Levomilnacipran 40mg modified-release capsules

Introduction Treatment choice when prescribing antidepressants for major depressive disorder (MDD) is often influenced by safety and tolerability profiles. A transient increase in suicidality following antidepressant treatment initiation is a key concern. Although rare, its unpredictability and consequences make them a significant worry. In 2004, the U.S. Food and Drug Administration (FDA) issued a “black-box” warning regarding a potential increase in suicidality in adolescents receiving antidepressant treatment for depression that was later expanded to include both young adults and a broader range of antidepressants. Objectives The aim of this study is to evaluate the risk of increased suicidality during the treatment with serotonin and norepinephrine reuptake inhibitors (SNRIs) in young adults with MDD. Methods We conducted a non-systematic literature search on PubMed using the combination of MeSH terms ([Serotonin and Noradrenaline Reuptake Inhibitors] OR [Levomilnacipran] OR [Desvenlafaxine Succinate] OR [Venlafaxine Hydrochloride] OR [Duloxetine Hydrochloride]) AND [Suicide] AND [Young Adult], and the keywords [(“Serotonin and Noradrenaline Reuptake Inhibitors” OR “Levomilnacipran” OR “Desvenlafaxine” OR “Venlafaxine” OR “Duloxetine”) AND (“Suicide” OR “treatment-emergent suicidal ideation”) AND (“Young” OR “Youth”)]. Results A total of 31 manuscripts were retrieved and 6 were selected, 3 original research and 3 non-systematic reviews of randomized clinical trials. Only studies written in English that provided information about suicidality with SNRIs in young adults with MDD. Globally, studies show that not only antidepressants decrease the risk of suicide attempt in depressed patients, but also there is no evidence of an increased suicidality in young adults treated with SNRIs. Interestingly, one study showed that increasing suicidality could be related to side effects of the treatment, such as anxiety, agitation and irritability. The authors found that poor antidepressant response and greater severity of depression during follow-up were associated with treatment increasing suicidal ideation, as it was suggested in another study. Another study reinforced that there may be an emotional component to the activating effects produced by some antidepressants that could explain their controversial association with rare cases of suicidal ideation and behaviour. Conclusions In conclusion, growing evidence shows that antidepressants overall decrease the risk of suicide attempt in depressed patients. Therefore, reducing antidepressant use over the FDA concerns about increased suicidal tendencies in young patients may actually increase suicide risks due to inadequate treatment of depression. Additional studies are essential to further confirm the importance of early treatment for depression. Disclosure of Interest None Declared

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OBJECTIVE: Gastrointestinal adverse effects are the most commonly reported adverse effects associated with the use of antidepressants. While existing studies on the gastrointestinal effects of antidepressant medications offer valuable insights, there are still opportunities to enhance the evidence base. METHODS: We included double-blind randomized controlled trials of major depressive disorder (MDD). Eligible studies must focus on comparing the use of 21 commonly used antidepressants in patients with MDD and reporting data on treatment-emergent gastrointestinal SEs. We selected 196 studies that reported specific numbers of individuals with gastrointestinal adverse effects, involving a total of 57,162 patients. A network and dose‒response meta-analysis was conducted. RESULTS: Compared with placebo, 16 antidepressants had higher odds ratios (ORs) for nausea and vomiting, 15 antidepressants had higher ORs for constipation, 8 antidepressants had higher ORs for diarrhoea, 8 antidepressants had higher ORs for anorexia, 12 antidepressants had higher ORs for dry mouth, and 3 antidepressants had higher ORs for dyspepsia. CONCLUSIONS: Commonly used antidepressants have different gastrointestinal effects. Duloxetine, levomilnacipran, and vilazodone carry a higher risk of inducing nausea and vomiting, whereas trazodone, amitriptyline, agomelatine, and mirtazapine tend to be better tolerated. Amitriptyline, clomipramine, and reboxetine are more prone to induce constipation. Diarrhoea is more commonly associated with vilazodone, fluvoxamine, and sertraline. Amitriptyline, reboxetine, and duloxetine are more likely to cause anorexia. Amitriptyline, reboxetine, and trazodone are related to causing dry mouth. Compared with the placebo, amitriptyline, fluoxetine, and paroxetine were associated with a greater incidence of dyspepsia.

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Objective: The aim of this meta-analysis was to evaluate the efficacy and safety of levomilnacipran extended-release (ER) in the treatment of major depressive disorder (MDD). Methods: Randomized controlled trials were searched by electronic databases. Unpublished data were also searched by the relevant websites. Weighted mean difference (WMD) and risk ratio (RR) with 95% confidence interval (CI) were calculated and pooled using fixed-effects model or random-effects model. Results: Five randomized placebo-controlled trials including 2,637 patients were analyzed. Compared with placebo, levomilnacipran ER had a greater reduction in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score and Sheehan Disability Scale (SDS) total score (MADRS: WMD -3.49 [95% CI -4.28, -2.70; P <0.00001]; SDS: WMD -2.41 [95% CI -3.05, -1.77; P <0.00001]). Significantly more patients in levomilnacipran ER achieved MADRS response rate (RR 1.35 [95% CI 1.23, 1.47; P <0.00001]) and MADRS remission rate (RR 1.30 [95% CI 1.06, 1.59; P =0.01]). In terms of safety, more patients discontinued due to adverse events (AEs) in levomilnacipran ER compared with placebo (RR 3.15 [95% CI 2.26, 4.39; P <0.00001]), but it was generally well tolerated in each eligible trial. The most common AEs were nausea, delay in ejaculation, erectile dysfunction, tachycardia, headache and increase in heart rate. Conclusion: Levomilnacipran ER is a safe and effective short-term treatment for MDD (≤10 weeks). Long-term and head-to-head trials comparing levomilnacipran ER with other antidepressants are needed to confirm the conclusion. Keywords: levomilnacipran ER, SNRI, major depressive disorder, meta-analysis

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Levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, has been reported to have anti-depressive effects. However, the detailed mechanisms underlying these effects are still unclear. This study aimed to investigate the antidepressant mechanisms of levomilnacipran to discover new perspectives on the treatment of depression in male rats. Intraperitoneal injection of lipopolysaccharide (LPS) was used to induce depressive behaviors in rats. Activation of microglia and apoptosis of neurons verified by immunofluorescence. Inflammatory related proteins and neurotrophic related proteins were verified by immunoblotting. The mRNA expression of apoptosis markers was verified by real-time quantitative PCR. Finally, electron microscopy analysis was used to observe the ultrastructural pathology of neuron. Here, we found that the anti-depression and anti-anxiety effects of levomilnacipran in the LPS-induced rat model of depression was resulted from the suppression of neuroinflammation and neuronal apoptosis within prefrontal cortex of rats. Furthermore, we found that levomilnacipran could decrease the number of microglia and suppress its activation in prefrontal cortex of rats. This effect may be mediated by suppressing the TLR4/NF-κB and Ras/p38 signaling pathways. In addition, levomilnacipran plays a neuroprotective role by increasing the expression of neurotrophic factors. Taken together, these results suggest that levomilnacipran exerts antidepressant effects by attenuating neuroinflammation to inhibit the damage in central nervous system and plays a neuroprotective role to improve depressive behaviors. These findings suggest that suppression of neuroinflammation in prefrontal cortex could ameliorate depressive behavioral disorder of rats induced by LPS, which provided a new perspective for the treatment of depression.

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