Effects of the Anti-inflammatory Flavonoid Luteolin on Behavior in Children With Autism Spectrum Disorders
Condition: Autism Spectrum Disorders
MeSH terms: Autism Spectrum Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      Background. Increasing evidence indicates that brain inflammation is important in the
      pathogenesis of neuropsychiatric disorders, including at least a significant proportion of
      subjects with Autism spectrum disorder (ASD). Natural flavonoids, such as luteolin and
      quercetin, exhibit potent antioxidant and anti-inflammatory activities, inhibit the release
      of inflammatory mediators from human mast cells, and reduce maternal interleukin 6-induced
      autism-like behavioral deficits related to social interactions in mice. In a case series of
      37 children with ASD who took a dietary supplement containing luteolin and quercetin for 4
      months reported gains in eye contact, attention and social interaction according to parental
      reports.

      Aim. The purpose of this study was to assess the effectiveness and tolerability in white
      children with ASD of a dietary supplement containing 2 flavonoids, luteolin and quercetin,
      and the quercetin glycoside rutin.

      Methods. Fifty children (42 boys and 8 girls) divided into 2 equal age groups (4-6 years old,
      and 7-10 years) with ASD were enrolled in a 26-week, prospective, open-label trial at the 2nd
      University Department of Psychiatry at "Attikon" General Hospital, Athens, Greece, the Ethics
      Committee of which approved the study. The parents of all subjects were informed of the
      study's aims, including risks versus benefits of participating and not participating as well
      as the inclusion and exclusion criteria, and they written consent for participation in the
      study.

      Participants had already been diagnosed with ASD based on clinical assessments, and this
      diagnosis was corroborated at the 'Attikon' clinic by meeting the cutoff scores on both the
      DSM-IV-TR, symptom list and the ADOS algorithm. All children were medication naive. Apart
      from the diagnostic evaluation, the assessment also included a thorough medical evaluation
      comprising a physical examination and health history (including a review of allergic and
      gastrointestinal symptoms, as well as any food allergies or food intolerance). All concurrent
      interventions were thoroughly noted (type and hours), and the same was done at all visits.
      After meeting screening criteria, subjects were evaluated at the baseline visit, mid-trial
      visit at 18 weeks, and final visit at 26 weeks.

      Children were administered a dietary formulation containing 2 flavonoids, luteolin (100
      mg/capsule) and quercetin (70 mg/capsule), and the quercetin glycoside rutin (30 mg/capsule).
      The dose used was 1 softgel capsule per 10 kg (22 lb) weight per day with food for 26 weeks.

      The primary outcomes were the age-equivalent scores in the 3 domains of the Vineland Adaptive
      Behavior Scales (VABS), communication, daily living skills, and socialization. The VABS was
      chosen because the impact of an agent on adaptive functioning in real life is even more
      important for obtaining a better quality of life than just alleviation of some symptoms. The
      raw scores from the interview can be also expressed as an age-equivalent score and a standard
      score compared with those of the subject's peers. There are also supplementary special norms
      for individuals with autism. Although standard scores could be more useful in subject
      characterization, their use as an outcome measure has been proven to be less sensitive due to
      floor effects and reduced variability, especially in short time periods, and thus these
      scores underestimate change. Conversely, scores of special norms tend to overestimate change,
      as a small increase in a raw score can produce a big improvement in special norm percentile
      rank. Thus, raw scores and age-equivalent scores seem to be the most appropriate for use as
      outcome measures, with the latter being more easily interpreted as change over time.

      Secondary outcomes included the Aberrant Behavior Checklist (ABC), the Autism Treatment
      Evaluation Checklist (ATEC), and the Clinical Global Impression-Improvement score (CGI-I). To
      explore other possible effects of the formulation not captured from the aforementioned
      instruments, we chose to record any other benefits observed and reported by the parents
      during its use. For this, the primary clinician (K.F.) conducted telephone or in-person
      interviews of the parents, independently of the assessing clinician (A.T.), to discuss the
      possible gains of the child. CGI-I was also independently coded by the primary clinician with
      personal assessments as well as with information gathered by parents and, in the majority of
      cases, by the subjects' trainers.

      Compliance was monitored by softgel capsule count and the parents' assurance that the
      capsules had actually been taken at each visit; in case of a capsule count <85% of the
      prescribed dosage at midterm and at the end of the study, the subject was excluded from the
      final analysis.

      Adverse events were systematically recorded on an adverse event form by using scales
      indicating severity, relationship to the study procedures, action taken, and any therapy
      required.
    


Intervention name(s): Luteolin, Quercetin and Rutin combined in a capsule
Intervention type(s): Dietary Supplement
Other intervention name(s): Neuroprotek
Intervention MeSH terms: Quercetin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment