New Data Support the Efficacy of Lurasidone for Bipolar Depression

August 24, 2012 · Posted in Potential Treatments · Comment 

depressed man

In two recent clinical trials that were presented at the annual meeting of the American Psychiatric Association in May 2012, the atypical antipsychotic lurasidone (Latuda), which is currently used to treat schizophrenia, was associated with significant improvement in bipolar depression compared to placebo. The studies, known as PREVAIL (or Program to Evaluate the Antidepressant Impact of Lurasidone), assessed lurasidone’s efficacy as an adjunctive treatment and as a monotherapy.

PREVAIL 1 assessed lurasidone’s efficacy and safety when the drug was added to treatment with lithium or valproate in bipolar patients who became depressed.  In this 6-week study, scores on the Montgomery-Asberg Depression Rating Scale (MADRS) improved significantly more in patients taking lurasidone (20 – 120mg/day; N=183) in addition to their mood stabilizer compared to those who received placebo (N=165) in addition to their mood stabilizer.

In PREVAIL 2, patients received lurasidone at either 20-60mg/day (N=166) or 80-120mg/day (N=169) or placebo (N=170) as a monotherapy for bipolar depression. As measured by MADRS scores, lurasidone was significantly more effective in improving bipolar depression than placebo was by the end of the 6-week study period.

In both studies lurasidone showed significant effects on other measures and endpoints including: improvement in Clinical Global Impressions severity of depression (CGI-BP-S) scores, reductions in anxiety symptoms, and improvement in social or occupational functioning. Lurasidone also produced higher rates of response (50% improvement on the MADRS). The CGI-BP-S improved in patients on lurasidone significantly more than in those on placebo as early as week one.

Editor’s Note: These two trials in bipolar depression suggest new possibilities for treating the depressed phase of bipolar disorder.

In studies of patients with schizophrenia, lurasidone has had an excellent safety and tolerability profile; it is relatively weight neutral and does not increase metabolic indices such cholesterol, triglycerides, or blood sugar.  

Lurasidone also has an unusual mechanism of action, blocking serotonin 5HT 7 receptors, that may be related to its antidepressant effects. Antagonism of 5HT 7 receptors has been closely linked to antidepressant effects in studies of animal models of depression by two different investigators, Stephen Stahl and Herb Meltzer. It remains to be seen whether this or some other mechanism of lurasidone accounts for its antidepressant effects.

As we have noted before, since all antipsychotic drugs used in the treatment of schizophrenia (which block dopamine D2 receptors) also show efficacy in mania, it is likely that lurasidone will show the same effects. Studies of the drug in mania have not yet been presented. Lurasidone is not yet FDA-approved for bipolar depression, but the PREVAIL studies may be sufficient for an application for FDA approval of lurasidone for this additional indication.

Currently quetiapine (Seroquel) is the only monotherapy approved for bipolar depression. Studies of two other atypical antipsychotics, ziprasidone (Geodon) and aripiprazole (Abilify), failed to show efficacy in bipolar depression when compared with placebo. Ziprasidone’s effects were similar to those of placebo, while aripiprazole showed evidence of significant improvement in the first weeks of treatment compared to placebo, but these failed to last, perhaps because of overly high doses that led to a high drop-out rate.

Antidepressants used for the treatment of unipolar depression are not FDA-approved for bipolar depression and did not appear to be beneficial compared to placebo in recent meta-analyses by Sidor and MacQueen. These antidepressants include the selective serotonin reuptake inhibitors (SSRIs), mixed serotonin and norepinephrine reuptake inhibitors (SNRIs), the dopamine active drug bupropion, and the older tricyclic antidepressants. Not only are these antidepressants not effective in bipolar depression, but some (especially the tricyclics and the SNRIs) appear to increase risk of switching into mania.

None of the mood stabilizers are FDA-approved for bipolar depression; these include lithium, valproate, carbamazepine, and lamotrigine. Thus, quetiapine has had the unique position of being FDA-approved to treat both phases of bipolar disorder—mania and depression—and for prevention of both mania and depression when used as an adjunct to lithium or valproate.  

If the lurasidone data lead to FDA approval of this drug as a monotherapy, it will be only the second monotherapy (after quetiapine) approved for bipolar depression. (The combination of olanzapine and fluoxetine is also approved for this indication.) Since bipolar depression can take a serious toll on patients’ health, cognition, and life expectancy, the prospect of having another effective drug for this phase of the illness is especially promising.

New Atypical Antipsychotic Lurasidone Has a Good Metabolic Profile

January 25, 2012 · Posted in Potential Treatments · Comment 

latudaAndre Pikalov and colleagues from Sunovion Pharmaceuticals Inc. reported at the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in 2011 on the weight and metabolic effects seen in short- and long-term trials of the atypical antipsychotic lurasidone (Latuda) in schizophrenia. The studies compared lurasidone to olanzapine (Zyprexa, at 15mg), haloperidol (Haldol, at 10mg), and placebo. Doses of lurasidone ranged from 20-120mg administered once daily. Short-term treatment for six weeks was associated with changes in weight and metabolic indices similar to those of placebo, while participants taking olanzapine gained substantial amounts of weight and had increases in triglycerides and cholesterol. Changes in glucose and hemoglobin A1C were similar on lurasidone, haloperidol, and placebo, but higher on olanzapine. In the long-term sample, mean weight gain on lurasidone at 12 months was 0.71 kg and metabolic parameters remained relatively unchanged.

Editor’s note:  Multiple posters at the meeting composed a substantial body of evidence concerning acute and long-term studies of lurasidone, which shows that the drug has a weight and metabolic profile relatively similar to placebo and more favorable than that of olanzapine.

Although lurasidone has not been studied acutely or in the long term in patients with bipolar disorder, the safety profile of this drug in schizophrenia indicates that it may eventually be useful for acute and long-term treatment strategies in bipolar disorder. All typical and atypical antipsychotic drugs that have been approved for treatment of schizophrenia have subsequently been shown to have efficacy in acute mania, and given lurasidone’s similar actions in blocking dopamine receptors, there is little reason to expect that this drug will be any different.  The results of actual studies of this drug in mania and depression are eagerly awaited.

New Atypical Antipsychotic Lurasidone Appears To Improve Schizophrenia Without Weight-Gain Side Effects

September 23, 2011 · Posted in Current Treatments · Comment 

medicationA 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. Read more

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