This material was presented in the 25th European Congress of Psychiatry which was organised by the European Psychiatry Association in Florence, Italy from 1-4th April 2017. I had access to the material as I attended the full Congress. Please note that this material remains the intellectual property of the European Psychiatry Association and its authors and any citation should include a full reference to it. For more information on the EPA and how to become a member, please visit: http://www.europsy.net/

1. Parkinson Disease: a Complex Interaction of Disease and Medication Related
Factors
S.I.Petrykiv1, L. de Jonge2, M.H.L. Arts3
1Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, the Netherlands
2Leonardo Scientific Research Institute, Department of Geriatric Psychiatry, Groningen, the Netherlands
3University of Groningen, University Medical Center Groningen, Department of Old Age Psychiatry, Groningen, the Netherlands
Clinical problem
A 61-year old man with recently diagnosed Parkinson disease
dementia and diabetes mellitus type 2 has been receiving the
combined treatment with metformin and gliclazide for the past
years. The worsening of glycemic control requires additional insulin
treatment. However, when dementia complicates the course of
diabetes, injections with insulin are practically not possible.
Alternatively, current guidelines recommend administration of oral
antidiabetic drugs like GLP-1 agonists or DPP-4 inhibitors. Which of
the two groups should he receive ?
Conclusion
As evidenced by the relative scarcity of studies on the modulation of
dopamine signaling by GLP-1, this field of study is in its infancy and is
exclusively limited to the rodents. Therefore it is impossible to present
clear mechanisms by which GLP-1 can influence the course of PD in
humans. However, the majority of the found studies hypothesize that
GLP-1 signaling alters DA homeostasis. Besides, there is evidence that
treatment with GLP-1a is highly likely to interact with L-DOPA, which is
a significant problem. Therefore, clinicians should be cautious with
prescribing of GLP-1a in patients with PD and parkinsonism till more is
known about GLP-1 mediated effects in the brain.
Copyright © 2017 Matheus H.L. Arts, M.D., M.Sc. email: m.arts@ggzwnb.nl
Introduction
Forecasts indicate that the global burden of Parkinson disease
dementia (PDD) and diabetes will become pandemic in 2030. It
means that comorbidity of this two diseases will become a frequent
phenomenon in the polyclinic setting. Motoric symptoms are the
major problem in the PD and they are caused by a complex interplay
of intrinsic – related to the course of the disease- and extrinsic
factors, such as medication. In general, dopamine agonists can
exacerbate motoric symptoms, and therefore their use is contra-
indicated in PD patients. While some of dopamine inhibiting drugs
are well known, there are also drugs, especially since recent in use,
which interaction with dopamine circuit is to date unclear.
The novel antidiabetic drugs glucagon-like peptide 1 analogues
(GLP1a) are an effective tool to achieve the glycemic control and,
interestingly, GLP1a may influence the course of PDD through the
dopamine reward system. As recent studies indicate, the GLP-1
receptors are localized in the neurons of the brainstem nucleus of
the solitary tract, which has widespread projections within the
central nervous system. Therefore prescribing of GLP-1a in PDD with
diabetes may potentially exacerbate motoric symptoms of the
disease with profound consequences for the patients and their
surroundings.
Considering this pharmacodynamics profile of GLP-1a, we will assess
their possible harms in PD subjects with diabetes.
Objectives
To assess effects of GLP-1a on dopaminergic system in the brain.
Phenomenology of PD and and relation to dopamine circuit
PD can develop at any age but it begins most commonly in older
adults, with a peak age at onset at around 60 years. Motoric
symptoms in PD comprise mainly bradykinesia, resting tremor,
rigidity, flexed posture, “freezing”, and loss of postural reflexes.
Symptoms begin insidiously and tend to gradual worsening.
Primarily, one side of the body is usually affected before
consequent spreading to involve the other side.
Motoric symptomes in PD result from deficiency of striatal
dopamine due to loss of the nigrostriatal neurons. Accompaying
this neuronal loss is an increase in glial cells in the nigra and a loss
of the neuromelanin normally contained in the dopaminergic
neurons.
Consequently , dopamine replacement therapy is the major
symptomatic therapy to treating PD, and a variety of dopaminergic
agents are available.
GLP1 agonists
Selective GLP-1 receptor agonists, e.g. liraglutide and exenatide
increase insulin secretion, decrease glucagon secretion and
gastric emptying and are used in the clinic to treat type 2
diabetes. Interestingly, GLP-1 is also known to reduce food
intake and body weight, most likely mediated via a central
effect.
Objectives
To assess effects of GLP-1a on dopaminergic system in the brain.
Methods
A systemic literature search in PubMed was performed to identify
known studies on GLP-1 effects on dopamine pathways in the
brain. The search was performed by using the MeSH terms:
"Glucagon-Like Peptide 1"[Mesh] AND "Dopamine"[Mesh] AND
English[lang]. References of the found articles were manually
scanned to obtain extra potentially relevant data.
Results
Seven studies were identified
Study Population Dopamine signaling
pathway
Effect of GLP-1 on
dopamine
Sorensen et al.
2015
Rodents Nucleus accumbens
(D1 - receptor)
Decrease
Anderberg et al.
2014
Rodents Amygdala (D2 –
receptors)
Increase
Reddy et al. 2014 Rodents Ventral tegmental
area and nucleus
accumbens
Decrease
Egecioglu et al.
2013
Rodents Nucelus accumbens Decrease
Egecioglu et al.
2013
Rodents Nucleus accumbens Decrease
Abuirmeileh et al.
2012
Rodents Substantia nigra Reduces the effect
of L-DOPA
Brunetti et al. 2008 In vitro Nucleus arcuatus,
nucleus
paraventricularis,
nucleus of the
solitary tract
No effect
Most of the found literature focuses on the role of dopamine in the
mesolimbic reward pathway, composed of ventral tegmental area
dopamine neurons and their projection on the nucleus accumbens.
In general, the anorexic effect of GLP-1 is thought to be dopamine
mediated and exerted at the level of the hypothalamus, the
brainstem NTS and the VTA with one study finding the amygdala as
a key terminal site for the elevated VTA dopamine production by
GLP-1.
Four studies described a negative feedback mechanism between
GLP-1a and dopamine, showing that elevated GLP-1a leads to
depletion of dopamine. One study has shown, besides, an
antagonistic effect of GLP-1a on L-DOPA. In one in vitro study,
Brunetti er al. could not find any relationship between GLP-1a and
dopamine.
EPA17-0825