Lurasidone
Latuda (brand name)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Schizophrenia | Adults and adolescents (13–17 years) | Monotherapy | FDA Approved |
| Bipolar I depression — monotherapy | Adults and pediatric patients (10–17 years) | Monotherapy | FDA Approved |
| Bipolar I depression — adjunctive | Adults | Adjunctive to lithium or valproate | FDA Approved |
Lurasidone was approved in 2010 and is notable as one of few atypical antipsychotics with a dedicated FDA-approved indication for bipolar depression, both as monotherapy and adjunctive therapy. Its receptor profile includes high-affinity antagonism at D2, 5-HT2A, and 5-HT7 receptors, partial agonism at 5-HT1A, and very low affinity for histamine H1 and muscarinic M1 receptors. This receptor selectivity underpins a favourable metabolic profile with minimal weight gain and lipid disturbances. Lurasidone is not approved for bipolar mania.
Major depressive disorder (augmentation) — Some clinicians use lurasidone as augmentation to antidepressants based on extrapolation from bipolar depression data. Evidence quality: Low.
Schizoaffective disorder — Used based on pharmacological similarity to other SGAs approved for this condition. Evidence quality: Moderate (extrapolation).
Autism-related irritability (paediatric) — Studied in open-label extension trials but not FDA-approved for this use. Evidence quality: Low.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Schizophrenia — acute episode or maintenance | 40 mg QD | 40–160 mg QD | 160 mg/day | No titration needed; take with food (≥350 kcal) Efficacy established at 40, 80, 120, and 160 mg/day in five 6-week trials |
| Bipolar I depression — monotherapy | 20 mg QD | 20–120 mg QD | 120 mg/day | Higher range (80–120 mg) did not show additional benefit on average over lower range (20–60 mg) in monotherapy trial Lower starting dose than schizophrenia |
| Bipolar I depression — adjunct to lithium or valproate | 20 mg QD | 20–120 mg QD | 120 mg/day | Same dosing as monotherapy; monitor lithium/valproate levels concurrently |
Paediatric Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Schizophrenia — adolescent (13–17 years) | 40 mg QD | 40–80 mg QD | 80 mg/day | No titration needed; take with food |
| Bipolar I depression — paediatric (10–17 years) | 20 mg QD | 20–80 mg QD | 80 mg/day | Increase after 1 week based on response; most patients stabilised at 20–40 mg in trial (67%) |
Dose Adjustments for Special Populations & Drug Interactions
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Moderate or severe renal impairment (CrCl <50 mL/min) | 20 mg QD | 20–80 mg QD | 80 mg/day | Applies to both schizophrenia and bipolar depression |
| Moderate hepatic impairment (Child-Pugh 7–9) | 20 mg QD | 20–80 mg QD | 80 mg/day | Reduced clearance expected |
| Severe hepatic impairment (Child-Pugh 10–15) | 20 mg QD | 20–40 mg QD | 40 mg/day | Further restricted maximum |
| Co-prescribed moderate CYP3A4 inhibitor (e.g. diltiazem, erythromycin) | 20 mg QD | Half of original dose | 80 mg/day | Restore original dose when inhibitor discontinued |
| Co-prescribed moderate CYP3A4 inducer | May need to increase lurasidone dose | Adjust after ≥7 days on the inducer | ||
Lurasidone must be taken with food containing at least 350 calories. Without food, AUC is reduced by approximately half and Cmax by approximately two-thirds, potentially leading to sub-therapeutic exposure. Additionally, lurasidone is heavily dependent on CYP3A4 for metabolism, making strong CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin) and strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John’s wort) contraindicated. Grapefruit and grapefruit juice should also be avoided.
Pharmacology
Mechanism of Action
Lurasidone is a benzisothiazole-derivative atypical antipsychotic with a distinctive receptor-binding profile. It acts as a full antagonist at dopamine D2 and serotonin 5-HT2A receptors, which is the shared pharmacological basis for atypical antipsychotic activity. Uniquely, lurasidone has high affinity for the serotonin 5-HT7 receptor (antagonist), which is believed to contribute to its procognitive and antidepressant effects. It is also a partial agonist at 5-HT1A, which may further support anxiolytic and antidepressant properties. Critically, lurasidone has very low affinity for histamine H1 and muscarinic M1 receptors, explaining its minimal propensity for weight gain, sedation, and anticholinergic side effects compared to agents such as olanzapine, quetiapine, or clozapine.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax 1–3 h; estimated bioavailability 9–19%; AUC ~2-fold and Cmax ~3-fold higher with food (≥350 kcal) vs fasting; food effect independent of fat content | Must always be taken with a meal; counselling on food requirement is essential for reliable drug exposure |
| Distribution | Apparent Vd = 6,173 L; ~99% protein-bound | Very large apparent volume indicates extensive tissue distribution; high protein binding unlikely to produce displacement interactions |
| Metabolism | Primarily CYP3A4; produces active metabolites (ID-14283 and ID-14326) with some pharmacological activity; dose-proportional PK across 20–160 mg range | Strong CYP3A4 modulators are contraindicated; moderate inhibitors require dose halving; active metabolites contribute to overall clinical effect |
| Elimination | t½ = 18 h; steady state in ~7 days; clearance 3,902 mL/min (apparent); excretion ~80% faeces, ~9% urine | 18-hour half-life supports once-daily dosing; predominantly hepatic elimination means renal impairment has modest impact but dose adjustment still recommended for moderate/severe |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Akathisia | 12.9% (schizo); 7.9–10.8% (bipolar) | Dose-related: 5.6% at 20 mg, 10.7% at 40 mg, 12.3% at 80 mg, 22% at 120 mg (vs 3% placebo); most clinically significant tolerability issue |
| Somnolence / Sedation | 11–14% (schizo); 7–14% (bipolar) | Dose-related; includes hypersomnia and sedation terms; higher in bipolar depression (80–120 mg arm 13.8%) |
| Nausea | 12% (schizo); 10–17% (bipolar) | One of the most common early adverse effects; typically transient; taking with food helps; higher in bipolar depression at higher doses |
| EPS (non-akathisia) | 13.5% (schizo) vs 5.8% placebo | Includes parkinsonism, dystonia, tremor, cogwheel rigidity; dose-related similar to akathisia pattern |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Insomnia | 8% | More common in bipolar depression paediatric trials; manage with evening dosing and sleep hygiene |
| Agitation | 6% | May overlap with akathisia; careful differentiation needed |
| Anxiety | 6% | More frequent in bipolar depression monotherapy trials (both dose groups met twice-placebo threshold) |
| Vomiting | 5–8% | More prominent in bipolar depression at higher doses; usually transient |
| Diarrhoea | 5% | Met twice-placebo threshold in bipolar depression monotherapy trial |
| Dystonia | 5% | EPS subtype; dose-related; includes oculogyric crisis and torticollis |
| Dizziness | 4% | Related to alpha-1 effects; advise positional caution during initiation |
| Weight gain | ≥7% gain in 4.8% (schizo) vs 3.3% placebo | Mean +0.43 kg (schizo adults); one of the most weight-neutral SGAs; long-term studies show weight stability or slight decrease |
| Back pain | 3% | Musculoskeletal complaint reported more frequently than placebo |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Neuroleptic malignant syndrome | Very rare | Days to weeks | Immediate discontinuation; ICU supportive care |
| Tardive dyskinesia | Rare (<1%) | Months to years | Consider discontinuation; screen with AIMS periodically |
| Angioedema | Very rare (postmarketing) | Any time | Permanent discontinuation; lurasidone contraindicated in known hypersensitivity |
| Suicidal thoughts/behaviours (youth, bipolar depression) | See boxed warning | Early weeks or dose changes | Close monitoring in all patients <25 years; family education |
| Leukopenia / Neutropenia | Rare | First months | Monitor CBC in patients with pre-existing low WBC; discontinue if significant decline |
| Seizures | Rare | Any time | Use with caution in patients with seizure history |
Akathisia is the most significant tolerability challenge with lurasidone and is clearly dose-related (escalating from 5.6% at 20 mg to 22% at 120 mg in schizophrenia trials). Strategies include dose reduction as the first step, switching to evening dosing, or a short course of propranolol (20–80 mg/day) or a benzodiazepine. In bipolar depression, starting at 20 mg rather than 40 mg and titrating slowly may help, particularly since the lower dose range (20–60 mg) showed equivalent efficacy to higher doses in the monotherapy trial.
Drug Interactions
Lurasidone is metabolised primarily by CYP3A4, making it highly sensitive to drugs that modulate this enzyme. Unlike many other antipsychotics, lurasidone does not significantly inhibit or induce CYP enzymes, so it has limited potential to alter the levels of co-administered medications.
Monitoring
- Fasting Glucose & HbA1cBaseline, 12 weeks, then annually
RoutineLurasidone has minimal glucose effects in clinical trials (mean change <3 mg/dL across doses), but class-wide monitoring remains standard per APA/ADA consensus. - Lipid PanelBaseline, 12 weeks, then annually
RoutineLurasidone generally produced decreases in total cholesterol and triglycerides in schizophrenia trials. Still monitor per guidelines. - Body Weight & BMIBaseline, monthly for 3 months, then quarterly
RoutineMean weight gain +0.43 kg in adults with schizophrenia (vs -0.02 placebo). Long-term open-label data show weight stability or slight decrease. One of the most weight-neutral SGAs. - EPS / AkathisiaEach visit
RoutineThe most common clinically significant adverse effect. Use Barnes Akathisia Scale for assessment. Monitor for dose-response relationship. AIMS every 6–12 months for tardive dyskinesia. - ProlactinIf symptoms develop
Trigger-BasedLurasidone can elevate prolactin (D2 antagonism). Assess if galactorrhoea, amenorrhoea, gynaecomastia, or sexual dysfunction reported. - Renal FunctionBaseline; periodically if risk factors
RoutineDose adjustment required at CrCl <50 mL/min. Monitor creatinine and eGFR, especially in elderly or patients with comorbidities. - Hepatic FunctionBaseline; periodically if risk factors
RoutineDose adjustment required in moderate (max 80 mg) and severe (max 40 mg) hepatic impairment. - Suicidality AssessmentWeekly for first 4 weeks, then at dose changes
Trigger-BasedParticularly important in patients <25 years receiving lurasidone for bipolar depression per the boxed warning.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to lurasidone or any formulation component (angioedema reported)
- Concomitant strong CYP3A4 inhibitors — ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil
- Concomitant strong CYP3A4 inducers — rifampin, carbamazepine, phenytoin, St. John’s wort
Relative Contraindications (Specialist Input Recommended)
- Dementia-related psychosis in elderly — increased mortality; not approved for this population
- Severe hepatic impairment — maximum 40 mg/day; monitor closely
Use with Caution
- Patients at risk for falls — somnolence, orthostatic hypotension, and motor instability
- History of seizures or conditions lowering seizure threshold
- Patients with Parkinson’s disease or Lewy body dementia — D2 blockade can worsen motor and neuropsychiatric symptoms
- Conditions predisposing to aspiration
- Exposure to extreme heat — antipsychotics may impair thermoregulation
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death (4.5% vs 2.6% in placebo, modal trial duration 10 weeks). Lurasidone is not approved for dementia-related psychosis.
Antidepressants (including lurasidone when used for bipolar depression) increased the risk of suicidal thoughts and behaviour in paediatric and young adult patients in short-term studies. All patients should be monitored for clinical worsening and emergence of suicidal thoughts, especially during the initial months of therapy or at dose changes.
Patient Counselling
Purpose of Therapy
Lurasidone helps balance brain chemicals involved in mood and thinking. For schizophrenia, it reduces hallucinations and disordered thinking. For bipolar depression, it helps lift mood and restore energy. Improvement may begin within the first 1–2 weeks, but full benefit often takes 4–6 weeks.
How to Take
Take lurasidone once daily with a meal or snack of at least 350 calories. Swallow the tablet whole. Taking it without food significantly reduces how much of the medicine your body absorbs. Do not stop taking it suddenly without discussing with your prescriber, as this could worsen your condition.
Sources
- Sumitomo Pharma America, Inc. LATUDA (lurasidone hydrochloride) Prescribing Information. Revised January 2025. FDA LabelPrimary source for all dosing, indications, contraindications, adverse reaction incidence data, and metabolic monitoring data in this monograph.
- FDA Pediatric Postmarketing Pharmacovigilance Review for Latuda (lurasidone). February 2025. FDA ReviewMost recent paediatric safety surveillance review confirming no new safety signals in patients <18 years.
- Nakamura M, Ogasa M, Guarino J, et al. Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70(6):829-836. doi:10.4088/JCP.08m04905Pivotal Phase III trial establishing efficacy of lurasidone 80 mg/day in acute schizophrenia with safety data.
- Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160-168. doi:10.1176/appi.ajp.2013.13070984Key trial supporting the bipolar depression monotherapy indication with dose-range data (20–60 mg and 80–120 mg arms).
- Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression. Am J Psychiatry. 2014;171(2):169-177. doi:10.1176/appi.ajp.2013.13070985Pivotal trial supporting the bipolar depression adjunctive indication with lithium or valproate.
- Citrome L, Cucchiaro J, Sarma K, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month, double-blind, active-controlled study. Int Clin Psychopharmacol. 2012;27(3):165-176. doi:10.1097/YIC.0b013e32835281efLong-term safety study comparing lurasidone with risperidone demonstrating favourable metabolic profile over 12 months.
- American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, 3rd edition. Am J Psychiatry. 2021;178(suppl). doi:10.1176/appi.books.9780890424841Current APA guideline including lurasidone among first-line oral antipsychotic options for schizophrenia.
- Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170. doi:10.1111/bdi.12609International guideline recommending lurasidone as a first-line treatment for acute bipolar I depression.
- Ishibashi T, Horisawa T, Tokuda K, et al. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-HT7 and 5-HT1A receptor activity. J Pharmacol Exp Ther. 2010;334(1):171-181. doi:10.1124/jpet.110.167346Foundational pharmacology study characterising lurasidone’s unique 5-HT7 antagonism and its potential role in cognitive and antidepressant effects.
- Preskorn S, Ereshefsky L, Chiu YY, et al. Effect of food on the pharmacokinetics of lurasidone: results of two randomized, open-label, crossover studies. Hum Psychopharmacol. 2013;28(5):495-505. doi:10.1002/hup.2338RCT establishing the food effect on lurasidone absorption (AUC 2x, Cmax 3x) and the 350 kcal minimum meal threshold.
- Caccia S, Pasina L, Nobili A. Critical appraisal of lurasidone in the management of schizophrenia. Neuropsychiatr Dis Treat. 2012;8:155-168. doi:10.2147/NDT.S25587Comprehensive review covering pharmacokinetics, CYP3A4 dependence, and clinical implications across special populations.