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The effect of single administration of intravenous ketamine augmentation on suicidal ideation in treatment-resistant unipolar depression: Results from a randomized double-blind study

Feeney, Anna; Hock, Rebecca S; Freeman, Marlene P; Flynn, Martina; Hoeppner, Bettina; Iosifescu, Dan V; Trivedi, Madhukar H; Sanacora, Gerard; Mathew, Sanjay J; Debattista, Charles; Ionescu, Dawn F; Fava, Maurizio; Papakostas, George I
This study aimed to assess the effect of a single infusion of intravenous (IV) ketamine on suicidal ideation in patients with treatment-resistant depression (TRD). Patients with TRD were randomized in a double-blind fashion to a single infusion of IV ketamine or IV midazolam placebo. Suicidal ideation was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) suicide item at 3, 5, 7, 14 and 30 days post infusion. Clinically significant suicidal ideation was defined as a MADRS suicide item score ≥2. Forty patients who received IV ketamine and 16 who received IV midazolam had suicide item scores of ≥2 at baseline (IV ketamine group mean 2.90±0.74; IV midazolam group 2.69±0.70). The mean suicide scores of these groups differed significantly from each other on day 30; the IV ketamine group had a lower mean score than controls (2.03±1.59 vs. 3.00±1.41, t-test p = 0.049; Hedges' g 0.71). Among patients with a suicide score of ≥2 at baseline and <2 at day 3, the two groups did not differ significantly on mean scores changes at days 3, 5, 7, 14 or 30. Recurrence of suicidal ideation was extensive in both treatment groups. A single infusion of IV ketamine may reduce suicidal ideation in TRD out to 30 days post infusion, but early anti-suicidal effects appear to diminish rapidly. This post-hoc analysis was not powered to compare different doses of ketamine. A single infusion of IV ketamine might have a role as an adjunct to standard treatments in patients with TRD and suicidal ideation. Trial registration: NCT01920555.
PMID: 34090255
ISSN: 1873-7862
CID: 4905922

Neural Mechanisms of Symptom Dimensions During Provocation in Obsessive-Compulsive Disorder [Meeting Abstract]

Charan, M; Eng, G K; Collins, K; Bragdon, L; Belanger, A; Tobe, R; Iosifescu, D V; Stern, E
Background: Obsessive-compulsive disorder (OCD) is highly heterogenous, yet it remains unclear how this heterogeneity may be related to differential neurocircuitry. This study investigated neural mechanisms associated with symptom heterogeneity in OCD by examining the relationship between fMRI activation during a provocation task and severity of four different symptom dimensions in OCD.
Method(s): 54 OCD patients viewed individually-relevant images (Berlin OCD picture set), as well as generally aversive and neutral images from the International Affective Picture System. The task presented 6 blocks each containing 6 images of each type (OCD, aversive, and neutral). Severity of different OCD symptom dimensions was measured with the self-report Dimensional Obsessive-Compulsive Scale (DOCS) to assess 'Concerns about Germs/Contamination'; 'Concerns about Responsibility for Harm'; 'Unacceptable Thoughts'; and 'Concerns about Symmetry/Not-Just-Right Experiences' (NJRE). Whole brain regressions specified DOCS symptom dimensions scores as predictors of activation when viewing OCD-relevant or aversive images (p<.005, uncorrected, k>100).
Result(s): Decreased default-mode network activity was associated with greater symptoms related to 'Concerns about Germs/Contamination' and increased activity in sensorimotor regions was associated with greater 'Symmetry/NJRE' symptoms, both when viewing aversive images. Although the overall pattern of relationships were similar for OCD images, effects were weaker. There were no associations at our specified threshold for other symptom dimensions.
Conclusion(s): These findings suggests that different symptom dimensions of OCD involve different neurocircuitry systems, although, unexpectedly, neural effects were stronger for aversive than OCD-relevant images. Gaining an understanding of differential neurocircuitry associated with specific symptoms in OCD can help further tailored treatments of the disorder. Supported By: R01MH111794 and R33MH107589 Keywords: OCD Symptom Dimensions, Obsessive Compulsive Disorder (OCD), Brain Imaging, fMRI
ISSN: 1873-2402
CID: 4857772

Insula Functional Connectivity During Urge Suppression in Obsessive-Compulsive Disorder [Meeting Abstract]

Eng, G K; Collins, K; Bragdon, L; Belanger, A; Charan, M; Tobe, R H; Fleysher, L; Iosifescu, D V; Stern, E R
Background: Individuals with obsessive-compulsive disorder (OCD) often report urges preceding their compulsions. Although the insula has a key role in interoception and prior work in OCD showed increased neural activity during the build-up of an urge using an eyeblink-suppression task, little is known about insula connectivity during urge-suppression in OCD.
Method(s): 30 OCD patients and 30 controls performed an eyeblink-suppression task in the MRI scanner, with eyeblinks measured using an eye-tracking device. Eight blocks of alternating blink-suppression (60s/block) and free-blinking (30s/block) were presented. Eyeblink data were available in a subset of 20 patients and 18 controls. Generalized psychophysiological interaction (gPPI) analysis was conducted to examine insula connectivity differences between early blink-suppression (first 30s) and late blink-suppression (last 30s) with free-blinking. Seeds for gPPI were bilateral 6-mm radius spheres around insula sub-divisions previously shown to be involved in sensory (posterior-insula[PI]), emotional (ventral-anterior-insula[vAI]), and cognitive (dorsal-anterior-insula[dAI]) aspects of interoception.
Result(s): OCD patients were less successful than controls in suppressing blinks during early and late blink-suppression (p<.05). Compared to controls, OCD patients showed reduced connectivity of the vAI-seed with dAI as well as secondary somatosensory, lateral prefrontal, and occipital cortices during early and late blink-suppression. Patients also showed increased connectivity of the dAI-seed with bilateral postcentral gyrus during late blink-suppression (all FDR-corrected p<.05). Within controls, reduced dAI-postcentral gyrus connectivity was associated with increased blink-suppression success during late blink-suppression (r=.504, p<.05).
Conclusion(s): OCD patients showed behavioral and insula connectivity differences during blink-suppression. Our findings suggest the involvement of affective, cognitive and somatosensory processes in urge-suppression in OCD. Supported By: NIMH grants R01MH111794 and R33MH107589 (awarded to ERS) Keywords: Obsessive Compulsive Disorder (OCD), Insula, Functional Connectivity, Urge Suppression, Interoception
ISSN: 1873-2402
CID: 4857762

Urges-For-Action in OCD: Blink Suppression Failure Relates to Clinical Heterogeneity [Meeting Abstract]

Bragdon, L; Eng, G K; Collins, K; Belanger, A; Charan, M; Fleysher, L; Tobe, R H; Iosifescu, D V; Stern, E
Background: Traditional conceptualizations of obsessive-compulsive disorder (OCD) emphasized the role of anxiety and harm-avoidance (HA) in motivating compulsions. However, OCD is heterogeneous, and many individuals describe an urge to alleviate a "not-just-right" feeling or sensation of incompleteness. This urge may be comparable to everyday "urges-for-action" (UFA), such as the urge to blink. While research has demonstrated altered functioning of brain regions related to UFA in OCD, little is known about how UFA relates to clinical heterogeneity.
Method(s): An urge-to-blink task was utilized to examine 1) urge suppression success in OCD (n=70) versus controls (n=23), and 2) associations between suppression success and clinical variables within OCD. In the task, 60-s blink suppression blocks (analyzed in 30-s halves) alternated with 30-s free-blinking (rest) blocks. Assessments included clinical and self-report scales.
Result(s): Blink counts were highest in rest blocks, followed by late (last 30-s) and finally early suppression phases (first 30-s; F (1.24,112.52) =337.20, p<.001). No significant BlockxGroup interaction was found, however OCD participants blinked more than controls in early and late suppression phases (t(91)=-2.77,p<.01; t(91)=-2.78,p<.01). Within the OCD sample, higher sensory phenomena scores related to increased blink suppression failure in early(r=.28) and late(r=.30) phases. No significant associations were found with HA or OCD severity.
Conclusion(s): Findings suggest that individuals with OCD demonstrate impaired urge suppression compared to controls, and within OCD, this impairment is associated with sensory phenomena and not HA or OCD severity. Research investigating behavioral mechanisms related to clinical heterogeneity has the potential to improve treatment through identification of new, individualized targets for interventions. Supported By: R01, R33 Keywords: OCD Symptom Dimensions, Obsessive Compulsive Disorder (OCD), Heterogeneity
ISSN: 1873-2402
CID: 4857712

Rapid Effects of AXS-05, an Oral NMDA Receptor Antagonist, in Major Depressive Disorder: Results From Two Randomized, Double-Blind, Controlled Trials [Meeting Abstract]

O'Gorman, C; Jones, A; Iosifescu, D V; Thomas, Z; Tabuteau, H
Background: AXS-05 (dextromethorphan-bupropion modulated delivery tablet) is an investigational, oral, NMDA receptor antagonist with multimodal activity being developed for MDD.
Method(s): AXS-05 was evaluated in two double-blind, randomized, controlled, 6-week trials. The GEMINI trial was placebo-controlled and the ASCEND trial used bupropion as the control. The primary efficacy variable in both was change in the MADRS total score. Here we examine the efficacy in the first 2 weeks of treatment.
Result(s): AXS-05 met the primary endpoint in both studies. In GEMINI (N=327), starting at Week-1, AXS 05 was superior to placebo on: mean MADRS improvement (7.3 vs. 4.9; p=0.007), MADRS response (>=50% improvement; 15% vs. 7%; p=0.035), CGI-I (22% vs. 13%; p=0.035), CGI-S (0.7 vs. 0.4; p=0.013) and Q-LES-Q-SF (9.0% vs. 5.8%; p=0.031). At Week-2, AXS-05 was superior to placebo on MADRS remission (<=10; 17% vs. 8%; p=0.013) and SDS (6.8 vs. 4.5; p=0.003). In ASCEND (N=80), starting at Week-1, AXS-05 was superior to bupropion on: CGI-I (18% vs. 3%; p=0.045) and MADRS-6 response (>=50% improvement; 16% vs. 3%; p=0.044). From Week-2, AXS-05 was superior to bupropion on: mean MADRS improvement (12.5 vs. 7.8; p=0.024), MADRS remission (<=10; 26% vs. 3%; p=0.004), and CGI-S (1.41 vs. 0.9; p=0.049).
Conclusion(s): AXS-05 demonstrated rapid and statistically significant improvements in depression at Weeks 1 and 2 in placebo- and active- controlled trials. In both studies, rapid remission from depressive symptoms was achieved by Week-2 and maintained over the 6-week treatment period. The novel mechanisms of action of AXS-05 may contribute to these rapid antidepressant effects. Supported By: Axsome Therapeutics Keywords: Rapid Anti-Depressant Effect, Major Depressive Disorder (MDD), NMDA Antagonists, Novel Treatments, Glutamate Neurotransmission
ISSN: 1873-2402
CID: 4857702

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial

Costi, Sara; Morris, Laurel S; Kirkwood, Katherine A; Hoch, Megan; Corniquel, Morgan; Vo-Le, Brittany; Iqbal, Tabish; Chadha, Nisha; Pizzagalli, Diego A; Whitton, Alexis; Bevilacqua, Laura; Jha, Manish K; Ursu, Stefan; Swann, Alan C; Collins, Katherine A; Salas, Ramiro; Bagiella, Emilia; Parides, Michael K; Stern, Emily R; Iosifescu, Dan V; Han, Ming-Hu; Mathew, Sanjay J; Murrough, James W
OBJECTIVE/UNASSIGNED:Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS/UNASSIGNED:Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Ã…sberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS/UNASSIGNED:The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS/UNASSIGNED:The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.
PMID: 33653118
ISSN: 1535-7228
CID: 4877972

Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation

McIntyre, Roger S; Rosenblat, Joshua D; Nemeroff, Charles B; Sanacora, Gerard; Murrough, James W; Berk, Michael; Brietzke, Elisa; Dodd, Seetal; Gorwood, Philip; Ho, Roger; Iosifescu, Dan V; Lopez Jaramillo, Carlos; Kasper, Siegfried; Kratiuk, Kevin; Lee, Jung Goo; Lee, Yena; Lui, Leanna M W; Mansur, Rodrigo B; Papakostas, George I; Subramaniapillai, Mehala; Thase, Michael; Vieta, Eduard; Young, Allan H; Zarate, Carlos A; Stahl, Stephen
Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.
PMID: 33726522
ISSN: 1535-7228
CID: 4903272

Influences on childhood depressive symptoms: The effects of trauma and distress tolerance across age and sex groups

Rette, Danielle N; Arnold, Molly S; McDonald, Erin M; Hoptman, Matthew J; Collins, Katherine A; Iosifescu, Dan V
BACKGROUND:Depression affects many children and adolescents, leading to poor academic performance, impaired psychosocial functioning, and an increased frequency of suicidal behavior. Depression has also been notably associated with trauma and distress tolerance. Our study sought to understand the relationships of these variables across age and sex categories in youth and adolescents. METHODS:The current study examined data from a total of 324 participants between the ages of 7 and 17 years-old who were a part of a larger study. Data related to age, sex, depression, trauma, and distress tolerance were examined. RESULTS:A multiple regression revealed a significant interaction between age and sex on depression severity. Further, trauma and age by sex categories significantly predicted depression score, as well as distress tolerance predicting depression score. Lastly, a regression analysis, including trauma, distress tolerance, and age by sex categories were significant predictors of depression. LIMITATIONS/CONCLUSIONS:The results are limited by the cross-sectional design. CONCLUSION/CONCLUSIONS:Clinicians should consider age by sex effects when treating childhood depression. Future research should further the understanding of depression across age and sex groups, as well as among children with extensive trauma experiences. Future research should also seek to further understand the implications of distress tolerance therapy on childhood depression.
PMID: 33578351
ISSN: 1573-2517
CID: 4793302

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

Czamara, Darina; Tissink, Elleke; Tuhkanen, Johanna; Martins, Jade; Awaloff, Yvonne; Drake, Amanda J; Khulan, Batbayar; Palotie, Aarno; Winter, Sibylle M; Nemeroff, Charles B; Craighead, W Edward; Dunlop, Boadie W; Mayberg, Helen S; Kinkead, Becky; Mathew, Sanjay J; Iosifescu, Dan V; Neylan, Thomas C; Heim, Christine M; Lahti, Jari; Eriksson, Johan G; Räikkönen, Katri; Ressler, Kerry J; Provençal, Nadine; Binder, Elisabeth B
Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.
PMID: 33526782
ISSN: 2158-3188
CID: 4789672

A systematic review and network meta-analysis of carbon dioxide provocation in psychiatric disorders

Tural, Umit; Iosifescu, Dan V
BACKGROUND:False suffocation alarm hypothesis has been widely used to explain carbon dioxide hypersensitivity in panic disorder (PD). However, hypersensitivity to carbon dioxide has been observed in other psychiatric disorders. We explored the specificity of carbon dioxide inhalation as a panic provocation test among psychiatric disorders via network meta-analysis. METHODS:A systematic literature search on PubMed, EMBASE, and PsycNET was performed to acquire the studies using the carbon dioxide provocation test in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklists. Odds ratios (OR) for a panic attack (PA) induced by the carbon dioxide inhalation tests were extracted from each of the original studies and were pooled using the random-effects model. RESULTS:Network meta-analysis on a pool of 2181 participants from 41 studies was used to compare the efficacy of carbon dioxide provocation tests among psychiatric disorders. The network meta-analysis showed that the odds for PA in response to carbon dioxide inhalation are higher in patients with PD, premenstrual dysphoric syndrome (PMDD), and social anxiety disorder (SAD) than healthy controls (HC). The odds for PA were not significantly different among patients with generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), and healthy controls (HC). CONCLUSIONS:The vulnerability to the carbon dioxide provocation test is not limited to PD. The specificity of the test for PD is questionable, as individuals suffering from PMDD and SAD are also significantly more responsive to carbon dioxide inhalation compared to HC, OCD, MDD, and GAD. There may be shared underpinning biological mechanisms between PD, PMDD, and SAD.
PMID: 33250190
ISSN: 1879-1379
CID: 4714352