dasotraline (SEP-225289) / Sumitomo Pharma - LARVOL DELTA

The Evolving Pharmacological Landscape for Paediatric and Adult ADHD. (PubMed, CNS Drugs) - "Considering agents with at least two positive trials for ADHD core symptoms without negative trials, only dasotraline, in children, and centanafadine, in adults, emerged as promising (however, the dasotraline development programme was halted in 2020). This review also includes a discussion of opportunities for advancing the development of novel, effective agents and maximising the benefits of currently available options."

Journal • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Pediatrics • Psychiatry

Characterization of the Safety Profile of the Triple Monoamine Reuptake Inhibitor Dasotraline Based on Clinical Trial Data and Disproportionality Analyses of Four Related Pharmacological Classes Using Real-World Data from the FDA Adverse Event Reporting System. (PubMed, Clin Drug Investig) - P2, P2/3, P3 | "The safety profile of the triple MRI dasotraline was not distinct from pharmacologically related classes indicated by a consistently higher incidence of class-related adverse events compared to placebo in randomized, controlled clinical trials. Bayesian disproportionality analyses utilizing post-marketing data from established drug classes can provide meaningful information for qualitative safety evaluation of drugs in clinical development."

Adverse events • Clinical • Journal • Real-world evidence • CNS Disorders • Mental Retardation • Psychiatry

A Physiologically-Based Pharmacokinetic Model to Characterize Dasotraline Pharmacokinetics and CYP-mediated Drug-Drug Interactions. (PubMed, Drug Metab Bioanal Lett) - "The PBPK model developed via the middle-out approach provides a quantitative tool to predict CYP-mediated DDI with dasotraline as either a victim or a perpetrator and the impact of polymorphic CYP2B6 on dasotraline PK. This model may aid in optimizing dosing strategies to minimize the risks associated with CYP-mediated interactions and significant accumulation following repeated dosing."

Journal • PK/PD data • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Binge Eating Disorder • CNS Disorders • Psychiatry • CYP2C19 • CYP3A4

Structural basis for pharmacotherapeutic action of triple reuptake inhibitors. (PubMed, Nat Commun) - "Tesofensine and dasotraline stabilize DAT in an outward-facing conformation, while centanafadine, ansofaxine, and nefazodone capture the inward-facing conformation. Notably, ansofaxine binds at a location which is much closer to the intracellular membrane surface. Through extensive structural analysis, we establish a comprehensive blueprint for the association of these TRIs, which is crucial for future drug development aimed at achieving potent antidepressant with fewer side effect."

Journal • CNS Disorders • Depression • Psychiatry

Estimating heterogeneity of treatment effect in psychiatric clinical trials. (PubMed, J Psychiatr Res) - "For example, heterogeneous response was found in a trial of venlafaxine for depression (peHTE = 0.034), and two trials of dasotraline for binge eating disorder (Phase 2, peHTE = 0.002; Phase 3, 4 mg peHTE = 0.011; Phase 3, 6 mg peHTE = 0.003). Significant response heterogeneity was detected in other datasets as well, often despite no difference in variance between placebo and drug arms. The implications of eHTE as a clinical trial outcomes, independent of central tendency of the group, is considered and the importance of the eHTE method and results for drug developers, providers, and patients is discussed."

Clinical • Heterogeneity • Journal • Binge Eating Disorder • CNS Disorders • Depression • Psychiatry

Pharmacotherapies for Binge Eating Disorder: Systematic Review and Network Meta-Analysis. (PubMed, Obes Rev) - "Topiramate, lisdexamfetamine, and dasotraline show significant potential in treating BED. However, the landscape of pharmacotherapy for BED lacks robust evidence and methodological standardization. Larger trials with expanded sample sizes and using validated scales are needed to guide clinical practice for this highly prevalent and damaging disorder."

Journal • Retrospective data • Review • Binge Eating Disorder • CNS Disorders • Genetic Disorders • Insomnia • Mental Retardation • Mood Disorders • Pain • Psychiatry • Sleep Disorder

Safety and efficacy of dasotraline for patients with attention deficit/hyperactivity disorder: a systematic review and meta-analysis of 1594 patients including GRADE qualifications. (PubMed, Psychopharmacology (Berl)) - "dasotraline showed a significant improvement in the primary outcome (MD -2.65, 95% CI [-4.14 to -1.17], P= 0.0004 The results showed that dasotraline demonstrated a significant improvement in both primary and secondary outcomes, establishing its efficacy as a novel treatment for ADHD symptoms. However, mild to moderate side effects were observed."

Clinical • Journal • Retrospective data • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Developmental Disorders • Mental Retardation • Psychiatry

Efficacy and safety of monoamine reuptake inhibitors in attention deficit hyperactivity disorder: A Bayesian network meta-analysis. (PubMed, J Psychiatr Res) - "The drugs showing significant reduction on the ADHD rating scale as compared to placebo are bupropion (SMD: 0.33; 95%CrI: 0.60,-0.059), dasotraline(SMD: 0.49; 95%CrI: 0.82,-0.16), venlafaxine(SMD: 0.71; 95%CrI: 1.3,-0.15), viloxazine(SMD: 0.45; 95%CrI: 0.77,-0.12). Other drugs (centanafadine, duloxetine, edivoxetine, reboxetine, tipepidine, vortioxetine) were no better than placebo in reducing symptom severity of ADHD...Among all, duloxetine (OR:15; 95%CrI:1.8130) showed significantly more treatment-emergent adverse events than methylphenidate. In conclusion, venlafaxine, viloxazine, and bupropion are the most efficacious MRIs for ADHD symptom reduction as compared to placebo with high certainty of evidence."

Journal • Retrospective data • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

The role of adrenergic neurotransmitter reuptake inhibitors in the ADHD armamentarium. (PubMed, Expert Opin Pharmacother) - "The authors conducted a PubMed literature search using the following key words: 'ADHD' AND 'adrenergic reuptake inhibitors' OR 'nonstimulants' OR 'atomoxetine' OR 'Viloxazine' OR 'Dasotraline' OR 'Centanafadine' OR 'PDC-1421' OR 'Reboxetine' OR 'Edivoxetine' OR 'Bupropion' OR 'Venlafaxine' OR 'Duloxetine.' They reviewed FDA fact sheets of available medications for safety/tolerability studies and reviewed published clinical studies of these medications for treatment of ADHD. Adrenergic neurotransmitter reuptake inhibitors fit the diverse needs of children and adolescents with ADHD with 1) poor tolerability to stimulants (e.g. due to growth suppression, insomnia, rebound irritability, co-morbid depression, anxiety and tic disorders, substance abuse or diversion concerns), 2) cardiac risks, and/or 3) need for extended duration of action. Their differences in receptor..."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Depression • Insomnia • Mood Disorders • Psychiatry • Sleep Disorder • Substance Abuse • Tic Disorders • Tourette Syndrome

Efficacy and safety of dasotraline in attention-deficit hyperactivity disorder: A systematic review and meta-analysis. (PubMed, Indian J Psychiatry) - "The incidence of decreased appetite showed dose dependence but not the incidence of insomnia. Dasotraline 4 mg (in children) and 6 mg (in adults) can improve the clinical outcome in patients with ADHD by improving symptoms and global functioning with acceptable tolerability.PROSPERO Registration number: CRD42022321979."

Journal • Retrospective data • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Insomnia • Pediatrics • Psychiatry • Sleep Disorder

Estimating heterogeneity of treatment effect in psychiatric clinical trials. (PubMed, medRxiv) - "For example, heterogeneous response was found in a trial of venlafaxine for depression (p eHTE =0.034), and two trials of dasotraline for binge eating disorder (Phase 2, p eHTE =0.002; Phase 3, 4mg p eHTE =0.011; Phase 3, 6mg p eHTE =0.003). Significant response heterogeneity was detected in other datasets as well, often despite no difference in variance between placebo and drug arms. The implications of eHTE as a clinical trial outcomes independent from central tendency of the group is considered and the important of the eHTE method and results for drug developers, providers, and patients is discussed."

Clinical • Heterogeneity • Binge Eating Disorder • CNS Disorders • Depression • Psychiatry

Using Class-Effect Queries Defined on Established Pharmacological Classes in Clinical Development of Novel Compounds (ASCP 2024) - "These results further substantiate this approach to summarize adverse events in clinical trials, where the cumulative burden of class-specific risks describes the emerging safety profile of an investigational new drug in clinical development, relative to reactions anticipated for 1 drugs in an established pharmacological class. From the AE profile, dasotraline is closest to NRI compared to other three drug classes it is compared to. A weighted combination of % safety subjects at EBGM ≥ 3, % AEs not found in class effect query and AE with highest EBGM in the class effect query is a viable model to quantify the association of an investigational compound with established drug classes."

Clinical • CNS Disorders

Association between sleep pattern and pharmacological treatment in children with attention deficit disorder with hyperactivity: a systematic review. (PubMed, Rev Paul Pediatr) - "The drugs used in the treatment of ADHD seem to have negative repercussions on the sleep quality of children, with the drug atomoxetine showing lesser effects on this variable."

Journal • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

The Future of Child and Adolescent Clinical Psychopharmacology: A Systematic Review of Phase 2, 3, or 4 Randomized Controlled Trials of Pharmacologic Agents Without Regulatory Approval or for Unapproved Indications. (PubMed, Neurosci Biobehav Rev) - "The only two compounds with evidence of significant effects that were replicated in ≥1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes."

Journal • P2 data • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Prader–Willi syndrome • Psychiatry

ADHD-A Clinician's Bird's Eye View of Current Status and New Vistas! (PubMed, Psychopharmacol Bull) - "Drugs for ADHD in the pipeline include-dasotraline, armodafinil, tipepidine, edivoxetine, metadoxine, and memantine. Literature on ADHD keeps expanding towards advancing our understanding of the complex and heterogeneous intricacies of this commonplace neurodevelopmental disorder and hence informing better decisions on how best to manage its diverse cognitive, behavioural, social and medical facets."

Journal • Review • ADHD (Impulsive Aggression) • Allergy • Attention Deficit Hyperactivity Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Immunology • Mood Disorders • Movement Disorders • Obesity • Psychiatry • Sleep Disorder

Novel algorithm using incidence and duration to calculate adverse event prevalence in randomized controlled trials (ECNP 2022) - "AE Prevalence curves were calculated for pooled drug treatment arms of RCTs in various psychiatric and neurological disorders (insomnia, partial onset seizures, ADHD/BED, bipolar disorder and schizophrenia) and for various drug treatments (eszopiclone, eslicarbazepine, dasotraline, lurasidone and ulotaront) and compared with their respective placebo arms. Whereas the benefits of drug treatment are evaluated by dedicated efficacy measures analyzed using common statistical Methods, use of analysis Methods beyond standard incidence tables for AE data in RCTs are less commonplace. Combining AE incidence with duration offers a new way to evaluate risk to patients for treatment vs. non-treatment."

Adverse events • Clinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Bipolar Disorder • CNS Disorders • Epilepsy • Insomnia • Mood Disorders • Psychiatry • Schizophrenia • Sleep Disorder

Novel algorithm using incidence and duration to calculate adverse event prevalence in randomized controlled trials (ECNP 2022) - "AE Prevalence curves were calculated for pooled drug treatment arms of RCTs in various psychiatric and neurological disorders (insomnia, partial onset seizures, ADHD/BED, bipolar disorder and schizophrenia) and for various drug treatments (eszopiclone, eslicarbazepine, dasotraline, lurasidone and ulotaront) and compared with their respective placebo arms. Whereas the benefits of drug treatment are evaluated by dedicated efficacy measures analyzed using common statistical Methods, use of analysis Methods beyond standard incidence tables for AE data in RCTs are less commonplace. Combining AE incidence with duration offers a new way to evaluate risk to patients for treatment vs. non-treatment."

Adverse events • Clinical • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Bipolar Disorder • CNS Disorders • Epilepsy • Insomnia • Mood Disorders • Psychiatry • Schizophrenia • Sleep Disorder

In vitro and in vivo pharmacological characterization of dasotraline, a dual dopamine and norepinephrine transporter inhibitor in vivo. (PubMed, Biomed Pharmacother) - "In summary, dasotraline preferentially inhibits DAT and NET relative to SERT. Together, the occupancy and neurochemical profile of dasotraline provide a mechanistic basis for the treatment of diseases that have an underlying causality involving dopamine and norepinephrine dysfunction."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry

"Do you think dasotraline will ever get approved? Or is it gone for good?" (,@JohnStaub16)

A Randomized, Placebo-Controlled Laboratory Classroom Study of the Efficacy and Safety of Dasotraline in Children With ADHD. (PubMed, J Atten Disord) - P3 | "Dasotraline 2 mg/day was found to be efficacious and generally well tolerated in this placebo-controlled, laboratory classroom study of children ages 6 to 12 years with ADHD. NCT03231800."

Clinical • Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Psychiatry

Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology. (PubMed, J Psychopharmacol) - "Lisdexamfetamine (LDX) is the only approved BED drug treatment...The evidence supports the hypothesis that BED is an impulse control disorder with similarities to ADHD, including responsiveness to catecholaminergic drugs, for example LDX and dasotraline...(2) The analysis revealed a large number of pharmacological mechanisms are unlikely to be productive in the search for effective new BED drugs. (3) The most promising areas for new treatments for BED are drugs, which augment noradrenergic and dopaminergic neurotransmission and/or those which are effective in ADHD."

Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • Binge Eating Disorder • CNS Disorders • Genetic Disorders • Psychiatry

Understanding the Polypharmacological Profiles of Triple Reuptake Inhibitors by Molecular Simulation. (PubMed, ACS Chem Neurosci) - "In this study, the solved X-ray crystallographic structure of hSERT in complex with escitalopram was used as a basis for modeling nine complexes of three representative TRIs (SEP225289, NS2359, and EB1020) bound to their corresponding targets. Furthermore, the combined protein-ligand interaction fingerprint and residue energy contribution analysis indicated that several conserved and nonconserved "Warm Spots" such as S149, V328, and M427 in hDAT, F317, F323, and V325 in hNET and F335, F341, and V343 in hSERT were responsible for the TRI-binding selectivity. These findings provided important information for rational design of a single drug with better polypharmacological profiles through modulating multiple targets."

Journal

[VIRTUAL] Evidence-based therapeutic management of binge-eating disorder (EPA 2021) - "Lisdexamfetamine dimesylate is the only FDA approved drug for this indication, as dasotraline was rejected by FDA and its research discontinued by the manufacturer. Fluoxetine, sertraline, escitalopram, duloxetine, bupropion, atomoxetine, reboxetine, armodafinil, disulfiram, baclofen, zonisamide, lamotrigine, topiramate, samidorphan, liraglutid, and orlistat need more trials in order to validate their efficacy, especially on long term.  Conclusions There is only one drug currently FDA approved for this indication, lisdexamfetamine, and a number of psychotherapies, with CBT and IPT being the most supported by evidence."

Binge Eating Disorder • CNS Disorders • Mood Disorders • Psychiatry

Dasotraline in adults with attention deficit hyperactivity disorder: a placebo-controlled, fixed-dose trial. (PubMed, Int Clin Psychopharmacol) - "Treatment with dasotraline was generally well tolerated. The results provide additional evidence that supports the potential efficacy of dasotraline, in doses of 6 mg/day, in adults with ADHD."

Clinical • Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Mental Retardation • Psychiatry

Efficacy and Safety of Dasotraline in Children With ADHD: A Laboratory Classroom Study. (PubMed, J Atten Disord) - "The three most common adverse events for dasotraline (vs. placebo) were insomnia (19.6% vs. 3.6%), headache (10.7% vs. 8.9%), and decreased appetite (10.7% vs. 3.6%). In this laboratory classroom study, dasotraline 4 mg was found to be an efficacious and generally well-tolerated treatment for ADHD in children aged 6 to 12 years."

Clinical • Journal • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Insomnia • Pain • Psychiatry • Sleep Disorder