Faculty Bibliography

Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus ((31)P) MRS. (31)P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21-84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (-0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using (31)P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non-demented and psychiatrically stable older adults and specifically analyzed gray-white matter differences in brain metabolism.

BACKGROUND: Recent data indicate that lithium use for bipolar disorder has declined over the last decade and that lithium largely has been replaced with alternate, commercially promoted medications that may or may not result in better outcomes. PURPOSE: This article describes the rationale and study design of LiTMUS, a multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. LiTMUS seeks to address whether initiating therapy at lower doses of lithium as part of optimized treatment (OPT, guideline-informed, evidence-based, and personalized pharmacotherapy) improves outcomes and decreases the need for other medication changes across 6 months of therapy. METHODS: LiTMUS will randomize 284 adults with bipolar disorder (Type I or II) across 6 study sites. The co-primary outcomes are overall illness severity on clinical global improvement scale for bipolar disorder and a novel measure, necessary clinical adjustments. This metric provides a composite that reflects both clinical response and tolerability. Other relevant outcomes include full symptomatic recovery, quality of life, suicidal behaviors, and moderators of suicidality. RESULTS: As of August 28th, 2009, we have consented 338 patients and randomized 281 for this study. LIMITATIONS: The potential limitations of the study include an arbitrary definition of 'low, but effective' doses of lithium, lack of a placebo-controlled group, open treatment, and use of a new outcome measure (i.e., necessary clinical adjustments). CONCLUSION: We expect that this study will inform our understanding of the effectiveness of low to moderate doses of lithium therapy for individuals with bipolar disorder.

OBJECTIVE: To investigate the role of frontal EEG as predictor of clinical response to SSRIs or venlafaxine in major depressive disorder (MDD). METHOD: 82 subjects (age 35.9+/-13.0; 47.6% female) meeting DSM-IV criteria for MDD entered an 8-week prospective treatment with SSRIs or venlafaxine. At baseline and week 1 we recorded serial, 4-channel EEGs (F7-Fpz, F8-Fpz, A1-Fpz, A2-Fpz). We evaluated prospectively the relative theta power as predictor of treatment outcome. We also developed an Antidepressant Treatment Response (ATR) index using EEG parameters assessed at baseline and week 1. RESULTS: 45 subjects (54.9%) responded to treatment (HAM-D-17 reduction>or=50%). At baseline, frontal relative theta power (i.e., 4-8 Hz power/2-20 Hz power) was significantly (p=0.017) lower (21%) in treatment responders than in non-responders (24%). Baseline relative theta power predicted treatment response with 63% accuracy [64% sensitivity, 62% specificity, 66% area under the receiver operator curve (AUROC) (p=0.014)]. Relative theta power at week 1 predicted treatment response with 60% accuracy [62% sensitivity, 57% specificity, 61% AUROC (p=0.089)]. ATR predicted response with 70% accuracy [82% sensitivity, 54% specificity, 72% AUROC (p=0.001)]. CONCLUSION: Using automated analysis of frontal EEG collected during the first week of antidepressant treatment it may be possible to facilitate prediction of SSRI or venlafaxine efficacy in MDD.

We examined the Antidepressant Treatment Response (ATR) index as a predictor of differential response and remission to escitalopram, bupropion, or a combination of the two medications, in subjects with major depressive disorder (MDD). Three hundred seventy-five subjects had a baseline quantitative electroencephalographic (QEEG) study preceding 1 week of treatment with escitalopram, 10 mg, after which a second QEEG was performed and the ATR index was calculated. Subjects then were randomized to continue escitalopram, switch to bupropion, or receive a combination of the two. Clinical response was assessed using the 17-item Hamilton Depression Rating Scale at 49 days of treatment. Accuracy of ATR in predicting response and remission was calculated. There were no significant differences between response and remission rates in the three treatment groups. A single ATR threshold was useful for predicting differential response to either escitalopram or bupropion monotherapy. Subjects with ATR values above the threshold were more than 2.4 times as likely to respond to escitalopram as those with low ATR values (68% vs. 28%). Subjects with ATR values below the threshold who were switched to bupropion treatment were 1.9 times as likely to respond to bupropion alone as those who remained on escitalopram treatment (53% vs. 28%). The ATR index did not provide a useful prediction of response to combination treatment. The ATR index may prove useful in predicting responsiveness to different antidepressant medications.

Patients with Major Depressive Disorder (MDD) may not respond to antidepressants for 8 weeks or longer. A biomarker that predicted treatment effectiveness after only 1 week could be clinically useful. We examined a frontal quantitative electroencephalographic (QEEG) biomarker, the Antidepressant Treatment Response (ATR) index, as a predictor of response to escitalopram, and compared ATR with other putative predictors. Three hundred seventy-five subjects meeting DSM-IV criteria for MDD had a baseline QEEG study. After 1 week of treatment with escitalopram, 10 mg, a second QEEG was performed, and the ATR was calculated. Subjects then were randomly assigned to continue with escitalopram, 10 mg, or change to alternative treatments. Seventy-three evaluable subjects received escitalopram for a total of 49days. Response and remission rates were 52.1% and 38.4%, respectively. The ATR predicted both response and remission with 74% accuracy. Neither serum drug levels nor 5HTTLPR and 5HT2a genetic polymorphisms were significant predictors. Responders had larger decreases in Hamilton Depression Rating Scale (Ham-D(17)) scores at day 7 (P=0.005), but remitters did not. Clinician prediction based upon global impression of improvement at day 7 did not predict outcome. Logistic regression showed that the ATR and early Ham-D(17) changes were additive predictors of response, but the ATR was the only significant predictor of remission. Future studies should replicate these results prior to clinical use.

OBJECTIVE: Post-stroke major depressive episode is very frequent, but underdiagnosed. Researchers have investigated major depressive episode symptomatology, which may increase its detection. This study was developed to identify the depressive symptoms that better differentiate post-stroke patients with major depressive episode from those without major depressive episode. METHOD: We screened 260 consecutive ischemic stroke patients admitted to the neurology clinic of a university hospital. Seventy-three patients were eligible and prospectively evaluated. We assessed the diagnosis of major depressive episode using the Structured Clinical Interview for DSM-IV and the profile of depressive symptoms using the 31-item version of the Hamilton Depression Rating Scale. For data analysis we used cluster analyses and logistic regression equations. RESULTS: Twenty-one (28.8%) patients had a major depressive episode. The odds ratio of being diagnosed with major depressive episode was 3.86; (95% CI, 1.23-12.04) for an increase of one unit in the cluster composed by the domains of fatigue/interest and retardation, and 2.39 (95% CI, 1.21-4.71) for an increase of one unit in the cluster composed by the domains of cognitive, accessory and anxiety symptoms. The domains of eating/weight and insomnia did not contribute for the major depressive episode diagnosis. CONCLUSION: The domains of retardation and interest/fatigue are the most relevant for the diagnosis of major depressive episode after stroke.

OBJECTIVE: Major depressive disorder is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional MRI (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that individuals with major depression would show reduced reward-related responses in basal ganglia structures. METHOD: A monetary incentive delay task was presented to 30 unmedicated individuals with major depressive disorder and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes. RESULTS: Relative to comparison subjects, participants with major depression showed significantly weaker responses to gains in the left nucleus accumbens and the caudate bilaterally. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in the major depression group emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although participants with major depression showed reduced activation to reward cues in a small sector of the left posterior putamen. In the major depression group, anhedonic symptoms and depression severity were associated with reduced caudate volume bilaterally. CONCLUSIONS: These results suggest that basal ganglia dysfunction in major depression may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in major depression is related to caudate volume.

BACKGROUND: Little is known about the treatment of depression in older patients with heart failure. This study was developed to investigate the effectiveness of antidepressant treatment for major depressive disorder (MDD) in the elderly with heart failure. METHODS: We enrolled 72 older outpatients with ejection fraction <50 and diagnosed with MDD by the structured clinical interview for DSM-IV. Thirty-seven patients, 19 on citalopram and 18 on placebo, initiated an 8-week double-blind treatment phase. Measurements were performed with the 31-item Hamilton Rating Scale for Depression (Ham-D-31), the Montgomery-Asberg rating scale (MADRS) and the Systematic Assessment for Treatment Emergent Effects (SAFTEE). A psychiatrist followed up the patients weekly, performing a consultation for about 20 min to field complaints after the measurements. RESULTS: A trend toward superiority of citalopram over placebo in reducing depression was observed in MADRS scores (15.05+9.74 vs 9.44+9.25, P=.082) but not on HAM-D scores. The depressive symptomatology significantly decreased in both groups (P < .001). The high rate of placebo response during the double-blind phase (56.3%) led us to conclude the study at the interim analysis with 37 patients. CONCLUSION: Citalopram treatment of MDD in older patients with heart failure is well-tolerated with low rates of side effects, but was not significantly more effective than placebo in the treatment of depression. Weekly psychiatric follow-up including counseling may contribute to the improvement of depression in this population. Scales weighted on psychological symptoms such as the MADRS are possibly better suited to measure depression severity and improvement in patients with heart failure.

Objective: To investigate the presence of psychiatric disorders in patients with chest pain not responsive to treatment. Method: We evaluated 18 patients judged by their physicians to have a chest pain not responsive to usual treatment, which included anti-pain medicines and investigation and treatment of possible etiological causes such as coronary artery disease, and gastroesophageal reflux disease. A psychiatrist interviewed the patients using the Present State Examination and made the diagnosis based on the DSM-III-R criteria. Current major depression was diagnosed in 6 (30%) patients, somatization in 1 (6%) and panic disorder in 1 (6%) patient. Seven patients were receiving tricyclics antidepressant with doses &gt;= 75 mg/day. Discussion: Patients were receiving doses of tricyclics antidepressants efficacious for pain but not for major depression. It is possible that the low dose of antidepressants used to treat pain may partially ameliorate depressive symptoms, making the appropriate diagnosis and treatment of major depression even more difficult, consequently contributing to the persistence of pain and other complains. Considering the wide alternatives to effectively treat depression, a focus on detection and treatment of major depression in patients with chest pain is warranted by clinicians and researchers.