Faculty Bibliography

OBJECTIVES: The aims of this study were to evaluate correlates and predictors of life functioning and quality of life in bipolar disorder during a comparative effectiveness trial of moderate doses of lithium. METHODS: In the Lithium treatment moderate-dose use study (LiTMUS), 283 symptomatic outpatients with bipolar disorder type I or II were randomized to receive lithium plus "optimal personalized treatment (OPT)", or OPT alone. Participants were assessed using structured diagnostic interviews, clinician-rated blinded assessments, and questionnaires. We employ linear mixed effects models to test the effect of treatment overall and adjunct lithium specifically on quality of life or functioning. Similar models are used to examine the association of baseline demographics and clinical features with quality of life and life functioning. RESULTS: Quality of life and impaired functioning at baseline were associated with lower income, higher depressive severity, and more psychiatric comorbid conditions. Over 6 months, patients in both treatment groups improved in quality of life and life functioning (p-Values<0.0001); without a statistically significant difference between the two treatment groups (p-Values>0.05). Within the lithium group, improvement in quality of life and functioning was not associated with concurrent lithium levels at week 12 or week 24 (p-Values>0.05). Lower baseline depressive severity and younger age of onset predicted less improvement in functioning over 6 months. CONCLUSIONS: Optimized care for bipolar disorder improves overall quality of life and life functioning, with no additional benefit from adjunct moderate doses of lithium. Illness burden and psychosocial stressors were associated with worse quality of life and lower functioning in individuals with bipolar disorder.

BACKGROUND: While antidepressant treatment response appears to be partially heritable, no consistent genetic associations have been identified. Large, rare copy number variants (CNVs) play a role in other neuropsychiatric diseases, so we assessed their association with treatment-resistant depression (TRD). METHODS: We analyzed data from two genome-wide association studies comprising 1263 Caucasian patients with major depressive disorder. One was drawn from a large health system by applying natural language processing to electronic health records (i2b2 cohort). The second consisted of a multicenter study of sequential antidepressant treatments, Sequenced Treatment Alternatives to Relieve Depression. The Birdsuite package was used to identify rare deletions and duplications. Individuals without symptomatic remission, despite two antidepressant treatment trials, were contrasted with those who remitted with a first treatment trial. RESULTS: CNV data were derived for 778 subjects in the i2b2 cohort, including 300 subjects (37%) with TRD, and 485 subjects in Sequenced Treatment Alternatives to Relieve Depression cohort, including 152 (31%) with TRD. CNV burden analyses identified modest enrichment of duplications in cases (empirical p = .04 for duplications of 100-200 kilobase) and a particular deletion region spanning gene PABPC4L (empirical p = .02, 6 cases: 0 controls). Pathway analysis suggested enrichment of CNVs intersecting genes regulating actin cytoskeleton. However, none of these associations survived genome-wide correction. CONCLUSIONS: Contribution of rare CNVs to TRD appears to be modest, individually or in aggregate. The electronic health record-based methodology demonstrated here should facilitate collection of larger TRD cohorts necessary to further characterize these effects.

Individuals with posttraumatic stress disorder (PTSD) experience cognitive impairments and disability in everyday activities. In other neuropsychiatric disorders, impairments in cognition and functional capacity (i.e., the ability to perform everyday tasks) are associated with impairments in real-world functioning, independent of symptom severity. To date, no studies of functional capacity have been conducted in PTSD. Seventy-three women with moderate to severe PTSD underwent assessment with measures of cognition (MATRICS Consensus Cognitive Battery: MCCB), functional capacity (UCSD Performance-Based Skills Assessment-Brief: UPSA-B), PTSD (Clinician-Administered PTSD Scale and PTSD Symptom Scale-Self-report (PSS-SR)), and depression (Montgomery Asberg Depression Rating Scale). Patients also reported their subjective level of disability (Sheehan Disability Scale). Over-reporting of symptom severity was assessed using six validity items embedded within the PSS-SR. Results indicated that on average PTSD patients manifested mild impairments on the functional capacity measure, performing about 1/3 standard deviation below healthy norms, and similar performance on the MCCB. Both clinician-rated and self-rated PTSD symptom severity correlated with self-reported disability but not with functional capacity. Self-reported disability did not correlate with functional capacity or cognition. Greater self-reported disability, depression, and PTSD symptoms all correlated with higher scores on the PSS-SR validity scale. The divergence between objective and subjective measures of disability suggests that individuals' distress, as indexed by symptom validity measures, may be impacting self-reports of disability. Future studies of disability should incorporate objective measures in order to obtain a broad perspective on functioning.

BACKGROUND: There is an urgent need for more effective treatments for major depressive disorder (MDD). As understanding of the cognitive and affective neuroscience underlying psychiatric disorders expands, so do opportunities to develop interventions that capitalize on the capacity for brain plasticity. Cognitive training is one such strategy. In this article, we report a proof-of-concept study of a novel cognitive-emotional training exercise designed to enhance cognitive control for emotional information processing and targeting components of the neural networks that have been implicated in MDD. METHODS: Twenty-one participants with MDD in a current episode were randomly assigned to one of the two treatment conditions: 11 participating in a cognitive-emotional training paradigm (emotional faces memory task (EFMT)) involving eight sessions over 4 weeks, and 10 participating in an active control condition (control training, CT). Assessments of MDD symptoms, negative affective bias in cognitive processing, and neurocognition (attention and working memory) were administered at baseline and after 4 weeks. RESULTS: Participants in the EFMT group exhibited a greater reduction in MDD symptoms compared to the CT group, and 6 of the 11 EFMT participants achieved clinical response (>/= 50% reduction in symptoms). EFMT participants also exhibited changes in negative affective bias in the hypothesized direction whereas the CT participants did not. Both groups exhibited similar, small improvements in attention and working memory. CONCLUSIONS: Cognitive-emotional training may represent a feasible and effective intervention strategy for MDD. This proof-of-concept study highlights the need for future studies to fully understand the effectiveness, and mechanisms of effect, of these training strategies.