Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)

Phase IIa intervention study, pilot, prospective, multicenter, randomized in 2 parallel arms, Li+ versus placebo, double-blind. The main objective of the study is to evaluate the effect of Li+ at 12 weeks, compared to placebo, on the social communication deficit in patients with Phelan-McDermid Syndrome (SHANK3 haploinsufficiency).

The Secondary Objectives are :

• To evaluate the effect of Li+ at 12 weeks on all cardinal and main symptoms in patients suffering from Phelan-McDemid Syndrome (PMS).
• Evaluate the tolerance of Li + for 12 weeks in children suffering from PMS.
• Demonstrate the feasibility of a phase III, randomized controlled trial.
• Evaluate the residual effect of treatment at 16 to 18 weeks after stopping treatment)
• Evaluate the parents' feelings at the end of the study regarding the child's behavior and the impact on their daily lives

The treatment of the study is lithium carbonate: Li+ carbonate capsules are prepared from the raw material for pharmaceutical use .

Inclusion will be ensured by the clinical genetics centers. Psychiatric evaluation will be carried out by the investigative child psychiatry service.

Patients will be followed up by 2 referring physicians:

• a child psychiatrist, blind of the treatment arm, who will carry out the evaluations of the judgement criteria;
• a physician from the clinical investigation center, the only one informed of the attribution arm, who will ensure the adaptation of the LI dosage; an adaptation of the dummy dosage will be proposed to the patients on placebo to maintain the blind in this group as well. A lithiaemia will be performed every 4 days (+/- 1 day) until the target lithiaemia of 0.4-0.6 meq/L is reached with progressive increment of the lithium dose administered. The target blood lithium level must be reached within 20 days

As the evaluation is based on hetero-evaluation (by the parents), a placebo treatment remains necessary in the control arm.

Pharmaceutical preparations will be carried out for this pilot study: unit blister packaging of the active ingredient and the placebo.

Inclusion criteria

• Children under 18 years of age
• Minimum weight of 20 kg for children aged 7 years old
• Patient with haplo deficiency SHANK3, i.e. carrier of a SHANK3 deletion (CNV) or a de novo truncating mutation in SHANK3 (Phelan McDermid syndrome);
• Total Social Responsiveness Scale - T score (SRS) of at least 66
• Patients of childbearing age who are sexually active must agree to use a highly effective form of contraception (estrogen-progestin or progestin-only contraception, or an intrauterine device, or contraceptive abstinence).
• Affiliation to a social security system
• Signature of the consent by the holders of parental authority
• Non-participation in another clinical trial
• Diagnosis of Autism Spectrum Disorders (DSM-5 criteria) confirmed by Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Scale (ADOS-II)
• IQ Assessment
• Beta-HCG negative

Exclusion criteria

• Hepatic or renal insufficiency (disturbed liver function tests, abnormal creatinine clearance);
• Unbalanced thyroid or diabetic pathology;
• Cardiac pathology: Brugada syndrome or family history of Brugada syndrome, heart failure;
• Addison's disease;
• Unstable epileptic disease.
• Patient with concomitant diseases judged for which the experimental treatment with Li + could compromise tolerance ;
• History of allergy to Li+;
• Allergy to lactose, lactose being the sole diluent and excipient of the prepared form.
• Initiation of co-occurring cognitive-behavioural therapy that is specifically focused on autistic symptoms within 6 weeks prior to inclusion;
• Any introduction of psychotropic drugs within 2 weeks prior to trial, including neuroleptics, monoamine oxidase inhibitors, stimulants, antidepressants. For neuroleptic drugs and Fluoxetine, this delay should be 4 weeks prior to the trial;
• Serious behavioural problems or refusal to take medication that does not allow for compliance;
• Inability to perform blood tests to check lithemia when the patient is included.