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Vyvanse: an Investigation of the New Breed of Adhd Treatment

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An Investigation of the New Breed of ADHD Treatment
Craig Leopold

Dr. Zoladz
9 May 2011

On April 23, 2008, Vyvanse (lisdexamfetamine) received FDA approval for the adult population. The approval of this drug marked a new era in evolution of Attention Deficit Hyperactivity Disorder treatments. After decades of criticism on the rampant abuse and alleged overprescribing of amphetamine ADHD medications New River Pharmaceuticals responded by developing lisdexamfetamine, a compound that is inactive until converted to dextroamphetamine by the gastrointestinal tract. This means that Vyvanse is only effective when taken orally, reducing the potential for abuse. Moreover, that Vyvanse lasts much longer than typical amphetamine ADHD medications. One administration of the drug lasts throughout an entire day. Although this drug removes a few issues pertaining to amphetamine treatment of ADHD, there has been questioning as to its efficacy in treating the full range of symptoms caused by ADHD because it is broken down into dextroamphetamine alone instead of a combination of amphetamines such as Adderall. Nevertheless, Vyvanse has been established as efficacious in the treatment of ADHD symptoms. In order investigate this new breed of ADHD treatment more completely one must understand the neurobiology of ADHD, the pharmacodynamics and pharmacokinetics of lisdexamfetamine, and what the empirical evidence on Vyvanse suggests. Before one can understand how lisdexamfetamine works to alleviate the symptoms of ADHD, further explanation of the disorder is required. According to the Diagnostic and Statistical Manual of Mental Disorders, Attention Deficit Hyperactivity Disorder can be broken down into three sections: inattention, hyperactivity, and impulsivity. Inattention consists of symptoms such as careless mistakes on schoolwork, trouble with organization, distractibility, inability to listen when spoken to directly, and avoiding tasks that require concentrated mental effort. Fidgeting, running about or climbing inappropriately, trouble enjoying leisurely activities, and excessive talking can indicate hyperactivity. Impulsivity is comprised of trouble waiting one’s turn, blurting out answers before one is finished speaking, and interrupting others. Noting 6 or more of these symptoms can make a diagnosis. With varying combinations of these symptoms, there are 3 types of ADHD that can be identified; Combined type, Predominantly Inattentive type, and Predominantly Hyperactive and Impulsive type. The methods of diagnosis for ADHD have been constantly evolving since its discovery, from merely observation to complicated clinical tests. Clinical procedures are still used to diagnose ADHD, yet the advancement of technology now allows the physical manifestations of ADHD to be made visible with Functional Magnetic Resonance Imaging (fMRI). This technology allows doctors and researchers to gauge the levels of neurotransmitters in the brain in association with the activity or lack of activity in certain brain regions. Dr. Helen Courvoisie completed one of the first studies on ADHD using this technology. Courvoisie states, “Our data show children with ADHD had a two-and-half-fold increased level of glutamate, an excitatory brain chemical that can be toxic to nerve cells… The data also suggest a decreased level of GABA, a neuro-inhibitor. This combination may explain the behavior of children with poor impulse control”. This study measured neurotransmitter metabolites in a specific section of the frontal lobe. Toxic levels of glutamate in the prefrontal cortex and temporal lobes of children with ADHD can lead to neuronal damage, cell death, and resulting inactivity in these regions. One theory proposes that, for those with ADHD, there is a dysfunction in the dopamine transfer system. A dysfunction in dopamine transfer suggests that while dopamine response to reinforcing stimuli occurs quickly and efficiently in the mesolimbic pathways of normal children, mesolimbic dopamine response in children with ADHD is delayed and decreased to the point that learning conditions are much slower and reinforcing stimuli are much less salient. This idea goes hand-in-hand with the Low Arousal Theory. The Low Arousal Theory suggests that, due to an inadequately functioning dopamine system, those with ADHD seek self-stimulation and extreme activity to transcend their condition of unusually low arousal. The underlying neurobiological abnormalities that cause ADHD are understood fairly well, however the factors that bring about these abnormalities are currently under investigation. As of now, it is believed that ADHD susceptibility is linked to genetics in cohorts with environmental factors. To date no specific gene has been found to play a chief role in ADHD. However, some genes have been found to have an association with the disorder. The most predominant are genetic variations in the D4 receptor (Swanson et al., 2000) and the DAT1 dopamine transporter (Gill et al., 1997). Environmental factors include alcohol and tobacco exposure to the fetus during pregnancy and exposure to lead very early in life (Braun et al., 2006). Furthermore, certain viruses and bacterial infections during pregnancy, birth, and early childhood are associated with an increased chance of developing ADHD (Millchap 2008). Although much headway has been made in understanding the factors leading to the development of ADHD, prevention is not possible. Thus, until preventative measures can be discovered and implemented, pharmacological treatments like Vyvanse are the only way to provide significant relief for those suffering from the disorder.
As previously mentioned, Vyvanse was developed in response to the growing rate of amphetamine abuse. Lisdexamfetamine is a prodrug to dextroamphetamine and consists of dextroamphetamine coupled with L-lysine, an essential amino acid. This configuration makes the drug inactive until it is metabolized in GI tract. Thus, the only route of administration is orally. Unlike other amphetamine medications, Vyvanse cannot be snorted or chewed to increase rate of absorption into the bloodstream. This novel configuration also increases the duration of effect so that multiple administrations throughout the day are not necessary. Vyvanse is usually taken in the morning with or without food. Vyvanse comes in oral doses ranging from 20 to 70 milligrams, increasing in increments of ten milligrams. Some common side effects include: rash, irritability, hyperactivity, difficulty falling asleep or staying asleep, and unusual changes in personality or behavior. Overuse of lisdexamfetamine may cause sudden death or serious heart problems. After oral administration, lisdexamfetamine dimesylate is rapidly absorbed in the gastrointestinal tract and converted to dextroamphetamine by first-pass intestinal and/or hepatic metabolism. In a 2008 study, 70mg of lisdexamfetamine was administered and the pharmacokinetics of the drug was measured extensively. This study found that lisdexamfetamine dimesylate was rapidly absorbed, extensively metabolized to d-amphetamine, and promptly eliminated. Moreover, systemic exposure to dextroamphetamine was about twenty times greater than systemic exposure to intact lisdexamfetamine dimesylate in healthy adults (Krishnan et al., 2008). This means that lisdexamfetamine is converted to dextroamphetamine very efficiently. Peripherally, dextroamphetamine causes an increase in noradrenaline, however, this drug works more centrally than peripherally in the nervous system, as it is able to cross the blood-brain barrier very efficiently.
In the brain, dextroamphetamine is believed to increase the activity of the phosphoinositol cycle by causing indirect release of dopamine and norepinephrine (Kuczenski et al., 1995) Augmentation of the phosphoinositol cycle increases the rate and strength of signals within neurons (Silverstone et al., 2002). At higher dosages, dextroamphetamine interferes with the dopamine transporter’s ability to clear dopamine from the synapse. DAT function is reversed; dextroamphetamine enters the presynaptic cell and causes an efflux of endogenous dopamine from the cell. This incites the release of dopamine from the mesocorticolimbic pathway and the nigrostriatal dopamine pathway. This amplified dopamine transfer counters the dysfunction of dopamine transfer present in those with ADHD. Due to the increase in dopamine transmission, dextroamphetamine causes dopamine release in the prefrontal cortex and activates D2 receptors, which inhibit glutamate release in the prefrontal cortex. This acts to combat the toxic levels of glutamate in this brain region that is implicated in ADHD. At still higher doses, dextroamphetamine stimulates the release of 5-hydroxytryptamine, and may act as a direct agonist on 5-HT receptors. These serotonergic effects may play a role in regulating dopamine levels and mediating the impulsivity associated with ADHD (O’Neill et al., 1999). In addition to these effects, dextroamphetamine prevents the re-uptake of monoamines by competing with endogenous monoamines for uptake into the presynaptic cell. Furthermore, dextroamphetamine may slow the metabolism of monoamines in the synaptic cleft by inhibiting monoamine oxidase.
As a result of this multitude of effects, a greater amount of endogenous monoamines are released from the presynaptic neuron and these monoamines remain in the synaptic cleft longer to stimulate receptors on the post-synaptic membrane more completely. A recent four-week study comprised of 314 adolescents determined that lisdexamfetamine at all doses is effective in treating adolescent ADHD (Findling et al., 2011). Another study, comprised of 420 adults, found that lisdexamfetamine was significantly more effective than placebo in the treatment of adults with ADHD, with improvements seen within one week (Adler et al., 2008). Lisdexamfetamine has also been proven efficacious in the treatment of ADHD in children. Children exhibited the same dose-response relationship as see in adolescent and adult trials (Findling et al., 2008). Common side effects seen in these studies included: decreased appetite, headache, insomnia, decreased weight, and irritability. Despite these side effects, lisdexamfetaime has been determined safe for children, adolescents and adults. All three of these studies were relatively short, yet the biggest limitation of these studies is the potential variability in rater assessment. Because these studies rely on behavioral assessments, there is no way to be certain that all investigators will rate behavior in the same way. In addition, though each study claims to have a group of patients with similar strength and symptoms of ADHD, there is no way to account for differences between subjects. Nevertheless, These and multiple other studies have confirmed that lisdexamfetamine is effective and safe in treating the symptoms of ADHD. The newly innovated method of administration combined with the reliability and efficacy of a proven psychostimulant makes Vyvanse an easy choice for those suffering from ADHD. ADHD medications will continue to evolve, but as of right now, vyvanse is one of the most effective and safest treatments available.

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