Inflammatory biotype of ADHD is linked to chronic stress: a data-driven analysis of the inflammatory proteome.

"data availability the data for proteins (npx values) and corresponding cluster attribution is available at https://gude uni-frankfurt de/handle/gude/323 10 25716/gude 0cha"

"Competing interests IS, AS, SL, SW, HF, HEJ, AS, TK, CRS, PIJ, SKRO, CF, MF, CL, JMR, VR, NR, AAV, ER, SM, and CS do not report any conflict of interest. GAH reported receiving personal fees from Janssen outside the submitted work. IB reported receiving consulting fees from Gedeon Richter and Janssen/Janssen-Cilag; speaker’s honoraria from Gedeon Richter, Hikma Pharmaceuticals, Janssen/Janssen-Cilag, KRKA, Lundbeck, and Medichem Pharmaceuticals Inc. by Unilab; research grant from Gedeon Richter; royalties from Oxford University Press. AR reported receiving personal fees from Medice, Shire/Takeda, SAGE/Biogen, Boehringen Ingelheim, Janssen, and Cyclerion outside the submitted work and funding from the European Union’s Horizon 2020 Research and Innovation Program under grant agreement No. 667302 and 964215. JARQ reported being on the speakers’ bureau and/or having acted as a consultant for Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogi, Sincrolab, Novartis, BMS, Medice, Rubió, Uriach, Technofarma and Rafo, received travel awards (air tickets + hotel) from Janssen-Cilag, Rubió, Shire, Takeda, Shionogi, Bial and Medice for taking part in psychiatric meetings, outside the submitted work."

"Funding Open Access funding enabled and organized by Projekt DEAL."

"Analyses on cytokine levels and the effect of medication on them in ADHD were conducted on data and material collected during the “PROBIA” study (Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT03495375). Ethical approval was obtained from each study center (Ethical Approval Frankfurt: 269/18; Budapest: 44101-1/2018/EKU; Barcelona: 311/2018). The PROBIA study aimed to address the effect of a synbiotic intervention on irritability (for details, see NCT03495375). For the purpose of this study, only baseline data of participants with ADHD was used. Prospective participants were recruited via advertising and hospital outpatient clinics. Participants had to be between 18 and 65 years of age, with no major neurological, cardiovascular, endocrine, pulmonary, or gastrointestinal illness nor any major psychiatric disorders with psychotic symptoms present in history or at screening. Participants with conditions related to inflammation and/or anti-inflammatory medication were permitted in the study as long as they were stable. Medication was recorded, and a supplemental analysis was performed, excluding those with medication for inflammatory disorders. Importantly, successful inclusion required stable medication for ADHD (e.g., type and stable dosage for at least 30 days, or alternatively, no medication for at least 30 days). Subjects were excluded if they were undergoing immunosuppression or if antibiotics, or probiotics were currently prescribed or taken within the last 30 days. All participants in the present study had to meet DSM-5 criteria for ADHD confirmed by a structured diagnostic interview [ADHD: Diagnostic Interview for Adult ADHD (DIVA 2-0) [], see below; Additionally, any BPD was assessed with the Structured Clinical Interview for DSM-IV (SCID-II) []]. All participants in the study had to have at least moderate illness severity as judged by the Clinical Global Impression Scale (CGI-S) ≥ 4 for study inclusion []. Irritability was measured by the self-reported Affective Reactivity Index scale (ARI-S) []. Participants were excluded if ADHD diagnosis was not confirmed, or the participant did not reach a score of ≥ 4 in CGI-S or ≥ 5 in ARI-S. At screening, informed consent was obtained prior to any study-related activity. Participants’ characteristics and demographics, such as sex, age, ethnicity, highest education level, tobacco use, salary per month, and current medication status, were documented. Additionally, nutrition intake was collected at each site, but with different methods: in Frankfurt a 3-day online dietary protocol (myfood24) was collected at baseline, whereas three 24 hour recall food frequency questionnaires were used in Barcelona and Budapest. From these protocols and questionnaires, we derived details on macro and micronutrients such as total energy consumption, protein, fat, fiber, omega 3/omega 6 ratio, saturated fatty acids, alcohol, and different vitamins. However, since the methods used were strikingly different, they were not directly comparable between sites and thus only served descriptive purposes. The structured DIVA-2.0 [] interview was performed by trained staff to assess ADHD symptoms during childhood (between the ages of 5–12) and adulthood. At least 6 of 9 attention deficit criteria, as well as 6 of 9 hyperactivity/impulsivity during childhood and adulthood, had to be reached to be enrolled as a participant with confirmed ADHD. A lifelong impairment caused by their symptoms in at least two life situations had to be reported as part of the structured interview. Partners or family members were not interviewed in the scope of the study. Current ADHD symptoms severity was assessed via the self-reported ADHD Rating Scale (ADHD-RS) []. The 18 items with a score ranging from 0–54 assess 9 in inattention, 5 hyperactivity, and 4 impulsivity symptoms in the last six months. Psychiatric comorbidities such as current MDE and Suicidality risk were assessed with the Mini International Neuropsychiatric Interview, DSM-IV (M.I.N.I.) []. IQ was assessed with the WAIS-III or WAIS-IV (Wechsler Adult Intelligence Scale) []. On all subsequent test days, a range of psychological questionnaires were administered. Chronic stress in the last month was self-reported with the Perceived Stress Scale (PSS) [], with scores possible from 0 to 40. Furthermore, the 59-item UPPS Impulsive Behavior Scale (UPPS-P) was used to explore impulsivity []. The UPPS-P indicates no time reference and evaluates five dimensions of impulsivity."