatment selection. We will review here a growing body of evidence suggesting that several electroencephalography (EEG)-based methods may be useful for predicting antidepressant response and eventually for guiding clinical treatment decisions. While most of these methods are based on resting-state EEGs (e.g., alpha- and theta-band EEG abnormalities, the combined Antidepressant Response Index (ATR), cordance, referenced EEG), others include EEG source localization and evoked potentials. The limitations of these technologies and the potential clinical uses will also be outlined.

OBJECTIVE: Patients with major depressive disorder (MDD) and significant anxiety are less responsive to antidepressants than those without anxiety. In this post hoc analysis of patients with insomnia and comorbid anxious depression, eszopiclone cotherapy with a selective serotonin reuptake inhibitor (SSRI) was compared with placebo cotherapy. METHOD: Data were pooled from 2 randomized, double-blind, 8-week trials. One trial (conducted from January 2004 to October 2004) included patients with DSM-IV insomnia and comorbid MDD treated with fluoxetine concurrently with eszopiclone 3 mg/d or placebo. The other trial (conducted from July 2005 to April 2006) included patients with DSM-IV-TR insomnia and comorbid generalized anxiety disorder treated with escitalopram concurrently with eszopiclone 3 mg/d or placebo. Anxious depression was defined as a baseline 17-item Hamilton Depression Rating Scale (HDRS-17) score >/= 14 (excluding insomnia items) and an anxiety/somatization factor score >/= 7. Treatment group differences were determined for mean changes in HDRS-17 scores (with and without insomnia items), HDRS anxiety/somatization scores, and response and remission rates. Severity of insomnia was assessed by the Insomnia Severity Index (ISI). RESULTS: In the combined dataset, 347 of 1,136 patients (30.5%) had insomnia and comorbid anxious depression. Significant improvements in insomnia were observed for eszopiclone cotherapy relative to placebo cotherapy (mean change from baseline on the ISI: -11.0 vs -7.8, respectively; P < .001). There were greater reductions in HDRS-17 scores at week 8 following cotherapy with eszopiclone compared with placebo when the insomnia items were included (mean change: -14.1 vs -11.2, respectively; P < .01) or excluded (-10.6 vs -8.9; P < .01), but not for anxiety/somatization (-4.3 vs -4.1; P = .23). Response rates were greater for eszopiclone cotherapy than for placebo cotherapy (55.6% vs 42.0%, respectively; P = .01; 50.0% vs 44.4% when insomnia items were removed; P = .3). Remission rates were not significantly different (32.6% vs 27.2%, respectively; P = .28). CONCLUSIONS: In this post hoc analysis of patients with insomnia and comorbid anxious depression derived from 2 trials, 8 weeks of eszopiclone therapy coadministered with an SSRI resulted in significantly greater improvements in insomnia, significantly greater reductions in HDRS-17 total score, and significantly greater HDRS-17 response rates compared with placebo coadministration. There were no significant differences in response rates (when insomnia items were excluded) and remission rates, as well as in anxiety/somatization scores. Further research is warranted to determine whether these modest antidepressant effects can be replicated, and anxiolytic effects demonstrated, when evaluated in a prospective manner.

Major depressive disorder is a common illness, particularly in patients with medical and neurologic conditions. This article summarizes current data on the epidemiology, diagnosis, and treatment of major depression, with special emphasis on the diagnosis and treatment of depression in medical and neurologic patients. We reviewed the role of pharmacotherapies, psychotherapies, somatic treatments, and alternative remedies and we included practical advice for clinician regarding the timing and sequence of these treatments, the role of standardized depression scales, and the criteria for referrals to specialty consultants.

OBJECTIVE: To evaluate the efficacy of rEEG((R))-guided pharmacotherapy for the treatment of depression in those circumstances where rEEG and STAR*D provided different recommendations. MATERIALS AND METHODS: This was a randomized, single-blind, parallel group, 12 center, US study of rEEG-guided pharmacotherapy vs. the most effective treatment regimens reported in the NIH sponsored STAR*D study. Relatively treatment-resistant subjects >/=18 years who failed one or more antidepressants were required to have a QIDS-16-SR score >/=13 and a MADRS score >/=26 at baseline. All subjects underwent a washout of all current medications (with some protocol-specified exceptions) for at least five half-lives before receiving a QEEG and rEEG report. Subjects randomized to rEEG were assigned a regimen based on the rEEG report. Control subjects who had failed only SSRI's in their current episode were randomized to receive venlafaxine XR. Control subjects who had failed antidepressants from >/=2 classes of antidepressants were randomized to receive a regimen from Steps 2-4 of the STAR*D study. Treatment lasted 12 weeks. The primary outcome measures were change from baseline for self-rated QIDS-SR16 and Q-LES-Q-SF. RESULTS: A total of 114 subjects were randomized and 89 subjects were evaluable. rEEG-guided pharmacotherapy exhibited significantly greater improvement for both primary endpoints, QIDS-SR16 (-6.8 vs. -4.5, p<0.0002) and Q-LES-Q-SF (18.0 vs. 8.9, p<0.0002) compared to control, respectively, as well as statistical superiority in 9 out of 12 secondary endpoints. CONCLUSIONS: These results warrant additional studies to determine the role of rEEG-guided psychopharmacology in the treatment of depression. If these results were confirmed, rEEG-guided pharmacotherapy would represent an easy, relatively inexpensive, predictive, objective office procedure that builds upon clinical judgment to guide antidepressant medication choice.

INTRODUCTION: Personality traits have been associated with primary depression. However, it is not known whether this association takes place in the case of depression comorbid with fibromyalgia. OBJECTIVE: The authors investigated the association between a current major depressive episode and temperament traits (e.g., harm avoidance). METHOD: A sample of 69 adult female patients with fibromyalgia was assessed with the Temperament and Character Inventory. Psychiatric diagnoses were assessed with the Mini-International Neuropsychiatric Interview severity of depressive symptomatology with the Beck Depression Inventory, and anxiety symptomatology with the IDATE-state and pain intensity with a visual analog scale. RESULTS: A current major depressive episode was diagnosed in 28 (40.5%) of the patients. They presented higher levels of harm avoidance and lower levels of cooperativeness and self-directedness compared with non-depressed patients, which is consistent with the Temperament and Character Inventory profile of subjects with primary depression. However, in contrast to previous results in primary depression, no association between a major depressive episode and self-transcendence was found. CONCLUSIONS: The results highlight specific features of depression in fibromyalgia subjects and may prove important for enhancing the diagnosis and prognosis of depression in fibromyalgia patients.

BACKGROUND: A retrospective chart review was undertaken in a private clinic to examine the clinical outcomes for patients with an eating disorder comorbid with depression or bipolar illness who underwent a referenced electroencephalographic (EEG) database analysis to help guide medication selection. METHOD: We examined 33 charts for patients with the primary psychiatric diagnosis of an eating disorder and comorbid major depressive disorder or bipolar disorder who underwent a quantitative EEG database assessment to provide additional information for choices of medication. The current analysis includes data from 22 subjects who accepted treatments based on information from the referenced-EEG medication database. Hamilton Depression Rating Scale, Clinical Global Impression-Severity, Clinical Global Impression-Improvement, and hospitalization data were examined for these patients. RESULTS: Patients whose EEG data was used for clinical treatment reported significant decreases in associated depressive symptoms (HDRS scores), overall severity of illness (Clinical Global Impression-Severity), and overall clinical global improvement (Clinical Global Impression- Improvement). This cohort also reported fewer inpatient, residential, and partial hospitalization program days following referenced-EEG compared with the two-year period prior to treatment. CONCLUSION: These findings are consistent with previously reported data for patients with eating disorders and suggest the need for future studies using EEG data correlated with those from other patients with similar quantitative EEG features.

There has been a rapid increase in the use of polypharmacy in psychiatry possibly due to the introduction of newer drugs, greater availability of these newer drugs, excessive confidence in clinical trial results, widespread prescribing of psychotropic medications by primary care, and pressure to augment with additional medications for unresolved side effects or greater efficacy. Even the new generation of medications may not hold significant advantages over older drugs. In fact, there may be additional safety risks with polypharmacy being so widespread. Washout, as a clinical tool, is rarely done in medication management today. Studies have shown that augmenting therapy with additional medications resulted in 9.1%-34.1% dropouts due to intolerance of the augmentation, whereas studies of medication washout demonstrated only 5.9%-7.8% intolerance to the washout procedure. These perils justify reconsideration of medication washout before deciding on augmentation. There are unwarranted fears and resistance in the medical community toward medication washout, especially at the moment a physician is trying to decide whether to washout or add more medications to the treatment regimen. However, medication washout provides unique benefits to the physician: it establishes a new baseline of the disorder, helps identify medication efficacy from their adverse effects, and provides clarity of diagnosis and potential reduction of drug treatments, drug interactions, and costs. It may also reduce overall adverse events, not to mention a potential to reduce liability. After washout, physicians may be able to select the appropriate polypharmacy more effectively and safely, if necessary. Washout, while not for every patient, may be an effective tool for physicians who need to decide on whether to add potentially risky polypharmacy for a given patient. The risks of washout may, in some cases, be lower and the benefits may be clearly helpful for diagnosis, understanding medication effects, the doctor/patient relationship, and safer use of polypharmacy if indicated.