Objective: 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). Methods: 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. Results: 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 lurasi-
done 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. Conclusions: 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 toler-
able profile. Individual patient characteristics, values and preferences will need to be considered when selecting lurasi-
done over other antipsychotics.
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?
Leslie Citrome 1
1 New York Medical College, Valhalla, NY
Address for correspondence: Leslie Citrome, MD, MPH,
11 Medical Park Drive, Suite 106, Pomona, NY 10970
Phone: 845-362-2081; Fax: 845-362-8745; E-mail: email@example.com
Submitted: October 17, 2011; Revised: January 3, 2012;
Accepted: February 9, 2012
Clinical Schizophrenia & Related Psychoses April 2012 • 1
Key Words: Efficacy, Lurasidone, Number Needed to Harm, Number Needed to Treat,
Safety, Schizophrenia, Tolerability
Lurasidone is a second-generation antipsychotic agent
that was approved by the U.S. Food and Drug Administra-
tion (FDA) in 2010 (1). Although it is similar to other atypi-
cal antipsychotics in terms of antagonism at dopamine D2
and serotonin 5-HT2A receptors, lurasidone also has high
Lurasidone NNT NNH
2 • Clinical Schizophrenia & Related Psychoses April 2012
Lurasidone is FDA-approved for the treatment of schizophrenia based on a subset of the clinical trial data now available.
NNT and NNH can help quantify efficacy, safety and tolerability outcomes and place lurasidone into clinical perspec-
tive. Advantages for lurasidone include a low propensity for weight gain and metabolic abnormalities. The five most
consistently encountered adverse events attributable to lurasidone are akathisia, nausea, sedation, somnolence and par-
kinsonism, 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.
binding affinity (antagonist) for the serotonin 5-HT7 recep-
tor. Lurasidone has moderate affinity for serotonin 5-HT1A
(partial agonist) and noradrenaline α2c (antagonist) recep-
tors. Lurasidone has little to no appreciable affinity for hista-
mine H1 and acetylcholine M1 receptors.
The efficacy and short-term tolerability of lurasidone
for the treatment of acute schizophrenia has been tested
in several 6-week, randomized, placebo-controlled trials at
fixed doses ranging from 20 to 160 mg, administered once
daily (2-6). As per the U.S. product label (1), and based on
the data available at the time of approval, the recommended
starting dose is 40 mg administered once daily. The maxi-
mum recommended dose is 80 mg/d. When examining
data from the 4 positive trials available at the time of FDA
approval, fixed doses of 120 mg/d did not produce greater
improvement than seen at lower doses, but were associated
with a higher propensity for somnolence and akathisia. As
per the product label, lurasidone is associated with minimal
weight gain and no clinically meaningful alterations in glu-
cose, lipids, prolactin, or the electrocardiogram QT interval.
Number needed to treat (NNT) and number needed to
harm (NNH) are measures of effect size and indicate how
many patients would need to be treated with one agent in-
stead of the comparator in order to encounter one additional
outcome of interest (7, 8). NNT is traditionally used to de-
note potential desirable outcomes (benefits) that a clinician
and patient would want to encounter and NNH is ordinar-
ily used to denote potential undesirable outcomes (harms)
that a clinician and patient would like to avoid. Both NNT
and NNH are calculated using the same formula. Some ad-
vocate for using the terms number needed to treat for an ad-
ditional beneficial outcome (NNTB) and number needed to
treat for an additional harmful outcome (NNTH), instead of
NNT and NNH, respectively (8). Both sets of terms are com-
monly found in the medical literature. Nevertheless, NNT
and NNH offer the clinician a means of quantifying clinical
relevance or “clinical significance.” Lower NNTs (or NNHs)
are evidenced when there are large differences between the
interventions in question. For example, a NNT of 2 would
be a very large effect size, as a difference is encountered after
treating 2 patients with one of the interventions versus the
other. A NNT of 50 would mean little difference between
the two interventions, as it would take treating 50 patients
to encounter a difference in outcome. A useful medication
is one with a low NNT and a high NNH when comparing
it with another intervention; a low NNT and a high NNH
would mean one is more likely to encounter a benefit than
a harm. A rule of thumb is that a single digit NNT vs. pla-
cebo for an efficacy measure suggests that the intervention
has potentially useful advantages, and that double digit or
higher NNHs vs. placebo for adverse outcomes indicate that
the intervention is potentially tolerable.
Likelihood of being helped or harmed (LHH) can be a
useful way of synthesizing data regarding benefits and risks
(10-12). LHH is calculated using the following formula:
LHH=(1/NNT)/(1/NNH)=NNH/NNT. In general, a LHH
greater than 1 would mean the likelihood to be helped is
greater than the likelihood to be harmed. For a LHH less
than 1, the reverse is true. Choosing which NNH and NNT
to use in calculating LHH requires careful consideration so
that the outcomes being assessed are well matched and con-
sistent with a patient’s values and preferences (11, 12).
The aim of this report is to apply NNT, NNH and LHH
in order to appraise the lurasidone acute schizophrenia clin-
ical trial data.
Study data were pooled from six Phase II and III, 6-week,
randomized, placebo-controlled trials that were conducted
to test the efficacy, safety and tolerability of lurasidone for
the acute treatment of schizophrenia and that were conduct-
ed either exclusively in the U.S. or that included study sites
within the U.S. (2, 3, 13-15). One additional 6-week lurasi-
done placebo-controlled trial (conducted entirely in Japan,
Korea and Taiwan) has been recently completed but was not
included in this analysis (16). Table 1 provides an outline of
the number of subjects in each arm for each of the six clini-
cal trials included in this report. More detailed descriptions
of the individual studies can be found elsewhere in peer-
reviewed journals (2, 3), posters presented at scientific meet-
ings (13, 14), or publicly available regulatory documents
(15). The subjects themselves were typical of those enrolled
in registration studies for the acute treatment of schizo-
phrenia (4, 5, 13, 15). Mean age ranged from approximately
36–41 years, depending on the treatment arm, with 64–79%
being men (13, 14). Mean baseline PANSS total score ranged
Lurasidone NNT NNH
10 • Clinical Schizophrenia & Related Psychoses April 2012
This study was funded by Sunovion Pharmaceuticals
Inc., Fort Lee, NJ. The analyses were conducted indepen-
dently by the author using data provided by Sunovion Phar-
In the past twenty-four months, Leslie Citrome has
engaged in collaborative research with or received consult-
ing or speaking fees from: Alexza, Alkermes, AstraZeneca,
Avanir, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck,
Merck, Novartis, Noven, Otsuka, Pfizer, Shire, Sunovion and
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www.latuda.com/LatudaPrescribingInformation.pdf [Last accessed 2011 May
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controlled trial. J Clin Psychiatry 2009;70(6):829-836.
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in the treatment of schizophrenia: a randomized, double-blind, placebo- and
olanzapine-controlled study. Am J Psychiatry 2011;168(9):957-967.
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and risks. Expert Rev Neurother 2008;8(7):1079-1091.
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Table S1 Responder Rates and NNT vs. Placebo-Pooled Data (Intent-to-Treat Population)
Shaded entries represent NNT values where the 95% CI does not include infinity and, hence, considered statistically significant. CI=confidence
interval; NA=not applicable; NNT=number needed to treat; ns=not significant (the 95% CI contains “infinity”); PANSS=Positive and Negative
Syndrome Scale; XR=extended release. *A negative NNT denotes an advantage for placebo regarding the potential benefit.
PANSS Reduction ≥20%
Lurasidone 20 mg/d
Lurasidone 40 mg/d
Lurasidone 80 mg/d
Lurasidone 120 mg/d
Lurasidone 160 mg/d
Haloperidol 10 mg/d
Olanzapine 15 mg/d
Quetiapine XR 600 mg/d
PANSS Reduction ≥30%
PANSS Reduction ≥40%
PANSS Reduction ≥50%