Lurasidone: a New Therapeutic Option for Bipolar Depression?

Two studies with the new compound lurasidone in bipolar depression, published in the February issue of the American Journal of Psychiatry,  as well as an accompanying editorial seem to be very noteworthy to me.Lurasidon is actually an antipsychotic medication. The compound is already approved in the U.S., both in the indications schizophrenia as well as bipolar depression. The European Committee for Medicinal Products for Human Use (CHMP) of the EMA issued a recommendation for approval on 23 January 2014. Thus, approval is to be expected in the EU in the near future. Since in bipolar depression treatment options have been very limited, this indication appears to be particularly important to me.

Lurasidone is, like many other second-generation antipsychotics, a combined D2-/5-HT2 receptor antagonist. At 5-HT1A serotonin receptors the substance acts as a partial agonist. What makes Luasidon interesting is the antagonism of 5-HT7 receptors. In animal models lurasidone has antidepressant properties. In mice in which the 5-HT7 receptor is being turned off (5-HT7 knockout), the compound loses these effects.

In the first of the two published studies lurasidone was given to patients with bipolar depression as monotherapy  and compared with the administration of placebo (Loebel et al., Am J Psychiatry 2014; 171:160–168). This was a three-arm study: Lurasidone was administered in two different flexible doses, with either 20-60 mg daily or 80-120 mg daily. The groups were comprised of 161 and 162 patients. The observation period was six weeks, primary outcome measures were the change in total scores of the Montgomery Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression Scale (CGI). Both dose ranges were significantly superior to placebo with regard to the primary outcome variables. After six weeks, the MADRS score had dropped in both groups of patients treated with verum by 15.4 points, but only by 10.7 points in the placebo group. This corresponds to an effect size of 0.51. The CGI score dropped by 1.1 points with placebo, by 1.8 points at 20-60 mg lurasidone (effect size 0.61), and by 1.7 points at 80-120 mg lurasidone (effect size 0.50). The treatment effect was significant at week two. Adverse effects occurred in all three groups at the same frequency. The magnitude of the antidepressant effect was generally comparable to that of quetiapine for this indication. Quetiapine is considered as the drug of first choice in bipolar depression in many treatment guidelines.

In the second study lurasidone was administered as adjunctive treatment to therapy with either lithium or valproate (Loebel et al., Am J Psychiatry 2014; 171:169–177). This study might be closer to clinical reality than the above monotherapy study, as patients with bipolar disorder are often treated with a mood stabilizer. This was a two-arm study, 183 patients were treated with lurasidone and 165 with placebo. Lurasidone was flexibly dosed between 20 and 120 mg daily. Treatment duration and outcome measures were the same as in the monotherapy study. After six weeks, the MADRS score had dropped  by 17.1 points under lurasidone and by 13.5 points under placebo (effect size 0.34). The CGI score decreased by 1.96 and 1.51 points, respectively (effect size 0.36). In this study, lurasidone separated  significantly from placebo after three weeks of treatment. Also, the incidence of adverse events in the two treatment groups was similar. For the authors the medication with a mood stabilizer could be a possible explanation for the higher response rate to placebo in monotherapy trials in bipolar depression.

The reported results are promising in view of the few therapeutic options in difficult to treat bipolar depression. The number needed to treat (NNT) to achieve a therapeutic response was 5 in the first study and 7 in the second. The NNT to achieve remission was in the two studies at 6 or 7, respectively, and 7. These are very good values ​​that raise hope that an important additional treatment option for bipolar depression will be available in the near future in the EU. Compared to quetiapine, lurasidone has the advantage to be weight neutral. However,  extrapyramidal side effects occur in a dose-dependent manner. It will be interesting whether the German Federal Joint Committee (G-BA) will grant the compound an additional benefit compared to available medications.


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One thought on “Lurasidone: a New Therapeutic Option for Bipolar Depression?

  1. The side-effect profile is profoundly harsh and FREQUENTLY includes extra-pyramidal symptoms. “…frequent side effects of lurasidone were akathisia, nausea, suicide (1) parkinsonism, dizziness and somnolence”. (2)

    (1)”Schizophrenia treatment guidelines in the United States.”. Clin Schizophr Relat Psychoses 5 (1): 40–9. Apr 2011. doi:10.3371/CSRP.5.1.6. PMID 21459738.

    (2) Yasui-Furukori N, Update on the development of lurasidone as a treatment for patients with acute schizophrenia. Drug Des Devel Ther. 2012; 6:107-15 (ISSN: 1177-8881)

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