New Atypical Antipsychotic Lurasidone Appears To Improve Schizophrenia Without Weight-Gain Side Effects
A study by a research group that included Antony Loebel of pharmaceutical company Sunovion; Steven Potkin of the University of California, Irvine; and Herbert Meltzer from Vanderbilt University summarizes data on a new atypical antipsychotic FDA-approved for treatment of schizophrenia. This agent, lurasidone (Latuda), was studied in a double-blind, placebo-controlled six-week trial in patients with schizophrenia.
The drug is a new psychotropic agent that has a high affinity for dopamine D2 receptors and serotonin 5HT2A, 5HT1A, and 5HT7 receptors. (New data suggest that antagonistic effects on 5HT7 receptors may be related to antidepressant efficacy.)
In the study, patients were randomized to receive lurasidone at 80mg/day, lurasidone at 160mg/day, quetiapine XR at 600mg/day, or placebo. Evening dosing was used. Both dose levels of lurasidone resulted in significant degrees of improvement compared with quetiapine XR and placebo.
The side effects profile for lurasidone was also promising; patients were no more likely to gain weight on lurasidone than on placebo, while there was a mean 2kg weight increase on quetiapine XR. In addition, total cholesterol and triglycerides on both doses of lurasidone were similar to that on placebo, in contrast to small but significant increases on quetiapine XR.
There were significant increases in levels of prolactin (a hormone related to lactation, sex function, and bone demineralization) on lurasidone at both 80mg (+ 0.8mg/dl) and 160mg (+ 3mg/dl), while small decreases in prolactin were observed on quetiapine XR (-0.3 mg/dl) and on placebo (-0.8 mg/dl).
The data suggest that lurasidone is effective in the treatment of patients with acute exacerbation of schizophrenia, with significant effects occurring as early as day 4. This study had a low rate of adverse events.Another study on the long-term safety and tolerability of lurasidone in subjects with schizophrenia was completed by Stephen Stahl of the University of California, San Diego. In that study, 246 patients who successfully completed a 6-week double-blind trial of lurasidone (at 40mg and 120mg) compared with olanzapine (at 15mg) went on to participate in a six-month open label extension phase in which all subjects were switched to lurasidone at 80mg daily. After one week, flexible dosing was permitted in the range of 40-120 mg/day. Clinical improvement in most areas of psychopathology continued during the open label extension phase.
Only two types of adverse events were common. Akathisia (restless legs) was observed in 13% of patients, and insomnia was observed in 11%. Twelve percent of participants discontinued the study due to an adverse event during the six-month open label extension. Body weight and BMI remained stable in the open extension phase, except in those who had been randomized from olanzapine to lurasidone, in whom a loss of 1.8kg was observed. Cholesterol, low-density lipoproteins, triglycerides, and whole blood hemoglobin A1C did not change in a clinically meaningful fashion, and prolactin, which had increased + 0.32 ng/ml in the acute double-blind phase of the study, showed an overall median decrease of -1.3 ng/ml during the open label extension. These data suggest that flexibly dosed lurasidone between 40 and 120mg daily was well tolerated for up to eight months and shows a low potential for weight gain and lipid abnormalities.
Editor’s note: While studies of lurasidone for the treatment of acute mania have not yet been published, it should be noted that without exception, all typical and atypical antipsychotics that have been introduced initially with acute efficacy in schizophrenia have eventually proven to have acute antimanic efficacy as well. Thus, lurasidone is likely to join this group and ultimately be used in the treatment of acute mania.
In addition, because of its overall tolerability, including lack of weight gain or increase in metabolic indices, long-term prophylactic studies in bipolar disorder are eagerly awaited.
In terms of other side effects, lurasidone exhibits little or no affinity for the for the acetylcholine M1 receptor, which is associated with anticholinergic side effects such as dry mouth and constipation, nor for the histamine H1 receptor, which has been associated with sedation and weight gain.
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