Circadian Rhythm Synchronicity A Unified Treatment for Affective Disorders

Have you ever felt "out of sync" with the world? Zigging when you ought to be zagging? Going up the down escalator? Heading down a one-way street the wrong way? Jet lagged? Sleepy when you should be awake? Awake when you should be sleepy? Anxious when you could be calm? Depressed when you could be serene? Sick when you could be healthy? Who hasn't? As more and more scientific studies are showing, there may be good physiologic reasons for these feelings. It may be that one or more of your biologic systems are literally marching to the beat of a "different drummer."

Affective disorders, such as depression and anxiety, are often the result of dysregulation in multiple neurochemical and neuroendocrine systems. Although many neurochemicals are secreted all day, the amount secreted varies depending on the time of day. With most such substances, peaks and valleys occur at regular intervals throughout the day and night. Imbalances in both the amplitude (hypo- or hypersecretions) and phase (time for secretions) of those peaks can disrupt internal biological clocks and lead to such clinical conditions as depression and anxiety. This chronobiological desynchrony can also contribute to the pathogenesis of migraine, hypertension (high blood pressure), neurologic diseases, myopathy, and premature aging.

The increasing awareness of the importance of chronobiologic factors in the normal functioning of the body, is the basis for a natural chronotherapeutic approach to mental health based on re-synchronizing the circadian rhythms controlling the synthesis and release of important catecholamine and indoleamine neurohormones.

 

The Beat Goes On

Even though medicine has traditionally viewed the healthy body as being in a homeostatic steady state, recent scientific evidence is suggesting that the steady state is really a constant, integrated, rhythmic ebb and flow of hormones, neurotransmitters, enzymes, receptor sensitivities, and other variables that affect every cell in the body.

Every living creature, from the lowliest one-celled amoeba on up, has normal daily (circadian) rhythms, such as the sleep/wake cycle, that are keyed to the earth's daily rotation. There are also daily rhythms that affect the function of the lungs, cardiovascular system, kidneys, blood flow, muscular activity, and cognitive function. Human females, of course, have monthly menstrual cycles. There are even subtle weekly and yearly cycles that affect reproduction, immune function, and many other systems.

Health is now coming to be viewed as a state when all the body's biological rhythms are closely "in sync." Moreover, many illnesses, including allergy, arthritis, asthma, cardiovascular disease, depression, and even cancer, are affected by bodily clocks. Desynchronization of these clocks can cause a variety of mental and physical problems, including depression, mental fogginess, memory loss, headaches, moodiness, short temper, tension, poor appetite, slow reflexes, fatigue, weakness, and off-schedule bowel movements.

Hormonal secretions of all kinds are closely tied to various biological rhythms. The one that comes most quickly to mind in this regard is the release of melatonin from the pineal gland each night. Because the pineal is sensitive to external light/dark cycles, and because it influences so many other functions in addition to the sleep/waking cycle, melatonin release is considered to be the body's major circadian "pacemaker" or "biological clock." The normal release of melatonin each night helps keep many of the body's other rhythmic functions synchronized.

In normal men, testosterone levels rise in the evening, and drop during the day (Fig. 1). In women, estrogen and progesterone levels rise and fall on a 26- to 28-day cycle (Fig. 2). Likewise, cortisol levels are highest in the early morning, and lowest in the evening.

It is well-known that most heart attacks and strokes occur between 7 and noon. This coincides with a sharp increase in pulse rate, blood pressure, and platelet aggregability (an important stage in clot formation), while plasma fibrinolytic (clot-dissolving) ability is at its lowest level of the day. Even our tolerance for alcohol varies throughout the day, peaking at about 5 PM, perhaps explaining the timing of "happy hours" at bars and taverns everywhere.

Seasonal Affective Disorder

Levels of neurohormones (neurotransmitters), such as the catecholamines [eg, norepinephrine [NE], epinephrine, dopamine] and indoleamines (eg, serotonin), also rise and fall on a cyclic basis throughout the day, and may help color the mood from bright and cheery to the darkest depths of depression. In fact, a growing body of research has linked disruptions in these circadian rhythms to the occurrence of depression. In one study, for example, circadian fluctuations in NE levels were compared in (1) people who were diagnosed with depression, (2) people with depression due to antidepressant drugs, and (3) normal volunteers. The results showed a clear circadian rhythm for NE in the normal controls. However, in the depressed patients, the amplitude of the NE peak was reduced and shifted to an abnormal position. The abnormalities tended to disappear in those who recovered from depression.1
 

 

A form of depression known as seasonal affective disorder (SAD) has been closely tied to a circadian rhythm abnormality. People with SAD tend to become depressed during the winter months, when the number of daylight hours is reduced. Analysis of their circadian rhythms finds them to be significantly out of sync with the normal 24-hour clock.2 Disrupted circadian rhythms have also been found in people with bipolar (manic-depressive) disorder.3 The body depends upon external cues for a smooth transition between the daytime catecholamine-driven cycle and the nighttime indoleamine sleep and repair cycle. But many endogenous (built-in) and exogenous (external to the body) factors contribute to the desynchronization of biological oscillations. These include abnormal patterns of light, excess stress, social isolation, long distance east-west jet travel, uneven work schedule, insufficient, excessive, or irregular sleep, improper diet, nutritional deficiencies, neurohormonal defects, certain medications and recreational drugs, an abusive or erratic lifestyle, as well as aging itself.

Age-Related Change
In Biological Rhythms

There appear to be two types of age-related changes in the organization of biological rhythms. In one type, the variable maintains its rhythmic character, but some aspect of the rhythm, such as the timing of the peak, may be altered. A shift in the peak, say from 2 AM to 6 AM, may then be followed by alterations in other rhythms with which it is normally entrained, thus amplifying the effect throughout the biological system. In the other type of age-related change, the rhythmic character of the variable diminishes to the point where the rhythm may no be longer be discernible.

When biological rhythms get out of sync, it is often possible to resynchronize them. In people with SAD, for example, exposure to natural or artificial sunlight has been shown to be therapeutic. The use of melatonin to help restore normal sleep/wake cycles has been booming in recent years. This may have important implications for normalizing the body's many other cycles. Low melatonin levels have also been implicated in depression and other psychiatric disorders.4-8

As mentioned earlier, depression may also be caused by a desynchrony in the production of neurotransmitters known as catecholamines and indoleamines. Catecholamines are the hormones of the arousal system. Their activities include raising blood pressure, increasing heart rate, opening airways, increasing alertness, and generally preparing the body for "fight-or-flight." Catecholamine levels tend to peak early in the day, which may contribute to the increased risk of heart attacks and strokes during the morning hours. Reduced levels of catecholamines have long been associated with clinical depression.

Treating Chronobiological Desynchronization

The first effective antidepressant drugs were the monoamine oxidase (MAO) inhibitors (eg, Nardil®, Parnate®) and the tricyclic antidepressants (TCAs) (eg, Elavil®, Tofranil® and Pamelor®). The therapeutic effect of these drugs appears to be based largely on their ability to increase catecholamine levels in the brain by blocking the normal metabolic destruction or reuptake of the catecholamine molecules that get released into the synapse (the space between communicating neurons).

Indoleamines, especially serotonin and melatonin, generally reach their peak levels in the evening. They are concerned primarily with maintenance functions, including sleep, cardiovascular activity, and appetite control. Unlike catecholamines, which tend to wake people up and make them more alert, indoleamines tend to lower arousal level and induce relaxation, decrease anxiety, and promote sleep.

Low levels of serotonin (and melatonin) have been closely tied not only to increases in anxiety and depression, but to obesity, insomnia, migraine, fibromyalgia, obsessive-compulsive disorder, and alcoholism as well. Not surprisingly, a major effort of the last decade in the treatment of depression and these other disorders has been to boost serotonin levels using pharmaceutical drugs like Prozac®, Zoloft®, Paxil®, and other selective serotonin uptake inhibitors (SSRIs). SSRIs block the reuptake of serotonin in the synapse, making more serotonin available to stimulate the various serotonergic receptors (Fig. 3).

It is also possible to boost daytime catecholamine levels and nighttime indoleamine levels naturally by taking supplements containing either their metabolic precursors or, in the case of melatonin, the hormone itself at the appropriate time of day or night. For example, l-phenylalanine and l-tyrosine are converted into the catecholamines norepinephrine and dopamine.

Taking these catecholamine precursors along with appropriate nutrient cofactors that include vitamin B6 and hypericin has been shown in numerous studies to relieve depression in a manner that rivals the actions of the TCAs and MAO inhibitors. Similarly, it is possible to boost the level of indoleamine serotonin levels in the brain naturally by supplying the body with its precursors tryptophan and 5-hydroxytryptophan (5-HTP). Both of these amino acids have well-documented antidepressant and anti-anxiety activity, comparable to that produced by the SSRIs. The major difference is that the nutrients do not cause many of the adverse effects associated with use of the various synthetic catecholaminergic and serotonergic drugs — especially the major adverse side effects of the SSRIs, which includes decreased sexual function.

If depressive and anxiety states reflect a disruption in the normal catecholamine and indoleamine activity cycles, it may be possible to restore those cycles and relieve the depression and anxiety by taking the appropriate precursors and hormones at the appropriate times: l-phenylalanine and l-tyrosine in the morning to boost catecholamines, and serotonin and melatonin at night to boost indoleamines.

Syncholamine™ and Positrol™

This is the thinking behind a revolutionary new form of chronotherapy for depression, anxiety, and bipolar disorders, sleep disturbances and other affective disorders. This approach consists of two different chronobiotic complexes designed to be used together to balance and restore normal circadian hormonal rhythms: 

The first is designed to be taken during the early part of the day, when its ingredients help restore the catecholaminergic peaks that normally occur during this time. It contains the amino acid catecholamine precursors l-phenylalanine and l-tyrosine along with nutrient cofactors to synthesize norepinephrine, epinephrine, L-DOPA, and dopamine. These nutrients also increase the concentrations of the endogenous (built-in) stimulant/antidepressant phenethylamine and the natural pain relievers known as enkephalins.

This nutritional complex would also contains extracts of Hypericum perforatum, better known as St. John's wort, one of the most popular and effective natural antidepressant nutrients in use today. Many studies have shown that St. John's wort can be effective in the treatment of depression, anxiety, apathy, sleep disturbances, insomnia, anorexia, and feelings of worthlessness. Even more impressive is the fact that St. John's wort produces these results with hardly any side effects.

St. John's wort seems to work by potentiating the effects of the catecholamines and indoleamines. For example, its MAO-inhibiting activity prevents the breakdown of norepinephrine and serotonin, thus helping amplify the cyclical peak that occurs during the morning hours. St. John's wort also improves the signal produced by serotonin after it binds to its appropriate receptor site, an effect that is even more important in the evening. In still another action, St. John's wort mimics benzodiazepine anti-anxiety drugs by binding gamma-aminobutyric acid (GABA) receptors.

Other ingredients in this compound should  include pyroxidol 5-phosphate, the active form of vitamin B6 in the body, folic acid, and vitamin B12. The body requires vitamin B6 to manufacture norepinephrine, dopamine, and serotonin, to produce phenylethylamine from phenylalanine. Vitamin B6 levels have been found to be low in depressed patients. Moreover, studies show that supplementing vitamin B6 in people with affective disorders is associated with increased levels of NE and serotonin and relief of depression.

Folic acid and vitamin B12 are necessary for the synthesis of a substance called S-adenosylmethionine, which is vital for neurotransmitter metabolism. A deficiency of either folic acid or vitamin B12 may cause similar neurologic and psychiatric disturbances, including depression, dementia, and demyelinating myopathy. A folate deficiency, in particular, may specifically affect the metabolism of catecholamines and indoleamines and aggravate depressive disorders.

Folic acid and vitamins B6 and B12 are also required for the conversion of homocysteine to methionine. This prevents the accumulation of homocysteine, which has been linked to the formation of atherosclerotic plaque in arteries as well as to neurotoxic effects that can produce neurologic and psychiatric disturbances.

The second nutritional complex is designed to be taken in the evening, when its ingredients help boost the normal nocturnal indoleamine peaks. It contains the neurotransmitter precursor 5-HTP, plus nutrient cofactors to synthesize serotonin and melatonin. It should also contain melatonin itself and St. John's wort.

The body makes 5-HTP from the essential amino acid tryptophan and turns it into serotonin. Taking supplements containing 5-HTP raises the level of serotonin in the brain, which can have profound effects on mood, behavior, and sleep patterns. Because serotonin is a circadian rhythm regulator, raising its levels at night promotes circadian synchrony. 5-HTP also boosts the levels of beta-endorphin and other neurotransmitters.

Numerous studies have demonstrated that this complex  can help relieve depression, anxiety, and obsessive-compulsive disorder. In one important comparative study, 5-HTP was found to be as effective as an SSRI drug (fluvoxamine) in reducing depression, with fewer adverse effects. 5-HTP can also help counteract other symptoms of a serotonin deficiency, such as insomnia, overeating, SAD, and fibromyalgia. Taking it in the evening helps maintain the body's temporal organization and coordinates its individual endogenous oscillations with the environment. The result is the relief of major affective disorders, such as depression, bipolar disorder, anxiety and dementia.

Resynchronizing Hormonal Cycles

Taking 1 st group in the early part of the day and the second group toward the end of the day produces stronger chronotherapeutic actions than taking either product alone. The combination of both represent a natural chronotherapeutic approach to mental health based on the circadian rhythm synchronism and control of homeostasis. They act as time keepers and synchronizers of the body's circadian rhythms. They promote the proper circadian switching and functioning of the daytime catecholamine energy production pathway and the nighttime indoleamine sleep and repair pathway.

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References

1. Soûetre E, Candito M, Salvati E, Pringuey D, Chambon P, Darcourt G. 24-hour profile of plasma norepinephrine in affective disorders. Neuropsychobiology. 1986;16:1-8.

2. Teicher MH, Glod CA, Magnus E, et al. Circadian rest-activity disturbances in seasonal affective disorder. Arch Gen Psychiatry. 1997;54:124-30.

3. Klemfuss H. Rhythms and the pharmacology of lithium. Pharmacol Ther. 1992;10:53-78.

4. Wetterberg L. Lighting. Nonvisual effects. Scand J Work Environ Health. 1990;16:26-8.

5. Wetterberg L. Melatonin and affective disorders. Ciba Found Symp. 1985;117:253-65.

6. Wahlund B, Grahn H, Saaf J, Wetterberg L. Affective disorder subtyped by psychomotor symptoms, monoamine oxidase, melatonin and cortisol: identification of patients with latent bipolar disorder [In Process Citation]. Eur Arch Psychiatry Clin Neurosci. 1998;248:215-24.

7. Beck-Friis J, von Rosen D, Kjellman BF, Ljunggren JG, Wetterberg L. Melatonin in relation to body measures, sex, age, season and the use of drugs in patients with major affective disorders and healthy subjects. Psychoneuroendo-crinology. 1984;9:261-77.

8. Thalen BE, Kjellman BF, Morkrid L, Wetterberg L. Melatonin in light treatment of patients with seasonal and nonseasonal depression. Acta Psychiatr Scand. 1995;92:274-84.

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