Archive for the ‘Medication: How They Work’ Category

Genomind

Genetic Testing

Genomind

 

The Genecept Assay Test Panel at a Glance

Pharmacodynamic

GENE PHYSIOLOGICAL ROLE IMPACT OF MUTATION TREATMENT IMPACT
Serotonin Transporter
(SLC6A4)
Protein responsible for reuptake of serotonin from the synapse Inhibition of this protein by SSRIs,
which may lead to increased risk for non-response/side effects
Use caution with SSRIs; atypical antidepressants or SNRIs may be used if clinically indicated
Calcium Channel
(CACNA1C)
A subunit of the calcium channel which mediates excitatory signaling Associated with conditions characterized
by mood instability/lability
Atypical antipsychotics, mood stabilizers, and/or
omega-3 fatty acids, which may help to reduce excitatory signaling, may be used if clinically indicated
Sodium Channel
(ANK3)
Protein that plays a role in sodium channel function and regulation of excitatory signaling Associated with conditions characterized
by mood instability/lability
Mood stabilizers and/or omega-3 fatty acids, which may help to reduce excitatory signaling, may be used if clinically indicated
Serotonin Receptor 2C
(5HT2C)
Receptor involved in regulation of satiety Blocked by atypical antipsychotics,
resulting in metabolic side effects
Use caution with atypical antipsychotics; inositol may be used to mitigate risk for weight gain if clinically indicated
Melanocortin 4 Receptor
(MC4R)
Receptor that plays a role in the control of food intake Increased risk for weight gain and higher BMI, which is exacerbated by atypical antipsychotics Use caution with atypical antipsychotics
Dopamine 2 Receptor
(DRD2)
Receptor affected by dopamine in the brain Blocked by antipsychotic medications and is associated with risk for non-response/side effects Use caution with antipsychotics
Catechol-O-Methyltransferase
(COMT)
Enzyme primarily responsible for the degradation of dopamine in the frontal lobes of the brain Altered dopamine states can have emotional/behavioral effects and impact response to dopaminergic agents Dopaminergic agents or TMS may be used if clinically indicated for Val/Val patientsUse caution with dopaminergic agents in
Met/Met patients
Alpha-2A Adrenergic Receptor
(ADRA2A)
Receptor involved in neurotransmitter release Associated with improved response to stimulant agents Stimulant agents may be used if clinically indicated
Methylenetetrahydrofolate Reductase
(MTHFR)
– A1298C
– C677T
Predominant enzyme that converts folic acid/folate to its active form (methylfolate) needed for synthesis of serotonin, dopamine, and norepinephrine Associated with varied activity and conversion of folic acid/folate to methylfolate Supplementation with L-methylfolate may be used if clinically indicated
Brain-derived
Neurotrophic Factor
(BDNF)
Important for proper neuronal development and neural plasticity Impaired BDNF secretion, which may be associated with altered SSRI response in Caucasians Increased physical activity/exercise may be beneficial for Met carriers if clinically indicated
μ-Opioid Receptor
(OPRM1)
Opioid receptor affected by natural and synthetic compounds Activated by opioids and associated with varied analgesic response, dosage, and abuse/addiction risk Use caution with opioids; non-opioid analgesics may be used if clinically indicated
Glutamate Receptor
(GRIK1)
An excitatory neurotransmitter receptor in the brain Associated with response to topiramate for alcohol abuse Topiramate may be used for treatment of alcohol abuse if clinically indicated

 

Pharmacokinetic

GENE PHYSIOLOGICAL ROLE IMPACT OF MUTATION TREATMENT IMPACT
CYP450
(CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5)
Enzymes that metabolize medications in the liver Large number of psychiatric medications are metabolized by CYP450s Dose adjustment (an increase or decrease) may be required

 

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COMPARISON OF VYVANSE AND ADDERALL

(more…)

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Can stimulants permanently stunt growth in children?

I have not seen previous reports of permanent growth suppression from long-term use of stimulants during childhood.  Expert consensus and my clinical experience is that height may be slightly delayed but is genetically determined (assuming adequate nutrition).

The package insert for methylphenidate products (Ritalin, Concerta, Focalin, Daytrana, Metadate), cautions that daily use in a controlled study versus a controlled group did show on average 2cm less height after 3 years – but it is assumed to eventually catch up.

Kids who don’t take medication on weekends or during summer don’t show this delay.  The presumed mechanism of the delay is that norepinephrine (increased by methylphenidate) leads to a decreased release of growth hormone during deep sleep, (normally in the first 3 hours).  This suppression of growth hormone can probably be prevented by use of Clonidine or possibly Guanfacine  taken at bedtime.

In the reader’s comment amphetamines were referenced but the statement was also made that the person referred to was treated with methylphenidate.  Of course both are stimulants but are significantly different.

The package insert on amphetamines (including Adderall and Vyvanse) cautions about below average weight gain over a one year period of daily use.  In the Vyvanse study the evidence was that at the beginning of the study the average child was at the 62nd percentile of body weight – since food is a natural booster of dopamine in the nucleus accumbens, patients on amphetamines are less likely to eat out of boredom and they usually lose weight.

In fairness, we do have more studies using methylphenidate in kids than amphetamines.  The longest controlled study ever, the MTA study was also predominantly methylphenidate.  Intuitively it would make sense that amphetamines would raise norepinephrine levels even more since they increase release in addition to blocking reuptake.  Empirically however, methylphenidate is associated with increased excretion of norepinephrine and amphetamines are associated with a decrease.  Presumably amphetamines are more likely to down regulate, ie, modulate norepinephrine levels.

The hardcore science for all of this is in its infancy.  We will undoubtedly find that there are “outliers”, but at this time with all the evidence I know of the long-term benefits outweigh potential risks for the spectrum of Attention Deficit Hyperactivity Disorder.

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Vyvanse: New Treatment for ADHD

 Vyvanse, the new ADHD medicine, has a unique prodrug delivery system developed to prevent abuse.  In addition to marked reduced abuse and misuse, studies have shown other major advantages over Adderall XR – the most prescribed medication for ADHD.  Vyvanse has been found to be more consistent in its effect, more effective, especially for attention, longer acting and to have less rebound symptoms in the afternoon.    

 How is Vyvanse different from Adderall?

  • Adderall is 75% dextroamphetamine (dexedrine) + 25% levoamphetamine (mostly effects norepinephrine) 
  • Vyvanse is 100% dextroamphetamine as the active ingredient but it is bound to an amino acid, L lysine.  Because the amino acid has to be removed by a protease enzyme located  primarily in the intestine before it works, it is designated as a "prodrug".

Note:  The additional norepinephrine effect of Adderall may help alertness and distractibility but it is also responsible for most of the risks and side effects of Adderall.  Many patients taking Adderall do better taking it with Tenex. test.askdrjones.com/  Men on Adderall XR are more likely to have erectile dysfunction and need Viagra type medication.  Some people, especially older men have trouble urinating when taking Adderall XR and may need Flomax.  Patients switching to Vyvanse have been less likely to have these side-effects. 

  Other side-effects related to norepinephrine include:

  • dry mouth
  • muscle tightness
  • nervousness
  • stomach aches
  • cardiovascular effect (so less risk of increasing blood pressure)

Vyvanse is much more consistent than Adderall XR from day to day and patient to patient.  Vyvanse consistently reaches peak blood levels in 3 1/2 to 5 hours at a concentration of 100-175 ng/ml for a 70mg capsule.  Adderall XR has 400% variability – it peaks anywhere from 3 to 12 hours at levels of 70-300 ng/ml for a 30mg capsule.

Acidity levels in the stomach and small intestine and levels of gastrointestinal motility significantly impact absorption of XR but not Vyvanse.  Food, especially fat in the stomach or intestine can delay Adderall XR up to 2 1/2 hours but maximum delay of Vyvanse absorption is less than an hour.  Since it takes 3 hours to digest a fatty meal, forgetting to take XR before eating can result in significant stretches of time with reduced focus and productivity.

Vyvanse may be more likely to increase insomnia, decrease appetite, and increase weight loss – probably because it has a longer duration of action.

In a study where patients took alternately Adderall XR and Vyvanse almost 75% did much better.  However, twice as many patients on Vyvanse did very much better.

"Effect size" is a statistical measure of efficacy when comparing different studies.  The effect size for Vyvanse was significantly higher than any other medication ever studied for ADHD.  Also, when tested in known stimulant abusers it was significantly less likable than oral or IV dexedrine which means it is less abuse prone.

I have tried Vyvanse in approximately 200 patients – these were mostly patients taking Adderall.  Almost everyone that switched prefers Vyvanse.  One woman said that Adderall made her nervous and jittery which caused her to smoke more.  On Vyvanse she’s not smoking.  I still have a few patients that prefer Adderall.  Some probably prefer the increased mood or likability effect.  Some probably need the norepinephrine effect.

My prediction:  Vyvanse will rapidly become the number one medication for ADHD.

 Related ADHD article: test.askdrjones.com/2007/09/06/only-13-of-adhd-kids-are-being-consistently-treated-why-are-we-not-taking-better-care-of-our-greatest-resource/

 

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Vitamins & Supplements: Are they really worth it?

  We have heard it since we were kids, but do we really need to take our vitamins? 

The answer is yes. 
Most Americans don’t get the nutrition they need simply from the foods they eat, and supplements insure that our body meets its nutrient “quota” enabling our body to function optimally at the cellular level.  However, the vitamin and supplement industry is not regulated by the FDA, so there is no guarantee that products bought from grocery and health food stores are effective or contain the stated ingredients.    
Cooper Complete Vitamins are backed by Science.
That is one reason we decided to make them available to our patients. Reputable physician Kenneth Cooper created the Cooper Institute, a non-profit organization that manufactures, researches and publishes studies on Cooper Complete vitamins. He ensures regular testing to measure efficacy, potency and absorption of Cooper supplements.  Not only does Dr. Jones promote these vitamins, but he takes them himself and he furnishes them to his staff at no charge to promote wellness among staff members.  To encourage patients to take these supplements over other store bought brands, Dr. Jones decided to make these supplements available to his patients at a discounted price, so we offer the Cooper Complete© line of products for less than you can get them at most grocery stores and even less than the price from ordering them directly from his website. 
If you are interested in ordering supplements or would like more information about the supplements, please feel free to contact our office or e-mail us your request to info@askdrjones.com.  


Studies published in the American College of Nutrition and
the American Journal of Medicine found Cooper Complete multi-vitamin lowered: 
· Oxidation rates of LDL Cholesterol by 14%

· Homocysteine levels by 17%

· C-reactive Protein Levels by 32%

High levels of these values are all associated with increased cardiovascular disease risk.


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What Do SNRI's Do?

Question: I read on your site that people that suffer from anxiety have increased serotonin, and SSRI’s reduce the amount of serotonin in the body. I suffer from GAD that manifests itself with my racing heart rate.
I have been taking Effexor now for about 3 weeks, and it seems like my heart rate has decreased. But I am still thinking the norepinephrine is going to keep my heart rate high. So, I was wondering, do SNRI’s reduce the amount of serotonin and norepinephrine?

— Ryan
Answer: SNRI stands for Serotonin & Norepinephrine Reuptake Inhibitor. SNRI’s initially increase synaptic serotonin and norepinephrine, but over time, they down regulate both systems (especially in anxiety disorders where both systems are upregulated). In conditions or areas of the brain where activity is too low, the SNRI can increase activity of serotonin and norepinephrine. In this sense, reuptake inhibitors can be thought of as modulators.
The degree to which norepinephrine is regulated by Effexor is dependent on dose. At 37 to 75 mg per day, norepinephrine effect is probably not clinically significant. At 150 mg norepinephrine activity is significant, and at 225 mg it’s probably equal in effect to the serotonin modulating effect.
Serotonin can also increase heart rate. Modulating serotonin and norepinephrine should help assuming that GAD is the cause of the rapid pulse.

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SSRI Type Antidepressants for ADHD?

Question:  I am searching for help with an issue my adult son with a history of ADHD has run into.  As an adult, his physician put him on Paxil for his ADHD as other medications for ADHD were not as effective.  My son is functioning very well, has never been depressed, suicidal or any other issues associated with taking Paxil.  Seven months ago, my son had a flight physical by a certified FAA medical examiner, told the physician he was taking Paxil and the physician passed him, thus allowing my son to proceed with obtaining his private pilot’s license.  Now, seven months later, after he has completed all requirements, and has been flying the FAA sent him a letter stating they would not allow his medical exam due to him taking Paxil. 

My question is: Is Paxil used to treat adult ADHD?  What other drug could be used?  We have always been told that he does not produce enough dopamine therefore resulting in a chemical imbalance.  With the Paxil he is able to maintain focus and carry on a very normal, busy, independent life of a 32 year old single male.  Any information or help you may offer us would be greatly appreciated as we are going to try to fight this issue.  Personally I feel it is discrimination against ADHD. – S.B.

Answer:  Consensus of experts in the area of ADHD is that there are imbalances in the dopamine and norepinephrine brain systems, primarily due to genetics.  There are many sources of evidence to support this view.  There is disagreement as to whether the problem is primarily in the dopamine system or whether it’s primarily in the norepinephrine system or equally both.  It will probably turn out to be mainly dopamine in some people who are ADHD and norepinephrine in others and both in still others.   The problem is compounded by many factors, one of which is that dopamine and norepinephrine impact each other and may be high in some areas of the brain and low in others. 

There is currently no scientific evidence that serotonin modulators such as Paxil help ADHD.  Paxil has a very weak modulating effect on norepinephrine, but this is not believed to be clinically relevant (unless one takes very high doses).  Most SSRI’s, including Paxil, will actually lower dopamine levels.  Norepinephrine modulating antidepressants, tricyclics (desipramine, imipramine), Strattera (actually approved for ADHD but not depression, higher doses of Effexor (150 mg and above), Wellbutrin, and theoretically Cymbalta can help ADHD – though on average 1/2 as effective as stimulants. 

Your son benefits from Paxil.  What does this mean?  My guess is that your son is not ADHD, or at least that’s not what Paxil is helping.  Many other things can cause some of the symptoms of ADHD.  Sustained concentration requires ignoring distractions, either in the environment or from the mind (“What if …?”).  Anxiety means “danger” and danger means monitoring the environment more closely and thinking about all the relevant “What ifs.” 

Clinical depression involves deficiencies in one or more brain transmitter systems that frequently interferes with focus.  Also, calm, sustained focus activates more left brain functions, but stress, anxiety and depression activate the right brain more.  I recommend a complete reevaluation before any other steps are taken.  Dealing with the FAA reminds me of my days as an Air Force psychiatrist.  You can’t let logic or fairness cloud your thinking.  It’s all about the regulations.  How to deal with them would need to come after the evaluation.

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Cymbalta: How quickly does is it work?

Question: How quickly does Cymbalta start working – relative to other antidepressants?

— M.F.

Answer: Some effects of Cymbalta may start within the 1st 2-3 days (it especially helps with chronic pain and possibly insomnia or anxiety). The antidepressant effects and most of the anti-anxiety effects usually take 2 weeks to begin. Typically this is 2 weeks from the time you start an effective dose (30-60 mg in most people, but occasionally 60-120 mg per day).
For antidepressants, the rate of onset of benefit seems to indirectly correlate with protein binding (i.e., the lower the binding, the higher the percent that crosses the blood-brain barrier). On this basis the relative order of speed of onset from quickest to slowest is Effexor, Lexapro, Wellbutrin & Celexa, Cymbalta, Paxil & Prozac, and Zoloft.
Faster rate of onset can also be associated with increased risk for side-effects in the 1st 2-3 days, but most of these dimminish or go away within the 2 weeks.

FAQs: How Meds Work

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Take 2 Benadryl and call me in the morning …

Last week, a rep from a pharmaceutical company that manufacture a sleep medication was in my office.  He said, “You have a unique practice because you see a lot of patients with sleep problems.” I said, “WRONG! I see the same patients that all psychiatrists and primary care doctors see. The problem is most patients that have sleep problems don’t mention it to their doctors, and unfortunately, most doctors don’t ask.”

I believe all patients need to be screened for all common, treatable problems every visit.

Sleep is the first thing I ask about on my screening questionnaire. Two days ago I was seeing a patient who happened to be the wife of a primary care physician. She told me recently her internist put her on Prozac for anxiety and depression. She immediately developed a significant sleep problem as a side effect. She asked him for a prescription for Ambien. He told her he didn’t prescribe Ambien because it is “highly addictive,” but she could take Benadryl. (See previous discussion on “pre-extraction disorder” P.E.D.) There are several problems with her internist’s response. First, Ambien isn’t addictive at all. An occasional patient will develop a mild physical dependence after several months of nightly use, but physical dependence is a physiologic adaptation and has “nothing to do with addiction.” This is not just my opinion but that of Dr. Robert DuPont, the first director of the National Institute on Drug Abuse. Fifteen percent of patients taking Ambien for one year every night will have one to two nights rebound insomnia if they stop it abruptly. This is hardly addiction.

Addiction is compulsive use or behavior in spite of negative consequences.

The second problem with her internist’s recommendation is that Benadryl is a horrible sleep medicine. There’s no scientific evidence that it’s effective. It doesn’t provide normal sleep (Stage IV deep sleep and dream sleep), and it frequently leaves you with a hangover. Other than that, it was a great idea. The third, and most important problem with his recommendation was that his ignorance with regards to the importance of a good night sleep.  The effect of sleep loss was studied in healthy young men awakened after 5 hours of sleep.  After just one night, they showed decreased concentration, marked irritability and increased levels of cortisol, a stress hormone that suppresses normal immune function and contributes to abdominal weight gain.

I consider good sleep (7-8 hours) the most important part of stress management.

Longevity studies show that too much sleep is actually worse than not enough. In the short term, excess sleep drains mental energy. A national survey found that 10% of people have a chronic nightly sleep problem, but 2/3 of the adult population has at least occasional sleep problems.  The good news is that we have effective, safe medications that provide normal sleep and are totally out of your system in 5-8 hours.  The bad news is many doctors are afraid to prescribe them and most people don’t have access to them. 

I think every home needs to have Tylenol and a good sleep medicine on hand.

Most people need to have a good sleep medicine (Ambien, Sonata, Lunesta).  We weren’t made for this world. We adapted from 1000’s of years in a world where we were outside and physically active all day.  The bright sunlight regulated our sleep, energy, and metabolism. Whereas, now most people are mainly indoors and sedentary. Life use to be hard but simple.  Now, it’s extremely complex and changing at an exponential rate, but we still have the old adaptive mechanisms.  We respond to mental stress with the same flight or fight mentality, but these aren’t appropriate responses to today’s stress.  It’s like driving your car hard all day but not putting it in gear.  It’s not good for your car, and it’s not good for our bodies. We end up hyper aroused, can’t relax and have problems sleeping.  We need a new stress management technology, but right now, the best we can do is great medicines.  It’s just a shame that most people either don’t know about them or can’t get them because our medical system is broken and most doctors just don’t get it.

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Antidepressants and Suicide Risk

Several years ago I was speaking in a family practitioners office in Marshall, TX. I started out with a question, "If you were treating President Clinton, what would you prescribe him?"

He immediately answered, "Prozac."

I said, "Good, and that’s because …"

He said, "It causes people to commit suicide."

Of course, I was thinking more along the lines of reducing libido, but he had raised an interesting point.

Does Prozac or other SSRI’s increase the risk of suicide?

The best answer is, usually not. Studies have shown that overall, antidepressants decrease suicide risk. In one large study, patients with depression were twice as likely to commit suicide if they weren’t on antidepressants. So you could say that antidepressants reduce the risk but don’t eliminate it. But, can antidepressants sometimes increase risk? Unfortunately, yes.

How can antidepressants increase suicide risk?

  1. Some patients are very sensitive to side effects and become very anxious or agitated on antidepressants, and anxiety is one of the main symptoms associated with acute suicide risk.
  2. A second possibility is that a person with depression associated with hopelessness and immobility may be activated enough by the antidepressant to carry out a suicide plan.
  3. More common would be a situation where someone is bipolar or at least has bipolar genetics and the antidepressants cause a dysphoric hypomania. This is one of the most suicidal states where someone has symptoms of depression and hypomania at the same time. (see bipolar newsletter for details of these states). Why would it be more of a problem in kids and teens? Because, the earlier the age of significant depression, the more likely they have bipolar genetics.

(1)"In June, the Child and Adolescent Advisory Commitee of the International Society for Bipolar Disorders issued a position statement on antidepressant medications for children and adolescents: ‘they (primary care doctors) should monitor their children for the emergence of specific symptoms that may warrant referral to a psychiatrist: anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity and severe restlessness.’

"The statement also identifies signs of mania in children, including a decreased need for sleep, exaggerated or inappropriate silliness, exaggerated optimism, behaving as if invincible, atypically high energy levels, exaggerated talkativeness, racing thoughts, extreme restlessness or impulsivity, and inappropriate sexual behavior.

"The committee stressed the need for extra attention when medication is first prescribed or when it is changed. In some children these events have been linked to an increased risk for suicidal behaviors, so they caution against abrupt discontinuation of medication, which can exacerbate the illness and its symptoms."

Would it just be better to avoid antidepressants in kids?

No. There are definite benefits, especially with anxiety disorders, but also some depressions. The important thing is that patients, parents and clinicians be aware that these paradoxical reactions occur. They must monitor for negative reactions, which usually occur in the first few days or weeks. Kids that have done well on these meds for several months are at very low risk of an adverse reaction.

(1)"A recent analysis of suicide rates in the Journal of American Academy of Child and Adolescent Pyschiatry (2004:43) showed no significant difference between SSRI’s and placebo."

But they recommend additional studies to separate the effects of the illness, the medication and the interaction of the two. Of course, in formal studies patients are more closely monitored than in most office practices.

A recent study of communities looking at number of kids/teens taking antidepressants and rate of suicide in them found that the highest suicide rates occur in the communities using the least antidepressants. So in general, the benefit outweighs the risk. But in any given individual a complete history, including family history, good patient/family education, and close monitoring are essential for good medical care.

Footnotes: (1) CNS News, October 2004

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