Antidepressants for Major Depressive Disorder and Dysthymic Disorder in patients with co-morbid Alcohol Use Disorders: state of the art and a meta-analysis of placebo-controlled randomized trials.

Abstract Major depressive disorder (MDD) and dysthymic disorder (DD) are often complicated by the co-occurrence of alcohol use disorders (AUDs), each condition often aggravating the course and outcome of the other in terms of severity, functional impairment, risk of suicide, relapse of depression and drinking behaviors, and chronicity. Recently, there has been some evidence that antidepressants may improve depressive symptoms in patients with concurrent AUDs, even if they have only a limited effect in decreasing alcohol use in these subjects. To date, however, there is a paucity of randomized, double-blind, placebo-controlled trials that have been conducted to evaluate the efficacy, safety, and tolerability of antidepressants as monotherapy for patients with MDD/DD and co-occurring AUDs. Although previous meta-analyses have found antidepressants to be more effective than placebo in the treatment of this specific patient population, efficacy for newer agents (i.e. the SSRIs) was questionable. The aim of this study is to examine the efficacy of antidepressants in patients with unipolar depression (MDD and/or DD) with co-morbid AUDs, and to compare compare study design characteristics, patient characteristics, and drug-/placebo- outcomes between depressed patients with or without co-morbid AUDs. Method Medline/Pubmed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for the acute-phase treatment of MDD and/or DD in patients with or without AUDs. The search was limited to articles published between January 1980 and March 2010 (inclusive). We selected for studies which focused on the treatment of adult patients, were at least 4 weeks of duration, used antidepressants in their oral formulation, and used either the Hamilton Depression Rating Scale (HDRS), the Montgomery-Asperg Depression Rating Scale (MADRS), or the Clinical Global Impression-Improvement Scale (CGI) as one of their outcome measures. The primary outcome for our meta-analysis was clinical response, defined as a 50% or greater reduction in HDRS or MADRS scores, baseline to endpoint, or a CGI-I<3 at the final visit. Results A total of 195 manuscripts were found eligible for inclusion in our analysis (n=46,820 patients), 11 of which focused on the treatment of MDD/DD in patients with co-morbid AUDs. We found that antidepressant therapy was more effective than placebo in patients with co-morbid AUDs (RR=1.336; p=0.021), but not when SSRIs were examined alone (RR= 1.145; p=0.316). There was no difference in the relative efficacy of antidepressants (versus placebo) when comparing studies in MDD/DD patients with or without AUDs (p=0.973). Meta-regression analyses yielded no significant differences in the RR of responding to antidepressants versus placebo in trials with co-morbid AUDs whether antidepressants were used alone or adjunctively to psychotherapy, whether used in patients actively drinking or recently sober, or whether used in pure MDD or in combined MDD and DD populations. Moreover, the baseline severity of drinking (assessed as the number of heavy drinking days in the week before randomization) did not predict a significantly difference in the response rate to antidepressants (coefficient= -0.644, p=0.467). Finally, there was no statistically significant difference in the percentage of heavy drinking days at the end of the study between antidepressant- and placebo- treated patients (RR = 0.691, p=0.275) Conclusions Our results suggests that antidepressants are more effective than placebo in treating depression in patients with co-morbid AUDs, and lend further support to the argument that antidepressants should represent first-line therapy for targeting depressive symptoms in patients with alcohol use disorders, a condition which is highly prevalent and is associated with high rates of medical and psychiatric comorbidity, disability, and increased use of general medical health services as well as psychiatric hospitalizations. However, the use of SSRIs for treating depression in such patients is not convincingly supported by the evidence. More data on the use of newer antidepressants, including SNRIs and SSRIs, for this select patient population are needed. Moreover, our work showed that the efficacy of antidepressants was not influenced whether patients were actively drinking or recently sober, and we did not find any relationship between the severity of baseline drinking and treatment outcome. This suggests that the decision whether to recommend antidepressants in this patient population should not be determined by these variables, at least as far as the potential efficacy of treatment is concerned

Small scale anisotropy in turbulent shearless mixing

We have imagined a numerical experiment to explore the onset of turbulent intermittency associated with a spatial perturbation of the correlation length. We place two isotropic regions, with different integral scales, inside a volume where the turbulent kinetic energy is initially uniform and leave them to interact and evolve in time. The different length scales produce different decay rates in the two regions. Since the smaller-scale region decays faster, a transient turbulent energy gradient is generated at the interface between the two regions. The transient is characterized by three phases in which the kinetic energy gradient across the interface grows, peaks and then slowly decays. The transient lifetime is almost proportional to the initial ratio of the correlation lengths. The direct numerical simulations also show that the interface width grows in time. The velocity moments inside this interaction zone are seen to depart from their initial isotropic values and, with a certain lag, the anisotropy is seen to spread to small scales. The longitudinal derivative moments also become anisotropic after a few eddy turnover times. This anisotropic behaviour is different from that observed in sheared homogeneous turbulent flows, where high transverse derivative moments are generated, but longitudinal moments almost maintain the isotropic turbulence values. Apart from the behaviour of the energy gradient transients, the results also show the timescaling of the interface diffusion width, and data on the anisotropy of the large and small scales, observed through one-point statistics determined inside the intermittency sublayer, which is associated with the interaction zone. Supplemental Material Online: http://prl.aps.org/supplemental/PRL/v107/i19/e19450

Small scale of subgrid scales in the Large Eddy Simulation of compressible turbulent flows

It is proposed a methodology for the automatic selective insertion-elimination of subgrid scale stresses in the numerical simulation of transitional laminar-turbulent flows in both compressible and incompressible regimes. By means of a functional of the filtered vorticity field, it is possible to approximatively locate the flow regions that are rich in small scale motions. In these regions, it can be opportune to filter the equations of motion to carry out a Large Eddy Simulation, that is, a simulation where the larger scales only are resolved, but the small scale dynamics is considered and represented through proper terms in the equations. In case of compressible regimes, a functional of the pressure local variation and divergence can be associated to the functional previously mentioned in order to determine the eventual presence of shocks. In such a way, it is possible to locate the regions where, to capture the shock, it is necessary to insert an explicit numerical dissipation and suppress the subgrid mode

Self-similarity of the turbulent mixing with a constant in time macroscale gradient

In the absence of kinetic energy production, we consider that the influence of the initial conditions is characterized by the presence of an energy gradient or by the concurrency of an energy and a macroscale gradient on turbulent transport. Here, we present a similarity analysis that interprets two new results on the subject recently obtained by means of numerical experiments on shearless mixing (Tordella & Iovieno, 2005). In short, the two results are: i -- The absence of the macroscale gradient is not a sufficient condition for the setting of the asymptotic Gaussian state hypothesized by Veeravalli and Warhaft (1989), where, regardless of the existence of velocity variance distributions, turbulent transport is mainly diffusive and the intermittency is nearly zero up to moments of order four. In fact, it was observed that the intermittency increases with the energy gradient, with a scaling exponent of about 0.29; ii -- If the macroscale gradient is present, referring to the situation where the macroscale gradient is zero but the energy gradient is not, the intermittency is higher if the energy and scale gradients are concordant and is lower if they are opposite. The similarity analysis, which is in fair agreement with the previous experiments, is based on the use of the kinetic energy equation, which contains information concerning the third order moments of the velocity fluctuations. The analysis is based on two simplifying hypotheses: first, that the decays of the turbulences being mixed are almost nearly equal (as suggested by the experiments), second, that the pressure-velocity correlation is almost proportional to the convective transport associated to the fluctuations (Yoshizawa, 2002

Dimensionality influence on passive scalar transport

We numerically investigate the advection of a passive scalar through an interface placed inside a decaying shearless turbulent mixing layer. We consider the system in both two and three dimensions. The dimensionality produces a different time scaling of the diffusion, which is faster in the two-dimensional case. Two intermittent fronts are generated at the margins of the mixing layer. During the decay these fronts present a sort of propagation in both the direction of the scalar flow and the opposite direction. In two dimensions, the propagation of the fronts exhibits a significant asymmetry with respect to the initial position of the interface and is deeper for the front merged in the high energy side of the mixing. In three dimensions, the two fronts remain nearly symmetrically placed. Results concerning the scalar spectra exponents are also presente

Solitons and nonsmooth diffeomorphisms in conformal nets

We show that any solitonic representation of a conformal (diffeomorphism covariant) net on S^1 has positive energy and construct an uncountable family of mutually inequivalent solitonic representations of any conformal net, using nonsmooth diffeomorphisms. On the loop group nets, we show that these representations induce representations of the subgroup of loops compactly supported in S^1 \ {-1} which do not extend to the whole loop group. In the case of the U(1)-current net, we extend the diffeomorphism covariance to the Sobolev diffeomorphisms D^s(S^1), s > 2, and show that the positive-energy vacuum representations of Diff_+(S^1) with integer central charges extend to D^s(S^1). The solitonic representations constructed above for the U(1)-current net and for Virasoro nets with integral central charge are continuously covariant with respect to the stabilizer subgroup of Diff_+(S^1) of -1 of the circle.Comment: 33 pages, 3 TikZ figure

Multiscale fluid--particle thermal interaction in isotropic turbulence

We use direct numerical simulations to investigate the interaction between the temperature field of a fluid and the temperature of small particles suspended in the flow, employing both one and two-way thermal coupling, in a statistically stationary, isotropic turbulent flow. Using statistical analysis, we investigate this variegated interaction at the different scales of the flow. We find that the variance of the fluid temperature gradients decreases as the thermal response time of the suspended particles is increased. The probability density function (PDF) of the fluid temperature gradients scales with its variance, while the PDF of the rate of change of the particle temperature, whose variance is associated with the thermal dissipation due to the particles, does not scale in such a self-similar way. The modification of the fluid temperature field due to the particles is examined by computing the particle concentration and particle heat fluxes conditioned on the magnitude of the local fluid temperature gradient. These statistics highlight that the particles cluster on the fluid temperature fronts, and the important role played by the alignments of the particle velocity and the local fluid temperature gradient. The temperature structure functions, which characterize the temperature fluctuations across the scales of the flow, clearly show that the fluctuations of the fluid temperature increments are monotonically suppressed in the two-way coupled regime as the particle thermal response time is increased. Thermal caustics dominate the particle temperature increments at small scales, that is, particles that come into contact are likely to have very large differences in their temperature. This is caused by the nonlocal thermal dynamics of the particles..

Philofluid turbulent flow database

A set of velocity and passive scalar fields and their statistics coming from direct numerical simulations and large-eddy simulations. The database includes: shearless mixings in two a three dimensions, turbulent channel flow, cavity flow. Username and password to access the netdisks is provided upon request