J Pharmacol Sci 126, 164 – 167 (2014)
Journal of Pharmacological Sciences
© The Japanese Pharmacological Society
Short Communication
Lurasidone Suppresses Rapid Eye Movement Sleep and Improves Sleep
Quality in Rats
Takeshi Murai1,*, Keiko Nakamichi2, Isao Shimizu3, and Kazuhito Ikeda1
Ikeda Lab., Drug Development Research Laboratories, 2Biomarker Group, Drug Development Research Laboratories,
Drug Development Research Laboratories, Sumitomo Dainippon Pharma, Co., Ltd.,
33-94 Enoki-cho, Suita, Osaka 564-0053, Japan
1
3
Received June 19, 2014; Accepted August 1, 2014
Abstract. Patients with psychiatric disorders, including schizophrenia, are reported to suffer
from sleep disorders. In this study, we investigated the effects of lurasidone, an atypical anti­
psychotic, on sleep architecture in rats using sleep electroencephalography. The course of sleep in
rats was classified into 3 stages: WAKE, non-rapid eye movement (NREM) sleep, and rapid eye
movement (REM) sleep. Lurasidone shortened REM duration and prolonged the mean duration
of one bout in WAKE and NREM. Quantitative frequency band analysis during NREM sleep
revealed that lurasidone increases slow waves and decreases fast waves. These results suggest that
lurasidone ameliorates sleep disorders associated with psychosis.
Keywords: lurasidone, antipsychotic, sleep
Lurasidone, a new antipsychotic drug approved by
the FDA in 2010, exhibits strong dopamine D2 and 5hydroxytriptamine (5-HT)2A receptors antagonistic activity
as well as 5-HT1A receptor partial agonistic activity and
5-HT7 receptor antagonistic activity. As such, lurasidone
is classified as a serotonin–dopamine antagonist (SDA)
(1). Lurasidone has been shown to enhance cognitive
function and improve psychosis in rodents and nonhuman primates (2 – 4). Recent clinical studies confirmed that lurasidone alone, or in combination with
valproate or lithium, is effective for the depressive state
of bipolar disorder type I (5, 6). Based on these findings,
a request for expansion of indication was submitted to
the FDA and was subsequently approved in June 2013.
Sleep problems, including prolonged sleep latency,
fragmented sleep, and early-morning awakening, have
been reported in patients with mood disorders such as
schizophrenia and bipolar disorder (7, 8). Especially,
researchers have found a correlation between increased
rapid eye movement (REM) sleep and the severity of
depressive state (9, 10). Thus, amelioration of sleep in
these patients can improve quality of life.
In the present study, we investigated the effects of
lurasidone on non-REM (NREM) and REM sleep in rats
using electroencephalography (EEG). The amount and
quality of sleep were assessed based on the number and
duration of bouts in each sleep stage and the ratio of
frequency bands (delta to gamma) during NREM.
All experimental procedures for the use of animals
were reviewed and approved by the Institutional Animal
Care and Use Committee of Sumitomo Dainippon Pharma,
Co., Ltd. Seven adult male Wistar rats (Charles River
Laboratories Japan, Kanagawa) were used in this study.
The animals were housed in an air-conditioned room
(temperature of 20°C – 26°C and humidity of 40% – 70%) with a 12:12 h light/dark cycle (light on at 7:00)
and allowed access to food and tap water ad libitum.
The rats were anesthetized with sodium pentobarbital
(40 mg/kg, i.p.), and a radio transmitter (TL11M2-F40EET; Data Science International, New Brighton, MN,
USA) was implanted subcutaneously in the back. A pair
of electrode wires was fed subcutaneously to a small
incision on the skull. One wire was implanted on the
dura 2-mm anterior to the bregma and 2-mm to the left
of the midline, and the other wire was placed 4-mm
posterior to the bregma and 4 mm to the right of the
midline. A stainless screw was also placed on the skull
2-mm anterior to the bregma and 2 mm to the left of the
*Corresponding author. [email protected]
Published online in J-STAGE on September 17, 2014
doi: 10.1254/jphs.14155SC
164
Effects of Lurasidone on Sleep in Rats
165
Fig. 1. Effect of lurasidone on NREM and REM sleep: A) NREM Duration, B) NREM Latency, C) REM Duration, D) REM
Latency. *P < 0.05, significantly different from the vehicle.
midline. The EEG electrodes and screw were fixed in
place using dental cement. Electromyograms (EMG)
were recorded from the dorsal neck muscle using another
pair of electrodes. Rats were administered antibiotics
and analgesics following wire implantation.
After surgery, the rats were allowed at least 2 weeks
recovery in individual plastic cages before EEG/EMG
recording. The lighting cycle was changed during this
period (light-on: 10:00 – 22:00). Lurasidone or solvent
was administered at the start of the light-on period,
and EEG/EMG was recorded for 6 h in a soundproof
box using Dataquest A.R.T. software (Data Science
International). To effectively evaluate the beneficial
effect of lurasidone, the animals were used in a crossover
design. A minimum one-week washout period was
allowed between recordings. Dosing was performed in
a pseudo-randomized order.
In sleep stage analysis, in which a 10-s period was
regarded as one epoch, WAKE, REM, and NREM were
automatically assessed based on EEG and EMG recordings using Sleepsign3 software (Kissei Comtec, Nagano).
A condition in which EMG exceeded the threshold
was defined as WAKE, that in which the power of delta
waves (0.5 – 4 Hz) was 1,500 mV2 or greater with no
EMG response was defined as NREM, and that in which
the power of theta waves (4 – 8 Hz) exceeded 40% of
the total power of 0.5 – 80 Hz waves with no EMG
response was defined as REM. Total REM duration,
NREM duration, and latencies to the initial REM and
NREM were calculated. REM and NREM were considered initial when they continued for 2 and 6 epochs,
respectively. In addition, the number and mean duration
of bouts in every 2-h period were calculated in each
stage.
After assessment of each sleep stage, EEG power in
each of the following frequency bands during NREM
sleep was quantified using Sleepsign3: delta, theta, alpha
(8 – 12 Hz), beta (12 – 30 Hz), and gamma (30 – 80).
The power ratio of each wave to all waves (0.5 – 80 Hz)
was calculated using Sleepsign3.
Lurasidone was prepared in our laboratories, suspended
in 0.5% methylcellulose (MC) as a vehicle, and orally
administered to rats in a volume of 2 mL/kg. All data
are expressed as means ± S.E.M. Differences between
groups were determined using Dunnett’s multiple comparison test. Differences in the ratio of each frequency
band between each dose and the vehicle were determined
with the paired t-test. A probability level of < 0.05 was
considered significant.
Lurasidone increased total NREM duration over the
6-h recording period (3 mg/kg: 251.4 ± 4.1, t24 = 3.8,
P = 0.0024; 10 mg/kg: 259.8 ± 2.8, t24 = 5.28, P < 0.0001),
but had no effect on the latency to initial NREM even
at 10 mg/kg (Fig. 1: A, B). Moreover, lurasidone
decreased the number of bouts in all sleep stages
and extended the mean duration of one bout in NREM
(Table 1). These results indicate that lurasidone promotes
sleep and suppresses its fragmentation. Quantitative
frequency band analysis during NREM sleep showed
that lurasidone increases delta-wave ratio and decreases
alpha-, beta-, and gamma-wave ratios (Table 2).
These findings indicate that lurasidone induces deep
166
T Murai et al
Table 1. Effect of lurasidone on sleep stage count
Number of bouts
Dose (mg/kg)
0
1
3
10
Bout duration (s)
WAKE
REM
NREM
WAKE
REM
NREM
14.3 ± 0.9
12.3 ± 1.2
10.1 ± 2.0
8.6 ± 1.5*
10.4 ± 1.6
7.4 ± 0.6
5.7 ± 1.2*
3.0 ± 1.0*
21.6 ± 1.6
17.1 ± 1.6
14.3 ± 1.9*
11.0 ± 1.5*
134.4 ± 17.8
157.7 ± 16.8
167.7 ± 38.0
257.9 ± 62.8
84.3 ± 11.0
98.9 ± 8.6
91.6 ± 13.3
50.5 ± 15.5
214.3 ± 26.3
281.7 ± 40.7
405.3 ± 58.8*
530.6 ± 68.9*
The number of bouts and mean duration of one bout in each sleep stage were evaluated over a 2-h period after lurasidone administration. *P < 0.05, significantly different from the vehicle.
Table 2. Effects of lurasidone on frequency bands
1 mg/kg
Delta
Theta
Alpha
Beta
Gamma
1.07 ± 1.2
-0.44 ± 0.4
-0.20 ± 0.3
-0.27 ± 0.6
-0.16 ± 0.2
3 mg/kg
10 mg/kg
2.34 ± 0.5*
-0.09 ± 0.2
-0.80 ± 0.1*
-1.21 ± 0.2*
-0.25 ± 0.1
4.55 ± 0.9*
-0.25 ± 0.3
-1.51 ± 0.3*
-2.32 ± 0.6*
-0.48 ± 0.2*
Differences in the ratio of each frequency band compared to the
vehicle (%) were evaluated. *P < 0.05, significantly different from
the vehicle.
sleep. Although benzodiazepine hypnotics also induce
sleep, they increase fast wave components (11). The
sleep induced by lurasidone, on the other hand, seems
to be closer to natural sleep (Table 2). Although this
study was performed in the former half of the non-active
phase, we intend to expand the measurement time to a
whole day in future studies. This will allow better understanding of the effects of lurasidone on sleep.
As shown in Fig. 1C, lurasidone decreased total REM
duration in a dose-dependent manner with significant
effect at 3 and 10 mg/kg (3 mg/kg: 44.4 ± 5.2, t24 = 2.59,
P = 0.042; 10 mg/kg: 35.0 ± 3.2, t24 = -4.24, P = 0.0008).
In addition, lurasidone slightly prolonged REM latency
(10 mg/kg: 79.8 ± 17.2, t24 = 2.41, P = 0.061; Fig. 1D).
It has been reported that REM sleep increases in the
depressive state and that antidepressants ameliorate
REM sleep concomitant with depressive symptoms. As
some antidepressants also suppress REM sleep even in
healthy subjects and naïve animals, it is believed that
REM suppression may be a useful biomarker for anti­
depressant effect (9, 10, 12). Indeed, paroxetine at a dose
of 10 mg/kg significantly decreased REM sleep duration
and prolonged REM sleep latency under the current
experimental conditions (data not shown). Thus, our
results in this study indicate that lurasidone might
have antidepressant effect. Lurasidone has already been
shown to be effective in animal models of depression (1)
and in patients with bipolar disorder (5, 6). The results
of this study add to this profile by supporting the efficacy
of lurasidone for depressive symptoms.
The sleep-inducing effect of lurasidone might be
caused by its antagonism of the 5-HT2A receptor. As
described by Morairty et al. (13), MDL100907, a 5-HT2A
receptor–selective antagonist, increased NREM sleep
and delta power during NREM sleep. Those effects are
consistent with the current results. However, MDL100907
did not affect REM sleep. With regard to REM suppression, 5-HT1A receptor activation and 5-HT7 receptor
inhibition might be candidate mechanisms. Indeed,
Monti et al. reported that administration of buspirone or
ipsapirone, both of which are 5-HT1A receptor partial
agonists, suppresses REM in rats. In addition, the 5-HT7
receptor antagonists, SB-269970 and JNJ-18038683,
have been reported to exhibit REM-suppressive and
antidepressant-like effects in animals and humans (12,
14, 15). Consistent with these findings, our unpublished
data show that tandospirone, a 5-HT1A receptor partial
agonist, and SB-258741, a 5-HT7 receptor antagonist,
suppress REM sleep (data not shown). As several
neurotransmitters and receptor subtypes control sleep
in a complex way, the effects of lurasidone on sleep
architecture in this study may have resulted from a
combination of mechanisms involving 5-HT2A, 5-HT1A,
and 5-HT7 receptors. To clarify the exact contribution
of each receptor, direct experiments aimed at inhibiting
the effects of lurasidone on sleep are needed.
In conclusion, analysis of rat sleep EEG in the nonactive phase revealed that lurasidone induces sleep and
suppress its fragmentation. Our results also show that
lurasidone suppresses REM sleep, which served as an
index of antidepressant effect. These findings suggest
that lurasidone can improve sleep disorders associated
with psychosis, including schizophrenia and bipolar
disorder.
Conflicts of Interest
All authors are employees of Sumitomo Dainippon Pharma Co.,
Ltd., and there are no known conflicts of interest associated with this
publication.
Effects of Lurasidone on Sleep in Rats
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