Faculty Bibliography

This study was designed to identify genes whose expression in peripheral blood may serve as early markers for treatment response to lithium (Li) in patients with bipolar disorder. Although changes in peripheral blood gene-expression may not relate directly to mood symptoms, differences in treatment response at the biochemical level may underlie some of the heterogeneity in clinical response to Li. Subjects were randomized to treatment with (n=28) or without (n=32) Li. Peripheral blood gene-expression was measured before and 1 month after treatment initiation, and treatment response was assessed after 6 months. In subjects treated with Li, 62 genes were differentially regulated in treatment responders and non-responders. Of these, BCL2L1 showed the greatest difference between Li responders and non-responders. These changes were specific to Li responders (n=9), and were not seen in Li non-responders or patients treated without Li, suggesting that they may have specific roles in treatment response to Li.

BACKGROUND: Efficacy-based double-blind placebo controlled trials were conducted to establish efficacy and safety for FDA approval. Such designs allowed and encouraged the use of exclusion criteria to improve assay sensitivity and internal validity. The LiTMUS trial increased the representation of real-world individuals with bipolar disorder despite the acknowledgment that this compromises assay sensitivity. METHOD: To maximize generalizability, LiTMUS used broad inclusion and narrow exclusion criteria: participants experiencing mood symptoms of sufficient intensity (at least with a CGI-BP >/= 3) that would warrant a change in treatment, and that lithium treatment would be a reasonable therapeutic option if they were randomized to it. At baseline demographic, illness, clinical, and treatment characteristics were collected. The LiTMUS study design and baseline sociodemographic data were compared to previous efficacy studies. RESULTS: As compared to the previous bipolar disorder efficacy studies, LiTMUS participants were of similar age, gender, weight and illness severity; however LiTMUS participants were more racially and ethnically representative of the general population, had a greater number of mood episodes in the past 12 months, more Axis I/II comorbidity, a greater number of prior suicide attempts, and higher functional capacity. CONCLUSIONS: LiTMUS was a comparative effectiveness trial that had broad inclusion and minimal exclusion criteria that produced a more representative sample comprised of real-world participants. This design enables the results of the LiTMUS study to be a more representative of real world pharmacotherapuetic outcomes. LIMITATIONS: Limitations include possible selection bias, paucity of sociodemographic data in efficacy trials, and lack of a placebo.

OBJECTIVE: Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium. METHOD: The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N=283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire. RESULTS: We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms. CONCLUSION: Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.

OBJECTIVES: Motivated by genetic association data implicating L-type calcium channels in bipolar disorder liability, we sought to estimate the tolerability, safety, and efficacy of isradipine in the adjunctive treatment of bipolar depression. METHODS: A total of 12 patients with bipolar I or II depression entered this pilot, proof-of-concept eight-week investigation and 10 returned for at least one post-baseline visit. They were initiated on isradipine at 2.5 mg and titrated up to 10 mg daily, with blinded assessments of depression using the Montgomery-Asberg Depression Rating Scale (MADRS) as well as adverse effects. RESULTS: Among the 10 patients, three had bipolar II disorder; all but two reported current episode duration longer than six months. In all, four of 10 completed the study; no significant adverse events were observed, although one subject discontinued treatment per protocol because of possible hypomanic symptoms which had resolved prior to study visit. In a mixed-effects model, mean improvement in depression severity, assessed by MADRS, was 2.1 (standard error = 0.36) points/week (p < 0.001). Two of the 10 subjects remitted and four of the 10 subjects experienced 50% or greater symptomatic improvement with treatment. CONCLUSIONS: Isradipine merits further investigation for the treatment of bipolar depression. This preliminary trial illustrates the potential utility of genetic investigation in identifying psychiatric treatment targets.

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.

BACKGROUND: Preliminary evidence suggests intravenous ketamine has rapid effects on suicidal cognition, making it an attractive candidate for depressed patients at imminent risk of suicide. In the first randomized controlled trial of ketamine using an anesthetic control condition, we tested ketamine's acute effects on explicit suicidal cognition and a performance-based index of implicit suicidal cognition (Implicit Association Test; IAT) previously linked to suicidal behavior. METHOD: Symptomatic patients with treatment-resistant unipolar major depression (inadequate response to >/=3 antidepressants) were assessed using a composite index of explicit suicidal ideation (Beck Scale for Suicidal Ideation, Montgomery-Asberg Rating Scale suicide item, Quick Inventory of Depressive Symptoms suicide item) and the IAT to assess suicidality implicitly. Measures were taken at baseline and 24 hr following a single subanesthetic dose of ketamine (n = 36) or midazolam (n = 21), a psychoactive placebo agent selected for its similar, rapid anesthetic effects. Twenty four hours postinfusion, explicit suicidal cognition was significantly reduced in the ketamine but not the midazolam group. RESULTS: Fifty three percent of ketamine-treated patients scored zero on all three explicit suicide measures at 24 hr, compared with 24% of the midazolam group (chi(2) = 4.6; P = .03). Implicit associations between self- and escape-related words were reduced following ketamine (P = .01; d = .58) but not midazolam (P = .68; d = .09). Ketamine-specific decreases in explicit suicidal cognition were largest in patients with elevated suicidal cognition at baseline, and were mediated by decreases in nonsuicide-related depressive symptoms. CONCLUSIONS: Intravenous ketamine produces rapid reductions in suicidal cognition over and above active placebo. Further study is warranted to test ketamine's antisuicidal effects in higher-risk samples.

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.

BACKGROUND: The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. METHODS: In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Asberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. RESULTS: Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Asberg Depression Rating Scale score difference of 7.6 +/- 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. CONCLUSIONS: This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.

BACKGROUND: Missing data are unavoidable in most randomized controlled clinical trials, especially when measurements are taken repeatedly. If strong assumptions about the missing data are not accurate, crude statistical analyses are biased and can lead to false inferences. Furthermore, if we fail to measure all predictors of missing data, we may not be able to model the missing data process sufficiently. In longitudinal randomized trials, measuring a patient's intent to attend future study visits may help to address both of these problems. Leon et al. developed and included the Intent to Attend assessment in the Lithium Treatment - Moderate dose Use Study (LiTMUS), aiming to remove bias due to missing data from the primary study hypothesis. PURPOSE: The purpose of this study is to assess the performance of the Intent to Attend assessment with regard to its use in a sensitivity analysis of missing data. METHODS: We fit marginal models to assess whether a patient's self-rated intent predicted actual study adherence. We applied inverse probability of attrition weighting (IPAW) coupled with patient intent to assess whether there existed treatment group differences in response over time. We compared the IPAW results to those obtained using other methods. RESULTS: Patient-rated intent predicted missed study visits, even when adjusting for other predictors of missing data. On average, the hazard of retention increased by 19% for every one-point increase in intent. We also found that more severe mania, male gender, and a previously missed visit predicted subsequent absence. Although we found no difference in response between the randomized treatment groups, IPAW increased the estimated group difference over time. LIMITATIONS: LiTMUS was designed to limit missed study visits, which may have attenuated the effects of adjusting for missing data. Additionally, IPAW can be less efficient and less powerful than maximum likelihood or Bayesian estimators, given that the parametric model is well specified. CONCLUSIONS: In LiTMUS, the Intent to Attend assessment predicted missed study visits. This item was incorporated into our IPAW models and helped reduce bias due to informative missing data. This analysis should both encourage and facilitate future use of the Intent to Attend assessment along with IPAW to address missing data in a randomized trial.

BACKGROUND: Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD. METHODS/DESIGN: Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months' duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks' exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects. DISCUSSION: Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01018992.Registered 6 November 2009. First patient randomized 14 January 2010.