Pharmacological Evaluation of the Long-Term Effects of Xanomeline on the M1 Muscarinic Acetylcholine Receptor

Xanomeline is a unique agonist of muscarinic receptors that possesses functional selectivity at the M1 and M4 receptor subtypes. It also exhibits wash-resistant binding to and activation of the receptor. In the present work we investigated the consequences of this type of binding of xanomeline on the binding characteristics and function of the M1 muscarinic receptor. Pretreatment of CHO cells that stably express the M1 receptor for 1 hr with increasing concentrations of xanomeline followed by washing and waiting for an additional 23 hr in control culture media transformed xanomeline-induced inhibition of [3H]NMS binding from monophasic to biphasic. The high-affinity xanomeline binding site exhibited three orders of magnitude higher affinity than in the case of xanomeline added directly to the binding assay medium containing control cells. These effects were associated with a marked decrease in maximal radioligand binding and attenuation of agonist-induced increase in PI hydrolysis and were qualitatively similar to those caused by continuous incubation of cells with xanomeline for 24 hr. Attenuation of agonist-induced PI hydrolysis by persistently-bound xanomeline developed with a time course that parallels the return of receptor activation by prebound xanomeline towards basal levels. Additional data indicated that blockade of the receptor orthosteric site or the use of a non-functional receptor mutant reversed the long-term effects of xanomeline, but not its persistent binding at an allosteric site. Furthermore, the long-term effects of xanomeline on the receptor are mainly due to receptor down-regulation rather than internalization

Treatment patterns associated with Duloxetine and Venlafaxine use for Major Depressive Disorder

<p>Abstract</p> <p>Background</p> <p>Duloxetine and venlafaxine extended release (venlafaxine XR) are SNRIs indicated for the treatment of MDD. This study addresses whether duloxetine and venlafaxine XR are interchangeable in their patterns of use with patients who are depressed or are used more selectively based on treatment history, background characteristics, and presenting symptoms.</p> <p>Methods</p> <p>This was a retrospective analysis of an administrative insurance claims database. We studied patients in managed care with major depressive disorder (MDD) treated with duloxetine or venlafaxine XR. Predictors of treatment and cost were assessed using Chi-square and logistic regression analyses of demographics and past-year medication use and comorbidities.</p> <p>Results</p> <p>Patients with MDD treated with duloxetine (n = 9,641) versus venlafaxine XR (n = 8,514) tended to be older, slightly more likely to be female, and treated by a psychiatrist (<it>P </it>< 0.0001). In the prior year, more duloxetine patients (vs. venlafaxine XR) received ≥3 unique antidepressants (20.8% vs. 16.6%), ≥3 unique pain medications (25.5% vs. 15.6%), and had ≥8 unique diagnosed comorbid medical and psychiatric conditions (38.6% vs. 29.1%). The prior 6-month total health care costs were $1,731 higher for duloxetine than for venlafaxine XR and declined for both medications in the 6 months after treatment began. Logistic regression analysis revealed that 61% of duloxetine patients and 61% of venlafaxine XR patients were predictable from prior patient and treatment factors.</p> <p>Conclusions</p> <p>Patients with MDD treated with duloxetine tended to have a more complex and costly antecedent clinical presentation compared with venlafaxine XR patients, suggesting that physicians do not use the medications interchangeably.</p

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Different Classes of Antidepressants

Various antidepressants are commonly used for the treatment of depression and several other neuropsychiatric disorders. In addition to their primary effects on serotonergic or noradrenergic neurotransmitter systems, antidepressants have been shown to interact with several receptors and ion channels. However, the molecular mechanisms that underlie the effects of antidepressants have not yet been sufficiently clarified. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to have therapeutic potential for several neuropsychiatric disorders and cardiac arrhythmias. In the present study, we investigated the effects of various classes of antidepressants on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2 or GIRK1/GIRK4 subunits, extracellular application of sertraline, duloxetine, and amoxapine effectively reduced GIRK currents, whereas nefazodone, venlafaxine, mianserin, and mirtazapine weakly inhibited GIRK currents even at toxic levels. The inhibitory effects were concentration-dependent, with various degrees of potency and effectiveness. Furthermore, the effects of sertraline were voltage-independent and time-independent during each voltage pulse, whereas the effects of duloxetine were voltage-dependent with weaker inhibition with negative membrane potentials and time-dependent with a gradual decrease in each voltage pulse. However, Kir2.1 channels were insensitive to all of the drugs. Moreover, the GIRK currents induced by ethanol were inhibited by sertraline but not by intracellularly applied sertraline. The present results suggest that GIRK channel inhibition may reveal a novel characteristic of the commonly used antidepressants, particularly sertraline, and contributes to some of the therapeutic effects and adverse effects

Duloxetine in the treatment of major depressive disorder: an open-label study

<p>Abstract</p> <p>Background</p> <p>Major depressive disorder (MDD) is a chronic and highly disabling condition. Existing pharmacotherapies produce full remission in only 30% to 40% of treated patients. Antidepressants exhibiting dual reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE) may achieve higher rates of remission compared with those acting upon a single neurotransmitter. In this study, the safety and efficacy of duloxetine, a potent dual reuptake inhibitor of 5-HT and NE, were examined.</p> <p>Methods</p> <p>Patients (N = 533) meeting DSM-IV criteria for MDD received open-label duloxetine (60 mg once a day [QD]) for 12 weeks during the initial phase of a relapse prevention trial. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD₁₇) total score ≥18 and a Clinical Global Impression of Severity (CGI-S) score ≥4 at baseline. Efficacy measures included the HAMD₁₇total score, HAMD₁₇subscales, the CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQ-SS). Quality of life was assessed using the Sheehan Disability Scale (SDS) and the Quality of Life in Depression Scale (QLDS). Safety was evaluated by recording spontaneously-reported treatment-emergent adverse events, changes in vital signs and laboratory analytes, and the Patient Global Impression of Sexual Function (PGI-SF) scale.</p> <p>Results</p> <p>The rate of discontinuation due to adverse events was 11.3%. Treatment-emergent adverse events reported by ≥10% duloxetine-treated patients were nausea, headache, dry mouth, somnolence, insomnia, and dizziness. Following 12 weeks of open-label duloxetine therapy, significant improvements were observed in all assessed efficacy and quality of life measures. In assessments of depression severity (HAMD₁₇, CGI-S) the magnitude of symptom improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment.</p> <p>Conclusion</p> <p>In this open-label phase of a relapse prevention study, duloxetine (60 mg QD) was shown to be safe and effective in the treatment of MDD.</p> <p>Trial registration</p> <p>NCT00036309.</p

Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils

It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD). A former study from our laboratory has shown that both methylphenidate (MP) and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC) of early traumatized gerbils (Meriones unguiculatus). The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model

Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease.

Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest ('task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems.This work was funded by the Wellcome trust (103838), Parkinson’s UK, National Institute for Health Research’s Cambridge Biomedical Research Centre and the Medical Research Council (MC_US_A060_0016 and RG62761) and the James F McDonnell Foundation (21st century science initiative on Understanding Human Cognition). The BCNI is supported by a joint award from the Wellcome Trust and Medical Research Council.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/npp.2016.1

Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4–methylenedioxy­methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence

Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder - Possible Role for Methoxyindole Pathway

10.1371/journal.pone.0068283PLoS ONE87-POLN