Tryptophan depletion in Parkinson*s disease patients treated with deep brain stimulation of the subthalamic nucleus: effects on mood and motor functions.

Parkinsons* disease (PD) is a neurodegenerative disorder typically
characterized by motor symptoms such as tremor, rigidity and bradykinesia
(slowness of movement). These symptoms are classically attributed to a
significant loss of the activity of the neurotransmitter dopamine in the
nigrostriatal dopamine system. This system is part of the basal ganglia, a set
of midbrain nuclei essential for movement. An important nucleus within this
circuit is the subthalamic nucleus (STN).

PD patients are initially treated with dopaminergic drugs such as levodopa.
However, long lasting levodopa treatment is associated with adverse effects
like dyskinesias, motor fluctuations and other problems like hallucinations. In
these cases, deep brain stimulation (DBS) of the STN offers the next
therapeutic option.

STN DBS significantly improves motor symptoms. Additionally, post-operative
dopaminergic medication can be greatly reduced. However, a substantial part of
the patients experiences both cognitive and psychiatric side effects caused by
the STN DBS. Cognitive decline, psychiatric adverse effects, such as increased
impulsivity, depression and (hypo)mania, and even suicide attempts pose a great
burden on both the patient and caretakers/family. Research has shown that up to
41% of patients undergoing STN DBS implantation show psychiatric and/or
cognitive changes post-operatively.

Different psychiatric and cognitive disorders are generally associated with a
dysfunction of the activity of the serotonin (5-hydroxytryptamine, or 5-HT)
neurotransmitter system. Research in rats has shown that STN DBS significantly
reduces the 5-HT release from the dorsal raphe, the major 5-HT production area
in the brain. In humans, the same may occur upon STN DBS: diminished 5-HT
levels may consequently lead to depression and other psychiatric disorders.

Additionally, it has been established that in the PD brain, not only the
dopamine content is altered, but that 5-HT levels are also reduced. PD patients
therefore suffer from a certain *5-HT vulnerability*: due to the diminished
5-HT levels, they are more susceptible to developing depression and other
psychiatric and cognitive problems.

Our hypothesis is that STN DBS in PD patients can lead to psychiatric adverse
effects through a further decrease in already lowered (vulnerable) 5-HT levels
in the PD brain. To elucidate whether STN DBS is indeed the trigger for
psychiatric and cognitive problems to arise in the PD patient, we will
manipulate the 5-HT levels in PD patients implanted with STN DBS. In order to
do this, we will make use of the tryptophan (TRP) depletion method, an
established research paradigm. In TRP depletion, the brain is depleted of TRP,
the precursor of 5-HT, which consequently leads to lowered 5-HT levels. In both
the normal and 5-HT depleted condition, we would like to assess mood- and
cognitive parameters of the PD patients both with the STN stimulation on (ON)
and off (OFF). This way we can shed more light on the effect of STN stimulation
on PD patients with a 5-HT vulnerability on 5-HT related mood and cognitive
behavior.

Our objective is to assess the effect of TRP depletion on mood and behavior in
PD patients treated with STN DBS. By doing, this, we hope to be able to
identify risk factors for and mechanisms underlying psychiatric side effects of
STN DBS. Ultimately, we would like to improve STN DBS management and treatment
for future PD patients.

This study will be an intervention study with a placebo controlled, randomized
cross-over design.

1. Tryptophan depletion vs placebo condition (= no depletion)
2. In both conditions patients will be tested with their DBS stimulator on and
off

In total, there will be 2 separate days of testing during which the subject
will have to stay from 9:00am until 5:00pm. During a testing day the patients
will drink an amino acid mixture to accomplish the TRP depletion or a control
placebo drink. Blood samples will be taken to check serum TRP levels. The
patient will be assessed at 3 time points with short questionnaires,
non-invasive physical examination and a short reaction time task and emotional
responsiveness task. Throughout the testing day the subjects are asked to
minimize their activity and only under take light activities, e.g. reading,
watching movies, taking a walk, etc.

No serious health risks are associated with participation in this study:
- Turning the STN DBS on and off: subjects will experience some degree of motor
discomfort due to the temporarily returning PD motor symptoms, but this does
not pose a health risk. Importantly, the normal STN DBS parameters are
programmed again before finishing the testing day and patients returning home.
- Drinking the amino acid mixture to accomplish the TRP depleted condition has
been reported to be safe. Nausea, headache and vomiting are reported in the
literature in a very small number of cases (Booij et al., 2005). See also
chapter 6, Non-investigational product.

Since the study objective is to assess the effect of TRP depletion on motor
symptoms, mood and cognition in PD patients treated with STN DBS, only PD
patients implanted with STN DBS can be included in this study. Other
comorbidities (e.g. malignancy, infection) are regarded as an exclusion
criterion.

Participation in this study does not directly yield any advantages for the
subjects. In the long term, however, we hope that study participation will
contribute to improving future DBS treatment and management.