The glutamate/GABA balance as novel therapeutic target for psychotic and cognitive symptoms in 22q11.2 deletion syndrome

22q11.2 deletion syndrome is a genetic disorder caused by a microdeletion on
the long arm of chromosome 22 and is associated with an increased risk of
developing a variety of psychiatric disorders, including psychotic disorders,
and cognitive dysfunction. Both idiopathic psychosis and 22q11DS are associated
with cognitive decline, which has been found to be steeper in those 22q11.2DS
patients developing psychosis. Patients with 22q11DS and comorbid psychosis
have been found to be less responsive to several dopamine-targeting
antipsychotics and more susceptible to their potential adverse effects.
Therefore, there is a strong need for novel therapeutics targeting other
neurotransmitters to reduce psychotic and cognitive symptoms, and disease
burden in these patients. Candidate neurotransmitters are glutamate and γ-
aminobutyric acid (GABA). The role of both neurotransmitters in psychosis is
increasingly acknowledged and studied. Altered glutamate and GABA transmission
in 22q11DS may be caused by reduced proline dehydrogenase (PRODH) (also known
as proline oxidase) enzyme activity resulting from haploinsufficiency of the
PRODH gene. PRODH is important for breaking down proline. Proline is converted
to glutamate and acts as a co-agonist at the glutamatergic NMDA receptor.
Decreased PRODH enzyme activity can thus lead to increased proline levels and
subsequently, increased activation of the NMDA receptor and excessive glutamate
release. Indeed, increased proline levels have been reported in 22q11DS.
Moreover, a previous study by our research group reported hyperprolinemia in
31.3% of 22q11DS patients. Although hyperprolinemia has been found to be a risk
factor for psychotic disorders, the association between hyperprolinemia and
proline levels and brain glutamate levels has not been directly studied
in-vivo. However, preclinical studies demonstrated altered glutamate and GABA
levels in PRODH knock-out mice. Therefore, it can be hypothesized that
modulating the glutamate/GABA balance will alleviate cognitive and psychotic
symptoms in 22q11DS, which is supported by our recent pilot data.

The objective of this study is to examine the effect of riluzole on the
glutamate/GABA balance in the brain in patients with 22q11.2DS. The secondary
objective is to examine the effects of riluzole on psychotic symptoms and
cognitive functioning. In this manner we can increase our insight in the
neurobiological underpinnings of these symptoms.

Partially blind, fixed-order cross-over trial in 22q11.2DS patients.

All subjects will undergo two 8-week intervention periods, once with placebo
and once with 100 mg. riluzole daily (50 mg. twice daily).

The burden and risks associated with this study are moderate. Patients will
undergo two 8-week intervention periods, once with placebo and once with
riluzole. Riluzole is an approved drug registered in the Netherlands for
amyotrophic lateral sclerosis (ALS). Potential side effects include a.o.
tiredness, nausea, headache and are mild and transient when they occur. In some
cases, riluzole can cause more serious side effects including neutropenia,
shortness of breath, symptoms of hepatitis and pancreatis. Patients are
instructed to contact the research team in case the experience acute fever,
acute and heavy stomach ache, shortness of breath or dark urine or jaundice. In
these case, clinical protocol will be followed and treatment with riluzole
terminated if necessary. Patients will be screened for contra-indications
(abnormal liver function tests and pregnancy). Subjects will have to come to
Scannexus in Maastricht twice and undergo MRI scanning. In addition, at the end
of both intervention periods a blood sample will be taken to determine liver
function and riluzole plasma levels. Potential disadvantages of the MRI
scanner for the participant are I) loud noise, II) dizziness and III) metallic
taste in the mouth. These potential effects of the MRI scan are considered mild
and transient. Furthermore, abnormalities in psychiatric questionnaires and
cognitive functioning can potentially be found. If an abnormality is found, we
will notify the participants* general practitioner. The study is group related;
it is only possible to examine the efficacy of riluzole on psychotic and
cognitive symptoms in 22q11.2DS in this particular population.