Immune Effects

“Almost all classes of [psychiatric medications] have been reported to cause blood dyscrasias” PMID 18098216. Blood dyscrasias are imbalances in blood cell types. This global connection defies compartmentalized explanations.

Purines and their monocyclic cousin pyrimidines mediate blood cell differentiation and survival: PMID 12734342.  Both neural cells and blood cells descend from undifferentiated precursors. It is generally accepted that once mature, fully differentiated cells have limited purine biosynthesis.  Instead, as purines are broken down, salvage enzymes recycle them.

Reliance on salvage pathways makes neurons and blood cells particularly susceptible to purine-based intervention.

Purinosome targets for psychiatric medications provide a potential global explanation for these widespread, although rare, adverse reactions.

Genome-wide association PMID 32093803 and correlation between blood cell types neorological/psychiatric disorders studies have shown significant connections. If, as hypothesized here, mental and psychiatiric illness is often based on purine imbalance, and purine balance also directs blodd cell differentiation, this is a natural correlation. Otherwise, this is mystifying.

NETs are implicated in autoimmune disorders, extracellular conversion from ATP to Ao is implicated in this process 30907983. IMG

Clozapine, an antipsychotic, can cause a temporary immune collapse termed agranulocytosis.  Adenosine deaminase deficiency causes similar general immune system collapse.  Clozapine shares the likely adenosine deaminase binding site with diazepam (discussed previously), as well as the other drugs most commonly associated with this reaction.  Adenosine deaminase inhibition provides a straightforward potential mechanism for otherwise mysterious clozapine-induced agranulocytosis.

Cladribine (2-Cl deoxy-adenosine) inhibits adenosine deaminase: PMID 21463108.  Similar structures in psychotropics may also inhibit adenosine deaminase.  In an active binding site, Cl/F are often interchangeable, but F has a stronger effect.  Several benzodiazepines share a not-quite-2-Cl/F, with F correlating with stronger effect.

Agranulocytosis is caused by the following antipsychotics in ascending order of frequency: ziprasidone, risperidone, then olanzapine, chlorpromazine, and clozapine (see above).  Adenosine deaminase inhibition provides a clear rationale for similar behavior among such different chemical structures as ziprasidone and olanzapine as compared to the those presented: PMID 18098216.

To reduce risk of agranulocytosis with chronic clozapine administration (1-2%/year), low-dose lorazepam vs. lamotrigine co-administration may be protective by providing non-specific adenosine deaminase inhibition: mirtazepine co-administration seems clinically associated with catatonia (e.g. PMID 32318305).

Note that the suffix -a/epine typically suggests a 7 member ring, often with 1-2 nitrogen substitutions, typically similar enough to expect some amount of AMP/adenosine deaminase inhibition.