Thyroid Profile in Attention Deficit With Hyperactivity Disorder (ADHD)

Abnormal Thyroid Profile in Children With Attention Deficit With Hyperactivity Disorder (ADHD)

Rationale: The observational data of University Children's Hospitals of Nice, suggest that about a quarter of children and adolescents with ADHD may present with an abnormal thyroid profile.

Main objective: To confirm that a subsample of children and adolescents with ADHD present with an abnormal thyroid profile using the gold standard for free fraction of hormones : chromatography with mass spectrometry.

Secondary objective: To examine to what extent this categorization holds using classic immuno-analytic assays. To characterize clinically and from a neuropsychological point of view this subsample and compare it to the other participants.

Study duration and design: 30 months (24 months for inclusion and 6 months for data analyses) open-label, (category 2 : interventional research with minimal risks or constraints), multicentre, without treatment or placebo administration.

Expected outcomes: Ancillary studies will investigate genetic physiopathological mechanisms (polymorphisms of deiodase or transmembrane carriers of thyroid hormones) and link this profile to other biological markers proposed in the literature (low ferritinemia, higher oxidative stress, atopic comorbid disease). The clinical trajectory of this subgroup and the persistence of this abnormal thyroid profile in adulthood will be a relevant issue in the future.

Rationale: The internal observational data on 514 children and adolescents with ADHD suggest that 16-28% of them have an abnormal thyroid profile in immuno-analysis: normal free thyroid-stimulating hormone TSH and T4 but abnormally high free T3. Several pathophysiological hypotheses can be formulated, some of which relate to possible polymorphisms of the deiodase or transmembrane carriers of thyroid hormones, and also with other suspected biological markers of ADHD reported in the literature (low ferritin, atopic disease and oxidative stress). This abnormal thyroid profile may be an endophenotype of a subgroup of children and adolescents with ADHD. However, the reference technique for the determination of free fractions of hormones is chromatography with mass spectrometry and not immuno-analysis.

Main objective : To confirm by chromatography with mass spectrometry the existence of a subgroup of children and adolescents with ADHD with this abnormal thyroid profile.

Secondary objectives:

• Describe this subgroup by sex (male/female) and age (before 12 and after 12 years) clinically and neuropsychologically (Attention Network Task and Tower of London coupled with eye-tracking) and compare it with the rest of the sample.
• Dose thyroid hormones and TSH levels with 4 different techniques of immuno-analysis
• Calculate the classification concordance (abnormal profile / normal profile) between all pairs of dosage methods (chromatography and 4 immuno-analysis based techniques)
• Calculate 95% reference intervals for all assays and techniques throughout the sample.

Main evaluation criterion: free T3 greater than the 97.5 percentile of the reference interval in chromatography, free T4 between the 2.5 percentile and the 97.5 percentile with this same technique, and free TSH between the 2.5 percentile and the 97.5 percentile of the immuno-analytical reference interval.

Secondary evaluation criteria:

• Describe the subgroup and compare it to the rest of the sample:

  • Number of criteria for inattention, hyperactivity-impulsivity and therefore clinical presentation of ADHD (Predominant Inattentive, Predominant Hyperactive-Impulsive, Combined)
  • Scores for inattention, hyperactivity-impulsivity and their sum on the ADHD-Rating Scale and score on the Clinical Global Impression - Severity
  • Pattern of comorbidities diagnosed with Kiddie-SADDS-PL, manual, ocular and pedestrian preference, presence of atopic disease
  • Performance at the Attention Network Task and Test of the Tower of London coupled with eye-tracking

• Calculate the classification concordance all pairs of dosage methods (chromatography and 4 immuno-analysis based techniques): correlation, concordance indices 2x2 (for example, Cohen's kappa)

• Calculate 95% reference intervals with age as co-variable and separately for boys and girls.

Study duration: 30 months (24 months for inclusion and 6 months for data analyses) Study design: Open-label, cross-sectional (category 2 : interventional research with minimal risks or constraints), multicentre, no treatment or placebo administration.

Selection criteria:

• Inclusion criteria: Boys or girls aged 7 to 17 with ADHD (as per Diagnostic and Statistical Manual DSM-5 criteria).

• Criteria for Non-Inclusion:

  • Known or concurrent diagnosis of Autism Spectrum Disorder, Schizophrenia or Psychotic Disorder (as determined by DSM-5), thyroid disease of any origin, genetic disease known to affect thyroid function.
  • Any psychotropic treatment (for ADHD or others) in the month before inclusion or any treatment that may affect thyroid function

• Exclusion criteria: Withdrawal of informed consent by at least one of the child's parents or their legal representative.

Course of the study: The criteria for non-inclusion are checked, the diagnosis is confirmed using the Kiddie-SADS-PL before the child can be included. The patient's participation stops after the venous blood collection and the administration of two neuropsychological tests (Attention Network Task and Tower of London). The tubes are transported to the biochemistry laboratory of the CHU of Nice which prepares five aliquots (4 for assays in immuno-analysis including 2 on site, and one for assay in chromatography with mass spectrometry at the CHU of Toulouse).

Expected outcomes: The identification and clinical characterization of a subgroup of children and adolescents with ADHD with an abnormal thyroid profile will support the clinical diagnosis for these at least. Ancillary studies will investigate genetic physiopathological mechanisms (polymorphisms of deiodases or transmembrane carriers of thyroid hormones) and link this profile to other biological markers proposed in the literature (low ferritinemia, higher oxidative stress, atopic comorbid disease). The clinical trajectory of this subgroup and the persistence of this abnormal thyroid profile in adulthood will be relevant in the future

Inclusion Criteria:

• Boys or girls aged by 7 and 17 years old included
• Diagnosed with ADHD according to DSM-5 criteria with either Inattentive predominant, Hyperactive-impulsive predominant or Combined presentations.
• Scoring at least 28 (maximum value 54) on the ADHD-RS total score that is the sum of 18 items each rated on a 0-3 scale.
• Scoring at least 4 (= Moderate) on the Clinical Global Impression - Severity scale
• Without any clinical symptom of either hypothyroidism or hyperthyroidism
• Who signed an informed consent form
• Whose at least of parents (or default a legal representative) signed an informed consent form

Exclusion Criteria:

Known or concomitant diagnosis of Autism Spectrum Disorder according to DSM-5 criteria Known or concomitant diagnosis of Schizophrenia or Psychotic Disorder according to DSM-5 criteria Known or concomitant diagnosis of any thyroid disorder (hypothyroidism or hyperthyroidism) whatever the cause might be Known or concomitant diagnosis of any genetic condition affecting the thyroid function (e.g. Down syndrome)

Intake in the last month of a psychotropic drug for:

ADHD: methylphenidate, atomoxetine, dexamphetamine, lisdexamphetamine, guanfacine or clonidine.

Any psychiatric disorder (antipsychotic, anxiolytics, antidepressant, etc.)

Intake in the last month of a molecule affecting the thyroid function:

• Any compound containing thyroid hormones
• Anti-thyroid drugs: carbimazole, thiamazole, propylthiouracil and perchlorate
• Any compound containing iodine
• Significant application on the skin of iodized products in the last six months
• Injection of water-soluble iodine contrast agents in the last 2 months or fat-soluble in the last 6 months