Smoking, Alcohol, Drug Use, Abuse and Dependence in Narcolepsy and Idiopathic Hypersomnia: A Case-Control Study

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1 pii: sp NEUROLOGICAL DISORDERS Smoking, Alcohol, Drug Use, Abuse and Dependence in Narcolepsy and Idiopathic Hypersomnia: A Case-Control Study Lucie Barateau 1 ; Isabelle Jaussent, PhD 2 ; Régis Lopez, MD 1,2,3 ; Benjamin Boutrel, PhD 4 ; Smaranda Leu-Semenescu, MD 3,5 ; Isabelle Arnulf, MD, PhD 3,5 ; Yves Dauvilliers, MD, PhD 1,2,3 1 Sleep Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, France; 2 Inserm, U1061, Montpellier, France; Université Montpellier 1, Montpellier, France; 3 National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome, Paris, France; 4 Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Switzerland; 5 Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, AP-HP, Brain Research Institute (CRICM-UPMC-Paris6; Inserm UMR_S 975; CNRS UMR 7225), Sorbonne Universities, UPMC Univ Paris 06, Paris, France Study Objectives: Basic experiments support the impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Our aim was to assess the frequencies of smoking, alcohol and drug use, abuse and dependence in narcolepsy type 1 (NT1, hypocretin-deficient), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) (non-hypocretin-deficient conditions), in comparison to controls. We hypothesized that NT1 patients would be less vulnerable to drug abuse and addiction compared to other hypersomniac patients and controls from general population. Methods: We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 450 adult patients (median age 35 years; 41.3% men) with NT1 (n = 243), NT2 (n = 116), IH (n = 91), and 710 adult controls. All participants were evaluated for alcohol consumption, smoking habits, and substance (alcohol and illicit drug) abuse and dependence diagnosis during the past year using the Mini International Neuropsychiatric Interview. Results: An increased proportion of both tobacco and heavy tobacco smokers was found in NT1 compared to controls and other hypersomniacs, despite adjustments for potential confounders. We reported an increased regular and frequent alcohol drinking habit in NT1 versus controls but not compared to other hypersomniacs in adjusted models. In contrast, heavy drinkers were significantly reduced in NT1 versus controls but not compared to other hypersomniacs. The proportion of patients with excessive drug use (codeine, cocaine, and cannabis), substance dependence, or abuse was low in all subgroups, without significant differences between either hypersomnia disorder categories or compared with controls. Conclusions: We first described a low frequency of illicit drug use, dependence, or abuse in patients with central hypersomnia, whether Hcrt-deficient or not, and whether drug-free or medicated, in the same range as in controls. Conversely, heavy drinkers were rare in NT1 compared to controls but not to other hypersomniacs, without any change in alcohol dependence or abuse frequency. Although disruption of hypocretin signaling in rodents reduces drug-seeking behaviors, our results do not support that hypocretin deficiency constitutes a protective factor against the development of drug addiction in humans. Keywords: narcolepsy, hypersomnia, addiction, hypocretin/orexin, substance abuse Citation: Barateau L, Jaussent I, Lopez R, Boutrel B, Leu-Semenescu S, Arnulf I, Dauvilliers Y. Smoking, alcohol, drug use, abuse and dependence in narcolepsy and idiopathic hypersomnia: a case-control study. SLEEP 2016;39(3): Significance Experiments in animal models showed that disruption of hypocretin signaling reduced drug-seeking behaviors with a key impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Conversely, there is a lack of convincing human narcolepsy data on addiction. Our results emphasized the low frequency of addictive behaviors among patients with central hypersomnia, whether hypocretin-deficient or not, whether drug free or not, comparable to our control group and the general population. This observation was intriguing since psychostimulant drugs (methylphenidate, amphetamine, and modafinil to a lesser extent) are known to promote impulsivity, risk-taking behaviors and addiction. The absence of increased risk of addiction is reassuring for clinicians who manage patients with central hypersomnia, as they need to prescribe addictive drugs for years. Further research studies may focus on drug craving and relapse in these patients. INTRODUCTION Narcolepsy with cataplexy has been recently renamed narcolepsy type 1 (NT1) or hypocretin (Hcrt) deficiency syndrome in the new classification of sleep disorders. 1 NT1 is frequently comorbid with obesity, reduction of quality of life, mood symptoms, cognitive alterations, abnormal reward processing, and risk-taking behavior. 2 8 Hcrt-containing neurons arise in the lateral hypothalamus (LH) and project widely through the brain, 9 with a dense innervation of anatomical sites involved in arousal regulation, motivation and stress conditions. Hcrts have been implicated in the modulation of noradrenergic, 10,11 cholinergic, 12 serotoninergic, 13 and dopaminergic systems. 14 Several preclinical studies demonstrated the key role of the Hcrt system in the regulation of food- and drug-seeking behaviors using either pharmacological studies or transgenic mice models Indeed, Hcrt knockout (KO) mice showed reduced signs of withdrawal from morphine 20 and nicotine. 21 Hcrt receptor-1 KO mice selfadministered less cannabinoids 22 and showed a blockade of reinstatement of cocaine seeking after abstinence. 23 In addition, daily injections of Hcrt receptor-1 (Hcrtr-1) antagonist prevented cocaine-induced locomotor sensitization and Hcrt transmission played an important role in regulating alcohol, cannabis, nicotine, and opiate seeking behaviors Reward processing for food and abused drugs are conveyed primarily by Hcrt receptor-1, whereas Hcrt receptor-2 with different brain distribution regulates arousal and response to stress that also maintain alertness in such conditions. The Hcrt system is also involved in the affective dysregulation observed in alcohol-dependent patients during alcohol withdrawal 27 in abstinent smokers during nicotine withdrawal 28 and in cannabis abusers. 29 All these observations indicate a strong functional interaction between Hcrt and reward pathways, in both animals and human beings. Clinical experience suggests that NT1 patients treated with addictive amphetamine-like stimulants and/or sodium oxybate for years rarely develop substance abuse. Indeed, these observations together with recent studies suggested that hypersomniac SLEEP, Vol. 39, No. 3, Addiction and Narcolepsy Barateau et al.

2 patients, especially those Hcrt deficient, could be less vulnerable to drug abuse and addiction compared to the general population. 4,8,30,31 A small clinically based well-characterized population sample revealed similar substance/alcohol abuse between patients with NT1, NT2, and healthy controls; however, patients with a past history of addiction were excluded. 8 Recently, a phone interview (Sleep-EVAL) study addressing the frequencies of comorbid psychiatric disorders in patients with narcolepsy showed similar alcohol abuse and dependence compared to the general population. 4 Although human narcolepsy could provide a fascinating insight into the role of the Hcrt system in addiction development, treatment and prevention, there is a lack of convincing human narcolepsy data on this topic. The aim of this study was to evaluate by face-to-face clinical interview the frequency of smoking, alcohol and drug use and addiction in NT1 patients (Hcrt-deficient) compared to patients affected by other central hypersomnias: narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH), which are not associated with Hcrt-deficiency, and controls from the general population. METHODS Participants Four hundred fifty consecutive adult patients (median age: 35 years [range 17 to 84]; 41.3% men and 58.7% women) with a central disorder of hypersomnolence were recruited and classified based on their primary International Classification of Sleep Disorders diagnosis. 1 Data were collected from a national research program for rare hypersomnia diseases (Narcobank study) carried out in reference centers between 2008 and Patients were diagnosed on the basis of the following criteria: (1) NT1 (i.e., history of clear-cut cataplexy and mean MSLT latency 8 min with 2 sleep onset REM periods (SOREMPs) or CSF Hcrt-1 deficiency, < 110 pg/ml); (2) NT2 (i.e., mean MSLT latency 8 min with 2 SOREMPs, no cataplexy, absence of CSF Hcrt-1 deficiency if performed); and (3) IH (i.e., normal polysomnography, mean MSLT latency < 8 min with < 2 SOREMPs, or total sleep time 11 h/24 h on longterm polysomnography, and normal CSF Hcrt-1 levels > 200 pg/ml, if performed). At time of study, patients were drugnaïve or treated with psychostimulants, and/or anticataplectic drugs for NT1 only. Seven hundred ten adult subjects (median age: 29 years [range 18 to 81]; 70% women) were recruited as controls from the general population. All controls were community-dwelling adults who were recruited during the same period by means of advertisements and from local association networks. The eligibility criteria for the group controls included being > 18 years old, French speaking, and without any significant sleep or neurological disorders. All participants agreed to take part in this research program, which included a systematic interview, a clinical examination, completion of questionnaires, and a biological collection. A lumbar puncture was performed in 54 patients prior to the study to measure cerebrospinal fluid (CSF) Hcrt-1 levels. CSF samples were collected and aliquots were frozen and stored immediately at 80 C until used. Hcrt-1 levels were determined in duplicate from CSF samples by direct I 125 radioimmunoassay (Phoenix Pharmaceuticals, Belmont, CA). CSF Hcrt-1 levels 110 pg/ml were considered as low, intermediate between 110 and 200, and normal > 200 pg/ ml. All values were back-referenced to Stanford reference samples (HHMI Stanford University Center for Narcolepsy, Palo Alto CA). All participants gave their written informed consent for the study, which was approved by the local ethics committees (Comité de Protection des Personnes Ile de France 06). Main Study Outcome: Addiction The face-to-face clinical interview for both patients (drugnaïve or not) and controls included questions on regular alcohol consumption (wine, beer, aperitif, or strong alcohol), and on smoking status by reported cigarette consumption at time of study. Substance (alcohol and illicit drug) use, abuse, and dependence diagnosis during the last 12 months were determined using the corresponding Mini International Neuropsychiatric Interview (MINI) sections. 32 Only trained clinicians can use this questionnaire for a diagnosis of abuse or dependence. Excessive alcohol consumption was assessed with the following question: In the past 12 months, have you had 3 or more alcoholic drinks within a 3-hour period on 3 or more occasions? If yes, other questions on alcohol habituation and withdrawal symptoms were asked to assess dependence according to guidelines. 32 If not, other questions were presented to assess alcohol abuse (i.e., dependence preempts abuse) (see supplemental material). Excessive drug use was assessed with the following question: I am going to show you a list of street drugs or medicines: cannabinoids, cocaine, inhalants, tranquilizers, hallucinogens, narcotics, and miscellaneous. In the past 12 months, did you take any of these drugs more than once, to get high, feel better, or change your mood? 32 We excluded the use of psychostimulant (amphetamines and methylphenidate) category for this study as being potential treatment for central hypersomnia per se. Dependence and abuse were defined when the patient answered yes to further systematically asked questions (see supplemental material). Demographic and Clinical Variables For all patients and controls the standardized interview also included questions on (1) gender; (2) age at inclusion; (3) educational level (dichotomized as high [ 12 years of studies] and low [ < 12 years]); (4) body mass index (BMI) category (< 25, 25 29, 30 kg/m 2 ); (5) presence and severity of depressive symptoms assessed by the Beck Depression Inventory (BDI) (dichotomized as none/mild symptoms [ 19] and moderate/severe symptoms [ > 19]); (6) delay at the diagnosis (i.e., delay between the onset of narcolepsy symptoms and diagnosis of narcolepsy); and (7) Epworth Sleepiness Scale (ESS) score at time of evaluation. For sub-analyses, the following additional disease-related features were considered for patients only: (1) drug to treat excessive daytime sleepiness (modafinil, methylphenidate, amphetamine, pitolisant, mazindol, and sodium oxybate) and cataplexy (antidepressants SLEEP, Vol. 39, No. 3, Addiction and Narcolepsy Barateau et al.

3 and sodium oxybate) at time of evaluation; (2) high daily doses of drugs defined by methylphenidate > 100 mg, modafinil > 800 mg, sodium oxybate > 9 g, or mazindol > 6 mg were specifically reported; (3) the presence of hypnagogic hallucination, sleep paralysis, and the frequency of cataplectic attacks at time of study on a scale from 0 to 5 as defined earlier 33 (for NT1 patients), and the mean sleep latency and the number of sleep onset REM periods on MSLT at diagnosis. Statistical Analysis The sample is described using percentages for categorical variables and median and range for quantitative variables; the latter are mostly skewed according to the Shapiro-Wilk test. The first step was to compare tobacco, alcohol, and drug use between 2 groups (Controls and NT1 patients). A comparison of demographic and clinical characteristics between NT1 patients and controls was done using χ 2 test or Fisher exact test (for categorical variables) and Mann-Whitney test or Kruskal-Wallis test (for continuous variables) (Table 1). Univariate comparisons between NT1 patients and controls were made using logistic regression analysis and quantified using odds ratios (OR) and 95% confidence intervals (CI) for exposure variables (tobacco, alcohol, and drug use). ORs were adjusted for variables associated with NT1 (at P < 0.10) in Table 1 which could be potential confounders (Table 2). When appropriate (i.e., when for example, excessive alcohol consumption and weekly regular alcohol consumption were significantly associated with an outcome variable), the interaction terms were tested using the Wald-χ 2 test given by the logistic regression model. The second step was to compare tobacco, alcohol, and drug use among the 3 groups of hypersomnia patients (IH, NT2, and NT1). Chi-square tests were used to compare demographic and clinical characteristics among the 3 groups (Table 3). When a significant relationship was found, two-by-two comparisons were required to know whether groups within the study were significantly different. A correction for multiple comparisons with the Bonferroni method was used for the two-by-two comparisons. Multinomial regression models were used to study the association between tobacco, alcohol, and drug use among the 3 groups (Table 4). Significance level was set at P < Analyses were performed using SAS statistical software (version 9.4; SAS Inc, Cary, North Carolina). RESULTS Subject Characteristics Among the 450 consecutive patients with a diagnosis of central hypersomnia, 243 were affected with NT1, 116 with NT2, and 91 with IH. CSF Hcrt-1 levels were determined in 54 patients: 31 NT1 (all with low levels), 17 NT2 (one patient with intermediate level and 16 with normal levels), and 6 IH (all with Table 1 Demographic and clinical features of patients with NT1 compared with controls. Controls (n = 710) NT1 (n = 243) Variable n % n % Global P Gender Men < Women Age, in years < < Educational level, in years < < BMI, kg/m 2 < < > BDI score < > ESS at study inclusion 5 (0 19) 17 (1 24) < < > Continuous variables were expressed by median (minimum maximum) value. BDI, Beck Depression Inventory; BMI, body mass index; ESS, Epworth Sleepiness Scale; NT1, narcolepsy type 1. normal levels). The presence of HLA DQB1*06:02 was found in 88.2% of NT1, 32% of NT2, and 16.2% of IH. Comparisons between patients with NT1 and controls revealed significant differences for gender, age, educational level, BMI, BDI, and obviously ESS scores (P < , for all the comparisons; Table 1). Subsequent analyses on the relationship between tobacco, alcohol, drug use, and NT1 were thus adjusted for these factors, except for ESS associated with NT1 per se (Table 2). Between-group differences in central hypersomnias were found for gender, age, BMI, ESS, and use of stimulant at time of study (P < 0.05 for all the comparisons; Table 3). Subsequent analyses were thus adjusted for these factors plus educational level associated with P < 0.10 (Table 4). Two-by-two comparisons revealed more women and lower BMI in patients with IH than NT1, and higher ESS in NT1 than NT2. Patients with NT1 were older than IH and NT2. Individual post hoc comparisons revealed no significant differences between drug intake and disease categories. Regular Tobacco and Alcohol Use The proportion of tobacco smokers was significantly higher in NT1 than controls (37.2% vs 21.7%) even after adjustments (Table 2). Heavy tobacco smokers (> 10 cigarettes/day) were more frequent in NT1 vs controls in both crude associations and adjusted models (Table 2, Model 2, P < ). The proportion of tobacco smokers was also significantly higher in NT1 SLEEP, Vol. 39, No. 3, Addiction and Narcolepsy Barateau et al.

4 Table 2 Tobacco, alcohol and drug use of patients with NT1 compared with controls. Controls (n = 710) NT1 (n = 243) Model 0 Model 1 Model 2 Variable n % n % OR (95% CI) Global P OR (95% CI) Global P OR (95% CI) Global P Regular alcohol use No < < Yes, 4 drinks/week (0.90;1.73) 1.13 (0.80;1.58) 1.41 (0.97;2.06) Yes, > 4 drinks/week (2.24;5.67) 2.85 (1.70;4.75) 3.44 (1.96;6.04) Regular tobacco use No current smoker < < < Yes 10 cigarettes/day (0.68;1.58) 1.07 (0.69;1.66) 1.29 (0.80;2.07) Yes, > 10 cigarettes/day (4.12;10.8) 6.37 (3.84;10.6) 7.33 (4.24;12.7) Excessive alcohol use No Yes (0.27;0.77) 0.42 (0.24;0.73) 0.50 (0.28;0.89) Alcohol abuse or dependence No Yes (0.21;1.84) 0.57 (0.18;1.75) 0.63 (0.20;1.98) Excessive drug use No Yes (0.65;2.14) 1.26 (0.67;2.37) 1.33 (0.67;2.64) Drug abuse or dependence No Yes (0.38;3.98) 0.96 (0.28;3.28) 0.77 (0.20;3.03) Model 0 is crude association. Model 1 was adjusted for gender, age, and educational level. Model 2 was adjusted for Model 1 plus BMI and BDI score. BDI, Beck Depression Inventory; BMI, body mass index; CI, confidence interval; NT1, narcolepsy type 1; OR, odds ratio. Table 3 Demographic and clinical features of patients according to categories of central hypersomnias. IH (n = 91) NT2 (n = 116) NT1 (n = 243) Variable n % n % n % Global P Post Hoc Gender Women IH < NT1* Men Age, in years < < NT2 < IH < NT Educational level, in years < BMI, kg/m 2 < IH < NT > BDI score > ESS at study inclusion 17 (6 24) 16 (4 24) 17 (1 24) 0.04 NT2 < NT1 < NT2 < NT Drugs intake at inclusion No Yes Continuous variables were expressed by median (minimum maximum) value. *A significant association was found between gender and the 3 groups (global P value < 0.05) and two-by-two comparisons indicate that only the percentage of men was greater in IH group than in NT1 group. BDI, Beck Depression Inventory; BMI, body mass index; ESS, Epworth Sleepiness Scale; IH, idiopathic hypersomnia; NT1, narcolepsy type 1; NT2, narcolepsy type 2. SLEEP, Vol. 39, No. 3, Addiction and Narcolepsy Barateau et al.

5 Table 4 Association between tobacco, alcohol and drug consumptions and the different categories of central hypersomnias. IH (n = 91) NT2 (n = 116) NT1 (n = 243) Model 0 Model Model 2 Variable n % n % n % Global P Global P Global P Regular alcohol use No Yes, 4 drinks/week Yes, > 4 drinks/week Regular tobacco use No current smoker Yes 10 cigarettes per day Yes, > 10 cigarettes per day Excessive alcohol use No Yes Alcohol abuse or dependence No NA NA NA Yes Excessive drug use No Yes Drug dependence or abuse No NA NA NA Yes Model 0 is crude association. Model 1 was adjusted for gender, age, educational level and BMI. Model 2 was adjusted for Model 1 plus ESS at the evaluation and drugs intake at the evaluation. BMI, body mass index; ESS, Epworth Sleepiness Scale; IH, idiopathic hypersomnia; NA, not applicable; NT1, narcolepsy type 1; NT2, narcolepsy type 2. patients compared to NT2 and IH patients (37.2%, 25.2%, and 18.9%, respectively) even after adjustments (Table 4). Similar results were also observed for heavy smokers in both crude associations and adjusted models (Table 4, Model 2, P = ) with post hoc analyses showing an increased smoking habit in NT1. Current regular alcohol consumption (> 1 drink/week) was significantly higher in NT1 compared to controls (62.7% vs 51.6%), even in adjusted models (Table 2). We also observed an increased proportion of frequent alcohol drinkers (> 4 drinks/ week) among NT1 patients, even after adjustment (Table 2, Model 2, P < ). A significant proportion of frequent alcohol users was reported in NT1 compared to either NT2 or IH patients (Table 4, Model 0, P = 0.009); however, this difference was nonsignificant after adjustment. Alcohol and Drug Addictive Behaviors In contrast to an increased proportion of regular but controlled alcohol consumption, we report a decreased proportion of heavy drinkers among NT1 patients compared to controls (7.5% vs 15.2%, respectively) even in adjusted models (Table 2, Model 2, OR = 0.50, 95% CI = ). This result remained significant even after further adjustment for regular alcohol consumption (OR = 0.30, 95% CI = ), without significant interaction between excessive alcohol consumption and weekly regular alcohol consumption in NT1 (P = 0.49). Excessive alcohol consumption was found in 7.5% of NT1, 4.4% of NT2, and 2.2% of IH patients, with no between-group differences in crude and adjusted associations (Table 4). In addition, no significant differences were found between regular alcohol and tobacco consumption between either patients with IH vs controls, or NT2 vs controls. However excessive alcohol consumption was lower in patients with either IH or NT2 versus controls even after adjustment for potential confounders (OR = % CI = P = 0.02, OR = % CI = , P = 0.003, respectively). The percentage of patients with alcohol dependence or abuse was low (from 0 to 1.7% across the different hypersomnia categories, and 2.7% in healthy controls; Tables 2 and 4). Only 3 patients with NT1 were diagnosed with alcohol dependence, 2 patients (one NT1 and one IH) with alcohol abuse, and 19 healthy controls with alcohol dependence (n = 6) or abuse (n = 13). No between-group (either NT1 versus controls or between-hypersomnia disorder categories) differences were found for alcohol abuse or dependence. Excessive drug use during the past year was rare (from 2.3% to 6.9% across the different hypersomnia categories, and 5.9% in controls) without any significant group differences between either NT1 versus controls, or between central hypersomnia categories (Tables 2 and 4). Only 3 illicit substances (codeine, cocaine, and cannabis) were used by 22 patients and 40 controls. Twenty patients smoked cannabis (15 NT1), 2 patients used cocaine (one NT1 and one NT2), and 2 patients took codeine for non-medical use (one NT1 and one NT2). Overall, 40 controls smoked cannabis and 2 of them also used cocaine. Current illicit substance dependence or abuse was extremely low (from 0 to 1.74% across the different hypersomnia categories, and 1.4% in controls) that includes 4 NT1 (3 with SLEEP, Vol. 39, No. 3, Addiction and Narcolepsy Barateau et al.

6 dependence and one abuse), one NT2 with dependence and 10 controls (6 dependence and 4 abuse) (Table 2). Patients with NT1 with drug dependence did not overlap with those with alcohol dependence. Only one patient among the 450 (a patient with IH) took high doses of stimulants, with a mean daily dose of modafinil at 1,600 mg. No significant differences were found for excessive alcohol and drug use, abuse or dependence in patients with a central hypersomnia diagnosis or with NT1 only, whether being treated with stimulants or not. Finally, NT1 patients with excessive alcohol or drug use, dependence or abuse (n = 26) compared to other NT1 patients did not differ in terms of age, age at onset, gender, level of education, BMI, ESS, depressive symptoms, cataplexy frequency, presence of hypnagogic hallucination or sleep paralysis, stimulant use, and MSLT results (mean sleep latency and number of SOREMPs). DISCUSSION This large cross-sectional study explored the frequency of tobacco, alcohol and illicit drug use, abuse and dependence in a well-defined population of patients with NT1, NT2, and IH in comparison to controls, and took into account a large variety of potential confounders. We report here an increased proportion of alcohol and tobacco users among NT1 compared to controls, and an enhanced proportion of tobacco smokers in NT1 compared to other hypersomniacs, whereas alcohol drinking habit did not differ between-hypersomnia categories after adjustment for potential confounders. In contrast, heavy drinkers were significantly reduced in NT1 versus controls but not compared to other hypersomniacs. The proportion of patients with excessive illicit drug use, substance dependence, or abuse was low in all hypersomniacs, and in controls as well. The prevalence of tobacco use was recently estimated between 20% and 30% in the French general population, 34 and is consistent with our results, which show 21.7% of tobacco smokers in our control group. Smoking habits were higher in NT1 patients compared to controls and other hypersomnia categories. This observation was unexpected due to recent evidence supporting the reinforcing properties of the Hrct system in major drug abuse including nicotine ,35,36 Since we adjusted our results for ESS, increased smoking behavior found in NT1 compared to NT2 and IH subjects did not support the idea that Hcrt deficiency may prevent tobacco addiction, or at least smoking habit. However, nicotine is considered as a cognitive enhancer, even a psychostimulant. 36,37 Thus, tobacco smoking likely helps alleviate signs of sleepiness and should be considered as a self-treatment for the stimulant effect of nicotine. Interestingly, nicotine was shown to activate Hcrt neurons, suggesting a possible hypocretinergic contribution to its effects on arousal and cognition. 38 One assumption which needs to be further examined is that the stimulant effect of tobacco smoking is reduced in NT1 patients, thus eliciting increased tobacco consumption in order to get the stimulant effects of cigarette smoking. We found here an increased proportion of regular and frequent alcohol drinking habit in NT1 versus controls, but not compared to other hypersomniacs in adjusted models. In contrast, heavy alcohol drinkers were significantly reduced in NT1, N2, or IH versus controls, without between-hypersomnia group differences. The reduced heavy alcohol drinking found in all three groups may relate to its sedative properties, patients with central hypersomnia being less likely to use sleep-inducing substances given their difficulty maintaining alertness. Another significant contribution of our study is the demonstration of a low frequency of illicit substance/alcohol abuse or dependence in hypersomniac patients, whether being Hcrt-deficient or not. For this assessment, we focused on the alcohol and drug dependence/abuse categories based on the validated MINI diagnostic interview developed for DSM IV-TR and ICD-10 psychiatric disorders. 32 At the beginning of each section, screening questions on excessive substance use within the past year are presented followed by further questions to assess dependence and abuse. Current excessive alcohol or illicit substance (i.e., codeine, cocaine, and cannabis) use was found in 26 cases (11.2%), while dependence or abuse was found in only 8 NT1 patients (3.3%). Most importantly, we did not observe any significant differences among demographic, clinical, depressive symptoms, neurophysiological data, and drug status between addict and non-addict NT1 patients. Our current findings are consistent with our previous study, which showed the absence of association between phenotype characteristics and increased risk-taking behavior in NT1. 6 Accordingly, abnormal activity in reward brain circuits with absence of modulation of ventral tegmentum area during high reward expectancy was found in a functional magnetic resonance imaging study in NT1. 39 We found here no significant differences for illicit substance use, dependence or abuse between either NT1 patients versus controls or between- hypersomnia disorder categories. Narcolepsy was previously reported to be associated with comorbid psychiatric disorders, including major depression and social anxiety 2,39 ; however, only one study assessed alcohol abuse or dependence in patients with narcolepsy compared to controls, without any significant differences. 4 Interestingly, recent studies highlighted that 23 million people reported using cannabis during the past year in Europe including France, while cocaine users were around 4 million, ranging respectively from 0.8% to 11.2% and 0.1% to 3% of the general population. 34,40 Although major discrepancies in methods made the comparison between studies really problematic, they provided data for comparison. Our results emphasized the low frequency of addictive behaviors among patients with central hypersomnia, comparable to our control group and the general population. Moreover, patients with excessive alcohol or drug use, dependence, or abuse did not differ in terms of demographic, narcolepsy symptoms, stimulant use, and depressive symptoms compared to patients without addictive behaviors. In contrast to patients with NT1, all patients with IH and 80% to 90% of patients with narcolepsy without cataplexy have normal CSF Hcrt-1 levels, especially in absence of HLA DQB1*06:02 41 ; however, we found no significant differences between hypersomnia-group for excessive illicit substance/alcohol consumption, dependence, or abuse. Our results are consistent with a previous experimental study using the Balloon Analog Risk Task performed on a modest sample size population showing that substance/alcohol abuse and compulsive gambling were similar between patients with NT1, NT2, and healthy controls, although patients with a past history of addiction were surprisingly excluded from this study. 8 SLEEP, Vol. 39, No. 3, Addiction and Narcolepsy Barateau et al.

7 Our present study also demonstrated that patients with central hypersomnias whether Hcrt-deficient or not, drugfree, or medicated with psychostimulant (± anticataplectic) did not differ in the risk of excessive illicit substance/alcohol use, dependence, or abuse. This observation was intriguing since psychostimulants are known to promote impulsivity and risk-taking behaviors, notably by stimulating dopaminergic pathways. 42 We previously reported that patients with central hypersomnia whether Hcrt-deficient or not, drug-free or medicated with psychostimulant, did not differ in risk-taking behaviors. 43 Clinical experience suggests that patients with hypersomnia, including those with Hcrt deficiency (NT1) and those without (NT2 and IH), rarely exhibit stimulant abuse despite years of treatment with addictive compounds (methylphenidate, amphetamine, gamma-hydroxybutyrate, and modafinil to a lower extent). Moreover, these patients rarely developed withdrawal symptoms after stopping their stimulant medication. 31 The absence of increased risk of addiction is reassuring for clinicians who manage patients with central hypersomnia, as they need to prescribe addictive drugs for years. Although all of these observations do not support any change in vulnerability to develop drug addiction in Hcrt-deficient patients, they contrast with the promising use of non-selective Hcrt receptor antagonists to treat drug addiction. 30,31 This study has limitations. First, all 450 patients were not assessed for CSF Hcrt-1 levels which limits the comparison between Hcrt and non-hcrt deficiency categories. However, almost all patients with narcolepsy with clear-cut cataplexy had low CSF Hcrt-1 levels, 10% to 20% in narcolepsy without cataplexy, with normal values for patients with IH. 41,44 Second, although 450 orphan disease patients were included, the sample size is limited and under-powered to assess addictive behavior and its determinants when major endpoints occur in less than 2% of the population. The proportion of patients with excessive alcohol/drug use, substance dependence or abuse was low in all subgroups, with a potential under-power to detect significant differences between central hypersomnia categories whether Hcrt-deficient or not. Similarly, the impact of the different classes of stimulant compounds, and anticataplectic drugs (for NT1 patients) on addictive behaviors could not be assessed due to the small sample size of each subgroup. However we included for this study a well-defined population of patients with central hypersomnia in comparison to controls, and took into account a large variety of potential confounders including depressive symptoms but no other psychiatric comorbidities. Third, the method for acquiring subject responses with inperson interview may contribute to the low prevalence of substance abuse and recreational drug use. Hence, patients may be reluctant to disclose substance abuse with clinical interviews if assessment appeared linked to their clinical care. However, the MINI questionnaire is well-validated, was used by trained clinicians, the interviews took into account both opinions of the clinicians and participants. Patients are aware that the data are anonymized for this study. Finally, our study focused on alcohol/illicit drug use, abuse and dependence occurrence for the last 12-month period that precludes to evaluate its lifetime prevalence and whether addiction, if any, started before hypersomnolence onset or not. To conclude, we first described a low frequency of illicit drug use, dependence, or abuse in patients with central hypersomnia, whether Hcrt-deficient or not, and whether drugfree or medicated, in the same range as in controls. Conversely, heavy drinkers were rare in NT1 compared to controls but not to other hypersomniacs, without any change in alcohol dependence or abuse frequency. From a clinical point of view, this observation supports the prescription of drugs for alleviating signs of excessive daytime sleepiness, without any addiction risk. 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Arnulf - acquisition of data and revising the manuscript for content; B. Boutrel - Interpretation of data analysis, revising the manuscript for content. SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication July, 2015 Submitted in final revised form September, 2015 Accepted for publication October, 2015 Address correspondence to: Pr. Yves Dauvilliers, Service de Neurologie, Hôpital Gui-de-Chauliac, 80 Avenue Augustin Fliche, Montpellier Cedex 5, France; Tel: (33) (72 77); Fax: (33) ; ydauvilliers@yahoo.fr DISCLOSURE STATEMENT This was not an industry supported study. The study was financed by the PHRC AOM from the French Health Ministry (promotor: Assistance Publique Hôpitaux de Paris, IA). Dr. Dauvilliers has received funds for speaking, board engagements, and travel to conferences with UCB Pharma, Jazz, and Bioprojet. Dr. Arnulf has received funds for speaking and board engagements and travel to conferences with UCB pharma. The other authors have indicated no financial conflicts of interest. SLEEP, Vol. 39, No. 3, Addiction and Narcolepsy Barateau et al.