IN THIS ISSUE:
February 2011

Lurasidone (Latuda)
The new antipsychotic lurasidone (Latuda) appears generally comparable in safety and efficacy to currently available agents.

Antipsychotics Increase the Risk of Venous Thromboembolism
Antipsychotics cause a small increase in the risk of venous thromboembolism in some patients.

Pramipexole for Cognitive Enhancement in Bipolar Disorder
In one study, adjunctive pramipexole (Mirapex and others) provided cognitive benefit for euthymic patients with bipolar disorder.

In Brief
Mindfulness-Based Cognitive Therapy Equivalent to Maintenance Antidepressant Treatment for Relapse Prevention; Docosahexaenoic Acid (DHA) Supplementation Does Not Slow Cognitive Decline in Patients with Alzheimer Disease

Anticonvulsants and Suicide Risk: The Saga Continues
A new study finds an increased risk of suicide in patients taking anticonvulsants for indications other than epilepsy but no additional risk in patients with epilepsy.

Lurasidone (Latuda)

February 2011

In October 2010, the US Food and Drug Administration (FDA) approved the new antipsychotic lurasidone (Latuda) to treat schizophrenia in adults. Lurasidone, manufactured by Sunovion, should be available in pharmacies in February 2011.

Lurasidone is an azapirone derivative and novel molecular entity. It has potent binding affinity for dopamine D2; serotonin 5-HT2A, 5-HT7, and 5-HT1A; and norepinephrine α2C receptors. It has weak affinity for norepinephrine α1 and α2A and serotonin 5-HT2C receptors and negligible affinity for histamine H1 and muscarinic acetylcholine receptors.1 In theory, low affinity for α1 noradrenergic receptors should predict a low probability of orthostatic hypotension, but orthostatic hypotension, dizziness, and syncope are risks with lurasidone—especially at the beginning of treatment. Although lack of affinity for histamine H1 receptors should predict a low likelihood of weight gain and sedation, lurasidone does cause some weight gain and dose-related sedation. Few anticholinergic side effects would be expected in a drug with low affinity for muscarinic acetylcholine receptors.

Preclinical studies suggest 5-HT7 receptors may act as modulators of striatal and cortical dopamine function and could play a role in cognition.2 In laboratory rats, lurasidone reversed memory impairment induced by an N-methyl-D-aspartate antagonist.2 But whether these basic science findings have any human application has yet to be determined.

Clinical trials suggest lurasidone is superior in efficacy to placebo for the acute treatment of schizophrenia in adults. The FDA reviewed data from more than 40 clinical trials involving approximately 2700 lurasidone-treated adult subjects. Four pivotal 6-week placebo-controlled trials led to its approval. Further research will be required to establish lurasidone's efficacy beyond 6 weeks and how it will compare with other antipsychotics.

In one of the 6-week trials, in which patients received either a fixed 80-mg/day dose of lurasidone or placebo, the most frequent adverse events associated with lurasidone were gastrointestinal: nausea, constipation, vomiting, and dyspepsia.3 On average, lurasidone-treated patients gained 0.5 kg (1.1 lb) more than placebo-treated patients, but the only adverse metabolic effect attributed to the drug was a small average increase in hemoglobin A1c levels.

Data from all lurasidone trials indicate dose-related akathisia and somnolence and a small increase in the cardiac QTc interval.4 Lurasidone's likelihood of causing extrapyramidal effects appears comparable to risperidone (Risperdal and others), olanzapine (Zyprexa and others), and ziprasidone (Geodon)—but not as low as clozapine (Clozaril and others). Significant prolactin elevation was observed in 3.6% of lurasidone-treated patients versus 0.7% of placebo-treated subjects. In women, there was an even greater incidence of significant prolactin elevation: 8.3% with lurasidone versus 1.0% with placebo. Increases in prolactin concentration were dose related.

After oral administration, the time to maximum lurasidone plasma concentration is 1 to 3 hours. Approximately 9% to 19% of an oral dose is absorbed, and the mean half-life has ranged from 29 to 37 hours (although the product label notes that the mean half-life with a 40-mg dose is 18 hours). Steady state is achieved within 7 days. Lurasidone is almost completely bound to protein.

Lurasidone's absorption is increased when it is taken with food, regardless of caloric count or fat composition. Lurasidone concentrations are elevated in patients with renal or hepatic impairment.

The primary metabolic pathway for lurasidone involves the cytochrome P450 (CYP) 3A4 enzyme. Inhibitors of CYP 3A4, such as ketoconazole (Nizoral and others) and diltiazem (Cardizem and others), can therefore raise lurasidone levels, while CYP 3A4 inducers, such as rifampin (Rifadin and others), can decrease levels. Lurasidone itself is a weak 3A4 inhibitor.

Lurasidone should be available in 40- and 80-mg tablets. The product label recommends a starting dose of 40 mg administered once daily with food, with a maximum dose of 80 mg/day. Somnolence and extrapyramidal effects appear more common with higher doses. Patients with severe renal or hepatic impairment should be treated with lower doses, as should patients taking a moderate CYP 3A4 inhibitor. Strong CYP 3A4 inhibitors, such as ketoconazole, or strong CYP 3A4 inducers, such as rifampin, are considered contraindications for lurasidone. In studies with higher-than-recommended doses, such as 120 to 160 mg/day, the most common adverse effects were anxiety, insomnia, restlessness, and fatigue—but not abnormal electrocardiograms.

Presumably, lurasidone will be priced similarly to other antipsychotics that remain on patent protection. Based on the short-term data currently available, it appears to be tolerated at a level comparable to that of other marketed agents, and its efficacy in short-term trials also appears equivalent. At this early stage of knowledge about the new agent, there is nothing to mark it as uniquely advantageous in either safety or tolerabilty. Where it will ultimately fit into an algorithm for the treatment of schizophrenia and perhaps other psychotic conditions remains to be established.

1Ishibashi T, Horisawa T, Tokuda K, Ishiyama T, Ogasa M, Tagashira R, Matsumoto K, Nishikawa H, Ueda Y, Toma S, Oki H, Tanno N, Saji I, Ito A, Ohno Y, Nakamura M: Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther 2010;334:171-181.

2Meyer JM, Loebel AD, Schweizer E: Lurasidone: A new drug in development for schizophrenia. Expert Opin Investig Drugs 2009;18:1715-1726.

3Nakamura M, Ogasa M, Guarino J, Phillips D, Severs J, Cucchiaro J, Loebel A: Lurasidone in the treatment of acute schizophrenia: A double-blind, placebo-controlled trial. J Clin Psychiatry 2009;70:829-836.

4Citrome L: Lurasidone for schizophrenia: A review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract 2010 Dec 3. doi:10.1111/j.1742-1241.2010.02587.x. [Epub ahead of print]