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Chronic pain and depression commonly occur together so dual-acting agents might be particularly useful. The population of patients with chemotherapy-induced neuropathy is increasing in parallel with the increase of population of cancer survivors and there is a compelling need for satisfactory treatment of symptoms of neuropathy and concomitant depression. We examined the effects of vortioxetine, a novel antidepressant with unique mechanism of action, on pain hypersensitivity and depression-like behavior in oxaliplatin-induced neuropathy model in mice (OIPN). Vortioxetine (1-10 mg/kg, p.o.) significantly and dose-dependently reduced mechanical allodynia in von Frey test and cold allodynia in acetone test in OIPN mice, in both repeated prophylactic and acute therapeutic treatment regimens. It also reduced depression-like behavior in the forced swimming test in OIPN mice, in both treatment paradigms. Its antiallodynic and antidepressive-like effects were comparable to those exerted by duloxetine (1-15 mg/kg, p.o.). The antiallodynic and antidepressive-like effects of repeatedly administered vortioxetine might be related to the increased content of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), detected in the brainstem of treated OIPN mice. These results indicate that vortioxetine could be potentially useful in prevention and treatment of chemotherapy-induced neuropathy, for the relief of pain and concomitant depressive symptoms. It should be further tested to this regard in clinical settings., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The antineoplastic agent oxaliplatin is a first-line treatment for colorectal cancer. However, neuropathic pain, characterized by hypersensitivity to cold, emerges soon after treatment. In severe instances, dose reduction or curtailing treatment may be necessary. While a number of potential treatments for oxaliplatin-induced neuropathic pain have been proposed based on preclinical findings, few have demonstrated efficacy in randomized, placebo-controlled clinical studies. This failure could be related, in part, to the use of rodents as the primary preclinical species, as there are a number of distinctions in pain-related mechanisms between rodents and humans. Also, an indicator of preclinical pharmacological efficacy less subjective than behavioral endpoints that is translatable to clinical usage is lacking. Three days after oxaliplatin treatment in Macaca fascicularis, a significantly reduced response latency to cold (10 °C) water was observed, indicating cold hypersensitivity. Cold-evoked bilateral activation of the secondary somatosensory (SII) and insular (Ins) cortex was observed with functional magnetic resonance imaging. Duloxetine alleviated cold hypersensitivity and significantly attenuated activation in both SII and Ins. By contrast, neither clinically used analgesics pregabalin nor tramadol affected cold hypersensitivity and cold-evoked activation of SII and Ins. The current findings suggest that suppressing SII and Ins activation leads to antinociception, and, therefore, could be used as a non-behavioral indicator of analgesic efficacy in patients with oxaliplatin-induced neuropathic pain., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Major depressive disorder (MDD) is a complex disorder with many pathways known to contribute to its pathogenesis, such as apoptotic signaling, with antidepressants having been shown to target these pathways. In this study, we explored microRNAs as predictive markers of drug response to duloxetine, a serotonin-norepinephrine reuptake inhibiter, using peripheral blood samples from 3 independent clinical trials (NCT00635219; NCT0059991; NCT01140906) comparing 6-8 weeks of treatment with duloxetine to placebo treatment in patients with MDD. Plasma microRNA was extracted and sequenced using the Ion Proton Sequencer. Rank feature selection analysis was used to identify microRNAs in the top 10th percentile for their differentiating ability between patients who remitted and did not remit with duloxetine treatment. The results were then compared between the 3 trials to see their replicability. To further validate our findings, we reasoned that the pathways targeted by these microRNAs would be those shown to be altered in MDD in pathway enrichment analysis. Hsa-miR-23a-3p, hsa-miR-16-5p, hsa-miR-146a-5p and hsa-miR-21-5p were identified in 2 or more trials as being able to differentiate patients who would remit with duloxetine treatment using samples collected before treatment initiation, suggesting that they may be good candidates for identification of predictive biomarkers of duloxetine response. Pathway enrichment analysis further showed that microRNAs identified as differentiating for duloxetine response target the apoptosis signaling pathway. Future studies examining these microRNAs outside of a clinical trial setting and exploring their role in MDD may further our understanding of MDD and antidepressant response., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders and is commonly treated with antidepressant drugs. However, large variability is observed in terms of response to antidepressants. Machine learning (ML) models may be useful to predict treatment outcomes. A sample of 186 MDD patients received treatment with duloxetine for up to 8 weeks were categorized as "responders" based on a MADRS change >50% from baseline; or "remitters" based on a MADRS score ≤10 at end point. The initial dataset (N = 186) was randomly divided into training and test sets in a nested 5-fold cross-validation, where 80% was used as a training set and 20% made up five independent test sets. We performed genome-wide logistic regression to identify potentially significant variants related to duloxetine response/remission and extracted the most promising predictors using LASSO regression. Subsequently, classification-regression trees (CRT) and support vector machines (SVM) were applied to construct models, using ten-fold cross-validation. With regards to response, none of the pairs performed significantly better than chance (accuracy p > .1). For remission, SVM achieved moderate performance with an accuracy = 0.52, a sensitivity = 0.58, and a specificity = 0.46, and 0.51 for all coefficients for CRT. The best performing SVM fold was characterized by an accuracy = 0.66 (p = .071), sensitivity = 0.70 and a sensitivity = 0.61. In this study, the potential of using GWAS data to predict duloxetine outcomes was examined using ML models. The models were characterized by a promising sensitivity, but specificity remained moderate at best. The inclusion of additional non-genetic variables to create integrated models may improve prediction., (Copyright © 2017. Published by Elsevier Ltd.)

The antidepressant vortioxetine exerts its effects via modulation of several serotonin (5-HT) receptors and inhibition of the 5-HT transporter (SERT). Additionally, vortioxetine has beneficial effects on aspects of cognitive dysfunction in depressed patients. However, a global examination of the drug effect on brain network connectivity is still missing. Here we compared the effects of vortioxetine and a serotonin norepinephrine reuptake inhibitor, duloxetine, on resting-state functional connectivity (RSFC) across the whole brain in awake rats using a combination of pharmacological and awake animal resting-state functional magnetic resonance imaging (rsfMRI) techniques. Our data showed that vortioxetine and duloxetine affected different inter-areal connections with limited overlap, indicating that in addition to different primary target profiles, these two antidepressants have distinct mechanisms of action at the systems level. Further, our data suggest that vortioxetine can affect specific brain areas with distinct 5-HT receptor expression profiles. Taken together, this study demonstrates that the awake animal fMRI approach provides a powerful tool to elucidate the effects of drugs on the brain with high spatial specificity and a global field of view. This capability is valuable to understand how different drugs affect the systems-level brain function, and provides important guidance to dissect specific brain regions and connections for further detailed mechanistic studies. This study also highlights the translational opportunity of the awake animal fMRI approach between preclinical results and human studies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Antidepressants remain one of the first line treatments prescribed to neuropathic pain patients despite their limited efficacy and/or their numerous side effects. More and more, pharmacotherapy for neuropathic pain has evolved towards the use of therapeutic combinations. The goal of the present study was to assess the efficacy of the combination of antidepressants - selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors-with a peptide (TAT-2ASCV) able to disrupt the interaction between serotonin type 2A (5-HT 2A ) receptors and associated PDZ proteins. Mechanical hypersensitivity was assessed in sciatic nerve ligation-induced neuropathic pain in rats using paw pressure test after acute treatment with TAT-2ASCV alone or in combination with repeated treatment with fluoxetine or duloxetine or clomipramine. First, we validated the anti-hyperalgesic effect of TAT-2ASCV on mechanical hypersensitivity at the dose of 100 ng/rat (single i.t. injection). Second, using selective receptor antagonists, we found that the effect of TAT-2ASCV on mechanical hypersensitivity involves 5-HT 2A as well as GABA A receptors. Finally, we showed that the association of TAT-2ASCV (100 ng, single i.t. injection) with fluoxetine (10 mg/kg, five i.p. injections) reveals its anti-hyperalgesic effect, while the association with duloxetine (1 mg/kg, five i.p. injections) or clomipramine (2.5 mg/kg, five i.p. injections) is only additive. Those results further accentuate the interest to develop small molecules acting like TAT-2ASCV in order to treat neuropathic pain as a monotherapy or in combination with antidepressants., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Convulsive seizures (CS) are deleterious consequences of acute cerebral insults and prejudicial events in epilepsy, affecting more than 50 million people worldwide. Molecular mechanisms of depression and epilepsy include an imbalance between excitatory and inhibitory neurotransmission provoking oxidative stress (OS). OS is intimately linked to the origin and evolution of CS and is modulated by antidepressant and anticonvulsant drugs. Although newer antidepressants have exhibited a possible protective role in CS, studies analyzing serotonin and norepinephrine reuptake inhibitors merit to be further investigated. Thus, this study challenged the traditional model of pentylenetetrazol-induced CS, with only one administration of duloxetine. Male Swiss mice were treated with duloxetine (dose corresponding to the therapeutic range for human depression or greater, by allometric calculation; 10, 20 or 40 mg/kg), 30 min before pentylenetetrazol. Behavioral and electroencephalographic alterations were monitored. Lipid peroxidation, nitrites and catalase and superoxidase activities were measured in cortex. Behavioral and electroencephalographic results suggested a possible biphasic effect of duloxetine on CS, with anticonvulsant actions at therapeutic doses and a proconvulsant effect at higher doses. Duloxetine (20 mg/kg) also prevented lipid peroxidation and decreased catalase and superoxide dismutase activities in the cerebral cortex, with no influence on nitrites levels. These data demonstrated an anticonvulsant effect of duloxetine in CS for the first time. This extra anticonvulsant effect may allow the doses of anticonvulsants to be reduced, causing fewer side effects and possibly decreasing morbidity and mortality due to drug interactions in polytherapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cognitive dysfunction is prevalent in patients with major depressive disorder (MDD), and cognitive impairments can persist after relief of depressive symptoms. The multimodal-acting antidepressant vortioxetine is an antagonist at 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist at 5-HT1B receptors, an agonist at 5-HT1A receptors, and an inhibitor of the serotonin (5-HT) transporter (SERT) and has pro-cognitive properties. In preclinical studies, vortioxetine enhances long-term potentiation (LTP), a cellular correlate of neuroplasticity, and enhances memory in various cognitive tasks. However, the molecular mechanisms by which vortioxetine augments LTP and memory remain unknown. Dendritic spines are specialized, actin-rich microdomains on dendritic shafts and are major sites of most excitatory synapses. Since dendritic spine remodeling is implicated in synaptic plasticity and spine size dictates the strength of synaptic transmission, we assessed if vortioxetine, relative to other antidepressants including ketamine, duloxetine, and fluoxetine, plays a role in the maintenance of dendritic spine architecture in vitro. We show that vortioxetine, ketamine, and duloxetine induce spine enlargement. However, only vortioxetine treatment increased the number of spines in contact with presynaptic terminals. In contrast, fluoxetine had no effect on spine remodeling. These findings imply that the various 5-HT receptor mechanisms of vortioxetine may play a role in its effect on spine dynamics and in increasing the proportion of potentially functional synaptic contacts., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Alcohol use disorder, anxiety disorders, and post-traumatic stress disorder (PTSD) are highly comorbid, and exposure to chronic stress during adolescence may increase the incidence of these conditions in adulthood. Efforts to identify the common stress-related mechanisms driving these disorders have been hampered, in part, by a lack of reliable preclinical models that replicate their comorbid symptomatology. Prior work by us, and others, has shown that adolescent social isolation increases anxiety-like behaviors and voluntary ethanol consumption in adult male Long-Evans rats. Here we examined whether social isolation also produces deficiencies in extinction of conditioned fear, a hallmark symptom of PTSD. Additionally, as disrupted noradrenergic signaling may contribute to alcoholism, we examined the effect of anxiolytic medications that target noradrenergic signaling on ethanol intake following adolescent social isolation. Our results confirm and extend previous findings that adolescent social isolation increases anxiety-like behavior and enhances ethanol intake and preference in adulthood. Additionally, social isolation is associated with a significant deficit in the extinction of conditioned fear and a marked increase in the ability of noradrenergic therapeutics to decrease ethanol intake. These results suggest that adolescent social isolation not only leads to persistent increases in anxiety-like behaviors and ethanol consumption, but also disrupts fear extinction, and as such may be a useful preclinical model of stress-related psychopathology. Our data also suggest that disrupted noradrenergic signaling may contribute to escalated ethanol drinking following social isolation, thus further highlighting the potential utility of noradrenergic therapeutics in treating the deleterious behavioral sequelae associated with early life stress., (Copyright © 2015 Elsevier Ltd. All rights reserved.)