Faculty Bibliography
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299
Grant Report on d-Serine Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia â€
We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N-methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a "gold-standard".
PMCID:7448686
PMID: 32856005
ISSN: 2398-385x
CID: 5070252
Neural Predictors of the Antidepressant Placebo Response
The antidepressant placebo response remains a barrier to the development of novel therapies for depression, despite decades of efforts to identify and methodologically address its clinical correlates. This manuscript reviews recent neuroimaging studies that aim to identify the neural signature of antidepressant placebo response. Data captured in clinical trials have primarily focused on antidepressant efficacy or predicting antidepressant response and have reliably implicated the rostral anterior cingulate cortex (rACC) in antidepressant placebo response, but also in medication response. Imaging and electroencephalography (EEG) experiments specifically interrogating the mechanism of antidepressant placebo response, while few, suggest the reward network, including opiate neurotransmission, is also involved. Therefore, while the rACC is likely involved in the antidepressant placebo response, its observation in isolation is unlikely to prospectively distinguish antidepressant placebo from medication responders. Instead, future studies of antidepressant placebo response should probe the reward network as a whole and incorporate sophisticated computational analytical approaches.
PMID: 31635043
ISSN: 1424-8247
CID: 4147052
Photobiomodulation, photomedicine, & laser surgery. 2019:37(10):651-656.DOI: 10.1089/photob.2019.4678
Reported Side Effects, Weight and Blood Pressure, After Repeated Sessions of Transcranial Photobiomodulation
PMID: 31647774
ISSN: 2578-5478
CID: 4147642
Time to relapse after a single administration of intravenous ketamine augmentation in unipolar treatment-resistant depression
OBJECTIVE:To examine the rate and time to relapse for remitters and responders to ketamine in treatment-resistant depression (TRD). METHODS:Subjects with TRD were randomized to a single infusion of one of several doses of intravenous ketamine, or midazolam. Using Kaplan-Meier survival function, the current report examines the rate and time to relapse, defined as MADRS ≥ 22, over a period of 30 days, in subjects who achieved remission (MADRS ≤ 10) or response (≥ 50% reduction in MADRS) on day three post-infusion of intravenous ketamine 0.1, 0.5, or 1.0 mg/kg. RESULTS:Of the 60 randomized participants who received a single ketamine (0.1, 0.5, or 1.0 mg/kg) infusion, 19 (34%) met criteria for remission and 27 (48%) for response, on day 3 post-infusion. A numerical dose-response relationship was observed, with remitters/responders on ketamine 1.0 mg/kg having the lowest relapse rate, followed by ketamine 0.5 mg/kg and 0.1 mg/kg, respectively (% of remitters who relapsed by day 14: 38% with 1.0 mg/kg, 50% with 0.5 mg/kg, 100% with 0.1 mg/kg;% of responders who relapsed by day 14: 30% with 1.0 mg/kg, 50% with 0.5 mg/kg, 80% with 0.1 mg/kg). LIMITATIONS/CONCLUSIONS:The sample size was small. No MADRS measurements at day one post-infusion. The study was not powered to assess differences in relapse prevention between different doses of ketamine. CONCLUSION/CONCLUSIONS:Time to relapse after successful treatment with a single infusion of ketamine appears to follow a dose-response relationship, where higher dosage leads to increased time to relapse.
PMID: 31494365
ISSN: 1573-2517
CID: 4085792
Lithium continuation therapy following ketamine in patients with treatment resistant unipolar depression: a randomized controlled trial
The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is associated with rapid but transient antidepressant effects in patients with treatment resistant unipolar depression (TRD). Based on work suggesting that ketamine and lithium may share overlapping mechanisms of action, we tested lithium compared to placebo as a continuation strategy following ketamine in subjects with TRD. Participants who met all eligibility criteria and showed at least an initial partial response to a single intravenous infusion of ketamine 0.5 mg/kg were randomized under double-blind conditions to lithium or matching placebo before receiving an additional three infusions of ketamine. Subsequent to the ketamine treatments, participants remained on lithium or placebo during a double-blind continuation phase. The primary study outcome was depression severity as measured by the Montgomery-Åsberg Depression Rating Scale compared between the two groups at Study Day 28, which occurred ~2 weeks following the final ketamine of four infusions. Forty-seven participants with TRD were enrolled in the study and underwent an initial ketamine infusion, of whom 34 participants were deemed to have at least a partial antidepressant response and were eligible for randomization. Comparison between treatment with daily oral lithium (n = 18) or matching placebo (n = 16) at the primary outcome showed no difference in depression severity between groups (t32 = 0.11, p = 0.91, 95% CI [-7.87, 8.76]). There was no difference between lithium and placebo in continuing the acute antidepressant response to ketamine. The identification of a safe and effective strategy for preventing depression relapse following an acute course of ketamine treatment remains an important goal for future studies.
PMID: 30858518
ISSN: 1740-634x
CID: 3732992
Correlation between white blood cell count and mood-stabilising treatment response in two bipolar disorder trials
BACKGROUND:Immune system markers may predict affective disorder treatment response, but whether an overall immune system marker predicts bipolar disorder treatment effect is unclear. METHODS:Bipolar CHOICE (N = 482) and LiTMUS (N = 283) were similar comparative effectiveness trials treating patients with bipolar disorder for 24 weeks with four different treatment arms (standard-dose lithium, quetiapine, moderate-dose lithium plus optimised personalised treatment (OPT) and OPT without lithium). We performed secondary mixed effects linear regression analyses adjusted for age, gender, smoking and body mass index to investigate relationships between pre-treatment white blood cell (WBC) levels and clinical global impression scale (CGI) response. RESULTS:Compared to participants with WBC counts of 4.5-10 × 109/l, participants with WBC < 4.5 or WBC ≥ 10 showed similar improvement within each specific treatment arm and in gender-stratified analyses. CONCLUSIONS:An overall immune system marker did not predict differential treatment response to four different treatment approaches for bipolar disorder all lasting 24 weeks.
PMID: 31169098
ISSN: 1601-5215
CID: 3918002
Temporal Stability of Cognitive Functioning and Functional Capacity in Women with Posttraumatic Stress Disorder
Objective/UNASSIGNED:In addition to clinical symptoms, patients with posttraumatic stress disorder (PTSD) often experience considerable disability and may evidence minor impairments in performance on measures of cognition and functional capacity (FC). The objective of the present study was to determine if cognitive and functional skills manifest temporal stability as observed in other neuropsychiatric conditions in the presence of greater fluctuations in clinical symptoms. Method/UNASSIGNED:Assessments of cognition, FC, and clinical symptoms were conducted over two time points as part of a pre- and post-treatment assessment in a placebo-controlled clinical trial in 96 women with PTSD. The goal of these analyses was to examine the relative stability of scores and intercorrelations of measures of cognition, FC, and clinical symptoms. Results/UNASSIGNED:Cognitive and FC performance manifested considerably greater cross-temporal stability compared to clinical symptoms. FC performance did not change over time. Similar to previous findings in patients with schizophrenia and bipolar disorder measures of symptoms and self-reported disability did not correlate with measures of functional skills or cognitive performance. Conclusions/UNASSIGNED:Cognitive performance and functional capacity were temporally stable in women with PTSD. In contrast, clinical symptoms had much more cross-temporal fluctuation. Self-reported disability was correlated with current symptomatology but unrelated to objective measures of performance. Similar to other neuropsychiatric conditions, mood symptoms likely influence estimates of current level of functioning more than cognitive or functional skills.
PMID: 30124744
ISSN: 1873-5843
CID: 3254982
The Prevalence of Mitral Valve Prolapse in Panic Disorder: A Meta-Analysis
BACKGROUND:Although most studies have suggested that mitral valve prolapse (MVP) is more prevalent in patients with panic disorder (PD) than in healthy controls, there is a substantial uncertainty in the rates of MVP across studies. OBJECTIVE:To investigate, through systematic review and meta-analysis, the relative risk of MVP in patients with PD compared to controls. METHODS:Embase, Proquest, Pubmed, and Google Scholar electronic databases were searched up to September 2018. All studies published in peer-reviewed journals, which included both PD and controls groups, were selected. Events (presence of MVP) and nonevents (absence of MVP) in PD and control groups were recorded. The main outcome was the measure of relative risk (RR) pooled with 95% confidence intervals, using fixed-effects model. Heterogeneity, small publication effect, and publication bias were evaluated. RESULTS:Fourteen studies, including 1146 participants, met eligibility criteria. There was no significant heterogeneity or publication bias. The prevalence of MVP in PD and healthy controls was 27.20% and 9.21%, respectively. Patients with PD had a significantly increased relative risk of MVP compared to controls in the pooled sample (RR = 2.469, 95% confidence interval = 1.848-3.300). Age did not significantly modify the RR. CONCLUSIONS:MVP is significantly more prevalent in patients with PD than in controls. This meta-analysis of published studies is sufficient to establish an association between PD and MVP; nevertheless, it is not clear that the association is specific to PD. Patients with PD should be evaluated for MVP to decrease possible negative adverse consequences of MVP.
PMID: 30448200
ISSN: 1545-7206
CID: 3479202
Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression
OBJECTIVE:To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment-resistant depression (TRD). METHODS:In a multisite, double-blind, placebo-controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0 mg/kg, or midazolam 0.045 mg/kg. The primary outcome measure was change in the six-item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety-Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion. RESULTS:N = 45 subjects had anxious TRD, compared to N = 54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84) = 0.02, P = 0.88; Day 3: F(1, 82) = 0.12, P = 0.73). CONCLUSION/CONCLUSIONS:In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD.
PMID: 30597688
ISSN: 1520-6394
CID: 3563282
Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression
BACKGROUND:While ketamine has been increasingly studied for treatment resistant depression (TRD), the impact of sex differences on treatment outcomes has not been well studied. The objective was to ascertain whether there were differences in response to a single administration of ketamine for TRD between men and women, and between pre- and post-menopausal women. METHODS:A randomized, double-blind, placebo-controlled trial (N = 99; N = 50 male; N = 49 female) was conducted to investigate the efficacy of intravenous ketamine versus active placebo as augmentation of antidepressant therapy for TRD. Patients were assigned to one of five arms; one-time administration of ketamine of varying doses (i.e., 0.1, 0.2, 0.5, and 1.0 mg/kg), and one group receiving active placebo (intravenous midazolam). A priori-planned analyses were conducted to compare responses between women and men, as well pre-vs. postmenopausal women. RESULTS:Analyses demonstrated no significant differences between women and men in terms of treatment response (F(1,80) = 0.06, p = 0.80). There were no significant differences in the frequency of adverse effects (AEs) reported by those assigned to ketamine treatment groups (p > 0.21 for all AEs reported more than once), although women reported more headaches (12% vs. 6%, p = 0.30) and nausea (10% vs. 6%, p = 0.47). In comparing pre-vs. postmenopausal women, no differences in efficacy were observed (F(1,76) = 0.36, p = 0.55). CONCLUSIONS:Results do not support differential efficacy or tolerability of ketamine for the treatment of TRD between women and men, nor based on menopause status among women. However, larger trials with these a priori aims are needed to confirm these results.
PMCID:6360121
PMID: 30641350
ISSN: 1879-1379
CID: 5070222
