Does Psycho-Motor Therapy Ameliorate Depression and Alter Striatal Dopaminergic Signaling and Brain Neuronal Connectivity During Depression?

Increasing physical activity, for example using exercise training (ET), is an
important non-pharmacological low-cost strategy that improves myriad aspects of
general health and mental well-being. Moreover, ET can alleviate health
impairments during several common disease states, including major depressive
disorder (MDD), obesity, type 2 diabetes mellitus, and drug addiction. All
these disorders are characterized by abnormalities in dopamine signaling in the
reward-related brain circuitry. For example, both the obese and drug-addicted
state are associated with lower in vivo striatal dopamine D2/3 receptor binding
potential (DRD2/3 BP). However, for MDD, which is a very heterogeneous
psychiatric condition, results have been inconsistent, reporting either higher
or unchanged in vivo striatal DRD2/3 BP in depressed subjects compared to
healthy controls. Preclinical studies with rodents have demonstrated that ET
modulates dopaminergic signaling in the reward-related brain circuitry. In line
with these preclinical observations, ET in two subjects with early Parkinson*s
disease, as well as in a cohort of methamphetamine-addicted subjects, increased
striatal DRD2/3 BP compared to non-exercised controls. Also, preclinical data
suggest that an increase in striatal DRD2/3 function may prevent drug
addiction. Together, these observations suggest that functional improvements in
striatal dopaminergic signaling may underlie some of the health benefits
associated with ET. Thus, it is crucial that we understand how ET modulates
striatal dopaminergic signaling, as this will allow us to optimize behavioral
or pharmacological treatments.
A consistent observation in MDD-related research is that ET
intervention programs can decrease depressive symptoms in human subjects. The
effects of ET can be quite acute, as a single exercise challenge can result in
immediate improvements in depressive symptoms. Despite the consistency and
clinical importance of these beneficial effects of ET on mental health, the
underlying biological mechanism(s) have remained incompletely characterized.
Pre-clinical data have revealed that functional adaptations in the dopaminergic
reward-related brain circuitry are likely involved. More specifically,
increases in ex vivo striatal DRD2/3 BP have been observed in endurance-trained
rats compared to sedentary controls 37,38. Interestingly, treatment with
antidepressants results in a similar effect in rodents, suggesting potential
mechanistic overlap. In humans, the effects of antidepressant treatment on
striatal DRD2/3 BP have been mixed, with studies reporting either higher,
similar or lower in vivo striatal DRD2/3 BP compared to pre-treatment levels
treatment. Notably, antidepressant treatment is not effective in a substantial
number of subjects with MDD, and this might underlie the inconsistent findings
in mechanistic studies.
Psycho-Motor Therapy (PMT) is a validated psychosocial behavioral
activation strategy that helps individuals to become more active in ways that
are meaningful to them, often by including various aspects of ET, with the
overarching goal to improve mood and quality of life. PMT programs are
effective in reducing depressive symptoms in subjects with MDD. Despite the
clinical importance that PMT programs or antidepressants can result in similar
improvements in mental health in subjects with MDD, a very limited number of
clinical studies have investigated the effects of PMT on functional adaptations
in the dopaminergic reward-related brain circuitry. Currently it has not been
investigated if an PMT intervention modulates striatal DRD2/3 BP in subjects
with MDD.
Aside from long-term molecular adaptations induced by ET, it is also
not clear if an acute exercise challenge can acutely increase striatal dopamine
signaling, which will result in a lower in vivo DRD2/3 BP (as DRD2/3 is
competitively bound by endogenous dopamine and thus becomes less available). A
previous study reported no effects on striatal dopamine release in response to
an exhaustive 30-minute treadmill run in a cohort of highly-trained subjects.
However, no information is currently available on (*non-stimulated* or acute
exercise-induced) dopamine release in other subject populations, including
subjects with MDD, in response to medium-intensity exercise. Full understanding
of how exercise or ET modulates striatal dopamine function will provide
mechanistic insight that can be used to optimize the therapeutic potential of
ET and PMT programs to prevent or treat disease states characterized by
deficits in dopaminergic signaling in the reward-related brain circuitry, such
as MDD. Furthermore, such mechanistic insight might also be used to prevent or
treat other diseases characterized by deficits in dopaminergic signaling in the
reward-related brain circuitry, such as obesity, type 2 diabetes mellitus, and
drug addiction.
To this end, we will measure *non-stimulated* and acute
exercise-induced striatal DRD2/3 BP in subjects with MDD before and after a
3-month in-house supervised PMT program, which is a primary and validated
intervention method for MDD at the Psychiatry clinic of the Amsterdam UMC (AMC
location). To increase the therapeutic potential and ensure high levels of ET
during the PMT program, all study subjects will participate in a specialized
PMT program. This program combines the standard PMT program at the AMC
Psychiatry clinic with an extra 3x 1h ergocycle exercise per week (hereafter
called PMTERGO). The PMTERGO program will be supervised by qualified and
experienced personnel of the Psychiatry clinic of the Amsterdam UMC (AMC
location), including a psycho motor-therapist, ergo-therapist, psychiatrists
(in training), and psychologists. We hypothesize that a successful 3-month
PMTERGO program decreases depressive symptoms, increases striatal DRD2/3 BP
compared to pre-intervention levels, and that changes in depressive symptoms
correlate to changes in striatal DRD2/3 BP. We consider the PMTERGO
intervention to be successful if the depressive symptoms of the patients are
decreased by 50% after the 3-month PMTERGO program. We also hypothesize that an
acute medium-intensity ergocycle exercise challenge lowers in vivo DRD2/3 BP
compared to pre-ergocycle exercise levels, indicative of acute striatal
dopamine release. Finally, functional Magnetic Resonance Imaging (fMRI) will be
used to assess differences in reward processing before and following the
3-month PMTERGO program.

Primary objectives
* To determine if 3-month PMTERGO decreases depressive symptoms in subjects
with MDD
* To determine if 3-month PMTERGO alters in vivo striatal DRD2/3 BP compared to
pre-intervention levels in subjects with MDD

Secondary objectives:
* To determine if medium-intensity ergocycle exercise acutely lowers in vivo
striatal DRD2/3 BP in subjects with MDD compared to pre-ergocycle exercise
levels.
* To determine whether 3-month PMTERGO modulates reward processing between key
reward-related brain regions.
* To determine correlations between acute medium-intensity ergocycle
exercise-induced changes in neuroendocrine hormones and metabolites and acute
changes in in vivo striatal DRD2/3 BP.
* To assess 3-month PMTERGO-induced changes in neuropsychological function,
lifestyle and dietary patterns.
* To determine correlations between 3-month PMTERGO-induced changes in fasting
neuroendocrine hormones and in vivo striatal DRD2/3 BP.

A one-arm 3-month PMTERGO study

Subjects with MDD will enter a 3-month in-house supervised PMTERGO at the
Psychiatry clinic of the Amsterdam UMC (AMC location).

Subjects with MDD that will participate in the supervised in-house PMTERGO
intervention program at the Psychiatry clinic of the Amsterdam UMC (AMC
location) will be contacted whether they want to participate in the FIT-BRAIN
study. Eligible subjects will visit the Amsterdam UMC (AMC location) on two
occasions before PMTERGO [for a cardiopulmonary exercise test (CPET) day and a
study day] and on two occasions after a 3-month PMTERGO intervention (a CPET
test day and a study day) (total study time: approximately 16 hours).
Fitness before and after the PMTERGO intervention will be assessed using a CPET
to assess (improvements in) VO2max, a well-accepted indication of fitness. The
effect of the PMTERGO intervention on dopaminergic reward processing will be
assessed by fMRI, which is a non-invasive imaging modality. At the start of the
study day, a venous puncture will be used to draw blood samples (60mL) to
measure fasting neuroendocrine hormones and blood-borne neurotransmitters. A
blood sample (20mL) will also be collected before and after the acute
medium-intensity ergocycle exercise challenge. Participants will undergo 30
minutes of MRI scans. In addition, all participants will perform approximately
60 minutes of neuropsychological tests probing reward-related function and
questionnaires to assess lifestyle and dietary behavior. The effect of the
PMTERGO intervention as well as an acute medium-intensity ergocycle exercise
challenge on striatal DRD2/3 BP will be assessed by a SPECT session using the
radioligand [123I]iodobenzamide ([123I]IBZM). [123I]IBZM has a European (CPMP)
registration, and has been shown to have no serious side effects. The dose
equivalent per IBZM-SPECT session is 4.9 mSv (in total 144 MBq [123I]IBZM will
be administered per session). Thus, the total dose equivalent will be 9.8 mSv,
which falls within the maximum recommended dose equivalent for the proposed
research participants, i.e. 9.8 mSv (WHO category IIb, males > 30 years) 46.To
minimize the risks associated with participation, subjects with MRI
contraindications are excluded, and the study is designed so that each
participant will not be exposed to more than two SPECT sessions.
Our study will determine if PMTERGO decreases depressive symptoms in male
subjects with MDD. As both PMT and ET programs are effective in reducing
depressive symptoms in subjects with MDD 8,42-44, we hypothesize that a
combination of both approaches, in the form of PMTERGO, has strong therapeutic
efficacy in MDD. This study will not only be of value to prevent or treat MDD,
it will also acquire mechanistic knowledge on how PMTERGO may influence the
dopaminergic brain circuitry. This is important for the prevention and
treatment of MDD, the most common neuropsychiatric disorder, but also for the
prevention and/or treatment of other common diseases characterized by a
dysregulated DRD2/3 BP, such as obesity, type 2 diabetes mellitus and drug
addiction. Therefore, we believe that the value of our findings will outweigh
the burden and risks associated with participation.