Faculty Bibliography

BACKGROUND: Electronic medical records (EMR) provide a unique opportunity for efficient, large-scale clinical investigation in psychiatry. However, such studies will require development of tools to define treatment outcome. METHOD: Natural language processing (NLP) was applied to classify notes from 127 504 patients with a billing diagnosis of major depressive disorder, drawn from out-patient psychiatry practices affiliated with multiple, large New England hospitals. Classifications were compared with results using billing data (ICD-9 codes) alone and to a clinical gold standard based on chart review by a panel of senior clinicians. These cross-sectional classifications were then used to define longitudinal treatment outcomes, which were compared with a clinician-rated gold standard. RESULTS: Models incorporating NLP were superior to those relying on billing data alone for classifying current mood state (area under receiver operating characteristic curve of 0.85-0.88 v. 0.54-0.55). When these cross-sectional visits were integrated to define longitudinal outcomes and incorporate treatment data, 15% of the cohort remitted with a single antidepressant treatment, while 13% were identified as failing to remit despite at least two antidepressant trials. Non-remitting patients were more likely to be non-Caucasian (p<0.001). CONCLUSIONS: The application of bioinformatics tools such as NLP should enable accurate and efficient determination of longitudinal outcomes, enabling existing EMR data to be applied to clinical research, including biomarker investigations. Continued development will be required to better address moderators of outcome such as adherence and co-morbidity.

OBJECTIVE: To examine the association between exposure to newer antidepressants and risk of gastrointestinal (GI) and other bleeding complications among individuals with major depressive disorder (MDD). DESIGN: This study uses an incident user cohort design to compare associations between incidence of vascular/bleeding events and the relative affinity (low, moderate or high) of the antidepressant for the serotonin transporter during an exposure risk period for each patient. SETTING: New England healthcare system electronic medical record database. PARTICIPANTS: 36 389 individuals with a diagnosis of MDD and monotherapy with a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor or other new-generation antidepressant were identified from among 3.1 million patients in a New England healthcare system. PRIMARY AND SECONDARY OUTCOME MEASURES: Rates of bleeding or other vascular complications, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures. RESULTS: 601 GI bleeds were observed in the 21 462 subjects in the high-affinity group versus 333 among the 14 927 subjects in the lower affinity group (adjusted RR: 1.17, 95% CI 1.02 to 1.34). Similarly, 776 strokes were observed in the high-affinity group versus 434 in the lower affinity treatment group (adjusted RR: 1.18, 95% CI 1.06 to 1.32). No significant association with risk for a priori negative control outcomes, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures, was identified. CONCLUSIONS: Use of antidepressants with high affinity for the serotonin transporter may confer modestly elevated risk for GI and other bleeding complications. While multiple methodologic limitations must be considered, these results suggest that antidepressants with lower serotonin receptor affinity may be preferred in patients at greater risk for such complications.

We previously reported on an objective new tool that uses quantitative electroencephalography (QEEG) normative- and referenced-electroencephalography sampling databases (currently called Psychiatric EEG Evaluation Registry [PEER]), which may assist physicians in determining medication selection for optimal efficacy to overcome trial-and-error prescribing. The PEER test compares drug-free QEEG features for individual patients to a database of patients with similar EEG patterns and known outcomes after pharmacological interventions. Based on specific EEG data elements and historical outcomes, the PEER Report may also serve as a marker of future severe adverse events (eg, agitation, hostility, aggressiveness, suicidality, homicidality, mania, hypomania) with specific medications. We used a retrospective chart review to investigate the clinical utility of such a registry in a naturalistic environment. RESULTS: This chart review demonstrated significant improvement on the global assessment scales Clinical Global Impression - Improvement and Quality of Life Enjoyment and Satisfaction - Short Form as well as time to maximum medical improvement and decreased suicidality occurrences. The review also showed that 54.5% of previous medications causing a severe adverse event would have been raised as a caution had the PEER Report been available at the time the drug was prescribed. Finally, due to the significant amount of off-label prescribing of psychotropic medications, additional, objective, evidence-based data aided the prescriber toward better choices. CONCLUSION: The PEER Report may be useful, particularly in treatment-resistant patients, in helping to guide medication selection. Based on the preliminary data obtained from this chart review, additional studies are warranted to establish the safety and efficacy of adding PEER data when making medication decisions.

Impairments in cognitive performance and inability to function in everyday life situations are present, in various degrees, in many severe mental illnesses, including major depressive disorder, bipolar disorder, and schizophrenia. Persistent mood symptoms (e.g., depression and mania) are associated with functional deficits in major depression and bipolar disorder, but also in conditions where mood symptoms are not the primary markers of the illness, such as in schizophrenia. While mood symptoms impact cognitive performance, both mood symptoms and cognitive deficits have a significant - and to some extent independent - impact on psychosocial functioning in psychiatric patients. Improved control of mood symptoms may represent an important strategy leading to improved functional outcomes. However, cognitive impairment may be an important independent dimension of many psychiatric disorders and such symptoms should also be considered a potential target of treatments aiming to reduce functional deficits.

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.