Lurasidone is a second generation (atypical) antipsychotic. It was initially approved by the U.S. Food and Drug Administration (FDA) for treatment of adults with schizophrenia. In 2009 the manufacturer decided to pursue approval for the treatment of bipolar depression by establishing the lurasidone bipolar program (PREVAIL). The goal was to determine a safe and effective medication for bipolar depression. Based on the results of this program, lurasidone received FDA approval for the treatment of bipolar depression in June 2013; this was a significant innovation because lurasidone was the first drug approved both as a monotherapy and as an adjunctive to lithium or valproate.
In January 2017, lurasidone received FDA approval for the treatment of schizophrenia in adolescents and in March 2018, the FDA expanded the usage to include pediatric patients (10 to 17 years of age) for the treatment of major depressive episodes associated with bipolar depression.
Lurasidone is sometimes used off-label to treat bipolar mania and irritability and anger in autism spectrum disorder.
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. Lurasidone is a full antagonist at dopamine D2 and serotonin 5-HT2A and 5-HT7 receptors. It is a partial agonist at 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. This activity level minimizes the risk of orthostatic hypotension, sedation, weight gain and cognitive blunting associated with other antipsychotic agents.
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%. 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. Lurasidone metabolism is primarily by cytochrome P450 enzyme, CYP3A4; therefore, caution is necessary when administered with strong CYP3A4 inducers or inhibitors.
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.
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 when compared to risperidone, quetiapine, and olanzapine.
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 when compared with other atypical antipsychotics such as quetiapine and risperidone. Several short term clinical trials observed significant increases in prolactin levels.
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.
Lurasidone, when used in pregnant patients, may case extrapyramidal or withdrawal symptoms in neonates when exposed in the third trimester.
Lurasidone metabolism is primarily via cytochrome P450 enzyme, CYP3A4. 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 20mg and a maximum dose of 80mg/day. Similarly, when combined with moderate CYP3A4 inducers, 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.
Lurasidone takes 1 to 3 hours to reach the maximum concentration after an oral dose of 40mg. 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. 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 effect lurasidone’s pharmacokinetics.
Lurasidone does not increase suicidal ideation or behavior. Although the FDA has issued a black box warning with the risk of death in elderly patients with dementia, there is no clinical trial data to prove this evidence. 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.
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 amount 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.
There is only one other documented case in the lurasidone leaflet regarding overdose. A patient took 560mgs of lurasidone and recovered without negative sequelae. No long term adverse effects were noticed 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.
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 80mgs 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. Additional clinical trials are necessary to prove the antisuicidal effects of lurasidone.
Patients with bipolar depression achieved an optimal clinical response at 20 to 60mgs 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 counsel the patients to take this medication with food at all times, of 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. (level V)
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. 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. The sponsorship of these clinical trials came from by the drug manufacturer; therefore there is a concern of bias. (level I, II)
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 safety and efficacy of lurasidone in bipolar depression.
Lurasidone therapy is best 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 V]
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