Allopurinol for bipolar mania / The brain on uric acid
Drug: Allopurinol (Zyloprim)
Pronunciation: AL oh PURE i nol / ZY lo prim
Mnemonic: “Alli purring”
Principal mechanism: Xanthine oxidase inhibitor
Secondary mechanism: Adenosine modulator
Formulation: 150 mg and 300 mg splittable tablets
Available since: 1966
Popularity: #43 prescribed drug in U.S.
Cost: $8 - $20 /month
❖ Gout prophylaxis
❖ Chemotherapy-related hyperuricemia
❖ Recurrent calcium oxalate calculi
Used off-label for:
❖ Refractory mania
❖ Refractory schizophrenia
❖ Intractable epilepsy
Allopurinol (Zyloprim) is a xanthine oxidase (XO) inhibitor used to reduce urinary and serum uric acid concentrations. The final step in purine metabolism (to uric acid) is catalyzed by XO, so allopurinol interferes with all o’ purine metabolism. Purines such as hypoxanthine and xanthine are found in high concentration in meat products. Allopurinol itself is a purine analog.
Background on gout
Gout is due to persistently elevated levels of uric acid in the blood, which results in the deposition of urate crystals in body tissues. Gout attacks occur suddenly with maximal intensity typically reached within 12 hours. Half of cases involve podagra (Greek “foot trap”), which is inflammation due to uric acid crystals in the the first metatarsophalangeal joint (big toe). Serum uric acid levels may be normal during an attack. Colchicine is used for acute treatment, while allopurinol or probenecid are used for prevention.
Involvement of Adenosine
Adenosine functions as a neurotransmitter involved in promoting sleep and suppressing arousal. See the figure below for the role of adenosine in purine metabolism. Allopurinol increases circulating pools of adenosine secondarily to accumulation of hypoxanthine and xanthine. Caffeine, theophylline, and istradefylline (Nourianz) are methylxanthines that block adenosine receptors. The mood stabilizer carbamazepine (Tegretol) is an adenosine receptor agonist. Electroconvulsive therapy (ECT) leads to upregulation of adenosine receptors.
Allopurinol for Mania
Bipolar mania appears to be associated with purinergic system dysfunction including reduced adenosine neurotransmission. During episodes of bipolar mania, subjects had higher levels of serum uric acid (Bartoli et al, 2016). Lithium, which was used as a treatment for gout in the nineteenth century, increases urinary excretion of uric acid. In the early phase of remission of bipolar mania (whether natural or lithium induced) urinary excretion of uric acid is increased.
Allopurinol is a viable add-on treatment for refractory mania, although evidence is insufficient for routine use of allopurinol for this purpose. Five randomized controlled trials (N=433) demonstrated efficacy of allopurinol for adjunctive treatment of bipolar mania (Bartoli et al, 2016). Allopurinol was well-tolerated and notably effective for severe mania, with small to moderate effect size. Another off-label mania treatment with a small evidence base is tamoxifen (N=69).
Allopurinol for Schizophrenia
Adenosine has been reported to interact with dopamine and glutamate, which are central to the pathophysiology of schizophrenia. Small clinical trials show that adjuvant allopurinol may provide benefit in treatment-resistant schizophrenia (Buie et al, 2006).
Allopurinol for epilepsy
Allopurinol is effective for refractory epilepsy in some individuals. Activation of adenosine receptors appears to have antiepileptic effects. The mechanism of antiseizure effects of allopurinol likely overlaps with the mechanism of antimanic effects.
What about caffeine?
Caffeine causes CNS activation, in part by blocking adenosine receptors—the opposite effect of allopurinol. There are case reports of caffeine inducing mania or seizures, although it appears to be a rare occurrence.
Uric acid and cognition:
In theory, uric acid is an endogenous antioxidant, accounting for about two-thirds of the plasma antioxidant power, which is thought to exert a neuroprotective effect (Tian et al, 2021). Uric acid has a stimulating effect on the brain growth, which theoretically allowed humans to evolve with higher cerebral cortex volume compared with other animals (De Giorgi et al, 2015). Increased uric acid levels appear to correlate with decreased risk of Alzheimer’s disease (Du N. et al, 2016) and Parkinson’s disease (Schlesinger & Schlesinger, 2008). It was theorized that a high purine diet, by increasing uric acid levels, could be beneficial to individuals with neurodegenerative conditions. However, elevated uric acid levels are associated with increased cardiovascular disease risk.
If high uric acids levels decrease risk of Alzheimer's disease, does allopurinol increase dementia risk? A meta-analysis suggested the opposite—decreased incidence of dementia with allopurinol, although eligible studies were few (Lai, Shih-Wei et al, 2022
Allopurinol can cause Stevens Johnson Syndrome. Consider screening those of African American, Han Chinese, Korean, Thai, Native Hawaiian, or Pacific Islander ancestry for the HLA-B*5801 allele before starting allopurinol.
For gout prophylaxis, the maintenance dose is 200–600 mg/day divided QD–QID, starting 100 mg QD and increasing by 100 mg/day weekly until uric acid <6 mg/dL, with maximum of 800 mg/day; For chemotherapy-related hyperuricemia, use 600–800 mg/day divided BID–QID with food x2–3 days starting 24–48 hours before chemo. Maintain urine output >2 L/day with neutral/slightly alkaline urine pH; To prevent recurrent calcium oxalate stones, give 200–300 mg/day divided BID–QID; For bipolar mania, subjects received either 300-600 mg/day (as 100 mg TID, 150 mg BID, or 300 mg BID).
The visual mnemonic framework for pharmacokinetic interactions can be found in Cafer's Psychopharmacology: Visualize to Memorize 270 Medication Mascots.