Lurasidone (/ljʊəˈræsɪdoʊn/; trade name Latuda) is an atypical antipsychotic developed by Dainippon Sumitomo Pharma[3] and marketed by Sunovion in the U.S. It has been an FDA approved treatment for schizophrenia since 2010 and for treating depressive episodes in adults with bipolar I disorder since 2013, and is frequently prescribed for the treatment of major depressive disorder (MDD). It can be used alone or in combination with mood stabilizers such as lithium or valproate (e.g., Depakote).[4] Lurasidone is approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia since 2010[5] and depressive episodes associated with bipolar I disorder since 2013.[6] It received regulatory approval in the United Kingdom in September 2014. In October 2014, NHS Scotland advised use of lurasidone for schizophrenic adults who have not seen improvements with previous antipsychotics due to problems that arise from weight gain or changes in metabolic pathways when taking other medications.[7] It received approval by the European Medicines Agency on 24 January 2014. It was launched in Canada for the treatment of schizophrenia in September 2012, Health Canada giving their Summary Basis of Decision (SBD) as favourable on 15 October 2012.[8] European Commission has granted a marketing authorization for once-daily oral lurasidone for the treatment of schizophrenia in adults.[9] It is approved for use in the EU.[10] In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, lurasidone demonstrated mild effectiveness. As effective as iloperidone, and 13 to 15% less effective than ziprasidone, chlorpromazine, and asenapine.[11] In July 2013 lurasidone received approval for bipolar I depression.[6][12] Few available atypical antipsychotics are known to possess antidepressant efficacy in bipolar disorder (with the notable exceptions being quetiapine,[13][14][15][16] olanzapine[17][18][19] and possibly asenapine[20]) as a monotherapy, even though the majority of atypical antipsychotics are known to possess significant antimanic activity,[21] which is yet to be clearly demonstrated for lurasidone. Lurasidone is not approved by the Food and Drug Administration (FDA) for the treatment of behavior disorders in older adults with dementia.[22] Lurasidone is contraindicated in individuals who are taking strong inhibitors of the liver enzyme CYP3A4 (ketoconazole, clarithromycin, ritonavir, levodropropizine, etc.) or inducers (carbamazepine, St. John's wort, phenytoin, rifampicin etc.).[23] The use of lurasidone in pregnant women has not been studied and is not recommended; in animal studies, no risks have been found.[24] Excretion in breast milk is also unknown; lurasidone is not recommended for breastfeeding women.[25] In the United States it is not indicated for use in children.[26] 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 gain and lipid-related adverse effects.[27] In a 2013 meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to produce the second least (after haloperidol) weight gain, the least QT interval prolongation, the fourth most extrapyramidal side effects (after haloperidol, zotepine and chlorpromazine) and the sixth least sedation (after paliperidone, sertindole, amisulpride, iloperidone and aripiprazole).[11] As with other atypical neuroleptics, lurasidone should be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack;[28][29] however, these risks are not likely to be greater than those associated with antipsychotics of other classes.[30] Similarly, lurasidone should not be used to treat dementia-related psychosis, as evidence has shown increased mortality with antipsychotic use.[31] Weight gain is reported in up to 15 and 16 percent of users.[32][33] Blood plasma concentrations may be increased when combined with CYP3A4 inhibitors, possibly leading to more side effects. This has been clinically verified for ketoconazole, which increases lurasidone exposure by a factor of 9, and is also expected for other 3A4 inhibitors such as grapefruit juice. Co-administration of CYP3A4 inducers like rifampicin or St. John's wort can reduce plasma levels of lurasidone and its active metabolite, and consequently decrease the effects of the drug. For rifamipcin, the reduction was sixfold in a study.[2] Lurasidone acts as an antagonist of the dopamine D2 and D3 receptors, the serotonin 5-HT2A and 5-HT7 receptors, and the α2C-adrenergic receptor, and as a partial agonist of the serotonin 5-HT1A receptor.[36][35] It has only low and likely clinically unimportant affinity for the serotonin 5-HT2C receptor, which may underlie its low propensity for appetite stimulation and weight gain.[35][37][38] The drug also has negligible affinity for the histamine H1 receptor and the muscarinic acetylcholine receptors, and hence has no antihistamine or anticholinergic effects.[36][39] Lurasidone is taken by mouth and has an estimated absorption rate of 9 to 19%.[1] Studies have shown that when lurasidone is taken with food, absorption increases about twofold. Peak blood plasma concentrations are reached after one to three hours. About 99% of the circulating substance are bound to plasma proteins.[2] Lurasidone is mainly metabolized in the liver via the enzyme CYP3A4, but has negligible affinity to other cytochrome P450 enzymes. It is transported by P-glycoprotein and ABCG2 and also inhibits these carrier proteins in vitro. It also inhibits the solute carrier protein SLC22A1, but no other relevant transporters.[2][28] Main metabolism pathways are oxidative N-dealkylation between the piperazine and cyclohexane rings, hydroxylation of the norbornane ring, and S-oxidation.[2][42]:59 Other pathways are hydroxylation of the cyclohexane ring and reductive cleavage of the isothiazole ring followed by S-methylation.[41] The two relevant active metabolites are the norbornane hydroxylation products called ID-14283 and ID-14326, the former reaching pharmacologically relevant blood plasma concentrations. The two major inactive metabolites are the N-dealkylation products (the carboxylic acid ID-20219 and the piperazine ID-11614[41]), and a norbornane hydroxylated derivative of ID-20219 (ID-20220). Of lurasidone and its metabolites circulating in the blood, the native drug makes up 11%, the main active metabolite 4%, and the inactive carboxylic acids 24% and 11%, respectively.[1][2] Several dozen metabolites have been identified altogether.[42]:59–61 Biological half-life is given as 18 hours or 20 to 40 hours in different sources. 80% or 67% of a radiolabelled dose was recovered from the faeces, and 9% or 19% from the urine.[1][2] Lurasidone was synthesized in 2003.[43] Lurasidone is a structural analogue of Ziprasidone (Zeldox). Lurasidone shows a very close pharmacological profile and has been synthesized similarly to Ziprasidone.[44] Lurasidone is chemically similar to Perospirone (also a chemical analogue of Zeldox), as well as Risperidone, Paliperidone and Iloperidone.[45] The FDA approved the drug in 2010.[42] In India, this drug is available under the brand names of Atlura, Lurace, Lurafic, Luramax, Lurasid, Lurastar, Latuda, Lurata[46] and additionally as Alsiva, Emsidon, Lurakem, Luratrend, Tablura, and Unison.[47] Lurasidone may be useful for treating the cognitive and memory deficits seen in schizophrenia. In animal studies, it reversed dizocilpine-induced learning and memory impairment and was found to be superior in doing this to all of the other antipsychotics examined, including risperidone, olanzapine, quetiapine, clozapine, aripiprazole, and haloperidol.[36][48] Lurasidone has activity at several serotonin receptors that are involved in learning and memory, and unlike most other antipsychotics, lacks any anticholinergic effects (which are known to impair cognitive processes and memory).[36] These properties may underlie its improved effectiveness in treating these symptoms relative to older agents.[36]