Phosphorylation, the link between Bipolar and Schizophrenia

When people think of Circadian Rhythms, they think of sleep cycles, or those silly Bio-rhythm horoscopes in the newspaper. Recently however science has shown that even cyanobacteria have clock-like systems in their cells. A recent article on CAIK in cyanobacteria noted that it was involved in the phosphorylation reactions in the bacteria, and created a multi-level timing system that regulated the cell bio-chemistry.

Phosphorylation is important because the cellular energy chemicals AMP, ADP, ATP, GMP, GDP, GTP all operate by attaching a phosphate group, to a reactive substrate, thus releasing the energy of the phosphate bond, which increases the likelihood of related chemical reactions.

Normally these energy chemicals, are protected from reaction by negative charges, but enzymes can increase the speed of a reaction to one of these chemicals, using stereo-chemistry to overcome the static repulsion.

One such enzyme is Adenosine Cyclase. Of interest to human health, is the link between PACAP, a pituitary secretion, and phosphorylation. Both Bipolar populations and Schizophrenic populations have vulnerability to PACAP based risk factors.

In PACAP knock out mice, researchers have found evidence of:

1. Energy level changes
2. Sleep disorders
3. An increase in Anxiety/Depression

The energy level changes, are of course linked to regulation of energy within the cell, The sleep disorders and anxiety are not however as easily explained, unless you accept a cellular circadian rhythm model, based on Phosphorylation

If PACAP's job is to advance phosphorylation, as it's name implies, then there is probably another enzyme that acts to slow phosphorylation. It is the nature of these regulatory chemicals, that true health can only be achieved when there is a balance between the two enzymes. This balance must be struck in such a way that the body stabilizes in a pattern associated with the day/night rhythm.

Failure to regulate the cellular circadian rhythm, results in inefficient bio-chemistry in the cell, and either hyperactivity, or hypoactivity. However, the cellular bio-chemical rhythms, are just one of the factors that is important to health. Evidence of sleep disturbances, in PACAP knockout mice, indicates that regulation of sleep is also affected by this same enzymic balance.

Those silly bio-rhyth horoscopes, are also based on the fact that the body has distinctive rhythms, and that at least 5 major rhythms have been found. These bio-rhythms, are simply cyclical processes in the body such as intellectual, sexual, cycles etc. What is important to note is that when these rhythms are in sync with the environment, the individual is relatively healthy. However consider that some of these rhythms are interdependent, and have other health risks associated with them. When the day/night rhythm of the bio-chemistry of the brain changes, so do these longer cycles, and they increase the risk of disorders related to the longer cycles.

This is why the pituitary tries to regulate the phosphorylation of the brain.

The link to Bipolar and Schizophrenia, lies in the fact that sometimes due to genetic, environmental, or other factors, the complex bio-chemical pathways that regulate these cyclic systems, break down. Like a clock, they often fail by running fast or slow. In essence creating an advanced phase, or a delayed phase, which have sometimes been called early phase or late phase error.

When this happens each cyclic system that fails to synchronize with the environment adds a stress factor on top of their inefficiencies, partly created by the inefficiencies, and partly created by inverse phase, situation where the bio-rhythms effect is to promote an inappropriate response, such as increasing the amount of sweat produced in the winter-time, or increasing the energy level during normal sleep periods.

Bipolar disorder is a periodic disorder that affects mood, The periodicity of the disorder is a clue that it is linked to circadian rhythms. However, people who have had this disorder untreated, or who's treatments have failed, tend to slowly become schizophrenic. Schizo-Affective Disorder is a case in point.

Many people question the connection between Schizophrenia and Bipolar disorder, since schizophrenics are less likely to report depression, than psychotic conditions. However there is a connection, and that connection has to do with the stress the body is under due to circadian rhythms.

Stress itself affects sleep, so there is a chicken and an egg problem that science finds it difficult to resolve, a low grade of sleep disorder does not seem dangerous, so it would not be seen to be germane in a study of major stressors. Psychotic episodes happen only at major stress peaks, so environmental factors might play a role, but if we factor into account the cumulative stress associated with bio-chemical inefficiencies, at multiple levels in the organism, it makes sense that a circadian upset, might trigger periodic stress peaks in the cumulative stress wave. If these stress peaks happen in an otherwise healthy individual, we don't notice the minor sleep disturbance associated with them, so we assume that they are based on some life stress, instead of a genetic anomaly, and relatively minor sleep disturbance.

However finding the PACAP gene as a risk factor in both Bipolar and Schizophrenic populations indicates that the speed of phosphorylation is critical to mental health.