New Drug Review: Lurasidone (Latuda®) - The new antipsychotic on the block
Lurasidone was approved by the Food and Drug Administration (FDA) in 2011. This article reviews clinically significant aspects of this new drug including: the FDA-approved indications, mechanism of action, administration, drug interactions, adverse effects, clinical trial evidence, innovative properties and place in therapy.
LJ is a 49 year-old male with schizophrenia who is routinely seen at your clinic for medication management. He has a long history of antipsychotic use, including haloperidol and ziprasidone. He is currently taking risperidone 6 mg daily and has gained approximately 25 pounds over the past year. He also recently developed diabetes and hypertriglyceridemia. Despite your encouragement for him to maintain a healthy diet and routinely exercise, he continues to spend most days indoors, alone, and watching TV. He reports a lack of motivation to "get out of the apartment" and does not have much of a desire to "work-out." He denies having any active positive symptoms of schizophrenia; however, he is still displaying numerous negative and cognitive symptoms. Are there any newer antipsychotic treatment options for LJ that would have minimal effect on his weight and provide better control of his negative and cognitive symptoms?
WHAT ARE THE FDA-APPROVED INDICATIONS FOR LURASIDONE?
Lurasidone (Latuda®) is currently indicated for the treatment of schizophrenia in adults, and its effectiveness beyond six weeks has not yet been established in clinical trials. Clinically, it is being used for both acute and maintenance treatment of schizophrenia. No published evidence presently exists evaluating its safety and/or efficacy for the treatment of bipolar disorder, major depression, or pediatric use.
WHAT IS THE RECEPTOR BINDING PROFILE OF LURASIDONE?
Lurasidone is the newest atypical antipsychotic to reach the US market in 2011. It is a second-generation antipsychotic that acts as a dopamine D2 and serotonin 5HT2A receptor antagonist, but also has 5HT7 antagonist and 5HT1A partial agonist activity.3 It has minimal affinity for alpha1 receptors and no affinity for the muscarinic (M1) and histamine (H1) receptors.1
HOW IS LURASIDONE DOSED AND HOW SHOULD IT BE ADMINISTERED?
Lurasidone should be initiated at a dose of 40 mg by mouth daily. It should be administered with food (at least 350 calories), which increases the drugs bioavailability, causing the Cmax to triple and the AUC to double.3 Steady-state blood concentrations are reached in 7 days. At oral doses of 40 mg, positron-emission tomography (PET) scans indicate 60–80% D2 receptor blockade; however, if symptoms persist, the dose can be increased to a maximum recommended 80 mg daily.1 Currently, no dosage adjustments are necessary for the elderly (65 – 85 years of age). Patients with moderate to severe renal impairment (CrCl of 10–49 mL/minute) or hepatic impairment (Child-Pugh class B or C) should be limited to a maximum daily dosage of 40 mg.3 Although lurasidone is categorized as Pregnancy Category B, safety data for use in humans are lacking.6
ARE THERE ANY CLINICALLY SIGNIFICANT DRUG INTERACTIONS WITH LURASIDONE?
Lurasidone is metabolized hepatically via the CYP3A4 system, and thus is susceptible to drug interactions. Doses should not exceed 40 mg/day when it is administered concomitantly with moderate CYP3A4 inhibitors, such as diltiazem and clarithromycin. Lurasidone is contraindicated for use in combination with strong CYP3A4 inhibitors (e.g., ketoconazole) and strong CYP3A4 inducers (e.g., rifampin).1–3 Unlike antipsychotics such as ziprasidone and haloperidol, there is minimal QTc prolongation risk associated with lurasidone.
WHAT ADVERSE EFFECTS SHOULD I DISCUSS WITH MY PATIENT?
The most common adverse effects reported in clinical trials (≥5%) were insomnia, akathisia, nausea, parkinsonism, and agitation.14 Insomnia and akathisia appear to be dose-related; it is not advised to increase the dose of lurasidone beyond 80 mg/day. Due to lurasidone's lack of affinity at the alpha1, histamine1, and muscarinic receptors, clinically we should expect minimal orthostasis and dizziness, sedation, and anticholinergic (e.g., dry mouth, constipation) adverse effects. The black box warning for increased mortality in elderly patients with dementia-related psychosis is the same for this antipsychotic as with other first and second-generation antipsychotics. The lurasidone package insert highlights the risk of metabolic changes associated with all antipsychotic treatments; however, lurasidone appears to have a benign metabolic and weight profile.1–4 Monitoring of waist circumference, weight, blood pressure, BMI, fasting lipid panel and glucose is still recommended.
HOW DID LURASIDONE PERFORM IN CLINICAL TRIALS?
Data from six 6-week randomized, placebo-controlled trials are available. Five studies demonstrated efficacy versus placebo using the Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS) and/or Clinical Global Impression-Severity (CGI-S) as major outcome measures.14 One of the five studies also used olanzapine 15 mg/day as an active comparator. Time to onset of response appeared to be 3–7 days. The one failed trial of the six, 6-week trials included arms of lurasidone and haloperidol. In this study, both lurasidone and haloperidol failed to show statistically significant separation from placebo on major outcomes of the BPRS, PANSS and CGI-S.14
WHAT IS INNOVATIVE ABOUT THIS NEW ANTIPSYCHOTIC?
Along with iloperidone and asenapine, this is the third second-generation antipsychotic to be approved for schizophrenia in the last two years. Some may refer to this antipsychotic as a potentially innovative new treatment option for psychosis, while others may view it as a "me-too" drug. Lurasidone's pharmacologic profile is very similar to ziprasidone while its adverse effect profile is similar to aripiprazole. The delivery system for lurasidone is not unique, as it is presently available as 40 and 80 mg oral tablets. No liquids, oral disintegrating tablets, or injections are available as delivery systems at this time, although a long-acting injectable formulation is under development.
WHAT PLACE DOES LURASIDONE HAVE IN THE TREATMENT OF SCHIZOPHRENIA?
If we review the original case presented in this article, it highlights a patient that developed significant metabolic adverse effects from risperidone therapy. Because this patient experienced weight gain and developed diabetes, antipsychotics such as clozapine, olanzapine, and quetiapine are less favorable treatment options. Lurasidone may provide clinicians and patients with an alternative antipsychotic treatment option when metabolic complications develop from other treatments. It may also be a more desirable option over medications such as ziprasidone due to its once daily dosing and minimal effect on the QTc interval. Researchers hypothesize that lurasidone may have cognitive and mood enhancing properties related to its antagonist effects on serotonin, specifically 5-HT7. Time, clinical experience, and more long-term trials will allow clinicians to have a better understanding of its true cognitive-enhancing effects. Because of the cost associated with a new antipsychotic treatment (~$500.00/month)5, and the possibility of limited insurance coverage, lurasidone should not generally be used as first-line therapy over less expensive and equally effective atypical antipsychotics.