General Hospital Psychiatry 65 (2020) 74–81

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General Hospital Psychiatry

journal homepage: www.elsevier.com/locate/genhospsych

Review article

Sleepwalking and sleep-related eating associated with atypical antipsychotic T

medications: Case series and systematic review of literature
⁎
Amit Chopraa, , Rikinkumar S. Patelb, Nisha Baligac, Anoop Naraharid, Piyush Dase
a
Psychiatry and Behavioral Health Institute, Department of Sleep Medicine, Allegheny Health Network, Pittsburgh, PA, United States
b
Department of Psychiatry, Griffin Memorial Hospital, Norman, OK, United States
c
Department of Psychiatry, Dartmouth Hitchcock Medical Center, Lebanon, NH, United States
d
Psychiatry and Behavioral Health Institute, Allegheny Health Network, Pittsburgh, PA, United States
e
Department of Sleep Medicine, CentraCare, MN, United States

A R T I C LE I N FO A B S T R A C T

Keywords: Background: Sleep walking (SW) is a parasomnia behavior characterized by repetitious occurrence of ambula-
Atypical antipsychotics tion during a partial arousal from non-rapid eye movement (NREM) sleep. Sleep-related eating (SRE) is one of
Sleep walking the complex sleep behaviors that may accompany SW. Emerging evidence suggests that NREM parasomnias can
Sleep-related eating be associated with atypical antipsychotic medication use.
Parasomnias
Methods: We present a case series (n = 5) and a systematic review of the literature of cases of SW, with or
Weight gain
without SRE (n = 23), associated with atypical antipsychotic use.
Results: Twenty-eight cases of SW, with and without SRE, with a mean age of 44.8 years (S.D. = 15.04) and a
male predominance (75%; n = 21) were identified. Quetiapine was the most commonly implicated medication
with SW and SRE (n = 14). Remission from SW/SRE was noted in all cases with measures including anti-
psychotic dosage reduction, discontinuation of medication, switching to an alternate medication, and use of
continuous positive airway pressure (CPAP) for comorbid obstructive sleep apnea (OSA) treatment.
Conclusions: Sleep walking (SW), with or without sleep related eating (SRE), can be a rare but reversible side
effect associated with use of atypical antipsychotics. More research is warranted to elucidate the mechanisms
underlying SW and SRE associated with atypical antipsychotic use.

1. Introduction childhood. SW occurs in 1.5% of adults, however, with roughly 80% of

Parasomnias are a group of disorders that are characterized by ab-
normal behavioral, experiential or physiological events that occur in
association with sleep, specific sleep stages, or sleep-wake transitions
[1]. These can be classified as either non-rapid eye movement (NREM)
or rapid eye movement (REM) parasomnia depending on the sleep stage
from which they arise. According to the Diagnostic and Statistical
Manual of Mental Disorders, 5th Edition (DSM-5), NREM parasomnias
are classified into two major types- sleepwalking (SW) and sleep terrors.
SW is characterized by repetitive occurrence of ambulation while
sleeping triggered by a partial arousal during stage N3 sleep usually in
the first half of sleep period [2]. The partial arousals may be sponta-
neous or result from sleep disruptors like apneas/hypopneas or periodic
limb movements. SW occurs with open eyes, has potential for injury to
self and others, can result in violence if interrupted, and ends sponta-
neously without full awakening. SW has a prevalence rate of 5% in
these cases having a continuation of childhood behavior [3,4]. The
prevalence is noted to be the greatest between three to ten years of age
and typically resolves by adolescence [5] thus indicating that first
episode of sleepwalking is rare in adults. This also suggests that if SW
happens for the first time in adulthood, there must be an extrinsic factor
triggering it like a new disease or medication which did not exist during
the childhood.
Sleep related eating (SRE) is one of the complex behaviors that may
accompany sleep walking. SRE is characterized by recurrent episodes of
involuntary eating and drinking that occur during partial arousal from
NREM sleep [6]. SRE is a unique behavior seen during SW which tends
to appear for the first time during early adulthood [7]. With the lifetime
prevalence of 4.5%, current prevalence (in the last three months) of
2.2%, and current prevalence (at least once per week) of 0.4%, it is
most commonly associated with primary sleep, medical, and psychiatric
disorders including restless legs syndrome (RLS), periodic limb

⁎
Corresponding author.
E-mail addresses: Amit.CHOPRA@ahn.org (A. Chopra), Nisha.P.Baliga@hitchcock.org (N. Baliga), anoop.narahari@ahn.org (A. Narahari),
Piyush.Das@centracare.com (P. Das).

https://doi.org/10.1016/j.genhosppsych.2020.05.014
Received 21 January 2020; Received in revised form 22 May 2020; Accepted 31 May 2020
0163-8343/ © 2020 Elsevier Inc. All rights reserved.

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A. Chopra, et al.
movement disorder (PLMD), obstructive sleep apnea (OSA), narcolepsy,
circadian rhythm sleep-wake disorders (particularly irregular sleep/
wake type), autoimmune hepatitis, encephalitis, eating disorders, and
nocturnal dissociative disorder [7].
The patients may engage in involuntary eating and drinking during
these occurrences with no or just partial recollection of SW or SRE upon
awakening. SRE is characterized by ingestion or consumption of aty-
pical foods, inedible or toxic substances (e.g., frozen pizzas, raw bacon,
buttered cigarettes, cat food and salt sandwiches, coffee grounds, am-
monia cleaning solutions); sleep related injury can result from careless
manipulation of kitchen utensils, consuming or spilling hot foods or
beverages, eating foods one is allergic to and ingesting toxic substances.
Other possible adverse health consequences include dental caries and
tooth chipping from biting frozen foods, weight gain, obesity, various
metabolic problems such as destabilization or precipitation of diabetes
mellitus, hypertriglyceridemia and hypercholesterolemia, non-
restorative sleep from sleep disruption, morning anorexia, abdominal
distention, depression and insomnia [7].
Many different classes of medications have been implicated in SW
during adulthood with the strongest association being noted with the
use of zolpidem use [8–12]. Other medications less commonly im-
plicated in emergence of SW during adulthood include other hypnotics
(zaleplon [13,14], zopiclone [8,15]), antidepressants (amitriptyline
[16], paroxetine [17], fluoxetine [18], sertraline [17], mirtazapine
[19], reboxetine [20] and bupropion [21]), mood stabilizers (lithium
[22–25]), first generation antipsychotics (chlorprothixene [26], per-
phenazine [26] and thioridazine [26,27]), beta blockers (propranolol
[28–30] and metoprolol [31,32]), and miscellaneous drugs (cipro-
floxacin [33], bromocriptine [34], methylphenidate [35], suvorexant
[36], sodium oxybate [37], varenicline [38] and montelukast [39]).
SRE has also been associated with the use of sedative-hypnotic medi-
cations including benzodiazepine receptor agonists (zolpidem), mirta-
zapine, lithium, anticholinergics, and various other psychotropic agents
[7,40]. A recent systematic review illustrated that there is significantly
elevated rates of parasomnias (including SW and SRE) in psychiatric
disorders with use of psychotropic medications being implicated as the
major cause of parasomnias in this population [41].
Use of atypical antipsychotics has been steadily increasing across
the world for a range of clinical indications including schizophrenia,
schizoaffective disorder, bipolar disorder, and major depression with
quetiapine, risperidone, and olanzapine being the most frequently
prescribed antipsychotic medications across 16 countries in an inter-
national study [42]. The atypical antipsychotic medications are asso-
ciated with lesser incidence of extrapyramidal side effects (EPSE) and
tardive dyskinesia; however, these medications have substantial meta-
bolic side effects leading to insulin resistance, weight gain and obesity
[43]. While various reasons have been cited for weight gain associated
with atypical antipsychotic medication therapy, SW with SRE may be
one of the rare but under-recognized reasons.
In this paper, we present five clinical cases of SW, with or without
SRE, and also systematically analyze the current literature to review the
clinical presentation, risk factors, and management of these parasomnia
behaviors associated with atypical antipsychotic use in psychiatric pa-
tients (Fig. 1) [76].
2. Methods
We conducted a systematic review of the literature based on the
guidelines by Preferred Reporting Items for Systematic Reviews and
Meta-Analysis (PRISMA) statement [Fig. 1].
MEDLINE database was searched from April 1996 to March 2017 for
English language case reports and case series on the topic of SW and
SRE associated with atypical antipsychotic use. We used search terms:
“sleep walking” or “sleep-related eating” or “somnambulism” and
“olanzapine” or “clozapine” or “quetiapine” or “risperidone” or “ilo-
peridone” or “paliperidone” or “ziprasidone” or “aripiprazole” or
75
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General Hospital Psychiatry 65 (2020) 74–81
“lurasidone” or “asenapine”. Case reports and case series were con-
sidered for analysis and all abstracts and titles were examined by two
independent reviewers (A.C. and R.P.).
3. Results
3.1. Patient characteristics
Based on our case series and the review of literature, we found a
total of twenty three published cases and five unpublished cases in our
outpatient clinic (n = 28) of sleep walking (SW), with or without sleep-
related eating (SRE), that were associated with atypical antipsychotic
use. The mean age of patients was 44.8 years (S.D. = 15.04) and a male
predominance (75%; n = 21) was noted. The majority of the SW/SRE
episodes occurred in patients aged 51–60 years (32.1%, n = 9), and
41–50 and 18–30 years (21.4%, each). More than half of the patients
with SW (53.6%, n = 15) also presented with SRE. About 75% (n = 21)
patients were amnestic to events upon awakening. Demographic and
clinical characteristics of the patients with SW/SRE associated with
atypical antipsychotic use are described in Table 1.
The majority of the SW/SRE episodes associated with atypical an-
tipsychotics were associated with use of quetiapine (50%; n = 14),
followed by olanzapine (25%; n = 7), risperidone (10.7%, n = 3), and
aripiprazole (10.7%, n = 2), ziprasidone, and asenapine (3.6% each).
Bipolar disorder type-I and type II, and schizophrenia (21.4% each)
constituted major proportions of patients with SW. However, SW with
SRE was most prevalent in bipolar disorder type-I (n = 4; 26.7%) fol-
lowed by major depressive disorder and bipolar disorder type-II (20%
each). Quetiapine (n = 8, 53.3%) followed by aripiprazole and risper-
idone (13.3% each) were most commonly implicated atypical anti-
psychotics in patients presenting with SW with SRE.
3.2. Clinical characteristics and outcomes
Majority of the SW events, with or without SRE, were associated
with use of quetiapine (n = 14, 50%). Among the patients with SW
episodes associated with quetiapine use, 57.1% (n = 8) of the patients
reported SRE [25,44–47] and about half (n = 6, 50%) of them had
associated parasomnia which ranged from leg jerks, jumping from bed,
property destruction, manipulating belongings and assaults to family
members [25,45,47]. In four cases, quetiapine was discontinued and
switched to a different antipsychotic [44–46], in three cases the dose
was tapered [45,47] and other three cases the medication was dis-
continued [25,45,48]. Olanzapine was noted to be second most com-
monly implicated atypical antipsychotic with seven patients presenting
with SW including one patient reporting SRE associated with SW [49].
Approximately 66.7% (n = 4) of patients taking olanzapine also pre-
sented with complex behaviors including head banging, trying to
throttle other members, relocating clothes/belongings, talking loud and
urinate at bedside [49–52]. In three cases olanzapine was switched to
another medication (aripiprazole [52] and risperidone [53]); in one
case the dose of olanzapine was reduced [51]; and in three cases this
medication was discontinued [48–50]. Remission was seen in all six
cases of olanzapine induced SW/SRE. Additionally, SW with SRE was
noted in two patients taking aripiprazole and remission of these para-
somnia behaviors was seen after switching the medication.
Three patients on risperidone reported SW and out of them two
reported associated SRE [54–56]. The dose of risperidone was tapered
down in all cases [54–56], with no improvement and so discontinued in
one case [54], whereas in another case it was managed by continuing
lower dose of risperidone with clonazepam 0.5 mg daily [55]. One
patient taking ziprasidone reported SW associated with SRE and para-
somnia including cooking food without recollection of such events next
morning. As a part of management of SW with SRE, ziprasidone 40 mg
QAM (daily morning) was continued and ziprasidone 80 mg QHS (daily
bed time) was switched to quetiapine 100 mg QHS with remission seen
A. Chopra, et al. General Hospital Psychiatry 65 (2020) 74–81

Identification
Records idenfied through
MEDLINE database searching
(n = 35)
Screening

Records screened
(n = 35)

Full-text arcles excluded

(n=20) with reasons-
text unavailable, safety
Full-text arcles assessed reviews, cross-seconal
for eligibility
Eligibility

studies, systemac reviews,

(n = 35) arcles on night eang
syndrome, combinaon of
medicaons

Studies included in
Included

qualitave synthesis
(n = 15)

Fig. 1. PRISMA Flowsheet

in two months [57]. One patient taking asenapine 15 mg daily for bi-
polar 1 disorder presented with SW associated with SRE [48] and these
symptoms resolved immediately after the discontinuation of asenapine.
None of the patients treated with olanzapine, risperidone and zi-
prasidone had a past or family history of SW. On the contrary, one
patient taking quetiapine had a past history of SW associated with use
of zolpidem 10 mg QHS [45] and another patient had a strong family
history of SW [45]. A patient taking asenapine had a past history of SW
associated with use of olanzapine 15 mg daily and quetiapine 600 mg
daily [48]. Clinical features and the management of SW, with or
without SRE, associated with use of atypical antipsychotics are sum-
marized from the published cases (n = 23) in Table 2.
3.3. Unpublished cases in an outpatient setting
We report four cases of SW with SRE and one case of SW in psy-
chiatric patients that were associated with the use of atypical anti-
psychotics in the outpatient sleep and psychiatry clinics at Allegheny
Health Network.
Case 1:
A 47-year-old married Caucasian male with bipolar disorder type II,
rapid cycling in nature, obsessive compulsive disorder and attention
deficit hyperactivity disorder was on treatment with divalproex sodium
2000 mg QHS, quetiapine 300 mg QHS, duloxetine 120 mg daily and
dextroamphetamine/amphetamine 20 mg TID (three times daily). He
reported having recurrent episodes of SW with SRE associated with
choking during sleep and weight gain after quetiapine was initiated for
mood stabilization. He reported weight gain secondary to SRE. He re-
ported having little awareness of his SW and SRE. Clinical history was
essentially negative for obstructive sleep apnea (OSA) and patient was
at low pre-test probability for OSA. His medical and neurological his-
tory was essentially negative except for chronic back pain. There was a
brief emergence of RLS after initiation of quetiapine which responded
well to short-term use of pramipexole with no resurgence of restless legs
symptoms subsequently. However, there was persistence of SW and SRE
with continuous use of quetiapine. He reported having a past history of
multiple episodes of depression and hypomania, but felt the current
medication regimen including quetiapine was superior to other medi-
cation trials for mood stabilization.
Topiramate was initiated at 25 mg QHS that was further titrated to
50 mg QHS over 4 weeks to control SW with SRE. He responded well to
topiramate trial with complete resolution of SW and SRE; un-
fortunately, he developed adverse drug reactions (ADRs) including
cognitive dysfunction and hair loss. Topiramate had to be discontinued
because of ADRs which resulted in relapse of SW and SRE. Patient was
unwilling to discontinue quetiapine due to its unparalleled efficacy as a
mood stabilizer. Due to documented efficacy of benzodiazepines in the
treatment of parasomnias, alprazolam 1.5 mg QHS was initiated with an
excellent response and complete resolution of SW and SRE symptoms.
Case 2:

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Table 1 polysomnography and for narcolepsy on multiple sleep latency test.

Demographic characteristics of patients with sleep walking (SW), with or
without sleep-related eating (SRE), both published and unpublished cases Case 4:
(n = 28).
Variable Cases (N) Proportion (%) A 26-year old single Asian male with history of Kleine-Levin syn-
drome (KLS) and major depressive disorder (MDD), who developed SW
Age
with SRE after initiation of aripriprazole for treatment of severe de-
18–30 years 6 21.4
31–40 years 3 10.7
pression. He was initially evaluated in the sleep clinic for complaints of
41–50 years 6 21.4 hypersomnia and sleep work-up unremarkable for sleep apnea and
51–60 years 9 32.1 narcolepsy. He had unsuccessful trials of modafinil, armodafinil, and
61–70 years 3 10.7 methylphenidate for management of hypersomnia. Patient endorsed
> 70 years 1 3.6
severely depressed mood for one year in the context of break up with
Gender girl-friend. He displayed symptoms of KLS such as hypersomnia
Male 21 75.0
(sleeping for three days, cognitive dysfunction, hyperphagia and hyper-
Female 7 25.0
sexuality). KLS symptoms first started when he was in high school,
Psychiatric diagnosis
decreased in frequency over the course of years. Sertarline was initiated
Schizophrenia 6 21.4
Bipolar disorder II 6 21.4
and titrated to 100 mg daily and aripiprazole 2 mg was subsequently
Bipolar disorder I 6 21.4 added due to suicidal depression. He noted a significant improvement
Major depressive disorder 5 17.9 in his mood and felt less sleepy with addition of aripiprazole. He
Schizoaffective disorder 2 7.1 wanted to continue aripiprazole despite noticing 30 lbs. weight gain
Psychotic disorder due to Vascular dementia 1 3.6
due to insatiable appetite as reason for weight gain. He was started on
ADHD 1 3.6
Conduct disorder 1 3.6 topiramate 50 mg BID (twice daily) for binge eating behaviors and
migraine prophylaxis due to history of migraines. Topiramate was in-
Antipsychotics
Quetiapine 14 50.0 effective in controlling weight gain and he gained 70 lbs. weight over
Olanzapine 7 25.0 six month period despite exercising and modifying his diet. On detailed
Aripiprazole 2 7.1 questioning, he reported that he may have been eating large amounts of
Ziprasidone 1 3.6 food without having any conscious awareness of his eating episodes.
Asenapine 1 3.6
For example, he found pizza boxes next to him which were ordered by
Risperidone 1 10.7
him during the day time. He did not remember either calling for food or
eating the food. He denied such eating behaviors as characteristic of
A 37-year-old married African-American female with bipolar dis- KLS and he was distinctly able to distinguish between SRE and ab-
order type I, rapid cycling, panic disorder and obsessive-compulsive normal eating behaviors due to KLS. Metabolic testing revealed fasting
disorder who was treated with quetiapine 300 mg QHS, lamotrigine 100 glucose to be in normal range, however, lipid panel showed moderate
mg daily, and clonazepam 1 mg QHS. Her medical and neurological elevation in LDL. Aripiprazole was stopped and he was placed on
history was negative, and she had no prior history of eating disorders. Wellbutrin XL 150 mg daily in addition to sertraline. Complete resolu-
She experienced SW with SRE after initiation of quetiapine but due to tion of SRE episodes was noted with cessation of aripiprazole treatment
sporadic nature of these events, she initially did not report these and symptoms never recurred upon long term outpatient follow-up.
symptoms. When the dose of quetiapine was subsequently increased to
300 mg daily, she reported significant increase in SW with SRE. She was Case 5:
incognizant of these episodes, which she found most troublesome. She
reported an increase in her weight due to SRE. Her metabolic profile A 41-year-old married Caucasian male, receiving rehabilitation for
including HbA1c and lipid profile were within normal limits. Sleep post-concussion syndrome, was referred to sleep clinic for complaints of
history was suggestive of low-risk for obstructive sleep apnea (OSA), insomnia. He was on venlafaxine 225 mg for headaches and anxiety at
absence of restless legs syndrome and prior parasomnia and eating time of initial presentation. Previous failed trials include sertraline,
disorders. Quetiapine was subsequently discontinued due to intolerable clonazepam, amantadine, amitriptyline, prazosin and zolpidem for
side effects such as parasomnias and significant weight gain. Complete anxiety, insomnia and PTSD symptoms. He was started on low dose of
resolution of SW with SRE was noted upon discontinuation of quetia- trazodone, which was discontinued due to worsening headaches at a
pine and initiation of risperidone 2 mg QHS for mood stabilization. higher dose of 75 mg. After he was started on quetiapine 50 mg QHS for
management of insomnia, he began to experience symptoms of sleep-
Case 3: walking. He had approximately six episodes of sleepwalking before he
decided to come off of this medication; after discontinuation, these
A 19-year-old single Caucasian male, with a medical history of type- adverse effects quickly resolved. No history suggestive of OSA and
1 diabetes mellitus, unsuccessful trials with multiple antidepressants for restless legs was evident. No prior history of parasomnia behaviors was
a mood disorder, presented to sleep clinic with complaints of initial reported. He was resumed on trazodone 50 mg QHS and referred to
insomnia and daytime hypersomnia. His medication regimen included trauma focused- cognitive behavioral therapy for PTSD as nightmares
aripriprazole 10 mg QHS and trazodone 100 mg QHS at the time of related to head injury were interfering with sleep maintenance.
initial presentation. He was experiencing episodes of sleep related
eating approximately two years. Psychiatric assessment revealed cyclic 4. Discussion
mood patterns including depression and week long periods of hypo-
mania. He was diagnosed with bipolar disorder, rapid cycling, and ar- The incidence of SW, with or without SRE, in context of atypical
ipiprazole was switched to lithium. The patient had significant im- antipsychotic use seemed to be anecdotal in nature initially; however,
provement in insomnia and sleep related eating completely resolved the growing literature on this topic merits further scientific inquiry. The
upon discontinuation of aripriprazole. Patient also had complaints of aim of our study was to review the literature to identify the risk factors
restless legs during nighttime, and some gasping episodes. However, and clinical correlates that may be associated with causation of SW,
sleep workup was unremarkable; negative for sleep apnea on with or without SRE, in patients taking atypical antipsychotic medica-
tions. This is particularly important and timely as these medications are

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Table 2
Summary of clinical features and outcomes of sleep walking (SW), with or without sleep-related eating (SRE), associated with use of atypical antipsychotics of
published cases from literature (n = 23).
Study N Age (years) Gender Diagnosis Antipsychotic Clinical Characteristics Treatment Remission

Das et al., 2016 1 28 Male Schizoaffective Disorder Ziprasidone 40 mg SW and SRE Ziprasidone 80 mg QHS Yes; in 2 months
QAM Parasomnia switched to quetiapine 100
Ziprasidone 80 mg Amnesia of SW episode mg QHS
QHS
Das et al., 2017 1 26 Male Schizophrenia Olanzapine 15 mg SW and SRE Olanzapine switched to Yes; in 2 months
daily Parasomnia aripiprazole
Amnesia of SW episode
Episode lasts for
10–20 min before 12 am
Dagan et al., 2013 3 52 Male Bipolar Disorder type-I Asenapine 15 mg SW and SRE Asenapine discontinued Yes; immediately
daily Parasomnia
Amnesia of SW episode
51 Male Bipolar disorder type- I Quetiapine 600 mg SW, parasomnia Quetiapine discontinued Yes; immediately
daily
41 Male Bipolar disorder type- I Olanzapine 15 mg SW, parasomnia Olanzapine discontinued Yes; immediately
daily
Tamanna et al. 2012 2 51 Male MDD with Sleep Apnea Quetiapine 150 mg SW and SRE Quetiapine discontinued. Yes; in three
QHS Parasomnia CPAP started for sleep apnea. months
Amnesia of SW episode
2–3 SW episodes at night
per week
50 Female MDD with Sleep Apnea Quetiapine 200 mg SW and SRE Quetiapine discontinued Yes; in three
QHS Amnesia of SW episode CPAP started for sleep apnea months
2–3 SW episodes at night
per week
Raja et al. 2013 4 59 Female Bipolar Disorder type-II Quetiapine 50 mg SW Quetiapine tapered to 25 mg Yes; immediately
with insomnia QHS Akathisia QHS
Confusion
Recall was vague
37 Male Bipolar Disorder type-II Quetiapine 50 mg SW and SRE Quetiapine discontinued Yes; immediately
with QHS Confusion
insomnia
53 Male Bipolar Disorder type-II Quetiapine 300 mg SW No medication changes Yes; in six months
daily Parasomnia
Confusion
75 Female MDD with insomnia Quetiapine 25 mg Sleep talking No medication changes No
QHS Parasomnia
Sleep arousal
Confusion
Faridhosseini et al. 1 42 Male Schizophrenia Olanzapine 20 mg SW Olanzapine tapered to 15 mg Yes, in six months
2012 daily Sleep talking daily.
Parasomnia Started Clonazepam 1 mg QHS
Amnesia of SW episode
Heathman et al. 1 48 Female Bipolar Disorder type- I Quetiapine SW and SRE Quetiapine discontinued Yes; immediately
2014 100 mg QHS
Chiu YH, et al. 2008 1 52 Male Bipolar Disorder type- II Olanzapine 20 mg SW Olanzapine discontinued Yes; immediately
daily Parasomnia
Episode within 2–3 h of
sleep
Amnesia of SW episode
Hafeez et al. 2007 2 52 Male Schizoaffective Disorder Quetiapine 200 mg SW and SRE Quetiapine tapered to 25 mg Yes; in eight
QHS Leg jerks QHS months
Parasomnia Started Clonazepam 1 mg QHS
Amnesia of SW episode
18 Male ADHD with PDD Quetiapine 400 mg Nightmares with Quetiapine tapered to 150 mg Yes, in one year
QHS shouting QHS
Parasomnia
Seeman et al. 2011 1 50 Female Schizophrenia Quetiapine 900 mg SW and SRE Quetiapine 900 mg QHS Yes; immediately
QHS Parasomnia continued with Clonazepam 2
Amnesia of SW episode mg QHS
Kolivakis et al. 2001 2 63 Male Schizophrenia Olanzapine 20 mg SW Olanzapine switched to Yes; in six months
daily Risperidone
62 Female Schizophrenia Olanzapine 20 mg SW Olanzapine switched to Yes; in three
QHS Risperidone months
Lu et al. 2004 1 68 Male Psychosis disorder Risperidone 2 mg SW and SRE Risperidone tapered to 1 mg Yes; immediately
daily Parasomnia daily
Amnesia of SW episode
Paquet et al. 2004 1 52 Male Bipolar disorder type- I Olanzapine 20 mg SW and SRE Olanzapine discontinued Yes; immediately
with MDD daily Parasomnia
Amnesia of SW episode
Gunes et al. 2016 1 16 Female Conduct disorder Risperidone 1 mg SW and SRE 2–3 times Risperidone tapered to 0.5 mg Yes; in one month
daily per week daily with no improvement.
Parasomnia Risperidone discontinued
(continued on next page)

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A. Chopra, et al.
Table 2 (continued)
Study N Age (years) Gender Diagnosis
Najmi et al. 2020 1 38 Male Schizophrenia
Abbreviations: SW: Sleep Walking; SRE: Sleep-related eating; CPAP: Continuous Positive Airway Pressure; MDD: Major Depressive Disorder; ADHD: Attention-deficit/
hyperactivity disorder; PDD: Pervasive Developmental Disorder.
increasingly prescribed for both FDA-approved and off-label indications
for a range of psychiatric and medical conditions. SW and SRE are
complex sleep-related behaviors that can lead to significant risks in-
cluding patient safety and cause side effects such as weight gain and
metabolic dysfunction.
Adult-onset SW is a relatively infrequent phenomenon; however, it
has been reported in higher proportion in psychiatric populations.
Additionally, adult-onset sleepwalkers have been noted to have higher
peak frequency of SW behaviors and a high comorbidity with sleep-
related eating features [58]. Komada and colleagues reported compared
clinical features of drug-induced SRE higher mean age of onset and
significantly lower rate of history of sleepwalking in patients taking
sedative drugs (benzodiazepines/benzodiazepine receptor agonists), as
compared to those with primary SRE (non-drug induced) [59]. Our data
resembles these prior findings in terms of higher mean age of onset of
SW/SRE behaviors and lower history of SW in patients with SW/SRE
associated with atypical antipsychotic use. Primary SRE has been de-
scribed mainly in females by Schenck and Mahowald [60]; however,
our preliminary findings suggest that SRE associated with atypical an-
tipsychotics is reportedly more common in males.
SW is an arousal disorder occurring in NREM sleep characterized by
complex behaviors such as leaving the bed and walking along with
memory impairment of the event. The underlying mechanisms for this
phenomenon remain unclear, although, the disordered arousal has been
largely attributed to an inability of the brain to fully awaken from slow-
wave sleep (SWS) followed by the motor automatisms characteristic of
SW [61]. Based on a neuroimaging study, as compared to healthy
subjects, reduction in regional cerebral perfusion frontal and parietal
areas has been reported in sleep walkers; and these regions have been
previously associated with slow wave sleep (SWS) generation and SW
episode occurrence [62]. Polysomnography (PSG) findings in patients
with SRE show a correlation with sleep-walking with states of arousal
leading to occurrence of SRE, mostly in SWS, in the affected individuals
[63].
Quetiapine and other atypical antipsychotics block 5-hydro-
xytryptamine-2A (5HT-2A) and dopamine receptors subtype 2 (D2) and
increase cortical dopamine release by 5HT-1A agonism [25]. Among all
serotonergic receptors, 5HT-2A receptors in the dorsal raphe nucleus
regulate frequency and amplitude of slow wave sleep (SWS) [64]. These
serotonergic neurons maintain the hypotonia of the antigravity muscles
during SWS. Normally, maintenance of SWS is synchronized with motor
inhibition such that there is no motor activity without an arousal [44].
A blockade of serotonergic input leads to withdrawal of motor inhibi-
tion, allowing the person to walk and perform other motor activities
[44]. Therefore, it is plausible that atypical antipsychotics, due to
blockade of 5-HT serotonergic receptors with resultant alteration of
central serotonin activity, can lead to SW without a complete arousal
[44].
SW aggravated by atypical antipsychotics may be explained by the
above hypothesis [44]; however, the mechanisms underlying its
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General Hospital Psychiatry 65 (2020) 74–81
Antipsychotic Clinical Characteristics Treatment Remission
Weight gain of 6.5 kg in
one month
Amnesia of SW episode
Risperidone 3 mg SW, parasomnia Tapered risperidone 2 mg Yes; in three
daily Amnesia of SW episode daily months
Started clonazepam 0.5 mg at
nigh time
association with SRE are still unclear. This may be related to atypical
antipsychotics effect on 5HT-2C receptor which regulates mood, an-
xiety, feeding, and reproductive behavior [65]. So, 5HT-2C antagonism
by atypical antipsychotics increases appetite and food intake and leads
to weight gain [66]. There is a significant association between elevated
leptin level and weight gain in patients on antipsychotics [67]. Altered
serotonin activity, 5-HT2C receptor blockade with resultant enhance-
ment of slow wave sleep (SWS) or NREM stage N3 sleep, increase in
appetite, 5-HT2A blockade with resultant withdrawal of motor inhibi-
tion during SWS, and induction of partial arousals during SWS resulting
from atypical antipsychotic medication therapy have been cited as
underlying mechanisms of SRE [25].
Upon review of the receptor profiles and mechanism of action of
various atypical antipsychotics, it is evident that quetiapine, olanza-
pine, risperidone, ziprasidone and asenapine have a high degree of
histamine (H1) receptor affinity. H1 receptor blockade can result in
sedation, increased appetite and increased PLMs (resulting in partial
arousals during NREM sleep) [25]. Quetiapine and olanzapine are
among the most potent H1 antagonists in the category of atypical an-
tipsychotics. It is plausible that H1 antagonism may also offer the ex-
planation for quetiapine and olanzapine being the most commonly
implicated among atypical antipsychotics in causation of SW and SRE.
Atypical antipsychotics are also known to precipitate restless legs syn-
drome (RLS) [68] which may further predispose patients taking these
medications to SW and SRE. RLS is a condition that needs particular
attention in the context of both SW and SRE as motor restlessness un-
derlying RLS may compel an individual to ambulate during sleep and
engage in unconscious or partly conscious eating [69,70]. Furthermore,
frequent periodic limb movements of sleep (PLMS) which are seen in
80% to 90% of patients with RLS can cause partial arousals during SWS
and result in SW with or without SRE. Dopaminergic blockade by aty-
pical antipsychotics has been conceptualized as the likely mechanism to
cause RLS. Although not well studied, H1 receptor blockade by atypical
antipsychotics may be another relevant mechanism to consider for RLS
causation/exacerbation as antihistaminic medications such as di-
phenhydramine have been implicated in causation/exacerbation of RLS
symptoms [71].
SW associated with atypical antipsychotics may respond to the
discontinuation of the offending agent. SW with SRE related to other
primary sleep disorders benefit most from the treatment of the under-
lying primary sleep disorder. For example, RLS-related SW with SRE is
best treated with dopamine agonists such as pramipexole [72]. For
patients with comorbid OSA, optimal treatment of OSA symptoms can
be effective in resolving SRE [44]. SW with SRE may respond to
treatment with low-dose benzodiazepines, such as clonazepam [73].
Treatment of idiopathic SRE includes SSRIs, topiramate and benzodia-
zepines such as clonazepam [74]. Topiramate has also been found to be
effective in patients with SRE, with one study demonstrating im-
provement or resolution of sleep related eating [73].
The main limitation of our study is inclusion of just anecdotal
79
A. Chopra, et al.
literature focusing on association of SW, with or without SRE, and
atypical antipsychotic use in psychiatric patients. The single case re-
ports or case series are useful for providing hypotheses about behavior
and opportunities for clinical innovation, permitting intensive study of
rare ADRs, challenging theoretical assumptions and coming up with
new putative mechanisms but they do not necessarily demonstrate
causation [75]. The long term follow-up of the majority of the un-
published cases in our clinics does support the fact that the episodes of
SW/SRE were associated with atypical antipsychotic use as these
parasomnia behaviors did not recur after appropriate clinical manage-
ment as detailed in this paper. However, the role of psychotropic
polypharmacy cannot be ruled out completely in causation of such
behaviors in psychiatric patients taking complex psychotropic regi-
mens.
Our study does have important clinical implications as it highlights
the need for clinicians to consider SW and SRE as potential ADRs of
atypical antipsychotic therapy, particularly in the context of weight
gain from use of this class of medications. Patient education along with
early recognition and management of SW with SRE can prevent harmful
consequences such as injury, weight gain and metabolic dysfunction.
The mechanisms underlying SW and SRE in context of atypical anti-
psychotic use are poorly understood. The etiology of this rare phe-
nomenon is likely multifactorial and further research studies are war-
ranted to determine patient risk factors, underlying neurobiological
mechanisms and optimal treatment strategies.
5. Conclusions
SW with or without SRE can be potentially disabling side effects
associated with atypical antipsychotic use. Prompt recognition of these
adverse side effects can prevent injury and metabolic side effects such
as weight gain and metabolic dysfunction. Sleep evaluation is helpful to
rule out comorbid primary sleep disorders including obstructive sleep
apnea and restless legs syndrome. Discontinuation of the causative
atypical antipsychotic medication often leads to complete resolution of
parasomnia behaviors. More research is warranted to elucidate the
mechanisms underlying SW and SRE associated with atypical anti-
psychotic use and to develop prevention and treatment strategies.
Acknowledgments
None.
Compliance with ethical standards
Our review was conducted on published studies and did not contain
patient identifiable information. So, our study does not require an in-
stitutional review board (IRB) approval.
Disclosures
On behalf of all authors, the corresponding author states that there
is no conflict of interest.
Funding sources
The authors report no external funding source for this study.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.genhosppsych.2020.05.014.
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