RESEARCH MONOGRAPH · KDC-MN-238
Lurasidone
Lurasidone (Latuda) is a Japanese atypical antipsychotic from Sumitomo Dainippon, approved by the FDA in 2010. It blocks dopamine D2, serotonin 5-HT2A, and 5-HT7 receptors in roughly balanced fashion, with very little activity at histamine or muscarinic receptors. That receptor profile gives it the lowest metabolic burden of the atypical antipsychotic class: minimal weight gain, minimal lipid or glucose disturbance, and minimal sedation. The 5-HT7 antagonism appears to contribute distinct procognitive and antidepressant effects, which is why it is approved for both schizophrenia and bipolar depression. The catch is that absorption is highly food-dependent: it must be taken with at least 350 calories or it does not work properly. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Atypical antipsychotic with 5-HT7 antagonism
A benzisothiazole atypical antipsychotic with prominent 5-HT7 receptor antagonism contributing to procognitive and antidepressant effects.
Abstract
Lurasidone ((3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]-cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione; CAS 367514-87-2; molecular formula C28H36N4O2S; molecular weight 492.68) is a benzisothiazole atypical antipsychotic developed at Sumitomo Dainippon and approved by the FDA in 2010 under the trade name Latuda. The receptor profile features full D2 antagonism (Ki approximately 1 nM), potent 5-HT2A antagonism (Ki approximately 0.5 nM), 5-HT1A partial agonism (Ki approximately 6.4 nM), and prominent 5-HT7 antagonism (Ki approximately 0.5 nM, the most potent in clinical use). The 5-HT7 antagonism is associated with procognitive effects and improvement in bipolar depression. H1 and muscarinic activity is minimal, producing low sedation and metabolic burden compared to olanzapine and quetiapine; the principal limitation is dose-related akathisia. Plasma half-life is 18 hours; absorption requires food (approximately 350 kcal). Metabolism is via CYP3A4. Approved for schizophrenia (acute and maintenance), bipolar I depression (monotherapy or with lithium/valproate). Used as the reference 5-HT7-prominent antipsychotic.
Mechanism of action
Full D2 antagonism, potent 5-HT2A and 5-HT7 antagonism, 5-HT1A partial agonism. Minimal H1 and muscarinic activity. Low metabolic burden.
Reported research dose ranges
Clinical 20 to 160 mg per oral administration daily, with food (>=350 kcal). Rodent studies 1 to 20 mg/kg/day.
References
- Ishibashi T, et al. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther 2010.
- Loebel A, et al. Lurasidone monotherapy in the treatment of bipolar I depression. Am J Psychiatry 2014.
- Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile. Int J Clin Pract 2011.
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