The research on allopurinol is new but looks quite promising.  Allopurinol (Zyloprim) is an old generic medicine which is widely used to treat gout and high uric acid levels.  It is very inexpensive, as little as $5 per month for 300 mg/day.  Two new studies have each found significant decreases in psychosis from the use of allopurinol for treatment-resistant schizophrenia when it was added to the standard treatment.  In one study with haloperidol, allopurinol also reduced the risk of extra-pyramidal side-effects.

Allopurinol works in the brain on adenosine receptors.  These have the opposite effect in the brain to dopamine.  Allopurinol enhances the adenosine effect, thereby achieving an effect in some ways similar to blocking dopamine function, the primary function of anti-psychotic medications.  Two other medications, diazoxide and dipyrimadole (Persantine), which also enhance adenosine function, have also been shown of value in treating schizophrenia in one study each.  

Allopurinol is generally well tolerated.  If a rash develops, something that occurs for 2% of patients, the allopurinol should be stopped immediately.  A rare allopurinol hypersensitivity syndrome with fever, eosiniphilia, leukocytosis, and multiple organ involvement, especially liver and/or kidney, can occur in a small percentage if the allopurinol is continued.  Such reactions are more common in patients on diuretics (e.g. HCTZ or Lasix) and most such reactions occur in patients who have kidney failure before starting allopurinol. 

Dipyridamole (Persantine) is another inexpensive medication with a low side-effect profile which has a similar effect on adenosine and was shown in one study to help schizophrenia.  Diazoxide is a more expensive drug, also increasing adenosine effect and also reported to help schizophrenia in one study.  Three of the four above studies were all done by the same research team at Tehran University.

Research Studies

Allopurinol (Zyloprim) Helped Treatment Resistant Schizophrenia as Add-On: In a 12-week DB PC crossover study of 35 treatment resistant schizophrenic patients, the xanthine oxidase inhibitor allopurinol (300 mg b.i.d.) when added to anti-psychotic treatment was well tolerated and produced significant improvement in Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general scores, particularly for positive symptoms compared with baseline and with placebo phase. Nine patients improved more than 20% in PANSS total score during allopurinol treatment, whereas none responded in the placebo phase. A Clinical Trial of Adjuvant Allopurinol Therapy for Moderately Refractory Schizophrenia. Brunstein MG, Ghisolfi ES, et al. Federal University of Rio Grande do Sul, Porto Alegre, Brazil. J Clin Psychiatry. 2005 Feb;66(2):213-219.

Allopurinol Helped Treatment Resistant Schizophrenia as Add-On: Adenosine plays a role opposite to dopamine in the brain. Adenosine agonists and antagonists produce behavioral effects similar to dopamine antagonists and dopamine agonists, respectively. Allopurinol, a hypouricemic drug, has an inhibitory effect of purine degradation, enhancing adenosinergic activity. In an 8-week DB PC study of 46 patients with chronic schizophrenia, allopurinol 300 mg/day or placebo were added to haloperidol 15 mg/day. Haloperidol and allopurinol showed a significant superiority over haloperidol alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores. Allopurinol also decreased the risk of extrapyramidal side-effect. Beneficial antipsychotic effects of allopurinol as add-on therapy for schizophrenia: a double blind, randomized and placebo controlled trial. Akhondzadeh S, Safarcherati A, Amini H. Tehran University, Iran. . Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb;29(2):253-9. Ed: 300 mg/d would cost as little as $5 per month, i.e., very affordable.

Allopurinal: Maybe Helped Two in Open Trial: Allopurinol inhibits degradation purines and indirectly enhances adenosine, a purinergic inhibitory neuromodulator which some suspect in the pathophysiology of schizophenia. Both patients had with long histories and multiple meds. Lara D et al: Allopurinol augmentation for poorly responsive schizophrenia. Int Clin Psychoph 01;16:235-7. Porto Alegre. Funded by PRONEX. Ed: Open trials are of minimal value, especially with just two patients. Also, see a crossover study of allopurinol administration to a schizophrenic child. Coleman M. J Autism Child Schizophr. 1974 Sep;4(3):231-40.

Allopurinol Used in Open Trial of Aggression in Dementia: After two elderly with dementia and aggression were given allopurinol improved, the psychiatrists gave allopurinol 300 mg a day orally for 6 weeks (increasing 300 mg every 2 weeks if the response was less than 50%) in six patients with dementia and prominent aggressive behavior who failed to respond to two previous treatment strategies. Five patients improved while on allopurinol (four with 300 mg within 2 weeks and one with 600 mg), apparently without side-effects. Allopurinol for the treatment of aggressive behaviour in patients with dementia. Lara DR, et al. Porto Alegre, Brazil. Int Clin Psychopharmacol. 2003 Jan;18(1):53-5. Ed: Open trials are of very little scientific value and frequently have been shown to be observer bias and not real benefit.

Diazoxide Helped as Add-on in Small Study: The dopamine-coupled adenosine triphosphate (ATP)-sensitive channels may function by hyperpolarizing cells during metabolic stress, a function that may be disrupted in people with schizophrenia. Therefore, application of potassium channel openers/activators may be beneficial in schizophrenia. Diazoxide is a benzothiadiazine derivative related to the thiazide diuretics and a potassium channel opener. In a DB PC study of 42 schizophrenic patients on haloperidol 20 mg/d, those also receiving diazoxide 200 mg/day for 8-weeks showed a significant superiority over haloperidol alone. The diazoxide group a rapid onset of action on the positive symptoms was observed in week 2, whereas in the placebo group there was no significant effect at week 2. No significant differences were observed between the two protocols on the negative scores.  Diazoxide in the treatment of schizophrenia: novel application of potassium channel openers in the treatment of schizophrenia. Akhondzadeh S, Mojtahedzadeh V, et al. Tehran University, Iran. J Clin Pharm Ther. 2002 Dec;27(6):453-9. . Therapeutic benefit of adjunctive dipyridamole in schizophrenia is probably due to adenosine-glutamate interactions. Brunstein MG, et al. J Clin Pharm Ther. 2001 Apr;26(2):155-6. Ed: Diazoxide is an old generic medication which inhibits release of insulin from the pancreas, so can be used to treat hypoglycemia or to counteract excessive effects of oral hypoglycemic diabetes medications. It also causes the muscles in the walls of blood vessels to relax, so can be used to lower blood pressure in emergency situation. Diazoxide is expensive, over $100 per month.

Dipyridamole (Persantine) Helped as Add-on in Small Study: Adenosine plays a role opposite to dopamine in the striatum and adenosine antagonists, like caffeine, produce similar effects to increased dopaminergic neurotransmission in the striatum. In particular, a strong antagonistic interaction between adenosine A2A and dopamine D2 receptors takes place in the striopallidal GABAergic neurones. In a DB PC study of 30 schizophrenic patients, all were given haloperidol 14-20 mg/d. Those on dipyridamole 75 mg/d in addition, did significantly better. Dipyridamole in the treatment of schizophrenia: adenosine-dopamine receptor interactions. Akhondzadeh S, Shasavand E, et al. Tehran University, Iran. J Clin Pharm Ther. 2000 Apr;25(2):131-7. Ed: Dipyridamole would cost as little as $12 per month and have a low side-effect profile.

Allopurinol Review: Allopurinol is a safe and well tolerated drug and is the standard treatment for hyperuricemia and gout, including the first-line treatment in patients with renal calculi, renal insufficiency, concomitant diuretic therapy and ciclosporin (cyclosporine) therapy, and urate overproduction. Drugs. 2004;64(21):2399-416. However, it can cause a serious exfoliative rash, a sign of allopurinol hypersensitivity syndrome. Allopurinol must be stopped at once in the 2% developing a rash, as there have been rare cases of fatalities. Impaired renal function, ampicillin and thiazide diuretics increase the risk of serious hypersensitivity reactions. Tidsskr Nor Laegeforen. 2004 Oct 21;124(20):2618-9. Allopurinol may actually help survival in heart failure (Circ Res. 2004 Nov 12;95(10):1005-11) as well as heart attacks (Circulation. 2004 Oct 12;110(15):2175-9).  It reduces mortality in heart bypass surgery (Ann Pharmacother. 2003 Nov;37(11):1708-11). It might also help recurrent herpes labialis. J Med Dent Sci. 2003 Jun;50(2):147-54.

Allopurinol: Adenosine A2a Receptors Increased in Schizophrenia: The reciprocal antagonistic interactions between adenosine A2a receptor (A2aAR) and the dopamine D2 receptors. Adenosine A(2A) and dopamine D(2) receptors have been shown previously to form heteromeric complexes and interact at the level of agonist binding, G protein coupling, and trafficking. Because dopamine D(2) and D(3) receptors show a high degree of sequence homology, A(2A) and D(3) receptors may also interact in a similar manner. Mol Pharmacol. 2005 Feb;67(2):400-7. Adenosine A (2A) receptors have been implicated in the pathophysiology of schizophrenia by clinical, anatomical, biochemical and genetic studies. The density of adenosine A (2A) receptors was investigated in human postmortem striatum of patients with schizophrenia (n = 9) and matched controls ( n= 9). The maximum number of binding sites (B) (max) was 70% higher in patients with schizophrenia than in matched controls (609 vs. 354 fmol/mg protein, p=0.04). The increase in receptor density correlated with the dose of antipsychotic medication in chlorpromazine equivalents (r =0.61, = 0.014). This supports a role of adenosine A (2A) receptors in the molecular effects of antipsychotic drugs. Up-regulation of striatal adenosine A(2A) receptors in schizophrenia. Deckert J, et al, University of Wurzburg, Germany. Neuroreport. 2003 Mar 3;14(3):313-6.

Allopurinol: Adenosine A2a Receptor Knockout Increases Anxiety: Adenosine A(2A) receptor knockout mice have anxiety, aggressiveness in males and a paradoxical response to caffeine. This is similar to the effects of functional antagonism of adenosine A(2A) receptors in humans and rodents. Increased anxiety in patients with panic disorder and increased psychotic symptomatology in patients with schizophrenia have been observed after caffeine administration. Recent genetic studies of panic disorder suggest an involvement of adenosine A(2A) receptor gene variation. The adenosine A(2A) receptor knockout mouse: a model for anxiety? Deckert J.University of Wurzburg, Germany. Int J Neuropsychopharmacol. 1998 Dec;1(2):187-190.

Allopurinol Review: Allopurinol is rapidly converted in the body to the active metabolite oxypurinol whose total body exposure may be 20-fold greater than that of the parent compound due to a much longer elimination half-life. Allopurinol undergoes several pharmacokinetic interactions with concomitant administered drugs, some of which may be potentially hazardous (especially with mercaptopurine and azathioprine). Contrib Nephrol. 2005;147:35-46. Impaired renal function, ampicillin and thiazide diuretics increase the risk of serious hypersensitivity reactions. Tidsskr Nor Laegeforen. 2004 Oct 21;124(20):2618-9.

Minor hypersensitivity reactions to allopurinol presenting as skin rash occur in approximately 2% of patients. A more severe, albeit quite rare, hypersensitivity reaction with fever, eosinophilia, dermatitis, renal failure, vasculitis and hepatic dysfunction carries a mortality of up to 20%. The incidence of this severe reaction can probably be reduced by adjusting the dose of allopurinol in patients with impaired renal function. Azathioprine and mercaptopurine are metabolised by xanthine oxidase, the enzyme that is inhibited by allopurinol. Concomitant administration can result in life-threatening neutropenia unless the dose of allopurinol is reduced by approximately 75%. The uricosuric agent benzbromarone has recently been withdrawn from the market because of several cases of fulminant hepatic failure with subsequent death of the patient or liver transplantation. Ther Umsch. 2004 Sep;61(9):575-7. Allopurinol causes rare cases of toxic epidermal necrolysis and Stevens-Johnson syndrome. There is a case of granulocytosis reported.

Uric Acid Elevation May Be Harmful: Elevation of serum uric acid is related to the onset of essential hypertension in children, reduced birth weight, and endothelial dysfunction. Normalization of uric acid appears to ameliorate new onset essential hypertension. Kidney Int. 2004 Jul;66(1):281-7.

Uric Acid Elevation Worsens Heart Failure: Hyperuricemia is a constant finding in CHF. The xanthine oxidase metabolic pathway increasingly is appreciated as an important contributor to both symptoms of CHF as well as progression of the disease. Recent data suggest hyperuricemia to be an independent marker of impaired prognosis in CHF. Uric acid in chronic heart failure. Doehner W, Anker SD. Humboldt University, Berlin, Germany. . Semin Nephrol. 2005 Jan;25(1):61-6. Survival in mice with heart failure was doubled by allopurinol. Circ Res. 2004 Nov 12;95(10):1005-11.

Heart Failure Endothelial Dysfunction Helped by Allopurinol:

Peripheral Circulation Helped by Allopurinol in Heart Failure Patients: In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow.  In 10 CHF patients with normal serum uric acid (UA) levels (315 micromol/L) and 9 patients with elevated UA (535 micromol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 microg/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (P<0.05). In a 1-week DB PC crossover design, allopurinol 300 mg/d reduced UA by 217 micromol/L, P<0.0001. Compared with placebo, allopurinol improved peak blood flow (in arms (+24%, P=0.027) and legs (+23%, P=0.029). Flow-dependent flow improved by 58% in arms (P=0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (P<0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (r=0.63, P<0.05). Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Doehner W, et al. Imperial College School of Medicine, London, UK. Circulation. 2002 Jun 4;105(22):2619-24.

Uric acid causes endothelial dysfunction when infused into the human brachial artery. Endogenous uric acid concentrations correlate with endothelial dysfunction. In numerous population studies, uric acid has been shown to be an independent predictor of mortality, including one large study in patients with chronic heart failure (CHF).

Uric Acid Elevation Predicts Hypertension: Several epidemiological studies have shown a positive association between serum uric acid levels and the risk of hypertension. In a prospective study with 23 years of follow-up of 4,489 adults who did not have hypertension, 289 developed hyptertension. Multivariate analysis found a 48% increased risk in men with hyperuricemia and 90% in women (OR = 1.48 and 1.90(p <0.05, respectively). Hyperuricemia as a predictor of hypertension in a screened cohort in Okinawa, Japan. Nagahama K, et al. University of the Ryukyus, Okinawa, Japan. . Hypertens Res. 2004 Nov;27(11):835-41.

Allopurinol: First Report?: A crossover study of allopurinol administration to a schizophrenic child. Coleman M. J Autism Child Schiz 1974 Sep;4(3):231-40.

Overdose Not Fatal in One Case of 200 Tablets: A patient with gout and schizophrenia is described who during a schizophrenic paroxysm with paranoid-hypochondriac-hallucinatory syndrome attempted to commit suicide and took 200 tablets milurit (20 g). He developed the picture of acute intoxication with nausea, vomiting, profuse diarrhea, abdominal pain, flushing, temperature, collapse manifestations, hepatomegaly, direct hyperbilirubinemia, elevated transaminase, leukopenia, accelerated ESR. After reanimation and infusion therapy, the patient recovered within 4 days and 2 weeks later all blood indices reached the limits of the norm. Acute allopurinol (milurit) poisoning. Chakurski I, et al. 1985.

Thomas E. Radecki, M.D., J.D.

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