Bipolar Mania

The first descriptions of bipolar mania over 100 years ago indicate awareness that changes in purine metabolism are correlated with mania. More recent studies have confirmed that the degree of purine metabolism disruption is correlated with symptom severity PMID 39268307. Purine metabolism returning to normal predicts sustained recovery PMID 31736796: lack of purine metabolism normalization predicts symptom recurrence PMID 29723720.

These studies depend on rudimentary measurement of purine metabolism: amount of uric acid (the sole purine end-product). Since elevated uric acid does not cause mania (lots of gout patients don't have mania), we should be looking at changes to purine metabolism that increase uric acid and may contribute to mania symptoms.

This chart represents the complex purine metabolism pathways. When the body creates purines, it creates IMP. Uric acid is the final end-product. The lower-half of the chart are called oxopurines, while the top-half are adenosine derivatives.

Decreased need for sleep/ circadian rhythm dissolution and grandiose delusions are some of the most characteristic symptoms of mania. These symptoms are tightly correlated in clinical practice: as the sleep cycle is restored, grandiose delusions fade. These core symptoms can be tied to two purines/ uric acid precursors: adenosine and guanosine.

Adenosine initiates sleep PMID 21401496: decreased adenosine may be to blame for decreased need for sleep. Excess adenosine is thought to be the cause of increased sleepiness associated with seizure medications PMID 1915589, including those that can also be used to treat mania.

Guanosine-mimicking medications can cause grandiose delusions and religious delusions in susceptible individuals PMID 19567772, 17651180.

A spike in the stress hormone cortisol may initiate mania symptoms PMID 32521383. The research is limited PMID 690130, but cortisol may inhibit the single purine metabolism pathway converting oxopurines (lower half) to adenosine-derivatives (upper half). The expected result is an increase in oxopurines (including guanosine and uric acid) and a decrease in adenosine derivatives. Small-scale cortisol spikes in athletes are correlated with psychiatric symptoms and increased uric acid PMID 35741598, consistent with this hypothesis.

Cortisol plays a significant role in both bipolar and epilepsy, including contributions to breakthru symptoms and treatment resistance, but is typically not considered in treatment recommendations. Clonidine is a widely available, inexpensive anti-cortisol with good evidence for mania PMID XXXX and epilepsy PMID XXXX treatment/ augmentation. There is evidence that clonidine's mechanism of action includes increasing adenosine signaling PMID 26257930. 

Decreased ATP signaling is typical in mania PMID 32076399. The primary mechanism of ECT may be increasing ATP PMID 21695518: ECT is one of the most direct, effective methods of treating mania. Lithium inhibits an ATP-adjacent enzyme PMID 4191451, valproate may inhibit another PMID 12221238. Carbamazepine may inhibit enzymes converting adenosine derivatives to oxopurines, increasing adenosine derivatives PMID 1148068. 

None of these pathways will be ultimately effective if cortisol continues to inhibit conversion to adenosine-derivatives, suggesting that anti-cortisols may be key to treatment resistance.

Lithium and valproate have been clinically adjacent for decades: their biochemical adjacency in purine metabolism is notable.

Many treatments for mania are also useful for epilepsy. Epilepsy is increasingly understood as a disorder of adenosine metabolism: adenosine is the body's primary anti-seizure chemical PMID 1449242 and chronic adenosine deficiency contributes to the development of epilepsy following injury PMID 35361967. Adenosine augmentation is gaining attention as an epilepsy treatment strategy PMID 18471903.

Effectiveness of mania treatments for epilepsy may be the result of secondarily increased adenosine following increased ATP. This is reflected in growing awareness and consideration of what had previously been considered primarily psychiatric treatments in epilepsy: lithium PMID 35410603, ECT PMID 22531207, etc.

We can use the stimulant methyl pattern to make sense of other recommended treatments for mania and add augmentation strategies.

Lorazepam and oxazepam (common metabolite of diazepam and temazepam) are recommended in mania. Likely mechanisms include preventing adenosine-derivative conversion to oxopurines PMID XXXX and activating conversion of guanosine to guanine. Carbamazepine and oxcarbazepine share enough action with lorazepam etc. that they can be used to mitigate lorazepam withdrawal symptoms PMID XXXX.

Used chronically, lorazepam can increase depression PMID XXXX. I have witnessed a similar effect to chronic carbamazepine and oxcarbazepine. Mania stabilization should be followed by taper/ discontinuation of these agents.

Many of these ideas have been published formally PMID 37820933.