INTRODUCTION
Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness (EDS) and dysregulation of rapid eye movement (REM) sleep, which may include symptoms such as cataplexy, sleep paralysis, and hypnagogic hallucinations [1-3]. Clinically, narcolepsy is classified into two types: type 1, characterized by the presence of cataplexy and/or hypocretin deficiency, and type 2, which lacks cataplexy and retains hypocretin function. In addition to its clinical phenotype, narcolepsy has long been recognized as a disorder with a significant genetic and familial component [4,5]. Previous family and twin studies have consistently shown that narcolepsy has a familial aggregation, along with a higher prevalence of sleep-related and psychiatric symptoms among first-degree relatives, even when there is no formal narcolepsy diagnosis [6,7].
Previous family-based studies indicate that first-degree relatives of patients with narcolepsy experience higher rates of subclinical sleep disturbances, increased sleepiness, and mood and behavioral symptoms compared to the general population [8,9]. These observations suggest that shared genetic or early environmental factors in narcolepsy may impact neuropsychiatric functioning [10].
Narcolepsy is increasingly recognized as a condition that carries a significant neuropsychiatric burden [11,12]. Depressive symptoms and attentional difficulties are common and often lead to significant functional impairment and a reduced quality of life [13,14]. However, interpreting these symptoms is challenging because key features of depression and attention-deficit/hyperactivity disorder (ADHD)—such as fatigue, impaired concentration, and psychomotor slowing—substantially overlap with the direct consequences of poor sleep quality and EDS [15-18].
Narcolepsy has a strong genetic association with HLADQB1* 06:02, indicating an inherited susceptibility to the disease. While most first-degree relatives do not exhibit overt narcolepsy, they may still be predisposed to subclinical symptoms due to shared genetic risk. From a neurobiological perspective, narcolepsy, especially type 1, is characterized by the loss of orexin (hypocretin) neurons, which are involved not only in wakefulness but also in emotional regulation and stress response [19]. These observations suggest that mood symptoms in narcolepsy may stem, at least in part, from an underlying genetic vulnerability. In contrast, attentional difficulties seem to be more directly linked to EDS and sleep fragmentation [12,20].
In family members of individuals with narcolepsy, it is particularly important to distinguish between symptoms that reflect underlying vulnerability and those that are secondary to sleep-related factors. Frequent sleep disturbances and daytime sleepiness can confound self-reported depressive and attentional symptoms [16,21]. Family-based comparisons offer a valuable framework for assessing whether psychological symptoms persist beyond sleep disturbances. If depressive symptoms indicate a shared vulnerability, they should remain elevated in first-degree relatives even after accounting for sleep-related factors. In contrast, symptoms that are primarily secondary to sleep disruption are expected to diminish following such adjustments [22-28].
This study examined depressive symptoms and ADHD-related traits in patients with narcolepsy and their first-degree relatives. It assessed the persistence of group differences after adjusting for sleep-related factors and compared the findings between narcolepsy type 1 (NT1) and type 2 (NT2) [8].
METHODS
Study Design and Participants
Participants were recruited from the sleep clinic at St. Vincent’s Hospital and its affiliated medical centers. The sample included three groups: 1) patients with narcolepsy (Group G2; n=253), 2) first-degree relatives of these patients (Group G0; n=156), and 3) healthy controls (Group G1; n=204). Patients were consecutively recruited during routine clinical visits. Board-certified sleep specialists diagnosed narcolepsy following the criteria outlined in the International Classification of Sleep Disorders, Third Edition. The diagnostic evaluation involved clinical assessment, overnight polysomnography, and a Multiple Sleep Latency Test (MSLT). NT1 (n=156) was characterized by the presence of cataplexy and/or cerebrospinal fluid hypocretin deficiency, along with MSLT findings (mean sleep latency ≤8 minutes with ≥2 sleep-onset REM periods). NT2 (n=97) was diagnosed in patients who met the MSLT criteria without experiencing cataplexy. Healthy controls were recruited from the community through advertisements. Potential participants underwent a brief clinical screening interview conducted by trained research staff to exclude anyone with a history of diagnosed narcolepsy or a family history of the disorder. Individuals with major neurological or severe psychiatric disorders were also deemed ineligible for participation. All procedures received approval from the Institutional Review Board of St. Vincent’s Hospital, and informed consent was obtained from all participants (No. VC-11QISE0225).
Measures
Depressive symptoms were assessed using the Beck Depression Inventory-II (BDI-II), a widely used 21-item self-report scale in both clinical and research settings. Attention problems were measured with the Adult ADHD Self-Report Scale (ASRS). Subjective sleep quality and daytime sleepiness were evaluated using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS).
Detailed clinical and psychological profiles were assessed using the following validated instruments:
• BDI-II: A 21-item self-report scale measuring the severity of depressive symptoms over the past 2 weeks. Scores range from 0 to 63, with higher scores indicating more severe depression [29].
• ASRS: An 18-item instrument developed by the World Health Organization to screen for adult ADHD symptoms. Total scores were used to assess attentional difficulties [30].
• PSQI: A 19-item questionnaire assessing subjective sleep quality and disturbances over a one-month period. A global score >5 indicates poor sleep quality [31].
• ESS: A self-administered questionnaire measuring the subject’s general level of daytime sleepiness. Scores ≥10 indicate EDS [32].
Information on clinical comorbidities and pharmacological treatments was collected through standardized patient questionnaires and verified against clinical records. This included sleep-related comorbidities (e.g., obstructive sleep apnea, insomnia, REM sleep behavior disorder, restless legs syndrome), psychiatric diagnoses (e.g., depressive disorders, ADHD), and current medications (e.g., psychostimulants, antidepressants).
Demographic variables included age, sex, and body mass index (BMI). Due to the strong associations between sleep measures and psychological symptoms, PSQI and ESS were included as key covariates in all adjusted analyses.
Statistical Analysis
Descriptive statistics were calculated as means±standard deviations for continuous variables and as frequencies (%) for categorical variables. Group differences in demographic and clinical characteristics were examined using one-way analysis of variance or chi-square tests. To assess the independent effects of group status on depressive and attentional symptoms, analysis of covariance (ANCOVA) was conducted, adjusting for age, sex, BMI, sleep quality (PSQI), and EDS (ESS). Prior to analysis, assumptions for ANCOVA, including normality and homogeneity of variance, were evaluated. When significant group effects were observed, Bonferroni-corrected post hoc comparisons were performed. Statistical significance was defined as p<0.05 (two-tailed).
RESULTS
A total of 613 participants were included in the analysis, consisting of patients with narcolepsy, first-degree relatives, and healthy controls. Demographic and clinical characteristics are summarized in Table 1. Patients were, on average, younger and exhibited significantly higher BMI, poorer sleep quality, and greater daytime sleepiness compared to controls. First-degree relatives displayed intermediate levels of sleep disturbance (Table 1).
Unadjusted analyses revealed that patients had substantially higher PSQI and ESS scores, indicating severe sleep fragmentation and EDS. They also reported high levels of depressive symptoms (BDI-II mean, 27.51) and attention symptom scores (ASRS mean, 11.47). Further subgroup analysis within the patient group identified distinct patterns. Notably, while NT1 is characterized by orexin deficiency, no significant differences were found between NT1 and NT2 regarding depressive symptoms (BDI-II: 25.51±15.65 vs. 26.29±15.96, p=0.704), sleep quality (PSQI, p=0.342), or inattention (ASRS, p=0.240). The only significant difference observed between the two subtypes was in daytime sleepiness, with NT1 patients reporting higher ESS scores than NT2 patients (17.76±4.20 vs. 15.31±4.69, p<0.001).
First-degree relatives exhibited intermediate sleep burden, with higher ESS and PSQI values than controls, suggesting subclinical sleep disturbance within families (Table 1).
In the patient group (G2), the prevalence of comorbid depressive disorders was 26.0% (NT1: 28.7%, NT2: 21.6%), while ADHD was diagnosed in 3.5% of patients (NT1: 3.8%, NT2: 3.1%). Notably, 89.8% of patients were receiving psychostimulants, and 31.9% were on antidepressants at the time of assessment. Despite this treatment, the mean BDI-II score remained high at 27.46±16.59, indicating significant residual depressive symptoms (Table 1).
Correlation analyses revealed strong associations between sleep measures and psychological outcomes: PSQI–ESS (r=0.655), PSQI–BDI (r=0.640), ESS–BDI (r=0.672), and ESS–ASRS (r=0.706). Depressive symptoms were strongly correlated with poor sleep quality (r=0.64, p<0.001) and daytime sleepiness (r=0.67, p<0.001) (Table 2). These strong correlations between sleep measures (PSQI, ESS) and both depressive (BDI-II) and attentional (ASRS) symptoms highlight the importance of including sleep quality and daytime sleepiness as covariates in subsequent adjusted analyses.
After adjusting for demographic variables, sleep quality, and EDS, depressive symptoms remained significantly elevated in patients compared to controls. ANCOVA revealed a robust main effect of group on the BDI-II total score (F=25.03, p<0.001) (Table 2). When clinical cutoff values were applied, the proportions of participants exceeding the thresholds for depressive symptoms (BDI-II), poor sleep quality (PSQI), and EDS (ESS) significantly differed among patients, first-degree relatives, and controls (Table 3).
Item-level ANCOVA identified a selective symptom in depression that retained a significant group effect after adjustment: sadness (Item 1), past failure (Item 3), loss of interest/anhedonia (Item 13), and changes in sleeping (Item 16) (Table 4). This profile is notable because it emphasizes affective–cognitive components (sadness, negative self-appraisal, anhedonia) alongside a sleep-related item that may partially reflect both narcolepsy physiology and depressive sleep disturbances.
Importantly, first-degree relatives showed higher adjusted depressive scores compared to the control group, while the adjusted differences in attention symptoms were no longer statistically significant (F=1.45, p=0.236) (Table 5). The lack of significant adjusted group effects indicates that attentional complaints in narcolepsy are primarily secondary to sleep disruption rather than indicative of an intrinsic ADHD-like phenotype.
DISCUSSION
In this study, we examined depressive symptoms and ADHD-related traits in patients with narcolepsy and their first-degree relatives. We specifically focused on whether observed group differences persisted beyond the effects of sleep-related factors and varied by narcolepsy subtype.
Depressive Symptoms of Family and Patients after Adjustment for Sleep-Related Factors
The key finding was that differences in BDI-II scores between groups remained significant even after adjusting for PSQI and ESS. If depressive symptoms were solely a consequence of poor sleep, controlling for these factors should have diminished the differences between patients and controls. However, even after accounting for subjective sleep quality and daytime sleepiness, first-degree relatives still exhibited higher depressive symptom scores than controls. This suggests that the increased depressive symptoms in relatives cannot be entirely attributed to sleep-related issues. While these results do not confirm a causal or biological mechanism, they indicate that susceptibility to depressive symptoms may extend beyond sleep disturbances in families affected by narcolepsy [22,28].
Item-level analyses of the BDI-II revealed a selective depressive profile rather than a general elevation of symptoms. After adjustments, persistent group differences were observed in sadness (Item 1), past failure (Item 3), loss of interest/anhedonia (Item 13), and sleep-related complaints (Item 16). These items conceptually represent affective tone, negative self-appraisal, and motivational dysfunction, indicating that depression in narcolepsy may primarily involve reward-related and cognitive-affective dimensions rather than a global mood disturbance. The ongoing presence of anhedonia may align with evidence suggesting that orexin signaling plays a role in reward salience and dopaminergic motivation, although it is not the sole determinant [19].
Orexin neurons project to monoaminergic and limbic circuits that are involved in reward processing, mood regulation, and stress responsiveness. The loss of these neurons may lead individuals to experience reduced behavioral activation and diminished reward responsiveness, thereby increasing their vulnerability to depressive symptoms [22,24-26]. Sleep-related complaints (Item 16) require cautious interpretation, as sleep disruption is intrinsic to narcolepsy. However, their persistence after adjustment indicates that residual sleep-related distress may represent a mixed construct that includes both disease-related sleep dysregulation and depression-associated sleep complaints [22,24-26].
Our data do not support a simple model in which orexin deficiency directly determines the severity of depressive symptoms. BDI-II scores did not differ between NT1 and NT2 in our sample, despite the well-established hypocretin deficiency in NT1. Importantly, this lack of difference should not be interpreted as evidence that orexin is irrelevant to mood symptoms [24,25]. NT2 is typically defined by the absence of documented hypocretin deficiency; however, orexin dysfunction may still be present in functional forms (e.g., altered receptor sensitivity, downstream signaling, or network-level regulation) even when hypocretin levels fall within the typical range. Consequently, the similar BDI-II scores observed in NT1 and NT2 may suggest that depressive symptoms are influenced by mechanisms shared across narcolepsy subtypes—such as chronic sleep–wake instability, sustained functional impairment, and stress-related dysregulation—rather than being solely attributed to hypocretin concentration [24,25]. In this framework, dysregulation of orexin may serve as one contributing factor within a broader set of interacting processes, rather than acting as the sole driver of depressive symptoms.
Attention Symptoms after Adjustment for Sleep-Related Factors
In contrast to depression, the apparent attentional phenotype diminished after adjusting for covariates. Although patients exhibited higher unadjusted ASRS scores, the adjusted group effect was not significant, and first-degree relatives did not show a clear elevation compared to controls. This pattern suggests that self-reported ADHD-like symptoms in narcolepsy may largely stem from state-dependent effects of sleepiness and poor sleep quality (e.g., vigilance lapses, slowed processing, and reduced executive control) rather than representing a stable ADHD trait. In practice, optimizing sleep-wake management before reassessing attention may be beneficial. Future studies utilizing structured ADHD interviews and objective neuropsychological testing could help clarify whether a distinct attentional liability exists in certain families.
Strengths and Limitations
This study has several strengths. First, the inclusion of first-degree relatives alongside healthy controls allowed for more comprehensive group comparisons beyond traditional patient-control designs. Second, adjusting for subjective sleep quality and EDS minimized sleep-related confounding when assessing depressive and attentional symptoms. Third, conducting an item-level analysis of depressive symptoms provided a more detailed characterization of symptom profiles, rather than relying solely on total scores.
However, several limitations should be noted. First, the cross-sectional design limits causal inference and does not enable the determination of temporal relationships between sleep disruption and psychological symptoms. Second, psychological symptoms were assessed using self-report instruments without objective cognitive testing. Third, not all participants underwent structured psychiatric diagnostic interviews, which may affect the accuracy of psychiatric comorbidity assessments. Fourth, most patients were receiving pharmacological treatment, including psychostimulants and antidepressants, which could have influenced their self-reported symptom severity. Finally, while healthy controls were screened to exclude major sleep and psychiatric disorders, the lack of structured diagnostic screening raises the possibility of undetected subclinical conditions.
Conclusion
In our study involving patients, first-degree relatives, and controls, we found that depressive symptoms remained elevated even after considering subjective sleep quality and daytime sleepiness. In contrast, ADHD-like complaints reported on a self-report scale did not show the same pattern. These findings suggest that depressive symptoms may indicate a shared vulnerability among families affected by narcolepsy, while attentional complaints may be more directly related to sleep disruption. To further investigate these implications, future research should employ prospective designs that include biomarker analysis and objective cognitive assessments.
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