Randomized placebo controlled trials of n-acetyl cysteine as adjunct therapy for schizophrenia and bipolar disorder

Glutathione is the principal antioxidant of the brain. There is evidence of oxidative stress, lowered brain glutathione and genetic linkage involve glutathione metabolic genes in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a safe, orally bioavailable, precursor of glutathione. NAC has been shown to reverse animal models of oxidative stress, and raises brain glutathione levels.<br /

Protocol and rationale-the efficacy of minocycline as an adjunctive treatment for major depressive disorder: a double blind, randomised, placebo controlled trial

While current pharmacotherapies are efficacious, there remain a clear shortfall between symptom remission and functional recovery. With the explosion in our understanding of the biology of these disorders, the time is ripe for the investigation of novel therapies. Recently depression is conceptualized as an immune-inflammatory and nitro-oxidative stress related disorder. Minocycline is a tetracycline antibiotic that has anti-inflammatory, pro-oxidant, glutamatergic, neurotrophic and neuroprotective properties that make it a viable target to explore as a new therapy. This double blind, randomised, placebo controlled adjunctive trial will investigate the benefits of 200 mg/day of minocycline treatment, in addition to any usual treatment, as an adjunctive treatment for moderate-severe major depressive disorder. Sixty adults are being randomised to 12 weeks of treatment (with a 4 week follow-up post-discontinuation). The primary outcome measure for the study is mean change on the Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcomes including the Social and Occupational Functioning Assessment Scale (SOFAS), Clinical Global Impressions (CGI), Hamilton Rating Scale for Anxiety (HAM-A), Patient Global Impression (PGI), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and Range of Impaired Functioning Tool (LIFE-RIFT). Biomarker analyses will also be conducted at baseline and week 12. The study has the potential to provide new treatment targets, both by showing efficacy with a new class of \u27antidepressant\u27 but also through the analysis of biomarkers that may further inform our understanding of the pathophysiology of unipolar depression

Pathways to new drug discovery in neuropsychiatry

There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success

Recovery from Hepatorenal Syndrome after Orthotopic Liver Transplantation

Three patients with progressive renal failure and advanced hepatic insufficiency due to cirrhosis of the liver underwent orthotopic liver transplantation. All three patients had immediate improvement in hepatic function and within two weeks after liver replacement regained nearly normal kidney function. However, the renal recovery was delayed in each case, and its course was not uniform. Plasma renin activity was high, and renin substrate was low before transplantation in one case in which these measurements were obtained; both returned to normal soon after liver replacement. (N Engl J Med 289:1155–1159, 1973). © 1973, Massachusetts Medical Society. All rights reserved

Stage managing bipolar disorder.

OBJECTIVES: Clinical staging is widespread in medicine - it informs prognosis, clinical course, and treatment, and assists individualized care. Staging places an individual on a probabilistic continuum of increasing potential disease severity, ranging from clinically at-risk or latency stage through first threshold episode of illness or recurrence, and, finally, to late or end-stage disease. The aim of the present paper was to examine and update the evidence regarding staging in bipolar disorder, and how this might inform targeted and individualized intervention approaches. METHODS: We provide a narrative review of the relevant information. RESULTS: In bipolar disorder, the validity of staging is informed by a range of findings that accompany illness progression, including neuroimaging data suggesting incremental volume loss, cognitive changes, and a declining likelihood of response to pharmacological and psychosocial treatments. Staging informs the adoption of a number of approaches, including the active promotion of both indicated prevention for at-risk individuals and early intervention strategies for newly diagnosed individuals, and the tailored implementation of treatments according to the stage of illness. CONCLUSIONS: The nature of bipolar disorder implies the presence of an active process of neuroprogression that is considered to be at least partly mediated by inflammation, oxidative stress, apoptosis, and changes in neurogenesis. It further supports the concept of neuroprotection, in that a diversity of agents have putative effects against these molecular targets. Clinically, staging suggests that the at-risk state or first episode is a period that requires particularly active and broad-based treatment, consistent with the hope that the temporal trajectory of the illness can be altered. Prompt treatment may be potentially neuroprotective and attenuate the neurostructural and neurocognitive changes that emerge with chronicity. Staging highlights the need for interventions at a service delivery level and implementing treatments at the earliest stage of illness possible

A comparison of incompressible limits for resistive plasmas

The constraint of incompressibility is often used to simplify the magnetohydrodynamic (MHD) description of linearized plasma dynamics because it does not affect the ideal MHD marginal stability point. In this paper two methods for introducing incompressibility are compared in a cylindrical plasma model: In the first method, the limit $\gamma \to \infty$ is taken, where $\gamma$ is the ratio of specific heats; in the second, an anisotropic mass tensor $\mathbf{\rho}$ is used, with the component parallel to the magnetic field taken to vanish, $\rho_{\parallel} \to 0$. Use of resistive MHD reveals the nature of these two limits because the Alfv\'en and slow magnetosonic continua of ideal MHD are converted to point spectra and moved into the complex plane. Both limits profoundly change the slow-magnetosonic spectrum, but only the second limit faithfully reproduces the resistive Alfv\'en spectrum and its wavemodes. In ideal MHD, the slow magnetosonic continuum degenerates to the Alfv\'en continuum in the first method, while it is moved to infinity by the second. The degeneracy in the first is broken by finite resistivity. For numerical and semi-analytical study of these models, we choose plasma equilibria which cast light on puzzling aspects of results found in earlier literature.Comment: 14 pages, 10 figure

Trapped 6^{6}Li : A high T_c superfluid ?

We consider the effect of the indirect interaction due to the exchange of density fluctuations on the critical temperature of superfluid $^{6}$Li . We obtain the strong coupling equation giving this critical temperature. This equation is solved approximately by retaining the same set of diagrams as in the paramagnon model. We show that, near the instability threshold, the attractive interaction due to density fluctuations gives rise to a strong increase in the critical temperature, providing a clear signature of the existence of fluctuation induced interactions.Comment: 4 pages, revtex, 1 figur