Lurasidone

Mechanism of Action

Lurasidone belongs to the benzisothiazole class. Although the mechanism of action of lurasidone is not fully understood, it is believed to affect both dopamine and serotonin receptors.[3]  Lurasidone is a full antagonist at dopamine D2 and serotonin 5-HT2A and 5-HT7 receptors.[4][5] It is a partial agonist at the serotonin 5-HT1A receptor. Lurasidone, when compared to other atypical antipsychotics, has the highest binding affinity for the 5-HT7 receptor.

It is the blockage of D2 and 5-HT2A receptors that confers the property of atypical antipsychotic to lurasidone. Antagonism at the 5-HT7 receptor and partial agonism at the 5-HT1A contributes to the antidepressant properties of lurasidone.

Lurasidone has low activity on muscarinic M1, histamine H1, alpha-1, and 2A adrenergic receptors.[5] This activity level minimizes the risk of orthostatic hypotension, sedation, weight gain, and cognitive blunting associated with other antipsychotic agents.[5][6]

Administration

Lurasidone is available as immediate-release tablets in 20, 40, 60, 80, and 120 mg strengths. It is poorly soluble in water and after oral ingestion. Therefore, the recommendation is that lurasidone should be administered with a meal of at least 350 calories, regardless of the fat content, which increases its bioavailability to 9 to 19%.[7] The Cmax increases by three times, and the area under the curve doubles. Lurasidone reaches peak serum concentration in approximately 1 to 3 hours with a steady-state concentration in 7 days.[8] Lurasidone metabolism is primarily by cytochrome P450 enzyme CYP3A4; therefore, caution is necessary when administered with strong CYP3A4 inducers or inhibitors.[6][9]

The recommended starting dose for schizophrenia in adults and adolescents is 40mg/day, with a maximum dose of 160mg/day in adults and 80mg/day in adolescents.

For bipolar depression, the recommended starting dose in adults and pediatric patients is 20mg/day, with a maximum treatment of 120mg/day in adults and 80mg/day in pediatric patients.

In the case of moderate renal and hepatic impairment, the recommended starting dose is 20mg/day with a maximum dose of 80mg/day. In severe hepatic impairment, the recommended maximum dose is 40mg/day.

Adverse Effects

Lurasidone offers a safety advantage when compared with some other atypical antipsychotic agents. Treatment with lurasidone has a decreased risk of metabolic side effects such as hypercholesterolemia, hyperlipidemia, hyperglycemia, and weight gain compared to risperidone, quetiapine, and olanzapine.[10] 

In patients with schizophrenia, the most common adverse effects experienced were nausea, akathisia, somnolence, sedation, and Parkinsonism. Long-term use of lurasidone is associated with modest weight gain compared with other atypical antipsychotics such as quetiapine and risperidone. Several short-term clinical trials observed significant increases in prolactin levels.[7]

Lurasidone offers a similar adverse effects profile in patients with bipolar depression. The most common side effects observed were nausea, akathisia, headache, extrapyramidal, and sedation. There have been reports that lurasidone causes a 7% increase in baseline body weight. More clinical trials need to be conducted to establish the safety and tolerability of long-term use of lurasidone in patients with bipolar depression.[11]

Lurasidone, when used in pregnant patients, may cause extrapyramidal or withdrawal symptoms in neonates when exposed in the third trimester.

Contraindications

Lurasidone metabolism is primarily via the cytochrome P450 enzyme, CYP3A4. Therefore, when used concomitantly with moderate CYP3A4 inhibitors, it is recommended to decrease the lurasidone dose to half of the original level with a starting dose of 20 mg and a maximum dose of 80 mg/day. Similarly, when combined with moderate CYP3A4 inducers, the lurasidone dose may be increased appropriately.

Examples of potent CYP3A4 inhibitors are clarithromycin, ritonavir, indinavir, ketoconazole, itraconazole, and grapefruit juice.

Examples of moderate CYP3A4 inhibitors are verapamil, diltiazem, erythromycin, fluconazole, fluvoxamine, and tofisopam. 

Examples of strong CYP3A4 inducers are rifampin, phenytoin, carbamazepine, and St. John's wort.

Examples of moderate CYP3A4 inducers are modafinil and armodafinil.

There is a black box warning for increased risk of death in elderly patients with dementia.

Monitoring

Lurasidone takes 1 to 3 hours to reach the maximum concentration after an oral dose of 40 mg. It reaches a steady-state concentration within seven days of dosing, and after absorption, lurasidone is mostly bound to plasma proteins, albumin, and alpha-1 acid glycoprotein.[12] Although albumin concentration decreases with age, alpha-1 acid glycoprotein increases with age; therefore, use in the elderly is cautioned.

Lurasidone is mostly excreted in feces approximating 80%, 9.2% in urine, and the remaining 10.7% is unknown. Dose monitoring is necessary for patients with renal and hepatic impairments. Dose adjustment is not recommended for mild impairment but rather for moderate and severe impairment.

The FDA has warned against lurasidone use with strong CYP3A4 inducers or inhibitors; close monitoring is necessary when used with mild inhibitors and inducers. As CYP1A2 does not metabolize lurasidone, smoking does not affect lurasidone’s pharmacokinetics.[13]

Lurasidone does not increase suicidal ideation or behavior.[11] Although the FDA has issued a black box warning about the risk of death in elderly patients with dementia, there is no clinical trial data to prove this evidence.[14] Furthermore, data on the incidence of serious adverse effects such as neuroleptic malignant syndrome, agranulocytosis, DKA, cancer, and osteoporosis remains undetermined.  There is some evidence showing high doses of lurasidone can cause small increases in TSH levels, the clinical significance of which is unclear.[15]  

Toxicity

There is insufficient data on lurasidone overdose. A literature search revealed only one case report of acute lurasidone overdose. This case report describes a 31-year-old man who overdosed on large amounts of lurasidone in an attempt to commit suicide. The quantity of lurasidone ingested was 8.5 times the upper maximum limit. Overdose took place shortly after lunch, which increased lurasidone’s absorption. The patient presented with mild hypertension and slightly elevated TSH. The patient only required IV fluids and recovered without sequelae. TSH normalized in 3 weeks after the overdose.[15] 

There is only one other documented case in the lurasidone leaflet regarding overdose. A patient took 560 mg of lurasidone and recovered without negative sequelae. Clinicians on the case noticed no long-term adverse effects with lurasidone overdose.

There are no specific antidotes for lurasidone. In case of overdose, it recommended close monitoring and supervision for prolongation of the QT interval, orthostatic hypotension, CNS depression, and tachycardia.[16]

Enhancing Healthcare Team Outcomes

Lurasidone is clinically beneficial in treating patients with schizophrenia and bipolar depression. Approximately 80% of the patients with schizophrenia achieve optimal response on 40 to 80 mg of lurasidone per day. Lurasidone is effective in treating depressive symptoms in schizophrenic patients; this is very important as the depressed mood correlates with suicide in these patients.[17] Additional clinical trials are necessary to prove the antisuicidal effects of lurasidone.

Patients with bipolar depression achieved an optimal clinical response at 20 to 60 mg of lurasidone per day. Lurasidone has minimal metabolic side effects but demonstrates akathisia, somnolence, sedation, and extrapyramidal side effects. These can be minimized by prescribing the right dose and administration of the medication in the evenings. Although lurasidone has no significant prolongation of the QTC interval, most sudden cardiac deaths in patients receiving atypical antipsychotics are dose-dependent. Careful monitoring is required when prescribing high doses of lurasidone. Lurasidone offers the convenience of once-daily dosing; this is especially important for patients suffering from complex mental illnesses. It is imperative that healthcare workers, including pharmacists, assist the team by counseling the patients to take this medication with food at all times, at least 350 calories, to increase absorption. To strictly follow these dietary guidelines may be challenging for some. The issue with absorption may resolve if the formulation of the tablet changes to water-soluble.[18] [Level 5]

In acute schizophrenia, lurasidone was found to be similar to quetiapine but not superior to risperidone in 12-month studies. Limited data are available on lurasidone’s efficacy in bipolar depression. In 2014, two randomized double-blinded clinical trials (PREVAIL) showed promising results in decreasing MADRS (Montgomery- Asberg Depression Rating Scale) and GCI-BP (Clinical Global Impressions Scale for use in bipolar illness ) scores, as monotherapy and adjunctive to lithium or valproate.[11][19] More recently, in 2017, a randomized, placebo-controlled trial of monotherapy of lurasidone in children and adolescents demonstrated a significant decrease in depressive and anxiety symptoms and improved the overall quality of life.[20] The sponsorship of these clinical trials was from the drug manufacturer; therefore, there is a concern of bias. [Level 1. 2]

There is a lack of data on the safety and efficacy of lurasidone use in elderly and pregnant/postpartum women. Clinical data on the safety and efficacy of lurasidone in schizophrenia reveals minimal adverse effects. More high-quality, long-term randomized control clinical trials need to be conducted to establish the safety and efficacy of lurasidone in bipolar depression.

Lurasidone requires the input of a healthcare team for therapy to be most effective. The prescribing clinician will, of course, initiate therapy based on their clinical judgment. Nursing staff can assist in counseling the patient on dosing and administration, monitoring treatment progress on subsequent visits, and letting the prescriber know if there are any issues to address. The pharmacist should check carefully for drug-drug interactions, especially in light of lurasidone's CYP450 metabolism, verify dosing, and providing additional patient counseling when the patient comes to pick up the medication. Nursing should be vigilant in monitoring during followup visits, answer any patient questions regarding therapy and report their findings to the managing clinician. Therapy optimization can only occur with the involvement of an interprofessional healthcare team, including physicians, specialists, specialty-trained nurses, and pharmacists, all communicating together to ensure optimal therapeutic results. [Level 5]