Authors: Lies Verstraete, Maarten Van Den Bossche
Categories: Original Article, Narcolepsy, Psychiatric disorders, Comorbidity, Review
Source: International Journal of Clinical and Health Psychology : IJCHP
Authors: Lies Verstraete, Maarten Van Den Bossche
Narcolepsy is a chronic sleep-wake disorder characterized by recurrent episodes of excessive daytime sleepiness, hypnagogic hallucinations, and sleep paralysis. There are two narcolepsy type 1 (with cataplexy) and narcolepsy type 2 (without cataplexy). This review aims to investigate the comorbidity of psychiatric disorders in narcolepsy.
We examined this association through a systematic literature review conducted on July 20, 2024. Searches were performed in PubMed and Embase.
In general, the prevalence of comorbid psychiatric disorders in patients with narcolepsy varies considerably. Depression, anxiety disorders and ADHD are considerably more prevalent in patients with narcolepsy than in the general population. The prevalence of comorbid psychotic disorders and a formal diagnosis of an eating disorder seems also higher in narcolepsy, albeit to a lesser extent. Neurodegenerative disorders and addictive problems were not more prevalent than in general population. More evidence is needed on bipolar disorder, obsessive compulsive disorder, autism, intellectual disability and personality disorders.
Overall psychiatric disorders are more prevalent in patients with narcolepsy, but prevalence rates vary widely across disorders. High prevalence of comorbid depression, anxiety disorders and ADHD is reported in narcolepsy. For other psychiatric disorders, current evidence is less conclusive. It is important that clinicians and patients are aware of the comorbidity of narcolepsy and psychiatric disorders.
Narcolepsy is a chronic sleep-wake disorder characterised by (1) excessive daytime sleepiness (EDS), (2) sleep paralysis (a transient disability to move while falling asleep or awakening), (3) hypnagogic or hypnopompic hallucinations (vivid hallucinations occurring while falling asleep or awakening respectively) and sometimes (4) cataplexy (a sudden loss of muscle tension with remaining consciousness, mostly evoked by strong emotions). There are two subtypes of narcolepsy, defined by the clinical presence (narcolepsy type 1 - NT1) or absence (narcolepsy type 2 - NT2) of cataplexy Narcolepsy usually begins in adolescence or early adulthood, with two peaks in age of around 15 years and around 35 years, although age of onset can also be later in life (Martens & Van Den Bossche, 2025). The etiology of narcolepsy involves a combination of polygenetic risk factors and environmental factors. The HLA allele DQB1×0602 is associated with an increased risk for NT1, and to a lesser extent for NT2 (Capittini et al., 2018). This points to the hypothesis of an autoimmune reaction, possibly triggered by environmental factors such as viral or streptococcal infections, leading in NT1 to the destruction of >90 % of hypocretin-1 neurons (Mahlios et al., 2013). Hypocretin is a neuropeptide produced in the hypothalamus that plays a crucial role in the regulation of sleep-wake rhythm. The etiology of NT2 is less clear.
The diagnosis of narcolepsy can be made by polysomnography (PSG), followed by a Mean Sleep Latency Test (MSLT), in which sleep onset latency (SOL) is evaluated (SOL ≤ 8 min is considered indicative of narcolepsy), together with the occurrence of sleep onset REM (rapid eye movement) periods (SOREMPs). For a diagnosis of narcolepsy generally two or more SOREMPs are required. More recently, measurement of the concentration of hypocretin-1 in cerebrospinal fluid (CSF) has enabled more direct diagnosis of NT1. A value of ≤ 110 pg/mL or less than a third of the mean standard value supports the diagnosis of NT1 (Bourgin et al., 2008).
The global prevalence of narcolepsy is estimated at 25 tot 50 per 100.000 persons, while the incidence has been estimated at around 0.74 per 100.000 person-years (Longstreth et al., 2007). Males and females are affected equally (Baldini et al., 2024a).
In clinical practice, narcolepsy is often found to be comorbid with other psychiatric conditions such as depression, anxiety, and ADHD. High comorbidities are also described in the literature, mainly with mood disorders, anxiety problems and ADHD (Hansen et al., 2023; Krahn et al., 2022; Morse & Sanjeev, 2018), but psychotic disorders and eating problems are also mentioned (Hansen et al., 2023; Morse & Sanjeev, 2018). Psychiatric comorbidity has been hypothesized to result from excessive sleepiness and/or disrupted circadian rhythms, or from shared pathophysiological mechanisms, including hypocretin-1 deficiency (Hansen et al., 2023).
In this literature review, we provide an overview of the comorbidity of narcolepsy with psychiatric disorders. First, the association between narcolepsy and psychiatric disorders in general is discussed, followed by a detailed analysis of specific psychiatric comorbidities and their prevalence in narcolepsy.
This research involves a systematic literature review, for which PubMed and Embase databases were searched. The literature search was conducted on July 20, 2024. The search terms used in Pubmed were "narcolepsy"[MeSH Terms] combined with (("mental disorders"[MeSH Terms] or "comorbidity"[MeSH Terms]) and "narcolepsy"[All Fields]) AND "psychiatric comorbidity"[All Fields]. The search terms used in Embase were “narcolepsy” AND “mental disease” as well as “narcolepsy” AND “psychiatric comorbidity”.
In addition, relevant articles from reference lists of the fully screened articles were included and 2 articles were additionally suggested during the review process.
The search strategy focused on English-language publications since 1945. Exclusion criteria (1) no full text available, (2) no clear diagnosis of narcolepsy, (3) animal studies, (4) absence of psychiatric comorbidity, (5) no clear diagnosis of psychiatric disorder, (6) sleep disorders without psychiatric conditions, and (7) somatic comorbidity. Inclusion criteria (1) clear diagnosis of narcolepsy type 1 or type 2, (2) psychiatric comorbidity, (3) a clear psychiatric diagnosis based on DSM criteria or made by means of validated instruments. No age restriction was applied.
After systematic screening of the databases, a total of 201 articles were identified and evaluated based on their abstracts. Of these, 134 articles met the inclusion criteria for full text review. After this review, 1 article was excluded because of the unavailability of the full text, 37 articles because of the lack of a clear diagnosis of psychiatric comorbidity or narcolepsy, 8 articles because of the lack of a distinction between narcolepsy and idiopathic hypersomnia, 11 articles because of no prevalence data available and 2 articles because of the presence of an organic brain disorder. Finally, 78 articles were included, consisting of 19 reviews, 14 case reports/case series, 20 case-control studies, 10 cross-sectional studies and 14 cohort studies (Fig. 1).Fig. 1PRISMA 2020 flow diagram of our literature search.Fig 1
The study by Krishnan et al. showed that two-thirds of patients with narcolepsy had a comorbid psychiatric disorder (formal diagnosis based on patient charts), although these findings were based on a small population of 24 patients and no control groups were included (Haba-Rubio, 2005; Krishnan et al., 1984).
A cross-sectional study by Hansen et al. examined 59 patients with NT1 for psychiatric comorbidity, with 30.5 % of participants having a single psychiatric disorder and 22 % having two or more psychiatric disorders according to clinical evaluation through a semi-structured interview (Hansen et al., 2023). Similarly, in a sample of 38 patients with narcolepsy, Szakács et al. found through clinical evaluation that 37.8 % (14/37) had at least one psychiatric comorbidity (Szakacs et al., 2015). A third study conducted by Nevsimalova et al. analyzed 148 patients with narcolepsy and idiopathic hypersomnolence. This showed that 38.1 % of the NT1 group and 45.5 % of the NT2 group had some form of psychiatric comorbidity based on self-report questionnaires (Nevsimalova et al., 2022). In contrast to these results, a study by Frauscher et al. discovered comorbid psychiatric problems in only 8 % based on patient charts (Frauscher et al., 2013). The reason for this lower prevalence could be due to the incompleteness of the files. The lack of control groups was a limitation in all these studies.
In a cross-sectional study by Kales et al. about 50 % of the 50 patients with narcolepsy studied were found to have psychiatric comorbidity according to clinical evaluation, consisting mainly of depressive disorders and personality problems (Kales et al., 1982). Cohen et al. observed in a cohort of 68 patients with narcolepsy that psychiatric comorbidity was present in 45.6 % at baseline and 57.4 % at follow-up, compared with 17.3 % and 28.7 %, respectively, in controls (Cohen et al., 2018). This result was statistically significant. Psychiatric diagnosis in this study was based on clinical evaluation. Yet another study by Alasim et al. found comorbid psychiatric disease in 45 % of 74 patients with narcolepsy compared to 15 % of the control group, a result that was statistically significant (Alasim et al., 2020). The most common comorbidity here was depression and psychotic disorders (diagnoses obtained from medical records).
However, a 2013 study analyzed a comprehensive cohort of 757 patients with narcolepsy and 3013 controls, where only 4 % of patients were found to have psychiatric comorbidity compared with 1.8 % of controls, a difference that was not statistically significant (Jennum et al., 2013). In an even larger study with data from medical claims, where 9312 patients with narcolepsy were compared with 46,559 control subjects for comorbidities, an excess prevalence of 31.1 % was found for mental illness, the highest of all categories (62.3 % versus 31.2 %) (Black et al., 2017).
Finally, Feketeova et al. showed that 20 % of patients with narcolepsy had a comorbid psychiatric disorder based on clinical evaluation, and that the presence of narcolepsy doubled the risk of a psychiatric disorder (Feketeova et al., 2020).
A summary of the above studies can be found in Table 1.Table 1Overview of articles on narcolepsy and general psychiatric comorbidity.Table 1TitleStudy designAuthorYearNarcolepsy (n =)NT1 (n =)NT2 (n =)Controls (n =)D/ NarcolepsyD/ Psychiatric comorbidityResultComorbidities in a community sample of narcolepsyCohort study**Cohen A. et al.2018**n = 68??n = 272PSG + MSLTClinical evaluation documented in the medical recordt1: 45.6 % with psychiatriccomorbidity versus 17.3 %of the controls.t2 (after years of follow-up):57.4 % with psychiatricdisorder versus 28.7 %of the controls.Both statistical significant.Associations between psychiatric comorbid disorders and executive dysfunctions in hypocretin-1 deficient pediatric narcolepsy type 1Cross- sectional study**Hansen, B.H. et al.2023**n = 59n = 59/nonePSG + MSLT and CSF level hypocretin-1DSM 5Semi-structured diagnostic interview obtained by a psychiatrist – clinical evaluation52.5 % psychiatric comorbidity;30.5 % one and22 % two or more psychiatric disorders.Narcolepsy: Preliminary Retrospective Study of Psychiatric and Psychosocial AspectsRetrospective study**Krishnan et al.1984**n = 24n = 19n = 5noneSelection from a narcolepsy clinicPsychiatric comorbidity according to DSM-III based on patient charts66 % with psychiatric diagnosis.Psychiatric Comorbidity and Cognitive Profile in Children with Narcolepsy with or without Association to the H1N1 Influenza VaccinationCross- sectional study**Szakács A. et al.2015**n = 38??noneICD-10 + ICSD 2005DAWBA, ASSQ, ADHDRS, PANNS questionnaires.DSM-IV.Diagnostic interview consisting of structured interviews, questionnaires, and rating techniques. Final rating made by a psychiatrist – clinical evaluation34.84 % withpsychiatric comorbidity.Central Disorders of Hypersomnolence: Association with Fatigue, Depression and Sleep Inertia Prevailing in WomenCross-sectional study**Nevsimalova S. et al.2022**n = 148n = 87n = 22nonePSG + MSLT and clinical informationHADS, FSS and SIQ questionnaire – self-report38.1 % of NT1 with psychiatric comorbidity and 45.5 % of NT2.Delayed Diagnosis, Range of Severity, and Multiple Sleep Comorbidities: A Clinical and Polysomnographic Analysis of 100 Patients of the Innsbruck Narcolepsy CohortCohort study**Frauscher B. et al.2013**n = 100n = 87n = 13noneSleep history, PSG and MSLT, HLA typing and hypocretine-1 level in CSF.Psychiatric comorbidity based on patient records and clinical interview8/100 had a psychiatricdisorder.Narcolepsy-Cataplexy II. Psychosocial Consequences and Associated PsychopathologyCross-sectional study**Kales A. et al.1982**n = 50??n = 50Selection from the Sleep Disorders Clinic + cataplexyPsychiatric interview, MMPI and SCL-90 – clinical evaluation30 % comorbid depressivedisorder.Comorbid psychiatric disorders among patients with narcolepsyCross-sectional studyAlasim H. et al2020**n = 74n = 30n = 44n = 265ICSD-3, PSG and MSLTMINI version 6 based on DSM-IV – clinical evaluation45 % psychiatric disordercompared with 15 %of the control group;statistically significant.Comorbidity and Mortality of Narcolepsy: A Controlled Retro- and Prospective National StudyA Case- Controlled Retro- And Prospective Study**Jennum P. et al.2013**n = 757??n = 3013PSG + MSLT, LP or clinical informationDiagnosis based on ICD-10 Information abstracted from the database4 % with a psychiatric disorderversus 1.8 % of the controls.Not statistical significant.Medical comorbidity in findings from the Burden of Narcolepsy Disease**(BOND) studyRetrospective data-analysisBlack, J. et al.2017**n = 9312n = 1890n = 7422n = 46,559Medicalclaims data, diagnosis code for narcolepsyDiagnosis code,clinicalclassificationsystem62.3 % mental illness innarcolepsy group versus31.2 % in control groupNarcolepsy in Slovakia e Epidemiology, clinical and polysomnographic features, comorbid a case-control studyCase- control study**Feketeova E. et al.2019**n = 61n = 51n = 10n = 244PSG + MSLT, HLA typing and hypocretin-1 level in CSFDiagnosis obtained by medical records review or based on a telephone interview20 % with comorbid psychiatric disorder.Narcolepsy and is there an association?Case-control studyVourdos, A. et al.*2002N* = 45??N = 50PSG + MSLTDiagnosis made by a structured psychiatric diagnostic interview obtained by a psychiatrist4/45 patients withComorbid psychotic disorder compared to none in the control group; statistically significant. But all related to amphetamine use.7/45 patients compared to 9/60 controls had a major depression; not statistically significant.2/45 patients and none of the controls met criteria for anxiety disorder NOS; not statistically significant.
Depression is often identified as the most common comorbidity in narcolepsy. In a meta-analysis of 31 studies, 32 % of patients with narcolepsy were found to have a comorbid depression (Li et al., 2021).
The prevalence of depression in patients with narcolepsy is between 10.55 % and 37.9 % according to several controlled studies, while in control groups it was only between 5 % and 13.8 % (Morse & Sanjeev, 2018). Most studies gave a similar prevalence of around 30 % for a comorbid depressive problem with a statistically significant difference compared to the control group although study designs and methods used for psychiatric diagnosis differed between studies (Alasim et al., 2020; Black et al., 2017; Cohen et al., 2018; Feketeova et al., 2020; Huang et al., 2016; Kales et al., 1982; Lee et al., 2017; Ohayon, 2013; Ruoff et al., 2017). In the study by Cohen et al. an increase of this percentage to 50 % was even observed at follow-up (Cohen et al., 2018). Furthermore, it was found that patients with narcolepsy showed more frequent depressive symptoms and had higher scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) than control groups (Chabas et al., 2007; Filardi et al., 2017).
However, three studies could not retain a significant difference with the control group (Fortuyn et al., 2010; Kamada et al., 2024; Vourdas et al., 2002). One of these is the study by Kamada Y. et al. which examined a large population of 4594 patients, but one of the control groups consisted of people with schizophrenia in which depressive disorder is also very common which could lead to a distorted picture (Kamada et al., 2024). Another study, where psychiatric diagnosis was based on a structured psychiatric interview, found no difference between the two groups, but those findings were based on small sample sizes of 45 narcolepsy patients and patients from a psychiatric service were excluded from the study (Vourdas et al., 2002). Finally, the study by Fortuyn et al. used the SCAN method to arrive at a DSM-IV diagnosis of depression, but in this method somatic complaints of sleep disturbance and fatigue are excluded, therefore potentially leading to a lesser overlap (Fortuyn et al., 2010).
In clinical studies without a control group, Krystal et al. showed that 28.1 % had a history of depression (Krystal et al., 2022), while Nevsimalova et al. reported a history of mixed anxiety-depressive disorder in 22 % NT1 patients (Nevsimalova et al., 2022) and in the French Harmony study 26.3 % had mild depressive disorder, 23.2 % moderately severe depressive disorder and 5.6 % severe depression (Dauvilliers et al., 2009). In a recent study of 88 narcolepsy children, 25 % were diagnosed with depressive symptoms, although a diagnosis of major depression was rare (Rocca et al., 2015). Three other studies recorded similar two cohort studies showed a comorbid depressive disorder in 28 % of 120 narcoleptic patients (Chin et al., 2023) and 26 % of 100 narcoleptic patients (Chin et al., 2024), similarly, a third study found a comorbid depression in 26 % of 111 NT1 patients and 11 % of 46 NT2 patients (Huang et al., 2017).
Finally, Chepke et al. describe a 31-year-old man with ADHD and depression in his past, but who also developed narcolepsy later in life (Chepke, 2023).
Detailed overview of these studies can be found in Table 2. A description of the case reports can be found in Table 9.Table 2Overview of articles on narcolepsy and affective disorders.Table 2TitleStudy DesignAuthorYearNarcolepsy (n=)NT1 (n =)NT2 (n = )Controls (n = )D/ NarcolepsyD/ Psychiatric comorbidityResultMedical comorbidity in findings from the Burden of Narcolepsy Disease (BOND) studyRetrospective data-analysis**Black, J. et al.**2017n = 9312n = 1890n = 7422n = 46559Medical claims data, diagnosis code for narcolepsyDiagnosis code, clinical classification system37.9% mood disorders in narcolepsy group versus 13.8% in control groupComorbidities in a community sample of narcolepsyCohort study**Cohen A. et al.**2018n = 68n = 28n = 40n = 272PSG+MSLTClinical evaluation documented in the medical recordt1: 39.7% comorbid depressive disorder and t2 (after follow-up): 50%.Associations between psychiatric comorbid disorders and executive dysfunctions in hypocretin-1 deficient pediatric narcolepsy type 1Cross- sectional study**Hansen, B.H. et al.**2023n = 59n = 59/nonePSG + MSLT and hypocretin-1 level in CSFDSM 5Semi-structured diagnostic interview obtained by a psychiatrist – clinical evaluation11.9% comorbid depressive disorder.Psychiatric Comorbidity and Cognitive Profile in Children with Narcolepsy with or without Association tot he H1N1 Influenza VaccinationCross- sectional study**Szakács A. et al.**2015n = 38??noneICD-10 and ICSD (2005)DAWBA, ASSQ, ADHDRS, PANNS questionnaires.DSM-IV.Diagnostic interview consisting of structured interviews, questionnaires, and rating techniques. Final rating made by a psychiatrist – clinical evaluationIn the post vaccination group, 6/30 had a major depression.Central Disorders of Hypersomnolence: Association with Fatigue, Depression and Sleep Inertia Prevailing in WomenCross-sectional study**Nevsimalova S. et al.**2022n = 148n = 87n = 22nonePSG+MSLTHADS, FSS and SIQ questionnaire – self-report4.1% depressive disorder of which 3.5% of the NT1 group and 0% of the NT2 group.Delayed Diagnosis, Range of Severity, and Multiple Sleep Comorbidities: A Clinical and Polysomnographic Analysis of 100 Patients of the Innsbruck Narcolepsy CohortCohort study**Frauscher B. et al.**2013n = 100n = 87n = 13noneSleep history, PSG with MSLT, HLA typing and hypocretin-1 determination in CSV.Psychiatric comorbidity based on patient records and clinical interview2/100 had bipolar disorder and 1/100 a first manic episode with psychotic featuresNarcolepsy-Cataplexy II. Psychosocial Consequences and Associated PsychopathologyCross-sectional study**Kales A. et al.**1982n = 50??n = 50Selection from the Sleep Disorders Clinic + cataplexyPsychiatric interview, MMPI and SCL-90 – clinical evaluation30% comorbid depressive disorder.Comorbid psychiatric disorders among patients with narcolepsyCross-sectional studyAlasim H. et al2020n = 74n = 30n = 44n = 265ICSD-3, PSG and MSLTMINI version 6 based on DSM-IV – clinical evaluation30% comorbid major depressive disorder compared with 9% of the controls; statistically significant. No one had bipolar disorder (in neither group).Narcolepsy in Slovakia e Epidemiology, clinical and polysomnographic features, comorbid a case-control studyCase- control study**Feketeova E. et al.**2019n = 61n = 51n = 10n = 244PSG, MSLT, HLA typing and hypocretin-1 defficiency.Diagnosis obtained by medical records review or based on a telephone interview21% had affective disorder.Comorbidity of narcolepsy and depressive a nationwide population-based study in TaiwanCohort study**Lee M-J. et al.**2017n = 258??n = 258ICD-9-CMDSM IVDiagnosis based on patient medical records32.7%, 24.8% and 10.9% depressive, dystyme or major depressive disorder respectively versus 6.3%, 4.4% and 1.6% of controls.High rates of psychiatric comorbidity in narcolepsyCross- sectional study**Ruoff C.M.**2017n = 9312??n = 46 559ICD-9Diagnosis based on ICD-9 obtained from the database35.8% depressive disorder compared to 13% in controls; statistically significant.Brain imaging and cognition in young narcoleptic patientsCase-control study**Huang Y-S.**2016n = 71??n = 20ICSD-3 criteria + clinical interview, actigraphy, PSG, MSLT and HLA typing. In some, hypocretin-1 level in CSFClinical interview24.6% of narcolepsy patients had depressive disorder compared to 0% in the control group.Narcolepsy is complicated by high medical and psychiatric a comparison with the general populationCross-sectional study**Ohayon M.**2013n = 320??n = 1464ICSD-2 criteria and DSM-IV-TRDiagnosis based on DSM IV-TR obtained by clinical interview17.1% major depressive disorder compared to 6.4% of controls; statistically significant. 2.4% dysthymia compared to 1.2% in controls; not statistically significant.Eating Disorder and Metabolism in Narcoleptic PatientsCase- control study**Chabas D. et al.**2007n = 13??n = 9Clinical symptoms, PSG + MSLT and HLA typingCIDI-2 EAT-40 EDI-2 MADRSCombination of self-report and clinical evaluationHigher MADRS scores in narcolepsy than controls.Attention impairments and ADHD symptoms in adult narcoleptic patients with and without hypocretin deficiencyCase- control study**Filardi M. et al.**2017n = 36n = 21n = 15n = 22ESS, PSG + MSLT and HLA typingANT, ASRS, OCIr, BDI and STAI questionnaires – self-reportMore depressive symptoms than controls.Anxiety and mood disorders in a case–control studyCase-control study**Fortuyn Droogleever, H.A.**2010n = 60??n = 120ICSD-2 criteriaSemistructured interview SCAN (DSM-IV) – clinical evaluation13% had a mood disorder compared to 5% of the controls. Of these, 7% major depressive disorder compared to 3% of the controls and 0% dystyme disorder compared to 3% of the controls. None statistically significant.Burden of narcolepsy in Japan: A health claims database study evaluating direct medical costs and comorbiditiesRetrospective cohort studyKamada, Y. et al.**2024n = 4594??n = 18376 (schizophrenia) n = 18376 (epilepsy) n = 4594 (ulcerative colitis)ICD-10ICD-10Clinical evaluation14% comorbid depression; not statistically significant relative to controls.Solriamfetal treatment of excessive daytime sleepiness in participants with narcolepsy or obstructive sleep apnea with a history of depression.Post hoc analysisKrystal A.D. et al.**2022n = 236??noneICSD-3 or DSM-5 criteriaHistory of depression at screening (recall)28.1% history of depression.Psychological health in central the French Harmony study*Cohort studyY Dauvilliers2009n = 517n = 424n = 68noneICSD-2 + PSG and MSLTS-BDISelf-report26.3% had mild depressive disorder, 23.2% moderately severe depressive disorder and 5.6% severe depression.Narcolepsy and is there an association?Case-control studyVourdos, A. et al.**2002n = 45??N = 50PSG + MSLTDiagnosis made by a structured psychiatric diagnostic interview obtained by a psychiatrist7/45 patients compared to 9/60 controls had a major depression; not statistically significantImpact of Taiwan’s 2021 COVID‑19 lockdown on the symptom severity and quality of life of patients with narcolepsyRetrospective study**Chin, W-C. et al.2022n = 120n = 80n = 40/PSG, MSLT, HLA typing, actigraphyDiagnosis based on records from the database28% of the narcolepsy patients had depression.Long‑term follow‑up of symptom and quality of life changes in patients with narcolepsy during and after the COVID‑19 pandemicRetro- and prospective cohort studyChin, W-C. et al.2024n = 100zelfde cohort?n = 67n = 33/PSG, MSLT, HLA typing, actigraphyDiagnosis based on records from the database26% of the narcolepsy patients had a comorbid depression.Multiple sleep latency test in narcolepsy type 1 and narcolepsy type A 5-year follow-up studyCohort studyHuang, Y. et al.**2018*n = 157n = 111n = 46/PSG + MSLTGeneral clinical evaluation, diagnosis based on DSM-IV26% of NT1 patients had a major depression and 11% of NT2.
A study by Feketeova et al. found affective disorders in 21 % of patients with narcolepsy, although this disorder was not specified (Feketeova et al., 2020). Two cross-sectional studies with large sample sizes reported a statistically significant difference with about 8 % of patients with narcolepsy diagnosed with comorbid bipolar disorder, compared with only about 2 % in the control group (Ohayon, 2013; Ruoff et al., 2017). The study by Ohayon et al. examined 320 patients with narcolepsy; psychiatric diagnosis was obtained by clinical interview (Ohayon, 2013). The study by Ruoff et al. examined as many as 9312 patients with narcolepsy (Ruoff et al., 2017). Two other studies also reported similar results, with 2 % to 5 % of patients having comorbid bipolar disorder (Fortuyn et al., 2010; Frauscher et al., 2013). However, one of these studies lacked a control group and psychiatric diagnosis was solely based on patient charts (Frauscher et al., 2013). In the other study, the result was statistically significant and here psychiatric diagnosis was obtained from a semi-structured interview (Fortuyn et al., 2010).
The above results are presented in Table 2.
In addition, two case reports were included in which, based on clinical symptoms, PSG and MSLT, the comorbid diagnosis of narcolepsy and bipolar disorder was made (Crosby et al., 2011; Trzepacz, 1987). Detailed data on these case reports can be found in Table 9.
Results regarding the prevalence of psychotic disorders in narcolepsy vary considerably. A 2005 review by Haba-Rubio et al. reported that between 0 % and 14 % of patients with narcolepsy would have comorbid schizophrenia (Haba-Rubio, 2005). This spans a range of a very significant increased risk to no increase at all, as the lifetime prevalence of schizophrenia is estimated to be between 0.3 % and 0.66 % (van Os & Kapur, 2009). Similarly, a study by Vourdas et al. found no evidence of an increased prevalence of schizophrenia in patients with narcolepsy (Vourdas et al., 2002). A 2011 review by Fortuyn et al. also seems to confirm these findings, with the majority of studies showing no increased prevalence of schizophrenia compared with a control group (Fortuyn et al., 2011). The 2018 review by Morse & Sanjeev additionally confirmed that the co-occurrence of narcolepsy and schizophrenia is rare (Morse & Sanjeev, 2018). However, none of these reviews has a detailed methodology.
A recent 2021 systematic review by Hanin C. et al. collected data from 100 articles. This showed that older studies suggested a relatively high prevalence, but that these results could not be confirmed in newer, methodologically better designed studies (Hanin et al., 2021). For example, Dauvilliers et al. studied 542 NT1 patients, of whom 1.8 % had a history of schizophrenia spectrum disorder (however no formal diagnosis was made) (Dauvilliers et al., 2016). In a prospective study 10 out of 102 NT1 patients had comorbid schizophrenia based on clinical evaluation through a psychiatrist (Huang et al., 2014). In contrast, none of the 38 narcolepsy children in a population-based study had a psychotic disorder (Szakacs et al., 2015). These inconsistencies can be due to difference in study design. As for the study of Szakacs et al., this was a cross-sectional study of children and adolescents with mean age of 15.3 years old. As we know that schizophrenia mostly starts at adolescent age, it is clear that there can be an underestimation of comorbidity rate in this study (Szakacs et al., 2015). The study of Huang et al. on the contrary followed patients with narcolepsy for four years, thereby probably leading to a greater comorbidity rate of psychotic disorders. Furthermore, in all studies patients used stimulants as a treatment for their narcolepsy but it is not known to which dosage. Some authors argue that (higher doses of) stimulants could play a role in inducing or aggravating psychotic symptoms (Auger et al., 2005). A lack of formal psychiatric diagnostic measures in the study of Dauvilliers et al. could have affected both the frequency and diagnosis of psychotic disorders (Dauvilliers et al., 2016).
A 2023 retrospective cohort study examined 69 patients with narcolepsy, of whom 4 % had experienced a psychotic episode and 1.5 % had a formal diagnosis of schizophrenia (Feketeova et al., 2022). Similarly, in another recent retrospective study 6 % of 120 narcolepsy patients had comorbid schizophrenia (Chin et al., 2023). In a cross-sectional study from 2022 conducted in 87 NT1 and 22 NT2 patients, only two patients had comorbid schizophrenia, although diagnoses were based on self-report questionnaires and since people with schizophrenia often lack insight in their own disorder, this may influence these results (Nevsimalova et al., 2022).
On the other hand, in an older 2005 study, Auger et al. concluded that 17 of 116 (14.6 %) patients with narcolepsy had a comorbid psychotic disorder (Auger et al., 2005) and Huang et al. showed that 12 % of 111 NT1 patients had comorbid schizophrenia, but none of the 46 NT2 patients, which could be due to the smaller sample size and the fact that comorbidity is often more frequent among NT1 patients (Huang et al., 2017). Similarly, Chin et al. revealed that 10 % of the 171 people with narcolepsy studied had comorbid schizophrenia (Chin et al., 2021).
It cannot be ruled out that the use of stimulants partly influenced these (higher) numbers. Stimulants can sometimes induce or exacerbate psychotic symptoms which are sometimes difficult to distinguish from psychotic symptoms due to schizophrenia. In the above studies all patients received at least 200 mg of modafinil (Auger et al., 2005; Huang et al., 2017; Chin et al., 2021). Additionally, in the studies by Auger et al. and Chin et al. psychiatric diagnosis was obtained through screening of medical records and it is not clear how initial diagnoses were made.
A limitation of all these studies is the lack of a control group.
When comparing studies with a control group, results continue to vary. Four studies showed a statistically significant outcome between both the narcolepsy group and the control group. In a first retrospective cohort study from 2020, 8.1 % of patients with narcolepsy had a comorbid psychotic disorder based on patient records, compared with 1.5 % in the control group (Yeh et al., 2020). Another cross-sectional study found schizophrenia in 3.4 % of patients with narcolepsy compared with 0.9 % in the control group (Ruoff et al., 2017), a third study found 14.1 % compared with 0 % in controls (Huang et al., 2016) and a fourth cross-sectional study showed a prevalence of 8 % (based on clinical evaluation by a psychiatrist) in patients with narcolepsy compared with 0 % in control subjects (Alasim et al., 2020). In the study by Huang et al., comorbidity in narcolepsy was not the set-up of the study but schizophrenia was present in the demographic data of the study population (Huang et al., 2016).
In contrast, the cross-sectional study by Fortuyn et al. discovered no difference in prevalence between the two groups. Diagnosis was based on clinical evaluation through a semi-structured interview (Fortuyn et al., 2009). The study by Feketeova et al. diagnosed only three patients with comorbid psychotic disorder through review of the medical records or based on a telephone interview at the moment of their medical visit, while information on the control group was missing (Feketeova et al., 2020). The study by Feketeova et al. was a case-oriented study in which data were manually reviewed and information was added through interviews leading to a better quality in assessment of the psychotic symptoms (Feketeova et al., 2020). Sample sizes of the latter studies were smaller.
In two additional studies, patients with a known diagnosis of schizophrenia were screened for the presence of comorbid narcolepsy. Douglass et al. reported in a 1993 study that 3.8 % of schizophrenia patients had comorbid narcolepsy (Douglass et al., 1993). However, in a well-designed 2016 cohort study, this result could not be replicated; no patients with schizophrenia were diagnosed with narcolepsy (Sansa et al., 2016).
See for a detailed overview (Table 3).Table 3Overview of articles on narcolepsy and psychotic disorders.Table 3TitleStudy DesignAuthorYearNarcolepsy (n =)NT1 (n =)NT2 (n =)Controls (n =)D/ NarcolepsyD/ Psychiatric comorbidityResultComorbidity of Narcolepsy and Psychotic Disorders: A Nationwide Population-Based Study in TaiwanRetrospective cohort study**Yeh J-Y. et al.2019**n = 258??n = 2580ICD-9 criteriaPatient records were screened to find a psychiatric diagnosis based on ICD-9 criteria.8.1 % comorbidpsychotic disordercompared with1.5 % of controls; statisticallysignificant.Psychiatric Comorbidity and Cognitive Profile in Children with Narcolepsy with or without Association to the H1N1 Influenza VaccinationCross-sectional studySzakács A. et al2015**n = 37??noneICD-10 and ICSD (2005)DAWBA, ASSQ, ADHDRS, PANNSDiagnostic interview consisting of structured interviews, questionnaires, and rating techniques. Final rating made by a psychiatrist – clinical evaluationNone withpsychoticsymptomsCentral Disorders of Hypersomnolence: Association with Fatigue, Depression and Sleep Inertia Prevailing in WomenCross-sectional studyNevsimalova S. et al2022**n = 109n = 87n = 22noneClinical examination, actigraphy, PSG and MSLT.HADS, FSS and SIQ questionnaire – self-report2 individuals inthe NT1 group developed schizophrenia.Comorbid psychiatric disorders among patients with narcolepsyCross-sectional studyAlasim H. et al2020**n = 74n = 30n = 44n = 265ICSD-3, PSG and MSLTMINI version 6 based on DSM-IV – clinical evaluation8 % with psychotic disordercompared to noone in the controlgroup; statistically significant.Narcolepsy in Slovakia e Epidemiology, clinical and polysomnographic features, comorbid a case-control studyCase- control study**Feketeova E. et al.2020**n = 61n = 51n = 10n = 244PSG, MSLT, HLA typing and hypocretin-1 deficiencyReview of medicalrecords ortelephone interview3 patients with a psychotic disorder.No info on thecontrol groupHigh rates of psychiatric comorbidity in narcolepsyCross-sectional study**Ruoff C.M.2017n = 9312??n = 46 559ICD-9Diagnosis based on ICD-9 obtained from the database3.4 % withcomorbidschizophreniacompared to 0.9 %in controls;statisticallysignificant.Brain imaging and cognition in young narcoleptic patientsCase- control study**Huang Y-S. et al.2016**n = 71??n = 20ICSD-3 criteria + clinical interview, actigraphy, PSG, MSLT and HLA typing. In some, hypocretin-1 level in CSFClinical interview14.1 % comorbid diagnosis of schizophreniacompared with0 % of the controlgroup.Absence of NMDA receptor antibodies in the rare association between Type 1 Narcolepsy and PsychosisCohort study**Dauvilliers Y. et al.2016**n = 542n = 542/nonePSG + MSLT, HLA typing, hypocretin-1 level in CSFDSM-IV-TRMedical records1.8 % comorbid schizophrenicdisorder, of which9 patients had schizophrenia and1 schizotypalpersonalitydisorder.Narcolepsy–cataplexy and schizophrenia in adolescentsRetrospective case-control study**Huang Y-S. et al.2014**n = 102n = 102/nonePDSS, ESS, sleep diary, HLA typing, PSG and MSLTK-SADS-E, PANNS, BDI and CGI-SS.DSM-IV.Clinical evaluation9.8 % developed schizophrenia.Psychotic Episode and Schizophrenia in Slovakian Narcolepsy DatabaseRetrospective cohort study and case analysis**Feketeová E. et al.2022**n = 69n = 69/noneICSD2/ 3ICSD2/ 3Clinical evaluation4 % with psychotic episode and 1.5 %with schizophrenia.Risks of High-Dose Stimulants in the Treatment of Disorders of Excessive Somnolence: A Case-Control StudyCase- control study**Auger R. et al.2005**n = 116??noneSelection from the Mayo Narcolepsy Research Center databaseReview of the record, according to the judgment of 2 board-certified psychiatrists14.6 % withcomorbidpsychotic disorder.Different positron emission tomography findings in schizophrenia and narcolepsy type 1 in adolscents and young adults : a preliminary studyProspective case-control study**Chin W-C. et al.2021**n = 171n = 171/noneQuestionnaires, action graph, PSG and MSLTClinical interviews,DSM-510.5 % comorbid schizophrenia.Psychotic symptoms in phenomenology and a comparison with schizophreniaCross-sectional study**Fortuyn H. et al.2008**n = 60n = 60/n = 120ICSD-2 + PSG and MSLTSemistructured interview SCAN of which DSM-IV-TRdiagnosis were derived.Clinical evaluation.In both narcolepsyand control group,2 people withpsychotic disorder.No difference in prevalencebetween the twogroups.Narcolepsy and is there an association?Case-control studyVourdas A. et al.*2002N* = 45??N = 50PSG + MSLTDiagnosis made by a structured psychiatric diagnostic interview obtained by a psychiatrist4/45 patients with comorbidpsychotic disorder compared to nonein the controlgroup; statistically significant. But all related toamphetamine use.Impact of Taiwan’s 2021 COVID‑19 lockdown on the symptom severityand quality of life of patients with narcolepsy*Retrospective studyChin, W-C. et al.2023**n = 120n* = 80n = 40/PSG, MSLT, HLA typing, actigraphyDiagnosis based on records from the database6 % of thenarcolepsypatients had schizophrenia.Multiple sleep latency test in narcolepsy type 1 andnarcolepsy type A 5-year follow-up study*Cohort studyHuang, Y. et al.2017**n = 157n* = 111n = 46/PSG + MSLTGeneral clinical evaluation, diagnosis based on DSM-IV12 % of NT1patients hadcomorbidschizophrenia butnone of NT2patients.Schizophrenia, narcolepsy, and HLA-DR15, Dq6Prospective cohort study**Douglass A. et al.1993**n = 56n = 56SADS-RDCStructured diagnostic interview obtained by a clinicianSDQ questionnaire, HLA typing, PSG and MSLT3.8 % comorbid narcolepsy.Exploring the presence of narcolepsy in patients with schizophreniaCohort study**Sansa G. et al.2016**n = 366noneSADS-RDCClinical evalutionSequence: first a semi-structured questionnaire and collection of ESS, if ESS > 11 or cataplexy referred to a neurologist. Third HLA typing. If positive, hypocretin-1 in CSV was determined. No PSG/ MSLT given irresponsible to pause medication long enough.No patients with comorbidnarcolepsy.
In addition, 8 case reports/case series were also included, a detailed description of which can be found in Table 9.
Most reviews report an increased prevalence of anxiety disorders in patients with narcolepsy (Krahn et al., 2022; Morse & Sanjeev, 2018; Rocca et al., 2015; Thorpy & Krieger, 2014). These are mainly panic attacks and social anxiety disorders (up to 53 % of patients with narcolepsy), but generalized anxiety disorders also occur (Morse & Sanjeev, 2018; Rocca et al., 2015).
A list of studies on comorbid anxiety disorders in narcolepsy is presented in Table 4. A 2023 cross-sectional study showed that 13 out of 59 patients with narcolepsy were diagnosed with a comorbid anxiety disorder (Hansen et al., 2023). Similarly, Nevsimalova et al. stated that 22 % of NT1 patients had a history of a mixed anxiety-depressive disorder (Nevsimalova et al., 2022). In two other cross- sectional studies, however, this percentage was much lower, between 1 % and 10 % (Frauscher et al., 2013; Szakacs et al., 2015). Similarly, in two retrospective studies of the same author this percentage was between 7 % and 8 % (Chin et al., 2023, Chin et al., 2024). All these studies lacked a control group, which was a limitation.Table 4Overview of articles on narcolepsy and anxiety disorders.Table 4TitleStudy DesignAuthorYearNarcolepsy (n =)NT1 (n =)NT2 (n =)Controls (n =)D/ NarcolepsyD/ Psychiatric comorbidityResultMedical comorbidity in findings from the Burden of Narcolepsy Disease(BOND) studyRetrospective data-analysis**Black, J. et al.2017**n = 9312n = 1890n = 7422n = 46,559Medicalclaims data, diagnosis code for narcolepsyDiagnosiscode, clinicalclassificationsystem25.1 % “mental illness” innarcolepsy group versus11.9 % in control groupComorbidities in a community sample of narcolepsyCohort study**Cohen A. et al.2018**n = 68n = 28n = 40n = 272PSG and MSLTClinical evaluation documented in the medical recordt0: 20.6 % anxiety disorder compared to 5.9 % of controls; statistically significant. t1 (follow-up): 25 % comorbid anxiety disorder compared to 15.1 % of controls; no longer statistically significant.Associations between psychiatric comorbid disorders and executive dysfunctions in hypocretin-1 deficient pediatric narcolepsy type 1Cross-sectional study**Hansen, B.H. et al.2023**n = 59n = 59/noneActigraphy, PSG, MSLT and hypocretin-1 level in CSFDSM 5Semi-structured diagnostic interview obtained by a psychiatrist – clinical evaluation22 % comorbid anxietydisorder.Psychiatric Comorbidity and Cognitive Profile in Children with Narcolepsy with or without Association tot he H1N1 Influenza VaccinationCross-sectional study**Szakács A. et al.2015**n = 37??noneICD-10 and ICSD (2005).DAWBA, ASSQ, ADHDRS, PANNSDiagnostic interview consisting of structured interviews, questionnaires, and rating techniques. Final rating made by a psychiatrist – clinical evaluationIn the post-vaccination group,3/30 with comorbidgeneralized anxiety disorder.Central Disorders of Hypersomnolence: Association with Fatigue, Depression and Sleep Inertia Prevailing in WomenCross-sectional study**Nevsimalova S. et al.2022**n = 109n = 87n = 22noneActigraphy, PSG and MSLTHADS, FSS and SIQ – self-report22 % of NT1 patients withhistory of mixedanxiety-depressive disorder.HADS anxiety scale did notdiffer between groups.Delayed Diagnosis, Range of Severity, and Multiple Sleep Comorbidities: A Clinical and Polysomnographic Analysis of 100 Patients of the Innsbruck Narcolepsy CohortCohort studyFrauscher B. et al2013**n = 100n = 87n = 13nonePSG, MSLT, HLA typing and level hypocretin-1 in CFSPsychiatric comorbidity based on patient records and clinical interview1/100 comorbid anxietydisorder.Comorbid psychiatric disorders among patients with narcolepsyCross-sectional study**Alasim H. et al.2020**n = 74n = 30n = 44n = 265ICSD-3, PSG and MSLTMINI version 6 based on DSM-IV – clinical evaluation4 % panic disorder in bothcontrol and narcolepsygroups. 1 % of controls had agoraphobia compared to3 % of narcolepsy patients.3 % social phobia in thecontrol group compared to4 % of the narcolepsy patients.0.8 % of the controls hadpost-traumatic stressdisorder compared to no one iin the narcolepsy group.1 % of the control group had generalized anxiety disorder compared to 7 % of thenarcolepsy group. None ofthese results werestatistically significant.High rates of psychiatric comorbidity in narcolepsyCross-sectional study**Ruoff C.M. et al.2017**n = 9312??n = 46 559ICD-9Diagnosis based on ICD-9 obtained from the database25.1 % comorbid anxietydisorder compared to 11.9 %in controls; stat. significant.Narcolepsy is complicated by high medical and psychiatric a comparison with the general populationCross-sectional study**Ohayon M. et al.2013**n = 320??n = 1464ICSD-2 and DSM-IV-TRDiagnosis based on DSM IV-TR obtained by clinical interview8.5 % agoraphobia comparedto 1.3 % in controls.21.1 % social anxietycompared to 8.7 % of controls.5.5 % generalized anxietydisorder compared to 1.7 %of controls and 5.2 % specificphobia compared to 1.3 % of controls. All results stat.significant. Panic disorder andpost-traumatic stressdisorder prevalent in > 10 %of narcolepsy patients; only significant in women.Attention impairments and ADHD symptoms in adult narcoleptic patients with and without hypocretin deficiencyCase-control study**Filardi M. et al.2017**n = 36n = 21n = 15n = 22ESS, PSG, MSLT and HLA typingANT, ASRS, OCIr, BDI and STAI – self-reportNon-significant trend forhigher anxiety levels and OCD features in narcolepsycompared to controls.Anxiety and mood disorders in a case–control studyCase-control study**Fortuyn Droogleever, H.A. et al.2010**n = 60??n = 120ICSD-2Semistructured interview SCAN (DSM-IV) – clinical evaluation35 % comorbid anxietydisorder of which 20 % socialphobia and 22 % panicdisorder.Burden of narcolepsy in Japan: A health claims database study evaluating****direct medical costs and comorbiditiesRetrospective cohort studyKamada, Y. et al.2024**n = 4594??n = 18,376 (schizophrenia) n = 18,376 (epilepsy) n = 4594 (ulcerative colitis)ICD-10ICD-10Clinical evaluation17.4 % comorbid anxietydisorder; not statisticallysignificant.Narcolepsy and is there an association?Case-control studyVourdas A. et al.*2002N* = 45??N = 50PSG + MSLTDiagnosis made by a structured psychiatric diagnostic interview obtained by a psychiatrist2/45 patients and none ofthe controls met criteria foranxiety disorder NOS; not statistically significant.Sex and age differences in the association between anxiety disorders and A nationwide population-based case control studyCase-control study**Chen T-Y. et al.2020**n = 478??n = 1912ICD-9-CMICD-9-CM based onclinical evaluation.14.23 % had any anxietydiagnosis compared to 4.29 % of the control group; statistically significant. This was before diagnosis of narcolepsy wasmade. No significantdifference in anxietydiagnosis after diagnosis of narcolepsy was made. Alsono differences in subtypes of anxiety disorders betweentwo groups.Impact of Taiwan’s 2021 COVID‑19 lockdown on the symptom severityand quality of life of patients with narcolepsy*Retrospective studyChin, W-C. et al.2023**n = 120n* = 80n = 40/PSG, MSLT, HLA typing, actigraphyDiagnosis based on records from the database7 % of the narcolepsypatients had anxiety.Long‑term follow‑up of symptom and quality of life changesin patients with narcolepsy during and after the COVID‑19 pandemic*Retro- and prospective cohort studyChin, W-C. et al.2024**n = 100n* = 67n = 33/PSG, MSLT, HLA typing, actigraphyDiagnosis based on records from the database8 % of the narcolepsypatients had comorbidanxiety
In the study of Hansen et al. psychiatric diagnosis was based on a semi-structured interview obtained by a psychiatrist, however Nevsimalova et al. used self-report questionnaires which theoretically may have led to an overrepresentation of anxiety diagnoses in this study (Hansen et al., 2023; Nevsimalova et al., 2022).
In a study by Fortuyn et al. up to 35 % of patients with narcolepsy had a comorbid anxiety disorder, with social phobia (20 %) and panic disorder (22 %) being the most common. Diagnoses were made based on a semi-structured interview obtained by a psychiatrist (Fortuyn et al., 2010).
One cohort study and two cross-sectional studies showed similar results, each of which was found to be statistically significant (Cohen et al., 2018; Ohayon, 2013; Ruoff et al., 2017). The study by Ruoff et al. showed comorbid anxiety disorder (extracted from information in a database) in 25.1 % of patients with narcolepsy, compared with 11.9 % in the control group (Ruoff et al., 2017). Cohen et al. found comorbid anxiety disorder based on medical records in 20.6 % of patients with narcolepsy, compared with 5.9 % in controls. However, this result was no longer significant after follow-up (Cohen et al., 2018). Ohayon et al. also reported a significant result for all subgroups regarding anxiety disorders; diagnosis was obtained from a clinical interview (Ohayon, 2013).
A study from 2020 stated that patients with anxiety disorders had a 2.7 fold risk of developing narcolepsy compared to controls (Chen et al., 2020). A large study based on medical claims data similarly found a 2.5 fold risk for anxiety disorders in patients with narcolepsy versus controls (25.1 % versus 11.9 %) (Black et al., 2017).
In contrast, a case-control study by Filardi et al. showed no significant increase in anxiety levels and features of OCD in patients with narcolepsy versus the control group (Filardi et al., 2017). Neither Alasim et al. Kamada et al. nor Vourdas et al. found a statistically significant increase in anxiety disorders in patients with narcolepsy compared to a control group (Alasim et al., 2020; Kamada et al., 2024; Vourdas et al., 2002). It is possible that these mixed results are partly due to very small study populations in 2 studies (Filardi et al., 2017; Vourdas et al., 2002), and a control group consisting of people with schizophrenia in which anxiety disorders are often comorbid in another study (Kamada et al., 2024).
Patients with narcolepsy could have an increased risk of developing an eating disorder (Fortuyn et al., 2011; Morse & Sanjeev, 2018; Rocca et al., 2015). A 2018 review (Morse & Sanjeev, 2018) included three case-control studies that were also included in this paper. For example, 17.3 % of patients with narcolepsy had a comorbid eating disorder compared to 8.4 % of the controls according to a 2017 study by Black et al. Fortuyn et al. found similar results, with 23.3 % of patients with narcolepsy meeting criteria for a comorbid eating disorder, compared with 0 % in the control group (Fortuyn et al., 2008; Morse & Sanjeev, 2018). According to Chabas et al. patients with narcolepsy had double the EAT-40 scores of controls. They also found that bulimia occurred in approximately 46 % of patients with narcolepsy versus 11 % in the control group (Chabas et al., 2007; Morse & Sanjeev, 2018). Similarly, Baldini et al. reported a higher risk of developing an eating concern in the narcolepsy group than in controls. For example, patients with narcolepsy had higher EDE-Q scores, but this was only statistically significant for the eating concern subscale. Unlike other studies, no significant differences were noted between the two groups for the bulimia-eating score. In general, patients with NT1 did have more severe eating concerns (Baldini et al., 2024b). The studies of Chabas et al. and Baldini et al. made use of self-report questionnaires which might have influenced the results leading to an overrepresenation of eating concerns in those studies (Chabas et al., 2007; Baldini et al., 2024b).
Another review confirms that bulimia appears to be more common in patients with narcolepsy. However, three case-control studies found no increased prevalence of anorexia, bulimia or binge eating disorder (Alasim et al., 2020; Dahmen et al., 2008; Fortuyn et al., 2011). Similarly, the cross-sectional study by Szakács et al. reported a comorbid eating disorder in only one of 37 included patients with narcolepsy (Szakacs et al., 2015). Those studies made use of clinical evaluation in obtaining a psychiatric diagnosis, except for Dahmen et al. where self-report questionnaires were used. These studies were also all cross-sectional studies, which means diagnosis later in life will not be included, thus potentially leading to an underrepresentation of comorbidity.
The above data is summarized in Table 5.Table 5Overview of articles on narcolepsy and eating disorders.Table 5TitleStudy DesignAuthorYearNarcolepsy (n =)NT1 (n =)NT2 (n =)Controls (n =)D/ NarcolepsyD/ Psychiatric comorbidityResultHigh Prevalence of Eating Disorders in Narcolepsy with Cataplexy: A Case-Control Study*Cross-sectional case-control studyFortuyn* et al.*2008n* = 60n = 60/n = 120PSG and MSLT, HLA typing. In some cases, hypocretin-1 level in CSFSemi-structured interview SCAN (DSM-IV).Clinical evaluation.23.3 % comorbid eatingdisorder compared with 0 %of controls. 15 % eatingdisorder not otherwisedefined, 6.7 % bulimianervosa and only 1/60 with anorexia nervosa.Psychiatric Comorbidity and Cognitive Profile in Children with Narcolepsy with or without Association tot he H1N1 Influenza VaccinationCross-sectional study**Szakács A. et al.2015**n = 37??noneICD-10 and ICSD (2005).DAWBA, ASSQ, ADHDRS, PANNSDiagnostic interview consisting of structured interviews, questionnaires, and rating techniques. Final rating made by a psychiatrist – clinical evaluationIn the post-vaccinationgroup consisting of 30narcolepsy patients, oneperson showed a comorbideating disorder nototherwise defined - typeanorexia.Comorbid psychiatric disorders among patients with narcolepsyCross-sectional studyAlasim H. et al2020**n = 74n = 30n = 44n = 265ICSD-3, PSG and MSLTMINI version 6 based on DSM-IV – clinical evaluationNo one had anorexianervosa. 3 % had boulemianervosa compared to noone in the control group;not statistically significant.Eating Disorder and Metabolism in Narcoleptic PatientsCase-control study**Chabas D. et al.2007**n = 13??n = 9Clinic, PSG, MSLT and HLA typingCIDI-2 EAT-40 EDI-2 MADRSCombination of self-report and clinical evaluationTwice as high EAT-40 scoresas control patients. Based on CIDI-2: 46 % with boulemia nervosacompared to 11 % ofcontrols. Only one withanorexia nervosa. Based on EDI-2: higherscore for boulemia innarcolepsy. However, noofficial diagnosis.Eating disorders in narcolepsy type Evidence froma cross-sectional Italian study*Cross-sectional studyBaldini, V. et al.2024b**n = 138??n = 162ESS, NSS, PSGDSM-5, EDE-Q, BES, NEQSelf-report questionnairesHigher EDE-Q scores innarcolepsy than in controls;only statistically significantfor the eating concernsubscale. For the BES nosignificant differencesbetween both groups.Patients with narcolepsytype 1 did have moresevere eating concernsthan controls.**Prevalence of eating disorders and eating attacksin narcolepsyCase-control studyDahmen, N.* et al.*2008n* = 116??n = 80Cataplexy or PSGSIAB (DSM-IV)Self-report questionnaires and clinical evaluationNo difference inprevalences of eatingdisorders..
Several studies show that addiction problems are not significantly more prevalent in narcolepsy than in the general population. Four relatively recent studies all show similar results. A first study found comorbid alcohol dependence problems in 7.5 % of patients with narcolepsy, compared with 15.2 % of subjects in the control group (Morse & Sanjeev, 2018). A second study reported a rate of 1.9 % for patients with narcolepsy versus 1.3 % in the control group (Ruoff et al., 2017), while a third study showed that 0.6 % of patients with narcolepsy had an alcohol dependence problem, compared with 0.9 % in the control group (Ohayon, 2013). In a fourth study by Feketeova et al. only two subjects were diagnosed with a comorbid alcohol dependence disorder (2/61) (Feketeova et al., 2020).
In the study by Frauscher et al. only two patients with narcolepsy had a comorbid substance abuse problem (2/100), although a control group was missing (Frauscher et al., 2013). In the study by Barateau et al. no difference was found between the two groups in the incidence of illicit substance use (Barateau et al., 2016) and another study neither could retain people with substance dependence problems (Alasim et al., 2020).
Only Ruoff et al., the largest study, could retain a statistically significant outcome between both groups regarding substance abuse, with 4 % of people in the narcolepsy group versus 1.2 % in controls (Ruoff et al., 2017).
The above data can be found in detail in Table 6.Table 6Overview of articles on narcolepsy and addiction disorders.Table 6TitleStudy DesignAuthorYearNarcolepsy (n =)NT1 (n =)NT2 (n =)Controls (n =)D/ NarcolepsyD/ Psychiatric comorbidityResultDelayed Diagnosis, Range of Severity, and Multiple Sleep Comorbidities: A Clinical and Polysomnographic Analysis of 100 Patients of the Innsbruck Narcolepsy Cohort*Cohort studyFrauscher B.* et al.*2013n* = 100n = 87n = 13noneSleep history, PSG, MSLT, HLA typing and if necessary determination of hypocretin-1 in CSFPatientrecords andclinicalinterview2/100 with comorbidsubstance abuse problems.Comorbid psychiatric disorders among patients with narcolepsyCross-sectional studyAlasim H. et al2020**n = 74n = 30n = 44n = 265ICSD-3, PSG ann MSLTMINI version 6 based on DSM-IV – clinical evaluationIn both the group ofnarcolepsy and controls, no addiction problems.Narcolepsy in Slovakia e Epidemiology, clinical and polysomnographic features, comorbid a case-control studyCase-control study**Feketeova E. et al.2019**n = 61n = 51n = 10n = 244PSG, MSLT, HLA typing and determination of hypocretin-1 level in CSFMedicalhistory ortelephoneinterview5 % comorbid alcoholdependence problem.High rates of psychiatric comorbidity in narcolepsyCross-sectional study**Ruoff C.M. et al.2017**n = 9312??n = 46 559ICD-9Diagnosis based on ICD-9 obtained from the database1.9 % with alcohol dependence versus 1.3 % of controls; not statistically significant.Significantly more people with substance dependenceproblem in narcolepsy (4 %)than in controls (1.2 %).Narcolepsy is complicated by high medical and psychiatric a comparison with the general populationCross-sectional study**Ohayon M. et al.2013**n = 320??n = 1464ICSD-2 and DSM-IV-TRDiagnosis based on DSM IV-TR obtained by clinical interviewAlcohol dependence problemin 0.6 % compared to 0.9 % of controls. Not statisticallysignificant.Smoking, Alcohol, Drug Use, Abuse and Dependence in Narcolepsy and Idiopathic Hypersomnia: A Case Control StudyCase-control study**Barateau, L. et al.2016**n = 359n = 243n = 116n = 710ICSD, MSLT, hypocretin in CSFMINIClinical evaluationIncreased proportion of bothtobacco and heavy tobacco smokers was found in NT1 compared to controls andother hypersomniacs,increased regular andfrequent alcohol drinkinghabit in NT1 versus controlsbut not compared to other hypersomniacs in adjusted models. Heavy drinkers were significantly reduced in NT1 versus controls but notcompared to other hypersomniacs.The proportion of patientswith excessive drug use(codeine, cocaine, andcannabis), substance dependence, or abuse waslow in all subgroups, without significant differencesbetween either hypersomnia disorder categories orcompared with controls.
The probability of narcolepsy co-occurring with Parkinson's disease or Alzheimer's disease is estimated at 4.75/ 1000 000 and 24/ 1000 000, respectively (Economou et al., 2012). Thus, this seems to be a rare comorbidity.
In a study by Ruoff et al. 4.6 % of patients with narcolepsy were found to have a comorbid neurocognitive disorder compared to 1.5 % in the control group. A result that was statistically significant although they did not distinguish between other cognitive disorders and neurodegenerative disorders (Ruoff et al., 2017). In another study by Scammell et al., 12 patients with narcolepsy were examined postmortem for amyloid deposition. 4 of the 12 patients were found to exhibit typical amyloid depositions pointing to the comorbid diagnosis of Alzheimer's disease. However, this percentage is compatible with the prevalence in the general population (Scammell et al., 2012).
Furthermore, another case report was included in which two cases were explored, one with comorbid Parkinson's disease and the other with comorbid Alzheimer's dementia (Economou et al., 2012).
Detailed results can be found in Tables 7 and 9.Table 7Overview of articles on narcolepsy and other disorders.Table 7TitleStudy DesignAuthorYearNarcolepsy****(n =)NT1 (n =)NT2 (n =)Controls (n =)D/ NarcolepsyD/ Psychiatric comorbidityResultAssociations between psychiatric comorbid disorders and executive dysfunctions in hypocretin-1 deficient pediatric narcolepsy type 1*Cross-sectional studyHansen, B.H.* et al.*2023n* = 59n = 59/noneActigraphy, PSG, MSLT and hypocretin-1 levelsDSM 5Semi-structured diagnostic interview obtained by a psychiatrist – clinical evaluation6.8 % comorbid OCDand10.2 % comorbidTourette.Narcolepsy-CataplexyII**. Psychosocial Consequences and Associated PsychopathologyCross-sectional studyKales A. et al.1982**n = 50n = 50/n = 50Patients selected from a clinical sleep centerPsychiatric interview, MMPI and SCL-90 – clinical evaluation11/50 with comorbidpersonality disorder.Obsessive-compulsive,passive-aggressive,histrionic and borderline personality disorder.Comorbid psychiatric disorders among patients with narcolepsyCross-sectional studyAlasim H. et al2020**n = 74n = 30n = 44n = 265ICSD-3, PSG and MSLTMINI version 6 based on DSM-IV – clinical evaluationOnly one person withcomorbid OCDcomparedto no one in the controlgroup; not significant.Narcolepsy in Slovakia e Epidemiology, clinical and polysomnographic features, comorbid a case-control studyCase-control study**Feketeova E. et al.2019**n = 61n = 51n = 10n = 244PSG, MSLT, HLA typing and determination of hypocretin-1 in CSFMedical historyand telephoneinterviewsMental retardation in14 % of narcolepsypatients.Comorbidity of narcolepsy and depressive a nationwide population-based study in TaiwanCohortstudy**Lee M-J. et al.2017**n = 258??n = 2580ICD-9-CMDSM-IVDiagnosis based on patient medical records2.3 % with comorbid intellectual disability; significantly more thanin the control group.High rates of psychiatric comorbidity in narcolepsyCross-sectional study**Ruoff C.M. et al.2017**n = 9312??n = 46 559ICD-9Diagnosis based on ICD-9 obtained from the database4.6 % cognitiveimpairment comparedto1.5 % of controls;statistically significantAttention impairments and ADHD symptoms in adult narcoleptic patients with and without hypocretin deficiencyCase-control study**Filardi M. et al.2017**n = 36n = 21n = 15n = 22ESS, MSLT and HLA typing.ANT, ASRS, OCIr, BDI and STAI – self-reportA non-significant trendof higher OCDsymptoms in narcolepsy patients thanin controls.Coexistence of narcolepsy and Alzheimer’s DiseaseCase reports**Scammell, T.E. et al.2012**n = 12??noneClinical symptom of cataplexyPostmortem analysis of amyloid deposits.4 out of 12 cases hadamyloid deposits typicalof Alzheimer's disease.This amounts to aprevalence of 33 %whichis similar to this in thegeneral population.Multiple sleep latency test in narcolepsy type 1 andnarcolepsy type A 5-year follow-up study*Cohort studyHuang, Y. et al.2017**n = 157n* = 111n = 46/PSG + MSLTGeneral clinical evaluation, diagnosis based on DSM-IV3 % of NT1 patients had comorbid OCD and 2 %ofNT2 patients.3 % of NT1 patients hada comorbid tic disorderand4 % of NT2 patients.
A recent study by Hansen et al. examined 59 patients with narcolepsy, of which 4 (6.8 %) were found to have comorbid obsessive-compulsive disorder (OCD) and 6 (10.2 %) were found to have comorbid Tourette syndrome (Hansen et al., 2023). Similarly, a cohort study by Huang et al. showed comorbid OCD diagnosis in 3 % of NT1 patients and 2 % of NT2 patients as well as a comorbid tic disorder in 3 % of NT1 patients and 4 % of NT2 patients (Huang et al., 2017). In another study by Filardi et al. comparing the results with a control group, there appeared to be a trend toward more OCD symptoms in people with narcolepsy, however this trend was not statistically significant (Filardi et al., 2017). Another study showed no significant difference from a control group, only one person had comorbid OCD compared to no one in the control group (Alasim et al., 2020). The studies by Hansen et al. and Alasim et al. were cross-sectional studies in which psychiatric diagnosis was obtained from clinical evaluation by a psychiatrist. The study by Hansen et al. only contained pediatric patients. Filardi et al. on the other hand made use of self-report questionnaires and excluded patients with a previous psychiatric disorder which may explain why the level of significance was not reached. Sample sizes of the studies conducted by Filardi et al. and Alasim et al. had only about half the sample size of the study by Hansen et al. possibly leading to an underdiagnosis of the comorbidity.
Some cases of comorbid OCD or tic disorder in patients with narcolepsy have also been described, but these cases also had an additional diagnosis of schizophrenia and autism, respectively, making this association difficult to interpret (Douglass et al., 1991; Prihodova et al., 2018).
All results can be found in Table 7, Table 9 below.
Only one study from 1982 describes the comorbid presence of personality disorders in people with narcolepsy. Mainly obsessive-compulsive, passive-aggressive, histrionic and borderline personality disorders occurred (Kales et al., 1982). A detailed account can be found in Table 7.
In two controlled studies, intellectual disability was found to be comorbidly present in narcolepsy with a prevalence of 2.3 % (Lee et al., 2017) in one study and 14 % in the other (Feketeova et al., 2020). detailed description can be found in Table 7.
A literature review by Posar et al. included seven cases in which narcolepsy co-occurred with autism spectrum disorder (ASD) (Posar et al., 2020). Four of these cases were also included in this study and can be found in Table 9 (3 others were excluded here because of diagnostic uncertainty). Two other cases described by Huang et al. had comorbid schizophrenia in addition to narcolepsy type 1 which could also explain the possible association with ASD (Huang et al., 2014; Posar et al., 2020).
In addition, the review of Posar et al. also included the study by Quaedackers et al. in which 53 children with NT1 were compared with 64 control subjects on social functioning. A T-score above 75 on the social response scale points to severely impaired social functioning, although no formal psychiatric diagnosis was established here. 11 of the 53 patients with narcolepsy showed this elevated T-score (20.8 %) compared to 1 patient in the control group (1.6 %) which was statistically significant (Quaedackers et al., 2019).
In a 2020 controlled study, 6 out of 258 patients with narcolepsy were found to have comorbid ASD (2.3 %) compared to 6 out of 2580 subjects in the control group (0.2 %) (Yeh et al., 2020). Four other uncontrolled studies found similar results where the range of patients with narcolepsy with comorbid ASD was between 2.3 % to 8.1 % (Hansen et al., 2023; Nevsimalova et al., 2022; Szakacs et al., 2015; Huang et al., 2018). In contrast, the study by Kamada et al. examined 4594 patients with narcolepsy of whom 3.5 % were found to have comorbid autism, however, this result was not statistically significant compared to the control group. However, this wasn’t a healthy control population, but people with schizophrenia, epilepsy or ulcerative colitis which can explain why comorbidity of ASD in these control groups were elevated since there is for example a known association between ASD and psychotic disorders (Kamada et al., 2024).
The above data are summarized in detail in Table 8.Table 8Overview of articles on narcolepsy and developmental disorders.Table 8TitleStudy DesignAuthorYearNarcolepsy (n =)NT1 (n =)NT2 (n =)Controls (n =)D/ NarcolepsyD/ Psychiatric comorbidityResultComorbidity of Narcolepsy and Psychotic Disorders: A Nationwide Population-Based Study in Taiwan*Retrospective cohort studyYeh J-Y.* et al.*2020n* = 258??n = 2580ICD-9Patient records were screened to find a psychiatric diagnosis based on ICD-9 criteria.2.3 % comorbid ASD comparedwith 0.2 % in controls.8.9 % comorbid ADHDcompared with 0.9 % in controlgroup.Associations between psychiatric comorbid disorders and executive dysfunctions in hypocretin-1 deficient pediatric narcolepsy type 1Cross-sectional study**Hansen, B.H. et al.2023**n = 59n = 59/noneActigraphy, PSG, MSLT and determination of hypocretin-1 in CSF in someDSM 5Semi-structured diagnostic interview obtained by a psychiatrist – clinical evaluation6.8 % comorbid ASD.13.6 % comorbid ADHD.Psychiatric Comorbidity and Cognitive Profile in Children with Narcolepsy with or without Association tot he H1N1 Influenza VaccinationCross-sectional study**Szakács A. et al.2015**n = 37??noneICD-10 and ICSD (2005).DAWBA, ASSQ, ADHDRS, PANNSquestionnaireDiagnostic interview consisting of structured interviews, questionnaires, and rating techniques. Final rating made by a psychiatrist – clinical evaluationOnly in the post-vaccinationgroup 1/30 had pervasive developmental disorder NOS(i.e., atypical autism)In the post-vaccination group,8/28 narcolepsy patients had comorbid ADHD diagnosis ofthe inanimate type as well as1/7 in the unvaccinated group.About 1/4 of the narcolepsypatients had comorbid ADHD.Central Disorders of Hypersomnolence: Association with Fatigue, Depression and Sleep Inertia Prevailing in WomenCross-sectional study**Nevsimalova S. et al.2022**n = 109n = 87n = 22noneActigraphy, PSG, MSLTHADS, FSS and SIQ – self-report2 of 87 NT1 patients and noneof NT2 patients had comorbidASD.4 of the patients studied(2 in the NT1 group and 2 inthe NT2 group) had a comorbid diagnosis of ADHD,representing a rate of 2.7 %.Comorbidity of narcolepsy and depressive a nationwide population-based study in TaiwanCohort study**Lee M-J. et al.2017**n = 258??n = 2580ICD-9-CMDSM-IV-TRDiagnosis based on patient medical records8.8 % had comorbid ADHD; significantly higher than in thecontrol group (0.9 %).High rates of psychiatric comorbidity in narcolepsyCross-sectional study**Ruoff C.M. et al.2017**n = 9312??n = 46 559ICD-9Diagnosis based on ICD-9 obtained from the database7.3 % with ADHD compared to1.3 % in the control group;statistically significant.Brain imaging and cognition in young narcoleptic patientsCase-control study**Huang Y-S. et al.2016**n = 71??n = 20ICSD-3 criteria + clinical interview, actigraphy, PSG, MSLT and HLA typing. In some, hypocretin-1 level in CSFClinical interview17.4 % of narcolepsy patientshad a comorbid ADHDdiagnosis compared with noone in the control group.Narcolepsy is complicated by high medical and psychiatric a comparison with the general populationCross-sectional study**Ohayon M. et al.2013**n = 320??n = 1464ICSD-2 criteria and DSM-IV-TRDiagnosis based on DSM IV-TR obtained by clinical interview5.4 % with comorbid ADHDversus 2.5 % in the controlgroup. Only statisticallysignificant in boys.Attention impairments and ADHD symptoms in adult narcoleptic patients with and without hypocretin deficiencyCase-control study**Filardi M. et al.2017**n = 36n = 21n = 15n = 22ESS, PSG, MSLT and HLA typingANT, ASRS, OCIr, BDI and STAI – self-report33.33 % of the NT1 group had significantly increased scoreson the ADHD tests as well as26.66 % of the N2 groupcompared to 0 % in the control population.Burden of narcolepsy in Japan: A health claims database study evaluating****direct medical costs and comorbiditiesRetrospective cohort studyKamada, Y. et al.2024**n = 4594??n = 18,376 (schizophrenia) n = 18,376 (epilepsy) n = 4594 (ulcerative colitis)ICD-10ICD-10Clinical evaluation3.5 % had comorbid autismspectrum disorder and12 % ADHD. Only ADHD was significant.Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms in Pediatric Narcolepsy: A Cross-Sectional StudyCross-sectional study**Lecendreux M. et al.2015**n = 108??n = 67PSG, MSLT, HLA typing and sometimes determination of hypocretin-1 level in CSFADHD-RS based on DSM-IV-TR.Self-report.In 45 % of patients withnarcolepsy, ADHD scores were significantly increasedcompared to 5–6 % in thecontrol group.A Retrospective Survey of Childhood ADHD Symptomatology Among Adult NarcolepticsRetrospective study**Modestino E.J. et al.2013**n = 161??n = 117PSG + MSLT and HLA typingWURSSelf-report questionnaire37.88 % showed ADHDsymptoms; significantly morethan in the control group. It was estimated that 8 %to 15 % of the narcolepsy group hhad comorbid ADHD diagnosisAssociation of Inattention, Hyperactivity, and Hypersomnolence in Two Clinic-Based Adult CohortsCross-sectional study**Lopez R. et al.2020**n = 60n = 32n = 28nonePSG, MSLT and determination of hypocetin-1 in CSFStructured clinical interview and self-report questionnaires (DSM 5)11 of 60 patients met thediagnosis of comorbid ADHD (18.33 %)..A comparison of mood, quality of life and executive function among narcolepsy type 1 patients with or without ADHD symptoms in ChinaCohort study**Qu S. et al.2022**n = 267n = 267/nonePSG, MSLT and HLA typingMINI Kid and ADHD-RS based on DSM-IV, clinical evaluation28.8 % with comorbid ADHD,mainly the inanimate type.High prevalence of ADHD symptoms in unmedicated youths withpost-H1N1 narcolepsy type 1*Cross-sectional studyHansen, B. et al.2020**n = 50n* = 50/noneICSD-3 + clinical interview, PSG, MSLT, HLA typing and hyopcretin-1 level in CSFADHD RS,DSM 5Parent-rated(self-report)52 % had levels of ADHD symptoms above the cut-off.Impact of Taiwan’s 2021 COVID‑19 lockdown on the symptom severityand quality of life of patients with narcolepsy*Retrospective studyChin, W-C. et al.2023**n = 120n* = 80n = 40/PSG, MSLT, HLA typing, actigraphyDiagnosis based on records from the database18 % of the narcolepsypatients had ADHD.Long‑term follow‑up of symptom and quality of life changesin patients with narcolepsy during and after the COVID‑19 pandemic*Retro- and prospective cohort studyChin, W-C. et al.2024**n = 100zelfde cohort?n = 67n* = 33/PSG, MSLT, HLA typing, actigraphyDiagnosis based on records from the database18 % of the narcolepsy patients had comorbid ADHD.Multiple sleep latency test in narcolepsy type 1 andnarcolepsy type A 5-year follow-up study*Cohort studyHuang, Y. et al.2017**n = 157n* = 111n = 46/PSG + MSLTGeneral clinical evaluation, diagnosis based on DSM-IV13 % of patients with NT1 had comorbid ADHD and 30 % ofNT2. 5 % of NT1 patients hadcomorbid Asperger and 2 % ofNT2 patients.Table 9Overview and description of the included case reports.Table 9**TitleAuthorYearGenderAgeClinical symptomsDiagnosisDual Cases of Type 1 Narcolepsy with Schizophrenia and Other Psychotic DisordersCanellas F. et al.2014F, n = 6 M, n = 412 - 74yn = 10 Schizoaffective disorder, n = 1 Delusional disorder, n = 1 Schizophrenic disorder, n = 2 Schizophrenia, n = 6 Symptoms: auditory hallucinations, disorganization and delusions. All with hypnagogic hallucinations and vivid dreams. Onset of psychotic symptoms after diagnosis of narcolepsy. Delusions and auditory hallucinations did not improve provided treatment for narcolepsy. In one case clear relationship between start of treatment and increase in psychotic symptoms.Narcolepsy based on PSG, MSLT, HLA typing and hypocretin-1 deficiency. Diagnosis of schizophrenia via a specialized questionnaire (DIGSAN) based on DSM-IV through clinical evaluation.Comorbidity of narcolepsy and schizophrenia in an adolescent patientChen M-H. et al.2014M13yFirst onset of narcoleptic symptoms, then auditory hallucinations, delusions, misidentification. Psychotic symptoms arose before initiation of medication.Narcolepsy based on PSG/MSLT after 3 w discontinuation of medication. After treatment for narcolepsy, psychotic symptoms persisted. Consequently, the diagnosis of comorbid narcolepsy and schizophrenia was made.Narcolepsy and psychosis; case reportDulcinea V-D. et al.2020F25yDiagnosis of narcolepsy at 17, subsequently symptoms of anorexia and boulemia but undiagnosed. At 23, onset of jealousy delusions, suspicion, identity delusions, erotic delusions and auditory hallucinations.Narcolepsy based on PSG/MSLT (4 SOREM), undetectable hypocretin-1 and positive HLADQB1×0602 typing. This combined with the nature of psychotic symptoms led by the clinician to the conclusion of a comorbid psychotic disorder in patient with narcolepsy.Schizophrenia and A review with a case reportKishi Y. et al.2004F25yAt 13y onset of narcoleptic symptoms. Subsequently at 19y onset of auditory hallucinations, haunting delusions and involvement delusions.Narcolepsy based on PSG/ MSLT and positive for HLA DR2. Diagnosis of schizophrenia based on DSM-IV. Psychotic symptoms persisted even after treatment for narcolepsy causing comorbid schizophrenia.Florid Refractory Schizophrenias that turn out to be treatable variants of HLA-associated narcolepsyDouglass A.B. et al.1991F, n = 530 - 48yn = 5 Case described in another paper not accessible to us. Case auditory hallucinations (hearing God's voice), multimodal vivid dreams, ideas of poisoning, sleep apnea. Case depression, social anxiety, hearing voices since 6yrs of age, auditory, visual, olfactory and tactile hallucinations, catatonic features, paranoid delusions. Case paranoid delusions, visual and auditory hallucinations, twice postpartum psychosis in history Case auditory and visual hallucinations, cataplexy and sleep apnea, daydreaming, sleep attacksNarcolepsy based on questionnaire, PSG/ MSLT and HLA typing. Diagnosis of schizophrenia based on structured interview (DIS), SANS, SAPS and BPRS by a clinician. Based on DSM-III.Diagnostic and Therapeutic Challenges in Narcolepsy-Related PsychosisKondziella D. et al.2006F38yRecurrent anxious and depressive symptoms with subsequent onset of haunting delusions, ideas of relationship (idea that radio and television are dictating things to her), poisoning delusions, zonaesthesia. Subsequent onset of narcoleptic symptoms as well.Narcolepsy based on PSG and MSLT (but unclear whether medication was discontinued). Given psychotic symptoms persisted despite treatment for narcolepsy, comorbid diagnosis of schizophrenia-like disorder was made.Missed diagnosis of long-stading narcolepsyChepke C. et al.2023M31yExcessive daytime sleepiness since childhood, only lessened by stimulants. Muscle weakness with anxiety. Dazed head. Hypnagogic and hypnopome hallucinations.Narcolepsy based on PSG and MSLT. ADHD diagnosed at age 9y and depression as a teenager (basis of diagnosis unclear).Development of Parkinson and Alzheimer Diseases in Two Cases of Narcolepsy-CataplexyEconomou N-T et al.2011M, n = 269y and 71yCase excessive daytime sleepiness, hallucinations, cataplexy and sleep apnea since age 17. At age 64, onset of resting tremor, micrographia and bradykinesia on the right and hyposmia. Case Since adolescence suffered from sleep attacks, cataplexy, insomnia and hypnopompic hallucinations. At 65 years of age onset of cognitive decline with particular difficulties in spatial orientation, word fluency, short-term memory and impaired attention.Case diagnosis of narcolepsy based on MSLT, PSG, positive HLA DQB1×0602 and undetectable hypocretin-1. Diagnosis of Parkinson's based on UPDRS score and improvement with l-dopa. Case diagnosis of narcolepsy based on PSG and MSLT, positive HLA DQB1×0602 and undetectable hypocretin-1. Diagnosis of Alzheimer's dementia based on MMSE and MRI brain.Childhood narcolepsy and autism spectrum four case reportsPrihodova I. et al.2018M, n = 2 F, n = 210y - 13yCase diagnosis of ASD and ADHD in history with subsequent development of cataplexy, excessive daytime sleepiness, sleep attacks. Also more irritable and aggressive mood. Case Learning disabilities in history. Progressively more sleepy, developing anxiety symptoms and depressive symptoms. Also, socially maladjusted behavior, little social interaction, communication problems, few skills, attached to structure, stereotyped interests, sensory hypersensitivity and emotional and behavioral problems. Additional also emergence of cataplexy. Case Chronic tic disorder in history. Excessive daytime sleepiness as well as cataplexy. Mood swings and depressive symptoms. Additional problems in social interaction, avoidance of play and social activities, difficulty understanding rules, resistance to physical contact. Case History of ADHD. From 9y emergence of prolonged sleep, more sleepiness during the day, more tired, more emotional instability and irritability, emergence of cataplexy. Since age 3 also problems in social interaction, communication difficulties, monotone speech, decreased emotional expression, behavioral difficulties, no fantasy play, repetitive behaviors, limited interests, rigidity, difficulty coping with changes and hypersensitive to tastes and smells.Narcolepsy diagnosed based on MSLT and diagnosis of ASD based on clinical symptoms, psychiatric assessment, ADOS, DNEPSY and WIS through clinical evaluation.The Association of Schizophrenia and Narcolepsy in Adolescents*Cavalier Y. et al2018F15yHistory of excessive sleepiness, cataplexy, sleepparalysis, insomnia and auditory hallucinations. Hallucinations involved one voice whispering fearful things to her. Psychostimulants were given with subsequent disorganization, idea that people could read her mind, that people knew things about her, changing body perception. There were auditory as well as olfactory and tactile hallucinations.Diagnosis of narcolepsy based on PSG and MSLT. The diagnosis of schizophrenia was based on clinical aspects, such as delusions and olfactory and tactile hallucinations which is not typical in narcolepsy.Severe Mania Complicating Treatment of Narcolepsy with CataplexyCrosby M.I.**2011M22yAfter treatment with Modafinil 300 mg and Venlafaxine 75 mg for irresponsible behavior, spending large amounts of money, verbosity, hyperactivity, grandiosity and sexual disinhibition.Narcolepsy based on MSLT (4.7 min) and REM sleep in all naps. Based on clinical symptoms assessed by a psychiatrist, diagnosis of narcolepsy and comorbid bipolar disorder was made.Concurrent narcolepsy and bipolar affective disorderTrzepacz, P.*1983F41yDecreased sleep, rumination, religious delusions, flight of thought, flood of words, unstable mood, euphoria, increased energy level, grandiosity, hypersexuality, pregnancy delusion. In addition, sleep attacks, cataplexy, sleep apnea and hypnagogic hallucinations.Narcolepsy based on PSG. In combination with clinical symptoms assessed by a psychiatrist, diagnosis of comorbid narcolepsy and bipolar disorder was made.Narcolepsy, Paranoid Psychosis, Major Depression, and Tardive DyskinesiaSchrader G. et al.1984M67yHistory of alcohol abuse. He reports daytime drowsiness, cataplexy, sleep apnea and sometimes hypnagogic hallucinations. After R/ with dextroamphetamine development of daytime visual hallucinations (small men and animals), subsequent delusional system involving idea that people were throwing things in his eyes, belief in black magic, that people were trying to sleep with his wife. Afterwards also developing depressed mood, loss of interest, insomnia, diurnal mood variation.Narcolepsy based on symptoms, 3x EEG was negative. Cataplexy however pathognomonic. Diagnosis of psychotic disorder and major depressive disorder made on the basis of symptoms assessed by a psychiatrist.
According to two systematic reviews, the prevalence of ADHD symptoms in patients with narcolepsy is reported to be above 30 % (Bioulac et al., 2020; Kim et al., 2020). Another systematic review from 2024 gathered info from 10 articles with a total of 839 patients with narcolepsy whose pooled prevalence of ADHD was 25 %. However, patients with NT2 showed higher prevalence values for comorbid ADHD (46 %) compared to patients with NT1 (20 %) (Ren et al., 2024). Similarly, Rocca et al. (2015) and Morse et al. (Morse & Sanjeev, 2018) report a two times higher prevalence of ADHD symptoms in patients with narcolepsy compared to control subjects, and Thorpy & Krieger describe a significantly higher frequency of ADHD in narcolepsy than in control groups (Thorpy & Krieger, 2014).
Some controlled studies confirm these findings. For example, a cross-sectional study with 108 patients with narcolepsy showed a prevalence of 45 % comorbid ADHD symptoms compared with 5 to 6 % in the control group (Lecendreux et al., 2015). Similarly, a case-control study found that 33.33 % of patients with NT1 and 26.66 % of patients with NT2 had significantly elevated ADHD symptomatology scores compared with none in the control group (Krystal et al., 2022). Two other case-control studies reported similar results, where in one study 17.4 % of patients with narcolepsy were diagnosed with comorbid ADHD, while no one in the control group had ADHD (Huang et al., 2016). In the other study, up to 37.88 % of patients with narcolepsy showed ADHD symptoms, although the prevalence of a comorbid ADHD diagnosis was estimated between 8 and 15 % (Modestino & Winchester, 2013). Similarly, Kamada al. showed comorbid ADHD in 12 % of the patients with narcolepsy, a result that was statistically significant, although the control group did not consist of healthy individuals (Kamada et al., 2024).
Comparable rates are described in two cohort studies and one cross-sectional study, in which 7.3 % to 8.9 % of patients with narcolepsy had a comorbid diagnosis of ADHD, compared with 0.9 % to 1.3 % in the control group (Lee et al., 2017; Ruoff et al., 2017; Yeh et al., 2020). Only one cross-sectional study found a statistically significant result exclusively in boys (Ohayon, 2013).
In seven uncontrolled studies, the prevalence of comorbid ADHD in patients with narcolepsy varied, with 2.7 % in one study (Nevsimalova et al., 2022), 13.6 % in another study (Hansen et al., 2023), 18 % in three other studies (Lopez et al., 2020; Chin et al., 2023, Chin et al., 2024), and around 25 % in another two studies (Qu et al., 2022; Szakacs et al., 2015). Similarly, a cohort study by Huang et al. found a comorbid ADHD diagnosis in 13 % of NT1 patients (n = 111) and 30 % of NT2 patients (n = 46) (Huang et al., 2018). A specific 2020 study by Hansen et al. examining post-influenza adolescents with NT1 found ADHD symptoms in 52 % (26/50). Reason for this increased prevalence could be due to the fact that these adolescents were not yet medicated so ADHD symptoms may be more pronounced given the fact that medication for narcolepsy simultaneously also treats ADHD symptoms (Hansen et al., 2020).
A detailed description of these results can be found in Table 8.
Overall, we can state that psychiatric disorders are prevalent in people with narcolepsy, although prevalence rates vary, ranging from 4 % to 66.7 % (Black et al., 2017; Cohen et al., 2018; Feketeova et al., 2020; Frauscher et al., 2013; Haba-Rubio, 2005; Hansen et al., 2023; Jennum et al., 2013; Kales et al., 1982; Nevsimalova et al., 2022; Szakacs et al., 2015). Only three studies could withhold a statistically significant result compared to a control group with between 45 and 62 % of patients with narcolepsy having a comorbid psychiatric disorder (Alasim et al., 2020; Black et al., 2017; Cohen et al., 2018). In contrast, another study found no significant difference (4 % vs. 1.8 %) (Jennum et al., 2013).
Differences in cohort sizes and studies conducted in different countries, could partly explain the large variation in these prevalence rates. Another important reason for discrepancies in these rates could be the way psychiatric diagnoses were made (for example extensive interview by a psychiatrist versus a self-report questionnaire), as well as a potential overlap in symptoms that exists between narcolepsy and some psychiatric disorders (Frauscher et al., 2013; Jennum et al., 2013). For example, excessive sleepiness and fatigue is also a symptom of depression, night terrors may be misinterpreted as panic attacks, and hypnagogic or hypnopompic hallucinations may be reminiscent of psychosis (Modestino & Winchester, 2013). Moreover, the design of studies may be so that comorbidity is underestimated. For example, a cross-sectional designed study including mainly patients with narcolepsy in early adolescence may largely miss psychiatric diagnoses that typically only occur later in life.
Nevertheless, there does seem to be an association between the presence of narcolepsy and the more frequent comorbid occurrence of psychiatric disorders. One hypothesis is that hypocretin deficiency plays a role in this. Hypocretin neurons project to several brain regions (including the amygdala, the nucleus accumbens, the ventral tegmental area and the prefrontal cortex) that regulate affect and mood, motivation and reward, stress sensitivity and cognition (Douglass et al., 1993; Ohayon, 2013). A deficiency of these could provide a direct link between NT1 and psychiatric disorders, but this may not provide sufficient explanation for people with NT2, suggesting that other factors, like sleep patterns, also may have an influence on the development of comorbid psychiatric disorders.
A study by B. Li et al. examined the genetic correlation among narcolepsy and three commonly associated psychiatric diseases, specifically depressive disorder, ADHD and psychotic disorders. They found a positive genetic correlation among narcolepsy and risk of psychotic disorder, but a negative correlation between major depressive disorder and risk for narcolepsy. No causal relationship was demonstrated with ADHD (Li et al., 2024).
Moving to specific categories of psychiatric disorders, depression and anxiety problems appear to be the most prevalent psychiatric disorders in patients with narcolepsy (Krahn et al., 2022; Morse & Sanjeev, 2018) with the prevalence of comorbid depressive/mood disorders ranging from 4.1 % to 37.9 % (Black et al., 2017; Cohen et al., 2018; Feketeova et al., 2020; Fortuyn et al., 2010; Hansen et al., 2023; Kales et al., 1982; Kamada et al., 2024; Szakacs et al., 2015; Chin et al., 2023, Chin et al., 2024; Huang et al., 2017) and that of anxiety disorder being between 1 % and 25.1 % (Black et al., 2017; Chabas et al., 2007; Cohen et al., 2018; Fortuyn et al., 2010; Frauscher et al., 2013; Hansen et al., 2023; Nevsimalova et al., 2022; Ruoff et al., 2017; Szakacs et al., 2015; Chin et al., 2023, Chin et al., 2024). The most common anxiety disorders are panic attacks and social anxiety disorder, but comorbid generalized anxiety disorder also occurs (Morse & Sanjeev, 2018; Rocca et al., 2015).
Quality of life is often impaired in people with narcolepsy and comorbid depression (Krahn et al., 2022). People with narcolepsy also have higher MADRS scores than control groups, with no link between this score and BMI or disease progression (Chabas et al., 2007).
Again, differences in comorbidity rate of these disorders across different studies could be due to the way psychiatric diagnoses were made. For instance, self-reporting questionnaires give a higher comorbidity than formal diagnostic instruments since there is a overlap in symptomatology between narcolepsy and depression (Fortuyn et al., 2010). Additionally cross-sectional design of studies may miss diagnoses.
For comorbid depression, one hypothesis assumes that increased daytime sleepiness as well as more interrupted sleep may lead to depressive symptoms. Another hypothesis assumes hypocretin deficiency. As described above, hypocretin neurons influence the amygdala. When hypocretin is deficient, changes in emotion regulation occur, disrupting emotional processes which can lead to depression. In addition, hypocretin normally excites serotonergic neurons. Consequently, a hypocretin deficiency will also lead to a deficiency of serotonin which, as is known, plays a crucial role in the evolution of depressive symptoms and anxiety disorders (Nevsimalova et al., 2022). Furthermore, hypocretin neurons also affect nociception causing patients with narcolepsy to develop more pain symptoms which could also be a trigger for the development of depression or anxiety (Modestino & Winchester, 2013).
The prevalence of bipolar disorder in narcolepsy is around 2 % to 8 % and several studies have shown that this disorder is significantly more common in patients with narcolepsy than in the general population (Fortuyn et al., 2010; Frauscher et al., 2013; Ohayon, 2013; Ruoff et al., 2017) although more research is needed.
Results regarding the prevalence of psychotic disorders in narcolepsy vary considerably, ranging from 0 % to 14.6 % (Alasim et al., 2020; Auger et al., 2005; Chin et al., 2021; Dauvilliers et al., 2016; Feketeova et al., 2022, 2020; Fortuyn et al., 2009, 2011; Haba-Rubio, 2005; Hanin et al., 2021; Huang et al., 2014, 2016; Morse & Sanjeev, 2018; Nevsimalova et al., 2022; Ruoff et al., 2017; Szakacs et al., 2015). Four of the included clinical studies showed a significant difference in the comorbidity of psychotic disorders in narcolepsy compared to control groups, yet one other study found a statistically non-significant result (Fortuyn et al., 2009; Huang et al., 2016; Ruoff et al., 2017; Yeh et al., 2020). Overall, we can say that the comorbid occurrence of narcolepsy and a psychotic disorder is rather rare (Fortuyn et al., 2011; Haba-Rubio, 2005; Hanin et al., 2021; Morse & Sanjeev, 2018).
Some studies indicate that there is a possible pathophysiological overlap between narcolepsy and schizophrenia which would be immune-mediated. Another possibility is that dopaminergic dysfunction underlies this overlap (Feketeova et al., 2020). Hypocretin neurotransmission regulates dopaminergic activity in the ventral tegemental area, nucleus accumbens and prefrontal cortex which may clarify the common pathophysiology of psychotic features in both diseases (Cavalier & Kothare, 2018).
In the above studies some inconsistencies in findings may be explained by the study designs in which cross-sectional studies might miss a later diagnosis of psychotic disorder, certainly when the population consists of pediatric patients (Szakacs et al., 2015).
It can also not be excluded that medication like stimulants could exacerbate psychotic symptoms in some patients. Some of the included studies set strict criteria not to take any medication during the study, where others did not, which could theoretically also partly influence the variation in comorbidity rate (Auger et al., 2005; Huang et al., 2017; Chin et al., 2021; Dauvilliers et al., 2016).
There seem to be three possible explanations for the comorbid occurrence of narcolepsy and (1) psychotic disorders present comorbidly with narcolepsy by chance, (2) there exists a psychotic variant of narcolepsy in which the psychotic elements are more strongly present than the normally described hypnagogic/hypnopompic hallucinations, (3) psychotic symptoms arise after treatment of narcolepsy with central stimulants (Chen et al., 2014; Hanin et al., 2021; Kishi et al., 2004). The distinction between psychotic symptoms as part of narcolepsy or a stand-alone psychotic disorder is not always clear, yet the hallucinations are different in both disorders. For example, patients with narcolepsy generally experience multisensory hallucinations whereas the hallucinations in schizophrenia are more often verbal-auditory in nature and also often involve comorbid delusions (Chen et al., 2014). In studies of patients with schizophrenia, 4–7 % are reported to have a psychotic variant of narcolepsy . However, these are old studies from 1991 to 1993 with sample sizes around 60 patients (Bioulac et al., 2020; Douglass et al., 1993). Another difficult distinction concerns the development of bipolar disorder or psychotic problems after treatment of narcolepsy by central stimulants. The risk of psychostimulant-induced psychosis would be around 3 % and higher if a higher dose is used for treatment (Auger et al., 2005; Kishi et al., 2004).
If narcolepsy co-occurs with a psychotic disorder, treatment is often difficult and the prognosis poor since antipsychotics often exhibit sedative effects that exacerbate narcolepsy symptoms and psychostimulants may induce or exacerbate psychotic symptoms (Chen et al., 2014; Kishi et al., 2004).
Furthermore, there is evidence that people with narcolepsy have an increased risk of developing an eating disorder, but the prevalence varies from 2.7 % to 46 % (Chabas et al., 2007; Fortuyn et al., 2008; Morse & Sanjeev, 2018; Szakacs et al., 2015). Overall, the prevalence seems rather low given that often the criteria for a formal diagnosis are not met (Frauscher et al., 2013). In the included studies, mainly eating disorder NAO and bulimia seem to be prevalent and more common in narcolepsy than in the general population (Chabas et al., 2007; Morse & Sanjeev, 2018), but a case-control study by Dahmen et al. could not confirm this (Dahmen et al., 2008). However, several of these studies used self-reporting instruments which might have influenced the results (Dahmen et al., 2008; Chabas et al., 2007; Baldini et al., 2024b).
There are several hypotheses that attempt to explain the relation between narcolepsy and a comorbid eating disorder. Patients with narcolepsy often have a higher BMI, which is partly linked to the deficiency of hypocretin neurons. This is because hypocretin, in addition to stimulating food intake, also has metabolic and endocrine regulation as its purpose. Patients with narcolepsy are less stimulated in food intake (hypocretin deficiency causes a less efficient reward system) but still have an increased BMI. This can be explained by the metabolic and endocrine function performed by hypocretin, which causes patients with narcolepsy to exhibit less spontaneous physical activity and lowers their basal metabolism (Frauscher et al., 2013; Krahn et al., 2022; Modestino & Winchester, 2013). Another hypothesis is that they develop eating disordered behavior by adjusting their eating patterns. Given food affects sleepiness, they start to adjust their eating habits accordingly, but in doing so, they eventually develop an eating disorder (Krahn et al., 2022).
In contrast to previous arguments, a third hypothesis states that patients with narcolepsy still experience an irresistible craving for food resulting in binge-eating and loss of control. One will then take restrictive actions to control weight in compensation; thus developing an eating disorder. Patients taking concomitant antidepressants, which is not uncommon in the treatment of narcolepsy, also experience more craving (Frauscher et al., 2013).
Addiction disorders, on the other hand, do not seem to be significantly more prevalent in narcolepsy than in the general population. In terms of comorbid alcohol dependence problems, results vary, ranging from 0.6 % to 7.5 %, but were not significant when compared with a control group (Feketeova et al., 2020; Morse & Sanjeev, 2018; Ohayon, 2013; Ruoff et al., 2017). The prevalence of comorbid substance abuse ranged from 0 % to 4 % with one study showing significant results compared to the control group (Ruoff et al., 2017), but other studies did not (Alasim et al., 2020; Frauscher et al., 2013; Morse & Sanjeev, 2018). The reason that drug use is more present in one study (Ruoff et al., 2017) may have to do with the large size of the cohort studied.
The comorbid occurrence of narcolepsy with neurodegenerative disorders appears to be rare with an estimate of 24/ 1000 000 for Alzheimer's disease (Economou et al., 2012). A postmortem study found that the comorbid occurrence of Alzheimer's disease in narcolepsy was in the same range as the prevalence of Alzheimer's disease in the general population (Scammell et al., 2012). In very late onset of narcolepsy some symptoms (like hallucinations) may mimic neurodegenerative disorders (like Lewy body dementia) (Martens & Van Den Bossche, 2025). However, studies in older populations are scarce.
The comorbidity of OCD or Tourette syndrome with narcolepsy has not been widely reported, but a study by Hansen et al. found 6.8 % to have comorbid OCD and 10.2 % to have comorbid Tourette syndrome (Hansen et al., 2023). Similarly, a cohort study by Huang et al. showed comorbid OCD diagnosis in 3 % of NT1 patients and 2 % of NT2 patients as well as a comorbid tic disorder in 3 % of NT1 patients and 4 % of NT2 patients (Huang et al., 2017). Yet another study only included one person compared to no one in the control group (Alasim et al., 2020). In a third study by Filardi et al. there appeared to be a trend toward more OCD symptoms in people with narcolepsy, however this trend was not statistically significant (Filardi et al., 2017). Filardi et al. made use of self-report questionnaires and excluded patients with a previous psychiatric disorder which may explain why the level of significance was not reached. Sample sizes of the studies conducted by Filardi et al. and Alasim et al. were also only half the sample size of the study by Hansen et al. possibly leading to an underdiagnosis of the comorbidity in these studies.
Similarly, there is only one study available on the comorbid presence of personality disorders in narcolepsy (Kales et al., 1982) and two controlled studies regarding the presence of comorbid intellectual disability (Feketeova et al., 2020; Lee et al., 2017), which did not provide conclusive results.
The included studies show that an autism spectrum disorder (ASD) is comorbidly present in narcolepsy in 2.3 % to 8.1 % of cases (Hansen et al., 2023; Nevsimalova et al., 2022; Szakacs et al., 2015; Yeh et al., 2020; Huang et al., 2017). However rates of developmental disorders may be underestimated in adult populations (like the populations studied by Nevsimalova et al., Yeh et al. and Huang et al.) certainly in mild cases.
Rates of a comorbid occurrence with ADHD are much more diverse, ranging from 2.7 % to 45 %
(Filardi et al., 2017; Hansen et al., 2023; Lecendreux et al., 2015; Lee et al., 2017; Lopez et al., 2020; Modestino & Winchester, 2013; Nevsimalova et al., 2022; Qu et al., 2022; Szakacs et al., 2015; Yeh et al., 2020; Chin et al., 2023, Chin et al., 2024; Huang et al., 2017). However, a comorbid occurrence of ADHD was significantly more frequent in patients with narcolepsy than in controls in all controlled studies (Filardi et al., 2017; Huang et al., 2016; Lecendreux et al., 2015; Lee et al., 2017; Ruoff et al., 2017; Yeh et al., 2020). Again, as with ASD, there may be underdiagnosis of comorbid ADHD in adult narcolepsy patients. The comorbid occurrence of ADHD and narcolepsy could, on the one hand, be due to the fact that disturbed sleep and increased daytime sleepiness in narcolepsy lead to disturbed attention (Nevsimalova et al., 2022), which is also verified by a cohort study revealing that patients with narcolepsy exhibit more severe ADHD features of the inattentive type (Qu et al., 2022). More hyperactive-impulsive symptoms occurred in NT1 patients potentially indicating that hypocretin also plays a role in the modulation of impulsivity (Qu et al., 2022). In addition, patients with narcolepsy show changes in the activation of the executive system in the prefrontal cortex, which is also part of the attention system in ADHD (Nevsimalova et al., 2022). Additionally, there would be an overlap between the genetic risk for narcolepsy and that for ADHD, and neuronal inflammation is part of both the development of narcolepsy and ADHD. Neuroinflammation alters the levels of monoamine neurotransmitters such as dopamine and norepinephrine but also histamine and orexin (Bioulac et al., 2020).
In this literature review we attempted to provide an overview of the prevalence of psychiatric comorbidity in narcolepsy. Since we included many different psychiatric disorders and the included papers are overall heterogeneous, no additional statistics were applied which can be seen as a limitation of this review. In addition, uncontrolled studies and case reports were also included.
There is a need for future studies to resolve some of the discrepancies in the current literature. Ideally, these studies should have a longitudinal design and large cohorts should be meticulously diagnosed for both narcolepsy and psychiatric disorders.
For clinicians and patients it is important to be aware of the high comorbidity of psychiatric disorders and narcolepsy.
In this way first symptoms of psychiatric disorders can be detected earlier, potentially enabling faster treatment and thus leading to better quality of life of patients with narcolepsy. Symptoms of narcolepsy and psychiatric disorders may overlap, so careful exploration is needed not to mistake one disorder for another. Comorbidity can also influence treatment in a bidirectional way. It can for example be important to monitor psychotic symptoms carefully when prescribing stimulants in patients with narcolepsy who have a specific vulnerability for psychosis. The other way around, clinicians should realize that pharmacological treatment of psychiatric disorders, like some antidepressants or antipsychotics, may worsen symptoms of fatigue and sleepiness in some patients with narcolepsy.
Overall psychiatric disorders are more prevalent in patients with narcolepsy, but prevalence rates vary widely across studies and disorders. Higher prevalence of comorbid depression, anxiety disorders and ADHD is reported in narcolepsy. For other psychiatric disorders, current evidence is less conclusive. For optimal patient care, it is important for clinicians and care organizations to be aware of this comorbidity between psychiatric disorders and narcolepsy.
MVDB is supported by grants from the Funds Malou, Perano, Georgette Paulus, JMJS Breugelmans and Gabrielle, François and Christian De Mesmaeker, Managed by the King Baudouin Foundation of Belgium (No. 2021-J1990130–222,081), the KU Leuven (C2M/23/053, GPUM/22/022 and CELSA/24/019), Paris Brain Institute & Mission Lucidity (Big Brain Theory program 4 – 2024) and the Klinische onderzoeks-en opleidingsraad (KOOR) of the University Hospitals Leuven.
However, no funding source was involved in the study design, collection, analysis and interpretation of data, writing of the report and decision to submit the article for publication.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.