Antimanic Similarities

In purine theory of bipolar mania, adenosine deficit is felt as decreased need for sleep, while increased G-derivatives cause psychosis and are converted into excess uric acid.

Carbamazepine and oxcarbazepine share chemical structure with diazepam, an apparent adenosine deaminase inhibitor: PMID 1676693. The terminal amine location approximates the adenosine-identifying 6-amino group. Carbamazepine estimated neutropenia rate (0.5%): PMID 18098216 between rates for clozapine and chlorpromazine suggests close fit. (more here)

Carbamazepine is clinically useful in the context of benzodiazepine withdrawal PMID 1686406. Measured effects of CBX/OXC are abolished with addition of adenosine deaminase PMID 25656478, consistent with adenosine deaminase inhibition. The potency of adenosine to induce AV block PMID 1552087 is increased when given with CBZ PMID 1148068, and this effect is also demonstrated in the context of excess CBZ without added adenosine PMID 31523299. Epilepsy researchers have noted with some distress that while CBZ behaves clinically as though it increases adenosine signal, it acts as an antagonist at the A1 receptor PMID 1915589. However, this binding is too weak to supplant diazepam, barbiturates, caffeine, etc., PMID 3097720. Adenosine analogue Sdz-wag-994 immediately displaces CBZ binding at the A1 receptor and was equally effective at stopping seizure-like activity in human brain slices both sensitive and resistant to CBZ treatment PMID 27087530. CBZ antagonism may be outstripped by the much larger impact of adenosine deaminase inhibition.

Lithium inhibits adenylate cyclase: PMID 4191451, increasing available ATP and adenosine. This mechanism was found in 1970, but, without a purine theory of bipolar, was thought only to relate to lithium side-effects.

Valproate is an antimanic medication with unknown mechanism of action. Given in early pregnancy, valproate can cause devastating neural tube (spinal cord and brain) birth defects.

SAM-e is a cofactor in the DNA methylation process that turns genes on and off: PMID 12676953.

Valproate has been shown to inhibit methionine adenosyltransferase in rats PMID 12221238. Pretreatment with methionine (expected to increase methionine adenosyltransferase activity) increases teratogenic impact of valproate in rats PMID 23983167, whereas dietary supplementation with S-Adenosyl methionine (SAM-e) prevents valproate-induced neural tube defects in mice: PMID 32466248.

Similar to lithium, valproate also decreases adrenergic activation of adenylate cyclase PMID 8873110.

Inhibiting methionine adenosyltransferase provides an apparent anti-mania mechanism of action for valproate: inhibiting SAM-e production increases available ATP, increasing available adenosine.

Lithium is a mineral salt chemically dissimilar from valproate, but both are first-line anti-manic agents. The proposed purine mechanisms of action are adjacent.

Valproate use and folate deficiency cause similar neural tube birth defects. It is unclear whether SAM-e dietary supplementation may prevent birth defects caused by folate deficiency or folate-analogue immunosuppressant methotrexate.

Folate is essential for methionine production: methionine is the M-e in SAM-e.

S-Adenosyl methionine (SAM-e) is the primary physiologic methyl-donor: PMID 27184279.  

Carnitine is an animal-sourced dietary supplement that reduces valproate adverse effects: PMID 28425821, possibly by providing an alternative methyl-donor. Treatment with valproate often causes decreased endogenous carnitine PMID 2002205.

Other than dietary restrictions, I am unaware of any rationale not to recommend carnitine with each valproate prescription.