BOTTOM LINE:
Lurasidone offers some advantages, including no need for titration, once-daily dosing, relatively low-moderate metabolic profile, and relatively low QT prolongation risk. It is also one of five antipsychotics approved for bipolar depression (along with cariprazine, lumateperone, olanzapine/fluoxetine, and quetiapine). However, its use is limited by the need to administer with at least 350 calories of food, potential for drug interactions, and side effects including sedation, akathisia, and extrapyramidal symptoms (EPS). In clinical practice, you might lump lurasidone with the other second-generation antipsychotics (SGAs) that cause little weight gain, such as aripiprazole and ziprasidone.

FDA INDICATIONS:
Schizophrenia (adults, adolescents age 13 and up); bipolar I depression (as monotherapy and adjunct; adults, children age 10 and up).

OFF-LABEL USES:
Mixed depression; treatment-resistant depression; impulse control disorders.

DOSAGE FORMS:
Tablets (G): 20 mg, 40 mg, 60 mg, 80 mg, 120 mg.

DOSAGE GUIDANCE:

• Schizophrenia (adults and adolescents): Start 40 mg once daily, with food (at least 350 calories); no titration required. Usual dose 40–120 mg/day. Maximum 160 mg once daily (80 mg/day for adolescents).
• Bipolar depression (adults and children): Start 20 mg once daily, with food (at least 350 calories); no titration required. Usual dose 20–120 mg/day (20–40 mg/day in kids). Maximum 120 mg once daily (80 mg/day in kids), although doses over 80 mg/day rarely more effective.

MONITORING: Fasting glucose, lipids. COST: $

SIDE EFFECTS:

• Most common: Sedation (dose related), akathisia (dose related), nausea, parkinsonism, agitation.
• Serious but rare: See class warnings in chapter introduction. Orthostatic hypotension and syncope reported (rarely).
• Pregnancy/breastfeeding: Not enough data to recommend.

MECHANISM, PHARMACOKINETICS, AND DRUG INTERACTIONS:

• Dopamine D2 and serotonin 5-HT2A and 5-HT7 antagonist; serotonin 5-HT1A partial agonist.
• Metabolized primarily through CYP3A4; half-life: 18 hours.
• Avoid use with medications that cause orthostasis, potent 3A4 inhibitors (eg, clarithromycin, ketoconazole), or inducers (eg, carbamazepine, rifampin, St. John’s wort). Exercise caution/monitor when using in combination with moderate 3A4 inhibitors (eg, diltiazem); decrease lurasidone dose by 50% in patients taking moderate 3A4 inhibitors.

CLINICAL PEARLS:

• Administration with food (at least 350 calories) increases bioavailability 2-fold and peak serum levels roughly 3-fold; fat content of meal is not important.
• Appears to be relatively weight-neutral, and cardiometabolic parameters were little affected in company-sponsored trials, although post-marketing observations have been limited. In kids, weight gain was a common side effect in studies.
• A network meta-analysis of 10 randomized controlled trials with 3,336 adults with schizophrenia found that 40 mg, 80 mg, 120 mg, and 160 mg of lurasidone were effective but 20 mg was not. The 160 mg dose was best for Positive and Negative Syndrome Scale score reduction. Side effects, especially sedation and EPS, increased as dose went up. A good target may be 80 mg, which produced efficacy in 50% of patients. If patients still symptomatic but tolerating, increase to 120–160 mg.
• While using lurasidone in bipolar depression has not been associated with increase in the development of mania, its efficacy in treating manic episodes has not been established, so its use should be reserved for depressive episodes.
• Patients with bipolar depression were as likely to discontinue lurasidone as quetiapine in a yearlong study—most often due to akathisia for lurasidone and somnolence for quetiapine.

FUN FACT:
One unique feature of Latuda is its high affinity for the 5-HT7 receptor, which has been linked to depression, learning/memory, cognition, anxiety, and pain. Unfortunately, to date, Latuda has shown no clear benefit over other SGAs on these measures.