Lurasidone for the acute treatment of adults with schizophrenia: what is the number needed to treat, number needed to harm, and likelihood to be helped or harmed?

New York Medical College, Valhalla, NY, USA.
Clinical Schizophrenia & Related Psychoses 07/2012; 6(2):76-85. DOI: 10.3371/CSRP.6.2.5
Source: PubMed

ABSTRACT To describe the efficacy, safety and tolerability of lurasidone for the acute treatment of schizophrenia using the metrics number needed to treat (NNT) and number needed to harm (NNH).
Study data were pooled from six Phase II and III, 6-week, randomized, placebo-controlled trials that were conducted to test the efficacy and safety of lurasidone for the acute treatment of schizophrenia. Included were the following interventions: fixed doses of lurasidone 20, 40, 80, 120 and 160 mg/d; haloperidol 10 mg/d; olanzapine 15 mg/d; quetiapine extended-release 600 mg/d; placebo. The following outcomes were assessed: responder rates as defined by a reduction of ≥20, 30, 40 or 50% from baseline on the Positive and Negative Syndrome Scale (PANSS) total score; study completion; discontinuation due to an adverse event (AE); weight gain ≥7% from baseline; incidence of spontaneously reported AEs; incidence of total cholesterol ≥240 mg/dL, low-density lipoprotein cholesterol ≥160 mg/dL, fasting triglycerides ≥200 mg/dL and glucose ≥126 mg/dL at endpoint. NNT for the efficacy outcomes were calculated after excluding one failed study. NNH for the safety/tolerability outcomes were calculated using all six studies. Likelihood of being helped or harmed (LHH) was also calculated to illustrate trade-offs between outcomes of improvement ≥30% on the PANSS vs. incidence of akathisia, nausea, sedation, somnolence and parkinsonism.
NNT vs. placebo for PANSS reductions ≥30% were 6, 6, 7 and 4 for lurasidone doses of 40, 80, 120 and 160 mg/d, respectively, and 4 and 3 for olanzapine 15 mg/d and quetiapine extended-release 600 mg/d, respectively. Lurasidone was not associated with any statistically significant disadvantages over placebo for weight gain or metabolic abnormalities; NNH vs. placebo for weight gain ≥7% from baseline was 4 for olanzapine and 9 for quetiapine extended-release in contrast to a NNH for this outcome ranging from 43 to 150 for lurasidone 40-160 mg/d. The 5 most consistently encountered adverse events attributable to lurasidone were akathisia, nausea, sedation, somnolence and parkinsonism, with NNH vs. placebo for lurasidone 40-120 mg/d ranging from 6 (akathisia with 120 mg/d) to 30 (parkinsonism with 80 mg/d). Lurasidone 160 mg/d appeared better tolerated than doses of 40, 80 or 120 mg/d for akathisia, nausea, sedation or somnolence, with no NNH values for these adverse events for 160 mg/d vs. placebo being statistically significant. LHH was favorable for lurasidone when contrasting PANSS reductions vs. adverse events.
NNT and NNH can help quantify efficacy, safety and tolerability outcomes and place lurasidone into clinical perspective. Advantages for lurasidone include a low propensity for weight gain and metabolic abnormalities. More commonly encountered adverse events include akathisia, nausea, sedation, somnolence and parkinsonism, but NNH values are generally in the double digits, reflecting an overall tolerable profile. Individual patient characteristics, values and preferences will need to be considered when selecting lurasidone over other antipsychotics.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Lurasidone is a newer “atypical” or “secondgeneration” antipsychotic that has received regulatory approval in the US and Canada for the treatment of schizophrenia. Recent changes in lurasidone product labeling include an expansion of the recommended dose range from 40–80 mg/day to 40–160 mg/day, administered once-daily with food. The recommended starting dose is 40 mg/day. Initial dose titration is not required. Efficacy for the treatment of acute episodes of schizophrenia was established in five, 6-week, fixed-dose, randomized, placebo-controlled trials. Additional short-term studies in patients with schizophrenia include a 3-week, randomized, double-blind trial comparing lurasidone with ziprasidone on safety and tolerability outcomes, and a 6-week, randomized, open-label switch study. Available long-term data includes a 12-month, doubleblind safety and tolerability study comparing lurasidone with risperidone; a 6-month, openlabel extension study for one of the shortterm registration studies where patients were initially randomized to receive lurasidone, olanzapine, or placebo; and a 12-month, doubleblind extension study comparing lurasidone with quetiapine extended-release after having received lurasidone, quetiapine extendedrelease, or placebo for 6 weeks. The totality of the evidence supports the overall tolerability of lurasidone, with minimal weight gain and no clinically-meaningful alterations in glucose, lipids, or the electrocardiogram corrected QT (ECG QTc) interval. The most commonly encountered adverse events that can be observed with lurasidone are somnolence, akathisia, nausea, and parkinsonism. Additional clinical trials are underway for the use of lurasidone in patients with bipolar disorder, including major depressive episodes in patients with bipolar I disorder, and in bipolar and schizophrenia maintenance. Principal advantages over some other second-generation antipsychotics are lurasidone’s highly favorable metabolic profile and once-daily dosing regimen. Additional studies are desirable to directly compare and contrast lurasidone’s efficacy with other antipsychotic agents.
    Advances in Therapy 10/2012; 29(10). · 2.44 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prior to recent FDA approval of lurasidone for treatment of bipolar depression there were only two approved treatments for this condition (quetiapine and olanzapine-fluoxetine combination), and these were as likely to provide therapeutic benefit as adverse effects. We assessed the efficacy, safety, and tolerability of lurasidone for major depressive episodes associated with bipolar I disorder, using number needed to treat (NNT, for benefits), number needed to harm (NNH, for harms), and likelihood of being helped or harmed (LHH, ratio of NNH to NNT, for trade-offs between benefits vs. harms). Data was collected from two 6-week multicenter, randomized, double-blind, placebo-controlled, flexibly-dosed acute bipolar I depression studies, one using lurasidone monotherapy at 20-60mg/d or 80-120mg/d, and the other using lurasidone 20-120mg/d adjunctive to lithium or valproate. The NNT or NNH was calculated for lurasidone vs. placebo for the following dichotomous outcomes: response (≥50% reduction from baseline on Montgomery Asberg Depression Rating Scale (MADRS) total score); remission (final MADRS total score ≤12); discontinuation due to an adverse event (AE); weight gain ≥7% from baseline; incidence of spontaneously reported AEs; and incidence of total cholesterol ≥240mg/dl, low-density lipoprotein cholesterol ≥160mg/dl, fasting triglycerides ≥200mg/dl and glucose ≥126mg/dl post-baseline. NNT vs. placebo for response was 5 for lurasidone monotherapy (both dose ranges) and 7 for adjunctive therapy. NNT vs. placebo for remission for lurasidone monotherapy was 6 for 20-60mg/d and 7 for 80-120mg/d and 7 for adjunctive lurasidone. NNH vs. placebo for discontinuation due to an AE for lurasidone monotherapy was 642 for 20-60mg/d and -181 for 80-120mg/d, and for adjunctive lurasidone was -54 (negative NNH denotes an advantage for lurasidone). Lurasidone was not associated with any clinically meaningful mean weight or metabolic changes compared to placebo; NNH vs. placebo for weight gain ≥7% was 29 for 20-60mg/d and 5550 for 80-120mg/d and 42 for adjunctive lurasidone. The three most frequently occurring AEs with the largest difference in incidence for lurasidone vs. placebo were nausea, akathisia, and somnolence, with NNH values for lurasidone vs. placebo ranging from 11 (nausea with lurasidone monotherapy 80-120mg/d) to 130 (somnolence with lurasidone monotherapy 20-60mg/d). LHH was substantially and consistently >1 (indicating benefit being more likely than harm) when contrasting response or remission vs. AEs or weight gain. Additional studies, including longer-term and open-label, "real world" data is needed to confirm the results reported here. NNT, NNH, and LHH help quantify relative benefits (efficacy) and harms (side effects), thus placing lurasidone findings in research studies into clinical perspective. Lurasidone, compared to other treatments approved for bipolar depression, yielded comparable benefits (all had single-digit NNT vs. placebo for response or remission), and less risk of harm (double-digit or greater NNHs with lurasidone compared to single-digit NNHs for sedation with quetiapine and for ≥7% weight gain with olanzapine-fluoxetine combination), and thus a substantially more favorable LHH (> or >1) with lurasidone monotherapy and adjunctive therapy, compared to quetiapine and olanzapine-fluoxetine combination (LHH<or ~1).
    Journal of Affective Disorders 10/2013; · 3.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE Few studies have been reported that support the efficacy of adjunctive therapy for patients with bipolar I depression who have had an insufficient response to monotherapy with mood-stabilizing agents. The authors investigated the efficacy of lurasidone, a novel antipsychotic agent, as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression. METHOD Patients were randomly assigned to receive 6 weeks of double-blind adjunctive treatment with lurasidone (N=183) or placebo (N=165), added to therapeutic levels of either lithium or valproate. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. RESULTS Lurasidone treatment significantly reduced mean MADRS total score at week 6 compared with the placebo group (-17.1 versus -13.5; effect size=0.34). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores compared with placebo (-1.96 versus -1.51; effect size=0.36) as well as significantly greater improvement in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were 6.0% and 7.9% in the lurasidone and placebo groups, respectively. Adverse events most frequently reported for lurasidone were nausea, somnolence, tremor, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone. CONCLUSIONS In patients with bipolar I depression, treatment with lurasidone adjunctive to lithium or valproate significantly improved depressive symptoms and was generally well tolerated.
    American Journal of Psychiatry 10/2013; · 14.72 Impact Factor