Faculty Bibliography
Searched for:
in-biosketch:yes
person:iosifd01
Total Results:
307
Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression
BACKGROUND: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. METHODS: Participants with TRD (n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. RESULTS: The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery-Asberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 +/- 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. CONCLUSIONS: Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.
PMCID:3725185
PMID: 22840761
ISSN: 1873-2402
CID: 2389272
A randomized, double-blind, placebo-controlled trial of pramipexole augmentation in treatment-resistant major depressive disorder
BACKGROUND: Multiple treatments for patients with major depressive disorder (MDD) have demonstrated efficacy, but up to one-third of individuals with MDD do not achieve symptomatic remission despite various interventions. Existing augmentation or combination strategies can have substantial safety concerns that may limit their application. METHOD: This study investigated the antidepressant efficacy of a flexible dose of the dopamine agonist pramipexole as an adjunct to standard antidepressant treatment in an 8-week, randomized, double-blind, placebo-controlled trial conducted in a tertiary-level depression center. We randomized 60 outpatients (aged 18 to 75 years) with treatment-resistant nonpsychotic MDD (diagnosed according to DSM-IV) to either pramipexole (n = 30) or placebo (n = 30). Treatment resistance was defined as continued depression (Montgomery-Asberg Depression Rating Scale [MADRS] score >/= 18) despite treatment with at least 1 prior antidepressant in the current depressive episode. Patients were recruited between September 2005 and April 2008. The primary outcome measure was the MADRS score. RESULTS: The analyses that used a mixed-effects linear regression model indicated a modest but statistically significant benefit for pramipexole (P = .038). The last-observation-carried-forward analyses indicated that 40% and 33% of patients randomized to augmentation with pramipexole achieved response (chi(2) = 1.2, P = .27) and remission (chi(2) = 0.74, P = .61), respectively, compared to 27% and 23% with placebo; however, those differences were not statistically significant. Augmentation with pramipexole was well-tolerated, with no serious adverse effects identified. CONCLUSION: For patients who have failed to respond to standard antidepressant therapies, pramipexole is a safe and potentially efficacious augmentation strategy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00231959.
PMID: 23945458
ISSN: 1555-2101
CID: 2389152
Effects of Intravenous Ketamine on Explicit and Implicit Suicdal Cognition: A Randomized Controlled Trial in Treatment-Resistant Depression [Meeting Abstract]
ISI:000318671800439
ISSN: 0006-3223
CID: 2390162
The Antidepressant Effects of Minocycline, a Glutamatergic and Antioxidant Agent, in Bipolar Disorder [Meeting Abstract]
ISI:000318671800485
ISSN: 0006-3223
CID: 2390172
A mega-analysis of genome-wide association studies for major depressive disorder
Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 x 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 x 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.
PMCID:3837431
PMID: 22472876
ISSN: 1476-5578
CID: 2389322
Feasibility of studying brain morphology in major depressive disorder with structural magnetic resonance imaging and clinical data from the electronic medical record: a pilot study
For certain research questions related to long-term outcomes or to rare disorders, designing prospective studies is impractical or prohibitively expensive. Such studies could instead utilize clinical and magnetic resonance imaging data (MRI) collected as part of routine clinical care, stored in the electronic medical record (EMR). Using major depressive disorder (MDD) as a disease model, we examined the feasibility of studying brain morphology and associations with remission using clinical and MRI data exclusively drawn from the EMR. Advanced automated tools were used to select MDD patients and controls from the EMR who had brain MRI data, but no diagnosed brain pathology. MDD patients were further assessed for remission status by review of clinical charts. Twenty MDD patients (eight full-remitters, six partial-remitters, and six non-remitters), and 15 healthy control subjects met all study criteria for advanced morphometric analyses. Compared to controls, MDD patients had significantly smaller right rostral-anterior cingulate volume, and level of non-remission was associated with smaller left hippocampus and left rostral-middle frontal gyrus volume. The use of EMR data for psychiatric research may provide a timely and cost-effective approach with the potential to generate large study samples reflective of the real population with the illness studied.
PMCID:3574623
PMID: 23149041
ISSN: 1872-7123
CID: 2389242
QT interval and antidepressant use: a cross sectional study of electronic health records
OBJECTIVE: To quantify the impact of citalopram and other selective serotonin reuptake inhibitors on corrected QT interval (QTc), a marker of risk for ventricular arrhythmia, in a large and diverse clinical population. DESIGN: A cross sectional study using electrocardiographic, prescribing, and clinical data from electronic health records to explore the relation between antidepressant dose and QTc. Methadone, an opioid known to prolong QT, was included to demonstrate assay sensitivity. SETTING: A large New England healthcare system comprising two academic medical centres and outpatient clinics. PARTICIPANTS: 38,397 adult patients with an electrocardiogram recorded after prescription of antidepressant or methadone between February 1990 and August 2011. MAIN OUTCOME MEASURES: Relation between antidepressant dose and QTc interval in linear regression, adjusting for potential clinical and demographic confounding variables. For a subset of patients, change in QTc after drug dose was also examined. RESULTS: Dose-response association with QTc prolongation was identified for citalopram (adjusted beta 0.10 (SE 0.04), P<0.01), escitalopram (adjusted beta 0.58 (0.15), P<0.001), and amitriptyline (adjusted beta 0.11 (0.03), P<0.001), but not for other antidepressants examined. An association with QTc shortening was identified for bupropion (adjusted beta 0.02 (0.01) P<0.05). Within-subject paired observations supported the QTc prolonging effect of citalopram (10 mg to 20 mg, mean QTc increase 7.8 (SE 3.6) ms, adjusted P<0.05; and 20 mg to 40 mg, mean QTc increase 10.3 (4.0) ms, adjusted P<0.01). CONCLUSIONS: This study confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk. Pharmacovigilance studies using electronic health record data may be a useful method of identifying potential risk associated with treatments.
PMCID:3558546
PMID: 23360890
ISSN: 1756-1833
CID: 2389222
Mitochondrial modulators for bipolar disorder: a pathophysiologically informed paradigm for new drug development
OBJECTIVES: Bipolar patients frequently relapse within 12 months of their previous mood episode, even in the context of adequate treatment, suggesting that better continuation and maintenance treatments are needed. Based on recent research of the pathophysiology of bipolar disorder, we review the evidence for mitochondrial dysregulation and selected mitochondrial modulators (MM) as potential treatments. METHODS: We reviewed the literature about mitochondrial dysfunction and potential MMs worthy of study that could improve the course of bipolar disorder, reduce subsyndromal symptoms, and prevent subsequent mood episodes. RESULTS: MM treatment targets mitochondrial dysfunction, oxidative stress, altered brain energy metabolism and the dysregulation of multiple mitochondrial genes in patients with bipolar disorder. Several tolerable and readily available candidates include N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q(10) (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin. The specific metabolic pathways by which these MMs may improve the symptoms of bipolar disorder are discussed and combinations of selected MMs could be of interest as well. CONCLUSIONS: Convergent data implicate mitochondrial dysfunction as an important component of the pathophysiology of bipolar disorder. Clinical trials of individual MMs as well as combinations are warranted.
PMID: 22711881
ISSN: 1440-1614
CID: 2389302
Lithium treatment moderate-dose use study (LiTMUS) for bipolar disorder: a randomized comparative effectiveness trial of optimized personalized treatment with and without lithium
OBJECTIVE: Lithium salts, once the mainstay of therapy for bipolar disorder, have tolerability issues at a higher dosage that often limit adherence. The authors investigated the comparative effectiveness of more tolerable dosages of lithium as part of optimized personalized treatment (OPT). METHOD: The authors randomly assigned 283 bipolar disorder outpatients to 6 months of open, flexible, moderate dosages of lithium plus OPT or to 6 months of OPT alone. The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder-Severity (CGI-BP-S) and "necessary clinical adjustments" (medication adjustments per month). Secondary outcome measures included mood symptoms and functioning. The authors also assessed sustained remission (defined as a CGI-BP-S score
PMID: 23288387
ISSN: 1535-7228
CID: 2389232
Quantitative electroencephalogram biomarkers for predicting likelihood and speed of achieving sustained remission in major depression: a report from the biomarkers for rapid identification of treatment effectiveness in major depression (BRITE-MD) trial
OBJECTIVE: Clinical trials in major depressive disorder (MDD) commonly assess remission at a single endpoint. Complementary, clinically relevant metrics include the likelihood and speed of achieving sustained remission. A neurophysiologic measure, the Antidepressant Treatment Response (ATR) index, previously predicted 8-week outcomes of pharmacotherapy. We retrospectively examined data from the Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE-MD) trial to evaluate this biomarker's properties in predicting sustained remission and time to achieve sustained remission. METHOD: In the BRITE-MD trial, 67 adults with DSM-IV MDD received escitalopram continuously for 13 weeks. The 17-item Hamilton Depression Rating Scale (HDRS17) was used to define sustained remission as achieving remission (HDRS17 score
PMID: 23419226
ISSN: 1555-2101
CID: 2389212
