Received: 18 March 2021

| Accepted: 21 March 2021

DOI: 10.1111/acps.13300

SYST E M AT I C R E V I E W

Narcolepsy and psychosis: A systematic review

Cyril Hanin1,2 | Isabelle Arnulf3 | Jean-­Baptiste Maranci3 | Michel Lecendreux4 |

Douglas F. Levinson5 | David Cohen1,2,6 | Claudine Laurent-­Levinson1,2

1
Centre de Référence des Maladies Rares
à Expression Psychiatrique, Department Abstract
of Child and Adolescent Psychiatry, Objective: Narcolepsy is a rare sleep disorder in which psychotic-­like symptoms can
Pitié-­Salpêtrière University Hospital,
present diagnostic and therapeutic challenges. We aimed to review the association be-
Assistance Publique-­Hôpitaux de Paris,
Sorbonne University, Paris, France tween, and medical management of, narcolepsy and psychosis in children and adults.
2
Faculté de Médecine Sorbonne Methods: We reviewed the full text of 100 papers from 187 identified by a PubMed
Université, Groupe de Recherche search on narcolepsy plus any of these keywords: psychosis, schizophrenia, delusion,
Clinique n°15 -­Troubles Psychiatriques
et Développement (PSYDEV, Paris, side effects, safety, and bipolar disorder.
France Results: Three relevant groups are described. (i) In typical narcolepsy, psychotic-­like
3
National Reference Center for Rare symptoms include predominantly visual hallucinations at the sleep-­wake transition
Hypersomnias, Pitié-­Salpêtrière
(experienced as “not real”) and dissociation because of intrusion of rapid eye move-
University Hospital, Assistance Publique-­
Hôpitaux de Paris, Sorbonne University, ment (REM) sleep phenomena into wakefulness. (ii) Atypical patients (“the psychotic
Paris, France form of narcolepsy”) experience more severe and vivid, apparently REM-­related hal-
4
Pediatric Sleep Center and National lucinations or dream/reality confusions, which patients may rationalize in a delusion-­
Reference Center for Narcolepsy and
Hypersomnia, Robert Debré University like way. (iii) Some patients have a comorbid schizophrenia spectrum disorder with
Hospital, Assistance Publique-­Hôpitaux psychotic symptoms unrelated to sleep. Psychostimulants used to treat narcolepsy
de Paris, Paris VII University, Paris,
may trigger psychotic symptoms in all three groups. We analyzed 58 published cases
France
5 from groups 2 and 3 (n = 17 and 41). Features that were reported significantly more
Department of Psychiatry and
Behavioral Sciences, Stanford University, frequently in atypical patients include visual and multimodal hallucinations, sexual
Stanford, CA, USA and mystical delusions, and false memories. Dual diagnosis patients had more disor-
6
CNRS UMR 7222, Institute for ganized symptoms and earlier onset of narcolepsy.
Intelligent Systems and Robotics,
Sorbonne University, Paris, France Conclusion: Epidemiological studies tentatively suggest a possible association be-
tween narcolepsy and schizophrenia only for very early-­onset cases, which could
Correspondence
be related to the partially overlapping neurodevelopmental changes observed in
Claudine Laurent-­Levinson, Département
de Psychiatrie de l'Enfant et de these disorders. We propose a clinical algorithm for the management of cases with
l'Adolescent, Hôpitaux Universitaires psychotic-­like or psychotic features.
Pitié Salpêtrière, Bâtiment Georges
Heuyer, 47-­83 Boulevard de l'Hôpital, KEYWORDS
Paris 75013, France.
delusion, hallucination, narcolepsy, psychosis, schizophrenia, side effects
Email: claudine.laurent-levinson@
sorbonne-universite.fr
Summations
• Besides substance-­induced psychotic events, there are three main groups of patients
with narcolepsy and psychotic-­like symptoms. Despite overlapping symptoms,

This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial-­NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made.
© 2021 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.

28 | 
wileyonlinelibrary.com/journal/acps Acta Psychiatr Scand. 2021;144:28–41.
HANIN et al.   
| 29

clinical cues may help differentiate between patients with narcolepsy and atypical-­
severe psychotic-­like symptoms and patients with a dual diagnosis of narcolepsy
and a psychotic disorder.
• Early-­onset narcolepsy or psychosis could be associated with a higher risk of co-­
occurrence of both disorders.
• Modafinil and pitolisant are apparently the wake-­promoting drugs with the least
propensity to induce psychotic symptoms in patients with narcolepsy.

Limitations
• The small number of cohort studies and the rarity of narcolepsy comorbid with
schizophrenia prevent us from conducting a formal meta-­analysis.
• The systematic review draws primarily on case reports and small cohort studies
using diverse research designs to explore the overlap between narcolepsy and psy-
chosis. Larger, well-­designed epidemiological and treatment studies (particularly
in children) will be needed to advance our understanding in this domain.

1 | IN T RO D U C T IO N Narcolepsy is typically caused by polygenic risk factors and

environmental factors.10 HLA allele DQB1*06:02 is carried
Narcolepsy is a chronic central disorder of hypersomno- by almost all NT1 patients (except for familial cases),1,11 and
lence, affecting 1:5000 to 1:3300 people.1 Subtypes include 42% of NT2 patients, vs. ~20% in the population.12 When cat-
Narcolepsy Type 1 (NT1, with cataplexy and/or hypocretin aplexy is unclear, genotyping may be used as a screening test
deficiency), and Narcolepsy Type 2 (NT2, without cataplexy before proposing lumbar puncture to assay CSF hypocretin-­1.
or hypocretin deficiency; 15–­25% of cases). Age at onset has Substantial evidence suggests that in most NT1 and some NT2
two peaks, at ages 15 and 35. The sex ratio is ~1.2,3 Sleep-­ cases, HLA, and other risk loci13 produce susceptibility to an
related daytime hallucinations are reported in 45–­87% of NT1 autoimmune response triggered by environmental factors (eg,
patients and 28% of NT2 patients.4 Dissociation or delusions streptococcus or H1N1 influenza infection or vaccination), re-
are less common. These symptoms may suggest a comorbid sulting in the destruction of >90% of hypocretin-­1-­expressing
or primary diagnosis of psychotic disorder,5-­8 generating di- neurons in NT1.14,15 Hypocretin-­1 stimulates wake-­inducing
agnostic, and therapeutic dilemmas. Here, we review the lit- monoamines, activating arousal systems which consolidate
erature on the association between narcolepsy and psychosis, wakefulness into a single daily episode. NT2 has been consid-
propose a framework for differential diagnosis, and suggest ered a prodromal/incomplete form of NT1,16,17 or a syndrome
an approach to pharmacotherapy in patients with psychotic-­ resembling idiopathic hypersomnia.18
like or psychotic symptoms. Narcolepsy impacts school and work functioning, driving,
By current criteria,2 the diagnosis of NT1 and NT2 re- interpersonal relationships, and quality of life.19 Typically, brief
quires excessive daytime sleepiness daily for 3 months. NT1 sleep attacks are followed by several hours of normal wakeful-
then requires either: ness. Total daily sleep time is usually normal but may be pro-
longed in children (rarely in adults) or around disease onset.20
(i) low CSF hypocretin-­1 (≤110 pg/mL or 1/3 of mean val- Cataplexy consists of seconds to minutes of sudden, bilateral loss
ues by a standard assay), or of muscle tone, with maintained consciousness, usually triggered
(ii) both cataplexy and two sleep study findings: mean by positive emotions.21 Weight gain is frequent at onset. Other
sleep latency ≤8 minutes; and ≥2 sleep-­onset rapid eye symptoms include sleep-­related hallucinations,1 sleep paralysis,
movement (REM) periods (SOREMPs) (either both on dyssomnia, nightmares, REM sleep behavior disorder, atypical
a Mean Sleep Latency Test [MSLT], or one on MSLT eating disorders, attention problems, and depression. Atypical
and one within 15 minutes of sleep onset on nocturnal features in childhood or at onset include general weakness in-
polysomnogram). stead of cataplexy, avoidance behavior,22 hyperactivity,23 com-
plex movement disorders, and loss of orofacial muscle tone.24
NT2 requires the above sleep study findings, without Psychotic disorders are characterized by delusions and
cataplexy or low CSF hypocretin-­1 (or untested hypocre- hallucinations. Delusions are firm beliefs that differ from con-
tin). Other causes of daytime sleepiness should be ruled out victions based on false or incomplete information, confabula-
(Table 1), especially in children. (See Ref.9 for discussion of tion, or dogma. True hallucinations are sensory experiences
diagnostic complexities.) in the absence of an external stimulus, perceived as “real.”
30
|    HANIN et al.

TABLE 1 Evaluation of medical causes of secondary narcolepsy

Type Specific diagnoses Evaluation

Neoplasm Brain tumor (hypothalamus: eg, craniopharyngioma); lymphocytic or Brain neuroimaging, complete blood count
non-­lymphocytic acute leukemia
Inflammatory Guillain Barré syndrome; acute encephalomyelitis; multiple sclerosis; Chronology, blood and/or CSF testing for
neurolupus; anti-­NMDA receptor anti-­Ma2 and anti-­aquaporin-­4 antibodies or inflammatory markers
encephalitis; neurosarcoidosis; post H1N1 vaccination or infection
narcolepsy
Infectious Infectious encephalitis; meningoencephalitis Lumbar puncture
Traumatic Head trauma; Diffuse axonal injury Chronology, neuroimaging
Iatrogenic Cerebral irradiation Chronology
Malformation Holoprosencephaly; callosal agenesis Imaging during pregnancy
Genetic Myotonic dystrophy, Prader Willi syndrome; Coffin-­Lowry syndrome; Neurological examination, DNA testing for
Moebius syndrome; Hereditary Sensory and Autonomic Neuropathy mutations
Type 1E (HSAN1E); Autosomal dominant cerebellar ataxia-­deafness-­
narcolepsy syndrome (ADCA-­DN); mutation of the preprohypocretin
Metabolic Niemann-­Pick type C; Rapid-­onset obesity, hypoventilation, Filipin staining test; clinical, hormonal
hypothalamic dysfunction and autonomic dysfunction (ROHHAD) explorations, methylation analysis,
cytogenetic and molecular analysis
Neurodegenerative Parkinson's disease Neurological examination (parkinsonism),
DAT scan
The table summarizes the known medical causes of secondary narcolepsy and the typical clinical/laboratory evaluations for each type. Consideration should be given
on a case-­by-­case basis to the possibility of any of these diagnoses and the need for evaluation, particularly in children presenting with possible narcolepsy.
CSF, cerebrospinal fluid; DAT, dopamine transporter positron emission tomography scan; NMDA, anti-­N-­methyl-­D-­aspartate.

They differ from dreaming because they occur during wake- narcolepsy cases with psychosis-­like symptoms vs. those
fulness, and from illusions (which are misperceptions of real with comorbid psychotic diagnoses.
stimuli). Here, we use “psychotic-­like symptoms” to describe
experiences of narcolepsy patients which are not classically
“psychotic”: (i) “hallucinations” (usually visual) occurring at 1.1 | Aims of the study
the sleep/wake boundary (hypnagogic hallucinations at sleep
onset or hypnopompic at sleep offset), rapidly recognized by The objectives are to (i) facilitate correct diagnosis by defin-
the patient as “not real”; (ii) delusion-­like explanations of- ing subgroups of cases with these features; and (ii) provide
fered by some patients for their vivid hallucination-­like expe- guidance for clinical management, including the safety and
riences; (iii) dissociation or derealization. Rarely, narcolepsy use of psychostimulants, and the indications and choice of
patients also have hallucinations when awake, for example, antipsychotic drug treatments.
while driving.4,25 Psychotic-­like symptoms are sometimes
mistaken for psychotic symptoms of schizophrenia,26-­28 for
example, in an adolescent with sleep disturbances and “vi- 2 | M ATERIAL S AND M ETHOD S
sions,” thus delaying appropriate narcolepsy therapy. But
some narcolepsy patients do experience classical psychotic 2.1 | Medline search
symptoms, apparently because of a comorbid psychotic dis-
order or side effects of stimulants. We searched pubmed.ncbi.nlm.nih.gov/on 27 April 2020 for
We report here on a systematic review of the literature narcolepsy[MeSH Major Topic] AND (psychosis OR schiz-
on psychotic and psychotic-­like symptoms in adults and chil- ophrenia OR delusion OR bipolar disorder OR side effect
dren with narcolepsy, a topic last fully reviewed in 2003.29 OR safety). We omitted “hallucinations” because, as a core
Less comprehensive discussions have appeared recently narcolepsy symptom, it yielded hundreds of largely non-­
in case reports or cohort studies.4,30-­32 We reviewed cohort relevant results. We examined articles in English or French
reports, reports of cases with narcolepsy and psychotic fea- since 1950, excluding those that were not about narcolepsy in
tures, and papers relevant to the treatment of cases with these humans, or did not address psychotic-­like or psychotic symp-
features (including drug-­induced psychosis). We also report toms. We selected additional relevant papers from the refer-
a statistical analysis of clinical differences between reported ences in papers reviewed in full text.
HANIN et al.   
| 31

2.2 | Quantitative analysis 3.3 | Psychotic-­like symptoms in

typical narcolepsy
The cohort reports were not amenable to meta-­analysis be-
cause of their variable study designs and outcome measures. Hallucinations are described in 20%34 to 80%25 of NT1, and
We performed quantitative analyses (using SPSS 23.0) com- in 28.2% of NT2 patients, when falling asleep (55% of those
paring 17 reported cases with psychotic-­like symptoms at- with hallucinations), waking up (3%), or both (42%), with
tributed to narcolepsy, and 41 diagnosed by the authors as 18% reporting daytime hallucinations while wide awake.4
narcolepsy plus a psychotic disorder. Each case was reviewed They increase when lying supine, which is not observed in
(by C.H.) with a checklist of clinical features (Table S3), psychotic disorders.
rating features “present” (mentioned/strongly suggested) or An observational study found that hallucinations (predomi-
“absent” (denied/not described). For ages at onset of sleep nantly non-­verbal) were as frequent in 28 NT1 patients without
and psychotic symptoms, normality of the distribution was psychotic diagnoses as in 21 schizophrenia patients.8 All sen-
inspected graphically and confirmed (Kolmogorov–­Smirnov sorial modalities were observed in both groups. Hallucinations
test), equality of variance confirmed (Levene's test), and the were predominantly sleep-­related in narcolepsy (75% vs. 4.8%,
groups were contrasted with Student's t tests. For dichoto- p < 0.0001) and multimodal (predominantly auditory verbal)
mous variables, χ2 tests were performed. in schizophrenia (76% vs. 3.6%, p < 0.0001). The groups had
similar proportions with visual hallucinations (shadows, mon-
sters, demons, or animals [zoopsia]).
3 | R E S U LTS Fortuyn et al. interviewed 60 patients with NT1, 102
with schizophrenia, and 120 healthy controls using the
3.1 | Literature search Schedules for Clinical Assessment in Neuropsychiatry 2.1.25
More NT1 patients than controls (83% vs. 2%, p < 0.001)
Systematic PubMed search identified 187 articles. Based on reported hallucination-­like experiences that are not consid-
abstracts, we excluded 44 articles that were not about narco- ered as definitely “psychotic” in psychiatric studies (pres-
lepsy and psychotic symptoms, 4 with inaccessible full text, ence of unseen-­unheard visitors, falling/flying sensations,
12 not in English or French; 9 in a non-­narcolepsy cohort, out-­of-­
body experiences, altered perception of time, dé-
15 about non-­relevant outcomes, and 1 letter to the editor jà-­vu, derealization), but this percentage was not different
without additional data/hypotheses. We reviewed the full in schizophrenia patients (70%). Compared with schizo-
text of the remaining 100 articles, including 26 reviews, 27 phrenia, narcolepsy patients more often reported visual hal-
case reports, 23 cohort studies, 20 clinical trials, and 4 meta-­ lucinations (15% for simple and 38% for complex images),
analyses (of narcolepsy treatment trials) (Figure 1; Table S2 non-­ verbal auditory hallucinations (footsteps, slamming/
lists citations for each article type). creaking of doors, animal sounds –­50% vs. 15%), kines-
thetic and tactile hallucinations (heat, pain, crawling under
the skin or in the genital area, 48%) and less frequently ol-
3.2 | Systematic review: Qualitative results factory hallucinations. Verbal hallucinations were less fre-
quent (18 vs. 45%). NT1 and schizophrenia patients equally
Since the first 13 cases published in 1884,33 case and cohort experienced multimodal hallucinations. NT1 patients had
reports have discussed the relationship between narcolepsy more fantastic delusions and false memories than controls.
and psychotic symptoms. Authors generally described three Rarely, NT1 patients reported grandiose (2%), fantastic
groups:27 (i) hallucinations as part of the narcolepsy process, (5%), or persecutory delusions (2%).
clearly different from psychosis; (ii) patients with narcolepsy Leu-­Semenescu et al4 studied the characteristics of hal-
and a comorbid, independent psychotic disorder (schizophrenia, lucinations in 100 narcolepsy patients (54 NT1, 46 NT2)
schizoaffective disorder, or more rarely a mood disorder with and 100 Parkinson's disease patients. Among the 45% of
psychotic features); and (iii) psychotic symptoms provoked by narcolepsy patients with hallucinations (59% in NT1, 28%
psychostimulants treatment. Based on a larger number of re- in NT2), 24% had auditory (changing voices, footsteps)
ports, we suggest a modified grouping approach. Group 1 is typ- or visual illusions (including dyschromatopsia); 15% had
ical narcolepsy. Group 2 (sometimes called “the psychotic form unformed hallucinations (presence of a person; a passing
of narcolepsy”) comprises more severe and atypical psychotic-­ animal); 95% had formed, visual hallucinations (human,
like symptoms thought to be driven by the same mechanisms as animal, or fantastic figures such as ghosts, vampires; com-
in Group 1. Group 3 patients probably have two independent di- plete or distorted, with vivid colors) with more than half of
agnoses, although an etiological relationship remains possible, these reporting kinetic hallucinations (lateral movement in
especially in childhood-­onset cases. Psychostimulant-­induced bed as if on a slippery surface, falling, being sucked into the
psychosis can occur in each group, particularly at high dosages. bed, flying, levitating, out-­of-­body experiences). One-­third
32
|    HANIN et al.

1. Records identified through the 2. Records identified from reference

planned Medline search lists and supplementary searches
Identification

(n = 187) (n = 64)

3. Records after duplicates removed

(n = 187 + 48 = 235) (no duplicates found)
(

Records excluded based on

Screening

Abstract (n = 44)
4. Records screened Not relevant to the review topic
(n = 235)

Records excluded based on full

text (n = 43) - Not in English or
5. Articles Reviewed French (n=12); not population of
Eligibility

(Full Text) interest (n=11); not outcome of

(n = 191) interest (n=15); letter to editor
(n=1); full text unavailable: (n=4)

6. Included Articles from 7. Included Articles from

Medline search (n = 100) other sources (n = 64)
case report (n=27); cohort
study (n=23); reviews (n=26);
Included

clinical trial (n=20); meta

analysis (n=4)
8. Studies included in
quantitative synthesis
(analysis of case reports)
(n = 27)

F I G U R E 1 Flow chart of review process. The systematic literature search was conducted on 27 April 2020, using the following Search
Builder: narcolepsy[MeSH Major Topic] AND (psychosis OR schizophrenia OR delusion OR bipolar disorder OR safety OR side effect, yielding
187 records. An additional 48 records were identified via reference lists from the 187 selected records, or from supplementary Medline searches
(15 papers on mechanisms or adverse effects of drugs used to treat narcolepsy; 12 with relevance to the discussion of the relationship between
narcolepsy and psychosis; and 21 with more relevance to discussion of narcolepsy or to psychosis but not their relationship). None of the additional
records were cohort or case reports. We list as excluded records those that were identified by systematic search but not selected as eligible for
inclusion in the qualitative or quantitative analyses for the reasons cited

of patients reported tactile hallucinations (air blowing on 3.4 | Narcolepsy with atypical psychotic-­
oneself, being touched, burned, bitten, trampled, stran- like symptoms
gled, or sexually abused). Auditory hallucinations could be
non-­verbal (44%, doors opening, alarm ringing, footsteps, The term “psychotic form of narcolepsy” has been suggested
plates breaking) or verbal (33%, being called by name, in patients with psychotic-­like features resembling more se-
hearing conversation fragments). Hallucinations were vere forms of typical narcolepsy symptoms, sometimes lead-
usually multimodal (98%, primarily NT1) and sometimes ing to a misdiagnosis of schizophrenia.27,36 They had vividly
holistic (42%). Hallucinations were associated with sleep realistic and emotional dreams (8% of narcolepsy patients
paralysis and REM sleep behavior disorder but not with in Leu-­Semenescu et al4) and hallucinations (which can be
cataplexy, HLA positivity, or sleepiness, consistent with nightly). Episodes of dream-­reality confusion were reported
other studies.35 by 83% of 46 NT1 patients vs. 15% of 41 healthy controls
HANIN et al.   
| 33

(p < 0.0001),37 lasting up to several weeks and associated More rarely,38 narcolepsy emerges as a possible primary
with severe, frequent cataplexy, and treatment-­ resistance. diagnosis in “schizophrenia” patients in whom antipsychotics
These symptoms may be worsened by antipsychotic drugs26,38 were poorly tolerated or overly sedating (as discussed further
and reduced by psychostimulants.39 below). This is a challenging clinical situation,10 because an-
Some patients explain these experiences with what appear tipsychotic medications interfere with polysomnography and
to be secondary “delusional” thoughts,38 with fantastic, per- MSLT by reducing REM sleep time and daytime mean sleep
secutory, sexual abuse, mystical, megalomaniacal, referen- onset latency. By contrast, antipsychotic withdrawal can pro-
tial, or paranormal themes. Several case studies mentioned duce REM sleep rebound and a false positive narcolepsy di-
medico-­legal consequences after sincere but possibly false agnosis.10 Undertaking prolonged antipsychotic washout is a
rape allegations.40,41 Several hypotheses have been proposed. difficult decision. An alternative is to measure CSF hypocre-
Fortuyn et al25 noted that some narcolepsy patients (other- tin-­1 levels, which remain in the normal range during anti-
wise mentally healthy) had difficulty in differentiating hal- psychotic treatment.113
lucinations from reality. Impaired insight was more common
in narcolepsy than in Parkinson's disease.4 Memory deficits
have been reported (false beliefs based on false memories).37 3.6 | Is there an association between
Narcolepsy patients often complain of memory problems and narcolepsy and psychotic disorders?
may have deficits in source memory (monitoring a memory's
origin),42 but show no deficits on formal memory testing.43,44 Older studies suggested an increased prevalence of nar-
Children with narcolepsy have hallucinations (39–­50%) colepsy among schizophrenia patients31,36 and (retrospec-
and may have difficulty in distinguishing dreaming from re- tively) a greater risk of schizophrenia among narcolepsy
ality.7 Clinicians sometimes misinterpret their hallucinations patients vs. among controls.46 Narcolepsy was diagnosed
and behavioral changes as psychotic disorganization.45 in 7% of a schizophrenia cohort,38 but the study design
was flawed (the estimation of 7% was based on 5 misdiag-
nosed in-­patients plus a small cohort of current out-­patients,
3.5 | Quantitative comparison of atypical rather than collecting an in-­patient cohort during a defined
narcolepsy and dual diagnosis cases time period). A well-­ designed study could not replicate
this finding32: narcolepsy symptom questionnaires were
Comorbidity of narcolepsy with a psychotic disorder administered to 366 consecutive hospitalized adults with
has been documented primarily in case reports or series schizophrenia spectrum disorders. Among 24 with possible
(Table S1). A separate psychotic disorder diagnosis has narcolepsy (after sleep medicine consultations), 5 carried
usually been assigned when the symptoms met diagnostic HLA DQB1*06:02, of whom 3 accepted lumbar puncture,
criteria and appeared unrelated to REM intrusion. Table S1 but all had normal hypocretin-­1 levels, thus no NT1 cases
describes 58 cases: 41 with a dual narcolepsy and psychotic were detected. Sleep studies were not performed because
disorder diagnosis (Group 3); and 17 described as “psy- antipsychotics could not be discontinued. Further, among
chotic” or “delusional” narcolepsy (Group 2). Table 2 sum- 548 adult NT1 patients in two large sleep centers, 1.8%
marizes analyses of group differences (Table S4 provides had a history of schizophrenia spectrum psychoses (close
details of our ratings). Dual diagnosis patients usually de- to population prevalence), in whom anti-­NMDA antibodies
veloped narcolepsy first, and then (6.8 years later on aver- were not detected.47 However, early-­onset NT1 (<16 years
age) psychosis, mostly (38/41 cases) in the schizophrenia old) was more common in patients with (60%) than without
spectrum. They more often had disorganized symptoms in- (35%) a comorbid psychotic disorder.
cluding thought disorder (65.9% vs. 17.6%). Group 2 cases A significant association of schizophrenia was reported in
were more likely to have visual (88.2% vs. 19.5%) and mul- early-­onset NT1 in a prospective study of 151 narcolepsy pa-
timodal hallucinations, zoopsia, sexual and mystical delu- tients in Taiwan's only child/adolescent sleep clinic.31 Ten of
sions, and false memories. 102 NT1 patients (9.8%) had comorbid schizophrenia based
These symptomatic differences are not a validation of on clinical and research interviews. Average age at onset was
these subgroupings. Rather, they quantify the clinical judg- 11.25 for NT1 and 15.8 for schizophrenia. Compared with 37
ments of the various authors (and probably a consensus of age-­matched NT1-­only and 13 schizophrenia-­only cases, co-
the field) that Group 2 patients are experiencing a more se- morbid cases had poorer antipsychotic response and increased
vere form of classical narcolepsy symptoms, with the same weight. However, in a population-­based study of 38 narcolep-
underlying pathophysiology. No large-­scale or prospective tic children in Western Sweden (most with cataplexy, sleep
data exist to better describe or validate these subgroups and study abnormalities, and exposure to anti-­H1N1 vaccination,
the gray areas between them, but they have implications for but no hypocretin deficiency), 43% had a psychiatric diag-
treatment as discussed below. nosis, but no psychotic disorder.48 Thus, the Taiwan finding
34
|    HANIN et al.

TABLE 2 Case reports of “psychotic form of narcolepsy” vs. comorbid narcolepsy and psychotic disorder: Differences in clinical features

All cases “Psychotic form” Comorbid cases

(n = 58) (n = 17) (n = 41)
a a a
Clinical feature (mean) t df p
Age at onset of sleep 19.0 25.3 16.6 2.40 46 0.02
symptoms
Age at onset of psychotic-­like 23.5 23.8 23.4 0.09 46 0.93
symptoms
Sleep symptoms, N (%) n = 52 n = 15 n = 37 χ2 df p
Cataplexy 48 (92.3%) 13 (86.7%) 35 (94.6%) 0.95 1 0.33
Sleep-­related hallucinations 40 (76.9%) 13 (86.7%) 27 (73.0%) 1.13 1 0.29
Sleep paralysis 33 (63.5%) 8 (53.3%) 25 (67.6%) 0.93 1 0.33
Psychotic-­like symptoms, N (%) n = 58 n = 17 n = 41 χ2 df p
Hallucinations 51 (87.9%) 17 (100%) 34 (82.9%) 1.27 1 0.26
Auditory 50 (86.2%) 16 (94.1%) 34 (82.9%) 1.27 1 0.26
Visual 23 (39.7%) 15 (88.2%) 8 (19.5%) 23.72 1 0.00
Multimodal 22 (37.9%) 14 (82.4%) 8 (19.5%) 20.16 1 0.00
Zoopsia 2 (3.45%) 2 (11.8%) 0 (0.00%) 5.00 1 0.03
Delusional thoughts 56 (96.6%) 17 (100%) 39 (95.1%) 0.86 1 0.35
Persecution 38 (65.5%) 11 (64.7%) 27 (65.9%) 0.01 1 0.93
Poisoning 1 (1.72%) 1 (5.88%) 0 (0.00%) 2.45 1 0.12
Sexual 10 (17.2%) 7 (41.2%) 3 (7.32%) 9.66 1 0.00
Megalomaniac 3 (5.17%) 0 (0.00%) 3 (7.32%) 1.31 1 0.25
Mystic 9 (15.5%) 6 (35.3%) 3 (7.32%) 7.18 1 0.01
Jealousy 4 (6.90%) 1 (5.88%) 3 (7.32%) 0.04 1 0.84
Hypochondriac 2 (3.45%) 1 (5.88%) 1 (2.44%) 0.43 1 0.51
Fantasy 1 (1.72%) 1 (5.88%) 0 (0.00%) 2.45 1 0.12
Influence 5 (8.62%) 2 (11.8%) 3 (7.32%) 0.30 1 0.58
Reference 6 (10.3%) 3 (17.6%) 3 (7.32%) 1.38 1 0.24
Fake memory 5 (8.62%) 4 (23.5%) 1 (2.44%) 6.79 1 0.01
Disorganized symptoms 30 (51.7%) 3 (17.6%) 27 (65.9%) 11.18 1 0.00
Derealization 1 (1.72%) 1 (5.88%) 0 (0.00%) 2.45 1 0.12
n = 58 n = 17 n = 41 χ2 df p
Possible drug-­induced 20 (34.5%) 4 (23.5%) 16 (39.0%) 1.95 1 0.16
psychosis?
We classified 58 cases (reported in 27 papers, Table S2) according to the authors’ diagnostic conclusion (psychotic form of narcolepsy vs. comorbid narcolepsy and
psychotic disorder). For each case, we recorded age at onset for sleep and psychotic-­like symptoms and presence/absence of the clinical features listed in the table. A
feature was considered “present” if it was explicitly mentioned or very clearly suggested by the clinical description, otherwise, it was considered “absent,” that is, we
attempted not to infer the presence of symptoms beyond the data in the report. P-­values less than 0.05 are bolded.
a
For age at onset variables (sleep problems or psychotic-­like symptoms), 10 cases were excluded from analysis because no numerical information was provided about
ages. In 4 of the 48 remaining cases, onset was described as occurring “before the age of X” and we entered X into the analysis. Thus, N for these analyses was 48 and
the t-­tests had 46 df).

awaits replication. We note that in the largest recent series 3.7 | Proposed mechanisms of psychotic-­like
of comorbid cases, onset of sleep symptoms occurred before symptoms in narcolepsy
16 years of age in 10/105 and 6/10 cases47 (Canellas et al5
provide a useful structured interview to evaluate such cases). Typical hallucinations in narcolepsy are attributed to par-
There is an ongoing discussion in the literature about tial REM sleep intrusions while awake.4,38,50 Typical sleep-­
possible common genetic or environmental risk factors or related hallucinations generally improve with adequate
shared hypocretin pathophysiology49 in producing overlap- wake-­promoting (and not with antipsychotic) treatment, and
ping symptoms.5 in some cases serotonergic antidepressants are added because
HANIN et al.   
| 35

they suppress REM activity (see discussion below), suggest- derivative armodafinil in schizophrenia showed no improve-
ing that these symptoms are directly related to narcolepsy.27,38 ment, and no increase in psychotic symptoms.76
Overlapping autoimmune mechanisms have been hypoth- Sodium oxybate (gamma hydroxybutyrate, GHB) inhib-
esized. There is an extensive literature on infectious and au- its dopamine release via activation of GABA-­B circuits and
toimmune factors in schizophrenia.51 Older studies suggested the GHB receptor77,78 which could upregulate dopamine re-
an association of HLA DQB1*0602 with schizophrenia,52 ceptors. It is generally well-­tolerated in adults and children
but recently Sekar et al53 reported strong evidence that ge- with narcolepsy.79-­83 Psychotic symptoms have been reported
netic association near the HLA region on chromosome 6 is (usually shortly after starting or resuming treatment).73,84-­87
largely explained by structural sequence variants in the com- Emergence or exacerbation of psychotic symptoms by sodium
plement 4 gene which has a role in synaptic pruning. There oxybate was retrospectively reported in 5 of 90 narcoleptic
are conflicting data regarding anti-­NMDA antibodies in dual patients with no psychiatric history,87 and 1 of 63 children in a
diagnosis cases.47,54 It has been proposed that loss of hypo- clinical trial.88 Mazindol, a sympathomimetic amine, reduces
cretin neurons (which project to the ventral tegmental area, dopamine and norepinephrine reuptake. Psychotic symptoms
prefrontal cortex, and nucleus accumbens) leads to impaired were not reported in a retrospective study of 94 adult and
mesocortical-­pathway signaling and psychosis,55 possibly in- child patients89 or a clinical trial (n = 37).90 Pitolisant en-
teracting with an independent susceptibility to psychosis.29 hances histaminergic transmission via inhibition of presyn-
aptic uptake (inverse histamine H3 receptor agonist effect).91
It indirectly increases release of dopamine, norepinephrine,
3.8 | Medication-­induced psychosis in and acetylcholine.92 Anxiety and depression have been ob-
narcolepsy patients served but not psychosis,93-­95 in limited data.

All primary narcolepsy drug treatments enhance dopamin-

ergic neurotransmission, a mechanism associated with a 3.9 | An algorithm for clinical practice
risk of provoking psychosis. Classical psychostimulants
(methylphenidate, amphetamines, and methamphetamine–­ Based on literature review, we suggest an algorithm for eval-
now considered second-­line narcolepsy treatments) increase uating and treating narcolepsy patients with psychotic symp-
synaptic dopamine primarily by noncompetitively blocking toms (Figure 2).
the dopamine transporter (reuptake site) without increasing Typical sleep-­related hallucinations of narcolepsy, recog-
presynaptic release.56 Methylphenidate57 and amphetamines nized as such by the patient, and without other psychotic fea-
are generally considered safe in narcolepsy.58 A Japanese-­ tures (Group 1), are treated with drugs for narcolepsy, and not
language paper on a study of 329 NT1 patients59 followed antipsychotics. The most common psychosis-­related compli-
up after a mean of 15.4 years (mentioned in reference27 but cation in all groups is the onset of psychotic or worsening
not accessible to us) reported a 3.2% rate of psychostimulant-­ atypical psychotic-­ like symptoms after a wake-­ promoting
induced psychosis. An English-­language chapter by the same drug has been introduced or its dosage increased. The new
author about the same study60 describes the methodology as drug is generally stopped, or the previous dosage restored;
retrospective data collection by self-­ report questionnaire. if symptoms resolve rapidly, drug-­induced psychosis is the
Another retrospective study (chart review) reported psychotic likely diagnosis. Brief treatment with a less sedating antipsy-
events in 5% of 58 patients on “standard” dosages of psycho- chotic (eg, aripiprazole or risperidone) may be helpful, but
stimulants, primarily methylphenidate, vs. 24% of 58 patients further optimization of narcolepsy treatment should then be
receiving “high” dosages (>120 mg/day; odds ratio = 12.0), attempted. If the psychosis was provoked by classical stimu-
with additional adverse psychiatric outcomes.61 lants, modafinil or pitolisant might be considered.
Modafinil, a first-­line treatment, indirectly reduces do- Both the typical wake-­state hallucinations of narcolepsy
pamine and norepinephrine reuptake through serotonin-­ (Group 1) and their atypical variants (Group 2) are pre-
mediated inhibition of aminobutyric acid (GABA) release62 sumed to represent REM intrusions into wakefulness, with
and enhances dopamine-­dependent modulation of adrener- atypical patients sometimes developing delusion-­like ideas
gic receptors,63 with a good safety profile in narcolepsy.64-­66 to rationalize the experiences. Antidepressants with seroto-
Psychiatric adverse events have been reported, including rare nergic activity are known to suppress REM sleep,96 and in
cases of psychosis,67,68 elated mood,69-­72 and switch to mania clinical practice, they are frequently prescribed for typical
with psychosis.72-­74 In a pharmacovigilance study, 2,416 narcoleptic patients to control REM intrusion phenomena
modafinil prescribers reported one manic and two psychotic such as cataplexy and hallucinations.97 This is based on an-
episodes.75 A small study of children with narcolepsy re- ecdotal observations98 and consensus guidelines99,100 rather
ported one case with exacerbation of a pre-­existing psychotic than controlled studies. The same strategy may be attempted
disorder.68 A meta-­analysis of adjunctive modafinil and its in Group 2 patients, in the hope that additional treatment
36
|    HANIN et al.

Typical narcolepsy hallucinations Narcolepsy with psychotic-like symptoms Narcolepsy + psychotic disorder
Primarily visual or multimodal More severe and vivid than in typical Classical psychotic symptoms
hallucinations narcolepsy. May be primarily auditory Disorganization, formal thought disorder
SUBGROUP

Good insight with complex hallucinations (e.g. Negative symptoms unrelated to

At sleep-wake transitions (not conversations). somnolence
always) Less related to sleep or sleepiness Onset is generally after years of clear
Depersonalization, derealization May be multimodal narcolepsy
Optimize narcolepsy therapy, avoid Reduced insight, “delusional” Typical narcolepsy hallucinations may
antipsychotic drugs interpretation of hallucinations also be present
Dream-wake confusion Poor insight
Possible source-memory deficit

Stimulant-induced psychosis? (any group, but especially dual diagnosis)

EVALUATION

Did psychosis start, worsen, or change Other illnesses, medications, personal or Psychiatric consultation.
(less typical) after starting/increasing family history of psychosis? Systematically elicit and follow psychotic
stimulants (or substance use)? Are full criteria met for a psychotic disorder and mood symptoms
based on non-sleep-related symptoms? Rarely, re-evaluation of a psychotic disorder
results in primary narcolepsy diagnosis

Stop the medication if it is new, or

reduce it to the previous dosage Prioritize and optimize narcolepsy treatment Dangerous thoughts/behaviors suggest
TREATMENT

Consider serotonergic antidepressant (wake-promoting drugs; antidepressants). prioritization of antipsychotic treatment

drugs to prevent REM sleep Consider drugs with less potential to provoke In most cases it is challenging to balance
intrusions. psychotic symptoms. stimulant and antipsychotic treatment
Consider switching to different class of Dangerous thoughts/behaviors suggest caution First consider wakefulness drugs with least
narcolepsy treatment (e.g., modafinil with stimulants, re-consideration of psychosis potential (modafinil, pitolisant),
or pitolisant) psychiatric diagnosis/treatment and antipsychotics with least sedation
Briefly add or increase antipsychotic if (aripiprazole, risperidone).
needed (choose less sedating drug)

FIGURE 2 Algorithm for evaluating and treating narcolepsy patients with psychotic symptoms

of REM intrusions will improve both the atypical halluci- recommended4,5,101,102; aripiprazole may stabilize rather than
nations and the delusion-­ like rationalizations. Optimizing simply block dopaminergic neurotransmission.102 In some
wake-­promoting medication or adding an SSRI/SNRI is rec- case reports, olanzapine, clozapine, haloperidol, or queti-
ommended to reduce psychotic-­like symptoms. Psychiatric apine was effective.30,47,103,104 The clinical management of
consultation is advised for patients with dangerous impulses these complex situations requires further study.
or behaviors.
A comorbid psychotic disorder should be considered if
hallucinations and delusional ideas emerge and appear un- 4 | DISCUSSION
likely to be related to REM intrusions. We found no published
clinical trials for the treatment of patients with dual diagno- Most narcolepsy patients with psychotic or psychotic-­like
ses. Narcolepsy misdiagnosed as schizophrenia is probably symptoms will fit into one of three groups, and patients in
rare in adults but might be more common in children with any group may experience drug-­induced psychosis (espe-
narcoleptic and psychotic-­like symptoms. Treatment of dual cially those on high doses of psychostimulants and those with
diagnosis cases is challenging because stimulants increase previous psychotic symptoms):
dopamine release which can induce psychosis, whereas an-
tipsychotic drugs can worsen sleepiness by blocking dopa- 1. Patients with typical hallucinations of narcolepsy. The in-
mine and histamine transmission. Kishi et al27 recommended trusion of REM sleep phenomena into wakefulness causes
maintaining a wake-­promoting drug (despite the small risk hallucinations (usually visual, at sleep-­wake transitions,
of psychotic exacerbation), preferably modafinil because of recognized by the patient as “not real”), cataplexy, and
its predominantly non-­dopaminergic mechanism.67 Pitolisant sleep paralysis. These patients are recognized as “not
may be useful in our experience, although there is limited psychotic” by sleep medicine specialists.
evidence regarding its potential to provoke psychosis. Less 2. Atypical narcolepsy with psychotic-­ like symptoms
sedating antipsychotics like risperidone or aripiprazole are (“psychotic form of narcolepsy”). These patients have
HANIN et al.   
| 37

more severe and vivid hallucinatory, daytime dream-­like the hypothalamus that extends beyond hypocretin neurons,115
experiences and may develop delusion-­like rationaliza- or an acute destabilization of dopaminergic-­hypocretinergic
tions (analogous to severe obsessive-­compulsive disor- interactions.24 Furthermore, Hcrt-­1 deficiency in childhood
der with delusion-­like ideas about obsessions). They may could impair normal neurodevelopment in ways that either in-
have deficits in insight and source memory. They may crease the child's risk of schizophrenia or that lead to an earlier
worsen on antipsychotic drugs and improve on psycho- age at onset in predisposed individuals. There is a partial over-
stimulants. Misdiagnosis is more common, especially in lap in the structural MRI changes observed in childhood-­onset
children. schizophrenia116 and in childhood NT1,117 including reduced
3. Narcolepsy with a comorbid psychotic disorder. These gray matter volume in prefrontal cortex and cerebellum. It is
patients have psychotic symptoms unrelated to sleep possible that these and other changes have a major impact on
phenomena, often including disorganized behavior and schizophrenia risk in a minority of children (representing a
thought disorder starting years after narcolepsy onset syndromic type of schizophrenia), or that they constitute an
(Table 2, Table S2). It is unlikely that narcolepsy is additional risk factor for schizophrenia which has a large num-
frequently misdiagnosed as schizophrenia in adults,32 ber of interacting genetic118,119 and environmental120 risk fac-
although case reports demonstrate that it can occur. tors. Larger-­scale data are needed on prospective follow-­up
However, children and adolescents with NT1 may be and on structural brain changes and cognitive functioning in
at increased risk of comorbid schizophrenia spectrum children and adolescents with narcolepsy. Future studies of
disorders.31 It remains unclear whether there are shared the association of childhood narcolepsy and schizophrenia
autoimmune mechanisms.105 could inform our understanding of the etiopathology of both
disorders.
The possible association of NT1 with schizophrenia
spectrum disorders in childhood deserves further study—­a
difficult challenge given that both presentations are rare in 5 | PERM ISSION TO REUSE A N D
the population. Studies of children with NT1 have consis- COPYRIGHT
tently found increases of more common psychiatric disor-
ders,45,106 including attention deficit-­hyperactivity disorder Figures, tables, and images will be published under a Creative
(ADHD), internalizing (depressive and anxiety) disorders, Commons CC-­BY license and permission must be obtained
and learning problems.48,107-­111 This broad vulnerability has for use of copyrighted material from other sources (includ-
been attributed in part to excessive daytime sleepiness111 and ing re-­published/adapted/modified/partial figures and images
impulsive/hyperactive counterstrategies to fight it,108 to per- from the Internet). It is the responsibility of the authors to
sistent, frightening sleep-­related hallucinatory experiences107 acquire the licenses, to follow any citation instructions re-
and to psychological distress because of the overall disease quested by third-­party rights holders, and cover any supple-
burden. However, an additional role of organic lesions is sug- mentary charges.
gested by the association of depression with severity of brain
white matter structural changes observed in adult NT1 using ACKNOWLEDGMENTS
diffusion tensor imaging.112 CH and CLL would like to express their appreciation for
If the association of early-­onset NT1 with schizophrenia the contributions and expertise of the Sleep Disorder Unit
is confirmed in future studies, several explanations are pos- of Pitié-­
Salpétrière Hospital and to the Department of
sible. A direct effect of central Hcrt-­1 deficiency has been Functional Exploration of Robert Debré Hospital. The au-
considered, because Hcrt-­1 influences dopaminergic neuro- thors declare that this study was conducted without funding.
transmission in the midbrain and prefrontal cortex, which are
involved in the pathophysiology of schizophrenia.55 However, CONFLICT OF INTEREST
schizophrenia is rare in adult-­onset NT1 patients despite the During the last two years, David Cohen reported past con-
dramatic loss of central Hcrt-­1, and CSF Hcrt-­1 is normal sultation for or the receipt of honoraria from Otsuka, Shire,
in schizophrenia113,114 (although these small studies do not Lundbeck, and IntegraGen. All other authors declare that the
exclude a low-­Hcrt-­1 subgroup). CSF Hcrt-­1 is also typically research was conducted in the absence of any commercial or
normal in adult major depression.55 It seems unlikely that re- financial relationships that could be construed as a potential
duced Hcrt-­1 directly leads to psychosis. conflict of interest.
Narcolepsy onset in childhood is typically associated with
symptoms never observed in adult-­onset cases, including com- AUTHOR CONTRIBUTIONS
plex movement disorders (lasting up to two years after onset CH conducted the literature search, reviewed references, and
and then disappearing), massive weight gain, and psychiatric wrote the first draft of the manuscript. CL and DC reviewed
symptoms. This suggests that there is transient inflammation in key papers and contributed to revisions. IA, ML, and JBM
38
|    HANIN et al.

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