Faculty Bibliography

OBJECTIVE: We investigated frontal quantitative EEG (QEEG) as predictor of changes in suicidal ideation (SI) during SSRI treatment in major depressive disorder (MDD). METHOD: Eighty-two subjects meeting DSM-IV criteria for MDD entered an 8-week, prospective, open-label treatment with flexible dose SSRIs and completed at least 4 weeks of treatment. We assessed MDD severity with the 17-item Hamilton Depression Rating Scale (HAM-D-17); change in SI was measured with HAM-D item no. 3. We recorded four-channel EEGs (F7-Fpz, F8-Fpz, A1-Fpz, A2-Fpz) before treatment. RESULTS: During the first 4 weeks of treatment 9 (11%) subjects experienced worsening SI. Left-right asymmetry of combined theta + alpha power correlated significantly with change in SI from baseline, even when adjusting for changes in depression severity (HAM-D-17) and for the SSRI utilized. CONCLUSION: Frontal QEEG parameters before treatment may predict worsening SI during SSRI treatment in MDD.

BACKGROUND: Bipolar disorder (BPD) features cycling mood states ranging from depression to mania with intermittent phases of euthymia. Bipolar disorder subjects often show excessive goal-directed and pleasure-seeking behavior during manic episodes and reduced hedonic capacity during depressive episodes, indicating that BPD might involve altered reward processing. Our goal was to test the hypothesis that BPD is characterized by impairments in adjusting behavior as a function of prior reinforcement history, particularly in the presence of residual anhedonic symptoms. METHODS: Eighteen medicated BPD subjects and 25 demographically matched comparison subjects performed a probabilistic reward task. To identify putative dysfunctions in reward processing irrespective of mood state, primary analyses focused on euthymic BPD subjects (n = 13). With signal-detection methodologies, response bias toward a more frequently rewarded stimulus was used to objectively assess the participants' propensity to modulate behavior as a function of reinforcement history. RESULTS: Relative to comparison subjects, euthymic BPD subjects showed a reduced and delayed acquisition of response bias toward the more frequently rewarded stimulus, which was partially due to increased sensitivity to single rewards of the disadvantageous stimulus. Analyses considering the entire BPD sample revealed that reduced reward learning correlated with self-reported anhedonic symptoms, even after adjusting for residual manic and anxious symptoms and general distress. CONCLUSIONS: The present study provides preliminary evidence indicating that BPD, even during euthymic states, is characterized by dysfunctional reward learning in situations requiring integration of reinforcement information over time and thus offers initial insights about the potential source of dysfunctional reward processing in this disorder.

BACKGROUND: Low cerebral bioenergetic metabolism has been reported in subjects with major depressive disorder (MDD). Thyroid hormones have been shown to increase brain bioenergetic metabolism. We assessed whether changes in brain bioenergetics measured with phosphorus magnetic resonance spectroscopy ((31)P MRS) correlate with treatment outcome during augmentation treatment with triiodothyronine (T3) in MDD. METHODS: Nineteen subjects meeting DSM-IV criteria for MDD who had previously failed to respond to selective serotonin reuptake inhibitor (SSRI) antidepressant drugs received open label and prospective augmentation treatment with T3 for 4 weeks. We obtained (31)P MRS spectra before and after treatment from all MDD subjects and baseline (31)P MRS from nine normal control subjects matched for age and gender. RESULTS: At baseline, depressed subjects had lower intracellular Mg(2+) compared with control subjects. Seven MDD subjects (38.9%) were treatment responders (>or= 50% improvement). Total nucleoside triphosphate (NTP), which primarily represents adenosine triphosphate (ATP), increased significantly in MDD subjects responding to T3 augmentation compared with treatment nonresponders. Phosphocreatine, which has a buffer role for ATP, decreased in treatment responders compared with nonresponders. CONCLUSIONS: The antidepressant effect of thyroid hormone (T3) augmentation of SSRIs is correlated with significant changes in the brain bioenergetic metabolism. This seems to be a re-normalization of brain bioenergetics in treatment responders. Further studies will determine whether these findings can be generalized to other antidepressant treatments.

OBJECTIVE: Anhedonia, the lack of reactivity to pleasurable stimuli, is a cardinal feature of depression that has received renewed interest as a potential endophenotype of this debilitating disease. The goal of the present study was to test the hypothesis that individuals with major depression are characterized by blunted reward responsiveness, particularly when anhedonic symptoms are prominent. METHODS: A probabilistic reward task rooted within signal-detection theory was utilized to objectively assess hedonic capacity in 23 unmedicated subjects meeting DSM-IV criteria for major depressive disorder (MDD) and 25 matched control subjects recruited from the community. Hedonic capacity was defined as reward responsiveness - i.e., the participants' propensity to modulate behavior as a function of reward. RESULTS: Compared to controls, MDD subjects showed significantly reduced reward responsiveness. Trial-by-trial probability analyses revealed that MDD subjects, while responsive to delivery of single rewards, were impaired at integrating reinforcement history over time and expressing a response bias toward a more frequently rewarded cue in the absence of immediate reward. This selective impairment correlated with self-reported anhedonic symptoms, even after considering anxiety symptoms and general distress. CONCLUSIONS: These findings indicate that MDD is characterized by an impaired tendency to modulate behavior as a function of prior reinforcements, and provides initial clues about which aspects of hedonic processing might be dysfunctional in depression.

The authors conducted exploratory analyses to determine whether specific symptoms of major depressive disorder (MDD) are associated with cardiac disease in 4,041 outpatients at baseline in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. MDD was diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; depressive symptoms were evaluated with the 30-item Inventory of Depressive Symptomatology, Clinician-Rated; and cardiac disease, with the Cumulative Illness Rating Scale. After adjustments for gender, age, ethnicity, education, and employment status, sympathetic arousal and early-morning insomnia were significantly associated with cardiac disease. Prospective studies are warranted to confirm these results.

OBJECTIVE: Depression and anger have been separately associated with cardiovascular risk factors. We investigated if major depressive disorder (MDD) with concomitant anger attacks was associated with cardiovascular risk factors. METHOD: We measured total serum cholesterol, glycemia, resting blood pressure, and smoking parameters in 333 (52.9% women) MDD nonpsychotic outpatients, mean age of 39.4 years. MDD was diagnosed with the Structured Clinical Interview (SCID) in accordance with the Diagnostic and Statistic Manual of Mental Disorders, Third Edition, Revised (DSM-III-R). The presence of anger attacks was established with the Massachusetts General Hospital Anger Attacks Questionnaire. RESULTS: In a logistic regression analysis, anger attacks were independently associated with cholesterol levels > or = 200 mg/dL (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.18-3.94) and years of smoking > 11 (OR, 2.59; 95% CI, 1.32-5.04). CONCLUSIONS: MDD with anger attacks was significantly associated with increased cholesterol levels and years of smoking.

The authors evaluated levels of inflammatory markers in 34 chronic heart failure (CHF) out-patients age 65 years and over, with (N=18) and without (N=16) major depressive disorder (MDD), and healthy-control subjects (N=13). Patients with CHF had left-ventricular ejection fractions <0.40 and were in the New York Heart Association functional class II or III. The authors used the SCID DSM-IV to diagnosis MDD. High-sensitivity C-reactive protein levels were significantly higher in patients with CHF and MDD as compared with healthy-control subjects. No differences regarding tumor necrosis factor(alpha) or interleukin(6) were found among the three groups.

AIM AND METHODS: The impact of medical comorbidity on the efficacy and tolerability of duloxetine in elderly patients with major depressive disorder (MDD) was investigated in this study. Data were obtained from a multicentre, randomised, double-blind, placebo-controlled study in 311 patients with MDD aged 65-89. The primary outcome measure was a prespecified composite cognitive score based on four cognitive tests: (i) Verbal Learning and Recall Test; (ii) Symbol Digit Substitution Test; (iii) 2-Digit Cancellation Test and (iv) Letter-Number Sequencing Test. Secondary measures included the Geriatric Depression Scale (GDS), 17-Item Hamilton Depression Scale (HAMD17), Clinical Global Impression-Severity (CGI-S) Scale, Visual Analogue Scale (VAS) for pain and 36-Item Short Form Health Survey (SF-36). Tolerability measures included adverse events reported as the reason for discontinuation and treatment-emergent adverse events (TEAEs). The consistency of the effect of duloxetine vs. placebo comparing patients with and without medical comorbidity (vascular disease, diabetes, arthritis or any of these) was investigated. RESULTS: Overall, duloxetine 60 mg/day demonstrated significantly greater improvement compared with placebo for the composite cognitive score, GDS and HAMD17 total scores, CGI-Severity, HAMD17 response and remission rates, and some of the SF-36 and VAS measures. There were few significant treatment-by-comorbidity subgroup interactions for these efficacy variables, or for adverse events reported as the reason for discontinuation and common TEAEs. CONCLUSIONS: The present analyses suggested that the efficacy of duloxetine on cognition and depression in elderly patients, and its tolerability, were not largely affected by the comorbidity status. These results further support the use of duloxetine in elderly patients with MDD.

Depression frequently is comorbid with a variety of medical illnesses; individuals who have such comorbidities may have increased morbidity and lower functional status. Usual antidepressant treatments can be effective in depressed patients who have comorbid medical illness. These patients, however, experience lower rates of recovery and remission of depressive symptoms and higher rates of relapse during follow-up than seen in patients who have MDD with no medical comorbidity. Comorbid medical illness therefore is a marker of treatment resistance in MDD. Collaborative treatments combining antidepressants, psychotherapy, education, and case management may be effective and could overcome the risk of treatment resistance. Two clinical strategies seem warranted in light of the studies presented here: (1) an increased index of suspicion for depression in medically ill patients, and (2) more intensive antidepressant treatment in depressed patients who have medical comorbidity.