Glutamatergic medication in the treatment of Obsessive Compulsive Disorder (OCD) and
Autism Spectrum Disorder (ASD)

Compulsivity is a cross-disorder trait underlying phenotypically distinct
psychiatric disorders that emerge in (early) childhood (ASD, OCD), or
adolescence (addiction to substance use). Compulsivity is defined as the
repetitive, irresistible urge to perform a behaviour, the experience of loss of
voluntary control over this intense urge, the diminished ability to delay or
inhibit thoughts or behaviours, and the tendency to perform repetitive acts in
a habitual or stereotyped manner (Chamberlain et al. 2006).
In this study the focus will be on compulsive behaviours across the different
clinical phenotypes and the developmental links between compulsivity and
impulsivity.

Obsessive Compulsive Disorders (OCD) are characterized by repetitive thoughts,
impulses or images (obsessions) and repetitive behaviours or mental acts
(compulsions). Autism Spectrum Disorders (ASD) are characterized by deficits in
(i) reciprocal social interaction and (ii) communication, and by (iii)
restricted, repetitive and stereotyped patterns of behaviour, interests and
activities.

Compulsivity and the closely associated impulsivity trait are characterized by
behavioural disinhibition maintained by maladaptive fronto-striatal circuits
(Fineberg et al. 2010). Compulsivity has also been considered an overarching
concept that includes both failure to resist an impulse or an urge
(impulsivity), maladaptive habitual behaviours (addiction), repetitive motor
behaviours, rituatlistic and stereotyped behaviours, and feelings of loss of
control (ECNP, 2010).

Glutamatergic projections to and from frontal subregions to the striatum play a
key role in the regulation of various compulsive behaviours in humans
including: 1) a maladaptive habitual pattern (addiction), 2) repetitive motor
behaviours (stereotypy in ASD) and 3) the feeling of loss of control (OCD).
Glutamatergic imbalance in fronto-striatal regions has been observed, e.g., in
childhood OCD (MacMaster et al. 2008).
This suggests that impaired functioning of both frontal and striatal areas may
be due to a common underlying pathophysiology, such as dysregulation of
glutamatergic mechanisms and glutamatergic genes.

Preclinical animal models of compulsivity support glutamatergic interventions,
e.g., excessive stimulation of the orbito-frontal cortex and the anterior
cingulate may result in the generation of excessive, erroneous glutamatergic
signals to the basal ganglia, leading to compulsive behaviour.
Ongoing rodent studies in the TACTICS project will add to pre-existing
knowledge by, e.g., providing proof-of-concept predictive data for
glutamatergic medication strategies in both male and female models, with high
relevance for the exploratory clinical studies in paediatric populations with
OCD and ASD outlined in this study protocol.

The Primary objective is:

1) To investigate clinical effectiveness of the glutamatergic compound
memantine in paediatric patients with:

- Obessive-Compulsive Disorder (OCD) GOAT-1
- Autism Spectrum Disorder (ASD) GOAT-2

with respect to symptoms of
- *compulsivity* (assessed as CY-BOCs Total score)

Secondary objectives are:

(1) To explore the effects of glutamategic interventions at the level of the
structure, function and biochemistry of the fronto-striatal circuits
(MRI, MRS) (in subgroups (disorders, age range, meeting
inclusion/exclusion criteria of the COMPULS study protocol from the TACTICS
project).
(2) To collect: blood for genetic analyses and
biomarkers.
(3) To explore: additional clinical outcomes, disorder-specific (e.g., core
symptoms, response rates, social
functioning).

This/these 15 week study(ies) has/have a
- Add-on, randomized, double-blind, placebo-controlled design of
- treatment with a glutamatergic compound (memantine),
- including an up-titration phase (forced flexible dose design),
- in paediatric patients with OCD, ASD.

Psychiatric and behavioural data will be collected, including measures of

(a) rigid and compulsive patterns of behaviour that are appropriate for these
disorders,
(b) MRI and MRS data will be collected in subgroups (age range, disorders
meeting inclusion/exclusion criteria of the COMPULS study protocol from the
TACTICS project, cf. Annex).
(c) Blood will be collected for genetic analyses and for biomarkers.

This study involves a comparison of an active drug (memantine) with matching
placebo. During Study Period II, medication will be initiated and modified
according to the weight group of the patient at Baseline (Visit 3). Dosing may
then be increased (or decreased) by 5 mg/d increments, respectively, at
specified visits/dates according to the weight of the subject. Stepwise
up-titration is recommended to the target dose or the highest tolerable dose by
week 4, accordingly. Dosing should remain stable during the last 4 weeks of
Study Period II, unless a dose reduction is necessary for safety or
tolerability reasons.

The proposed study includes invasive measures, namely the collection of blood
samples, and MRI sessions, both at different time points. To answer our main
questions about the effect of glutamatergic interventions on the severity of
clinical symptoms of compulsivity and on the underlying neural and biomarker
mechanisms of compulsivity, it is necessary to measure neural aspects and
biomarker aspects of the fronto-striatal circuits at two time poins, i.e. pre-
and post-intervention.

Children of 6 years (ASD) or 8 years (OCD) -17 years will be included in this
study, since these disorders have their most typical manifestation in childhood
and early adolescence, and we examine them as these disorders are developing
over childhood and adolescence (DSM 5, ICD 10).
Participants will undergo a total of (up to) 10 visits (incl. phone visit;
examination, interviews, questionnaires, neuroimaging (in subgroups; MRI/ MRS
assessments). If children and adolescents show any resistance the procedures
will be stopped immediately. All centres involved have extensive experience
with the type of research we are proposing in this protocol; potential adverse
events have to be considered and special risks associated with the medications
proposed in this kind of reseach. However this compound has earlier been used
and investigated (at minimum in an open-label exploratory way), both in adult
and paediatric patient populations, partly in other somatic or psychiatric
conditions/disorders. Memantine has regulatory approval for Mb. Alzheimer in
various countries, for many years.

The anticipated scientific merits justify the proposed study. There will
potentially be a therapeutic benefit for the participants (depending on the
balance of clinical effect/effectiveness and adverse events (per patient)) both
on the individual and the group level; an assessment of the risk/benefit ratio
will continuously be performed. In case of clinically/ethically inacceptable
burdens or risks, single patients will be discontinued from the study, or the
entire study may be stopped (also based on consultations with sponsor and
scientific advisory board).