Psychiatric co-morbidity in dystonia-(plus) syndromes: is serotonin the common pathway?

Dystonia is a disabling movement disorder characterized by involuntary,
sustained muscle contractions that result in twisting and repetitive movements
of abnormal postures. Growing evidence indicates an important non-motor
component including psychiatric symptoms to primary dystonia. In DRD
(dopa-responsive dystonia), M-D (myoclonus dystonia) and CD (cervical
dystonia), psychiatric symptoms are part of the phenotype, with a
significantly higher incidence of major depression, obsessive-compulsivity, and
anxiety compared to the general population. Psychopathology in dystonia can not
solely be attributed to a reaction to chronic disability, but a
neurotransmitter dysfunction underlying the movement disorder is hypothesized
to also influence the psyche. This assumption is supported by the findings that
the psychiatric symptoms often precede the motor symptoms in patients with
dystonia There are several important clues for the involvement of serotonin,
but surprisingly this has thus far not been investigated in patients. This in
spite of the accumulating evidence that the psychiatric symptoms in particular
put the greatest strain on the quality of life. Serotonin is involved in the
pathophysiology of a variety of mood and anxiety disorders and many
psychotropic drugs act by modulating serotonin metabolism. We hypothesize that
a hyposerotonergic metabolism is the common pathway in different forms of
dystonia: DRD, M-D and CD and psychiatric comorbidity. Since not all patients
with CD, M-D or DRD exhibit psychiatric symptoms, genetic susceptibility and
environmental influences are thought to play an additional or modifying role in
the eventual phenotype.

Primary Objective is to determine whether (A) patients with dystonia(plus)
syndromes exhibit more psychiatric symptoms compared to a healthy control group
and (B) whether dystonia patients show an altered serotonin metabolism
(serotonin transporter status on PET-scanning of the brain).

Secondary objectives are to evaluate:
- whether an altered serotonin metabolism (serotonin transporter status) is
associated with
a) psychiatric comorbidity
b) the severity of dystonia
c) a lowered concentration of serotonin in platelets
d) the presence of SERT polymorphisms
e) the methylation rate of the serotonin transporter gene

- whether a lowered concentration of serotonin in platelets/ the presence of
polymorphisms/ the methylation rate of the serotonin transporter gene
correlates with
a) psychiatric comorbidity
b) the severity of dystonia

Observational case-control study

The serotonin transporter (SERT) status in the brain of adult participants will
be assessed with PET scan. A single intravenous catheter for the administering
van radioligand will be placed in the antecubital vein of subjects. In total
the scan will result in a radiation dose of 2,8 mSv, equivalent to less than 2
times the normal yearly background radiation. All participants will undergo a
standardised interview including medical history, family history, psychiatric
evaluation, a standardised neurologic examination and standardised video
recording. The psychiatric evaluation will consist of the Mini International
Neuropsychiatric Interview (MINI-PLUS; DSM IV) and several questionnaires.
Blood will be drawn in all participants to determine concentrations of
serotonin in platelets and for the genetic analysis.
With this study we will be able to provide new insights in the pathophysiology
of psychiatric and dystonic symptoms in patients with cervical dystonia and
dystonia-plus syndromes. There are no good (pharmaco)therapeutic options for
dystonia at this moment. If our hypothesis of a hyposerotonergic metabolism
proves to be correct, we will proceed to modulate the serotonin level in future
studies with serotonin medication and investigate the effect on both clinical
aspects (including quality of life) as on PET scans. This may directly lead to
the implementation of new therapeutic strategies. In this case the dystonia
patients will benefit from participating in this study.

Participation of the minors in the DRD subgroup: DRD typically presents in the
first decade of life. In more rare case when it presents in adult patients the
presenting symptoms differ from whose in the childhood. As far as the
neurotransmitter metabolism in children differs from those in adults it is
necessary to include pediatric patients with DRD in this study in order to
obtain the biochemical explanation of the disease symptoms in the childhood.