1. Lurasidone
Flavio Guzmán, MD

2. 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

3. Pharmacodynamics

4. 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,

5. Other 5HT1A agonists Buspirone Vilazodone Lurasidone Aripiprazole
Brexpiprazole
Ziprasidone

6. Clinical uses

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

8. 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.

9. Efficacy as monotherapy in bipolar depression
Monotherapy 6-week, placebo-controlled clinical trial
Outcome measure: changes in MADRS score
Lurasidone mg/day
N=166
Lurasidone 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. Efficacy as adjunct to lithium/valproate
6-week, placebo-controlled clinical trial
Primary outcome measure
MADRS score
Lurasidone 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.

15. 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.

16. 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.

17. 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.

18. Pharmacokinetics

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

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

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

22. 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.

23. Side effects

24. 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.

25. 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),

26. 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),

27. Prescribing information

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

29. 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. 

30. 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. 

31. 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. 

32. Lurasidone summary Pharmacodynamics: Approved for 5-HT2A/D2 antagonist
5-HT1A agonist
5-HT7 antagonist
Approved for
Schizophrenia: mg/day
Bipolar depression: mg/day

33. 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