Lurasidone Flavio Guzmán, MD

Outline Mechanism of action: effects on 5-HT2A/D2, 5HT1A, 5HT7 Efficacy in schizophrenia and bipolar depression Pharmacokinetics: CYP3A4 metabolism Common side effects and tolerability profile Dosing

Pharmacodynamics

Lurasidone pharmacodynamics 5-HT1A partial agonism Probably linked to antidepressant effects Antipsychotic effects 5-HT7 antagonism Improved cognition in animal models Loebel, A., Citrome, L. (2014). Lurasidone: a novel antipsychotic agent for the treatment of schizophrenia and bipolar depression. Psychiatric Bulletin, 1, 5. Horisawa, T., et al  (2013). The role of 5-HT7 receptor antagonism in the amelioration of MK-801-induced learning and memory antipsychotic lurasidone. Behavioural brain research, 244, 66-69.

Other 5HT1A agonists Buspirone Vilazodone Lurasidone Aripiprazole Brexpiprazole Ziprasidone

Clinical uses

FDA-approved indications Schizophrenia (2010) 40-160 mg/day Bipolar depression (2013) Monotherapy Adjunct to lithium or valproate 20-120 mg/day Latuda (Lurasidone) [Prescribing Information] Marlborough, MA: Sunovion Pharmaceuticals Inc. 

Efficacy in schizophrenia Approval based on five 6-week, fixed-dose, placebo-controlled studies Long-term comparison studies (12 months) Risperidone Comparable improvement in efficacy Similar relapse rates at 12 months Quetiapine XR Lurasidone noninferior to quetiapine in risk for relapse Harvey, P. D. (2015). The clinical utility of lurasidone in schizophrenia: patient considerations. Neuropsychiatric disease and treatment, 11, 1103.

Efficacy as monotherapy in bipolar depression Monotherapy 6-week, placebo-controlled clinical trial Outcome measure: changes in MADRS score Lurasidone 20-60 mg/day N=166 Lurasidone 80-120 mg/day N=169 Placebo N=170 Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Efficacy as monotherapy Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Efficacy as monotherapy Difference: 23-21% Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Efficacy as monotherapy Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Efficacy as monotherapy Difference 17-15% Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Efficacy as adjunct to lithium/valproate 6-week, placebo-controlled clinical trial Primary outcome measure MADRS score Lurasidone 20-120 mg + lithium/valproate Placebo + lithium/valproate Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Efficacy as adjunct to lithium/valproate Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Efficacy as adjunct to lithium/valproate Difference: 15% Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

One failed trial in bipolar depression: Lurasidone failed to separate from placebo Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Pharmacokinetics

Half-life: 18 hours Once-daily dosing Pharmacokinetics Latuda (Lurasidone) [Prescribing Information] Marlborough, MA: Sunovion Pharmaceuticals Inc. 

Lurasidone: metabolized by CYP3A4 Latuda (Lurasidone) [Prescribing Information] Marlborough, MA: Sunovion Pharmaceuticals Inc. 

Lurasidone: metabolized by CYP3A4 Inducers Carbamazepine Reduced LUR levels Latuda (Lurasidone) [Prescribing Information] Marlborough, MA: Sunovion Pharmaceuticals Inc. 

Lurasidone: metabolized by CYP3A4 Inhibitors Fluvoxamine Fluoxetine Increased LUR levels Paul, S., Cooke, B. K., & Nguyen, M. (2013). Glossopharyngeal Dystonia Secondary to a Lurasidone-Fluoxetine CYP-3A4 Interaction. Case reports in psychiatry, 2013.

Side effects

Side effects Lurasidone Placebo Somnolence 17% 7% Akathisia 13% 3% Nausea 10% 5% Parkinsonism Akathisia and EPS: dose related Harvey, P. D. (2015). The clinical utility of lurasidone in schizophrenia: patient considerations. Neuropsychiatric disease and treatment, 11, 1103.

Minimal metabolic side effects Minimal effects on weight Minimal effects on lipids De Hert, M., et al (2012). Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder. CNS drugs, 26(9), 733-759.

Effects on prolactin levels Haloperidol Risperidone Paliperidone Lurasidone Aripiprazole Quetiapine Lower increase than haloperidol, risperidone and paliperidone Higher increase than aripiprazole and quetiapine Leucht, S., et al (2013). Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, 382(9896), 951-962.

Prescribing information

Dosage forms Scored tablets 20 mg 40 mg 60 mg 80 mg 120 mg

Lurasidone should be taken with food Increases drug absorption Twofold in AUC Threefold increases in Cmax (peak serum concentration) Should be taken with food At least 350 calories Latuda (Lurasidone) [Prescribing Information] Marlborough, MA: Sunovion Pharmaceuticals Inc. 

Can be increased to 160 mg/day Schizophrenia dosing No titration required Once-daily dosing Recommended starting dose 40 mg/day: therapeutic dose Can be increased to 160 mg/day Latuda (Lurasidone) [Prescribing Information] Marlborough, MA: Sunovion Pharmaceuticals Inc. 

Bipolar depression dosing No titration required Once-daily dosing Recommended starting dose 20 mg/day: therapeutic dose Can be increased to 120 mg/day Latuda (Lurasidone) [Prescribing Information] Marlborough, MA: Sunovion Pharmaceuticals Inc. 

Lurasidone summary Pharmacodynamics: Approved for 5-HT2A/D2 antagonist 5-HT1A agonist 5-HT7 antagonist Approved for Schizophrenia: 40-160 mg/day Bipolar depression: 20-120 mg/day

Lurasidone summary Side effects: Should be taken with food Most common: sedation and akathisia Akathisia and Parkinsonism are dose related Minimal effects on weight and lipids Should be taken with food At least 350 calories