Thyroid/ Akathisia

Thyroid, cAMP, norepinephrine, and stimulants are all tied up together, collectively implicated in akathisia, which is tied to elevated norepinephrine.

Start at norepinephrine: norepi typically increases cAMP via activating adenylate cyclase, in a (xanthine) Ca++ dependent process 7531751. Elsewhere, xanthine analogue allopurinol/oxypurinol has been used to treat psoriasis PMID 4274726, possibly as a xanthine-similar PDE 4,7,8 inhibitor. SSRI-based benefit to psoriasis is supported by meta-analysis, either as a N-methyl adenosine (sertraline/ apremilast) or xanthine (mirtazapine, mianserin, oxypurinol). 

Lithium blocks adenylate cyclase PMID 4191451 (and by decreasing cAMP. can cause psoriasis). 

Paroxetine is expected to block xanthosine/ xanthine conversion in particular: causes akathisia PMID 10742880, 8860197, review PMID 8654061 and causes psoriasis (decreased xanthosine leading to increased PDE activity) PMID 12450972. Buspirone is also xanthosine-similar, known to block Ca++ channels PMID 12552360 and can similarly cause dystonia and akathisia PMID 32191616. Antipsychotics most likely to cause akathisia share xanthosine/ xanthine inhibition (aripiprazole, brexpiprazole, cariprazine). Xanthine reduction, especially by xanthosine-similar amlodipine, can cause akathisia: PMID 28583166 and can cause hypoglycemia, especially when paired with oral antihyperglycemics PMID 34473261.

Xanthine's association with metabolic syndrome, and apparent xanthine inhibition in prevention and treatment of metabolic syndrome suggests that statins and anti-hyperglycemics can also deplete xanthine (psoriasis? akathisia?). Metformin's ability to ameliorate post-methamphetamine dysphoria PMID 35673936 is consistent with xanthine reduction as a mechanism. Stimulants are typically associated with weight loss, possibly via reduction in xanthine, and are also associated with akathisia (e.g. cathinones PMID 36620653), termed "Jonesing." Bupropion's anti-norepi action at adenylate cyclase PMID 6320035, 6312356 may be clinically outweighed by its stimulant-similar anti-xanthine effect, demonstrated effective for weight loss PMID 17187492, 11557835.

Pyridoxine is non-inferior to propranolol for antipsychotic induced akathisia 29796037, and 600mg BID is no better than 300mg BID. Pyridoxine must be phosphorylated prior to becoming active: it may interfere with structurally similar 5-phosphoribose, which is then recycled via HGPRT. If pyridoxine inhibits xanthine to XMP conversion, the increase in xanthine could be the treatment mechanism. Pramipexole may act to inhibit HGPRT and is associated with OCD-behaviors (IMP deficiency) and weight gain in some patients PMID 16261618, but does not seem to significantly affect Lesch Nyhan patients (HGPRT is already inactivated) PMID 21506156.

TSH signal transduction is dependent upon cAMP PMID 6299622: lithium induces TSH resistance/ hypothyroidism. Discontinuation of lithium allows cAMP to be produced normally, typically reversing lithium-induced hypothyroidism PMID 31670617.

Treatment can affect thyroid hormones: 18262705, with some patients responding to treatments that lower T4 (reboxetine), and others responding to treatments that raise T4 (sertraline). Sertraline's use as a PDE4,7,8 inhibitor.

Sometimes upper extremity akathisia is referred to as restless arms syndrome: could restless legs syndrome be alternatively described as akathisia? Treated with xanthine-similar gabapentin PMID 12451200 or xanthine-increasing pramipexole (above) or with guanine-similar ropinirole, although ropinirole's tendency to cause dystonia review PMID 10908503 suggests this may unfortunately decrease xanthine (wt loss is a common listed side-effect).

Vitamin C?

Quetiapine and olanzapine are xanthine-similar and decrease T4 30292780, less strongly affecting TSH 25292398

It may be that TSH tonicly inhibits epi/norepi production: when TSH is low in hyperthroidism, epi/norepi levels increase PMID 9588501. Epi/norepi is expected to increase I and G-derivatives, decreasing X-derivatives, decreasing appetite, weight gain propensity of xanthine (x), common symptoms of hyperthyroidism. IMG

Lithium inhibition of adenylyl cyclase decreases cAMP: TSH signal transduction is dependent upon cAMP PMID 6299622, similar to RAAS signaling. Discontinuation of lithium allows cAMP to be produced normally, reversing lithium-induced hypothyroidism PMID 31670617, as is typically observed. IMG

Beta-blockers are occasionally used in treatment of hyperthyroidism, especially acute thyrotoxicosis: atenolol is preferred for this application. Mechanism of action is unknown, but epinephrine is known to activate adenylyl cyclase: blocking the action of epinephrine on adenylyl cyclase would be expected to decrease cAMP and therefore, to impair TSH signal transduction. IMG

Norepi increases cAMP via adenylate cyclase activation, mediated by a Ca++ channel 7531751 (associated with xanthine)