The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression

BackgroundSubanesthetic ketamine has accumulated meta-analytic evidence for rapid antidepressant effects in treatment-resistant depression (TRD), resulting in both excitement and debate. Many unanswered questions surround ketamine’s mechanisms of action and its integration into real-world psychiatric care, resulting in diverse utilizations that variously resemble electroconvulsive therapy, conventional antidepressants, or serotonergic psychedelics. There is thus an unmet need for clinical approaches to ketamine that are tailored to its unique therapeutic properties.MethodsThis article presents the Montreal model, a comprehensive biopsychosocial approach to ketamine for severe TRD refined over 6 years in public healthcare settings. To contextualize its development, we review the evidence for ketamine as a biomedical and as a psychedelic treatment of depression, emphasizing each perspectives’ strengths, weaknesses, and distinct methods of utilization. We then describe the key clinical experiences and research findings that shaped the model’s various components, which are presented in detail.ResultsThe Montreal model, as implemented in a recent randomized clinical trial, aims to synergistically pair ketamine infusions with conventional and psychedelic biopsychosocial care. Ketamine is broadly conceptualized as a brief intervention that can produce windows of opportunity for enhanced psychiatric care, as well as powerful occasions for psychological growth. The model combines structured psychiatric care and concomitant psychotherapy with six ketamine infusions, administered with psychedelic-inspired nonpharmacological adjuncts including rolling preparative and integrative psychological support.DiscussionOur integrative model aims to bridge the biomedical-psychedelic divide to offer a feasible, flexible, and standardized approach to ketamine for TRD. Our learnings from developing and implementing this psychedelic-inspired model for severe, real-world patients in two academic hospitals may offer valuable insights for the ongoing roll-out of a range of psychedelic therapies. Further research is needed to assess the Montreal model’s effectiveness and hypothesized psychological mechanisms

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

peer reviewedDespite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain–specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA’s predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies

Generation and Characterization of Recombinant Influenza A (H1N1) Viruses Harboring Amantadine Resistance Mutations

The emergence of resistance to amantadine in influenza A viruses has been shown to occur rapidly during treatment as a result of single-amino-acid substitutions at position 26, 27, 30, 31, or 34 within the transmembrane domain of the matrix-(M)-2 protein. In this study, reverse genetics was used to generate and characterize recombinant influenza A (H1N1) viruses harboring L26F, V27A, A30T, S31N, G34E, and V27A/S31N mutations in the M2 gene. In plaque reduction assays, all mutations conferred amantadine resistance, with drug concentrations resulting in reduction of plaque number by 50% (IC(50)s) 154- to 3,300-fold higher than those seen for the wild type (WT). M2 mutants had no impairment in their replicative capacities in vitro on the basis of plaque size and replication kinetics experiments. In addition, all mutants were at least as virulent as the WT in experimentally infected mice, with the highest mortality rate being obtained with the recombinant harboring a double V27A/S31N mutation. These findings could help explain the frequent emergence and transmission of amantadine-resistant influenza viruses during antiviral pressure in the clinical setting

Disseminated herpes simplex virus type 1 primary infection in a healthy individual

BACKGROUND: Primary herpes simplex virus (HSV) infection usually involves one mucosal region

Compartmentalization of a Multidrug-Resistant Cytomegalovirus UL54 Mutant in a Stem Cell Transplant Recipient with Encephalitis

We report a case of cytomegalovirus encephalitis in a hematopoietic stem cell transplant recipient. A previously uncharacterized V787E mutation in UL54 was identified in cerebrospinal fluid but not plasma specimens. For the V787E recombinant virus, the half maximal effective concentrations for ganciclovir, foscarnet, and cidofovir were 8.6-, 3.4- and 2.9-fold higher than for wild-type virus, and the replicative capacity was lower. The introduction of a bulkier and negatively charged glutamate residue at position 787 could destabilize the finger domain of UL54 DNA polymerase. Viral genotyping of cerebrospinal fluid is warranted in subjects with cytomegalovirus encephalitis, owing to the low penetration of antivirals in this compartment

Microglia are involved in phagocytosis and extracellular digestion during Zika virus encephalitis in young adult immunodeficient mice

Background Zika virus (ZIKV) has been associated with several neurological complications in adult patients. Methods We used a mouse model deficient in TRIF and IPS-1 adaptor proteins, which are involved in type I interferon production, to study the role of microglia during brain infection by ZIKV. Young adult mice were infected intravenously with the contemporary ZIKV strain PRVABC59 (1 × 10⁵ PFUs/100 µL). Results Infected mice did not present overt clinical signs of the disease nor body weight loss compared with noninfected animals. However, mice exhibited a viremia and a brain viral load that were maximal (1.3 × 10⁵ genome copies/mL and 9.8 × 10⁷ genome copies/g of brain) on days 3 and 7 post-infection (p.i.), respectively. Immunohistochemistry analysis showed that ZIKV antigens were distributed in several regions of the brain, especially the dorsal hippocampus. The number of Iba1⁺/TMEM119⁺ microglia remained similar in infected versus noninfected mice, but their cell body and arborization areas significantly increased in the stratum radiatum and stratum lacunosum-moleculare layers of the dorsal hippocampus cornu ammoni (CA)1, indicating a reactive state. Ultrastructural analyses also revealed that microglia displayed increased phagocytic activities and extracellular digestion of degraded elements during infection. Mice pharmacologically depleted in microglia with PLX5622 presented a higher brain viral load compared to untreated group (2.8 × 10¹⁰ versus 8.5 × 10⁸ genome copies/g of brain on day 10 p.i.) as well as an increased number of ZIKV antigens labeled with immunogold in the cytoplasm and endoplasmic reticulum of neurons and astrocytes indicating an enhanced viral replication. Furthermore, endosomes of astrocytes contained nanogold particles together with digested materials, suggesting a compensatory phagocytic activity upon microglial depletion. Conclusions These results indicate that microglia are involved in the control of ZIKV replication and/or its elimination in the brain. After depletion of microglia, the removal of ZIKV-infected cells by phagocytosis could be partly compensated by astrocytes.Medicine, Faculty ofNon UBCBiochemistry and Molecular Biology, Department ofReviewedFacult