final ritalin paper - nicole brooker · ritalin2! nicolebrooker!! ritalin is a stimulant drug that...
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Ritalin Drug Discovery, Development, and ADHD
Nicole Brooker
Ritalin 2 Nicole Brooker
Ritalin is a stimulant drug that was prescribed to nearly 9 million people in
1999 and the statistics continue to rise by a significant rate each year. Ritalin
primarily treats ADHD, and it is ranked 39 among the top drugs in the United
States pharmaceuticals. In this paper the history and background of ADHD will
be discussed, the scientific discoveries that identified the disorder, and how
many people suffer with this disorder and why the drug is needed. The clinical
trials and efficacy will also be considered, including side effects and the Ritalin
developmental timeline. To delve deeper in the pathways and mechanisms, the
drug pathways of Ritalin and competing drugs will be examined, and finally the
sales and the patent of the drug will be analyzed.
The history of ADHD and Ritalin begins with Sir Alexander Crichton in
1798 who gave an example of a similar disorder to ADHD. Crichton’s work and
discoveries were due to his interests in mental illnesses, and he wrote a series of
books called “An inquiry into the nature and origin of mental derangement:
comprehending a concise system of the physiology and pathology of the human
mind and a history of the passions and their effects” during his clinical research
observing mental illnesses (Lange et al. 2010). In his second book, Crichton
wrote about attention and its alterations in mental illnesses, and how
inattentiveness was due to a nervous disorder and brain dysfunction (Lange et al.
2010). Following Crichton’s studies, modern medicine and science was able to
link his observations to the current idea of ADHD, suggesting that the disorder or
a related disorder dates back to the eighteenth century.
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The history of ADHD continues on to 1844 with the German physician
Heinrich Hoffmann and his children’s stories titled “Fidgety Phil” (Lange et al.
2010). The stories tell of a young child, Philip, sitting at dinner with his family.
The father wonders whether his son will
behave at the dinner table or not, suggesting
that Phil had some behavior problems. Phil
squirmed and tilted in his chair, not listening
to what his father told him. The story
continues with Phil’s misbehavior until he
falls back in his chair, taking the tablecloth with the food, silverware, and drinks
with him crashing to the floor. This story represents inattentiveness and bad
behavior in the nineteenth century, and many scientists and authors are
convinced that this is another piece of evidence reflecting current ideas of ADHD
(Lange et al. 2010). In 1902, George Frederic Still gave lectures on post-
encephalitic behavior disorders demonstrating what most authors today believe
was the first scientific recognition of ADHD (Lange et al. 2010). In his lectures he
discusses origins of hyperactivity and minimal brain dysfunction in children,
which can be viewed as a precursor to ADHD. Later on in 1932, Franz Kramer
and Hans Pollnow reported “On a hyperkinetic disease of infancy” where they
discussed impulsivity and all of the signs and symptoms of what we know as
modern day ADHD (Lange et al. 2010). It wasn’t long after their discoveries that
treatment research started.
Figure 1: "Fidgety Phil" illustrates what appears to be ADHD in the 19th century.
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We then move on to 1937 where we see the first treatment of the disease
by Charles Bradley (Lange et al. 2010). Bradley studied the positive effect that
stimulants had on children with behavioral disorders. Bradley’s discovery of the
positive effect of stimulant drugs was found by chance during his neurological
examinations (Lange et al. 2010). He tested the way children focused and did
school work while on Benzedrine. The improvement seen would be revolutionary
and lead to future studies in ADHD treatment.
After Bradley used Benzedrine, other scientists worked with stimulants to
correct behavior, including the most commonly used stimulant drug today:
“Ritalin” or Methylphenidate. Leandro Panizzone was the first to synthesize the
drug in 1944 and he named it after his wife, Rita (Lange et al. 2010). It was first
used to treat depressive behavior and lethargy, and wasn’t until later that it was
linked to and used for ADHD treatment.
Attention deficit hyperactivity disorder is characterized by inattention,
hyperactivity, and impulsivity, and is seen mostly in children. The average age of
diagnosis is 7 years ("Attention-deficit / hyperactivity," 2013). ADHD has three
subtypes: Predominantly hyperactive-impulsive, Predominately inattentive, and
combined hyperactive-impulsive and inattentive ("What is attention,”). Most
children have the combination of hyperactive-impulsive and inattentive behavior.
In order to diagnose a child with this disorder they need to have at least six
symptoms from these three subtypes. Some of the symptoms for hyperactive
behavior include fidgeting and constantly being in motion, unable to sit down at
dinner, and touching or playing with anything in sight. Symptoms of impulsive
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behavior include blurting out inappropriately, impatience, and no restraint of
emotions. Inattentive behavior can include lack of focus, easily distracted,
daydreaming, inability to complete assignments, often losing things, and
becoming bored with a task unless its enjoyable ("What is attention,”).
As for the causes of ADHD, there have been studies on the potential
factors but it is still unknown if there is an underlying cause. Some of the factors
that have been found to cause ADHD include genes, environmental factors, brain
injuries, sugar, and food additives. Studies have shown that children with ADHD
have thinner brain tissue in the areas associated with attention that can be
causative by genes. Environmental factors such as cigarette smoking and
alcohol use during pregnancy have been seen in children with ADHD. Brain
injuries have caused ADHD in very few cases, and sugar and food additives such
as colors and preservatives are also being considered as factors causing ADHD
because they result in an increase in activity ("What is attention,”).
ADHD diagnosis has increased at a significant rate since the early 1990’s,
and over 6.4 million children are affected by this disorder. As of 2011, 11% of
children ages 4-17 years of age have been diagnosed with ADHD. The rate of
diagnosis continues to increase from an average of 3% per year from 1997-2006
to a 5% average per year from 2003-2011 ("Attention-deficit / hyperactivity,"
2013). The average age of diagnosis is 7 years of age and 13.2% of boys are
diagnosed versus 5.6% of girls who are diagnosed ("Attention-deficit /
hyperactivity," 2013). This is clearly an escalating issue among the younger
generations and an effective drug for treatment is necessary, and thus far Ritalin
Ritalin 6 Nicole Brooker
has been proven to be a great solution for those who suffer with this disorder.
ADHD is an amenable target for Ritalin because the drug acts on the prefrontal
cortex of the brain. This anterior part of the frontal lobes is important in complex
cognitive and social behavior, which is the type of behavior that children with
ADHD lack ("Ritalin targets prefrontal," 2012).
Wiseberg and Robin did clinical trials in 1958 while testing the efficacy and
effects of Ritalin on depressive states (Robin & Wiseberg, 1958). Some patients
in the trial declined due to unpleasant side effects and those who stayed denied
any change to their depressive states, therefore the Ritalin was denied for use to
treat depression symptoms (Robin & Wiseberg, 1958).
Later in 2007, trials on methylphenidate had been done by Novartis to test
the safety and efficacy of Ritalin in children with ADHD with the variant being
different breakfast conditions (Novartis, 2011). The results from the trial showed
overall that the drugs are safe, and safe under all different breakfast conditions
(Novartis, 2011). Other studies have been done to test the efficacy of
methylphenidate among differently behaved children with ADHD. Although the
results didn’t show that Ritalin helped all children in reducing hand movements
and distracted behavior, it did show an overall decrease in aggressive behavior
(Wulbert & Dries, 1977). Ritalin might not work for every child with ADHD but the
efficacy and safety overall puts this drug in the category of best drugs for ADHD
treatment.
Lastly, there was a study done to test efficacy of Ritalin based on the
therapeutic doses given. The results of the study showed that the Ritalin
Ritalin 7 Nicole Brooker
effectively reduced the “signal to noise
ratio” and the therapeutic amount of
dopamine was effective in improving
performance and motivation (Volkow et al.
2001). Considering that ADHD and Ritalin
use is fairly new, there have been very
few studies on long-term effects. There
has been a study, however, on the effects of oral methylphenidate use on the
brain after 12 months of use. These studies showed that as time progressed, the
density of dopamine transporters in the brain increased as drug use progressed.
This could eventually lead to a tolerance and resistance to Ritalin long-term if the
dopamine transporters begin beating the drug to binding the dopamine in the
synapse (“Long-term adhd treatment,” 2013).
Other studies have been released relating Ritalin to other dangerous
drugs such as cocaine. Many parents and other users had concerns about
possible “highs” that they could get
following Ritalin use. A study was done to
test if the cocaine and methylphenidates
did compete for the same binding sites in
the brain, and if so, was the uptake of the
drug different in either case (Volkow et al.
1995). The results suggested that
Figure 2: Red shows the higher amount of DAT's present after a year of methylphenidate use.
Ritalin 8 Nicole Brooker
although both of the drugs inhibit the reuptake of the dopamine in the brain,
Ritalin does it at a significantly slower rate (90 minutes) compared to cocaine (20
minutes) (Volkow et al. 1995). Because of the very fast uptake of the Cocaine in
the brain, the user feels a high while Ritalin has a slower uptake and clearance of
methylphenidate from the brain. In Figure 3 above we can see that even with
different percent occupancies of dopamine transporters for those taking Ritalin,
most of the subjects reported zero for their self-
reported high.
Ritalin has several different side effects,
both common and more severe. Some
common side effects include nervousness,
anxiety, insomnia, nausea, loss of appetite, dry
mouth, increased heart rate, stomachache, and
headache. More severe side effects include
chest pain; shortness of breath, or irregular
heart beat in which immediate medical
attention is necessary (Barkley et al. 1990).
Insomnia and decreased appetite were seen to
increase in severity as the dosage increased.
Decreased appetite increased in severity from 7% to 18% while Insomnia
increased from 1% to 13% (Barkley et al. 1990). Research has also shown that
several different side effects decreased with a higher dose of Ritalin such as nail
Ritalin 9 Nicole Brooker
biting, daydreaming, anxiety, and irritability.
These side effects were reported to decrease significantly when dosage was
increased from 0.3 mg/kg to 0.5 mg/kg (Barkley et al. 1990). Girls also reported
stomachaches, nail biting and headaches more often than boys (Barkley et al.
1990). Very few children experienced severe side effects and there were no
significant variations among different ages (Barkley et al. 1990).
The timeline for the development of Ritalin begins in 1944 when Leandro
Panizzon first synthesized it for his wife’s fatigue and depression. For the next six
years Ritalin was modified and improved by Panizzon and other groups for better
targeting of the disorder and the new formula was patented in 1950 (Lange et al.
2010). After the modifications were done, human trials began in 1954. CIBA filed
Ritalin 10 Nicole Brooker
to trademark the drug and in 1956 the FDA approved the patent (Daemmrich &
Bowden 2005). CIBA began the marketing of Ritalin for depression, fatigue, and
narcolepsy in 1957 (Ritalin, 2013). During this time up to the 1960’s, the
therapeutic effects of Ritalin on ADHD were being studied. In 1960, Ritalin was
primarily made into a cocktail of vitamins and hormones called Ritonic, which
was used to increase mood and vitality (Ritalin, 2013). Finally in the 1970’s, after
Ritalin and its therapeutic affects on ADHD had been studied, Ritalin was being
prescribed to children with ADHD (Daemmrich & Bowden 2005). Starting in the
1990’s Ritalin sales boomed by 500% and the U.S. made 85% of the world’s
Ritalin. Today, methylphenidate is the most common drug prescribed in treating
ADHD (Lange, et al. 2010).
ADHD can be treated with several different drugs, classified as either
stimulants or non-stimulants. Today, the disorder is treated primarily by
stimulants. It was a strange finding when a stimulant was used to treat
hyperactivity. However, this works because it has a calming effect on those with
ADHD, but has an opposite effect on those who do not have the disorder.
Psychostimulants work in the nervous system and they all work by affecting the
Ritalin 11 Nicole Brooker
release and reuptake of the neurotransmitters dopamine and epinephrine. The
following paragraph will discuss the different drug competition for Ritalin and
break it down more specifically into the difference between two classes of drugs
most used in treating ADHD: methylphenidates and amphetamines.
Ritalin has many competitors on the market including other brands of
methylphenidates, amphetamines, lisdexamfetamines, and
dexmethylphenidates. Drugs with similar mechanisms and structure include
Concerta, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin SR,
Ritalin LA, Daytrana, and Quillivant XR (Quinn, 2012). Each of these
methylphenidates is a pipiridine compound and has the formula C14H19NO2, and
they work by binding to the dopamine
transporters (DAT) in the synapse to reduce
reuptake of the dopamine from the synaptic
space (Sherzada, 2012). Ritalin therefore acts
as a norepinephrine-dopamine reuptake
inhibitor allowing these neurotransmitters to remain in the extracellular space,
thus allowing more motivation and concentration for the user. The inhibiting drug
increases concentration because there will be more norepinephrine in the
synapse for longer which is the monoamine responsible for concentrated
behavior. Motivation will be increased as well because of the greater amount of
dopamine, which is the reward-motivation neurotransmitter (Sherzada, 2012).
Perhaps the biggest question and competition involving attention deficit
disorder medications is whether methylphenidates or amphetamines are best,
Ritalin 12 Nicole Brooker
which leaves Adderall and the other amphetamines (such as Dexedrine) to be
the most competition to Ritalin on the market. These two types of ADHD
stimulant drugs are different in their
structure, mechanism, and target. As
explained previously, Ritalin (or
methylphenidate) works primarily by
targeting and binding dopamine transporters in the brain and inhibiting reuptake
of these neurotransmitters. Amphetamines, such as Adderall, have the formula
C9H13N and work in an opposite manner. During metabolism the aromatic ring in
amphetamine oxidizes to form hydroxyamphetamine, which then deaminates to a
phenylacetone and finally oxidizes to benzoic acid (Sherzada, 2012). The goal of
Adderall and amphetamines is similar to that of methylphenidates, to increase
dopamine and norepinephrine levels in the synaptic space. However, they do it in
a much different way than Ritalin. It can be said that the amphetamines affect
DAT’s in reverse. Rather than binding to inhibit dopamine reuptake, the
amphetamine enters the presynaptic neuron and expels dopamine by creating an
action potential that forces the molecules out of their storage vesicles into the
synaptic space (Sherzada, 2012). Amphetamines can also inhibit monoamine
oxidase, the enzyme that is responsible for breaking down of neurotransmitters
(Sherzada, 2012).
The difference in the drug response is that typically Adderall is faster
acting, but for a shorter period of time. This is because of the rapid mechanism of
expelling the neurons stimulating monoamine release and inhibiting the enzyme
Ritalin 13 Nicole Brooker
that breaks down these neurotransmitters. Ritalin is slower acting but over a
longer period of time because of the DAT binding and inhibition, which allows the
neurotransmitters to remain in the extracellular synaptic space.
Vyvanse is another type of ADHD drug that isn’t categorized as a
methylphenidate or amphetamine, but rather a Lisdexamfetamine. Its formula is
C15H25N3O. This drug is a
psychostimulant like the others
but it is also coupled with Lysine.
Vyvanse was developed so the amphetamine in it is activated and released
slower than the other drugs previously discussed. This happens when it is
metabolized, the drug is hydrolyzed which then allows cleaving off of the amino
acid (“lisdexamfetamine”). Focalin is another drug that didn’t fit in the previous
categories; it is classified as a dexmethylphenidate. Focalin has the formula
C14H19NO2. This drug functions most similarly to amphetamines, as in binds the
DAT’s and releases monoamines into the synaptic space by entering the neuron.
It is also a central nervous
system stimulant like the drugs
previously discussed.
As the diagnosis and
prescription of Ritalin increases,
so have the sales over the
years. In 1991 roughly 2 million
prescriptions of Ritalin were
Ritalin 14 Nicole Brooker
given, and in 1999 over 9 million people have been prescribed (“Statistics on
stimulant”). As mentioned earlier, in 2003, 7.8% of children ages 4-17 were
diagnosed with ADHD and in 2011 that number grew to 11% and it continues to
be on the rise. Ritalin sales have drastically increased over the years from
roughly $180,000,000 in 2011 to over $350,000,000 in 2013 (“Methylphenidate
Sales Data,” 2013). The drug is currently ranked number 39 in the U.S. among all
pharmaceutical drugs.
We can also see that as demand goes up from increased diagnosis,
production goes up as well. There is a significantly greater amount of
methylphenidate produced compared to amphetamine. We can see that in 1990
around 2,000 kilograms of Ritalin was produced in the U.S., which has
skyrocketed over the following 10 years
to over 150,000 kilograms a year in the
U.S. (“Statistics of stimulant”). It is also
interesting to see the geographical
Ritalin 15 Nicole Brooker
statistics, over the average amount of Ritalin is prescribed in northern U.S.
The patenting of the drug began in 1950, when CIBA filed for the
trademark of what would soon be the brand name drug Ritalin that was a
methylphenidate drug, derived from amphetamine to treat hyperactivity (Lange et
al. 2010). In 1956, the FDA approved the methylphenidate drug and it was put
on the market to treat depressive mood disorders, fatigue, and narcolepsy. It
wasn’t until 1967 when the patent expired that Ritalin was discovered to actually
treat ADHD (Daemmrich & Bowden 2005). Since the original patent expired,
Novartis Corporation now owns the patent and it expires in 2015.
Ritalin has had a lot of success in treating ADHD over the years,
especially when sales and production boomed in the 1990’s. According to
history, symptoms of ADHD date back to the 17th century and are still seen in
millions of children and some adults today. Ritalin is an important drug on the
market as the expected diagnosis of ADHD is increasing at a rapid rate over the
years. Methylphenidate has been shown to be the safest and most effective
among the ADHD stimulant drugs, as there are several other variants of
methylphenidate similar to Ritalin. The other competing drugs were discussed
such as Adderall and other amphetamines, and how their mechanisms differ from
methylphenidate, which can explain why their effects on people differ. Studies
showed that different drugs affected children in different ways, although each
drug had a lot in common with the others being tested. For future research it
would be relevant to study in depth the long-term effects of Ritalin on those with
ADHD. Brief studies have been shown that over time with extended use of
Ritalin 16 Nicole Brooker
methylphenidate, the number of dopamine transporters is increased in the brain,
posing a potential threat for future tolerance or drug resistance. Another area of
research could be to study the reasoning behind the intellectual boost that those
who don’t have ADHD get when taking Ritalin. Few studies have been done on
the effects of Ritalin on college students and studying for exams. More studies
also need to be done on the actual mechanism of action in the brain, since it is
so closely related to Cocaine and its pathway of stimulus.
Ritalin has provided scientists today with
a lot of faucets for further drug discovery and
research for ADHD. It is important to recognize
that not all drugs end up treating the symptoms
and disorders one might expect, and often
discoveries can be surprising. It was an
unexpected revelation to find that Ritalin would be used to treat hyperactivity
rather than depression, and that a stimulant would be a great drug for
hyperactivity. The known history and discovery of Ritalin and its target in ADHD
is an important step in the direction of better understanding mental health and
childhood psychiatric development.
Ritalin 17 Nicole Brooker
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Robin, A. A., & Wiseberg, S. (1958). A controlled trial of methyl phenidate (ritalin) in the treatment of depressive states. J Neurol Neurosurg Psychiatry,21(1), Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC497294/ Sherzada, A. (2012). An analysis of adhd drugs: Ritalin and adderall. JCCC Honors Journal, 3(1), Retrieved from http://scholarspace.jccc.edu/cgi/viewcontent.cgi?article=1021&context=honors_journal Statistics on stimulant use. PBS. Retrieved from http://www.pbs.org/wgbh/pages/frontline/shows/medicating/drugs/stats.html Volkow, N. et al. (1995). Is methylphenidate like cocaine? studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry., 52(6), Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7771915 Volkow, N. D. et al. (2001). Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. The Journal of Neuroscience, 21, Retrieved from http://www.jneurosci.org/content/21/2/RC121.full.pdf Wulbert, M., & Dries, R. (1977). The relative efficacy of methylphenidate (ritalin) and behavior-modification techniques in the treatment of a hyperactive child. Journal of