Antidepressant prescribing patterns and factors influencing the choice of antidepressant for the treatment of depression were examined in the Factors Influencing Depression Endpoints Research ...(FINDER) study, a prospective, observational study in 12 European countries of 3468 adults about to start antidepressant medication for their first episode of depression or a new episode of recurrent depression. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed antidepressant (63.3% patients), followed by serotonin-norepinephrine reuptake inhibitors (SNRIs, 13.6%), but there was considerable variation across countries. Notably, tricyclic and tetracyclic antidepressants (TCAs) were prescribed for 26.5% patients in Germany. The choice of the antidepressant prescribed was strongly influenced by the previous use of antidepressants, which was significantly associated with the prescription of a SSRI (OR 0.64; 95% CI 0.54, 0.76), a SNRI (OR 1.49; 95% CI 1.18, 1.88) or a combination of antidepressants (OR 2.78; 95% CI 1.96, 3.96). Physician factors (age, gender, speciality) and patient factors (severity of depression, age, education, smoking, number of current physical conditions and functional syndromes) were associated with initial antidepressant choice in some models. In conclusion, the prescribing of antidepressants varies by country, and the type of antidepressant chosen is influenced by physician- as well as patient-related factors.
The evidence that the effects of the antidepressant duloxetine on painful physical symptoms in depression and chronic pain disorders are a direct analgesic effect rather than an indirect ...antidepressant effect is reviewed. Data from placebo-controlled acute studies of duloxetine in major depressive disorder, diabetic peripheral neuropathic pain and fibromyalgia syndrome are included in this review. In placebo-controlled studies of duloxetine in patients with major depressive disorder, non-depressed diabetic peripheral neuropathic pain, and fibromyalgia syndrome, duloxetine has a statistically significantly greater effect on pain than placebo. Path analysis suggests that in these patient populations, approximately 50, 90, and 80%, respectively, of the observed effect on pain is a direct analgesic effect rather than an indirect antidepressant effect. In fibromyalgia syndrome studies, duloxetine had similar and substantial effects on pain regardless of whether patients had comorbid major depressive disorder. Pain is a complex experience, involving both the physiological responses of the nociceptive system and the processing of that information in brain regions associated with emotion. While some effects of duloxetine on painful symptoms can be accounted for by its antidepressant action, the data strongly suggest that duloxetine also exerts a substantial direct analgesic effect over and above its antidepressant effects, in patients with major depressive disorder, diabetic peripheral neuropathic pain, and fibromyalgia syndrome.
Abstract Painful physical symptoms (PPS) are common in patients with depression. Our objective was to evaluate the presence of PPS in a sample of SSRI non- or partial-responders with MDD and examine ...the effect of a switch to duloxetine on those PPS. Outpatients who met criteria for MDD despite having taken an SSRI antidepressant for at least 6 weeks, and who had a Hamilton depression rating scale total score of at least 15 and a clinical global impression of severity score of at least 3, were randomized to switch to duloxetine by either a direct switch or a start-taper switch method. PPS were assessed at baseline and at the study endpoint using various measures including six visual analog scales (VAS) for pain (overall pain, headache, back pain, shoulder pain, interference with daily activities, and time in pain while awake), the pain subscale of the symptom questionnaire-somatic subscale, and the bodily pain subscale of the short form-36 item health survey. Clinically significant levels of pain (mean baseline VAS scores >30 mm) were seen across all VAS pain measures prior to switching. Switch to duloxetine was associated with significant improvements on all pain measures regardless of switch method, and there was evidence for an earlier reduction in pain in the start-taper switch group. In summary, MDD patients who were non- or partial-responders to SSRI treatment were found to have clinically significant pain which improved significantly following switch to duloxetine regardless of the switch method utilized.
Previous studies demonstrated the efficiency of the Molecular Dynamics with excited Normal Modes (MDeNM) method on the characterization of large structural changes at a low computational cost. We ...present here MDeNM-EMfit, an extension of the original method designed to the flexible fit of structures into cryo-EM maps. Here, instead of a uniform exploration of the collective motions described by normal modes, sampling is directed toward conformations with increased correlations with the experimental map. Future perspectives to improve the accuracy of fitting and speed of calculations are discussed in light of the results.
Abstract Background Clinical trials assessing antidepressant therapies typically include separate assessments of efficacy (benefit) and adverse events (risk). Global benefit–risk (GBR) assessment ...allows the simultaneous evaluation of both efficacy and adverse events. The objective was to compare the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine using GBR assessment. Methods Data were combined from two similarly designed, multicenter, randomized, double-blind, parallel group studies in which patients with major depressive disorder were randomized to either duloxetine 60 mg/day or venlafaxine extended release (XR) 150 mg/day (75 mg/day for the first 2 weeks) for a 6-week fixed dosing period followed by an additional 6 weeks of treatment in which the dose could be increased up to 120 mg/day for duloxetine and 225 mg/day for venlafaxine. Patients completing the study (or receiving study drug for 2 weeks or more) were eligible to enter a taper period where the dose of study drug was gradually reduced over 1–2 weeks prior to drug discontinuation. The primary outcome measure (defined a priori ) was the GBR comparison of duloxetine 60 mg/day and venlafaxine XR 150 mg/day after 6 weeks of treatment. In the GBR analysis, benefit was defined as remission at endpoint 17-item Hamilton Depression Rating Scale (HAMD17) ⩽ 7. Risk was defined by four categories: patients having either no adverse events (AEs), AEs with no severity rating greater than moderate, AEs with at least one severity rating of severe, or having discontinued with a reason of self-reported adverse event (regardless of any AE severity). Additional efficacy measures included HAMD17 total score and subscales, HAMA, CGI-S, and PGI-I. Safety and tolerability were assessed via analysis of reasons for discontinuation, treatment-emergent adverse events (TEAEs), discontinuation-emergent adverse events, and changes in vital signs, weight, and laboratory analytes. Results There were no significant differences between duloxetine 60 mg/day and venlafaxine 150 mg/day as measured by GBR assessment at the end of 6 weeks (−1.418 vs. −1.079, P = 0.217) or 12 weeks (−0.349 vs. −0.121, P = 0.440), nor were there significant differences between treatment groups on the majority of efficacy measures. Significantly more venlafaxine-treated patients (74.5%) completed 12 weeks of treatment compared with duloxetine-treated patients (64.8%, P = .006). Nausea was the most common treatment-emergent adverse event (TEAE) for both drugs, and was significantly higher with duloxetine 60 mg/day compared to venlafaxine 150 mg/day during the first 6 weeks of treatment (43.6% vs. 35.0%, P ⩽ 0.05). During the taper period, significantly more venlafaxine-treated patients reported discontinuation-emergent adverse events (DEAEs) than duloxetine-treated patients. From a safety perspective, significantly more venlafaxine-treated patients ( n = 4) than duloxetine-treated patients ( n = 0, P = .047) experienced sustained elevations of systolic blood pressure during the fixed dosing period. Otherwise, there were few significant differences in safety measures found between treatment groups during 6 and 12 weeks of therapy. Conclusions Duloxetine 60 mg/day and venlafaxine XR 150 mg/day have similar benefit–risk profiles on the basis of a comparison utilizing GBR assessment. The implications of the more subtle differences between these drugs, as well as for interpreting the GBR assessment, are discussed.
Abstract Background Health-related quality of life (HRQoL) data in depression are limited. We studied the impact of antidepressant (AD) treatment on HRQoL outcomes in depressed patients and ...investigated factors associated with these outcomes in routine practice settings. Methods The Factors Influencing Depression Endpoints Research (FINDER) study was a 6-month, European, prospective, observational study, designed to estimate HRQoL in 3468 adult patients with a clinically diagnosed episode of depression at baseline and at 3 and 6-months after commencing AD treatment. HRQoL was assessed by the Medical Outcome Short-Form (36) Health Survey (SF-36) and European Quality of Life-5 Dimensions (EQ-5D). Regression analysis identified baseline and treatment variables independently and significantly associated with HRQoL outcomes. Results Most HRQoL improvement occurred within 3 months of starting treatment. Better HRQoL outcomes were strongly associated with fewer somatic symptoms at baseline, AD treatment taken and not switching within AD groups. Education and occupational status were also important. Depression variables (number of previous depressions and current episode duration) were consistently associated with worse HRQoL outcomes. Self-rated depression severity was associated with poorer outcomes on the SF-36 mental component only. Limitations As this was an observational study, the important finding that between and within AD group switching impacted HRQoL will need to be investigated in more controlled settings. Conclusions Receiving an AD treatment was associated with large improvements in HRQoL, but switching within AD groups was consistently associated with poorer outcomes. Somatic symptoms, including painful symptoms, are often present in depressed patients and appear to negatively impact HRQoL outcomes.
Molecular Dynamics Flexible Fitting (MDFF) is a widely used tool to refine high-resolution structures into cryo-EM density maps. Despite many successful applications, MDFF is still limited by its ...high computational cost, overfitting, accuracy, and performance issues due to entrapment within wrong local minima. Modern ensemble-based MDFF tools have generated promising results in the past decade. In line with these studies, we present MDFF_NM, a stochastic hybrid flexible fitting algorithm combining Normal Mode Analysis (NMA) and simulation-based flexible fitting. Initial tests reveal that, besides accelerating the fitting process, MDFF_NM increases the diversity of fitting routes leading to the target, uncovering ensembles of conformations in closer agreement with experimental data. The potential integration of MDFF_NM with other existing methods and integrative modeling pipelines is also discussed.
The human neuroendocrine enzyme glutamate decarboxylase (GAD) catalyses the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) using pyridoxal 5'-phosphate as a cofactor. GAD ...exists as two isoforms named according to their respective molecular weights: GAD65 and GAD67. Although cytosolic GAD67 is typically saturated with the cofactor (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo form. GAD65, but not GAD67, is a prevalent autoantigen, with autoantibodies to GAD65 being detected at high frequency in patients with autoimmune (type 1) diabetes and certain other autoimmune disorders. The significance of GAD65 autoinactivation into the apo form for regulation of neurotransmitter levels and autoantibody reactivity is not understood. We have used computational and experimental approaches to decipher the nature of the holo → apo conversion in GAD65 and thus, its mechanism of autoinactivation. Molecular dynamics simulations of GAD65 reveal coupling between the C-terminal domain, catalytic loop, and pyridoxal 5'-phosphate-binding domain that drives structural rearrangement, dimer opening, and autoinactivation, consistent with limited proteolysis fragmentation patterns. Together with small-angle X-ray scattering and fluorescence spectroscopy data, our findings are consistent with apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 in its autoantigenicity. Although conformational diversity may provide a mechanism for cofactor-controlled regulation of neurotransmitter biosynthesis, it may also come at a cost of insufficient development of immune self-tolerance that favors the production of GAD65 autoantibodies.
To assess the efficacy of duloxetine 60-120 mg once daily in the prevention of depressive recurrence in outpatients with recurrent major depressive disorder (MDD).
Eligible patients with at least 3 ...episodes of MDD (DSM-IV diagnosis) in the past 5 years received open-label duloxetine 60-120 mg/day for up to 34 weeks. Patients meeting response criteria were then randomly assigned to either duloxetine or placebo for up to 52 weeks of double-blind maintenance treatment. The primary outcome measure was time to recurrence of a major depressive episode. Safety and tolerability were assessed via analysis of treatment-emergent adverse events (TEAEs), vital signs, weight, and laboratory measures. Patients were recruited from 43 study centers in 5 European countries (France, Germany, Italy, Russia, and Sweden) and the United States. The study was conducted from March 2005 to January 2008.
A total of 288 patients were randomly assigned to duloxetine or placebo. Time to a depressive recurrence was significantly longer in duloxetine-treated patients compared with placebo-treated patients (p < .001). During the double-blind maintenance phase, 33.1% of placebo-treated patients experienced a depressive recurrence compared with 14.4% of duloxetine-treated patients (p < .001). There were no significant differences between treatment groups in TEAEs, discontinuations due to adverse events, vital signs, or weight.
Treatment with duloxetine was associated with a longer time to depressive recurrence and a significantly lower recurrence rate compared with placebo.
(ClinicalTrials.gov) Identifier: NCT00105989.
Molecular dynamics with excited normal modes (MDeNM) is an enhanced sampling method for exploring conformational changes in proteins with minimal biases. The excitation corresponds to injecting ...kinetic energy along normal modes describing intrinsic collective motions. Herein, we developed a new automated open-source implementation, MDexciteR (https://github.com/mcosta27/MDexciteR), enabling the integration of MDeNM with two commonly used simulation programs with GPU support. Second, we generalized the method to include the excitation of principal components calculated from experimental ensembles. Finally, we evaluated whether the use of coarse-grained normal modes calculated with elastic network representations preserved the performance and accuracy of the method. The advantages and limitations of these new approaches are discussed based on results obtained for three different protein test cases: two globular and a protein/membrane system.
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