Faculty Bibliography

OBJECTIVES: Few prospective studies examine the impact of ethnicity or race on outcomes with lithium for bipolar disorder. This exploratory study examines differences in lithium response and treatment outcomes in Hispanics, African Americans, and non-Hispanic whites with bipolar disorder in the Lithium Treatment Moderate Dose Use Study (LiTMUS). METHODS: LiTMUS was a six-site randomized controlled trial of low-dose lithium added to optimized treatment (OPT; personalized, evidence-based pharmacotherapy) vs. OPT alone in outpatients with bipolar disorder. Of 283 participants, 47 African Americans, 39 Hispanics, and 175 non-Hispanic whites were examined. We predicted minority groups would have more negative medication attitudes and higher attrition rates, but better clinical outcomes. RESULTS: African Americans in the lithium group improved more on depression and life functioning compared to whites over the 6 month study. African Americans in the OPT only group had marginal improvement on depression symptoms. For Hispanics, satisfaction with life did not significantly improve in the OPT only group, in contrast to whites and African Americans who improved over time on all measures. Attitudes toward medications did not differ across ethnic/racial groups. CONCLUSIONS: African Americans show some greater improvements with lithium than non-Hispanic whites, and Hispanics showed more consistent improvements in the lithium group. The impact of low-dose lithium should be studied in a larger sample as there may be particular benefit for African Americans and Hispanics. Given that the control group (regardless of ethnicity/race) had significant improvements, optimized treatment may be beneficial for any ethnic group.

BACKGROUND: Anhedonia represents a core symptom of major depression and may be a potential marker for melancholia. However, current understanding of this construct in depressive sub-types is limited. METHOD: Participants were recruited from the Black Dog Institute (Sydney) and Massachusetts General Hospital (Boston). Diagnostic groups were derived on the basis of agreement between clinician and DSM-IV diagnosis from structured interviews. Currently depressed unipolar melancholic, non-melancholic and healthy control participants were administered a probabilistic reward task (PRT) to assess a behavioural correlate of anhedonia-blunted reward-based learning. Self-reported measures of anhedonia, approach and avoidance motivation were completed by the Sydney sample. RESULTS: Relative to healthy controls and non-melancholic participants, melancholic depressed participants had reduced response bias, highlighting blunted reward learning. Moreover, although non-melancholic participants were characterized by a delayed response bias, melancholic depressed participants failed to develop a bias throughout blocks. Response bias showed no associations with self-report measures of hedonic tone in depressed participants. Positive associations were observed between response bias, approach and avoidance motivation in non-melancholic participants only. LIMITATIONS: Possible medication, fatigue and anxiety effects were not controlled; small sample sizes; inclusion criteria may have excluded those with severe melancholia and led to underestimation of group differences. CONCLUSIONS: Melancholia is characterised by a reduced ability to modulate behaviour as a function of reward, and the motivational salience of rewarding stimuli may differ across depressive sub-types. Results support the view that melancholia is a distinct sub-type. Further exploration of reward system functioning in depressive sub-types is warranted.

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24 h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions. Twenty patients with TRD free of concomitant antidepressant medication underwent fMRI at baseline and 24 h following administration of a single intravenous dose of ketamine (0.5 mg kg(-1)). Adequate data were available for 18 patients for each task. Twenty age- and sex-matched healthy volunteers were scanned at one time point for baseline comparison. Whole-brain, voxel-wise analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05. Compared with healthy volunteers, TRD patients showed reduced neural responses to positive faces within the right caudate. Following ketamine, neural responses to positive faces were selectively increased within a similar region of right caudate. Connectivity analyses showed that greater connectivity of the right caudate during positive emotion perception was associated with improvement in depression severity following ketamine. No main effect of group was observed for the sad faces task. Our results indicate that ketamine specifically enhances neural responses to positive emotion within the right caudate in depressed individuals in a pattern that appears to reverse baseline deficits and that connectivity of this region may be important for the antidepressant effects of ketamine.

OBJECTIVE: Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD. METHOD: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation. RESULTS: The overall antidepressant response rate, defined as a >/= 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information. CONCLUSIONS: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430.

OBJECTIVES: Treatment-resistant depression is a common clinical occurrence among patients with major depressive disorder (MDD), but its neurobiology is poorly understood. We used data collected as part of routine clinical care to study white matter integrity of the brain's limbic system and its association to treatment response. METHODS: Electronic medical records of multiple large New England hospitals were screened for patients with an MDD billing diagnosis, and natural language processing was subsequently applied to find those with concurrent diffusion-weighted images, but without any diagnosed brain pathology. Treatment outcome was determined by review of clinical charts. MDD patients (n = 29 non-remitters, n = 26 partial-remitters, and n = 37 full-remitters), and healthy control subjects (n = 58) were analyzed for fractional anisotropy (FA) of the fornix and cingulum bundle. RESULTS: Failure to achieve remission was associated with lower FA among MDD patients, statistically significant for the medial body of the fornix. Moreover, global and regional-selective age-related FA decline was most pronounced in patients with treatment-refractory, non-remitted depression. CONCLUSIONS: These findings suggest that specific brain microstructural white matter abnormalities underlie persistent, treatment-resistant depression. They also demonstrate the feasibility of investigating white matter integrity in psychiatric populations using legacy data.

OBJECTIVE: This study examined general medical illnesses and their association with clinical features of bipolar disorder. METHOD: Data were cross-sectional and derived from the Lithium Treatment - Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n = 264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score >/=4 and <4 respectively. RESULTS: The baseline prevalence of significant medical comorbidity was 53% (n = 139). Patients with high medical burden were more likely to present in a major depressive episode (P = .04), meet criteria for obsessive-compulsive disorder (P = .02), and experience a greater number of lifetime mood episodes (P = 0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P = .002). Sixty-nine per cent of the sample was overweight or obese as defined by body mass index (BMI), with African Americans representing the racial group with the highest proportion of stage II obesity (BMI >/=35; 31%, n = 14). CONCLUSION: The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns.

OBJECTIVE: Late-life depression has been hypothesized to have a neurodegenerative component that leads to impaired executive function and increases in subcortical white matter hyperintensities. Phosphorus magnetic resonance spectroscopy (MRS) can quantify several important phosphorus metabolites in the brain, particularly the anabolic precursors and catabolic metabolites of the constituents of cell membranes, which could be altered by neurodegenerative activity. METHODS: Ten patients with late-life major depression who were medication free at time of study and 11 aged normal comparison subjects were studied using (31)P MRS three-dimensional chemical shift imaging at 4 Tesla. Phosphatidylcholine and phosphatidylethanolamine comprise 90% of cell membranes in brain but cannot be quantified precisely with (31)P MRS. We measured phosphocholine and phosphoethanolamine, which are anabolic precursors, as well as glycerophosphocholine and glycerophosphoethanolamine, which are catabolic metabolites of phosphatidylcholine and phosphatidylethanolamine. RESULTS: In accordance with our hypotheses, glycerophosphoethanolamine was elevated in white matter of depressed subjects, suggesting enhanced breakdown of cell membranes in these subjects. Glycerophosphocholine did not show any significant difference between comparison and depressed subjects but both showed an enhancement in white matter compared with gray matter. Contrary to our hypotheses, neither phosphocholine nor phosphoethanolamine showed evidence for reduction in late-life depression. CONCLUSION: These findings support the hypothesis that neurodegenerative processes occur in white matter in patients with late-life depression more than in the normal elderly population.