The effect of intranasal (R,S)-ketamine on symptoms of fatigue in severe major depressive disorder or bipolar depression with and without comorbid alcohol use disorder: Results from a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fatigue is a multidimensional condition that may overlap with depression. Initial studies found that fatigue responds in only a limited way to standard monoaminergic antidepressants and mood stabilizers but does respond positively to intravenous (IV) racemic (R,S)-ketamine (ketamine). However, IV ketamine's use is limited by cost and access barriers. To date, no study has evaluated intranasal (IN) ketamine in individuals with fatigue. This study sought to evaluate the anti-fatigue effects of a single 50 mg dose of IN ketamine in individuals with major depressive disorder (MDD) or bipolar depression (BDep), both with and without comorbid alcohol use disorder (AUD). METHODS: Twenty-eight individuals with primary diagnoses of MDD or BDep I/II currently experiencing a depressive episode with active suicidality were enrolled; approximately 60 % had comorbid AUD. Changes in the NIH-Brief Fatigue Inventory (NIH-BFI) were assessed at baseline and at 4, 24, and 48 h post-treatment. RESULTS: The group x time interaction for NIH-BFI score was significant (F = 3.44, p = 0.022), favoring IN ketamine over placebo. IN ketamine was well-tolerated with minimal adverse effects. LIMITATIONS: Limitations include the limited sample size, short duration, and single, fixed dose. CONCLUSIONS: IN ketamine appears to induce rapid anti-fatigue effects in individuals with severe MDD and BDep both with and without comorbid AUD. This suggests that IN ketamine holds potential as an alternative, rapid-acting, anti-fatigue option for different medical conditions.

A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of the Acute Antisuicidal and Antidepressant Effects of Intranasal (R,S)-Ketamine in Severe Unipolar and Bipolar Depression With and Without Comorbid Alcohol Use Disorder.

Objective: Although individuals with a family history of alcohol use disorder (AUD) have a superior antidepressant response to ketamine, outcomes in patients with current AUD remain unclear. This study sought to investigate whether intranasal (IN) racemic (R,S)-ketamine had antisuicidal and antidepressant effects in unipolar and bipolar depression and whether comorbid AUD conferred superior antisuicidal outcomes for patients.Methods: This was a double-blind, randomized, placebo-controlled trial (May 2018 to January 2022) of single administration, fixed-dose (50 mg) IN (R,S)-ketamine (or saline comparator) in unmedicated inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for a current major depressive episode (bipolar or unipolar), with current suicidal ideation (SI) and past attempt. Patients with and without comorbid AUD were enrolled. Change in Scale for Suicide Ideation score was the primary outcome measure, and change in Montgomery-Åsberg Depression Rating Scale score was the secondary outcome measure.Results: No significant group × time effect was noted for SI (F = 1.1, P = .36). A statistical trend toward superior improvement in suicidality was observed in participants with comorbid AUD. The group × time interaction was significant for improvements in depression (F = 3.06, P = .03) and largely unaffected by comorbid AUD or primary mood disorder type. Within the ketamine group, a significant correlation was observed between improvement in depressive symptoms and SI for patients without comorbid AUD (r =0.927, P = .023) that was absent in patients with AUD (r = 0.39, P = .44).Conclusion: IN ketamine induced rapid antidepressant effects compared to placebo but did not significantly alter SI scores. The treatment was well tolerated. Continued investigation with IN ketamine as a practical alternative to current formulations is warranted.Trial Registration: ClinicalTrials.gov identifier: NCT03539887.

Case Report: Necrotizing Erythema Nodosum as a Manifestation of Lepromatous Leprosy Relapse 50 Years after the Initial Infection.

Leprosy is a chronic infection caused by Mycobacterium leprae and Mycobacterium lepromatosis that preferentially compromises peripheral nerve, skin, and mucous membranes. Colombia achieved the goal of leprosy elimination in 1997. However, in Urabá (Colombia), there has been an increase in leprosy cases beginning in 2020. This case report shows a leprosy relapse 5 decades after the initial infection debuted as a necrotizing erythema nodosum leprosum. Therefore, long-term follow-up of patients with risk factors for relapse is emphasized, especially those treated before the standard of multidrug therapy (dapsone, clofazimine, and rifampin). This case report stresses the importance the importance of clinical follow-up and surveillance of patients with these events of interest for the public health.

The role of lithium treatment on comorbid anxiety symptoms in patients with bipolar depression.

BACKGROUND: Comorbid anxiety is pervasive and carries an immense psychosocial burden for patients with bipolar disorder. Despite this, trials reporting anxiety-related outcomes in this population are uncommon, particularly with regards to monotherapies. METHODS: Patients (n = 31) with both bipolar I or II disorder in current depressive episodes were enrolled in a six-week, open-label, single-center trial assessing the efficacy of lithium monotherapy in treating symptoms depression and comorbid anxiety. Patients were mostly medication-free and lithium-naïve at baseline. RESULTS: Significant improvements in depression (HAMD) and anxiety (HAM-A) were observed at the six-week endpoint, with remission and response rates greater than 50%. There was a positive correlation between endpoint HAM-A scores and HAM-D scores, r = 0.80, (p < 0.01). Improvements were realized at low serum lithium concentrations (0.49 ± 0.20 mEq/L). LIMITATIONS: Lack of placebo control and small sample size warrants validation in larger randomized studies. CONCLUSIONS: Taken in the context of prior evidence, lithium may have an important role in treating comorbid anxiety in bipolar disorder, both as adjunct and monotherapy. Lower doses of lithium may provide equivalent efficacy and enhance tolerability and compliance.

Perceived Racial Discrimination and Pain Intensity/Disability Among Economically Disadvantaged Latinos in a Federally Qualified Health Center: The Role of Anxiety Sensitivity.

The present study examined the role of anxiety sensitivity (AS; fear of the negative consequences of anxiety) in the relation between perceived racial discrimination and pain-related problems among Latinos seeking health services at a Federally Qualified Health Center. Participants included 145 adult Latinos (87.80% female, Mage = 38.07 years, SD = 11.98, and 96.2% reported Spanish as their first language). Results indicated that perceived racial discrimination was indirectly related to the pain intensity and pain disability through AS. These effects were evident above and beyond the variance accounted for by gender, age, marital status, educational status, employment status, years living in the United States, and number of axis I diagnoses. Overall, the present findings highlight the merit in focusing further scientific attention on the interplay between perceived racial discrimination and AS to better understand and inform interventions to reduce pain problems among Latinos in primary care.

Characterization of a protozoan Phosducin-like protein-3 (PhLP-3) reveals conserved redox activity.

We recently identified three novel thioredoxin-like genes in the genome of the protozoan parasite Plasmodium that belong to the Phosducin-like family of proteins (PhLP). PhLPs are small cytosolic proteins hypothesized to function in G-protein signaling and protein folding. Although PhLPs are highly conserved in eukaryotes from yeast to mammals, only a few representatives have been experimentally characterized to date. In addition, while PhLPs contain a thioredoxin domain, they lack a CXXC motif, a strong indicator for redox activity, and it is unclear whether members of the PhLP family are enzymatically active. Here, we describe PbPhLP-3 as the first phosducin-like protein of a protozoan organism, Plasmodium berghei. Initial transcription analysis revealed continuous low-level expression of pbphlp-3 throughout the complex Plasmodium life cycle. Attempts to knockout pbphlp-3 in P. berghei did not yield live parasites, suggesting an essential role for the gene in Plasmodium. We cloned, expressed and purified PbPhLP-3 and determined that the recombinant protein is redox active in vitro in a thioredoxin-coupled redox assay. It also has the capacity to reduce the organic compound tert-Butyl hydroperoxide (TBHP) in vitro, albeit at low efficiency. Sequence analysis, structural modeling, and site-directed mutagenesis revealed a conserved cysteine in the thioredoxin domain to be the redox active residue. Lastly, we provide evidence that recombinant human PhLP-3 exhibits redox activity similar to that of PbPhLP-3 and suggest that redox activity may be conserved in PhLP-3 homologs of other species. Our data provide new insight into the function of PhLP-3, which is hypothesized to act as co-chaperones in the folding and regulation of cytoskeletal proteins. We discuss the potential implications of PhLP-3 as a thioredoxin-target protein and possible links between the cellular redox network and the eukaryotic protein folding machinery.

Development of pyoderma gangrenosum during therapy with infliximab.

BACKGROUND: Pyoderma gangrenosum is a rare inflammatory disease of unknown etiology and a poorly understood pathogenesis. Its clinical presentation is variable and a large percentage of cases are associated with inflammatory bowel diseases. Peristomal pyoderma gangrenosum represents a variant of the diseases, occurring in patients with colostomy. Multiple cases demonstrate efficacy of infliximab and other anti-TNF-alpha drugs in treatment of pyoderma gangrenosum. MAIN OBSERVATIONS: A 47-year-old male with ulcerative colitis and proctocolectomy with ileal pouch reconstruction protected by ileostomy in the course of diseases received infliximab therapy together with azathioprine for his inflammatory bowel diseases. Six months after initiation of infliximab therapy the patient developed multiple pyoderma gangrenosum lesions on the trunk, abdomen, genitalia, gluteus, extremities, left preauricular region and peristomal area. After systemic corticosteroid therapy, combined with topical tacrolimus, the lesions slowly improved. Seven months later, during ongoing infliximab therapy, the patient developed a sepsis with fatal outcome. CONCLUSION: Constant trauma generated by colostomy may be a contributing factor to the development and persistence of pyoderma gangrenosum. It may be hypothesized that this patient developed pyoderma gangrenosum despite infliximab or that pyoderma gangrenosum may represent a rare adverse effect of the drug.

Expression of adhesion molecules in lungs of mice infected with Paracoccidioides brasiliensis conidia.

In infected tissues, leukocyte recruitment is mediated by interactions between adhesion molecules, expressed on activated vascular endothelial cells, and ligands present on circulating cells. We evaluated the inflammatory response and the expression of cellular adhesion molecules (ICAM-1, VCAM-1, CD18, LFA-1 and Mac-1) in lungs of BALB/c mice infected with Paracoccidioides brasiliensis conidia. When compared with uninfected animals, infected mice had a significant increase in the inflammatory response during the first 4 days, peaking 2-3 days post-challenge, 40.3% vs. 0.0% and 41.8% vs. 0.7%, respectively. This inflammatory infiltrate was composed mainly of neutrophils and macrophages with a few eosinophils and lymphocytes. An increase in the intensity of immunofluorescence (IF) for ICAM-1 was also observed during days 1-4. ICAM-1 was present in bronchiolar epithelium, type II pneumocytes, and macrophages, as well as on vascular endothelium. The control animals presented ICAM-1 constitutively. In infected mice, VCAM-1 was only observed on vascular endothelium during the first 2 days, with some macrophages expressing this molecule throughout the study periods. CD18 and Mac-1 but not LFA-1 were expressed with a high intensity on neutrophils and macrophages present in the inflammatory infiltrate. In addition, we observed a significant decrease in Colony forming units (CFUs) after the first 2 days post-challenge. These findings suggest that during these early stages, up-regulation of ICAM-1, VCAM-1, CD18 and Mac-1 expression occurs, participating in the inflammatory process and as such, in the pathogenesis of paracoccidioidomycosis (PCM).