Monday, September 24, 2018

Comments by garyg

Showing 5 of 5 comments.

  • Great article. Read about the Cast Trial:

    “The Cardiac Arrhythmia Suppression Trial (CAST) was a double-blind, randomized controlled study designed to test the hypothesis that suppression of premature ventricular complexes (PVC) with class I antiarrhythmic agents after a myocardial infarction (MI) would reduce mortality. It was conducted between 1986 and 1989 and included over 1700 patients in 27 centres.[1] The study found that the tested drugs increased mortality instead of lowering it as was expected.[2] The publication of these results in 1991/92, in combination with large follow-up studies for drugs that had not been tested in CAST, led to a paradigm shift in the treatment of MI patients. Class I and III antiarrhythmics are now only used with extreme caution after MI, or they are contraindicated completely.[3] Heart Rhythm Society Distinguished Scientist D. George Wyse was a member of the CAST trial’s steering and executive committees.”

    “The drugs used (encainide, flecainide, and moracizine) successfully reduced the amount of PVCs, but consequently led to more arrhythmia-related deaths. Total mortality was significantly higher with both encainide and flecainide at a mean follow-up period of ten months. Within about two years after enrollment, encainide and flecainide were discontinued because of increased mortality and sudden cardiac death.”

    This is a great example of followup science. The cardiologist had to know whether the drugs they prescribed were helping people. They had no idea that suppressing PVC’s was harming patients. This required a large and powerful multi-center study.

    At this point, even JAMA recognized that this needs to be done especially in children. We do not know if drugs being prescribed to children are harming them in the long run. Children cannot give true consent. Their parents sign for them. Current theories in medical ethics suggest that parents still must do what is best for a child. Thus a parent who is against a blood transfusion cannot prohibit a blood transfusion that would save a child’s life.

    From the data, CBT is very helpful for anxiety, anger management, behavioral modification. Psychotherapy is more effective for depression. WBT appears to be a form of positive structured psychotherapy. The benefit of CBT is that it is a form of education, and children really benefit, and there are no side effects, but it requires effort. WBT also seems to involve emotional effort, and adults benefit from listening to other adults. The reality is that a pill is a product that requires no effort. You do not even need to look up the chemical structure, you just take the pill.

    From what I can see, CBT and Psychotherapy are a form of learning. You are learning to cope, how to deal with your issues. Taking a pill is a buffer, it suppresses learning as nearly everyone will attest to. This can be demonstrated by testing long term memory functions. When people take medications, they often have far softer memories. The entire purpose of psychotherapy was to access memories, and to use those memories to prepare yourself for the present and thus the future. The entire purpose of CBT is to learn a general outline of reinforcement, to remember a way to think and act. It is not clear how medication in the long term facilitates the memory process, although in the short run, medication can often demonstrate effectiveness when compared to placebo.

    But as was demonstrated in the CAST trial, short term effectiveness is different than improvement in mortality. CAST demonstrated that short term effectiveness can increase mortality. This was also demonstrated with Welbutrin, which GSK hid, and was the subject of a multi-billion dollar liability. Retrospectively, you would expect that a buytl substituted amphetamine might increase impulsiveness. Thus, patients on Wellbutrin felt “better” but committed suicide at a higher rate. The point was not that they were depressed, but that the medication affected the right frontal lobe, hyper stimulated delta FosB and made them impulsive, and they acted on their impulses, hence the paradoxical higher rate of suicide, no different than the CAST trial where suppressing PVC’s during myocardial ischemia led to increased mortality.

  • Two drugs showed tremendous efficacy, but had significant side effects leading to removal of the drug then reinstatement.

    1) Lithium: This was in carbonated soda: Bib-Label Lithiated Lemon-Lime Soda known as 7-up. Well, it was removed from the market, under federal law. Lithium was reintroduced for treatment for Bipolar disorder, and remains the only treatment that lower suicidal rates in Bipolar disorder.
    2) Clozapine: The first atypical anti-psychotic, was really a chemotherapeutic, and offered 30% rate of remission for individuals with psychosis but was removed from the market because of agranulocytosis.

    These medications are unique and have no equivalent. I suspect these medications affect nucleolar transcription, the protein regulators of mRNA transcription, as both Schizophrenia and Bipolar disorder are generalized disorders overall.

    But the fact remains, that American society does not reward saving a life as much as it punishes a medical complication. We have come to expect that lives “should be saved”. Thus, if Clozaril affects 0.17% of patients with agranulocytosis and 1 in 2,000 die, Novartis will get sued, unless (1) The psychosis was refractory (2) There was signed consent. It does not matter that if you treat 2,000 people with Clozaril, 20 people would be prevented from committing suicide. We will not tolerate 2o potential saved lives for one death unless their are extreme circumstances. Thus, Clozaril is hardly ever used.

    For some reason, all the other “Atypical” antipsychotics do not have the power of Clozaril, nor the side effects, nor demonstrate the powerful remission. Only Clozaril was demonstrated to improve the negative symptoms of schizophrenia in study after study. This has been demonstrated today in developing countries which have continued success with Clozaril. But in the United States, the drug will not be used.

    We will see a change in prescription practice with new imaging models. When fMRI and SPECT can:

    1) Visualize with biomarkers in real time for bipolar and schizophrenia
    2) When the drugs can be given, and demonstrate on direct visualization “normalization” of the brain
    3) When we have genetic markers that can map the disease within the cell associated with the damaged protiens
    4) We will then be able to use targeted therapy beyond neurotransmitter modification to treat or potentially cure the disease

    If we take a look at the molecular structure of a medication, we often can guess the effect. Look at Zoloft and look at Ativan. Then read the packet insert for Zoloft:

    “The efficacy of ZOLOFT in maintaining a response, in adult patients with panic disorder who
    responded during a 52-week treatment phase while taking ZOLOFT and were then observed for
    relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see
    Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects
    to use ZOLOFT for extended periods should periodically re-evaluate the long-term usefulness of
    the drug for the individual patient (see DOSAGE AND ADMINISTRATION).”

    Read the followup studies about patients who reported being “addicted” to Zoloft and having benzo withdrawal.

    Then read the cross reactivity:

    Psychiatry (Edgmont). 2009 Jul; 6(7): 36–39.
    Published online 2009 Jul.
    PMCID: PMC2728940
    False-Positive Urine Screening for Benzodiazepines: An Association with Sertraline?
    A Two-year Retrospective Chart Analysis

    If the tox screen cross reacts with Zoloft, it is because it was a mild anti-anxiety benzo medication marketed as an antidepressant. A similar medication mis-marketed is Welbutrin, which is a bytl substituted phenyl-ethyl-amine amphetamine. Prozac is superior overall to Zoloft and Welbutrin because it is Benadryl analog.

    Modern psychiatric medications are often designer drugs. It is not uncommon that a pharmaceutical company will develop thousands of potential compounds, one substitution after another, hoping to find a medication that works in people. The reality, is that the medications almost always follows the nature of the mother classifications. Once the pharmaceutical company nails the compound, and the compound works in people, it is now a medication. It ceases to be a rubber and is now a tire, and soon, will cease to be a tire, it will be a Michelin or a Goodyear until the day it goes generic, an then, it will become a tire, and the world will one day forget about the drug, efficacious or not, and it will be seen as mere rubber, no different than countless NSAIDS and countless past anti-depressants.

  • Through the No Child Left Behind Act, each student has a universal PIN. We have the statistical power now to have each prescription registered to that PIN, and we can followup the students. We need to know how these students performed longitudinally. Did they graduate? Did they have problems with drugs as adolescents?

    It is not right to use children as test subjects based on adult projections. Children in general fight all the time at home and act in ways that adults deem inappropriate. Having said that, children don’t use drugs or alcohol under 12, so they don’t wind up in the emergency department because they spiraled out of control in their petty domestic violence fits. Basically, they hit each other, and they stop.

    As such, we have to ask ourselves, what is our goal. If the goal is well adjusted adults that learn to cope with their emotional frustrations, then drugs are not the solution in the vast majority of cases for children. Yes, a valid case of true attention deficit may benefit selectively. But physicians are now questioning the use of these drugs because of obvious abuse and increased visits to the emergency departments throughout the nation.

  • The scientific data supports your approach. Pain management takes many forms. One form is forgiveness and accepting the challenge and moving forward, the example of the injured knee. The other form is to blame the pain, and seek chronic pain management. I am not sure this is an easy choice.

    I think that we are conditioned to the stimuli around us. Only aerobic outdoor exercise offers:

    1) No conditioned place preference
    2) No psycho-stimulant cross sensitivity
    3) Attentuation

    Fatty foods and sugar are substitutes for stimulants that people crave, including pain medication and sensationalism. Enrichment is much like Aerobic activity, but is sensitive to conditioned place preference, which is why we go to the movie theater to watch movies when we could stay at home.

    The reality is that exercise is a lot like the lottery, you have to “be in it to win it”.

    I recently had a patient with a panic attack, and the patient had been offered Zoloft. I asked if the Zoloft worked, and he said that Zoloft did not work. I explained that I can treat the panic in the short term, but the best treatment for anxiety is to get outside, go to the park, and walk for one hour a day. This was recently demonstrated on fMRI at Stanford. There is a difference in walking on a busy street and in the Open Space.

    The point is that the science demonstrates that aerobic activity decreases our desire for stimulation. When we exercise, we no longer need stimulants, and we learn to accept our challenges. The real challenge is that physical activity attenuates, so it is very hard to prescribe. Personally, I would rather go for a mountain bike ride than take vitamins, but I recognize that I am not in the majority. The mountain biking trail is empty, and the vitamin aisle is full of customers. Pharmaceuticals remain a tremendous business model, that in the age of poly pharmacy continue to grow in economic and social importance. Ask yourself, “Today are people thinner?” and the answer is no. Pharmaceutical companies have developed a pill for that, but everyone knows that people eat more to compensate.

  • I think that America is about short term solutions. For this reason, we look to short term solutions despite long term disadvantages. Think about credit card debt versus mortgages. Think about texting over reading a book. The short term offers an immediate gratification.

    If your child gets kicked out of class because he is jumping off the walls, you see a specialist who suggests medication. The behavior gets better but the memory function goes down. If you believe school is about behavior, you are happy. If you believe that school is about learning, you are dissatisfied. The three year data on Ritalin and other stimulants now suggest this.

    Ritalin treats the classroom at the expense of the child, and this is why parents often agree to educator suggestions, because they want their children to “do well” in school. This is also why Congress passed the Individuals with Disability Act to protect the rights of these children. Yes, an intelligent child with hyperactivity is often painful to deal with. But it is not a teachers role to judge a young child below 12, it is their job to educate.

    Attention Deficit, which primarily affects girls sitting in the back of the class and not paying attention, did respond to Ritalin and other medications. The fact remains that the key issue is the formulation. Only Concerta is reasonably safe after a child has been enrolled in CBT. This is the Japanese approach, and they are reluctant to prescribe medication to young children.

    Hyperactivity is not attention deficit. It is true that fMRI can now visualize these disorders but psychiatrists refuse to distinguish the disorders as separate. The entire purpose of visualization is to have a scientific basis to progress. The real problem with all amphetamines is the over expression of delta FosB. This is not a small risk. Individuals exposed to amphetamines have a higher risk of addiction. Those who prescribe medication for more than a 1 month period are not currently held to longitudinal followup. We saw the same challenge with benzodiazapenes.

    If you go to the emergency department with chest pain and anxiety, and get ruled out for myocardial ischemia, and the doctor treats you with Ativan, you are not going to get addicted. But if you are prescribed 90 Ativan, you run a risk. This is no different than if a doctor prescribes a year of antibiotics. You can get antibiotic resistance and C. Difficile.

    The real challenge is that psycho-pharmacology has resorted to long term treatments. Had the model focused on short term stabilization with immediate CBT followup and psychological counseling in ALL cases, with longitudinal databases mandatory, we would have seen more progress.

    The reality is that many psychiatrists refuse to recognize a test that eliminates the diagnosis. For instance, if a child can pass the Stroop test, they do NOT have Attention Deficit. This has been highly validated. A child may have Oppositional Defiance, but they can absolutely pay attention to tasks that they do not like to perform. As such, the Stroop test functionally tests the frontal and parietal lobe circuit, no different than if you brought your car in, and the car started, and drove, and the engine light was still on. Well, it was not the battery, and not the fuel pump, and not the tires. Well psychiatrists have a hard time in eliminating a diagnosis. They also cannot admit when they do not know the diagnosis. They cannot simply test a person and say, at this point, the problem is not clear. This is why psychiatrists currently are so focused on comorbidity.

    Many countries are legitimately worried that early use of amphetamines can lead to affective disorders as an adult. The real challenge is that the young brain is still developing. There is zero association with failing out of school and ADHD or going to prison and ADHD. Failing out of school and prison is usually directly related to a broken family structure. So we have to ask ourselves, what are the end points? If the end point is a a child that has time to develop into a responsible adult, and have a happy childhood, then medication is not usually the answer. There are some exceptions. What we have decided as a nation is the opposite, that we medicate first. As such, addiction is way up. We now have a cohort of heroin addicts throughout the US. Where did this come from? Predictably, a stepping stone from Ecstacy, an amphetamine, to Methamphetamine, to more powerful injectable narcotics.

    The fact is that in 1960, at the high point of the summer of love revolution, drugs were neither as powerful or as prevalent. What changed is American culture. Americans love sensational short term solutions. Every new medication is touted as superior, when in fact, many barely beat placebo. Old medication, no longer profitable, are often superior, especially when taken only on an as needed basis.

    I think this is the real challenge. Medications approved by the FDA have “passed the test”. But they have “passed the test” only for their only label indications, and often only in the short term. There are very few followup long term studies. The only validated model has been cholesterol medications in individuals with heart disease. Hypertension was also another model with long term followup. Glaucoma another model. Anti-Coagulation another model. In all these cases, there are clear scientific and objective end points, HDL, Systolic Blood Pressure, Intra-Ocular Pressure, INR. When fMRI can be used to diagnose, exclude, and demonstrate treatment success, it will be useful. SPECT has recently been able to demonstrate the effect of benzodiapenes in panic disorders. Panic disorders are different from long term anxiety. During the Panic phase, the brain develops functional asymmetry, with decreased firing in the left temporal lobe, and increased firing in the right frontal cortex, causing a flight reaction. When patients were treated with benzodiapenes, the patients improved, and their SPECT scans normalized. This suggested that in the acute phase, the drug worked as promised. However, there is no evidence that Ativan or Valium works chronically. It should only be used on an as needed basis, and does not offer any prophylactic benefit when studied.

    This is true of Attention Deficit. If a child has true Attention Deficit, and they MUST pay attention, the drug helps. But what if they MUST pay attention and remember what they paid attention to? That is more complex, and that is the problem. What happens, is these children on Ritalin can finish their homework, great. But the challenge, is their long term memory is affected, and they do no better than children than do not finish their homework. WHAT! Yes, the child that does half his homework, remembers that half off Ritalin. The child that completes his homework on Ritalin only remembers half his homework. So if the end point is completing the homework, behavior, Ritalin works. If the end point is learning, Ritalin begins to fail as the brain adapts to the Ritalin, and the memory function ratchets downwards, which is exactly what was seen in the long term followup studies on children with ADHD that were medicated with Ritalin.