CNS Spectrums Safety and effectiveness of lurasidone in

www.cambridge.org/cns
adolescents with schizophrenia: results of a
2-year, open-label extension study
Christoph U. Correll1,2,3* , Robert L. Findling4, Michael Tocco5, Andrei Pikalov5,
Original Research
Ling Deng5 and Robert Goldman5
Cite this article: Correll CU, Findling RL,
1
Tocco M, Pikalov A, Deng L, and Goldman R Department of Psychiatry, Northwell Health, The Zucker Hillside Hospital, Glen Oaks, New York, USA, 2Department
(2022). Safety and effectiveness of lurasidone of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra Northwell,
in adolescents with schizophrenia: results of a Hempstead, New York, USA, 3Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin,
2-year, open-label extension study. CNS
Germany, 4Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA, and 5Sunovion
Spectrums 27(1), 118–128.
Pharmaceuticals Inc., Marlborough, Massachusetts, USA
https://doi.org/10.1017/S1092852920001893

Received: 29 July 2020 Abstract

Accepted: 02 October 2020
Background. Minimal long-term benefit: Risk data are available regarding antipsychotic
Key words: treatments for schizophrenia in pediatric populations. This study evaluated the long-term
atypical antipsychotic; lurasidone; safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia.
schizophrenia; adolescent; long-term;
Methods. Patients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-
maintenance
controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose
Author for correspondence: (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting,
*Christoph U. Correll, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness mea-
Email: [email protected]
sures included the Positive and Negative Syndrome Scale (PANSS) total score.
Results. About 271 patients completed 6 weeks of DB treatment and entered the 2-year OL
extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events.
During OL treatment, the most common adverse events were headache (24.0%); anxiety
(12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngi-
tis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean
change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg,
respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based
on the sex- and age-matched US Center for Disease Control normative data. Continued
improvement was observed in PANSS total score, with mean change from OL baseline of
15.6 at week 52 and 18.4 at week 104.
Conclusion. In adolescents with schizophrenia, long-term lurasidone treatment was associated
with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued
improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.

Introduction
The percentage of patients with schizophrenia who demonstrate symptom onset during ado-
lescents may be as high as 25%; however, the proportion of patients with an early-onset diagnosis
of schizophrenia appears to be much lower.1–5 Compared with adult-onset, early-onset schizo-
phrenia occurs more commonly in males and typically is associated with greater illness severity,
chronicity, and functional impairment, resulting in a less favorable prognosis.6–11
Because the vast majority of patients with schizophrenia require chronic treatment, long-term
safety and tolerability are paramount considerations when choosing an antipsychotic agent. This
is especially true in adolescents, a particularly vulnerable population at higher risk for experienc-
ing adverse effects from antipsychotics.12–17
In a recent network meta-analysis based on 28 short-term, randomized controlled trials of
schizophrenia in adolescence, the most efficacious antipsychotic (vs placebo) was clozapine,
© The Author(s), 2020. Published by Cambridge followed by olanzapine, risperidone, and lurasidone.18 However, the American Academy of
University Press. This is an Open Access article, Child and Adolescent Psychiatry guidelines (AACAP)9 recommend use of olanzapine as a
distributed under the terms of the Creative second-line agent due to safety concerns, most notably high risk of weight gain, and metabolic
Commons Attribution licence (http:// abnormalities (eg, dyslipidemia). The guideline also recommended caution in the use of
creativecommons.org/licenses/by/4.0/), which
permits unrestricted re-use, distribution, and
clozapine. Additionally, a recent meta-review of 78 adverse events of 80 psychotropic medica-
reproduction in any medium, provided the tions in children and adolescents with mental disorders found lurasidone to have the best safety/
original work is properly cited. tolerability profile among 15 antipsychotics with data.19
Minimal data are available from long-term studies assessing the safety, tolerability, and
effectiveness of antipsychotic agents for schizophrenia in adolescent populations.20,21 The
current study is one of the only large-scale antipsychotic treatment studies we are aware of that
prospectively followed adolescent patients with schizophrenia for 2 years.

https://doi.org/10.1017/S1092852920001893 Published online by Cambridge University Press

 CNS Spectrums 119

Lurasidone is an atypical antipsychotic agent with high binding any other movement disorder, were willing to use medically appro-
affinity for D2, 5-HT2A, and 5-HT7 receptors (antagonist); moder- priate contraception if sexually active.
ate affinity for 5-HT1A receptors (partial agonist); and no appre- All patients enrolled in the current extension study were
ciable affinity for H1 and M1 receptors.22 Lurasidone has started on a dose of 40 mg/d for 1 week, regardless of their
demonstrated efficacy and safety in the acute and long-term treat- treatment group assignment in the original DB study. The dose
ment of adults with schizophrenia in the dose range of 40-160 mg/ of lurasidone could be adjusted at regularly scheduled visits
day23–30 and has shown a low propensity for weight gain or (biweekly up to week 8, monthly thereafter) in the flexible dose
metabolic disturbance.31 The minimal effect of lurasidone on range of 20, 40, 60, or 80 mg/day. Dose adjustment should occur
weight appears to be largely attributable to its absence of activity increments or decrements of one (20 mg) dose level at these
at 5HT2C and histamine H1 receptors.32,33 scheduled visits; however, dose reductions for tolerability or
In a previously reported double-blind (DB), placebo-controlled, safety purposes were permitted, based on investigator judgment,
fixed-dose, 6-week trial in adolescents with schizophrenia, patients between study visits, as early as day 2, and could include dose
randomized to lurasidone 40 mg/d or 80 mg/d demonstrated sig- reductions of a maximum of two dose levels at a time. Lurasidone
nificantly greater improvement in schizophrenia symptoms than was taken orally, once daily in the evening with a meal or within
placebo-treated patients; and lurasidone treatment was found to be 30 minutes after eating.
generally safe and well tolerated.34 We report here the results of the
2-year, open-label (OL) follow-up of that study designed to eval-
Concomitant medication
uate the long-term safety and effectiveness of lurasidone in this
adolescent population. Concomitant treatment with benzodiazepines, antidepressants,
and stimulants (for Attention deficit hyperactivity disorder
(ADHD)) was permitted; treatment with benztropine (≤ 6 mg/
Methods day), or alternative medications, was permitted as needed for
movement disorders, and treatment with propranolol (≤ 120 mg/
This was a 104-week, OL extension study (clinicaltrials.gov iden- day) was permitted as needed for akathisia. Prophylactic use of
tifier: NCT01914393) that enrolled patients from 13 to 17 years of medications to treat movement disorders was not permitted. Con-
age who completed an initial 6-week, DB, placebo-controlled trial comitant use of lorazepam, or equivalent benzodiazepine, was
evaluating the efficacy and safety of two fixed doses of lurasidone permitted at the discretion of the investigator (≤ 6 mg/day or
(40 and 80 mg/d) for the treatment of schizophrenia equivalent dose) for intolerable anxiety/agitation. Benzodiazepine
(NCT01911429).34 and nonbenzodiazepine sedative-hypnotic agents were also per-
The study was conducted from November 2013 to October mitted on an as-needed basis for insomnia.
2018 at 65 centers in 14 countries (Bulgaria, Columbia, Spain, For patients who were hospitalized at the conclusion of the
France, Hungary, South Korea, Mexico, Malaysia, Philippines, original DB study, continued hospitalization for up to 14 days in
Poland, Romania, Russia, Ukraine, and USA). The study was the current extension study was permitted. Patients that could not
approved by an Institutional Review Board/ethics committee at be transitioned to an outpatient setting within 14 days were dis-
each investigational site and was conducted in accordance with the continued from the study.
International Conference on Harmonisation Good Clinical Prac-
tices guidelines and with the ethical principles of the Declaration of
Helsinki. The study was monitored by an independent Data and Safety and tolerability assessments
Safety Monitoring Board. After a full explanation of the study was The presence and severity of adverse events were recorded at each
provided, written informed consent was obtained from a parent or study visit, including any treatment-emergent worsening in pre-
legal guardian, and assent was obtained from each adolescent existing symptoms or conditions that the patient spontaneously
patient. For patients who became 18 years of age during the course reports. As requested by the European Medicines Agency, adverse
of the study, written informed consent was obtained as soon as event reporting was supplemented by administration of the Udvalg
possible after their birthday. for Kliniske Undersogelser (UKU) Side Effect Rating Scale, a
clinician-rated scale consisting of 48 adverse effect items (each
rated on a 0-3 point scale, 0—no side effects, 1—mild, 2—moder-
Patients and study design
ate, 3—severe) divided into four categories (psychic [0-30], neuro-
Entry into the preceding acute treatment study34 was limited to logic [0-24], autonomic [0-33], and other [0-48]).35 Mean severity
patients with a DSM-IV-TR diagnosis of schizophrenia who were scores were calculated for each side effect category and for the total
experiencing an acute exacerbation (≤ 2 months in duration), with score. Movement disorders were assessed by the Simpson-Angus
a Positive and Negative Syndrome Scale (PANSS) total score ≥ 70 Scale,36 the Barnes Akathisia Rating Scale,37 and the Abnormal
and ≤ 120, and a Clinical Global Impression-Severity (CGI-S) Involuntary Movement Scale.38 The Columbia Suicide Severity
score ≥ 4 (at least moderately ill). Patients were excluded if they Rating Scale (C-SSRS)39 was used to assess suicidal ideation and
had a history of intellectual disability or any neurologic disorder or behavior. Additional safety evaluations included vital signs, height,
an alcohol or substance use disorder diagnosis in the previous 6 weight and body mass index (BMI), laboratory tests (metabolic
months. parameters, hormonal parameters, and other blood chemistry and
Patients were included in the current extension study if they hematology values), 12-lead electrocardiogram (ECG), Tanner
were judged by the investigator to be suitable for participation in a staging, menstrual cyclicity (female patients), and physical exam-
104-week OL study, were able to comply with the protocol, were ination.
not considered by the investigator to be at imminent risk of suicide The effect of treatment on cognitive function was evaluated with
or injury to self or others, exhibited no evidence of moderate or the Cogstate Brief Battery40 and will be reported in a separate
severe extrapyramidal symptoms, dystonia, tardive dyskinesia, or publication.

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 120 C.U. Correll et al.

Effectiveness assessments Remission, sustained remission, and recovery

In posthoc analyses, the following criteria were used to define
Effectiveness assessments were performed by qualified site-based
remission (at a given assessment time point): PANSS item scores of
raters at each monthly assessment visit. In the current OL study,
≤ 3 at one assessment visit on all of the following PANSS items (N
effectiveness measures were considered secondary outcomes and
= 8 items): P1 (delusions), P2 (conceptual disorganization), P3
consisted of the following: the PANSS, and the PANSS Positive,
(hallucinatory behavior), G5 (mannerisms/posturing), G9
Negative, General Psychopathology, and Excitability subscales41;
(unusual thought content), N1 (blunted affect), N4 (social with-
the Clinical Global Impression, Severity scale (CGI-S)42; the
drawal), and N6 (lack of spontaneity).49 Sustained remission
clinician-rated Children’s Global Assessment Scale (CGAS)43;
required all of these PANSS item severity scores to remain ≤ 3
and the Pediatric Quality of Life Enjoyment and Satisfaction Ques-
for at least 6 months.49 Patients met criteria for recovery at a given
tionnaire (PQ-LES-Q).44 The CGAS is a clinician-administered
visit if they met all PANSS item severity criteria for remission at
measure that evaluates global impairment on a scale of 0-100.
that visit and also had a CGAS score ≥ 70 indicating no clinically
Higher scores indicate better functioning; scores ≥ 70 are consid-
significant functional impairment at that visit. Number and pro-
ered in the normal range of functioning.45 The PQ-LES-Q is a
portion of patients who met remission or recovery criteria were
quality-of-life measure that has demonstrated reliability and valid-
summarized, respectively, by study visit. A Kaplan–Meier analysis
ity in children ages from 6 to 17 and its percentage maximum
of time-to the first event was performed to evaluate time-to sus-
possible score range from 0% to 100%. A score PQ-LES-Q score of
tained remission and sustained recovery.
58% (within 10% of normative community mean score) was the
criterion level used to qualify a patient as returning to a normative
level of quality of life.46,47
Results
A combined total of 285 adolescents completed the 6-week, DB,
Statistical analysis placebo-controlled trial, of whom 271 patients (95.1%) provided
The safety population consisted of all patients who completed the informed consent/assent and continued into the current OL exten-
DB, acute-phase trial, continued into the current extension study, sion study, including 181 patients initially randomized to lurasi-
and received at least one dose of lurasidone in the OL phase of the done (40 mg/d or 80 mg/d) and 90 patients initially randomized to
study. All safety and effectiveness summaries were based on the placebo (Figure 1). Demographic and clinical characteristics at
safety population. No inferential statistics were calculated. For extension phase baseline are summarized in Table 1. In the current
continuous variables (including both safety and effectiveness vari- extension study, 186 (68.6%) of patients completed 52 weeks, and
ables), descriptive summary statistics (N, mean, median, 95% 156 (57.6%) completed 104 weeks of treatment (Figure 1). Reasons
confidence interval [CI] etc.) were reported at DB Baseline, OL for premature discontinuation were withdrawal of consent
Baseline, each post-OL visit, week-52 endpoint, and endpoint in the (14.0%), adverse event (10.7%), lost to follow-up (4.4%), lack of
OL study. In addition, changes from DB Baseline and OL Baseline efficacy (4.1%), and miscellaneous other reasons (9.2%; Figure 1).
were also reported in a similar way using summary statistics as The mean daily dose of lurasidone averaged across the 104-week
described above. OL treatment period was 57.0 mg/d. The modal daily dose of
For treatment-emergent adverse events, number and percent- lurasidone utilized by patients during OL treatment was 20 mg
age of subjects with one or more events were summarized for (by 3.3% of patients), 40 mg (35.4%), 60 mg (24.4%), and 80 mg
overall incidence, serious adverse events, and discontinuations (36.9%). Mean daily dose of lurasidone across the 104-week OL
due to adverse events. treatment is similar between patients in the 13 and 14 years and
To analyze the effects of lurasidone on growth parameters, age- patients in the ≥ 15 years age groups (60.1 mg vs 56.0 mg). Pill
and sex-specific z-scores of height and BMI were reported using the counts indicated that adherence was high, with only one patient
World Health Organization (WHO) 2007 growth charts, and age- being nonadherent on three or more visits during 104 weeks of
and sex-specific z-scores for body weight were reported using the study treatment. The most frequently used, as-needed, concomi-
Centers for Disease Control and Prevention (CDC) 2000 growth tant medications were benzodiazepines (23.2%) and anticholiner-
charts.48 In this OL extension study, to better interpret growth gic medications (9.6%).
changes in the absence of a placebo-controlled group, expected
value of weight per CDC growth reference and expected value of
Safety
height and BMI per WHO growth chart were derived for each
subject at study visits; mean expected changes relative to DB Adverse events with an incidence ≥ 5% are summarized in Table 2.
Baseline were summarized for these growth parameters. Overall, 20/271 patients (7.4%) reported an adverse event as severe.
PANSS total and subscale scores (Positive, Negative, General The incidence of extrapyramidal symptom–related adverse events
Psychopathology, Excitability), CGI-S score, the CGAS total score, (excluding akathisia) was 9.6%. The incidence of individual adverse
and the PQ-LES-Q score were summarized as continuous variables. events was similar (< 5% difference), regardless of initial DB treat-
Treatment response was defined a priori as ≥ 20% reduction in ment assignment (lurasidone or placebo).
PANSS total score from baseline (either DB baseline or OL base- At DB baseline, the mean severity score for each Udvalg for
line), calculated based on both observed case data and last obser- Kliniske Undersogelser (UKU) side effect category, and UKU total,
vation carried forward (LOCF) data. An exploratory analysis was were as follows: psychic (4.48), neurologic (.26), autonomic (.34),
also performed to examine the proportion of patients who met other side effects (.34), and total (5.42). Change from OL baseline
stringent responder criteria, defined posthoc as ≥ 50% reduction in generally showed a gradual improvement over time in UKU total
PANSS total score from baseline (DB baseline or OL baseline). The score and psychic side effect subscale score. Changes from DB
number and proportion of responders relative to baseline by study Baseline were less pronounced for the remaining UKU subscale
visit were summarized. scores (Table 3).

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 CNS Spectrums 121

Figure 1. Patient disposition.

The proportion of patients reporting a serious adverse event was Treatment with lurasidone was associated with small changes
10.3% (28/271), translating into an event rate of .115 events per from DB baseline at both weeks 52 and 104 in total, high-density
patient-year of exposure. Specific serious adverse events consisted lipoprotein (HDL), low-density lipoprotein (LDL), cholesterol,
of fever, appendicitis, hematuria, concussion, foot fracture, soft triglycerides, glucose, hemoglobin A1C, and insulin (Table 4),
tissue injury, new-onset type 1 diabetes (n = 1 for each), and the and median changes in prolactin were minimal (≤ 1.2 ng/mL) in
following psychiatric disorders: schizophrenia (n = 11), suicidal both male and female patients (Table 4).
ideation (n = 8), psychotic disorder (n = 5), intentional overdose During OL treatment with lurasidone, no clinically meaningful
(n = 2), and one each of the following: abnormal behavior, aggres- changes were observed in heart rate, electrocardiogram (ECG), ortho-
sion, agitation, confusional state, depression, depressive symptom, static blood pressure (systolic or diastolic), respiratory rate, or body
suicidal behavior, and suicide attempt. There were no deaths in the temperature. On serial ECG assessments during up to 104 weeks of
study. OL treatment, no patient had a QT interval, Fridericia’s Correction
A similar proportion of patients in the 13-14 vs ≥ 15-year age (QTcF) value > 460 ms, and no patient had an increase from OL
group reported at least one adverse event (83.3% vs 77.4%), an baseline in QTcF that was ≥ 60 ms.
adverse event leading to study discontinuation (11.1% vs 10.1%),
and a serious adverse event (13.9% vs 9.0%).
Effectiveness
On the C-SSRS, the proportion of patients with emergent or
worsening suicidal ideation (relative to the DB treatment period) For the extension study patient population, 6 weeks of initial DB
was 4.8% (n = 13), and the proportion with emergent suicidal treatment was associated with greater improvement in PANSS total
behavior was 1.1% (n = 3). score in patients randomized to lurasidone (n = 181) compared to
Mean changes from OL baseline to weeks 52 and 104, respec- those randomized to placebo (n = 90: 19.8 vs 12.9). For all
tively, were small and not clinically meaningful for the Simpson– patients entering the extension study, mean change in PANSS total
Angus scale 10-item mean score ( .01 and .01), the Barnes score from DB baseline to OL baseline (6 week) was 17.5 resulting
Akathisia Scale total score ( .1 and .1), and the Abnormal in a PANSS total score of 76.0 at OL baseline. After 12 weeks of OL
Involuntary Movement Scale total score ( .02 and .05). treatment with lurasidone, mean change from DB baseline in
In this population of adolescents, mean change from DB base- PANSS total score was comparable for both patients initially ran-
line in actual weight (kg) during 104 weeks of OL treatment with domized to lurasidone or placebo in the DB phase ( 27.8 vs
lurasidone was very similar to the expected change in weight based 26.8). For the combined group, continued improvement from
on CDC growth charts (Figure 2). Mean change in BMI was also DB baseline was observed for PANSS total and subscale scores
similar to the expected change in BMI based on WHO growth during up to 104 weeks of treatment with OL lurasidone (Figure 3a).
charts (Table 4; Figure 2). The proportion of patients with normal Mean observed change from OL baseline in the PANSS total score
weight (ie, BMI between 5th and 84.9th percentile based on WHO was 15.6 at week 52 and 18.4 at week 104 ( 12.2 at LOCF-
reference values) was 62.7% at DB baseline, and this proportion endpoint). Continued improvement from DB baseline was also
increased at week 52 (66.1%) and week 104 (73.7%; Table 4). observed for the CGI-Severity score (Figure 3b).

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 122 C.U. Correll et al.

Table 1. Baseline Demographic and Clinical Characteristics (Safety Population) Table 2. Adverse Events in at Least 5% of Patients (Safety Population)

Lurasidone 20-80 mg Lurasidone 20-80 mg (N = 271), %

Patient Characteristics (N = 271)
Headache 24.0
Male, n (%) 170 (62.7)
Anxiety 12.9
Age, years, mean (SD) at OL Baseline 15.5 (1.4)
Nausea 12.5
Age 13-14 y, (%) 72 (26.6)
Schizophrenia 12.5
Age 15-17 y, (%) 185 (68.3) a
Somnolence (combined) 12.2
Age 18 y, (%) 14 (5.1) b
Extrapyramidal events 9.6
Race, n (%)
Nasopharyngitis 8.9
White 197 (72.7)
Insomnia 8.5
Black 38 (14.0)
Akathisia 8.1
Asian 11 (4.1)
Agitation 7.7
Other 25 (9.2)
Weight increased 7.7
At screening (at entry to DB study)
Toothache 7.0
Age at onset of psychotic symptoms, y, mean 13.1 (2.8)
(SD) Depression 7.0

Prior hospitalizations for schizophrenia, % Viral infection 6.3

0 47.6% Dizziness 6.3

1 26.9% Vomiting 5.9

≥2 25.5% Constipation 5.2

a
Patient has previously taken an antipsychotic 81.5% Hypersomnia, sedation, somnolence, hypersomnolence.
b
Parkinsonism, dyskinesia, dystonia, extrapyramidal disorder, hypokinesia, salivary hyperse-
medication, %
cretion, tardive dyskinesia, torticollis, or psychomotor hyperactivity.
PANSS total score, mean for DB / OL baselines
Lurasidone 40 mg in DB phase (N = 90) 93.9 / 74.6
Lurasidone 80 mg in DB phase (N = 91) 93.9 / 73.6 Table 3. Change from Double-blind (DB) and Open-Label (OL) Baselines in
Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale Scores (Safety
Placebo in DB phase (N = 90) 92.7 / 79.8 Population)
CGI-severity score, mean for DB / OL baselines Week 52 Week 104
Lurasidone 40 mg in DB phase (N = 90) 4.9 / 3.9 (N = 187) (N = 154)

Lurasidone 80 mg in DB phase (N = 91) 4.8 / 3.8 Psychic side effects score

Placebo in DB phase (N = 90) 4.7 / 4.2 DB / OL baseline, meana 4.75/3.48 5.03/3.66

Weight, kg, mean for DB / OL baseline 64.2/64.6 Change from DB / OL baseline, mean 2.94/ 1.66 3.74/ 2.37

Z-score for weight at DB / OL baselinea 0.45/0.45 Neurologic side effects score

2
BMI, kg/m , mean for DB / OL baseline 22.7/22.8 DB / OL Baseline, meana .24/.22 .27/.24

BMI category for OL baseline Change from DB / OL baseline, mean .03/ .02 .16/ .12

Underweight (< 3rd percentilea), n (%) 2 (0.7) Autonomic side effects score

a
Normal (3rd-85th percentile ), n (%) 174 (64.2) DB / OL Baseline, meana .30/.27 .29/.31

Overweight (> 85th-97th percentilea), n (%) 71 (26.2) Change from DB / OL baseline, mean .01/+.02 .10/ .12

Obese (> 97th percentilea), n (%) 24 (8.9) Other side effects score
DB / OL Baseline, meana .27/.44 .26/.40
Abbreviations: BMI, body mass index; DB, double-blind; OL, open-label; PANSS, Positive and
Negative Syndrome Scale; SD, standard deviation. Change from DB / OL baseline, mean +.09/ .08 .10/ .24
a
Age- and gender-adjusted z-score for weight are based on CDC growth charts for the United
States (2000); age- and gender-adjusted z-score for BMI are based on WHO growth charts UKU side effect total score
(2007).
DB / OL Baseline, meana 5.57/4.42 5.85/4.62

To verify the impact of early dropouts on change in PANSS total Change from DB / OL baseline, mean 2.89/ 1.74 4.09/ 2.86
score, two sensitivity analyses were conducted to explore the Abbreviations: DB, double-blind; OL, open-label; UKU, Udvalg for Kliniske Undersogelser.
robustness of change from DB baseline and change from OL Higher baseline scores indicate greater severity; range of 0 to 30 for psychic, 0 to 24 for
neurologic, 0 to 33 for autonomic, and 0 to 48 for other.
baseline in PANSS total score. The results of these sensitivity a
DB baseline means are shown for the subgroup of patients available at weeks 52 and 104,
analyses, summarized in the online Supplemental Appendix A, respectively.

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 CNS Spectrums 123

Figure 2. Change from double-blind (DB) baseline in weight and body mass index (BMI): actual vs expected.

Table 4. Changes in Selected Laboratory Parameters and Growth Parameters (Safety Population)

Lurasidone 20-80 mg
Week 52 (N = 189) Week 104 (N = 156)
Metabolic, median change, mg/dL, from DB baseline
Total cholesterol (fasting) 3.0 ( 3.0) 2.0 ( 3.0)
HDL (fasting) 3.0 ( 3.0) 3.0 ( 3.0)
LDL cholesterol (fasting) 0 (0) +1.0 (+1.0)
Triglycerides (fasting) +3.0 (+3.5) +9.0 (+8.0)
Glucose (fasting) +1.0 (+1.0) +1.0 (+2.0)
Hemoglobin A1C, % 0 0
Insulin, mU/L (fasting) +.5 (+.7) 1.3 ( 2.4)
Prolactin, median change, ng/mL, from DB baseline
Female +1.2 .5
Male +.2 +.3
Growth parameters, mean change, from DB baseline
Body weight, kg, actual (vs expected)a +3.3 (+3.4) +4.9 (+5.7)
BMI, kg/m2, actual (vs expected)a +.64 (+.64) +.84 (+1.02)
Normal weight (BMI between 3rd and 85th percentile), % (DB baseline = 62.7%) 66.1% 73.7%

Abbreviations: BMI, body mass index; DB, double-blind; HDL, high-density lipoprotein; LDL, Low-density lipoprotein; WHO, World Health Organization.
a
Age- and gender-adjusted weights are based on CDC growth charts for the United States (2000) and BMI is based on WHO growth charts (2007).

confirmed the effectiveness of lurasidone therapy in term of change across 104 weeks of lurasidone treatment, with the CGAS total
in PANSS total score. score reaching normative levels of functioning at approximately
Functioning and quality of life, measured by the CGAS and 52 weeks, and the PQ-LES-Q total score reaching normative quality
PQ-LES-Q, respectively, demonstrated progressive improvement of life levels by week 28 (Figure 4).

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 124 C.U. Correll et al.

A. PANSS Total and Factor Scores

B. CGI-Severity Score
LS Mean Change in CGI-Severity Score

Figure 3. Change from double-blind (DB) baseline in Positive and Negative Syndrome Scale (PANSS) and CGI-S (OC analyses). (a) PANSS total and factor scores; (b) CGI-severity
score.

Response, remission, and recovery modestly lower for patients in the observed case analysis versus
LOCF-endpoint analysis (82.8% vs 91.0%). More stringent
Responder rates (≥ 20% reduction from DB baseline in PANSS responder rates (≥ 50% reduction in PANSS total score from DB
total score) increased during long-term treatment with lurasidone baseline) at OL baseline, weeks 52, and 104 were 18.5%, 58.2%, and
until reaching an asymptote of approximately 90% at week 28 58.3%, respectively. Remission rates also reached an asymptote of
(Figure 5a). Notably, the responder rates at week 104 were only approximately 65% at week 28 (Figure 5a).

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 CNS Spectrums 125

Figure 4. Mean value over time in Children’s Global Assessment Scale (CGAS) total score and Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) score
(OC).

During long-term treatment with lurasidone, 52.8% (143/271) of atypical antipsychotics in adolescents with schizophre-
of patients met a stringent definition of sustained remission, nia.20,21,53,54
requiring patients to meet remission criteria continuously for Consistent with the results of long-term studies in adults with
6 months. The Kaplan–Meier estimate of median time to first onset schizophrenia, the present study found 2 years of treatment with
of sustained remission was 64.1 weeks (95% CI: 40.4, 76.1 weeks) lurasidone to have minimal effects on physiologic growth-adjusted
(Figure 5b). weight, lipids, and glycemic indices.25,27,31 This finding is in contrast
Patients who met remission criteria (cross-sectional) and who to previously reported effects of selected atypical antipsychotics on
also met CGAS criteria for normative levels of functioning (total weight and metabolic parameters.12,13,18 A network meta-analysis of
score ≥ 70) were considered to be recovered. Recovery rates at week short-term treatment studies in children and adolescents with
52 and week 104 were 43.9% (83/189) and 51.3% (80/156), respec- schizophrenia found lurasidone to have a lower risk of weight gain
tively. than risperidone, quetiapine, olanzapine, clozapine, and paliperi-
done.18 The current results extend the findings of the previous short-
term study.34 During long-term lurasidone therapy, no clinically
meaningful changes were noted in prolactin levels, and no
Discussion prolactin-related adverse effects occurred (eg, galactorrhea, amen-
The results of this multicenter, OL study in adolescent patients with orrhea). In addition, no meaningful changes were observed in vital
schizophrenia found lurasidone to be generally well-tolerated dur- signs or ECG parameters. These results are consistent with the
ing 2 years of OL treatment, with a safety profile consistent with finding of a recent meta-review in youth with psychiatric disorders,
results from previously reported short- and long-term studies in in which among 15 different antipsychotics, lurasidone was the one
adult patients with both schizophrenia and bipolar depression and with the fewest adverse events that were significantly greater than
with results of short-term studies in children and adolescents with placebo relative to adverse events not dissimilar from placebo.19
bipolar depression.23–31,34,50-52 No new or unexpected adverse Continued reduction in symptom severity on standard efficacy
events were reported, no deaths occurred, and no serious drug- measures (PANSS total and factor scores; CGI-S) occurred during
related effects were observed. Results from the structured UKU side 2 years of OL treatment with lurasidone. Improvement in schizo-
effect rating scale yielded tolerability findings similar to spontane- phrenia symptom severity was substantial, with the magnitude of
ous adverse event reporting, with reductions in adverse event improvement that occurred during OL treatment being compara-
severity noted across all assessment domains during the course of ble to what was observed during initial 6-week DB treatment. The
treatment, resulting in a 70% overall reduction in severity for the magnitude of improvement during extension phase treatment was
UKU side effect total score. The incidence of extrapyramidal not solely attributable to attrition of patients, as illustrated by a
symptoms and akathisia was low, and movement disorder assess- comparison of summary results over time between observed and
ments showed no clinically meaningful changes. Overall, 58% of LOCF values, and by further comparison with sensitivity analysis
patients completed 2 years of lurasidone treatment, with only 11% results based on multiple imputations of missingness.
discontinuing prematurely due to an adverse event. These rates In posthoc analyses to test the durability of improvement during
compare favorably to rates in other prospective, long-term studies the OL long-term treatment, stringent criteria were applied to

https://doi.org/10.1017/S1092852920001893 Published online by Cambridge University Press

 126 C.U. Correll et al.

A. Responder and Remier Rates

B. Kaplan-Meier Plot of Time to the Earliest Sustained (for 6 months) Remission

First Sustained Remission Occurrence
Cumulave Probability of

Figure 5. Response and remission during open-label (OL) treatment with lurasidone. (a) Responder and remitter rates; (b) Kaplan–Meier plot of time to the earliest sustained (for
6 months) remission.

evaluate the proportion of patients who met a consensus definition levels of functioning (CGAS) and quality of life (PQ-LES-Q)
of sustained remission, requiring patients to meet remission criteria returned to normative levels, providing further corroboration of
continuously for 6 months.49 Altogether, 53% of patients met the effectiveness of longer-term therapy with lurasidone.
criteria for sustained remission, with a Kaplan–Meier analysis Several important study limitations should be noted. This was
indicating that the median time to first onset of sustained remission an OL trial that was not randomized or blinded and had no placebo
was 64 weeks. After approximately 28 weeks of OL treatment, mean or active comparator control. Eligibility for enrollment in the DB

https://doi.org/10.1017/S1092852920001893 Published online by Cambridge University Press

 CNS Spectrums 127

trial was based on inclusion and exclusion criteria for the initial DB 2. Thorup A, Waltoft BL, Pedersen CB, Mortensen PB, Nordentoft M. Young
efficacy study that may reduce the generalizability of the results. In males have a higher risk of developing schizophrenia: a Danish register
addition, entry into the current OL extension study was limited to study. Psychol Med. 2007;37(4):479–484.
patients who completed the DB study. This may have introduced a 3. McGrath JJ, Saha S, Al-Hamzawi AO, et al. Age of onset and lifetime
projected risk of psychotic experiences: cross-national data from the world
selection bias resulting in more severely ill patients electing not to
mental health survey. Schizophr Bull. 2016;42(4):933–941.
continue in the current study. Several of the efficacy analyses
4. Kelleher I, Connor D, Clarke MC, et al. Prevalence of psychotic symptoms
(sustained remission using Kaplan–Meier analysis) were posthoc in childhood and adolescence: a systematic review and meta-analysis of
analyses. Finally, the UKU Side Effect Rating Scale was specifically population-based studies. Psychol Med. 2012;42(9):1857–1863.
required by the European Medicines Agency; however, the scale 5. Kelleher I, Keeley H, Corcoran P, et al. Clinicopathological significance of
has not been validated for use in adolescent populations. psychotic experiences in non-psychotic young people: evidence from four
population-based studies. Br J Psychiatry. 2012;201(1):26–32.
6. Rabinowitz J, Levine SZ, Häfner H. A population based elaboration of the
Conclusion role of age of onset on the course of schizophrenia. Schizophr Res. 2006;88
(1–3):96–101.
In this study, one of the longest and largest prospective schizo- 7. Frazier JA, McClellan J, Findling RL, et al. Treatment of early-onset
phrenia trials in a pediatric population, 2 years of treatment with schizophrenia spectrum disorders (TEOSS): demographic and clinical
lurasidone, was found to be safe and well tolerated, with a high rate characteristics. J Am Acad Child Adolesc Psychiatry. 2007;46(8):979–988.
of patient retention. These safety results are consistent with previ- 8. Mattai AK, Hill JL, Lenroot RK. Treatment of early-onset schizophrenia.
ous long-term lurasidone studies in adults and short-term studies Curr Opin Psychiatry. 2010;23(4):304–310.
in children. Long-term treatment with lurasidone was also associ- 9. McClellan J, Stock S. American Academy of Child and Adolescent Psychi-
ated with continued improvement in the symptoms of schizophre- atry (AACAP) Committee on Quality Issues (CQI). Practice parameter for
the assessment and treatment of children and adolescents with schizophre-
nia, resulting in a majority of patients achieving symptomatic
nia. J Am Acad Child Adolesc Psychiatry. 2013;52(9):976–990.
remission. The effectiveness of lurasidone was supported by 10. Schimmelmann BG, Schmidt SJ, Carbon M, et al. Treatment of adolescents
observed improvement across multiple outcome parameters. with early-onset schizophrenia spectrum disorders: in search of a rational,
Taken together, the current results suggest that lurasidone has a evidence-informed approach. Curr Opin Psychiatry. 2013;26(2):219–230.
favorable benefit–risk profile that places it as a potential first-line 11. Immonen J, Jääskeläinen E, Korpela H, et al. Age at onset and the outcomes
treatment of schizophrenia in adolescent patients. of schizophrenia: a systematic review and meta-analysis. Early Interv
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Acknowledgments. Dr. Edward Schweizer of Paladin Consulting Group 12. Correll CU. Assessing and maximizing the safety and tolerability of
provided editorial and medical writing assistance, which was funded by Suno- antipsychotics used in the treatment of children and adolescents. J Clin
vion Pharmaceuticals Inc. Psychiatry. 2008;69(suppl 4):26–36.
13. Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-
Funding. This was funded by Sunovion Pharmaceuticals Inc. generation antipsychotic medications during first-time use in children and
adolescents. JAMA. 2009;302(16):1765–1773.
14. De Hert M, Dobbelaere M, Sheridan EM, et al. Metabolic and endocrine
Disclosures. Dr. Correll has been a consultant and/or advisor to or have adverse effects of second-generation antipsychotics in children and ado-
received honoraria from: Acadia, Alkermes, Allergan, Angelini, Axsome, lescents: a systematic review of randomized, placebo-controlled trials and
Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, guidelines for clinical practice. Eur Psychiatry. 2011;26(3):144–158.
Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck,
15. Carbon M, Kapoor S, Sheridan E, et al. Neuromotor adverse effects in
Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo
342 youth during 12 weeks of naturalistic treatment with 5 second-
Dainippon, Sunovion, Supernus, Takeda, and Teva. He provided expert testi-
generation antipsychotics. J Am Acad Child Adolesc Psychiatry. 2015;54
mony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for
(9):718–727. e3.
Lundbeck, Rovi, Supernus, and Teva. He has received grant support from
16. Galling B, Roldán A, Nielsen RE, et al. Type 2 diabetes mellitus in youth
Janssen and Takeda. He is also a stock option holder of LB Pharma.
exposed to antipsychotics: a systematic review and meta-analysis. JAMA
Dr. Findling receives or has received research support, acted as a consultant
Psychiatry. 2016;73(3):247–259.
and/or has received honoraria from Acadia, Adamas, Aevi, Akili, Alcobra,
17. Al-Dhaher Z, Kapoor S, Saito E, et al. Activating and tranquilizing effects of
Alkermes, Allergan, Amerex, American Academy of Child & Adolescent Psy-
first-time treatment with aripiprazole, olanzapine, quetiapine, and risper-
chiatry, American Psychiatric Press, Arbor, Axsome, Daiichi-Sankyo, Gedeon
idone in youth. J Child Adolesc Psychopharmacol. 2016;26(5):458–470.
Richter, Genentech, KemPharm, Luminopia, Lundbeck, MedAvante-
18. Krause M, Zhu Y, Huhn M, et al. Efficacy, acceptability, and tolerability of
ProPhase,Merck, NIH, Neurim, Noven, Nuvelution, Otsuka, PCORI,
antipsychotics in children and adolescents with schizophrenia: a network
PaxMedica,Pfizer, Physicians Postgraduate Press, Q BioMed, Receptor Life
meta-analysis. Eur Neuropsychopharmacol. 2018;28(6):659–674.
Sciences, Roche, Sage, Signant Health, Sunovion, Supernus Pharmaceuticals,
19. Solmi M, Fornaro M, Ostinelli EG, et al. Safety of 80 antidepressants,
Syneos, Syneurx, Takeda, Teva, Tris, TouchPoint,and Validus.
antipsychotics, anti-attention-deficit/hyperactivity medications and mood
Dr. Tocco, Pikalov, Deng, and Goldman are employees of Sunovion
stabilizers in children and adolescents with psychiatric disorders: a large
Pharmaceuticals Inc.
scale systematic meta-review of 78 adverse effects. World Psychiatry. 2020;
19(2):214–232.
Supplementary Materials. To view supplementary material for this article, 20. Savitz A, Lane R, Nuamah I, et al. Long-term safety of paliperidone
please visit http://dx.doi.org/10.1017/S1092852920001893. extended release in adolescents with schizophrenia: an open-label, flexible
dose study. J Child Adolesc Psychopharmacol. 2015;25(7):548–557.
21. Correll CU, Kohegyi E, Zhao C, et al. Oral aripiprazole as maintenance
treatment in adolescent schizophrenia: results from a 52-week, random-
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