The Brain Hypometabolism Hypothesis Part 121: Footnote – Garrod and Uric Acid Metabolism


Sir Alfred Baring Garrod (1819-1907)

In a previous post I have written about Sir Alfred Baring Garrod and his influence in the adoption of Lithium in Psychiatry.

The discussion around Garrod’s contribution centres around the hypothesis that the pathological processes occurring in gout extend to the brain and that Lithium would be a suitable therapy. This hypothesis has since been discarded. However it is interesting to review this hypothesis in light of over a century of subsequent research.

We saw in a previous post that the brain has specialised receptors (GLUT receptors) for processing Glucose as well as a number of other metabolites.  When we talk about how the brain processes uric acid, the receptor we need to talk about is GLUT 9.


In their paper ‘Glucose Transporters in the 21st Century‘, Thorens and Mueckler discuss evidence to suggest that GLUT 9 is a urate transporter and is implicated in hyperuricaemia which can lead to Gout and is also seen in Lesch-Nyhan syndrome. Urate is an end-product of Purine metabolism and is usually excreted.

Nevertheless there is this paper which suggests that urate may be neuroprotective (although high levels can also cause neuronal damage). There are also lines of evidence suggesting a possible interaction between Insulin and urate.

Could Urate Play a Role in Mental Illness?

There are many types of mental illness and there are many biological causes of different types of illness. So the short answer is that it would be unlikely that uric acid metabolism did not play a role in any episodes of mental illnesses at all. However the hypothesis that mania always results from an increase in uric acid is false.

A quick search of pubmed using the term “uric acid and psychosis” produces 34 results.

The following Norwegian study examines uric acid levels in 55 people with Bipolar Disorder (manic episode) and 59 people with Schizophrenia and compares them with a healthy control group. The researchers find elevated uric acid levels in people with Mania and Schizophrenia compared with the control group but also that this is not a dose related effect. They do however find a decrease in uric acid in the first two group as they respond to treatment of the illness.

The following study investigated uric acid levels in the cerebrospinal fluid and the researchers found that the levels were 1/10 of the level in the blood. The researchers were investigating both neurological and psychiatric illnesses and remark on an identified increase with L-Dopa treatment and seizures.

The following study finds a decreased level of plasma uric acid in Schizophrenia compared to a control group.

The authors of this paper look at some of the biochemistry of purine metabolism in relation to first episode psychosis.

Using other search terms in medline identified the following studies.

This study finds a reduction in uric acid in people with Depression.

I thought it would be straightforward to find a relationship between Gout and Delirium but there is only one report (using the term “gout and delirium” in medline). Similar combining the search terms “uric acid and delirium” generates only two papers.

Turning to Dementia, there is a meta-analysis by Khan et al. The researchers look at the Dementia subtypes and find that MMSE scores are correlated with plasma uric acid levels only in Parkinson’s Disease with Dementia. Interestingly in terms of the other study looking at L-Dopa treatment and CSF levels of uric acid it is straightforward to generate a testable hypothesis to further explore this possible relationship. In terms of the subtypes of Dementia, the researchers found a reduction in serum uric acid levels in people with Alzheimer’s Type Dementia. This is followed by a discussion of both the possible neuroprotective and oxidative stress related relationships of uric acid at different plasma concentrations.

Lithium and Uric Acid

Turning next to Lithium, is there a relationship with Uric Acid? The term “uric acid and lithium” in pubmed generates 126 results.

This study suggests further exploration of the role of Lithium Carbonate in relation to uric acid calculi.

This paper looks at Lithium toxicity and also references a period of widespread use of Lithium from 1860-1930 (for the ‘uric acid diathesis’) albeit it seems at a lower dosage than that introduced by Cade.

This paper looks at the use of an adjunctive medication usually used for gout in people with Mania who are being treated with Lithium.

This Indian study looks at uric acid excretion after long term Lithium treatment.

Did Garrod Get it Right?

Garrod essentially set up the hypothesis that a number of mental illnesses were due to uric acid (“the uric acid diathesis”) and that Lithium could treat this. We know from the above studies that plasma and CSF levels of uric acid are significantly different, that there are heterogenous relationships with different types of mental illnesses and that treatments may possibly influence uric acid levels.

So whilst Garrod didn’t get it right, he influenced the widespread understanding of a possible biochemical cause of a mental illness as well as the adoption of Lithium which later turned out to be quite useful. Garrod therefore started the conversation which two centuries later is still continuing.

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