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Sleep wake cycles are frequently disturbed in patients with Attention Deficit and Hyperactivity Disorders. We hypothesized that the origin of the sleep problems may be the consequence of an abnormal circadian clock setting regulated by the melatonin pathway. Here, we sequenced all the genes of the melatonin pathway AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 in 328 individuals from Sweden including 108 patients with ADHD and 220 from the general population. Non-synonymous mutations were identified in all genes at a similar frequency in patients with ADHD and in controls. Among the functional variations, a splice site mutation (IVS5+2T>C) in ASMT and one stop mutation (Y170X) in MTNR1A were only detected in patients with ADHD. Biochemical analyses indicated that these mutations abolish the activity of ASMT and MTNR1A. We also identified clusters of SNPs within MTNR1B showing significant difference in the allelic frequency between ADHD patients and control (maximum signal at rs10830961 P=0.0002). Taken together, these genetic and functional results shed light on one new compelling candidate pathway for susceptibility to circadian rhythms alterations that could help clinicians for providing better treatments of patients with ADHD and sleep problems.

Background: Attention-Deficit/Hyperactivity Disorder (ADHD), and Autism Spectrum Disorders (ASDs) are clinically found to be comorbid with each other and with other psychiatric conditions to a greater extent than what is previously assumed. It is, however, difficult to capture this complexity using current diagnostic systems, where exclusion criteria prevent simultaneous diagnosis. Thus, in order to describe this complexity and its consequences for the individual, it is important to describe actual comorbidity in different clinical contexts. Aims: The overall purpose of this thesis was to describe the prevalence and comorbidity between ASD and ADHD, and other psychiatric conditions. Specific aims were to: describe comorbidity in a group of adult out-patients with ADHD and/or ASDs (Paper I); investigate the prevalence of personality disorders and describe the personality profiles of the same group (Paper II); describe psychiatric symptoms associated with aggressive behaviors in adult psychiatric patients (Paper III); describe comorbidity in a group of adolescents placed in special youth institutions (Paper IV); and to investigate whether comorbid ADHD and substance abuse is associated with a more negative outcome, that is, more criminal recidivism, health care needs, and untimely death (Paper V). Methods and results: Paper I-II are based on diagnostic and demographic cross-sectional data showing that ADHD and ASD overlap greatly with each other, and that there is a significant overlap between ADHD and bipolar disorder and ASDs and psychosis. Personality disorder diagnoses are also common in these diagnostic groups, showing specific personality profiles associated with ADHD, ASD, and those with comorbid ADHD and ASD. In Paper III aggressive behaviors in a group of policlinic psychiatric patients have been compared with a group of forensic psychiatric patients, and both groups reported similar high levels of aggressive scores. Paper IV is based on cross-sectional data on institutionalized adolescents, which in Paper V has been combined with longitudinal follow-up data. Psychiatric diagnoses in general, and specifically the occurrence of ADHD and ASD, is high. Criminal recidivism and health care use was overall very high, while there were small differences between the groups with comorbid ADHD and SUD, SUD only, and, finally, no SUD in respect to criminal recidivism, health care needs and untimely death. Conclusion: Comorbidity between ADHD and ASD and other psychiatric diagnoses are common among psychiatric patients, and in many cases associated with character immaturity, aggression and personality disorders. It also seems as the outcome over time tends to worsening with increasing comorbidity, especially in cases with comorbid substance abuse and neuropsychiatric disorders. These complex states constitute diagnostic and treatment challenges for psychiatry and its classic divisions between child and adolescent versus adult psychiatry, mental illness versus personality disorders, and psychological versus medical interventions.

Background Reliable, valid, and easy-to-administer instruments to identify possible caseness and to provide proxies for clinical diagnoses are needed in epidemiological research on child and adolescent mental health. The aim of this study is to provide further validity data for a parent telephone interview focused on Autism - Tics, Attention-deficit/hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC), for which reliability and preliminary validation data have been previously reported. Methods Parents of 91 children clinically diagnosed at a specialized Child Neuropsychiatric Clinic, 366 control children and 319 children for whom clinical diagnoses had been previously assigned were interviewed by the A-TAC over the phone. Interviewers were blind to clinical information. Different scores from the A-TAC were compared to the diagnostic outcome. Results Areas under ROC curves for interview scores as predictors of clinical diagnoses were around 0.95 for most disorders, including autism spectrum disorders (ASDs), attention deficit/hyperactivity disorder (AD/HD), tic disorders, developmental coordination disorders (DCD) and learning disorders, indicating excellent screening properties. Screening cut-off scores with sensitivities above 0.90 (0.95 for ASD and AD/HD) were established for most conditions, as well as cut-off scores to identify proxies to clinical diagnoses with specificities above 0.90 (0.95 for ASD and AD/HD). Conclusions The previously reported validity of the A-TAC was supported by this larger replication study using broader scales from the A-TAC-items and a larger number of diagnostic categories. Short versions of algorithms worked as well as larger. Different cut-off levels for screening versus identifying proxies for clinical diagnoses are warranted. Data on the validity for mood problems and oppositional defiant/conduct problems are still lacking. Although the A-TAC is principally intended for epidemiological research and general investigations, the instrument may be useful as a tool to collect information in clinical practice as well.