Parkinson’s Disease: Dopamine & The Placebo Effect – Theories & Application
Parkinson’s Disease:
Dopamine &
The Placebo Effect –
Theories & Application
BRETT WARTHEN
HTTPS://PARKINSON.FIT
MARCH 2019
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Placebo Effect
A beneficial effect that is a
result of a drug or treatment
that has no therapeutic value.
The beneficial effect is
attributed to the patient’s
belief in that treatment.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Presentation
Objective
Understand what the placebo effect is, and why it is significantly
more common with studies of Parkinson’s Disease treatments.
Understand dopamine’s role in Parkinson’s Disease treatment.
Understand
Understand dopamine’s role in the brain’s reward pathway.
Understand
Leverage these lessons to create your own placebos.
Understand
Leverage
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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What is a Placebo?
Clinical trials of new drugs or treatments use a methodology known
as a “Double Blind Study”
Participants in the study are divided into two groups:
One group receives the actual treatment being tested
The other group receives a fake treatment, called a placebo
“Double Blind” means:
Participants do not know whether they are receiving the real treatment
or the placebo
Health professionals responsible for monitoring and evaluating the
participants do not know which group each participant belongs to
Only the pharmacist knows
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Treatment vs.
Placebo:
Is It Better Than
Nothing?
In order for the study to succeed, the
treatment group needs to outperform the
placebo group in a way that is statistically
significant
In other words, the study must prove that the
treatment is better than nothing
With such a low bar, why do so many
Parkinson’s Disease trials fail or report
inconclusive results?
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Reason #1: Parkinson’s Disease is a
Syndrome
What we refer to as Parkinson’s Disease is a collection of symptoms
We do not know the underlying disease pathology
There are likely a dozen or more diseases or triggers causing the
body to exhibit Parkinson’s symptoms
A treatment may be perfect for one set of patients, but have no
effect on other patients
This is one reason why a lot of research attention is focused on
known genetic triggers (LRKK2), where there is more confidence that
the patients are experiencing the same disease process
(And also because Sergey Brin, co-founder of Google has this gene,
and has committed a lot of money toward research)
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Reason #2: PD Severity/Progression
Based on Symptoms, not Disease
Clinical assessment of Parkinson’s Disease severity is observational
Clinician rates the severity of PD symptoms to give an overall “score”
assessment
Hoehn and Yahr scale – 5 stages of Parkinson’s
Unified Parkinson’s Disease Rating Scale (UPDRS) – Severity of
different symptoms assessed independently. Results added together
for overall score. UPDRS Part 3, the motor examination is what most
of us have experienced in the neurologist’s office
Scores can vary widely from day to day, even time of day
Research continues to search for biomarkers – a measurable
biological indicator of the disease
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Reason #3: The Placebo Effect
In clinical trials related to Parkinson’s
Disease, there are consistently a significant
numbers of individuals that see
improvement during these studies as part
of the placebo group.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Placebo Effect Causes
ANTICIPATION/EXCITEMENT OF
POSSIBLE CURE ENHANCES
DOPAMINE PRODUCTION
THIS EFFECT MAY BE ENHANCED
BY GENETIC FACTORS IN SOME
INDIVIDUALS
(~25% OF PEOPLE PRODUCE A COMT
ENZYME THAT IS LESS EFFECTIVE AT
BREAKING DOWN DOPAMINE – COMT
V158M RS4680 MET/MET)
THE DESIGN OF A DOUBLE
BLIND STUDY FOLLOWS A
FORMULA THAT HAS BEEN
SHOWN TO MAXIMIZE THE
DOPAMINE RESPONSE IN
PARTICIPANTS
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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We Don’t Know What Causes PD or How to
Stop Progression, but…
The motor effects of PD are caused by a
lack of the neurotransmitter dopamine in a
particular area of the brain
Prevailing wisdom is that by the time PD is
diagnosed, more than half of the
dopaminergic neurons in this area, the
substantia nigra, are no longer functioning
Dopamine is the neurotransmitter used to
relay messages to initiate and control
movement, and the dopamine deficiency
causes the motion disorders characteristic
of PD, including tremors and difficulty
initiating movement
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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PD Drug Treatments Focus on
Dopamine
Carbidopa levodopa (Sinemet) is a combination of carbidopa and
levodopa.
Levodopa (L-dopa) is a precursor that the brain can easily convert to
dopamine
Carbidopa is combined with levodopa to help the levodopa cross the blood
brain barrier, so that can reach the brain.
Dopamine agonists (Mirapex/pramipexole, Requip/ropinirole) are
chemical compounds that bind to receptors in the brain and act like
dopamine.
MAO and COMT are enzymes that break down dopamine after it has
been used. MAO inhibitors (Azilect/rasagiline, selegiline) and COMT
inhibitors (entacapone, tolcapone) inhibit these enzymes to help
dopamine that has already been produced to last a little bit longer.
Provide symptomatic treatment only, they do not stop or delay the
progression of Parkinson’s Disease.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Dopamine’s Reputation in Popular
Psychology
DOPAMINE = THE PLEASURE CHEMICAL THE “FEEL GOOD” NEUROTRANSMITTER
THAT IS RELEASED WHEN YOU ARE
EXPERIENCING PLEASURE.
BUT, THE REALITY IS A BIT DIFFERENT…
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Dr. Robert
Sapolsky
Professor of Biology, and
Professor of Neurologyand
Neurological Sciences at
Stanford University.
Author of “Behave: The
Biology of Humans at Our Best
and Worst”
TED Talk: “The Uniqueness of
Humans”
http://www.ted.com/talks/robert_sapolsky_the_
uniqueness_of_humans.html
The anticipation of a
pleasurable reward causes
dopamine to be produced,
not the receiving of the
reward itself
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Dopamine: Primate Study
Monkeys are trained that when a light goes on,
they can press a lever and receive a reward
Once the primate began to associate the light
with the reward, the researchers could measure
that more dopamine was produced when the
light turns on than by the reward.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Popular
Perception
of
Dopamine
(from “The Uniqueness of Humans”)
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© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
How It Actually
Works:
Goal Directed
Behavior
(from “The Uniqueness of Humans”)
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© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
The Power of
Uncertainty:
Introducing
the Maybe
Factor
(from “The Uniqueness of Humans”)
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© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
Intermittent Reinforcement
WHAT IF THE REWARD IS ONLY
GIVEN RANDOMLY,
AVERAGING 50% OF THE TIME?
FAR MORE DOPAMINE IS
PRODUCED EVERY TIME, EVEN
WITHOUT THE REWARD.
THE “MAYBE FACTOR”
CREATES MORE ANTICIPATION
AND EXCITEMENT.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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See Any
Parallels to a
Typical Clinical
Trial?
Patients full of anticipation that this is the clinical trial
that cures their disease!
50% real treatment, 50% placebo
The “Maybe Factor” is optimized for maximum
dopamine release
Some of this excess dopamine finds its way to other parts
of the brain, and voila, we see an improvement in
Parkinson’s symptoms, similar to that of taking levodopa.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Dopamine Drives Goal
Directed Behavior
Dopamine is not the reward, it’s what drives
you to get the reward.
The belief that you will receive a reward
produces dopamine.
The work/effort in pursuit of a reward
produces dopamine.
The reward is just a reward.
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© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
Delayed Gratification
HUMANS HAVE A HIGHER
TOLERANCE THAN ANIMALS
TO WAIT FOR A REWARD.
FOR EXAMPLE, WE ARE WILLING
TO WORK HARD TO GET INTO A
GOOD SCHOOL, TO GET A
GOOD JOB, TO BUY A NICE
HOUSE, AND EARN ENOUGH
MONEY TO AFFORD TO SEND
OUR KIDS TO A GOOD SCHOOL.
INSTEAD OF THE PURSUIT OF
HAPPINESS, WE PRODUCE
DOPAMINE THROUGH THE
HAPPINESS OF PURSUIT.
EVEN IN RELIGION, MAKE
SACRIFICES TODAY IN
ANTICIPATION OF THE
PROMISE OF A HEAVENLY
AFTERLIFE.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Dopamine
Supports
Learning
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University of Michigan Study - “Mesolimbic
dopamine signals the value of work”
2015doi:10.1038/nn.4173
Dopamine can also signal errors in reward
prediction, providing a learning signal
Dopamine is a “teaching signal,” like a coach
who tells his player “good job” or “bad job” to
encourage a future reward.
Study results indicate that dopamine conveys
a single, rapidly evolving decision variable, the
available reward for investment of effort,
which is employed for both learning and
motivational functions.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
Connecting These Two Sides of
Dopamine
One of the most common side
effects of PD medications is
addictive behavior, such as
gambling, hyper sexuality,
obsessive involvement with
new hobbies.
These side effects are most
common with dopamine
agonists, which act like
dopamine, but fool the brain’s
reward anticipation circuitry,
leading to unusual addictive
behavior.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Creating a
Placebo
Effect
The idea is not to create a placebo, it is to
create an effect similar to the placebo effect.
Manufactured Placebo Effect = increased
dopamine production
May involve a placebo therapy
May involve goal directed activity
You don’t have to limit yourself to one
placebo effect
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Motivation
and
Learning
Engage in Activities that you Enjoy
Activities that give you motivation
Activities that require Work/Effort to produce
Enjoyment
Engage in Constant Learning – Learn
something new every day
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Recognize
Goal
Directed
Behavior
Find Activities/Causes that You Believe In
Set Goals and Work Hard to Achieve Them
Use Your Powers for Good, Not Evil
A Negative Placebo Effect is called a Nocebo,
where negative expectations lead to negative
results
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
Maintain a Positive Attitude
Behavior and attitude can have an impact on our dopamine production, both positively and negatively.
If PD makes you feel sorry for yourself, and you see nothing but struggle in your future, nothing to look forward
to, then, you have no anticipation…and there is no reason for your brain to produce any dopamine. (Nocebo)
By contrast, a positive attitude…where you celebrate the smallest of victories…can trigger dopamine
production. Looking forward to seeing your children and/or grandchildren grow and succeed in life…getting
together with friends…planning a trip…making time to engage in an activity that you enjoy…these activities
give your brain reason to release dopamine.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Alternative
Treatments
Uncertain and Unproven
Maybe the treatment will work, maybe it
won’t.
Maybe you’ll benefit from a placebo effect.
Try alternative treatments within reason
Don’t jeopardize your health (Is it safe?)
Don’t get ripped off (Is it expensive?)
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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There is an interesting argument for how
the action of volunteering and fund raising
for PD research not only helps enable
research that will benefit Parkinson’s
patients in the future, but can also improve
your Parkinson’s symptoms today.
THEUNEXPECTED PLACEBO EFFECT OF VOLUNTEERISM
(A.K.A., FEELING GOOD BY DOING GOOD)
(A.A.K.A., GIVING IS ITS OWN REWARD)
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Be Active, Volunteer
Raising funds, and trying to reach a fundraising goal, creates anticipation, motivation, and satisfaction. It
also creates opportunities for learning.
There is also a sense of delayed gratification knowing that you are helping an organization like the Michael
J. Fox Foundation, Parkinson’s Foundation, or Cure Parkinson’s Trust, fund and promote research that may
ultimately find a cure for PD.
This type of activity can only help to boost dopamine production.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Be Active, Exercise
Exercise also boosts dopamine. Find physical activities that you can enjoy and look
forward to. If there’s a sport you enjoy, you’ll be more motivated to participate.
Group activities, or activities with a friend tend to be more motivating than solo
exercise. For solo exercise, set goals & celebrate small achievements.
Stay positive, and remember that your goal is to slow/delay disease progression.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Socialize, Plan Get-togethers with Friends,
Plan Trips
Leverage the power
of anticipation.
Take part in activities
that you enjoy, but
require work/effort.
Create your own
placebo effect.
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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Good Luck With Your
Placebo Effect!
HTTPS://PARKINSON.FIT
© 2019 by Brett Warthen (Parkinson.FIT). This is not medical advice. Slides may be freely duplicated with this notice.
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