Lurasidone is similar to many older antipsychotics in its affinity for D2 and 5-HT2A and, as with atypical agents, it exerts antipsychotic activity with a limited risk of EPS. On the basis of its potent antagonism of 5-HT7 and high affinity for other receptors implicated in the enhancement of cognitive function, particularly 5-HT1A at which is acts as a partial agonist, lurasidone was hypothesized to have favorable effects on cognition, memory, and mood, although this hypothesis is not currently supported by clinical evidence. The drug is also expected to possess anxiolytic- or antidepressant-like activity in clinical use because of its higher affinities for 5-HT7 and 5-HT1A receptors. Moreover, it shows little binding affinity for α1-adrenergic receptors, suggesting that it should have a low risk for orthostatic hypotension and sedation.
Affinity at the histamine H1 and muscarinic M1 receptors was also very low, which supports a favorable side-effect profile for this drug. Clinical trials to date indicate that the most common adverse events associated with lurasidone are mild akathisia, sedation, and Parkinsonism. The rates of these events are low and dose-related. Early data also showed minimal risks for weight gain and metabolic abnormalities, similar to some other new antipsychotics such as aripiprazole, iloperidone, and ziprasidone. Additionally, there are only minimal increases in prolactin levels with no significant increases in QTc, which is in contrast to iloperidone and ziprasidone. This may give lurasidone an advantage over some atypical antipsychotics, but further trials with a broader population of patients would be useful to explore these areas.
Although lurasidone was effective and generally well tolerated in several short-term placebo controlled trials, these enrolled only small numbers of highly selected patients, and studies that compared lurasidone with an active comparator were not designed to directly test the differences among antipsychotics. These weaknesses limit the general extension of the results to patients with other psychological or clinical comorbidities, those with comorbid drug use and/or dependence, patients who are resistant to treatment with other antipsychotics, and adolescents or elderly patients. Moreover, data are limited on lurasidone’s effectiveness in the maintenance treatment of schizophrenia. The only data on the drug’s long-term efficacy come from the extension phase of some short-term studies.
Although none of the patients treated with lurasidone experienced significant QTc change, electrocardiographic changes for haloperidol and ziprasidone, which are included in the list of drugs associated with the risk of torsades de pointes, are lower than expected.56
However, to date lurasidone has been tested in a small sample of patients and the risk of torsades de pointes in the general populations remains unknown. Additional studies on larger samples of patients are therefore required. Lurasidone also appears to have a low potential for causing weight gain and adverse metabolic effects, but longer-term trials are needed to assess the risk of new-onset diabetes, which is of particular concern with second-generation antipsychotics.59
Long-term treatment with antipsychotic drugs, especially at high dosages, is also associated with the risk of tardive dyskinesia, and this potential adverse reaction may be underestimated because of the limited information available at this time from long-term clinical trials.
When compared with other recent second-generation antipsychotics that also have a low propensity for causing the adverse effects of older antipsychotics, lurasidone has further potential advantages including once-daily administration (unlike the twice-daily administration required for asenapine, iloperidone, and ziprasidone) and the fact that dosing titration is not necessary (in contrast to asenapine, iloperidone, sertindole, and ziprasidone).25
Lurasidone’s advantage of once-daily dosing (which is shared by the long t1/2
aripiprazole and sertindole, among the newer antipsychotics),30
should also help improve patient compliance.
Beneficial features of lurasidone include the lack of clinically significant age-, sex-, or race-related effects.28
These results must, however, be extended to its active metabolites, whose pharmacological and pharmacokinetic profiles and potential contributions to the overall outcome are still largely unknown.
Although clinicians will need to consider lurasidone’s favorable side-effect profile when making a therapeutic decision, this new antipsychotic has some disadvantages. Whereas food does not significantly affect the absorption of most antipsychotics, lurasidone must be administered carefully in relation to meals in order to optimize bioavailability (another exception is ziprasidone, although this has a higher caloric threshold than lurasidone).28
Dose adjustment is recommended in moderate and severe renal or hepatic impairment, in contrast to the dose reductions recommended for paliperidone in renal impairment and for iloperidone and sertindole in hepatic impairment, while no adjustments are needed for aripiprazole and ziprasidone.25
Being primarily biotransformed by CYP3A4, co-administration with strong inducers and inhibitors of CYP3A4 is contraindicated, a disadvantage shared by most of the newer lipophilic antipsychotics, although carbamazepine and ketoconazole have less effect on the clearance of antipsychotics that have significant alternative pathways (for example, ziprasidone is partly metabolized by aldehyde oxidase, while paliperidone’s clearance is largely due to urinary excretion of the drug itself). Unlike aripiprazole, iloperidone, sertindole, and many older antipsychotics, however, lurasidone does not present any of the polymorphic metabolism characteristics mirroring the CYP2D6 phenotype,25
and can therefore be administered in combination with CYP2D6 inhibitors, regardless of patient’s genetic status.41
Lastly, the clinical advantages of the new antipsychotic agents have not been well evaluated in direct superiority comparative studies. The lack of well-designed long-term comparative studies and the unnecessary and excessive use of placebo in the few short-term studies that are available add to the difficulty of establishing the place of lurasidone and the other new agents in therapy, and providing clinicians with clear guidance on the choice of the best treatment for each patient. Well-designed and appropriately powered clinical studies are now needed to assess the therapeutic role of lurasidone in schizophrenia.