Faculty Bibliography

OBJECTIVE: We examined the relationship between mood symptoms and episodes in patients with bipolar disorder and burden reported by their primary caregivers. METHOD: Data on subjective and objective burden reported by 500 primary caregivers for 500 patients with bipolar disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were collected using semistructured interviews. Patient data were collected prospectively over 1 year. The relationship between patient course and subsequent caregiver burden was examined. RESULTS: Episodes of patient depression, but not mood elevation, were associated with greater objective and subjective caregiver burden. Burden was associated with fewer patient days well over the previous year. Patient depression was associated with caregiver burden even after controlling for days well. CONCLUSION: Patient depression, after accounting for chronicity of symptoms, independently predicts caregiver burden. This study underscores the important impact of bipolar depression on those most closely involved with those whom it affects.

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: 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.

Selecting the most effective antidepressant for depressed subjects having failed previous treatments is difficult; the rates of success are relatively low. There is a clear need for objective biomarkers which could assist and optimize such treatment selection. We review here the current literature and recent developments on the role of quantitative EEG (QEEG) predictors of treatment outcome in major depressive disorder.

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.

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.

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.

Distinct factors have been identified as potential predictors of antidepressant treatment response. Although autonomic function changes have been described in depressive subjects, their value as predictors of antidepressant response has not been systematically evaluated. Eight un-medicated patients with major depressive order (MDD) have their skin conductance (SC) and heart rate variability (HRV) measured at basal condition and during four induced emotional states: happy, angry, sad and neutral. The high frequency (HF) and low frequency (LF) power parameters of HRV were assessed. Subsequently, patients were treated with fluoxetine 20 mg/day for 8 weeks. The antidepressant response was measured with the Beck Depression Inventory (BDI). The BDI percentage reduction correlated significantly with HRV responses during sad condition in LF power, and during happy condition with LF/HF ratio. The BDI percentage reduction also correlated significantly with HR responses in happy and in neutral conditions, and also with SC responses in neutral condition. These preliminary findings indicate that automatic responses to induced emotions may predict antidepressant response in MDD patients. Confirmatory studies are warranted.