Lurasidone

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.

Clinical effects
In clinical studies, lurasidone alleviates positive symptoms (e.g., hallucinations, delusions) without inducing extrapyramidal side effects except for akathisia, despite its potent D2 antagonistic actions. Effectiveness against negative symptoms of schizophrenia has yet to be established.

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. 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). These properties may underlie its improved effectiveness in treating these symptoms relative to older agents.

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 be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack; however, these risks are not likely to be greater than those associated with antipsychotics of other classes.

Pharmacodynamics
Lurasidone acts as an antagonist of the following sites:


 * α2C-adrenergic receptor (Ki = 10.8 nM)
 * D2 receptor (Ki = 1.0 nM)
 * 5-HT2A receptor (Ki = 0.5 nM)
 * 5-HT7 receptor (Ki = 0.5 nM)

And as a partial agonist of the following sites:


 * 5-HT1A receptor (Ki = 6.8 nM)

Note: All values are rounded to the nearest tenth.

It has only weak or negligible actions at the 5-HT2C, α1-adrenergic, H1, and mACh receptors.

Pharmacokinetics
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.