Clinical Effectiveness of Intravenous Racemic Ketamine Infusions in a Large Community Sample of Patients With Treatment-Resistant Depression, Suicidal Ideation, and Generalized Anxiety Symptoms: A Retrospective Chart Review.

Introduction: Few studies have been published to date exploring the effectiveness of ketamine for treatment-resistant depression (TRD) in large clinical samples. We report on the clinical outcomes of a large cohort treated with ketamine as part of clinical practice.Methods: Deidentified electronic chart data were obtained from a multisite private ketamine infusion clinic for 424 patients with TRD seen from November 9, 2017, to May 4, 2021. Ketamine infusions were administered at a starting dose of 0.5 mg/kg/40 minutes for 6 infusions within 21 days. Maintenance infusions were offered based on clinical response. Changes in outcome measures (scores on the Patient Health Questionnaire-9 [PHQ-9] and Generalized Anxiety Disorder-7 [GAD-7]) within subjects were analyzed using longitudinal multilevel modeling with Kaplan-Meier estimates. Logistic regression was used to analyze for a priori theorized potential moderators of response.Results: Significant improvements from baseline were observed over time on the main outcomes (all P < .001). Based on PHQ-9 self-report data, within 6 weeks of infusion initiation, a 50% response rate and 20% remission rate for depressive symptoms were observed. Response and remission rates were 72% and 38%, respectively, after 10 infusions, and there was a 50% reduction in self-harm/suicidal ideation (SI) symptom scores within 6 weeks. Half of patients with SI at baseline no longer had it after 6 infusions. A 30% reduction in anxiety symptoms (per the GAD-7) was observed.Conclusions: Ketamine was effective at reducing symptoms of SI, depression, and anxiety. The high rates of response and remission were similar to those for interventional treatments in community samples of TRD. Comparative efficacy trials with other interventions and randomized controlled trials of racemic ketamine infusion as the primary treatment for SI are needed.

A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine.

Cocaine use disorder (CUD) patients display heterogenous symptoms and unforeseeable responses to available treatment approaches, highlighting the need to identify objective, accessible biobehavioral signatures to predict clinical trial success in this population. In the present experiments, we employed a task-based behavioral and pharmacogenetic-fMRI approach to address this gap. Craving, an intense desire to take cocaine, can be evoked by exposure to cocaine-associated stimuli which can trigger relapse during attempted recovery. Attentional bias towards cocaine-associated words is linked to enhanced effective connectivity (EC) from the anterior cingulate cortex (ACC) to hippocampus in CUD participants, an observation which was replicated in a new cohort of participants in the present studies. Serotonin regulates attentional bias to cocaine and the serotonergic antagonist mirtazapine decreased activated EC associated with attentional bias, with greater effectiveness in those CUD participants carrying the wild-type 5-HT2CR gene relative to a 5-HT2CR single nucleotide polymorphism (rs6318). These data suggest that the wild-type 5-HT2CR is necessary for the efficacy of mirtazapine to decrease activated EC in CUD participants and that mirtazapine may serve as an abstinence enhancer to mitigate brain substrates of craving in response to cocaine-associated stimuli in participants with this pharmacogenetic descriptor. These results are distinctive in outlining a richer "fingerprint" of the complex neurocircuitry, behavior and pharmacogenetics profile of CUD participants which may provide insight into success of future medications development projects.

Dynamic Causal Modeling Self-Connectivity Findings in the Functional Magnetic Resonance Imaging Neuropsychiatric Literature.

Dynamic causal modeling (DCM) is a method for analyzing functional magnetic resonance imaging (fMRI) and other functional neuroimaging data that provides information about directionality of connectivity between brain regions. A review of the neuropsychiatric fMRI DCM literature suggests that there may be a historical trend to under-report self-connectivity (within brain regions) compared to between brain region connectivity findings. These findings are an integral part of the neurologic model represented by DCM and serve an important neurobiological function in regulating excitatory and inhibitory activity between regions. We reviewed the literature on the topic as well as the past 13 years of available neuropsychiatric DCM literature to find an increasing (but still, perhaps, and inadequate) trend in reporting these results. The focus of this review is fMRI as the majority of published DCM studies utilized fMRI and the interpretation of the self-connectivity findings may vary across imaging methodologies. About 25% of articles published between 2007 and 2019 made any mention of self-connectivity findings. We recommend increased attention toward the inclusion and interpretation of self-connectivity findings in DCM analyses in the neuropsychiatric literature, particularly in forthcoming effective connectivity studies of substance use disorders.

Aryl hydrocarbon receptor-induced activation of the human IGH hs1.2 enhancer: Mutational analysis of putative regulatory binding motifs.

The human hs1.2 enhancer within the Ig heavy chain gene (IGH) is polymorphic and associated with a number of autoimmune diseases. The polymorphic region is characterized by tandem repeats of an ∼53-bp invariant sequence containing possible binding sites for several transcription factors. Our previous studies suggest the human hs1.2 enhancer is sensitive to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental toxicant and high affinity ligand of the aryl hydrocarbon receptor (AhR). TCDD induced hs1.2 enhancer activity in an AhR-dependent manner and the number of invariant sequences influenced the magnitude of activity. To better understand the regulation of human hs1.2 enhancer activity, the objective of the current study was to utilize mutational analysis and luciferase reporter constructs to evaluate the contribution of putative transcription factor binding sites to overall hs1.2 enhancer activity and modulation by TCDD. Basal and LPS-induced activity of the hs1.2 enhancer appeared to be most affected by mutation of sites outside of the invariant sequence or deletion of the entire invariant sequence; whereas sites influencing the effect of TCDD were dependent on the cellular activation state (i.e. unstimulated vs. LPS stimulation) and relatively independent of the putative AhR binding site within the invariant sequence. These results suggest that AhR activation affects human hs1.2 activity through an as yet undetermined non-canonical pathway. A better understanding regarding the role of the hs1.2 enhancer in human Ig expression and how AhR ligands modulate its activity may lead to insights into overall Ig regulation and mechanisms of dysfunction.

Expression pattern of id proteins in medulloblastoma.

Inhibitor of DNA binding or inhibitor of differentiation (Id) proteins are up regulated in a variety of neoplasms, particularly in association with high-grade, poorly differentiated tumors, while differentiated tissues show little or no Id expression. The four Id genes are members of the helix-loop-helix (HLH) family of transcription factors and act as negative regulators of transcription by binding to and sequestering HLH complexes. We tested the hypothesis that Id proteins are overexpressed in medulloblastoma by performing immunohistochemistry using a medulloblastoma tissue microarray with 45 unique medulloblastoma and 11 normal control cerebella, and antibodies specific for Id1, Id2, Id3, and Id4. A semi-quantitative staining score that took staining intensity and the proportion of immunoreactive cells into account was used. Id1 was not detected in normal cerebella or in medulloblastoma cells, but 78 % of tumors showed strong Id1 expression in endothelial nuclei of tumor vessels. Id2 expression was scant in normal cerebella and increased in medulloblastoma (median staining score: 4). Id3 expression was noted in some neurons of the developing cerebellar cortex, but it was markedly up regulated in medulloblastoma (median staining score: 12) and in tumor endothelial cells. Id4 was not expressed in normal cerebella or in tumor cells. Id2 or Id3 overexpression drove proliferation in medulloblastoma cell lines by altering the expression of critical cell cycle regulatory proteins in favor of cell proliferation. This study shows that Id1 expression in endothelial cells may contribute to angiogenic processes and that increased expression of Id2 and Id3 in medulloblastoma is potentially involved in tumor cell proliferation and survival.

Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models.

Myotubular myopathy (MTM) is a severe congenital muscle disease characterized by profound weakness, early respiratory failure and premature lethality. MTM is defined by muscle biopsy findings that include centralized nuclei and disorganization of perinuclear organelles. No treatments currently exist for MTM. We hypothesized that aberrant neuromuscular junction (NMJ) transmission is an important and potentially treatable aspect of the disease pathogenesis. We tested this hypothesis in two murine models of MTM. In both models we uncovered evidence of a disorder of NMJ transmission: fatigable weakness, improved strength with neostigmine, and electrodecrement with repetitive nerve stimulation. Histopathological analysis revealed abnormalities in the organization, appearance and size of individual NMJs, abnormalities that correlated with changes in acetylcholine receptor gene expression and subcellular localization. We additionally determined the ability of pyridostigmine, an acetylcholinesterase inhibitor, to ameliorate aspects of the behavioral phenotype related to NMJ dysfunction. Pyridostigmine treatment resulted in significant improvement in fatigable weakness and treadmill endurance. In all, these results describe a newly identified pathological abnormality in MTM, and uncover a potential disease-modifying therapy for this devastating disorder.

Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype.

X-linked myotubular myopathy (MTM) is a severe neuromuscular disease of infancy caused by mutations of MTM1, which encodes the phosphoinositide lipid phosphatase, myotubularin. The Mtm1 knockout (KO) mouse has a severe phenotype and its short lifespan (8 weeks) makes it a challenge to use as a model in the testing of certain preclinical therapeutics. Many MTM patients succumb early in life, but some have a more favorable prognosis. We used human genotype-phenotype correlation data to develop a myotubularin-deficient mouse model with a less severe phenotype than is seen in Mtm1 KO mice. We modeled the human c.205C>T point mutation in Mtm1 exon 4, which is predicted to introduce the p.R69C missense change in myotubularin. Hemizygous male Mtm1 p.R69C mice develop early muscle atrophy prior to the onset of weakness at 2 months. The median survival period is 66 weeks. Histopathology shows small myofibers with centrally placed nuclei. Myotubularin protein is undetectably low because the introduced c.205C>T base change induced exon 4 skipping in most mRNAs, leading to premature termination of myotubularin translation. Some full-length Mtm1 mRNA bearing the mutation is present, which provides enough myotubularin activity to account for the relatively mild phenotype, as Mtm1 KO and Mtm1 p.R69C mice have similar muscle phosphatidylinositol 3-phosphate levels. These data explain the basis for phenotypic variability among human patients with MTM1 p.R69C mutations and establish the Mtm1 p.R69C mouse as a valuable model for the disease, as its less severe phenotype will expand the scope of testable preclinical therapies.