Ketamine for major depressive disorder during an inpatient psychiatric admission: Effectiveness, adverse events, and lessons learned.

OBJECTIVE: Most studies examining the efficacy of ketamine for Major Depressive Disorder (MDD) have been conducted in outpatient or mixed inpatient/outpatient settings. Less is known about effectiveness and tolerability of ketamine for psychiatrically hospitalized patients. Efficacy and tolerability data from a naturalistic sample of acute inpatients may help inform institutions considering ketamine therapy for inpatient services. METHODS: We performed a retrospective chart review of inpatients with non-psychotic MDD treated during the initial 3 years of a ketamine infusion program. Treatment effectiveness was defined using change in Montgomery Asberg Depression Rating Scale (MADRS) scores over five infusions. MDD treatment response was defined by a 50 % reduction of MADRS score, and remission was defined as MADRS score ≤ 10 at any point during the treatment. We also report the frequency of adverse events. RESULTS: 41 patients with MDD were treated and had outcome data. 19 patients (46.5 %) met criteria for response and 15 patients (26.5 %) met criteria for remission during treatment. Four patients (10 %) had adverse psychological or behavioral outcomes. LIMITATIONS: MADRS scales were administered by psychiatrists, psychologists, and trainees in each discipline who did not undergo standardized training in scale administration. Consistent data regarding the race/ethnicity of the patients was not available. CONCLUSION: Twice weekly racemic ketamine infusion is an effective treatment option for patients hospitalized with MDD. Unmonitored or at home ketamine therapy may pose substantial risks.

Expanding Access to Psychiatric Care Through Universal Depression Screening: Lessons from an Urban Student-Run Free Clinic.

The purpose of this study is to report the utility of a universal depression screening in a student-run free clinic (SRFC) to improve bridging to psychiatric care. Patients (n = 224) seen by an SRFC between April 2017 and November 2022 were screened for depression in the patient's primary language using the standardized Patient Health Questionnaire (PHQ-9). A PHQ-9 score greater or equal to 5 prompted psychiatry referral. Retrospective chart review was conducted to determine clinical characteristics and length of psychiatry follow-up. Out of 224 patients screened, 77 patients had positive depression screens and were referred to the SRFC's adjacent psychiatry clinic. Of these 77 patients, 56 patients (73%) were female, the average age was 43.7 (SD = 14.5), and the mean PHQ score was 10 (SD = 5.13). Thirty-seven patients (48%) accepted referral, while 40 (52%) declined or were lost to follow-up. There were no statistical differences in age or number of medical comorbidities between the two groups. Patients who accepted referrals were more likely to be female, as well as to have psychiatric histories, higher PHQ-9 scores, and a history of trauma. Reasons for declining and being lost to follow-up included transition to insurance, geographic relocation and deferral due to hesitancy in seeking psychiatric care. Implementation of a standardized depression screening reveals a significant rate of depressive symptoms among an urban uninsured primary care population. Universal screening may serve as a tool to improve the delivery of psychiatric care to underserved patients.

Serum neutralization activity declines but memory B cells persist after cure of chronic hepatitis C.

The increasing incidence of hepatitis C virus (HCV) infections underscores the need for an effective vaccine. Successful vaccines to other viruses generally depend on a long-lasting humoral response. However, data on the half-life of HCV-specific responses are lacking. Here we study archived sera and mononuclear cells that were prospectively collected up to 18 years after cure of chronic HCV infection to determine the role of HCV antigen in maintaining neutralizing antibody and B cell responses. We show that HCV-neutralizing activity decreases rapidly in potency and breadth after curative treatment. In contrast, HCV-specific memory B cells persist, and display a restored resting phenotype, normalized chemokine receptor expression and preserved ability to differentiate into antibody-secreting cells. The short half-life of HCV-neutralizing activity is consistent with a lack of long-lived plasma cells. The persistence of HCV-specific memory B cells and the reduced inflammation after cure provide an opportunity for vaccination to induce protective immunity against re-infection.

Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection.

Pegylated interferon-α (PEG-IFN-α), where IFN-α is attached to polyethylene glycol (PEG), is an approved treatment for chronic hepatitis B virus (HBV) infection, a disease that causes liver-related morbidity and mortality in 257 million people worldwide. It is unknown why only a minority of patients respond to PEG-IFN-α. Using sequential blood samples and liver biopsies of patients with chronic HBV infection before, during, and after PEG-IFN-α treatment, we find that patients with early natural killer (NK) cell activation after PEG-IFN-α injection experienced greater liver inflammation, lysis of HBV-infected hepatocytes, and hepatitis B surface antigen (HBsAg) decline than those without. NK cell activation was associated with induction of interferon-stimulated genes and determined by PEG-IFN-α pharmacokinetics. Patients with delayed increases in PEG-IFN-α concentrations had greater amounts of PEG-specific immunoglobulin M (IgM) immune complexes in the blood and more PEG and IgM detected in the liver than patients with rapid increase in PEG-IFN-α concentration. This was associated with reduced NK cell activation. These results indicate that the immunomodulatory functions of PEG-IFN-α, particularly activation of NK cells, play a pivotal role in the response to treatment and further demonstrate that these functions are affected by PEG-IFN-α pharmacokinetics. Accelerated clearance of antibody-complexed pegylated drugs by Kupffer cells may be important beyond the field of HBV therapeutics. Thus, these findings may contribute to improving the efficacy of pegylated drugs that are now being developed for other chronic diseases and cancer.

TGF-ß-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis.

The complexity of intracellular signalling requires both a diversity of molecular players and the sequestration of activity to unique compartments within the cell. Recent findings on the role of liquid-liquid phase separation provide a distinct mechanism for the spatial segregation of proteins to regulate signalling pathway crosstalk. Here, we discover that DACT1 is induced by TGFß and forms protein condensates in the cytoplasm to repress Wnt signalling. These condensates do not localize to any known organelles but, rather, exist as phase-separated proteinaceous cytoplasmic bodies. The deletion of intrinsically disordered domains within the DACT1 protein eliminates its ability to both form protein condensates and suppress Wnt signalling. Isolation and mass spectrometry analysis of these particles revealed a complex of protein machinery that sequesters casein kinase 2-a Wnt pathway activator. We further demonstrate that DACT1 condensates are maintained in vivo and that DACT1 is critical to breast and prostate cancer bone metastasis.