Seizures

In addition to its role in circadian rhythm/ need for sleep, adenosine is increasingly recognized as the primary physiologic mechanism for seizure-termination and postictal recovery: PMID 32566903.

Diazepam is the preferred agent for acute seizure termination, consistent with diazepam’s apparent adenosine deaminase inhibition.

Electroconvulsive therapy induces seizures as a particularly rapid and effective treatment for depression, bipolar disorder, and catatonia.

One prominent response to ECT in animal models is an increase in adenosine production that occurs rapidly (for seizure termination) and persists (chronic symptomatic recovery): PMID 18775464. Although the changes are likely most prominent in the brain, they also measurable in serum.

Increase in adenosine also explains the increased seizure threshold seen in ECT, including its role as a treatment for seizures unable to be terminated by other means: PMID 22877995. IMG

This increase in A-derivatives following ECT is hypothesized to be the mechanism of action for the improvements seen in ECT: PMID 21695518, even in the absence of a generalized purine theory. This is certainly consistent with apparent adenosine deficit in bipolar mania and frequent responsiveness to ECT treatment. IMG

Other anti-epileptic treatments, especially those also used to treat bipolar, share apparent adenosine-related mechanisms of action.

Other antiepileptic medications are sometimes used off-label for treatment of bipolar symptoms. The primary antiepileptic mechanism may be valproate-similar inhibition of methionine adenosyltransferase, but use may be limited by dissociative side effects attributable to xanthine-similarity. IMG

ECT is also used to treat depression. Adenosine is hypothesized to be involved in the pathophysiology of depression: PMID 33285234. SAM-e dietary supplementation and subsequent increase in adenosine may be the mechanism of action for this emerging adjunct: RTC PMID 32589828, Review PMID 28682528. IMG

Increased cortisol has been consistently linked to depression since the 1980s and reproduced in recent studies: PMID 30844940. The apparent effect of cortisol on adenylosuccinate synthase and proposed effect of adenylosuccinate on CRH receptors ties this association to adenosine deficiency and is consistent with the ECT's proposed mechanism of action above.

However, clinical response to benzodiazepines (BZD), likely adenosine deaminase inhibitors, argues against adenosine as being the primary mediator of depression, since chronic BZD use is associated with worsened depressed mood PMID 32459725 and increased, rather than decreased risk of suicide PMID 9408553, review 28257172. This suggests that the primary modulator of depression is downstream from adenosine: potentially inosine. IMG

Several antidepressants have purine-similar chemical structures or substructures. Citalopram, venlafaxine, and duloxetine all share a general chemical structure roughly analogous to inosine, since the propensity of amine groups is to donate electrons to surrounding atoms, making the methyl-amine similar to inosine's carbonyl group. IMG

We previously deduced the degree of adenosine deaminase inhibition from the reported frequency of agranulocytosis.

The propensity for causing seizures lists some of the same agents in the same order.

It is easy to imagine that adenosine similarity causes improved fit/ inhibition of adenosine deaminase and improved fit/blockade of the adenosine receptor, resulting in increased risk of both agranulocytosis and seizures.

Diazepam directly activates the adenosine receptor in addition to adenosine deaminase activity: PMID 1676693, accounting for a lack of seizure risk and role in acute seizure termination.

Seizure risk is prominent and clinically relevant in clomipramine, chlorpromazine, and clozapine: PMID 11888352, but not in closely related trimipramine, promethazine, and quetiapine. The mechanism of increased seizure risk is not well understood. In each case, seizures are typically avoided by gradual titration.

Note the correlation in chemical structures and seizure risk: it may be that chloride pulls electron density away from adjacent atoms, making them look more like an appropriately positioned (and identifying) 6-amino group. Among the MAOi antidepressants, moclobemide is associated with seizures PMID 9512919 and has an analogously placed chloride group. IMG

Many of the phenothiazines demonstrate elevated seizure risk and carry the correlating chloride. In further evidence that this correlation is causative, the phenothiazine with the least seizure risk is fluphenazine: PMID 11888352, in which halides draw electron density to an adjacent location rather than the problematic chloride location. Sulphur is also expected to draw electron density away, but to a lesser degree, consistent with comparative seizure risk.

Clopenthixol (mixed) and zuclopenthixol (cis-only) are phenothiazine-similar first-generation antipsychotics available as long-acting injectables in other countries. The double bond, replacing a N in phenothiazines, gives rise to trans and cis forms. 

Zuclopenthixol is clinically described as much less sedating and effective at lower doses. When the guanine-similar shape is held constant, the trans and cis forms are identical except for the location of chloride: the more sedating trans-clopenthixol includes the tell-tale chloride, while zuclopenthixol does not. 

Seizure risk may also vary, but has not apparently been directly compared between the two forms, despite the difference in clinical experience. Flupentixol's clinical behavior follows our expectation: it does not demonstrate excess sedation and is prescribed as a mixed enantiomer.

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