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Chapter 22

The Science

INTRODUCTION

The Road Back Program and the development of the program:1. There are basic common denominators of psychotropic drug side effects.2. How our individual DNA affects drug metabolism.3. The effect of psychotropic medication within the Hypothalamic-Pituitary- Adrenal Axis and immune system.4. Utilizing DNA clinical trials, test subject trials and psychotropic drug clinical trials to formulate specific nutritional products to eliminate, reduce or avert withdrawal side effects, while not creating drug/supplement interactions.

This research and development complexity has been transformed into an easy to understand, systematic program, which allows an individual to taper off their medication while alleviating a vast percentage of the debilitating side effects of withdrawal.

The sequence of this program and the application of each step is the key to success. Your patient will not begin to reduce a medication until the pre- taper is complete. The pre-taper is a 7-day process.

Statements of fact: All psychoactive medications metabolize through specific pathways. All psychoactive medications alter the Hypothalamic Pituitary-Adrenal Axis to some degree. To some extent, you can predict the duration before drug- adverse reactions begin with most psychoactive drugs if the patient’s P450 (CYP) enzymes have been screened. A poor metabolizer as well as an extensive metabolizer will eventually reach the same saturation point; the poor metabolizer much faster, of course. If one were to look at the basic structure of the human body, the chemical structure of psychoactive drugs, and include how psychoactive drugs are metabolized, how foods, vitamins, minerals, DNA, amino acids, hormones, glands, proteins, fatty acids and enzymes work, in relation to psychoactive drugs, you have The Road Back Science.

The patient has been under some duress and stress before a diagnosis was given and the prescription was written. With this in mind, the patients JNK gene would have been overly expressed for some duration. Balancing the JNK gene activation will lead to a normalization of the patient in time.

Drug targets for most disorders will be the purinergic system, the dynorphin opioid neuropeptide system, the cholinergic system (muscarinic and nicotinic systems), the melatonin and serotonin system, and the HPA axis. An additional reason the supplements were selected to be used in this program; their natural action of helping to balance the same drug targets.

DNA and Prediction of Drug Adverse Reactions

The following charts detail the P450 enzymes used to metabolize the most common antidepressants, anti-psychotics, benzodiazepines and ADHD stimulant medications. An X in the row denotes that the medication utilizes that specific pathway. Below each chart, you will find other routes of metabolism if applicable. These medications inhibit metabolism via listed CYP pathways.

Marked medications (*) will also use other routes for metabolism.

Adapin – ABCB1-P-pg, UGT1A3, UGT1A4Anafranil – UGT2B10, CYP3A4, UGT1A4, UGT1A4, UGT2B7, ABCB1-P-gp, CYP3A4Amitriptyline – 3A4, UGT2B10, UGT1A4, SLC22A1- OCT1, ABCB1-P-gp, UGT2B7, CYP3A4, CYP2C8, CYP2D6Celexa – ABCB1-P-gp, CYP3A4Clomipramine – UGT2B10, CYP3A4, UGT1A4, UGT2B7, UGT1A4, UGT1A3Doxepin – ABCB1-P-gp, UGT1A3, UGT1A4Desyrel – CYP3A4, ABCB1-P-gp, P-pg

Effexor – CYP3A4, ABCB1-P-gp, P-gp

Effexor XR – CYP3A4, ABCB1-P-gp, P-gp

Elavil – UGT1A4, UGT1A3, P-gp

Imipramine – UGT2B10, ABCB1-P-gp, UGT1A4, CYP3A4, SLC22A2-OCT2, UGT1A3, UGT2B7, SLC22A1-OCT1, SLC22A3-OCT3, CYP3A4Luvox – 2B6, P-gp, intestinal 3A, ABCB1-P-gp, CYP2B6, CYP3A4Norpramin – SLCC22A1-OCT1, SLC22A2-OCT2, SLC22A3- OCT3, CYP3A4Pamelor – CYP3A4, ABCB1-P-gp, CYP2C8 Paxil – 2B6, P-gp, CYP3A4, CYP2B6, ABCB1-P-gpPaxil CR – CYP3A4, CYP2B6,ABCR1-P-gpPristiq – Assorted UGT isoforms

Prozac – 2B6, P-gp, ABCG2-BCRP, SLC22A3-OCT3, CYP3A4, SLC22A1- OCT1, ABCB1-P-gpSarafem – 2B6, P-gp, ABCG2-BCRP, SLC22A3-OCT3, CYP3A4, SLC22A1- OCT1, ABCB1-P-gpSerzone – U

Sinequan – UBCB1-P-gp, UGT1A3, UGT1A4Tofranil – UGT1A4, UGT1A3, P-gp,

Triptil – ABCB1-P-gpWellbutrin – 2E1, 2A6, 2B6, CYP2B6Wellbutrin SR – CYP2B6Zoloft – UGT2B7, UGT1A4, P-gp, 2B6, CYP2B6, MAO, CYP3A4, ABCB1-P-gp

Marked medications (*) will also use other routes for metabolism:

Chlorprom – UGT1A4, UGT1A3, P-gp

Chlorpromanyl – UGT1A4, ABCB1-P-gpClozaril – FMO, UGT1A4, UGT1A3, ABCB1-P-gp, FMO3, ABCG2-BCRP Geodon – Aldehyde oxidase substrate

Haldol – Glucuronidation, P-gp, UGT2B7, CYP3A4, CYP3A5, UGT1A9, ABCB1-P-gpMellaril – CYP3A4, CES1, P-gp

Ridazine – UGT1A4, ABCB1-P-gpRisperdal – P-gp, renal extraction, CYP3A4, ABCB1-P-gp, ABCG2-BCRPSaphris – Various UGT

Seroquel – Glucuronidation, P-gp, intestinal 3A, epoxide by quetiapine, CYP3A4, ABG2-BCRP, ABCB1-P-gpZyprexa – Glucuronidation, FMO, UGT1A4Marked medications (*) will also use other routes for metabolism.

Ativan – UGT2B15, UGT2B7

BuSpar – Intestinal 3A, 3a4

Carbatrol – 3A4, CYP2C8, SLC22A5-OCT2N, UGT2B7, CES1, CYP2B6, ABCB7-ASAT, SULT1A1, ABCC2-MRP2, ABCG2- BCRP, SLCO1A2- DATP1A2

Depakene – CYP2B6, UGT1A6, CYP2A6, UGT2B15, UGT2B7, UGT1A9, ABCB1-P-gp

Depakote – UGT2B7, UGT1A6, UGT1A9, UGT2B15, UGT1A4, UGT1A3Dilantin – UGT1A4, UGT1A6, UGT1A9, ABCB1-P-gp, CYP2C9, CYP2C8, UGT1A1, CYP3A5, UGT2B7, CYP3A4, CYP2B6, UGT2B15Halcion – CYP3A4, CYP3A5

Klonopin – NAT2, CYP3A4

Lamictal – UGT1A3, UGT2B7, UGT1A4

Librium – CYP3A4

Neurontin – SLC22A4-OCTN1

Valium – CYP3A4, CYP2B6, CYP3A5, UGT2B7

Xanax – Hepatic 3A, CYP3A5, CYP3A4

Marked medications (*) will also use other routes for metabolism:

Concerta – Glucuronidation, CES1A1.

Medate – CES1A1.

Methylin – CES1A1.

Ritalin – Glucuronidation, CES1A1.

Ritalin – CES1A1.

Vyvanse – CYP3A4, MAO

How to Use Charts to Decide Sequence of Medication Reduction

If you have two or more medications sharing the same CYP pathway to metabolize, reduce the medication that uses the fewest pathways first. Example: Ambien used concurrently with Luvox, Paxil, Prozac, Wellbutrin or Zoloft. Reduce the Ambien first.

If you were to reduce any of the antidepressants listed first, the Ambien would begin to clear the body faster and the patient would experience Ambien withdrawal without the current Ambien dosage being reduced. Ambien would be reduced by as much as 43% if the antidepressant were reduced first. (See Ambien product insert.) The best approach is to always taper the anticonvulsant, antianxiety, benzodiazepine or sleep medication first and then tackle the antipsychotic and antidepressant.

If taking two antidepressants concurrently, or taking an antidepressant and an antipsychotic, selecting which one to reduce first would also follow the format outlined earlier in this section. The drug using fewer common CYP pathways should be reduced first.

If taking two antidepressants or one antidepressant and one antipsychotic, and the CYP pathways match, evaluate the current side effects, when each side effect started, when each medication was introduced, and determine from those side effects which taper schedule to follow and which drug to taper first. From time to time, a person will also be taking a drug as an inducer of the CYP pathways.

Determine if this “inducer” was prescribed to help offset the inhibitor drug’s effect or is the inducer drug prescribed for other health reasons not related. You will generally find that those who are also taking the inducer medication will be suffering from a wide variety of adverse side effects. When reducing any medication attached to the same pathway as an inducer medication, reduce the normal taper speed by one-half for at least the first 2 months.

You may need to alternate reduction of the inducer drug and the inhibitor drug every other reduction in order to maintain a balance.

Other medications must be closely evaluated. Lipitor, as an example, is an inhibitor of the CYP 2C19, 2D6, and 3A, along with inhibiting the UGT1A3, UGT1A1, P-gp, and intestinal 3A.Use drug product inserts to determine metabolism route or the Physicians’ Desk Reference.

Example 1: If taking multiple medications and each medication uses the same metabolic route, each of the medications is competing for clearance. If one medication is reduced, the other medications will also be reduced or clear the body faster.

Decide which medication to taper off first based on: CYP charts.

Full evaluation of side effects.

When side effects started with which medication.

If patient has used Viibryd for two years and used Risperdal for 2 months and side effects increased dramatically once Risperdal was introduced, taper the Risperdal first.

Example 2: If multiple medications are being taken and all medications can metabolize through several routes, the impact will be lessened, and selecting which medication to taper first would not be pathway dependent.

Avoid all supplements that compete with the same pathways, and eliminate as much as possible all foods that compete with the medication by inducing or inhibiting the metabolism routes of the medications.

With the advancements of The Road Back Program, as described in this book, patients can now taper off antidepressants, antipsychotics and ADHD medications and stimulants simultaneously. Reduce the medications as slowly as possible, as close to 10% reduction as possible, and only increase the rate of reduction once the patient has shown tapering success at lower reductions.

Supplements, Herbs and Foods

Supplements, herbs or certain foods can have a direct impact on the success of the taper.

Datum: If a person smokes or drinks coffee before starting the pre- taper, do not suggest they quit. Cigarette smoke induces the CYP1A2, 2E1, 3A and UGT2B7. Nicotine inhibits UGT1A1, UGT1A4, UGT2A6, and UGT1A9. If taking Depakote and starting or stopping smoking, the impact on the medication will be dramatic. If a patient starts to smoke or quits smoking while taking Cymbalta, the drug will be altered by as much as 15%. In theory, this should apply as well to any other drugs sharing the same metabolism routes.

Coffee or caffeine inhibits the CYP1A2, 2E1 and the 3A.

A high percentage of these medications metabolize through these pathways and caffeine usage will dramatically increase the medication, or if the person were to quit drinking caffeine, they would begin to go into withdrawal to some degree because the pathways will begin to metabolize the medication faster.

The times a person takes medication and when they drink two cups of coffee can have an impact as well. If the person drinks two cups of coffee every morning about one hour after their medication, and they change the time of the morning they drink the coffee, expect a slight to above average side effect from the medication.

The person’s current daily routine should not be changed. If they were on a poor diet before starting this program, do not change their diet drastically. If they did not exercise before starting this program, do not advise them to do more than a casual walk.

Once off all medication for 45 days, a healthy diet can be implemented, an exercise program that matches their current physical condition can be started, the patient can stop smoking, etc.

A trace amount of an herb or supplement will not create an adverse reaction or alter the metabolism speed.

DNA Drug Reaction Testing and Taper Prediction

For the past several years, DNA drug reaction testing has been available to determine the patient’s ability to metabolize medication through the CYP450 enzymes.

We have conducted over 200 drug reaction tests with the objective of determining how well drug-adverse reactions could be predicted, and if there were clinical use of this DNA data for tapering.

Prediction of a drug-adverse reaction: The individuals who were slow or poor metabolizers or hyper metabolizers experienced drug-adverse reactions faster than normal or intermediate metabolizers.

However, the normal or intermediate metabolizers still experienced adverse drug reactions, but after longer usage of the medication. The metabolism type of the individual was not indicative of the severity of adverse reactions or duration. Once the drug had saturated the CYP enzyme used for metabolism, all the individuals experienced the same side effect profile regardless of their metabolism speed noted from the DNA drug reaction test.

The test results from the DNA drug-reaction test did not lead to a worthwhile taper guide. It was postulated; if you were to induce the enzymes or inhibit an enzyme to match a specific test result and medication, you would be better able to adjust the metabolism and avoid withdrawal, or predict the withdrawal sequence. Again, this did not assist in tapering or eliminating withdrawal side effects in the slightest. This seems to parallel the results using an inducer drug to counteract the inhibition of the main drug.

If a DNA drug-reaction test has any use to a physician, it would be for predicting the dosage of the medication Coumadin. The initial prescription could be limited to a narrow band, and the correct therapeutic dosage would be found in a few weeks, instead of several months.

Nutritional DNA Test

Nutritional DNA testing provided this program substantial information to work with. We tested the ability of over 100 subjects to metabolize B vitamins, folate, calcium, Omega 3, phase II liver detox genes, Interleukin-6, and an assortment of other genetic differences that ultimately determine overall health and physical well-being.

The Road Back Program and all suggested nutritionals used for medication tapering address the most common genetic variations of the population at large. Though DNA science is not precise at this date, enough evidence is available to formulate part of a program to address the highest percentage of the population. Hypothalamic-Pituitary-Adrenal Axis (HPA).

Psychoactive medications play havoc with the HPA. While benzodiazepines usually help with anxiety for a certain time period, the feedback loop sending incorrect data will eventually cause cortisol levels to increase, and the result will be increased anxiety in the morning and mid-afternoon. Insomnia will usually follow the cortisol level increase. Other psychoactive medications have their own unique side effect profile and ultimate effect upon the HPA.

First year medical school textbooks describe the hypothalamus as: “Hypothalamus/ homeostasis or maintaining the body’s status quo.” As an example, blood pressure, body temperature, fluid, the electrolyte balance and body weight are held in a precise value labeled the “set-point.” The body’s set-point may change over time, but from day to day, the set-point will remain nearly fixed. With the HPA receiving continual input about the state of the body and the ability of the HPA to initiate changes, as anything might sporadically fall out of balance, it is vital for the HPA to have at hand all necessary nutrients to assist with the compensation. When the HPA is out of balance, you will have a problem with insulin, stress, anxiety, weight gain, thyroid problems, fatigue, unbalanced sexual hormones and countless other body difficulties.

The hormone, ACTH, will eventually become out of balance, as will the other hormones and adrenals.

Psychoactive medication directly alters specific areas within the HPA. Examine any patient using a psychoactive medication for more than three months and you will probably find a problem with hormones, thyroid, adrenals, cortisol and immune system or other areas within the HPA.

However, it will be equally important to move beyond the normal view of the HPA. Psychoactive medication side effects are quite varied and diverse. This is not to rehash data from medical school, but to tie in the knowledge gained in the educational process with psychoactive medication.

Some fibers from the optic nerve go directly to a small nucleus within the hypothalamus (suprachiasmatic nucleus). This nucleus regulates circadian rhythms, and couples the rhythms to the light/dark cycles.

The nucleus of the solitary tract will collect sensory data from the vagus and relay the data to the hypothalamus. This data will include blood pressure and gut enlargement.

The reticular formation receives a vast supply of inputs from the spinal cord and relays that data to the hypothalamus. Part of that data will be skin temperature. Nuclei, circumventricular organs, are unique in their own right as they lack a blood-brain barrier. They monitor substances in the blood and have the ability to monitor substances normally shielded by the neural tissue. Here you will find regulation of fluid and electrolyte balance, by controlling thirst, sodium excretion, blood volume regulation and vasopressin secretion. Include in this the area postrema, and you have the detection of blood toxins and the vomit-inducing center. The OVLT and area postrema project to the hypothalamus.

The limbic and olfactory systems project to the hypothalamus. Psychoactive medication side effects, such as eating problems and reproduction difficulty, will probably be traced to this area.

Ionic balance and temperature will be subject to the hypothalamus via the receptors, thermoreceptor and osmorecepter.

When the hypothalamus is aware of a problem, it will assert repair mechanisms. Neural signals to the autonomic system will attempt to regulate heart rate, vasoconstriction, digestion, sweating etc., and the endocrine signals to and or through the pituitary.

The pituitary side effects will include one or all six hormones, to include ACTH and the thyroid-stimulating hormone (TSH). The repair output attempt, and the psychoactive medication side effect profile, seem to run near a 50 percent occurrence. Furthermore, you can directly trace psychoactive medication side effects to the autonomic nervous system in both the sympathetic and parasympathetic systems.

The hypothalamus can alter blood pressure; control every endocrine gland in the body, body temperature, adrenal levels via ACTH, and metabolism. The repetition of HPA information in this Chapter has been intentional. Do not be surprised to find a male patient with extremely high estrogen levels, a female with high testosterone or any other problems that can be associated within the HPA axis.

Taper the medication first, wait 45 days after the last dosage of the medication, reevaluate the patient, and then gradually bring all parts of the HPA back into balance. The nutritionals used with The Road Back Program were developed to help the body overcome this imbalance gradually. Gradually is italicized because this is where most problems occur with psychoactive drug-taper programs. Either they do not address the HPA or the program is really a detoxification or heavy metal chelating program.

The Road Back Program utilizes specific nutritionals to address the drug side effects and to begin the process of balancing the HPA. Specifics on each nutritional, what each nutritional is addressing within the HPA or the body in relation to psychoactive medications, can be found in The Road Back Program patent when published by the U.S. Patent Office.

Immune System

The immune system and the HPA are in constant communication and actions within one system will induce response in the other. The supplements used in this program are designed to also influence the immune response.

Reducing oxidative stress has been shown to balance Interleukin-2 (IL-2) as well as Interleukin-6. If you were to test your bipolar patients IL-2 levels, you will find they will be too high during the manic phase and IL-6 levels will have shot up high during the depressive phase. A schizophrenic will have either too high or too low IL-2 levels and will usually exhibit high IL-6 levels constantly.

The JNK supplement will reduce oxidative stress and lower IL-2 levels as well as IL-6 levels. The specific cascading effect is; JNK gene over expression leads to increase of Interleukin-2 levels which create an imbalance of Th1 and Th2. CD4 will usually show dysfunction after prolonged Th1 and Th2 alteration.

Titrating Medication

The Road Back has tried titrating medication gradually without the use of nutritionals with limited success. About 50% of the people could taper off their medication without using these nutritionals but they still suffered extreme withdrawal side effects.

Using a gradual titration combined with a basic detoxification approach had lower than 50% success.

The normal supplements used to remove heavy metal or for a liver detox produced undesirable results.

A gradual titration with the use of the suggested nutritionals gives our standard successful results.

The Key to a Successful Taper With The Road Back Program

Following the pre-taper exactly as described is critical. The pre-taper is the make or break point for every successful taper.

Most problems occur when:

The pre-taper is done too quickly.

Patient does not stop increasing a nutritional once a positive change occurs.

Patient changes the time of day they take medication.

Patient changes the time of day they take nutritionals.

Medication is reduced too quickly.

A new medication is prescribed in addition to existing medication.

Patient is switched to a new medication.

Doctor has patient use additional supplements or vitamins not in this program.

Patient begins taking other supplements.

Patient makes a major change to their daily routine.

Patient skips days of taking medication.

Titrating Psychoactive Medication:

Have the patient compound his/her medication whenever possible. An exact reduction of the medication each week provides prediction, no guessing, and the highest chance of success.

In the early days of psychoactive drugs, psychiatry did not titrate psychoactive drugs up slowly on patients and the results were catastrophic. Many drugs, other than psychoactive drugs, must be titrated up as well as down before complete discontinuing.

There seems to be a medical community consensus that psychoactive drugs can be reduced quickly, or patients can abruptly be taken off one psychoactive drug and prescribed another psychoactive drug without an adverse consequence. This is not the case. Even switching a patient from a tablet form of a psychoactive drug to the liquid form of the same psychoactive drug can cause extreme adverse drug reactions.

Dr. Donald E. McAlpine, psychiatrists at the Mayo Clinic states: “It’s important to taper off slowly, extending the taper over several weeks under your physician’s direction. When you stop too quickly, you may experience so-called discontinuation symptoms, which can masquerade as relapse.

”The discontinuation process and side effects therein can be confusing to both the patient and physician. Which side effect is coming from the medication, or is it a return of the original symptom?

With a full pre-taper completed before reducing the medication, rest assured the side effect starting during the taper is due to one of the following: The patient changed something.

The reduction of the medication is too large.

A change made by the patient can be the most difficult to find. It might be something the patient does not feel is a change.

Years ago, I had a person nearly halfway off Paxil. This person experienced no withdrawal side effects tapering the Paxil to that point. When trying to taper off Paxil in the past, the individual had extreme withdrawal side effects after the first reduction attempt and would then need to return to a full dosage.

With no valid explanation, this person began to suffer withdrawal side effect symptoms similar to those earlier. Two weeks passed and I could not find anything the person had changed. Finally, it was mentioned to me by the individual he or she had started an all-protein diet and began the diet 3 days before the side effects started.

For this person doing this diet was not a change. He or she would go on this all- protein diet every six months. I give you this example to point out that the change a patient makes may not be so obvious. You may need to dig.

If a patient is keeping a complete Daily Journal these changes can be spotted more quickly and trouble tapering can be avoided.

Use the Suggested Supplements

If you want the standard results with The Road Back Program, use the exact supplements suggested. Read through Chapter 3, “Nutritionals” Used on The Road Back Program for a list of all supplements, basic description of each and where they are available. Most, if not all of the manufacturers of these supplements offer a healthcare provider distributor program, if you wish to carry them in your practice.