ORIGINAL RESEARCH published: 26 May 2021 doi: 10.3389/fpsyt.2021.663889 Insomnia Disorder in Adult Attention-Deficit/Hyperactivity Disorder Patients: Clinical, Comorbidity, and Treatment Correlates Christian Fadeuilhe 1,2,3,4*, Constanza Daigre 1,2,3,4 , Vanesa Richarte 1,2,3,4 , Lara Grau-López 1,2,3,4 , Raul F. Palma-Álvarez 1,2,3,4 , Montse Corrales 1,2,3,4 and Josep A. Ramos-Quiroga 1,2,3,4 1 Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 2 Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain, 3 Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Edited by: Institute, Barcelona, Spain, 4 Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Alexander Prehn-Kristensen, Barcelona, Spain University Medical Center Schleswig-Holstein, Germany Reviewed by: Introduction: Several investigations have been performed on insomnia symptoms in Rosalia Cesarea Silvestri, adult attention-deficit/hyperactivity disorder (ADHD). However, the relationship between University of Messina, Italy insomnia disorder and adult ADHD has been neglected in research. The main objective Noelia Ruiz-Herrera, Universidad Internacional De La of the current study is to analyze the differences between adult ADHD patients with and Rioja, Spain without insomnia disorder, in terms of ADHD clinical severity, medical and psychiatric *Correspondence: comorbidity, psychopharmacological treatment, and quality of life. Christian Fadeuilhe cfadeuilhe@vhebron.net Material and Methods: Two hundred and fifty-two adult patients with ADHD (mean age 37.60 ± 13.22 years; ADHD presentations—combined: 56.7%, inattentive: 39.7%, Specialty section: hyperactive/impulsive: 3.6%) were evaluated with an exhaustive clinical and This article was submitted to Psychopathology, psychological evaluation protocol including semistructured interviews (for comorbidities a section of the journal and ADHD assessment) and symptom rating scales for ADHD. The diagnosis of Frontiers in Psychiatry ADHD and insomnia disorder was made according to DSM-5 criteria. Furthermore, the Received: 03 February 2021 Accepted: 16 April 2021 Pittsburgh Sleep Quality Index, Insomnia Severity Index, and Epworth Sleepiness Scale Published: 26 May 2021 were administered. Citation: Results: Insomnia disorder was found in 44.4% of adult ADHD patients and was more Fadeuilhe C, Daigre C, Richarte V, Grau-López L, Palma-Álvarez RF, common in combined presentation (64.3%) and in patients with more ADHD severity. Corrales M and Ramos-Quiroga JA Comorbidities (both medical and psychiatric), especially mood disorders (42%), anxiety (2021) Insomnia Disorder in Adult Attention-Deficit/Hyperactivity disorder (26.8%), personality disorder (39.3%), and any substance use disorder (11.6%), Disorder Patients: Clinical, were associated with a higher insomnia disorder prevalence. ADHD stimulant treatment Comorbidity, and Treatment was related to lower insomnia disorder compared to patients without medication, as well Correlates. Front. Psychiatry 12:663889. as ADHD stable treatment. Additionally, worse health-related quality of life was associated doi: 10.3389/fpsyt.2021.663889 with insomnia disorder. Frontiers in Psychiatry | www.frontiersin.org 1 May 2021 | Volume 12 | Article 663889 Fadeuilhe et al. Insomnia Disorder and Adult ADHD Conclusion: Insomnia disorder is highly prevalent in adult ADHD and is related to higher ADHD severity and more psychiatric and medical comorbidities. Some stimulants and stable pharmacological ADHD treatment are associated with better outcomes of insomnia disorder. Keywords: attention deficit and hyperactivity disorder, insomnia disorder, adult ADHD, sleep disorder, severity, comorbidity INTRODUCTION Insomnia symptoms and several psychiatric comorbidities have a bidirectional relationship. Mental comorbidities increase Attention-deficit/hyperactivity disorder (ADHD) is a the risk of insomnia symptoms (21), and insomnia symptoms neurodevelopmental disorder characterized by the presence can also increase psychiatric comorbidity severity (19). In adult of persistent symptoms of inattention and/or hyperactive– ADHD patients, depressive symptoms, substance use disorder, impulsive behavior (1, 2). The Diagnostic and Statistical Manual and family history of mood disorders have been related to more of Mental Disorders 5th edition (DSM-5) (1) requires for adult insomnia symptoms (19, 21). In any case, few studies have been ADHD diagnoses five or more symptoms of inattention and/or conducted on this issue and their results are heterogeneous of hyperactivity/impulsivity. These symptoms should be present among adult ADHD (22). before the age of 12, have lasted 6 months, and interfere with The relationship between ADHD treatment and insomnia is daily life activities. ADHD frequently persists into adulthood not well-established. Van Veen et al. reported that about 80% of up to 40–60%, with the prevalence of ADHD in adults ranging untreated ADHD patients had sleep-onset insomnia symptoms between 2 and 3% (3). Adult ADHD has been related to several (23). On the other hand, atomoxetine and psychostimulants psychiatric comorbidities (note that comorbidity refers to any can induce insomnia symptoms as an adverse effect (24, 25). co-occurring disorder associated to ADHD), including anxiety However, after 2 months, this adverse effect seems to be mitigated disorders, mood disorders, substance use disorders (SUD), (26, 27), and some patients report improvement of insomnia behavior disorders, and sleep disorders (2). symptoms with methylphenidate (11). Insomnia disorder is one of the most frequent health problems Most of the studies have focused on insomnia symptoms in the adult general population, with an estimated prevalence instead of insomnia disorder, with insomnia disorder in adult between 6 and 15% (4, 5). However, less than half who suffer from ADHD patients being frequently neglected in research. Hence, insomnia disorder receive any type of treatment (6, 7). According the main objective of the current study is to analyze the to the DSM-5 (1), the insomnia disorder diagnosis is reached if differences between adult ADHD patients with and without there is a predominant dissatisfaction in the quantity or quality insomnia disorder, in terms of ADHD clinical severity, medical of sleep for at least three nights a week for at least 3 months and psychiatric comorbidity, psychopharmacological treatment, in initiating or maintaining sleep or early morning awakening, and quality of life. We hypothesize that insomnia disorder causing significant discomfort or clinical impairment in any area would be associated with greater clinical ADHD severity and of the person’s functioning. psychiatric comorbidities, an unstable ADHD treatment, and a In children, several researchers have reported a significant poorer health-related quality of life. association between ADHD and sleep disturbances, using Furthermore, we intend to analyze the differences between objective (actigraphy and polysomnography) and subjective patients with insomnia disorders and those with insomnia studies (8–10). In adults, the relationship between ADHD and symptoms. It is hypothesized that insomnia disorder would sleep disorders has been scarcely studied and several questions be associated with greater clinical ADHD severity and and controversies are unresolved (8). psychiatric comorbidities. The prevalence of insomnia symptoms in this population has a wide range between 43 and 85% (11–14), being more prevalent in women (15). In this vein, there are discrepancies regarding MATERIALS AND METHODS the relationship between insomnia and some variables associated with ADHD (11, 16). Considering the different presentations Study Design and Patients of ADHD, some investigations did not report differences (17), This cross-sectional study was conducted at the Adult ADHD whereas others report poorer quality of sleep in inattentive Program of the Hospital Universitari Vall d’Hebron in Barcelona presentation than in the combined presentation (13). However, (Spain). Participants referred for the first time to the ADHD other studies indicate that sleep problems are more frequently Program were recruited consecutively between April 2019 and associated with combined or hyperactive/impulsive presentation February 2020 whether ADHD diagnosis was confirmed. This (11, 18). Besides, ADHD severity may be associated with worse study was approved by the Clinical Research Ethics Committee insomnia presentation (19). The severity of insomnia and the of the Hospital Universitari Vall d’Hebron. All the participants consequent presence of daytime sleepiness has been related to a voluntarily agreed to get involved in the study and did not receive greater number of ADHD symptoms (20). any financial compensation. Frontiers in Psychiatry | www.frontiersin.org 2 May 2021 | Volume 12 | Article 663889 Fadeuilhe et al. Insomnia Disorder and Adult ADHD The participants fulfilled the following inclusion criteria: used scales to measure anxiety both in the clinic and in research were over 18 years, met ADHD criteria according to DSM-5, (Cronbach’s alpha = 0.91 for anxiety state and 0.89 for anxiety accepted to participate, and signed the informed consent. Those trait) (40). patients diagnosed with a sleep disorder other than insomnia The Barratt Impulsiveness Scale (BIS-11) was used for disorder (e.g., circadian rhythm disorder), intellectual disability measuring trait impulsivity as this instrument provides a total (intelligence quotient < 70), or any medical condition that could score and three subscale scores (cognitive impulsivity, motor explain the symptoms of ADHD (such as hearing and vision impulsivity, and unplanned impulsivity), and therefore, this scale impairments, epilepsy, traumatic brain injury, or thyroid disease) measures impulsivity as a multidimensional construct with good were excluded. reliability (Cronbach’s alpha = 0.83) (41). Instruments and Variables Insomnia and Other Sleep Disorders ADHD Diagnosis Three instruments were used to evaluate insomnia, sleep, and The Conners’ Adult ADHD Diagnostic Interview for DSM-IV related disorders. The first instrument was the Insomnia Severity part I (CAADID-I) (28) is a semistructured interview that Index (ISI) which evaluates insomnia severity in the last month collects information on ADHD from childhood to adulthood. and includes several sleep dimensions: severity of sleep onset, This instrument has good sensitivity (98.86%) and specificity sleep maintenance, early morning awakening problems, sleep (67.68%). The diagnostic precision was 91.46% and the kappa dissatisfaction, interference of sleep difficulties with daytime index concordance was 0.88 (28). functioning, noticeability of sleep problems by others, and The Diagnostic Interview for ADHD in Adults (DIVA 2.0) (29) distress caused by the sleep difficulties (42). The ISI sensitivity consists of a structured interview for ADHD that evaluates in was 82.4% and its specificity was 82.1% (43). The second adults each of the 18 symptom criteria for ADHD, in childhood instrument was the Pittsburgh Sleep Quality Index (PSQI). This and adulthood. This has good sensitivity (90.0%) and specificity is a 19-item self-reported instrument that assesses sleep quality (72.9%) (30). and its disturbances during the last month (44). The PSQI The Conners’ Adult ADHD Rating Scales—Long Version evaluates seven components: sleep quality, sleep latency, sleep (CAARS) is a 66-item self-reported instrument designed to duration, habitual sleep efficiency, sleep disturbance, use of assess ADHD in adults and has high degrees of sensitivity and sleeping medication, and daytime dysfunction. It is interpreted specificity, with an overall diagnostic efficiency rate of 85% (31). as the higher the score, the worse the subjective quality of sleep All these instruments were used to assess and confirm ADHD (45). The reported psychometric values are 89.6% for sensitivity diagnosis. They have been validated in a Spanish population, have and 86.5% for specificity (44). Finally, the third instrument used good psychometric properties in ADHD diagnosis (28, 29, 32), was the Epworth Sleepiness Scale (ESS) which is a self-reported and were used based on DSM-5 criteria. questionnaire with eight items that allows measuring the subject’s overall level of daytime sleepiness (46) with 70% sensitivity ADHD Severity and 55.6% specificity (47). These instruments are validated The clinical severity of ADHD was evaluated by using the and have good psychometric features for sleep assessment in ADHD Rating Scale (ADHD-RS). It is a self-administered 18- clinical research. item validated scale that provides a consistent way for clinicians to diagnose ADHD according to the DSM-5 criteria, with high Health-Related Quality of Life Evaluation sensitivity (81.9%) and specificity (74.7%) and a kappa coefficient The short-form questionnaire SF-36 was used for assessing the of 0.78 (33). Also, the Clinical Global Impression—Severity Scale health-related quality of life (HRQoL) (48). This instrument (CGI-S) was used. It is a reference scale in the evaluation of has eight domains (physical functioning, role limitations due the disorders severity and has also shown good psychometric to physical problems, bodily pain, general health perceptions, properties (34). vitality, social functioning, role limitations due to emotional problems, and mental health) that can be aggregated into two Psychiatric Comorbidities and Psychological summary measures: physical component summary (PCS) and Characteristics mental component summary (MCS). With a Cronbach’s alpha The Structured Clinical Interviews for Axis I (SCID-I) and Axis- > 0.85 (49), this instrument is one of the most accurate for II (SCID-II) (35) were used to evaluate patients’ psychiatric measuring HRQoL. comorbidities other than ADHD and insomnia disorder. SCID is considered the gold standard for all psychiatric research to increase reliability of diagnostic assessment and minimize clinical Procedure judgment that could lead to unreliable diagnoses (36). The Adult ADHD Program of the Hospital Universitari Vall The Beck-II Depression Inventory II (BDI-II) was administered d’Hebron is a multidisciplinary and comprehensive program that for measuring depressive symptomatology (37). This reference evaluates and treats referred patients from primary care centers, instrument in depression research has good sensitivity (89.6%) community mental health centers, and addiction treatment units. and specificity (86.5%) (38). Once referred to the ADHD Program, a complete assessment The State-Trait Anxiety Inventory (STAI) was used to measure of the patient is carried out to establish the diagnosis and anxiety (both trait and state) (39). It is one of the most widely the treatment. Frontiers in Psychiatry | www.frontiersin.org 3 May 2021 | Volume 12 | Article 663889 Fadeuilhe et al. Insomnia Disorder and Adult ADHD For the current study, the evaluation process consisted of differences in sociodemographic features except for employment five visits conducted by trained staff specialized in ADHD and characteristics (ADHD patients with insomnia disorder were sleep disorders (psychiatrists and psychologists). At the first visit, more unemployed). No significant differences were found the psychiatrist obtains a complete medical history, including on IQ between patients with insomnia disorder (101.08 ± a clinical approach for ADHD and insomnia disorder. Besides 11.91; T: 1.467; p = 0.144) and those without that disorder clinical assessment, a standardized evaluation with validated (103.42 ± 13.10) and neither also when family psychiatric instruments for ADHD (CAADID-I, DIVA 2.0, CGI-S) and records were compared. Any medical record and high body insomnia disorder (ISI, ESS, and PSQI) was conducted during index mass (BMI) were related to a higher prevalence of the first visit. At the next three visits, the psychologist carried out insomnia disorder. Regarding specific medical comorbidities, the CAARS, ADHD-RS, STAI, BDI, SF-36, SCID-I, and SCID-II due to the small sample size, some medical diseases could not interviews. Finally, at the fifth visit, the psychiatrist responsible be statistically analyzed. However, it was observed that the for the patients reviewed all the information and communicated group with insomnia disorder had a higher prevalence of pain the final diagnosis to the patient at the end of the study. The syndrome compared with the group without insomnia disorder diagnosis of insomnia disorder and ADHD was made by the (18.9 vs. 13.2%) but a lower prevalence rate regarding diabetes psychiatrist according to DSM-5 criteria. Whether the diagnosis mellitus (1.9 vs. 7.9%) and arterial hypertension (3.8 vs. 18.4%). of ADHD was confirmed, the patient was offered to perform No differences were found regarding other comorbidities, a psychiatric and psychological treatment and follow-up in the including cardiac, endocrine, gastrointestinal, respiratory, program (the treatment offered adheres to the clinical guidelines and neurological diseases. Similarly, several pharmacological for ADHD and insomnia disorder). treatments for those medical diseases were not analyzed because The Wechsler Adult Intelligence Scale-IV (WAIS-IV) was of small size. In any case, non-opioid analgesics were more used to assess patients’ intelligence quotient (IQ). used in patients with insomnia disorder (29.5 vs. 19.4%), while a fewer use of antihypertensive (4.5 vs. 22.6%) and Statistical Analysis oral antidiabetic medications (2.3 vs. 9.7%) was observed. Bivariate and multivariate analyses were executed using SPSS No differences were found for other medication categories version 20 for Windows. First, a descriptive analysis of all for medical conditions (e.g., endocrinological, neurological, variables as percentages, means, and standard deviations was cardiologic, and gastrointestinal medications) and psychiatric conducted. To compare ADHD patients with and without disorders (e.g., antidepressants, anxiolytics, anticonvulsants, insomnia disorder, chi-square test was used for nominal variables and antipsychotics). and Student’s t-test and ANOVA were used for quantitative ADHD patients with any psychiatric comorbidity are more variables. Bonferroni correction for multiple testing was used likely to present insomnia disorder, especially those who in order to minimize type I error. Finally, a logistic regression currently have mood disorders, anxiety disorder, any SUD, and analysis was conducted using the variables that remained any personality disorder (mainly cluster B personality disorders). statistical significance Bonferroni correction. In order to avoid Congruently, ADHD patients with insomnia disorder had higher collinearity, variables related to sleep were not included in the BDI-II, STAI, and BIS-11 scores. Finally, a worse HRQoL (both multivariate analyses. The dependent variable was insomnia physical and mental score) was observed in ADHD patients with disorder diagnosis (0 = no insomnia disorder and 1 = insomnia insomnia disorder (Table 1). disorder). A conditional entrance method was used to select Regarding ADHD variables and insomnia disorder, it was variables in the model. All statistical hypotheses were two-sided observed that insomnia disorder was most frequently presented and a value of p < 0.05 was considered statistically significant. in patients with the combined presentation of ADHD or with higher severity of ADHD (according to CGI, CAARS, and RESULTS ADHD-RS). Patients who were in any pharmacological treatment had less prevalence of insomnia disorder (specifically those Sample Recruitment and Sample Features receiving methylphenidate). Longer periods of stable treatment During the recruitment period, 252 patients (58% males; mean were associated with lower rates of insomnia disorder (Table 2). age 37.6 ± 13.2 years old) met the inclusion criteria and Regarding sleep assessment, patients with insomnia disorder accepted to participate in the study. In order of frequency, presented higher scores on the ISI scale and the PSQI. When the combined presentation of ADHD was the most common the PSQI subscales were analyzed, statistically significant results (56.7%), followed by the inattentive presentation (39.7%) and were reported. Likewise, patients with insomnia disorder had hyperactive/impulsive presentation (3.6%). Regarding insomnia, greater daytime sleepiness reported on the ESS. Finally, both 44.4% of patients met the criteria for insomnia disorder and the prescription of hypnotic medications and their number were 63.9% of the total sample participants had insomnia symptoms. higher in patients with insomnia disorder. No differences were found among the different groups of hypnotic medications and Results in Relation to the Presence of in the concomitant prescription of other psychotropic drugs Insomnia Disorder (Table 3). Sociodemographic, clinical, and psychometric variables are When the different insomnia phenotypes were analyzed, presented in Table 1 according to the presence of insomnia sleep-onset insomnia was the most frequent (32.9%), followed by disorder. Regarding the bivariate analysis, there were no sleep maintenance insomnia (31.0%), mixed insomnia (25.4%), Frontiers in Psychiatry | www.frontiersin.org 4 May 2021 | Volume 12 | Article 663889 Fadeuilhe et al. Insomnia Disorder and Adult ADHD TABLE 1 | Sociodemographic and clinical characteristics according to insomnia disorder. Total Insomnia disorder X 2 or t p % (n) or mean ± SD % or mean ± SD Yes (44.4%) No (55.6%) Sociodemographic features Sex (males) 58.7 (148) 58 59.3 0.4 0.841 Age 37.60 ± 13.22 38.49 ± 12.25 36.86 ± 13.95 0.967 0.334 Nationality (Spanish) 90.9 (229) 87.5 93.6 2.765 0.096 Marital status (single) 32.1 (81) 31.3 32.9 0.074 0.786 Level of studies (university studies) 56.3 (142) 50 61.4 3.304 0.069 Employment (employment) 59.5 (150) 52.7 65 6.098 0.047 Clinical characteristics Family psychiatric records 51.6 (130) 58 46.4 3.357 0.067 BMI 25.25 ± 4.41 26.24 ± 5.01 24.46 ± 3.70 3.126 0.020 Any medical records 36.5 (92) 47.3 27.9 10.170 0.001* Previous psychiatric comorbidities 63.1 (159) 76.8 52.1 16.227 < 0.0001* Mood disorders 44.0 (111) 53.6 36.4 7.419 0.006 Depressive disorders 27.0 (68) 32.1 22.9 2.723 0.099 Adaptation disorders 23.0 (58) 30.4 17.1 6.132 0.013 Anxiety disorders 32.5 (82) 45.5 22.1 15.511 < 0.0001* Bipolar disorders 0.8 (2) 0.9 0.7 0.025 0.874 Substance use disorders 23.8 (60) 34.8 15 13.476 < 0.0001* Alcohol use disorder 12.7 (32) 18.8 7.9 6.660 0.010 Cannabis use disorder 17.9 (45) 24.1 12.9 5.369 0.021 Cocaine use disorder 10.3 (26) 15.2 6.4 5.149 0.023 Any current psychiatric comorbidities 49.2 (124) 69.6 32.9 33.688 < 0.0001* Current psychiatric comorbidities (without PD) 46.0 (116) 66.1 30 32.589 < 0.0001* Any mood disorders 26.2 (66) 42 13.6 25.948 < 0.0001* Depressive disorders 8.7 (22) 15.2 205 10.521 0.001 Adaptation disorders 17.5 (44) 26.8 10 12.165 < 0.0001 Anxiety disorders 17.9 (45) 26.8 10.7 10.957 0.001 Bipolar disorders 0.8 (2) 0.9 0.7 0.250 0.874 Autism disorders 4.0 (10) 3.6 4.3 0.083 0.773 Any substance use disorders 7.5 (19) 11.6 4.3 4.784 0.029 Alcohol use disorders 4 (10) 6.2 2.1 2.754 0.097 Cannabis use disorders 4.4 (11) 6.2 2.9 1.716 0.190 Cocaine use disorders 2 (5) 3.6 0.7 2.612 0.106 Any personality disorders 27.4 (69) 39.3 17.9 14.369 < 0.0001 Cluster A personality disorder 0.8 (2) 1.8 0 2.52 0.112 Cluster B personality disorder 10.7 (27) 16.1 6.4 6.048 0.014 Cluster C personality disorder 12.7 (32) 16.1 10 2.069 0.150 Personality disorder not specified 3.2 (8) 3.6 2.9 0.103 0.748 Psychometric features Depressive symptoms (BDI) 11.44 ± 10.27 15.81 ± 10.74 7.95 ± 8.41 6.344 < 0.0001* Anxiety trait (STAI) 28.73 ± 12.81 34.84 ± 11.25 23.84 ± 11.87 7.485 < 0.0001* Anxiety state (STAI) 25.86 ± 13.85 32.14 ± 13.73 20.84 ± 11.76 7.038 < 0.0001* Impulsivity (BIS-11) 66.45 ± 16.08 70.93 ± 13.82 62.86 ± 16.89 4.078 < 0.0001* Physical component summary of HRQoL (SF-36) 49.79 ± 8.47 47.15 ± 9.05 51.91 ± 7.35 4.509 < 0.0001* Mental component summary of HRQoL (SF-36) 41.86 ± 11.32 34.26 ± 9.07 47.94 ± 9.04 11.916 < 0.0001* PD, personality disorder. *The result is statistically significant after Bonferroni correction. Frontiers in Psychiatry | www.frontiersin.org 5 May 2021 | Volume 12 | Article 663889 Fadeuilhe et al. Insomnia Disorder and Adult ADHD TABLE 2 | ADHD variables related to insomnia disorder. Variables Total Insomnia disorder X 2 or t p % (n) or mean ± SD % or mean ± SD Yes (44.4%) No (55.6%) ADHD presentation Inattentive 39.7 (100) 31.2 46.4 6.082 0.048 Hyperactive/impulsive 3.6 (9) 4.5 2.9 Combined 56.7 (143) 64.3 50.7 Clinical global impression—severity scale Borderline mentally ill (2) 6.0 (15) 0 10.7 101.134 < 0.0001* Mildly ill (3) 32.5 (82) 10.7 50 Moderately ill (4) 25.0 (63) 20.5 28.6 Markedly ill (5) 27.8 (70) 50.9 9.3 Severely ill (6) 8.7 (22) 17.9 1.4 Extremely ill (7) 0 (0) 0 0 ADHD evaluation DIVA 2.0 (A) 7.29 ± 1.20 7.53 ± 1.27 7.11 ± 1.11 2.792 0.006 DIVA 2.0 (H/I) 5.05 ± 2.77 5.68 ± 2.81 4.55 ± 2.64 3.28 0.001* CAARS (direct score) 20.87 ± 6.84 22.87 ± 5.85 19.28 ± 7.17 4.376 < 0.0001* ADHD-RS 26.02 ± 10.75 31.46 ± 9.69 21.67 ± 9.52 8.039 < 0.0001* Pharmacological treatment Any pharmacological treatment 59.5 (150) 51.8 65.7 5.01 0.025 Methylphenidate 34.1 (86) 25.9 40.7 6.08 0.014 Lisdexamfetamine 19.4 (49) 22.3 17.1 1.065 0.302 Atomoxetine 6.3 (16) 4.5 7.9 1.205 0.272 Guanfacine 1.6 (4) 0 2.9 3.252 0.071 Months in stable treatment 12.32 ± 15.89 4.97 ± 7.89 18.19 ± 18.11 7.767 < 0.0001* *The result is statistically significant after Bonferroni correction. DIVA (A), Diagnostic Interview for ADHD in Adults criteria for attention deficit; DIVA (H/I), Diagnostic Interview for ADHD in Adults criteria for hyperactivity-impulsivity. TABLE 3 | Sleep variables related to insomnia disorder. Variables Total Insomnia disorder X 2 or t p % (n) or mean ± SD % or mean ± SD Yes (44%) No (55.6%) Screen use 71.4 (180) 87.5 58.6 25.515 < 0.0001* Total sleep time (h) 6.63 ± 1.32 5.82 ± 1.13 7.28 ± 1.09 10.42 < 0.0001* Insomnia severity index 8.96 ± 8.72 18.08 ± 4.07 1.67 ± 1.85 39.504 < 0.0001* Epworth sleepiness scale 5.46 ± 4.63 8.83 ± 3.30 2.76 ± 3.68 13.632 < 0.0001* Pittsburgh sleep quality index global score 6.98 ± 5.40 12.12 ± 3.33 2.87 ± 2.38 25.659 < 0.0001* Sleep treatment variables Use of sleep medication 15.9 (40) 25.9 7.9 15.157 < 0.0001* Sleep medication Benzodiazepines 7.9 (20) 15.2 2.1 14.471 < 0.0001* Antidepressants 4.4 (11) 6.2 2.9 1.716 0.190 Antipsychotics 3.2 (8) 3.6 2.9 0.103 0.748 Anticonvulsants 3.6 (9) 5.4 2.1 1.867 0.172 Melatonin 2.0 (5) 3.6 0.7 2.612 0.106 Psychiatric comorbidity medication without hypnotic effect 24.2 (61) 29.5 20 4.438 0.109 Number of baseline medication 0.22 ± 0.58 0.36 ± 0.70 0.11 ± 0.43 3.389 0.001* Number of medications after first assessment 0.43 ± 0.85 0.83 ± 1.06 0.11 ± 0.41 7.385 < 0.0001* *The result is statistically significant after Bonferroni correction. Frontiers in Psychiatry | www.frontiersin.org 6 May 2021 | Volume 12 | Article 663889 Fadeuilhe et al. Insomnia Disorder and Adult ADHD and early morning awakening (11.5%). These phenotypes insomnia (40.78 ± 12.80), mixed insomnia (41.70 ± 11.43), and were compared based on sociodemographic, ADHD, and early awakening insomnia were the predominant phenotypes psychiatric comorbidity characteristics. No statistically (43.50 ± 6.36). significant differences were found, except for age. Younger Insomnia disorder and insomnia symptoms groups were age was associated with sleep-onset insomnia (29.32 ± 9.50; characterized and compared in terms of contribution to F = 8.426; p ≤ 0.001), while in older patients, maintenance cast more insight on the role of specific factors influencing TABLE 4 | Sociodemographic and clinical features of ADHD patients according to insomnia disorder or insomnia symptoms. Total Insomnia disorder Insomnia symptoms X 2 or t p % (n) or mean ± SD (n = 112) (n = 49) (n = 161) % or mean ± SD Sociodemographic features Sex (males) 59.6 (96) 58 63.3 0.387 0.602 Age 38.51 ± 12.70 38.49 ± 12.25 35.55 ± 13.79 0.27 0.978 Clinical characteristics BMI 25.69 ± 4.69 26.24 ± 5.01 24.43 ± 3.59 2.581 0.011 Any medical records 43.5 (70) 47.3 34.7 2.212 0.168 Any current psychiatric comorbidities 60.9 (98) 69.6 40.8 11.892 0.001* Any mood disorders 35.4 (57) 42.0 20.4 6.926 0.012 Anxiety disorders 23.0 (37) 26.8 14.3 3.009 0.083 Bipolar disorders 0.6 (1) 0.9 0 NA Autism disorders 4.3 (7) 3.6 6.1 0.533 0.465 Any substance use disorders 9.3 (15) 11.6 4.1 2.285 0.154 Any personality disorders 34.2 (55) 39.3 22.4 4.296 0.047 Psychometric features Depressive symptoms (BDI) 13.82 ± 10.71 15.81 ± 10.74 9.27 ± 9.20 3.710 < 0.0001* Anxiety trait (STAI) 34.46 ± 11.98 34.84 ± 11.25 27.02 ± 11.92 3.985 < 0.0001* Anxiety state (STAI) 29.50 ± 13.68 32.14 ± 13.73 23.45 ± 11.58 3.869 < 0.0001* Impulsivity (BIS-11) 68.61 ± 14.77 70.93 ± 13.82 63.31 ± 15.62 3.093 0.002* Physical component summary of HRQoL (SF-36) 48.26 ± 9.14 47.15 ± 9.05 50.80 ± 8.92 2.368 0.019 Mental component summary of HRQoL (SF-36) 38.02 ± 10.74 34.26 ± 9.07 46.62 ± 9.27 7.900 < 0.0001** ADHD variables ADHD presentation Inattentive 35.4 (57) 31.2 44.9 2.800 0.247 Hyperactive/impulsive 4.3 (7) 4.5 4.1 Combined 60.2 (97) 64.3 51.0 Clinical global impression—severity scale Borderline mentally ill (2) 3.1 (5) 0 10.2 NA Mildly ill (3) 19.3 (31) 10.7 38.8 Moderately ill (4) 24.8 (40) 20.5 34.7 Markedly ill (5) 39.8 (64) 50.9 14.3 Severely ill (6) 13.0 (21) 17.9 2.0 Extremely ill (7) 0 (0) 0 0 ADHD evaluation DIVA 2.0 (A) 7.40 ± 1.25 7.53 ± 1.27 7.10 ± 1.14 2.008 0.046 DIVA 2.0 (H/I) 5.37 ± 2.82 5.68 ± 2.81 4.65 ± 2.75 2.146 0.033 CAARS (direct score) 21.94 ± 6.57 22.87 ± 5.85 19.82 ± 7.63 2.496 0.015 ADHD-RS 28.91 ± 10.32 31.46 ± 9.69 23.10 ± 9.40 5.077 < 0.0001* Pharmacological treatment Months in stable treatment 8.83 ± 12.65 4.97 ± 7.89 17.65 ± 16.60 5.103 < 0.0001** NA: Chi-square test was considered not applicable when one or more of the cells had an expected count < 5. *The result is statistically significant after Bonferroni correction. **The result is statistically significant after logistic regression. Frontiers in Psychiatry | www.frontiersin.org 7 May 2021 | Volume 12 | Article 663889 Fadeuilhe et al. Insomnia Disorder and Adult ADHD the transition between them. Compared with the insomnia DISCUSSION symptoms group, it was observed that patients with insomnia disorder presented more current psychiatric comorbidities; In line with our hypothesis, the current study highlights that higher depression, anxiety, and impulsivity psychometric scores; ADHD and insomnia disorder comorbidity in adults is highly and a higher severity of ADHD according to ADHD-RS. The prevalent. Moreover, patients who suffer both conditions are logistic regression showed that the months of stable ADHD more clinically severe. Therefore, our hypothesis is confirmed as treatment and the mental quality of life were greater among patients are characterized by a greater severity of ADHD, more the patients with insomnia symptoms than among the patients psychiatric comorbidities, an unstable ADHD treatment, and a with insomnia disorder and were independently associated (X 2 poorer health-related quality of life. = 66.932; p ≤ 0.0001, Nagelkerke R2 = 0.481; constant value In the current sample, 44.4% of patients met the criteria 1.129). On the other hand, no differences were found comparing for insomnia disorder according to DSM-5 and 63.9% had personality disorders and SUD variables. Likewise, no differences insomnia symptoms. This high prevalence of insomnia disorder were reported considering the different ADHD medications and insomnia symptoms in ADHD patients is in line with the (Table 4). prevalence of insomnia symptoms previously reported to be between 43 and 80% (11, 12, 14). These results may contribute to delimiting this wide range and provide more insights into the Logistic Regression Models prevalence of insomnia symptoms (better known) and insomnia Finally, three logistic regression models were conducted disorder (scarcely reported) in adults with ADHD. using the variables that retained statistical significance after Current results on ADHD presentations and insomnia Bonferroni correction and considering insomnia disorder as disorder were similar to previous studies that describe combined the dependent variable (Table 5). The first model evaluated presentation is more associated with insomnia symptoms (11). ADHD characteristics. It was observed that higher ADHD However, it is important to highlight that some studies reported severity, ADHD-RS, and fewer months of stable ADHD worse sleep quality and greater fatigue for the inattentive treatment were independently related to a higher prevalence of presentation (13), while other investigations found no differences insomnia disorder (X 2 = 139.95; p ≤ 0.0001, Nagelkerke R2 among ADHD presentations (12). In any case, differences among = 0.571; constant value 6.239). The second logistic regression ADHD presentations may be related or mediated by ADHD model analyzed medical and psychiatric comorbidities. In severity (50). Our results point out that ADHD severity is this model, current psychiatric disorders, previous history of independently associated with insomnia disorder. These findings anxiety disorders, and SUD were independently related to reflect the negative impact that both hyperactivity/impulsivity insomnia disorder (X 2 = 47.84; p ≤ 0.0001, Nagelkerke R2 = and attentional symptoms severity have on sleep onset and 0.232; constant value 1.338). Finally, the relationship between maintenance (9, 51). psychological features and insomnia disorder was explored When analyzing sociodemographic variables, only by using the variables that were statistically significant in unemployment was significantly associated with more risk the bivariate analysis. Low scores on physical and mental of insomnia disorder. These results have been already reported components of HRQoL were independently associated with a in previous studies, suggesting that unemployment is associated higher prevalence of insomnia disorder (X 2 = 108.48; p ≤ 0.0001, with poorer mental health and lower physical activity, which Nagelkerke R2 = 0.467; constant value 7.358). could cause insomnia (52). Note that other sociodemographic TABLE 5 | Multivariate analysis of variables associated with insomnia disorder. Variables Wald gl. Sig. OR 95% CI Lower Upper Model 1: ADHD-related variables CGI 42.048 1 <0.0001 3.800 2.538 5.688 Stable ADHD treatment (months) 14.453 1 <0.0001 0.943 0.915 0.972 ADHD-RS 5.221 1 0.022 1.045 1.000 1.085 Model 2: variables related to medical and psychiatric comorbidities Any current psychiatric comorbidity 19.437 1 <0.0001 3.542 2.019 6.215 Previous anxiety disorder 7.441 1 0.006 2.263 1.258 4.069 Previous SUD 5.789 1 0.016 2.225 1.160 4.267 Model 3: variables related to the psychological evaluation of comorbidity Physical component of HRQoL 3.902 1 0.048 0.961 0.923 1.000 Mental component of HRQoL 58.064 1 <0.0001 0.874 0.844 0.905 Frontiers in Psychiatry | www.frontiersin.org 8 May 2021 | Volume 12 | Article 663889 Fadeuilhe et al. Insomnia Disorder and Adult ADHD characteristics (e.g., sex, age, civil status) were not significantly In any case, it is important that more research is conducted on related to insomnia disorder. this issue. In line with other studies, patients with insomnia disorder had Concerning insomnia phenotypes, when considering the higher BMI (53). Obesity is usually related to greater morbidity different risk factors, only age had statistically significant and, in young adults, also to a worse lifestyle and health factors association. As previous studies reported (62, 63), younger that may bring on the presence of insomnia disorder. Regarding patients had more frequently sleep-onset insomnia phenotype. medical conditions, due to the sample size, the current study However, in contrast to those studies, no differences were found was not able to find the results from previous reports about regarding psychiatric and medical characteristics (63). This how insomnia disorder is related to a higher prevalence of finding could be related to a sample bias as the current sample hypertension, diabetes, gastrointestinal diseases, and cardiologic had a high prevalence of psychiatric comorbidities. problems (54, 55). Only a higher frequency of pain syndrome was The current analysis exposed a higher incidence of insomnia observed among patients with insomnia disorder, as well as their disorder in patients who use screens in the half-hour before respective analgesic treatment. bedtime. Exposure to blue light from these devices has been Congruently with prior research (9, 56), psychiatric associated with a greater alteration of circadian rhythms, as comorbidities were independently related to insomnia disorder. well as a higher prevalence of sleep-onset insomnia and poorer Regarding specific comorbidities, previous history of anxiety sleep quality (64). Some authors point out an excessive use of disorders and SUD, as well as current anxiety disorders, mood technology at night in the ADHD population (65). disorders, and SUD, were statistically significant in the bivariate Regarding health-reported quality of live, insomnia disorder analysis. SUD patients use to have a higher prevalence of was independently related to a negative impact on both physical insomnia disorder due to the disruptive effect that drugs of and mental components of HRQoL. Only patients without abuse and alcohol have on sleep (57). This interferes with the insomnia disorder presented normal scores in the physical ease of falling asleep, increasing the difficulty in maintaining component of HRQoL. Physical and mental components were sleep and altering the cycling of the sleep stage. The relationship affected in patients with insomnia disorder compared with of previous SUD with insomnia disorder could be explained normative data (66). Therefore, insomnia disorder is associated by the sleep disruptions that drug consumption may have with functionality and worse HRQoL in these patients. On the generated, as well as the lack of healthy habits usually associated. other hand, different studies have found a negative correlation Additionally, personality disorder comorbidity was statistically between ADHD symptoms, the severity of ADHD, and its significant, specifically those from cluster B. Interestingly, comorbid pathologies, and the scores on the quality of life some highly characteristic traits of these disorders such as scales (67–69). Our results point out that insomnia disorder impulsive behavior and emotional instability have been linked contributes to worsening of this perception in adults with ADHD, to a higher prevalence of insomnia and sleep disturbances (58). and conversely, its treatment and remission may imply an Additionally, regarding psychopharmacological treatments used improvement in the quality of life. for psychiatric comorbidities, our data showed a low frequency Finally, when characterizing the insomnia symptoms group, of prescription, which could be related to the high prevalence of our results point that patients with insomnia symptoms had psychiatric comorbidity. lower clinical severity of ADHD according to the ADHD-RS Regarding pharmacological treatment, stimulant medications and a greater number of months of stability of the ADHD have shown to have a greater effect size on ADHD symptoms treatment. Furthermore, our results showed lower psychiatric compared with atomoxetine (59). Probably, the drug dose and comorbidity and better mental component of the HRQoL in formulation are among the main factors that influence insomnia patients with insomnia symptoms when they were compared as an adverse effect. While some medication action can exceed with patients with insomnia disorder. These results, which 12 h, others last between 4 and 8 h. Although this adverse effect support our hypothesis, could contribute to identify the factors seems to be mitigated after 2 months of treatment (26, 27), of severity of ADHD, psychiatric comorbidity, and quality of life it is possible that the long release presentations may cause that could be associated with the transition between both clinical greater insomnia by extending their effect until the beginning of categories: insomnia disorder and insomnia symptoms. the night. This study should be analyzed regarding its limitations. Our results are congruent with the studies that indicate that First, objective or electrophysiological measures of sleep such pharmacological treatment would improve insomnia symptoms as polysomnography or actigraphy were not used. The use of (11), even in adult drug-naive ADHD patients (60). Subjects these instruments would provide more strength to the results. who were in pharmacological treatment showed significantly less Second, the cross-sectional design does not allow analyzing prevalence of insomnia disorder, specifically those who were the bilateral association. Third, the effect of pharmacological prescribed with methylphenidate. Note that longer periods of prescriptions for the treatment of psychiatric comorbidities, stable treatment were associated with lower rates of insomnia specifically mood disorders, was not controlled. Fourth, except disorder (even when confounding variables were controlled for the use of screens before sleeping, no other patient sleep for). Some authors describe that the pharmacological treatment hygiene measures were recorded and neither do the patients diet effect on insomnia symptoms should be analyzed from a broad characteristics. On the other hand, this research has important perspective that considers the clinical characteristics and severity strengths. To the best of our knowledge, this would be the of ADHD, suggesting the existence of a specific phenotype in first published study evaluating the relationship of adult ADHD ADHD patients who might respond better to this treatment (61). with insomnia disorder according to the diagnostic criteria of Frontiers in Psychiatry | www.frontiersin.org 9 May 2021 | Volume 12 | Article 663889 Fadeuilhe et al. Insomnia Disorder and Adult ADHD DSM-5 in adult patients. Furthermore, to avoid confounding ETHICS STATEMENT factors, those patients who suffered any other sleep disorder that could be confused with insomnia disorder (e.g., obstructive sleep The studies involving human participants were reviewed apnea, circadian rhythm disorder) were excluded from the study. and approved by Clinical Research Ethics Committee of the Finally, we must emphasize that the sample has included naive Hospital Universitari Vall d’Hebron. The patients/participants patients and treated patients, which allows us to better assess the provided their written informed consent to participate impact of the treatment, as well as to bring the results closer to in this study. the reality of clinical practice. The current study points out that adult ADHD patients with AUTHOR CONTRIBUTIONS insomnia disorder have a worse clinical presentation due to a higher ADHD severity, more comorbidities, and worse quality CF, CD, LG-L, and JR-Q conceived, designed, and supervised of life. These results may contribute to a better understanding the study. CF, CD, VR, and MC contributed data or analysis and clinical approach of insomnia disorder in the context tools. CF, VR, and MC collected the data. CF, CD, LG-L, and of a wide and heterogeneous pathology such as ADHD, by RP-A performed the data analysis. CF, CD, VR, LG-L, RP-A, MC, allowing to identify some of the sociodemographic, clinical, and and JR-Q wrote the manuscript. JR-Q secured funding for the comorbidity characteristics associated with both disorders when study. All authors contributed to the article and approved the they occur together. submitted version. DATA AVAILABILITY STATEMENT FUNDING The datasets generated for this study can be available on request to the corresponding author. Part of the data may not be allowed The research leading to these results has received funding from for distribution to others than the research group that conducted the Instituto de Salud Carlos III (PI18/01788) and supported by the study as may violate ethical and/or legal regulations of the EU’s Horizon 2020 Programme (Grant No. 667302, CoCA written consent. and Grant No. 728018 Eat2beNICE). REFERENCES levels of troubled sleep, restless legs, and cataplexy. Front Psychol. (2017) 8:1–11. doi: 10.3389/fpsyg.2017.01621 1. American Psychiatric Association (APA). Diagnostic and Statistical Manual 12. Fisher BC, Garges DM, Yoon SYR, Maguire K, Zipay D, Gambino of Mental Disorders. 5th ed. Washington, DC: American Psychiatric AM. Sex differences and the interaction of age and sleep issues in Association (2013). neuropsychological testing performance across the lifespan in an add/adhd 2. 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LG-L has received fees to give talks for et al. Association between screen viewing duration and sleep duration, sleep Janssen-Cilag, Lundbeck, Servier, Otsuka, and Pfizer. RP-A has received fees to quality, and excessive daytime sleepiness among adolescents in Hong Kong. give talks for Exeltis, Lundbeck, MSD, Mundipharma, and Takeda. JR-Q was Int J Environ Res Public Health. (2014) 11:11201–19. doi: 10.3390/ijerph111 on the speakers’ bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, 111201 Novartis, Shire, Takeda, Bial, Shionogui, Lundbeck, Almirall, Braingaze, Sincrolab, 65. Thoma VK, Schulz-Zhecheva Y, Oser C, Fleischhaker C, Biscaldi M, Klein C. Medice, and Rubió in the last 5 years. He also received travel awards (air tickets Media use, sleep quality, and ADHD symptoms in a community sample and a + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, sample of ADHD patients aged 8 to 18 years. J Atten Disord. (2020) 24:576–89. Takeda, Shionogui, Bial, Medice, and Eli- Lilly. The Department of Psychiatry doi: 10.1177/1087054718802014 chaired by him received unrestricted educational and research support from 66. Daigre C, Grau-López L, Rodríguez-Cintas L, Ros-Cucurull E, Sorribes- the following companies in the last 5 years: Eli-Lilly, Lundbeck, Janssen- Cilag, Puertas M, Esculies O, et al. The role of dual diagnosis in health-related Actelion, Shire, Ferrer, Oryzon, Roche, Psious, and Rubió. quality of life among treatment-seeking patients in Spain. Qual Life Res. (2017) 26:3201–9. doi: 10.1007/s11136-017-1668-4 The remaining authors declare that the research was conducted in the absence of 67. Agarwal R, Goldenberg M, Perry R, Ishak WW. The quality of life of adults any commercial or financial relationships that could be construed as a potential with attention deficit hyperactivity disorder: a systematic review. Innovat Clin conflict of interest. Neurosci. (2012) 9:10–21. 68. Lensing MB, Zeiner P, Sandvik L, Opjordsmoen S. Quality of life Copyright © 2021 Fadeuilhe, Daigre, Richarte, Grau-López, Palma-Álvarez, Corrales in adults aged 50+ with ADHD. J Atten Disord. (2015) 19:405–13. and Ramos-Quiroga. This is an open-access article distributed under the terms doi: 10.1177/1087054713480035 of the Creative Commons Attribution License (CC BY). The use, distribution or 69. Gudjonsson GH, Sigurdsson JF, Eyjolfsdottir GA, Smari J, Young S. The reproduction in other forums is permitted, provided the original author(s) and the relationship between satisfaction with life, ADHD symptoms, and associated copyright owner(s) are credited and that the original publication in this journal problems among university students. J Atten Disord. (2009) 12:507–15. is cited, in accordance with accepted academic practice. No use, distribution or doi: 10.1177/1087054708323018 reproduction is permitted which does not comply with these terms. 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