Bipolar Mania

Bipolar mania is a clinical syndrome that includes a curious collection of symptoms: decreased need for sleep/ circadian rhythm disturbance, psychosis (delusions or hallucinations) and sometimes hypersexuality, usually lasting days to weeks.

Symptoms are reliably treated with medications, and respond to treatment together (i.e. a single medication may be adequate). There is no known biochemical basis for bipolar mania: no identified medication target.  IMG

One of the few biochemical hints about bipolar is its association with increased uric acid, first noticed more than 100 years ago. More recent studies show that the connection is tight: More severe bipolar symptoms correlate with higher uric acid levels: PMID 24382179. Poor uric acid control is linked to symptom recurrence: PMID 29723720. Bipolar patients whose symptoms have resolved have lower uric acid levels than they did when symptomatic: PMID 31736796.

Most patients with increased uric acid don’t have bipolar (e.g. patients with gout). Uric acid is typically considered an end product of purine precursors: what if imbalance of certain purines cause bipolar symptoms?

Although other psychiatric problems have been correlated with increased uric acid, the degree of excess differentiates bipolar from depression PMID 32686367.

There are 4 main classes of purines: A, I, X, and G.

Each class has a number of modified purines: for example, adenosine has a ribose, adenine does not. AMP has a phosphate connected in one place, etc.

Purine classes are identified by the groups added at the 2 and the 6 position: 6-amino (N) is an A-derivative, 6-oxo (O) and 2-amino (N) is a G-derivative, etc.

Purines are made from scratch as the cell matures, then mostly recycled/ interchanged thereafter.

Longdaysin is an adenosine-similar drug used in labs to modify circadian rhythm. It works in animals across the evolutionary tree: fruit fly, zebrafish, mammals, etc.

Longdaysin shares the purine backbone and the 6-amino (N) site that identifies adenosine derivatives.

In a recent discovery, a colored-light-activated switch changes modified-longdaysin’s chemical structure to hide or reveal the 6-amino site in living (transparent) zebrafish, giving researchers ability to adjust sleep/wake cycles in real-time: PMID 34039965.

This provides some of the most direct evidence yet that adenosine derivatives (identified by the 6-amino site) controls circadian rhythm/ need for sleep.

The pharmaceutical class that includes longdaysin, small molecule/ non-protein circadian rhythm modulators called CK1 inhibitors, typically share a purine-similar backbone and an adenosine-defining 6-amino group: PMID 31931005.

Adenosine likely promotes sleep as a physiologic CK1 inhibitor and by directly activating the adenosine receptor.

In humans, the connection between adenosine and need for sleep is most commonly experienced during caffeine consumption: caffeine temporarily decreases need for sleep by blocking the adenosine receptor: PMID 20164566.

Decreased need for sleep/ circadian rhythm dysfunction could be caused by inadequate adenosine (limited production or excess breakdown) in bipolar mania.

Because purines are typically interconverted, less A-derivatives means more I,X,G-derivatives.  Uric acid is created from I,X,G derivatives.

Increased uric acid and decreased need for sleep may be compensatory signs of the same imbalance.

What about psychosis and hypersexuality? Are there purine connections there?  IMG