Latuda: new atypical antipsychotic

Latuda (lurasidone) is a new atypical antipsychotic approved for the treatment of schizophrenia in adults.

Antipsychotic medication primarily suppresses dopamine receptor activity in the brain. SCIENCE PHOTO LIBRARY
Antipsychotic medication primarily suppresses dopamine receptor activity in the brain. SCIENCE PHOTO LIBRARY

PHARMACOLOGY

Lurasidone is a full antagonist at dopamine D2 and serotonin 5HT2A receptors. It also has high affinity for serotonin 5HT7 receptors, moderate affinity for alpha 2c and alpha 2a adrenergic receptors, and acts as a partial agonist at 5HT1A receptors. Lurasidone has no activity at cholinergic (muscarinic) receptors.1

CLINICAL STUDIES

Efficacy of lurasidone was assessed in a 6-week placebo-controlled trial involving 180 patients with acute schizophrenia who were randomised to receive lurasidone 74mg or placebo once daily.2

Efficacy in acute schizophrenia

Improvement on the Brief Psychiatric Rating Scale (BPRSd) of the Positive and Negative Syndrome Scale (PANSS), the primary efficacy measure, was significantly greater in the lurasidone group than in the placebo group at 6 weeks (least squares [LS] mean change ±SE: -8.9 ±1.3 vs -4.2 ±1.4, p=0.012). The onset of improvement in the lurasidone group was rapid, with significance compared with placebo achieved by day 3.2

Similar patterns of significant early and sustained improvement with lurasidone compared with placebo were observed for the PANSS total score and the Clinical Global Impressions-Severity of Illness scale (CGI-S) score.2

Evaluation of different doses

The efficacy of two doses of lurasidone compared with placebo was evaluated in a 6-week study involving 478 patients with acute schizophrenia. Patients were randomised to receive a once-daily dose of lurasidone 37mg (n=119) or 111mg (n=118), olanzapine 15mg (n=122, included to test for assay sensitivity) or placebo (n=114).3

The change from baseline to week 6 in PANSS total score was significantly greater for the lurasidone 37mg and 111mg groups (-25.7 [adjusted p=0.002] and -23.6 [adjusted p=0.022], respectively) than for the placebo group (-16.0). The change in PANSS total score was also significantly greater for olanzapine than placebo, thereby confirming the assay sensitivity of the study. Significant separation from placebo was evident from week 1 onward in the lurasidone 37mg and olanzapine groups and from week 3 in the lurasidone 111mg group.3

Significantly greater improvements on the PANSS positive, negative and general psychopathology subscale scores and the CGI-S score were also observed for both lurasidone groups and olanzapine compared with placebo at week 6.3

Evaluation of high-dose lurasidone

In another 6-week study, patients with acute schizophrenia (n=488) were randomised to receive lurasidone 74mg (n=125) or 148mg (n=121), prolonged-release quetiapine 600mg (n=119, included to test for assay sensitivity) or placebo (n=121).4

The LS mean change from baseline to week 6 in PANSS total score was significantly greater for the lurasidone 74mg and 148mg groups (-22.2 and -26.5, respectively, adjusted p<0.001 for both) than for placebo (-10.3) with significant separation from placebo evident by day 4 for both dosages. Similar results were observed for the quetiapine group, thereby confirming the assay sensitivity of the study.4

Significantly greater improvements on the PANSS positive and negative subscale scores and the CGI-S score were also observed for all three treatment groups compared with placebo.4
The responder rate at week 6 (≥20% improvement from baseline in PANSS total score) was significantly higher in the lurasidone groups than in the placebo group and was significantly higher for the lurasidone 148mg dose than for the 74mg dose (p=0.018).4

Long-term safety and tolerability

The long-term safety and tolerability of lurasidone were evaluated in a 12-month double-blind study involving 629 patients with stable (non-acute) schizophrenia who were randomised to receive lurasidone 74mg daily (adjusted after 7 days within the range 37-111mg daily, n=427) or risperidone 2mg daily increasing to 4mg daily on day 3 (adjusted from day 8 within the range 2-6mg daily, n=202).5

Lurasidone was generally well tolerated over the 12 months, with minimal effects on weight and metabolic outcomes. Similar proportions of patients in the two treatment groups reported one or more treatment-emergent adverse effects or serious treatment-emergent adverse effects (84.5% and 11%, respectively, for lurasidone vs 84.7% and 9.9% for risperidone), although the rate of study withdrawal due to treatment-emergent adverse effects was higher in the lurasidone group than in the risperidone group (21.5% vs 14.4%).5

The rates of relapse did not differ significantly between the lurasidone and risperidone groups (20% vs 16%).5

Non-inferiority study

Non-inferiority of lurasidone (37-148mg daily) to prolonged-release quetiapine (200-800mg daily) in terms of relapse prevention was investigated in a 12-month follow-on study involving 292 patients with schizophrenia who had recently completed a 6-week placebo-controlled trial with either of these treatments; patients who received placebo in the initial trial were started on lurasidone.6

Patients in the lurasidone group were found to have a 27.2% reduction in risk of relapse during 12 months of treatment compared with those in the quetiapine group (hazard ratio=0.728, 95% CI 0.410-1.295), meeting non-inferiority criteria. In addition, lurasidone was associated with higher rates of remission and a reduced risk of hospitalisation compared with prolonged-release quetiapine.6

Safety

Lurasidone was generally well tolerated in clinical trials.2-6 The most commonly reported adverse reactions were akathisia and somnolence, which were dose-related up to 111mg daily.1

References

  1. Latuda Summary of Product Characteristics, March 2014.
  2. Nakamura M et al. J Clin Psychiatry 2009; 70: 829-36.
  3. Meltzer HY et al. Am J Psychiatry 2011; 168: 957-67.
  4. Loebel A et al. Schizophr Res 2013; 145: 101-9.
  5. Citrome L et al. Int Clin Psychopharmacol 2012; 27: 165-76.
  6. Loebel A et al. Schizophr Res 2013; 147: 95-102.

View Latuda drug record

Further information: Sunovion

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