Part I: ADRENALINE OVERVIEW.

A. Understanding adrenaline and body function
B. Understanding how medications may affect adrenaline
C. Presentation of hyperadrenergic states in humans.
1. Symptoms of Alpha-Adrenergic Over-reactivity
2. Symptoms of Beta-Adrenergic Over-reactivity

Part II: ADRENALINE ACTIVITY IN PSYCHIATRIC STATES. CLASSIFICATIONS OF ADRENALINE IMBALANCE DISORDERS.

A. Syndromes caused mostly by acute adrenaline overactivity.
1. Speaker’s fright.
2. Fright rage
3. Predator rage
4.Hyperactivity disorder
B. Diseases caused by chronic dysregulation of adrenaline systems.
C. Adrenaline dysregulation states which contribute to the symptoms of other psychiatric disorders.

Part III: DYSFUNCTIONAL ADRENALINE REACTIVITY IN THE MR/DD POPULATION.

A. Early understandings about “adrenaline” and behavior
B. Acute disorders of adrenaline imbalance.
1. Beta adrenergic rage (brain injury rage/anxiety rage)
2. Hyperactivity due to beta hyperadrenergic state
3. Psychotic rage. Discovering a treatment of alpha-adrenergic rage ("crazy rage") in the DD population.
C. Diseases (disorders) caused by chronic dysregulation of adrenaline systems.

Part IV: UNDERSTANDING NORMAL BETA- AND ALPHA-ADRENERGIC SYSTEMS THROUGH THE LIFE CYCLE.

A. Beta-adrenergic over-reactivity – Childhood’s natural state
B. Alpha-adrenergic activity – The natural state of adulthood

Part VI: SUMMARY.

PART I: ADRENALINE OVERVIEW

From 1950 to 1980, behavioral science paid much attention to adrenaline as a mediator of psychological changes. Especially emphasized was adrenaline’s role in anxiety. Furthermore, early anti-depressant medications worked chiefly through adrenaline receptor activity. From 1980 to 2000, much more emphasis has been placed on serotonin activity. For this reason, many modern psychiatrists have limited understanding of adrenaline function in the body. Madisondoctrine developed extensive experience dealing with the nature of adrenaline reactivity because the developmentally disabled population tends to have less mature control of the innate adrenergic reflexes. This section on adrenaline will be one of the largest sections dedicated to one topic. Much of the material presented here is review; some of it is new. This section gives a preliminary sketch of adrenaline systems and their relationship to psychiatric disorders and their treatment.

A. UNDERSTANDING ADRENALINE AND BODY FUNCTION.

1. There are two chemicals natural to the body with adrenaline activity – norepinephrine [NE] and epinephrine [EPI]. These are also called noradrenaline and adrenaline.

2. NE in the body is mostly secreted by nerve cells within the brain and by sympathetic nerves in the body, but on occasion by the adrenal gland into the blood stream. EPI is mostly secreted by the adrenal gland into the blood stream and extremely rarely by nerve cells in the brain.

3. There are two major classes of adrenaline receptors – alpha and beta.

4. There are three types of beta-receptors – Two are significant to the whole body: beta-1 receptors, which are stimulated by NE and EPI; and beta-2 receptors, which are stimulated only by EPI in the body. Beta-3 receptors are related to fat cell metabolism.
5. There are two types of alpha-receptors – post-synaptic alpha-1 receptors, which stimulate activity in the body and brain; and alpha-2 receptors, which are mostly pre-synaptic and modulate the function of nerves that secrete NE and other neuro-transmitters. Alpha-1 receptors in the body are stimulated by both NE and EPI. Alpha-1 receptors in the brain and alpha-2 receptors in nerve terminals are stimulated by NE and are not typically exposed to EPI.

6. There are two systems of Noradrenergic neurons in the body: 1. The sympathetic division of the autonomic system in the body, whose cell bodies are in the sympathetic ganglia. 2. The Locus Ceruleus (LC) and related nuclei in and near the midbrain, which supply fibers to the brain and the meningeal blood vessels..
Ref. Dahlstrom A and Fuxe K: Evidence for the Existence of Monoamine – Containing Neurons in the Central Nervous System. Acta Physiologica Scandinavica. 1964; 62 (suppl.) 232).

7. a) Beta-1 receptors are found in the heart and brain where they are the main adrenergic modulators. The heart receptors are routinely stimulated by both NE and EPI. Beta-1 receptors in the brain are stimulated exclusively by NE.
b) Beta-2 receptors are found mostly in the body. They are especially located in smooth muscles, where they cause a relaxation or dilatation. Medicines which stimulate Beta-2 receptors are standard treatment for asthma. Beta-2 receptors are also found in small quantities in the heart and the brain.
c) Beta-3 receptors affect fat cell activity. They are of special interest to certain weight control programs found on the internet. There are no standard prescription medicines which exclusively affect Beta-3 receptors
d) Alpha-1 receptors are found mostly in the body, especially in smooth muscles where they oppose beta-2 receptors by causing contraction or constriction of the smooth muscles. Alpha-2 receptors modulate the reactivity of NE secreting neurons. They are found on cell bodies and in the synapses of NE secreting cells. When alpha-2 receptors are stimulated, the neuron secretes less NE into the synapses to stimulate NE receptors on the postsynaptic neuron. Thus their most significant function is lowering the activity of NE-secreting neurons. They also act as regulators on other neurons, such as serotonin in the brain and acetylcholine in the lungs.

8. a) There are no alpha-1 receptors in the muscles of the lungs.
b) The alpha-1 receptors in heart muscle have little significance in normal hearts, but apparently are of more significance in a heart in heart failure.
c) There are some alpha-1 receptors in brain tissue. One known function is related to hypothalamic hunger activity.
(Ref. Liebowitz S. Reciprocal Hunger Regulating Circuits Involving Alpha- and Beta-Adrenergic Receptors Located, Respectively, in the Ventromedial and Lateral Hypothalamus. Proceedings of the National Academy of Science. 67 (Oct 70) 1063-70.
d) There are alpha-1 receptors in the blood vessels of the heart, lungs, and brain.

9. After NE is secreted into the synapse by a nerve, there is a mechanism to carry it back into the nerve. This is called a re-uptake mechanism. Many anti-depressants have as their immediate action a blocking of this re-uptake, thus allowing the NE to stay longer in the synapse.

10. There is also an enzyme mechanism called monoamine oxidase (MAO), which destroys NE when it is secreted out of the nerve. Another mechanism for anti-depressant action is provided by medications which prevent the MAO enzyme from destroying NE; thus prolonging its effect in the synapse. These medications are called MAO Inhibitors.

11. Where alpha and beta-receptors exist in the same tissue, they generally oppose each other’s actions. In smooth muscle, stimulation of alpha receptors causes muscle contraction or tightening of sphincter muscles. Stimulation of beta receptors causes muscle relaxation or dilatation of sphincter muscles. In the liver, stimulation of alpha receptors releases insulin and lowers blood sugar. Stimulation of beta receptors releases glucagon and raises blood sugar through gluconeogenesis. ( It is to be noted that alpha adrenaline’s contractile effect on the smooth muscles is similar to another neuro-transmitter – acetylcholine, but acetylcholine is the main transmitter during normal function and NE is more significant during crisis function.)

12. EPI stimulates both alpha and beta receptors – thus it can cause smooth muscle constriction or relaxation – depending on the concentration of the EPI and prevalence of receptors. .

13. NE stimulates only alpha receptors on blood vessels, not beta-2 receptors, thus causing only vasoconstriction. It does stimulate Beta-1 receptors of the heart and brain.

14. Many times, the “two adrenaline systems” work in coordination. For example, in response to an injury, blood vessels will first contract because of stimulation by NE through sympathetic nerves – presumably to prevent excess blood loss. They will later dilate from EPI carried in the blood stream – presumably to allow for material needed for body repair mechanisms to flow to the injured area.

15. There are, however, distinctions between arousal states that are brought on by either predominantly alpha (NE) adrenaline activity or beta (EPI) activity. This distinction is very significant in some psychiatric conditions.

16. Beta-adrenergic over-arousal is the state of panic/fright. Individuals demonstrating such fear arousal have a high EPI blood level with rapid heartbeat, dilation of blood vessels, and a panic/fright reaction within the brain. (This is the state of the antelope running from the lion.)

17. Alpha-adrenergic arousal is the state seen in predator aggression arousal or in the aggression associated with territorial and mating functions. The body and brain are intensely aroused and prepared for intense, but controlled, aggressive activity. (This is the lion stalking the antelope.)

18. When alpha adrenaline reactivity becomes sufficiently intense, there is a change in the “blood brain barrier” and the brain undergoes functional changes, which can lead to a temporary psychosis. This is one significant origin of that type of psychotic rage during which there can be amnesia for the event..

19. Rage behavior may be a beta adrenergic fright reaction, alpha adrenergic focused fight reaction, or a mixture of both.

20. There are some exceptions to the above rules.
a) There are Post-synaptic Alpha-2 receptors which cause vasoconstriction in the peripheral circulation –some are related to arteriolar-venous shunts in the limb circulation.
b) There are other exceptions I do not know about – these are hidden in very obscure literature.

B. UNDERSTANDING HOW MEDICATIONS MAY AFFECT ADRENALINE.

VARIOUS CLASSES OF MEDICINES ACT IN THE FOLLOWING WAYS ON THE COMPLEX ADRENALINE SYSTEMS.

1. Alpha 1 receptor agonists. ( agonist = a stimulant to the receptor) E.g. pseudephedrine /Sudafed for nasal congestion and urinary incontinence, mididrine /Proamitine for hypotension.
2. Alpha-2 receptor agonist. E.g. clonidine/Catapres, guanfacine/Tenex. For hypertension, some forms of diarrhea, various psychiatric uses.
3. Alpha-1 receptor blockers. E.g. doxazosin/Cardura for hypertension and urinary retention. (and used by MadisonDoctrine for control of “predator rage”. )
4. Alpha-2 receptor antagonist. E.g. yohimbine/Yocon for impotence, mirtazapine /Remeron for depression.
5. Beta receptor agonists. E.g. albuterol /Proventil for bronchospasm. (Beta-2 agonist). [Older drugs such as isoproterenol /Isuprel had both Beta 1 and Beta 2 agonist effect.]
6. Beta-1 and Beta-2 receptor blockers (Non-selective). E.g. propranolol/Inderal for hypertension, migraine prophylaxis, cardiac disease. Also for control of certain rage and anxiety states.
7. Beta-2 selective receptor blockers. (metropolol/Lopressor, Toprol) These medications have a partial selectivity. They block mostly Beta-1 receptors at lower doses, but both Beta-1 and Beta-2 at higher doses. Used like Non-selective blockers. Generally less side effects
8. Monoamine Oxidase Inhibitors (preventing breakdown of secreted NE) phenylzine /Nardil for depression.
9. NE reuptake inhibitors. (prevent re-absorption of NE from the synapse) E.g. nortriptyline /Pamelor for depression.
10. Neurotransmitter storage depletors. (Cause less NE to be stored in nerve cells) E.g. reserpine for hypertension. (Reserpine acts on dopamine and serotonin also.)
11. Blockers of Neurotransmitter production. (Preventing the formation of normal amounts of NE and EPI). E.g. metyrosine/Demser for adrenal gland tumors. (And psychiatric uses by Madisondoctrine.)
12. Production of a “false transmitter” which competes with NE at the receptor site. E.g. methyldopa/Aldomet for hypertension – and some psychiatric uses.
13. Precursor chemicals to increase the production of NE and EPI. E.g. phenylalanine and tyrosine. May increase the production of dopamine, NE, and EPI.
14. NE neuron stimulants. Cause an increase in release of stored NE and reuptake blockade (some also affect Dopamine) E.g. methylphenidate /Ritalin for stimulant effect and Attention Deficit Hyperactivity Disorder.
15. Ganglion stimulants. Indirect increase in output of NE neurons through stimulation of nicotinic brain and autonomic nerve centers. This is the action of Nicotine.
16. Ganglion blockers: Block the release of NE from neurons by blocking the controlling autonomic nerve centers. E.g. mecamylamine (Inversine). Was used to treat severe hypertension – newly suggested (2001) for treating Tourette’s and possibly many other Nervous System disorders.

C. PRESENTATION OF HYPERADRENERGIC STATES IN HUMANS. In order to diagnose and treat disturbed homeostasis adrenergic states, clinicians must learn to distinguish the presenting signs and symptoms which may indicate either alpha hyper-activity or beta hyper-activity. Distinct clusters of symptoms distinguish the alpha hyper-arousal state from that of the beta hyper-arousal state since the two adrenergic systems have different reactions on various body organs. (The most significant difference is the alpha-adrenergic smooth muscle contraction versus beta-adrenergic smooth muscle relaxation). The following signs and symptoms can be seen in cases of moderate hyper-reactivity:

1. Symptoms of Alpha-Adrenergic Over-reactivity
a. Sensation of mind racing
b. Inability to turn off mind at bedtime
c. Brief, controlled anger reactions
d. Excessively goal-oriented personality
e. Feeling of "shaking inside" without external tremor
f. Episodic high systolic and diastolic blood pressure with or without rapid heart rate.
g. “Pounding" palpitations (may include pain).
h. Tightness of chest, feeling unable to get a deep breath.
i. Reactive asthma
j. Vascular headaches.
k. Numbness and tingling of extremities.
l. Cold or blue hands.
m. Bowel cramping.
n. Nervous diarrhea.
o. Esophageal tightness.
p. Poor appetite in the morning.
q. Increase in tendency for autoimmune disease.

2. Symptoms of Beta-Adrenergic Over-reactivity
a. Fidgety restlessness
b. Biting of nails
c. Picking of skin around fingers
d. Chewing objects (pencils, etc.)
e. Anger reactions with spontaneous uncontrolled verbalizations (e.g. swearing) and
blind aggression with increased strength
f. High resting pulse rate – may have wide pulse pressure (high systolic, low
diastolic)
g. “Fluttery" heart palpitations
h. Feeling hot and sweating easily
i. Flushing of face
j. Tension headaches
k. Essential-type tremor (fine finger tremor –especially when holding something).

PART II: DESCRIPTION OF THE TYPES OF TARDIVE PHENOMENON

Adrenaline activity is one of the most significant influences in the body’s attempts to adjust itself to the various changes in life. Therefore, adrenaline activity affects psychiatric states in multiple ways—sometimes acutely and sometimes chronically. However, there is much less attention directed to understanding the effect of adrenaline dysregulation on psychiatric disorders than to the effects of other neurotransmitters such as serotonin and dopamine.

Because the Developmentally Disabled (DD) population is generally less mature than the standard population, DD individuals with psychiatric difficulties will demonstrate more problems related to adrenaline dysregulation. In the twenty years of Madisondoctrine experience, over 3000 patients have been treated specifically for some form of adrenaline upset—surely one of the largest groups of patients ever so treated by one clinician. The purpose of this material is to provide detailed understanding of conditions related to various adrenaline dysregulation states. Understanding adrenaline function is especially helpful when treating the DD population. However, up to ten percent of the non-DD population with psychiatric disorders can also benefit from receiving treatment directed at adrenaline imbalance. However, psychiatry tends to pay little attention to this area of body function. For years, the Madisondoctrine practice has looked for those special disorders caused by adrenaline dysregulation. . These disorders can be divided into three groups:

A. Those which seem to be pure acute adrenergic upset and respond best to adrenaline-acting medications.
B. Those which are caused by the body’s adjustment to a chronic adrenaline over-arousal state.
C. Those in which the adrenaline imbalance is complicating other psychiatric or physical disorders.

A. SYNDROMES CAUSED MOSTLY BY ACUTE ADRENALINE OVERACTIVITY.

There are at least 4 psychiatric sub-syndromes which are due to acute over-activity in adrenaline arousal and which can be treated with medications that directly alter the adrenaline activity of the body. These are not standard psychiatric diagnoses, but are states of dysfunctional physiology related to uncontrolled adrenaline activity. Of these four only the first is well known to standard psychiatry.

1) SPEAKER’S FRIGHT. This is a fairly well described short-term condition marked by fine tremor, rapid heart rate, palpitations, and voice tremor. This is seen especially in speakers and performers and has long been treated by use of low dose beta-blockers such as 10 to 20 mg of propranolol. This problem occurs because of sudden beta-adrenergic over-activity and is caused by excess release of EPI from the adrenal gland.

(Note that this problem and its treatment have been known for over twenty years, but there is still not an “official” disease diagnosis nor an “approved” treatment. Generally, it is talked about as a part of a disorder termed Social Phobia even though its symptoms and treatment are different from Social Phobia. This situation is a typical example of the lack of flexibility on the part of the authorities responsible for making official diagnoses and approving medication uses. Infrequent transient conditions are rarely included in the register of “real diseases” with “real treatments”; so that their diagnosis and treatment are downgraded to “anecdotal” or “non-official.” This problem is seen several times in the various presentations of the Madisondoctrine material.)

2) FRIGHT RAGE. This is one of the forms of rage reaction seen in children, the Developmentally Disabled, the brain injured, and others. It frequently has a sudden onset and often occurs with only minor provocation. Rage is frantic and blindly unfocused.. Blood pressure shows a high systolic reading and a variable diastolic. Heart rate is very high. Afterwards, individuals will often state that they tried to stop but could not, and they subsequently feel remorse for having demonstrated violent behavior. (Many times care-givers will make the incorrect remark that if the individuals were truly sorry they would not have the rage.) This is a beta-adrenaline rage reaction and can be treated with prophylactic beta-blockers. Sometimes it will calm in the presence of forceful authority or perceived authority. It is similar to the panic demonstrated by the fledging bird in the rookery who is lost from its nest, and similarly resolves once there is a sense of being back under the care of the security of a stable dominant figure.

3) PREDATOR RAGE (PSYCHOTIC RAGE, CRIMINAL RAGE). This is a focused, "go for the jugular", wild-eyed, "He does not even seem to recognize me" rage. The individual loses emotional control but does not necessarily lose the ability to make calculated mental decisions. Individuals can become transiently psychotic and may not remember the events afterwards. They generally lack a profound sense of being sorry for their actions. This type of rage is due to a surge of alpha-adrenergic reactivity and can be treated with prophylactic alpha-blocking medications. In nature this would be the feeding frenzy of the shark or other predator. (This is a diagnosis and treatment developed in Madisondoctrine clinic.)

4) HYPERACTIVITY DISORDER: Attention Deficit Hyperactivity Disorder is now a well-accepted diagnosis. It has been described with various labels and treated with stimulant medications for over sixty years. However, it is not a pure diagnosis. It is well-known that some individuals have hyperactivity or conduct disorder along with their attention deficit symptoms and others do not. Less understood are those individuals who do not have Attention Deficit Disorder but do have hyperactivity manifested by the need for constant physical activity. Many of these individuals have unregulated adrenergic reactivity, especially demonstrating a persistently high pulse rate. They respond to adrenaline lowering medications such as Alpha-2-agonists (clonidine and others) and Beta-Blockers (propranolol and others). Most children and many adults with DD have this type of adrenaline-induced overactivity.

B. DISEASES CAUSED BY CHRONIC DYSREGULATION OF ADRENALINE SYSTEMS. There are many disease states which can be traced to chronic adrenaline reactive states and body adjustment. “Psycho-physiological” disorders such as hypertension, hypotension, spastic bowel disease, and various autoimmune reactions are common examples. Some of these will be discussed individually later on.

C. ADRENALINE DYSREGULATION STATES WHICH CONTRIBUTE TO THE SYMPTOMS OF OTHER PSYCHIATRIC DISORDERS.

Adrenaline dysregulation is frequently the cause of symptoms in many psychiatric conditions including Anxiety Disorder, Panic Disorder, Depression, and Attention Deficit Hyperactivity Disorder. But the adrenergic component of psychiatric disease states has been long overlooked because the nature of adrenergic dysfunction is very specific to each patient. The symptoms, caused by primitive adrenaline reflexes which are unleashed in any particular psychiatric patient, are related to that patient’s genetic make-up and personality experiences. Any given patient diagnosed with psychosis, depression, or anxiety may exhibit alpha over-reactivity, beta over-reactivity, or some mixture of the two.

In the course of treating psychiatric disorders, physicians need to identify and treat associated dysfunctional adrenergic states – thereby lowering the morbidity of the total disease and perhaps also increasing the chances of complete remission. Treating dysfunctional adrenergic reactions has essentially the same purpose as treating a high fever in an individual with an acute infection. The fever represents a blind reaction to an invasion of a pathogenic organism. A clinician can remove the difficulties of having the high fever since such a blind reflex is not as important to the ultimate cure as the specific treatment regime of the physician. In some cases, the negative effects of a high fever are more significant than the actual disease; likewise, excessive hyperadrenergic states can be a major hindrance to successful treatment of the major psychiatric disorders.

 PART III: DYSFUNCTIONAL ADRENALINE REACTIVITY IN THE MR/DD POPULATION. 

(PARALLEL MATERIAL IS FOUND IN THE TOPIC <RAGE> ON MAIN PAGE)

A) EARLY UNDERSTANDINGS ABOUT “ADRENALINE” AND BEHAVIOR.. My introduction to hyperadrenergic states in psychiatry occurred in 1980 while I was working in Ohio’s largest state residential center for mentally retarded and developmentally disabled (MR/DD) individuals. Many of the overactive, agitated, aggressive, injurious people were unaffected by the "super-duo" pharmacology prevalent at that time (i.e. daily doses of 1000+ mgs of chlorpromazine /Thorazine and 40+ mgs of diazepam/ Valium). While attempting to develop a better mode of treatment, I realized that many individuals constantly ran high pulses in the range of 120/minute to 140/minute. When I told others about this observation, the standard response was, "Well, if you were that agitated, your pulse would be elevated too." However, a 1976 textbook stating that the beta-adrenergic blocker propranolol/Inderal was useful in anxiety gave me some encouragement.

". . . Anxiety is characterized by palpitations, rapid heartbeat, tremor, tingling, cold sweats, chest constriction, and twitching. Physiologically, many of these symptoms can be caused by epinephrine secreted during stress. This point raises the question of whether one of the components in anxiety is the perception of these internal epinephrine-induced physiological events or even a hyper-awareness of normal adrenergic functioning.

Many of these peripheral autonomic events can be blocked by B-adrenergic blocking agents, such as propranolol (Inderal). The hypothesis here is that the B-adrenergic agent may block the autonomic signals of anxiety and, thus, may benefit anxiety through a peripheral mechanism. Propranolol, given either intravenously or orally in beta-receptor-blocking doses, produces improvements in patients with anxiety, particularly improvements in the somatic manifestations of anxiety.

The use of B-blockers for anxiety is still in the investigation stage and is mentioned here for its theoretical relevance . . ."

Modern Synopsis of Psychiatry/III: Freedman AM, HI Kaplan, and BJ Sadock. 2nd Ed. Williams & Wilkins Co: Baltimore, 1976. Page 982.

Within three years, I had treated over 200 of the facility’s residents with propranolol and had generally good success, which allowed lowering or eliminating high dose "tranquilizers." Later, I became aware of literature showing the successful use of Propranolol for rage behavior – such as studies by Frank Elliott, Stuart Yudofsky, and Daniel Williams.

Ref. Elliott FA: Propranolol for the Control of Belligerent Behavior Following Acute Brain Damage. Ann Neurol, 1977; 1:489-491.

Yudofsky S, Williams DT, Gorman, J: Propranolol in the Treatment of Rage and Violent Behavior in Patients with Chronic Brain Syndromes. Am J Psych, 1981; 138:218-220.

Williams DT, Mehl R, Yudofsky S, et al: The Effect of Propranolol on Uncontrolled Rage Outbursts in Children and Adolescents with Organic Brain Dysfunction. J Am Acad Child Psych, 1982; 21:120-135.

B) DISORDERS OF ACUTE ADRENALINE IMBALANCE. In my years of work at the MR/DD institution, I saw two distinct patterns of behavior related to dysfunctional beta-adrenergic activity which responded consistently to beta-blockers. Beta-adrenergic rage, and beta-adrenergic-driven hyperactivity. Later it became evident that there were behavior patterns related to alpha adrenaline over-activity.

1. BETA ADRENERGIC RAGE (BRAIN INJURY RAGE/ANXIETY RAGE)

This disorder has the same criteria as that described for "episodic dyscontrol" in Elliott’s pioneer study published in 1977. Individuals with this disorder often have sustained an identifiable brain injury and may have a stable personality except during emotional upsets – when they develop an instantaneous, uncontrollable rage reaction. The violent episodes often are followed by genuine remorse. My MR/DD patients with that profile responded remarkable well to propranolol therapy just as Elliott’s patients had. Some demonstrated no further symptoms after the first dose of medication.

Early case history CASE 1ADR (1980): One individual, a 22 year old non-verbal male with obsessive-compulsive traits demonstrated no improvement of his intensive explosive behaviors while on 300 mg of thioridazine/ Mellaril per day. During rages, his pulses were in the 120/minute range. He was placed on propranolol 90 mg a day and the thioridazine was discontinued. On propranolol, his pulses were in the 60-70/minute range, and his obsessive activities began to respond behavioral intervention, which had previously been ineffective. He had no rage reactions for over six months, but his pulse gradually dropped – requiring a tapering down of the propranolol. Within two weeks after a trial discontinuation of the propranolol, he had a rage reaction with a pulse of 120/minute. He was placed back on 60 mg of propranolol daily and remained stable.

2. HYPERACTIVITY DUE TO BETA HYPERADRENERGIC STATE

A far larger group of the MR/DD residents had a different profile. They were physically overactive, impulsive, intrusive, and continuously or intermittently showed high pulses and somewhat high blood pressures. Although they had short tempers, they were easily distinguished from "episodic dyscontrol" patients because their rages did not always occur suddenly and they did not often express sorrow after an outburst. They were more a part of their immature self-centered personality.

A high percentage of the institutional population had this type of hyperadrenergic reaction and I became known jokingly as "Dr. Inderal" as the staff began to spend hours monitoring blood pressures and pulses while I adjusted doses of propranolol. Many cases showed exceptional and instant improvement – PRN injections of Thorazine and Valium became fairly rare. However, the bountiful use of propranolol did not solve all the behavior problems in the facility any more than excess chlorpromazine and diazepam had. Several individuals "broke through" after an initial positive response, and others ran lower pulses and blood pressures without any change in their disruptive behavior.

At that time, I had no real diagnostic criteria to identify potential responders from non-responders. Only much later did I realize that the general success of propranolol at that institution was not because it treated a specific disease state, but because many of these MR/DD patients had been physiologically immature. Their impulsive behavior and outbursts of anger had been activated primarily by their excessive beta-adrenergic tone. When their vital signs were brought down to what I now term "basal levels" (blood pressure of 90/60 and pulse 60/minute), they had "better behavior" A decrease in adrenergic tone allowed them to respond far more calmly to environmental variations and develop more mature patterns of reactivity. On the other hand, the individuals who had underlying psychiatric or neuro-psychiatric disorders did not stabilize significantly with propranolol therapy because the excess beta reactivity represented only a superficial part of their problem.

3. PSYCHOTIC RAGE. DISCOVERING A TREATMENT OF ALPHA-ADRENERGIC RAGE ("CRAZY RAGE") IN THE DD POPULATION.

This type of rage is distinguished by its transient psychotic state and extreme high blood pressure. The following case, treated in 1989, provided breakthrough understanding:

CASE 2ADR- A 20 year old mentally retarded male admitted for rage behavior was identified as having the "crazy rage" syndrome. At that time clonidine and propranolol were considered to be the most likely medications for treatment. He had been admitted on the anti-psychotic thioridazine/Mellaril, but this had been changed to an equivalent dose of haloperidol/Haldol because of the drug interaction between the low potency fat-soluble antipsychotics, such as thioridazine, and the fat-soluble beta-blockers, such as propranolol. Several weeks after his discharge from the hospital, his caregivers reported that his rages were less frequent -- but were actually more intense when they did occur. A review of his medication changes revealed that the most significant difference was the elimination of the thioridazine – which has a significant alpha-adrenergic blocking effect. Restarting the thioridazine in his medication regime caused a substantial decrease in the psychotic symptoms of his rage.

(Note that the frequency of the rages diminished because the propranolol and clonidine lowered his basic adrenaline reactivity; but when he did break through and have a rage, it was worse because of the vasoconstrictor effect of the propranolol and. the loss of the alpha-blocking effect of the thioridazine.)

Another early case shows the seemingly excessive use of adrenaline-acting medications that may be necessary to stop predator rage when it accompanies other mental illness.

CASE 3ADR. A 28 year old male with Moderate Mental Retardation was seen for multiple complaints including poor night sleep, obsessive compulsive behavior, "psychotic rage," anxiety, phobia, and panic attacks. Though his psychiatric symptoms were quite confusing, he did maintain a consistent pattern of hypertension toward the evening (up to 150/100). Vital signs during anger episodes included pulses of 140/minute and blood pressures in the 160/100 range. He demonstrated absurd expectations, which were followed by intense, nearly psychotic frustration when the expectations were not met. Within five days his receiving an intense regime of anti-adrenergic medications, hospital staff were noting how pleasant he was – stating, "He is almost a different person." During the last seven days of hospitalization, his blood pressure never rose above 100/80 and his pulses averaged 70-80/minute.

The patient was discharged on mid-range therapeutic levels of carbamazepine and lithium because his history suggested that he had Bipolar Disorder. He was also on thioridazine/Mellaril 250 mg a day, clomipramine/Anafranil 50 mg a day for obsessive compulsive symptoms, reserpine 0.4 mg a day, guanfacine/ Tenex 3 mg a day, terazosin/ Hytrin (a pure alpha-adrenergic blocker) 2 mg a day, and Labetalol (alpha-and beta-blocker) 2400 mg a day. Prior to initiation of the regime designed specifically to lower the alpha-adrenergic tone, no combination of antipsychotics and anti-cyclic medications alone had produced any type of normal, predictable behavior.

NOTE THAT HE WAS ON FIVE MEDICATIONS THAT AFFECTED THE ADRENALINE REACTIVITY!!.
Reserpine lowers the quantity of NE in nerve cells; guanfacine/Tenex lowers nerve adrenaline reactivity by stimulating presynaptic alpha-2 receptors; labetalol/Normodyne is both an alpha-and a beta-blocker, and both terazosin/Hytrin and thioridazine/Mellaril have alpha-blocking activities. The use of so many adrenaline-lowering medications together is often necessary because of the wildly uncontrolled adrenaline state that these individuals have learned as part of their reaction to environmental stress. However, it is very difficult for clinicians to initiate such a formidable medication regime – especially since there is little tradition in standard psychiatry for use of these medications together.

This patient has been treated for over ten years and in general is adequately functional –however, he still requires a medication regime having four different classes of medications which act on adrenergic function.

C) DISEASE (DISORDERS) CAUSED BY CHRONIC DYSREGULATION OF ADRENALINE SYSTEMS

(a) COMPLEX CHRONIC STATES OF ADRENALINE DYSREGULATION.--TRYING TO UNDERSTAND “THE MARY JANE SYNDROME”

In the initial enthusiasm of finding individuals who had beta-adrenaline over-reactivity or alpha-adrenaline over-reactivity, it seemed as if everyone’s hyper-arousal problem could be solved by giving a medicine which either lowered beta function or alpha function or both. It seems so ridiculously easy. Why hadn’t this been figured out as soon as the anti-adrenergic medications came on the market? THEN I MET MARY JANE.

CASE 4ADR. Mary Jane was a 25-year old non-verbal institutionalized woman who weighed about 89 pounds. She ate huge volumes of food and spent the entire day running around her enclosed “classroom” occasionally hitting other humans and objects that were in her way; but most of the time she was just going extremely fast. Her pulse also was fast – above 120/minute all of the time. She did not have hyperthyroidism. She seemed a prime candidate for beta-blocker therapy – except for one major problem. Her blood pressure ran approximately 80/50 and was generally hard to hear. More significantly, she had the coldest, bluest hands and feet of anyone I had ever seen – the hands were blue to the elbow! Naturally, when I attempted to give propranolol, the blueness and coldness of her arms increased in intensity and rose higher on the limbs due the vasoconstriction effect. The blood pressure dropped to a point of being unobtainable.

Clearly, there was more to dysfunctional adrenaline reactivity than the simple concept that there was just “too much adrenaline there”. Lacking a more sophisticated concept of adrenaline reactivity, I was not able to treat Mary Jane at that facility. Such treatment requires an understanding the adrenaline-balancing act that occurs in the body in response to stress, and changes of body reactivity occurring through the day. It also requires understanding of the concept of psycho-physiological “disease” states – states in which the body changes its normal reactivity patterns, develops different set points, and thus develops a “functional disorder.” Although adrenaline is not the only chemical reactor involved in these abnormal states, it certainly makes a major contribution. Therefore, one can state that most disorders of the body which are caused exclusively by disordered function of body mechanisms are influenced in part by shifting adrenaline activity. The most significant disorders of this class relates to blood pressure regulation. Madisondoctrine considers that both hypertension and hypotension relate strongly to chronic adrenaline dysfunction. (These two disorders are so significant that they are listed independently on the main page.

PART IV: UNDERSTANDING NORMAL BETA- AND ALPHA-ADRENERGIC SYSTEMS THROUGH THE LIFE CYCLE

Before moving on the material about adrenaline variation and its role in blood pressure regulation, the reader is encouraged to gain a more complete understanding of the normal variations in adrenaline through life.

A. BETA-ADRENERGIC OVER-REACTIVITY – CHILDHOOD’S NATURAL STATE

1. BETA PLAYFULNESS: One could characterize the normally functioning beta-adrenergic system as the activating system that helps a child enthusiastically play, learn, and grow; and characterize the normally functioning alpha-adrenergic system as the activating system that helps an adult concentrate on productive work efforts and reproductive activities.

For example, a cheerful, playful young boy’s body is seething with beta-receptors. His heart beats fast, his fingers will easily demonstrate essential-type tremor on excitement, and his young muscles toned with abundant beta-adrenaline receptors move with overactive exuberance. Such strong physical responses to environmental stimuli produce the atmosphere for the continuous learning experience called "play." Children do not necessarily have excessive Epinephrine blood levels. Instead, their bodies have an exorbitant number of beta-receptors – which begin dropping out as the child matures.

2 PLAY TO PANIC The bubbliness of a child playing is a product of the beta-adrenergic tone of youth, but lurking directly beneath the enthusiasm is the potential for sudden terror or rage reactions. Furthermore, the conversion between the two states is nearly instantaneous. The idyllic joy that a child experiences riding his tricycle is countered by the terror of following down and scraping his knees and the anger at the tree root that caused the fall. An important survival mechanism of the vulnerable young mammal is its innate, beta-adrenergically-driven system which transforms playful frolic into panicky flight or blind rage in seconds. The adrenergic tone of children is an instinctive, impulsive reactivity that is not highly governed by cerebral control. It can, however, be controlled by an outside influence, and external influences teach children their first lessons about learning to control their natural beta responses.

3. SOCIAL DOMINANCE AND BETA-ADRENERGIC REACTIVITY. Children have instinctive and/or learned reflexes whereby their beta-adrenergic reactivity shuts down in response to a dominant authority figure – and an important function of parenting is the inhibition of a child’s adrenergic over-reactivity. Take, for example, bear cubs tumbling over logs, hunting for grubs, and otherwise exploring the world in a state of beta-adrenergically stimulated giddiness. When the mother bear smells danger in the air and gives a short grunt, the cubs instantly freeze – having an instinctive reflex to react to the mother and also having learned reflexes from past punishments when they failed to heed her. The same principle is demonstrated when an infant suddenly realizes it has wandered away from its care-giving parent. The child instantly begins to scream, cry, and run wildly until it is back within its parent’s proximity – where it abruptly calms. This phenomenon is linked to feelings of both fear and security in relationship to the superior social figure. A similar hierarchy of dominance develops within social groups. In the language of the behavioral
psychologists, this principle is called "alpha dominance." (The leader of the wolf pack is considered the alpha dominant male. The hen which roosts on the highest perch has won all the fights and is the alpha dominant in the "pecking order" of the hen house.)

4. DOMINANCE IS NOT TOTALLY RATIONAL. The word "perceived" is used above because the social dominance of a leader figure depends upon the perception of those submitting. Many times dominance is based on genetic or class distinctions – for example, individuals who are larger, older, or masculine are usually perceived as being more dominant than individuals who are smaller, younger, or feminine. Yet, this generalization is not always true. Many times, a physically smaller individual who has, in some way, demonstrated nurturing or disciplinary or aggressive influence may have the social dominance to inhibit the adrenergic reactivity of a larger individual. A story that illustrates the unpredictability of social dominance is that of Frazier – a toothless, "over-the-hill" male lion who lived in a "Safari Land" exhibit in California. Frazier became a folk hero because he successfully sired over thirty cubs in a few months in a pride of females who had previously attacked and injured several potential mates who looked much more virile and dominant than Frazier.

B. ALPHA-ADRENERGIC ACTIVITY – THE NATURAL STATE OF ADULTHOOD

1. CONTROL IS THE RULE OF ADULTHOOD. As an individual matures, the overwhelming EPI reactivity of childhood should gradually fade away and the more rational NE system should have increasing regulatory control. According to the model proposed in this paper, the Locus Ceruleus (LC) neuron network using NE as a neurotransmitter represents the most significant activating and de-activating force within the brain. Although EPI release from the adrenal is still the response of an adult human during an extreme crisis, the adult LC system is the standard governor that regulates whether rationally-induced or emotionally-induced drives will accelerate or decelerate physical and mental activity.

2. CONTROLLED OVERUSE IS THE COMMON EXCEPTION TO THE RULE. However, within the natural life cycle of an adult, there are times when NE-regulated internal controls change, and the body purposely develops a more "predator" state of alpha-adrenergic over-reactivity. For instance, far more alpha-adrenergic output is needed to produce the heightened excitatory states involved with mating, reproduction, and child-nurturing behaviors. Since the business of adults—especially modern, educated adults—is maintaining their own and their offspring’s lives at very high levels of stability, alpha reactivity is used excessively. This leads to various imbalanced states of function, which can be lumped into the classification of psycho-physiological dysfunctions. Blood pressure regulation is one of the most significant areas of this type of dysfunction.

PART V: SUMMARY

This extensive material is presented with the hope that readers will learn to include the variations on adrenergic function as a constant part of their thinking about the body’s activity. Especially there needs to be enhanced awareness of the negative effects of excess use of the NE mediated focused predator arousal, which is the driving force of so much of civilization – and also the driving force toward multiple destructive reactions within the body. The readers may have also gained a sense of how variable the adrenergic levels can be, and how many types of medicines and other therapies may be necessary to stabilize bodies whose adrenergic systems have become chronically imbalanced. It is my hope that clinicians will pay special attention. So many times have individuals been referred to me after other good physicians have made good, solid attempts at medication, and good programmers have devised good behavioral care plans. However, little had been accomplished because neither group had directed any attention to lowering the adrenergic over-reactivity. It is certainly hoped that the readers will also investigate the topics of Essential Hypertension, “Essential Hypotension”, and Rage, which are so much involved with adrenergic imbalance.

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