Thursday, December 18, 2008

Evaluation of Vyvanse for ADHD Treatment

A new drug called Vyvanse (Lisdexamfetamine) has entered the world of ADHD stimulant medications relatively recently. Vyvanse was originally marketed as an ADHD treatment for children, but has recently been approved by the FDA for adult and adolescent use this past April. A cousin of the popular ADHD medications Dexedrine and Adderall, Vyvanse includes some key modifications from these other meds. Some reports (unverified) suggest that Shire Pharmaceuticals, the makers of Vyvanse, are pushing this new drug aggressively over Adderall XR. While Adderall is a chemical mixture of amphetamine salts including enantiomers, Vyvanse only contains the one enantiomer thought to be more "active".

A quick side note on enantiomers: Entantiomers are essentially "mirror images" of the same chemical compound, like a person's left and right hand. The body, like most objects in nature, react differently to and often heavily prefer one "mirror image" over the other. Certain ADHD medications such as Focalin, have already employed this technique. Focalin is an isolation of only one of the two mirror images that make up Ritalin, another popular ADHD medication. In addition, the ADHD medication Dexedrine also employs this mirror-image selectivity regarding its composition.

The second major difference between Vyvanse and other amphetamines such as Adderall, is that Vyvanse is listed as a "pro-drug". A pro-drug is essentially an inactive form of a drug, which, when broken down or metabolized by the body, releases the active drug form. Vyvanse contains an amphetamine which is chemically linked to an amino acid (a building block component of proteins) called lysine. In the body, this chemical linkage is severed by special enzymes which separate Vyvanse into the amphetamine drug and leftover lysine fragment (which is easily disposed of, since lysine is a naturally occurring amino acid in its own right).

***Blogger's note: I will be citing a number of studies previously conducted on the drug lisdexamfetamine. Keep in mind that this is a relatively new drug, so it does not have the history of a drug such as methylphenidate. Nevertheless, I have tried to keep a good balance of sample studies on the drug to report on. The list of studies mentioned and referred to here, are by no means exclusive! While not all of the studies used the Vyvanse brand of the drug, I will be using the terms "Vyvanse" and lisdexamfetamine interchangeably throughout the post.

***Additionally, please do not take this information as official medical advice. I am simply trying to highlight some of the pluses and minuses of the drug and arm you with information so you can better consult with your physician on the merits of this drug.

This chemically-modified form carries several apparent advantages for Vyvanse:
  • Since the lysine link must be cleaved to release the active form of the amphetamine drug, Vyvanse naturally lasts longer in the system than do straight amphetamines. While most other stimulant medications rely on the capsules encasing the drugs to slowly dissolve and thereby slow down the release of the drug, Vyvanse already has what is essentially a controlled release built in to the drug itself. As a result, a single dose taken early in the day can last up until the evening hours, which allows individuals to avoid the hassle or stigma of needing to take the medication during the work or school day.

  • Most of amphetamines problems stem from their addiction potentials. Generally, the faster the amphetamine gets into the blood stream and gets into (as well as out of), the brain, the greater the "high", and the more addiction-forming the drug. Again, by its built-in slow release mechanism, Vyvanse enters the blood (as well as the nervous system) at a slower, more controlled pace, thereby reducing its addiction potential. Even when snorted or injected, lisdexamfetamine exhibits notably reduced addiction potentials, when compared to other amphetamine-based stimulants. For example, when injected via IV, subjects who took Vyvanse needed 1-3 hours to feel the drug effects while isolated d-amphetamine (analogous to Dexedrine) felt the effects in only 15 minutes.

  • Due largely in part to the fact that Vyvanse's drug effect needs to be "activated" biochemically, it is poses less risk for tampering and related abuses (i.e., crushing and snorting) as well.

Additionally, Vyvanse also carries some other distinctive advantages:

  • While many drugs effectiveness are often dependent on the level of acidity in the stomach and intestinal tract, Vyvanse appears to be only mildly affected. It dissolves quickly in the gastro-intestinal tract, and its solubility is minimally affected by digestive pH.

  • The presence of food only results in a slight delay in Vyvanse's absorption. When taken alongside a fatty meal (fatty foods generally impede the absorption process, as they themselves are slow to clear the gastro-intestinal tract) the delay in amphetamine release from Vyvanse was only about an hour. This was in contrast to around a 2.5 hour delay when Adderall was taken with fatty foods. As a result, Vyvanse appears to be less affected by the presence of food than other well-known amphetamines, suggesting an increased versatility as an ADHD stimulant medication treatment.

  • This next statement is the blogger's opinion and is not supported by direct evidence. Nevertheless I believe this is a topic worthy of investigation: In a previous blog post, we discussed celiac disease and how it can ravage the digestive tract and result in ADHD-like symptoms. While these symptoms are likely the result of a different path than ADHD caused by genetic or environmental factors, it may be worth noting that Vyvanse may alleviate some of these inattentive symptoms better than other ADHD medications, due to the fact that it may absorb better in a digestive system damaged by celiac disease or the pH changes which often accompany it (poorly digested carbohydrates can alter the pH in the digestive system immensely). While this will not treat the underlying cause of celiac disease, it may mask the some of the ADHD-like symptoms better than other medications. This assertion is simply a personal hypothesis and is yet to be studied or verified.

  • In addition to its resiliency regarding foods and digestive pH, it appears that Vyvanse may be less susceptible to negative drug-drug interactions than many other agents. Many medications target a key metabolic system referred to as Cytochrome P450. While to complex to discuss in detail in the limited scope of this post, the P450 system of proteins plays an integral role in drug metabolism, the body's antioxidant levels, and regulation of toxicities, it appears that the effects of the drug lisdexamfetamine on the P450 system are minimal. Since many drugs do operate via this system, Lisdexamfetamine should therefore pose less of a threat regarding negative drug-drug interactions.

  • The drug apparently has a good track record as far as behavioral improvements and attention span are concerned. A study was done using a rating scale called SKAMP (which stands for the initials of its creators: Swanson, Kotkin, Agler, M-Flynn and Pelham), which is used to determine classroom behavior. According to the study using this particular rating scale, measurable improvements were seen in both attention span and classroom conduct for periods of up to 12 hours after taking their last dose of lisdexamfetamine. Prolonged behavioral changes are typically not seen to this degree, and the fact that the subjects were diagnosed and medicated previously suggest the potential effectiveness of Lisdexamfetamine even for "stubborn" ADHD cases.

  • The same study also employed a mathematics-based test called PERMP (short for Permanent Product Measure of Performance). Notable improvements were seen in both both speed and accuracy on this test following a 5-week amphetamine treatment program. Lisdexamfetamine's positive effects on this cognitive task peaked around 4.5 hours after the last dose was administered and held relatively steady for the next 7-8 hours. The results of this study suggest that Lisdexamfetamine can improve the inattentive and behavioral symptoms of ADHD as well as enhance cognitive performance abilities for a prolonged period of time. This suggests great potential for use as a "school drug".

  • A study on adult stimulant drug abusers by Jasinski and Krishnan presented at the 2006 US Psychiatric and Mental Health Congress found that the study's subjects found Lisdexamfetamine to be much less "likable" than other amphetamines, further suggesting a reduced addiction potential for an already-at-risk group.

  • When taken around breakfast time (7:30-8:00 a.m.), Vyvanse showed remarkable "staying power" throughout the day, based on results from a behavioral rating scale taken in the mid-morning, afternoon and evening time (the last being around 6:00 p.m.). This is good news for teachers and parents, and suggests a more gradual tapering-off of effects, and a lesser "rebound effect", in which negative symptoms rapidly reappear, often within the hours of 4 and 6 p.m.

  • Amphetamine levels delivered via the lisdexamfetamine system are thought to stabilize within about 5 days. This is good news, especially since many ADHD medications can take up to 3 weeks to normalize their effects.

  • Lisdexamfetamine has also shown more consistency than many other drugs as far as less variation from patient to patient. While this is neither good or bad by itself, it does suggest a greater inherent stability in that it appears to be less susceptible to the effects of other bodily functions which are variable from person-to-person. As a result, I see this greater predictability will make it a preferable choice for many prescribing physicians. Of course, the flip side is that ADHD is an extremely complex and multi-faceted disorder, and clinicians may fall into the trap of seeing a "one-size-fits-all" solution and begin to treat Lisdexafetamine as a fall-back, default prescription.

This blog, of course, is not designed to sound like some sort of promotional "infomercial" touting all of the benefits of Vyvanse while leaving out potential risk factors. To keep things balanced, I have included some of the negative attributes of this particular stimulant medication as well:

  • While the study by Jasinski and Krishnan on the reduced "likability" of Vyvanse was encouraging, it is not recommended for individuals with a history of drug abuse, as previous non-prescription drugs can interfere with its effectiveness.

  • Additionally, Vyvanse reduces the presence of a key enzyme in the body which is targeted by anti-depressants called monoamine oxidase. A number of anti-depressants called monoamine oxidase inhibitors (MAOI's) also target this enzyme and reduce its presence. Due to the potentially harmful combination of amphetamines and MAOI's, these MAOI drugs should not be taken alongside Vyvanse. Please note that certain substances, such as cigarettes, and even turmeric or curry (in large doses) can also have potentially negative effects with Vyvanse.

  • Slight elevations in heart rate and blood pressure (mainly the diastolic pressure, which is the smaller of the two numbers and represents the blood pressure at the "resting" phase of the heart) and slight changes in heart rhythms were seen with Vyvanse, especially in the upper dose (70 mg) levels. However, this is a relatively common occurrence within the family of stimulant medications. For further information, please see the earlier post Are ADHD Stimulant Drugs Bad for your Heart?

  • Like most stimulant medications used to treat ADHD, appetite suppression was also a common side effect (this is due, in part, to increased levels of free dopamine, an important signaling agent in the nervous system, which, also plays a role in the feeling of "fullness" in an individual. By artificially boosting free levels of this neuro-chemical, a reduction of hunger symptoms are often seen), even at the lower 30 mg doses. However, actual weight loss did not become a huge symptom until the upper levels (around 70 mg doses) were approached.

  • The "classic" side effects (that almost all medications now somehow seem to evoke!) such as headache, nausea, vomiting, etc. all remained relatively low until the 70 mg level was approached.

  • Keep in mind that this drug still functions as a stimulant, and is therefore inherently better-suited for the more inattentive or impulsive forms of ADHD. Given the negative interactions with the MAOI class of antidepressants and the fact that stimulant drugs in general can worsen depressive symptoms, I recommend that extreme caution be used when prescribing this medication for individuals with comorbid ("comorbid" means "occurring alongside of") depressive symptoms alongside their attention deficit disorder.

Medication Doses Available:

30 mg, 50 mg and 70 mg were the original strengths available, but recently 20 mg, 40 mg and 60 mg doses have been added. The amount of amphetamine delivered in Vyvanse compared to Dexedrine approximately a 5:2 ratio. For example, 50 mg of Vyvanse corresponds roughly to 20 mg Dexedrine, 25 mg Vyvanse to 10 mg Dexedrine, etc. 30 mg is often a starting point for children, but doses can be carefully ramped up under the guidance of a physician. In general, it appears that many of the negative side effects can be kept at bay by staying under the 70 mg amount.

A quick side note: For another good source of information on medication dosages, I recommend the blog of Dr. Charles Parker. His blog can be found here. Additionally, he talks about a paradox called the therapeutic window. This is interesting to note, because sometimes ADHD medications which are prescribed at too high of a dosage actually result in ADHD symptoms to re-emerge and give the false impression of underdosage. You can check out this blog article here.

With regards to upper limits and safety measures, based on the studies mentioned above, negative side effects tend to increase around the 70 mg mark. Nevertheless, studies have been done at levels up to 130-150 mg. It is interesting to note that once this high range was reached, the amphetamine concentration in the blood began to taper off. This is good news with regards to the potential for overdose and buildup of toxic levels (note the relatively efficient rate of clearance of Vyvanse mentioned earlier in this post).

As a final word of caution: Remember that Vyvanse is essentially a new delivery method of amphetamines. I have highlighted some of the positives such as lower addiction potential and prolonged modes of action. However, keep in mind that there is often a strong "publication" bias, in that studies which find a drug to be ineffective or even counter-effective are often not reported or published. I therefore urge you to take some of these "glowing" reports on the drug with a grain of salt. Nevertheless, I remain at least cautiously optimistic with regards to the potential merits of lisdexamfetamine for treating ADHD and related disorders. We will be investigating other ADHD medication options shortly in future blog posts.