Lurasidone

Lurasidone

Systematic (IUPAC) name
(3aR,4S,7R,7aS)-2-[((1R,2R)-2-{[4-(1,2-benzisothiazol-3-yl)-piperazin-1-yl]methyl}cyclohexyl)methyl]hexahydro-1H-4,7-methanisoindol-1,3-dione
Clinical data
Trade names	Latuda
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a611016
Licence data	US FDA:link
Pregnancy cat.	B (US)
Legal status	℞-only (US)
Routes	Oral
Pharmacokinetic data
Metabolism	CYP3A4
Identifiers
CAS number	367514-87-2
ATC code	None
PubChem	CID 213046
ChemSpider	184739
UNII	22IC88528T Y
ChEMBL	CHEMBL1237021
Synonyms	SM-13,496
Chemical data
Formula	C28H36N4O2S
Mol. mass	492.676 g/mol
SMILES	eMolecules & PubChem

Lurasidone (trade name Latuda) is an atypical antipsychotic developed by Dainippon Sumitomo Pharma. It was approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia on October 28, 2010 after a review that found that two of the four Phase III clinical trials supported efficacy, while one showed only marginal efficacy and one was not interpretable because of high drop-out rates. It is currently pending approval for the treatment of bipolar disorder in the United States.

Pharmacology

Pharmacokinetics and interactions

Lurasidone is metabolized in the liver via the enzyme CYP3A4. This means that its plasma concentrations may be increased when combined with CYP3A4 inhibitors like ketoconazole or grapefruit juice, possibly leading to more side effects. Co-administration of CYP3A4 inducers like rifampicin or St. John's wort can reduce plasma levels and consequently the effects of the drug.

Pharmacodynamics

Lurasidone acts as a D₂ (K_i = 0.994 nM), 5-HT_2A (K_i = 0.47 nM), 5-HT₇ (K_i = 0.495 nM), and α_2C-adrenergic (K_i = 10.8 nM) receptor antagonist, and 5-HT_1A (K_i = 6.75 nM) receptor agonist. It has only weak or negligible actions at the 5-HT_2C, α₁-adrenergic, H₁, and mACh receptors.

Uses

In clinical studies, lurasidone alleviates positive (e.g., hallucinations, delusions) without inducing extrapyramidal side effects except for akathisia, despite its potent D₂ antagonistic actions. Clinical evidence of lurasidone's effect on negative symptoms of schizophrenia has yet to establish efficacy.

Lurasidone may be useful for treating cognitive and memory deficits seen in schizophrenia for several reasons: 1) unlike many other antipsychotics, lurasidone does not block the muscarinic acetylcholine receptors, an action well-known to impair learning and memory; 2) lurasidone has prominent activity at 5-HT_1A, 5-HT_2A, 5-HT₇, and α_2C-adrenergic receptors, all of which have been implicated in enhancement of cognitive function if modulated properly. In animal studies, lurasidone was found to be superior to all of the other antipsychotics examined in reversing dizocilpine-induced learning and memory impairment, including risperidone, olanzapine, quetiapine, clozapine, aripiprazole, and haloperidol.

Side effects

Side effects are generally similar to other antipsychotics. The drug has a relatively well-tolerated side effect profile, with low propensity for QTc interval changes, weight, lipid and glucose-related adverse effects. Side effects reported in at least 5% of subjects and at least twice the frequency of placebo include akathisia (17.6% vs 3.1% placebo), somnolence (11.7% vs 5.5%), parkinsonism (6.8% vs 0%), and weight gain (5.1% vs 2.4%).

Severe but infrequent side effects include neuroleptic malignant syndrome and tardive dyskinesia. As with other atypical neuroleptics, lurasidone should not be used in elderly patients because it puts them at an increased risk for a stroke or transient ischemic attack.