Major depressive disorder is one of the most prevalent mental health disorders. Monoamine-based antidepressants were the first drugs developed to treat major depressive disorder. More recently, ketamine and other analogues were introduced as fast-acting antidepressants. Unfortunately, currently available therapeutics are inadequate; lack of efficacy, adverse effects, and risks leave patients with limited treatment options. Efforts are now focused on understanding the etiology of depression and identifying novel targets for pharmacological treatment. In this review, we discuss promising novel pharmacological targets for the treatment of major depressive disorder. Targeting receptors including N-methyl-D-aspartate receptors, peroxisome proliferator-activated receptors, G-protein-coupled receptor 39, metabotropic glutamate receptors, galanin and opioid receptors has potential antidepressant effects. Compounds targeting biological processes: inflammation, the hypothalamic-pituitary-adrenal axis, the cholesterol biosynthesis pathway, and gut microbiota have also shown therapeutic potential. Additionally, natural products including plants, herbs, and fatty acids improved depressive symptoms and behaviors. In this review, a brief history of clinically available antidepressants will be provided, with a primary focus on novel pharmaceutical approaches with promising antidepressant effects in preclinical and clinical studies.

/pdf/novel-pharmacological-approaches-to-the-treatment-of-3cy8ha6s.pdf

Novel Pharmacological Approaches to the Treatment of Depression

Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1B receptor antagonists have been synthesized, and the efficacies of some V1B receptor antagonists have been investigated in both animals and humans. V1B receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V1B receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1B receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.

/pdf/vasopressin-v1b-receptor-antagonists-as-potential-3xsu2u5ln2.pdf

Vasopressin V1B Receptor Antagonists as Potential Antidepressants

Abnormal hypothalamic-pituitary-adrenal (HPA) axis has been implicated in major depressive disorder (MDD). A number of studies have attempted to use HPA-modulating medications to treat depression. However, their results are inconsistent. The efficacy of these drugs for MDD remains uncertain. The aims of this meta-analysis were to determine the effect and safety profile of HPA-targeting medications for MDD. World of Science and PubMed databases were comprehensively searched up to March 2021. All randomized controlled trials (RCTs) and open-label trials exploring antiglucocorticoid and related medications in patients with depression were included. Standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for continuous or dichotomous outcomes, respectively. In the meta-analysis, we identified 16 RCTs and seven open-label studies that included 2972 subjects. Pooling the change data that assessed the efficacy across all included HPA-targeting medications for depression showed a significant difference between interventions and controls with very small heterogeneity after influence analysis (SMD = 0.138, 95%CI = 0.052, 0.224, p = 0.002; I2 = 20.7%, p = 0.212). No obvious publication bias was observed (p = 0.127). Effectiveness remained significant in patients with MDD (SMD = 0.136, 95%CI = 0.049, 0.223, p = 0.002). Subgroup analysis showed a significant difference favoring mifepristone and vasopressin 1B (V1B) receptor antagonist treatment. Adverse events were reported by 14 studies and our analysis of high-quality studies showed a significant difference in favor of controls (RR = 1.283, 95%CI = 1.134, 1.452, p = 0). Our study suggested that patients with MDD may benefit from mifepristone and V1B receptor antagonist treatments that have tolerable side effects. HPA-based medications are promising for depression treatment. However, additional high-quality RCTs, including head-to-head trials, are needed. Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier registration number: CRD42021247279.

/pdf/efficacy-of-treatments-targeting-hypothalamic-pituitary-3758nv2lug.pdf

Efficacy of Treatments Targeting Hypothalamic-Pituitary-Adrenal Systems for Major Depressive Disorder: A Meta-Analysis

Background High placebo response in ADHD can reduce medication-placebo differences, jeopardizing the development of new medicines. This research aims to 1) determine placebo response in ADHD, 2) compare the accuracy of meta-regression and MetaForest in predicting placebo response, and 3) determine the covariates associated with placebo response. Methods A systematic review with meta-analysis (SRMA) of RPCCTs investigating pharmacological interventions for ADHD was performed. Placebo response was defined as the change from baseline in ADHD symptom severity assessed according to the 18-item, clinician-rated, DSM-based rating scale. The effect of study design-, intervention- and patient-related covariates in predicting placebo response was studied by means of meta-regression and MetaForest. Results Ninety-four studies including 6,614 patients randomized to placebo were analysed. Overall, placebo response was -8.9 points, representing a 23.1% reduction in the severity of ADHD symptoms. Cross-validated accuracy metrics for meta-regression were R 2 = 0.0012 and RMSE = 3.3219 for meta-regression and 0.0382 and 3.2599 for MetaForest. Placebo response amongst ADHD patients increased by 63% between 2001 and 2020 and was larger in the US than in other regions of the world. Conclusions Strong placebo response was found in ADHD patients. Both meta-regression and MetaForest showed poor performance in predicting placebo response. ADHD symptom improvement with placebo has markedly increased over the last two decades and is grater in the US than the rest of the world.

Placebo response and its predictors in Attention Deficit Hyperactivity Disorder: a meta-analysis and comparison of meta-regression and MetaForest.

THY1773 is a novel arginine vasopressin 1B (V1B ) receptor antagonist that is under development as an oral drug for the treatment of major depressive disorder (MDD). Here we report our strategy to predict a clinically effective dose of THY1773 for MDD in the preclinical stage, and discuss the important insights gained by retrospective analysis of prediction accuracy. To predict human pharmacokinetic (PK) parameters, several extrapolation methods from animal or in vitro data to humans were investigated. The fu correction intercept method and two-species-based allometry were used to extrapolate clearance from rats and dogs to humans. The physiologically based pharmacokinetics (PBPK)/receptor occupancy (RO) model was developed by linking free plasma concentration with pituitary V1B RO by the Emax model. As a result, the predicted clinically effective dose of THY1773 associated with 50% V1B RO was low enough (10 mg/day, or at maximum 110 mg/day) to warrant entering phase 1 clinical trials. In the phase 1 single ascending dose study, TS-121 capsule (active ingredient: THY1773) showed favorable PKs for THY1773 as expected, and in the separately conducted phase 1 RO study using positron emission tomography, the observed pituitary V1B RO was comparable to our prediction. Retrospective analysis of the prediction accuracy suggested that the prediction methods considering plasma protein binding, and avoiding having to apply unknown scaling factors obtained in animals to humans, would lead to better prediction. Selecting mechanism-based methods with reasonable assumptions would be critical for the successful prediction of a clinically effective dose in the preclinical stage of drug development.

Prediction of a clinically effective dose of THY1773, a novel V 1B receptor antagonist, based on preclinical data.

Asverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach. The sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatment, randomized, parallel group, double-blind, placebo-controlled trial recruiting 6–17-year-old children and adolescents diagnosed with ADHD. A total of 216 patients were randomized according to the CYP2D6 phenotype. The primary end-point was ADHD Rating Scale IV-J changes. Furthermore, effects of CYP2D6 phenotype on the efficacy in the subgroup analysis were investigated. TS-141 had the sustained-release profile, and the CYP2D6 phenotype had effects on the plasma exposure of tipepidine. ADHD RS-IV-J scores in all TS-141 dosages decreased from their baseline scores; however, no significant difference was observed in ADHD RS-IV-J score changes between the placebo and TS-141-administered groups. In patients with intermediate metabolizer CYP2D6, ADHD RS-IV-J score changes in the 120 mg group tended to be larger than that in the placebo group. ADHD RS-IV-J changes on TS-141 may depend on the interaction between the TS-141 dose and CYP2D6 phenotype, suggesting that further clinical trials should be conducted with careful consideration of polymorphism. Drug repositioning approach of TS-141 was attempted at the same dose as that of antitussive; however, dose setting according to the indication was necessary. Phase I study: JapicCTI-205235
 (Registered 25 March 2020), Phase II study: JapicCTI-163244
 (Registered 9 May 2016), https://www.clinicaltrials.jp/cti-user/trial/Show.jsp

/pdf/using-the-drug-repositioning-approach-to-develop-a-novel-3lu27ylx4r.pdf

Using the drug repositioning approach to develop a novel therapy, tipepidine hibenzate sustained-release tablet (TS-141), for children and adolescents with attention-deficit/hyperactivity disorder.

The histamine H3 receptor has emerged as one of the most promising targets of novel pharmacotherapy for narcolepsy. Studies now aim to investigate the optimal dose of enerisant, a novel H3 antagonist/inverse agonist, for the treatment of excessive daytime sleepiness in patients with narcolepsy.We conducted two phase 2, fixed-dose, double-blind, randomized, placebo-controlled trials in patients with narcolepsy. The first phase 2 study (Study 1) was conducted to investigate the efficacy and safety of enerisant at dosages of 25, 50, and 100 mg/day administered for 3 weeks based on the results of a phase 1 study conducted on healthy volunteers. The primary endpoint was mean sleep latency in maintenance of wakefulness test (MWT), and the secondary endpoint was the total score on the Epworth Sleepiness Scale (ESS). The dosages of enerisant in the second phase 2 study (Study 2) were set at 5 and 10 mg/day based on the simulation of receptor occupancy results from positron emission tomography study.Forty-six and fifty-three patients were randomized in Study 1 and Study 2, respectively. The efficacy of enerisant was partially confirmed in Study 1 with ESS; however, the doses were not tolerated, and there were many withdrawals due to adverse events (mainly insomnia, headache, and nausea). The doses in Study 2 were well tolerated, with a lower incidence of adverse events in Study 2 than in Study 1, although the efficacy could not be confirmed with MWT and ESS in Study 2.The optimal dose of enerisant could not be determined in these two studies. Although enerisant has a favorable pharmacokinetic profile, it is thought to have large interindividual variabilities in terms of efficacy and safety, suggesting the necessity of tailored dosage adjustments.ClinicalTrials.gov identifier: NCT03267303 ; Registered 30 August 2017 (Study 2). Japic identifier: JapicCTI-142529 ; Registered 7 May 2014 (Study 1) and JapicCTI-173689 ; Registered 30 August 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?clinicalTrialId=29277 (Study 2). 

/pdf/optimal-dose-determination-of-enerisant-ts-091-for-patients-3pmc1jpl.pdf

Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials

Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study.

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Using the drug repositioning approach to develop a novel therapy, tipepidine hibenzate sustained-release tablet (TS-141), for children and adolescents with attention-deficit/hyperactivity disorder.

Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials

Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study.