Lurasidone

Lurasidone is a second-generation antipsychotic used for schizophrenia and bipolar depression. It has minimal weight gain, metabolic effect or QT prolongation, but it causes akathisia and nausea, and it must be taken with food. Strong CYP3A4 inhibitors and inducers are contraindicated.

Classification. Second-generation antipsychotic, benzisothiazol derivative.

Mechanism. Antagonism of dopamine D2, 5-HT2A and 5-HT7 receptors, and partial agonism at 5-HT1A receptors.

Pharmacokinetics. Bioavailability about 9 to 19% and about doubled by food (at least 350 kcal). Metabolised by CYP3A4. Half-life about 18 hours.

All regimens are oral with no loading dose.

Schizophrenia, adults.

• Start 40 mg once daily with food.
• Titration: increase based on response; no more than weekly.
• Usual 40 to 160 mg daily. Maximum 160 mg daily.
• Duration: at least 12 months after a first episode.

Bipolar depression, adults (monotherapy or with lithium or valproate). Start 20 mg once daily with food; increase to 120 mg daily as needed (monotherapy 20 to 120 mg; adjunct 20 to 120 mg).

Adolescents. Aged 13 to 17 years with schizophrenia: start 40 mg, usual 40 to 80 mg daily. Aged 10 to 17 years with bipolar depression: start 20 mg, usual 20 to 80 mg daily.

Dose limits. Creatinine clearance under 50 mL/min and moderate liver impairment: start 20 mg, maximum 80 mg daily. Severe liver impairment: maximum 40 mg daily. Moderate CYP3A4 inhibitors (diltiazem, erythromycin, fluconazole): start 20 mg, maximum 80 mg daily.

Contraindications. Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir) and strong inducers (rifampicin, carbamazepine, phenytoin, St John’s wort), hypersensitivity. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis, and suicidal thinking in under 25 years for depression.

Serious adverse effects. Neuroleptic malignant syndrome, tardive dyskinesia, akathisia, orthostatic hypotension, seizures, hyperglycaemia, leucopenia (rare), severe cutaneous reactions.

Common adverse effects. Akathisia, nausea, somnolence, parkinsonism, agitation, vomiting, insomnia.

Interactions. Strong CYP3A4 inhibitors and inducers are contraindicated, which excludes rifampicin used in tuberculosis treatment and ritonavir-boosted antiretrovirals. Grapefruit juice raises levels. Alcohol and sedatives add effects. Antihypertensives add hypotension. Levodopa is antagonised.

Common prescribing errors. Giving on an empty stomach; starting during rifampicin or ritonavir treatment; not reducing the dose in kidney or liver impairment; titrating too quickly.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: avoid; limited data.
• Children: licensed from 10 to 13 years in some regions; specialist use.
• Older adults: start low; mortality risk in dementia.
• Kidney impairment: start 20 mg, maximum 80 mg daily when creatinine clearance is under 50 mL/min.
• Liver impairment: start 20 mg; maximum 80 mg daily in moderate and 40 mg daily in severe impairment.

Formulations. Tablets 18.5 mg, 20 mg, 37 mg, 40 mg, 74 mg, 80 mg and 120 mg, depending on the salt expressed. Give once daily with a meal of at least 350 kcal.

Baseline. Weight, BMI, waist, blood pressure, fasting glucose or HbA1c, lipids, and a baseline rating of extrapyramidal symptoms and akathisia.

Monitoring. Weight and waist at baseline, 4, 8 and 12 weeks, then annually; fasting glucose or HbA1c and lipids at baseline, 12 weeks, then annually. Check for akathisia and extrapyramidal symptoms at each review; rate abnormal movements every 6 to 12 months. Review the medicines list whenever an antibiotic, antifungal or antiretroviral is started.

Stopping. Reduce gradually over several weeks.

Referral and escalation. Refer to psychiatry for first-episode psychosis or treatment resistance. Fever with rigidity or seizures needs emergency care.