Venlafaxine’s therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis

Introduction The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. Objectives We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. Methods Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. Results High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75–225 mg/day). The population-based concentration ranges (25–75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225–450 ng/ml for the AM and (ii) 144–302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140–600 ng/ml. Conclusion VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN’s dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations

Jet Precession Driven by Neutrino-Cooled Disc for Gamma-Ray Bursts

A model of jet precession driven by a neutrino-cooled disc around a spinning black hole is present in order to explain the temporal structure and spectral evolution of gamma-ray bursts (GRBs). The differential rotation of the outer part of a neutrino dominated accretion disc may result in precession of the inner part of the disc and the central black hole, hence drives a precessed jet via neutrino annihilation around the inner part of the disc. Both analytic and numeric results for our model are present. Our calculations show that a black hole-accretion disk system with black hole mass $M \simeq 3.66 M_\odot$, accretion rate $\dot{M} \simeq 0.54 M_\odot \rm s^{-1}$, spin parameter $a=0.9$ and viscosity parameter $\alpha=0.01$ may drive a precessed jet with period P=1 s and luminosity $L=10^{51}$ erg s$^{-1}$, corresponding to the scenario for long GRBs. A precessed jet with $P=0.1$s and $L=10^{50}$ erg s$^{-1}$ may be powered by a system with $M \simeq 5.59 M_\odot$, $\dot{M} \simeq 0.74 M_\odot \rm s^{-1}$, $a=0.1$, and $\alpha=0.01$, possibly being responsible for the short GRBs. Both the temporal and spectral evolution in GRB pulse may explained with our model. GRB central engines likely power a precessed jet driven by a neutrino-cooled disc. The global GRB lightcurves thus could be modulated by the jet precession during the accretion timescale of the GRB central engine. Both the temporal and spectral evolution in GRB pulse may be due to an viewing effect due to the jet precession.Comment: 5 pages, 4 figures, accepted for publication in Astronomy and Astrophysic

Black hole spin: theory and observation

In the standard paradigm, astrophysical black holes can be described solely by their mass and angular momentum - commonly referred to as `spin' - resulting from the process of their birth and subsequent growth via accretion. Whilst the mass has a standard Newtonian interpretation, the spin does not, with the effect of non-zero spin leaving an indelible imprint on the space-time closest to the black hole. As a consequence of relativistic frame-dragging, particle orbits are affected both in terms of stability and precession, which impacts on the emission characteristics of accreting black holes both stellar mass in black hole binaries (BHBs) and supermassive in active galactic nuclei (AGN). Over the last 30 years, techniques have been developed that take into account these changes to estimate the spin which can then be used to understand the birth and growth of black holes and potentially the powering of powerful jets. In this chapter we provide a broad overview of both the theoretical effects of spin, the means by which it can be estimated and the results of ongoing campaigns.Comment: 55 pages, 5 figures. Published in: "Astrophysics of Black Holes - From fundamental aspects to latest developments", Ed. Cosimo Bambi, Springer: Astrophysics and Space Science Library. Additional corrections mad

Polarization Modulation from Lense-Thirring Precession in X-Ray Binaries

It has long been recognized that quasi-periodic oscillations (QPOs) in the X-ray light curves of accreting black hole and neutron star binaries have the potential to be powerful diagnostics of strong field gravity. However, this potential cannot be fulfilled without a working theoretical model, which has remained elusive. Perhaps, the most promising model associates the QPO with Lense-Thirring precession of the inner accretion flow, with the changes in viewing angle and Doppler boosting modulating the flux over the course of a precession cycle. Here, we consider the polarization signature of a precessing inner accretion flow. We use simple assumptions about the Comptonization process generating the emitted spectrum and take all relativistic effects into account, parallel transporting polarization vectors toward the observer along null geodesics in the Kerr metric. We find that both the degree of linear polarization and the polarization angle should be modulated on the QPO frequency. We calculate the predicted absolute rms variability amplitude of the polarization degree and angle for a specific model geometry. We find that it should be possible to detect these modulations for a reasonable fraction of parameter space with a future X-ray polarimeter such as NASA's Polarization Spectroscopic Telescope Array (the satellite incarnation of the balloon experiment X-Calibur)