Depression

Purine Metabolism and Depression

Multi-omics suggests that changes in purine metabolism predict depression treatment response in mouse models and human subjects PMID 27731396. Purine metabolism pathways are also the most directly affected biological pathway in a model of depression induction PMID 40350745.

Low Uric Acid

Symptomatic depression is most often associated with lower uric acid levels PMID 28917195, 22040815, meta-analyses 28620773, 26445247, 26579881.

Symptomatic remission is associated with resolution of low uric acid 28917195, 22040815 meta 28620773, 26579881.

Less severe uric acid deficits are associated with less severe depression: decreased risk of antidepressant treatment, less risk of depression hospitalization 28845530, and shorter hospitalization if hospitalized 32130258.

Depression can be reasonably construed to be related to a purine/ uric acid precursor deficit.

Depression Subtypes

Either hypersomnia or insomnia can occur in depression. Based on what is known about adenosine contributing to sleep PMID 28646346, this suggests that purine-deficit depression can co-occur with either an adenosine deficit or surplus.

This suggests that there may be multiple different purine metabolism changes that result in symptomatic depression, consistent with multiple depression subtypes and variable response to antidepressants.

Direct Purine Supplementation As Treatment

Supplemental inosine has been described as having antidepressant effects in a mouse model PMID 27966087.

Supplemental SAM-e is a well-established, but often overlooked, treatment for depression PMID 38423354, 32939220, 31712971 and is metabolized into inosine.*

While depression is traditionally associated with serotonin deficit PMID XXXX, excess inosine and hypoxanthine in purine-metabolism disorder Lesch-Nyhan Disease are associated with excess serotonin PMID XXXX, suggesting that serotonin levels may be correlated with inosine and inosine-metabolite hypoxanthine levels.

*SAM-e activity as a methyl-donor was an early proposed mechanism PMID 2183633, but is not consistent with more recent evidence PMID 31712971.

Identifying Subtypes and Treatments

Inosine is in the center of a complicated series of purine metabolism steps. For simplification, we can think of enzymes as arrows and jot down the precursors and products.

An inosine deficit is likely to come from either too little production or too much consumption: precursor deficits or product excess. We'll remove IMP as a product excess, since this product circles back as a precursor. Now we'll replace the purine abbreviations with deficit and excess syndromes.

Identifying Subtypes and Treatments

What we see is a map consistent with practitioner experience:

Many practitioners have learned to screen depressive patients for OCD* since failure to recognize OCD may lead to subtherapeutic treatment (SSRI doses tend to be much larger for treating OCD compared to depression) or treatment resistance (e.g. bupropion is not indicated for OCD and is unlikely to be helpful treating OCD-associated depression).
It's commonly understood that inadequate sleep will make depression treatment less effective. The purine hypothesis makes a particular case for addressing sleep initiation problems via anti-cortisol treatments (e.g. clonidine, ashwagandha) and decreased adenosine-blockers (caffeine), which will add precursors to address the inosine deficit, not just provide insomnia relief.
Depression associated with weight gain is traditionally designated atypical depression and is associated with treatment resistance. Targeting reduced conversion of inosine to hypoxanthine via duloxetine, vortioxetine, allopurinol, or eugenol may be particularly helpful in this subgroup.

Importantly, these pathways are connected to specific medication recommendations and warnings: in cases of too much metabolism (e.g. depression associated with weight gain), adding more precursor via dietary SAM-e, inosine or sertraline (see discussion of mechanism below) would not address the root problem and is likely to exacerbate weight gain.

*Sleep and weight-gain correlations are well-supported by the purine literature. OCD association with IMP deficit may be unique to this site.

Purine-mimics as Treatment

Several antidepressants can be considered to have inosine-similar chemical structures, which may facilitate changes to purine metabolism, increasing supply of inosine and hypoxanthine.

Perhaps the strongest chemical similarity to inosine among antidepressants is trazodone, which has clinically important side-effects consistent with purine metabolism changes related to inosine: increasing adenosine (pro-sleep via adenosine deaminase product inhibition) and increasing cGMP (pro-priapism) similar to PDE5 inhibitors, which share the inosine-identifying chemical structure.

*The ring-size is opposite to expectations: 5,6 in inosine is replaced by 6,5 in trazodone. Other psychoactive drugs employ various combinations of 5-7 member rings, although typically with the larger ring carrying the purine-identifying additions.

Avoiding Unwanted Effects

Most antidepressants try to avoid looking too much like inosine in order to avoid unwanted changes in purine metabolim (excessive sleepiness, priapism, etc.). Instead, they use the chemical principle that something next to an O looks like an N and something next to an N looks like an O.

The N at the end of a smooth tail pulls the line into a loop: the CH3 group next to the N mimics the oxopurine-identifying O. This tail is most of the difference between antidepressant imipramine and pro-depressant/antimanic carbamazepine.

Fluoxetine and duloxetine mimic N via an O-bridge below. Duloxetine matches the 5-member ring and uses S, which attracts the N to make the loop more stable.

Sertraline: Chemical Structure and Purine Metabolism Insights

Sertraline is uniquely adenosine-similar among SSRIs. If we consider sertraline to be an AMP-mimic*, there are several predicted effects that align with otherwise esoteric clinical findings. We would predict that sertraline

would be helpful in cases with comorbid epilepsy
- case report PMID 32474383
- product inhibition of adenosine kinase should increase anti-seizure adenosine, consistent with PMID 26830290 which uses sertraline used as a comparator to a new antiseizure medication
would be helpful in cases with comorbid psoriasis
- note structural similarity to PDE4 inhibitor apremilast PMID 26089047, which changes purine metabolism, increasing cAMP to treat psoriasis. Sertraline may account for SSRI-use correlated with less need for psoriasis treatment PMID 23711088, despite fluoxetine increasing the risk of psoriasis PMID 36926437
would potentially be problematic when combined with AMP-similar lamotrigine
- this recognized clinical finding is attributed to as-yet unspecified CYP metabolism interaction
Without an overall increase in adenosine-derivatives, these shifts would reduce dSAM-pathway derivatives, resulting in adenine deficit (here hypothesized to cause akathisia).
- Sertraline-induced akathisia has been observed PMID 8147471, 7962686, 9018398, 8354739, 8253701, 8494087, and can be treated with beta-blockers, which inhibit cAMP production PMID 2478812, 17216434 (and are correlated with psoriasis PMID 2903871, 29387611), diverting flow back to the dSAM pathway and adenine.

*for now, consider a phenyl ring with more than one halide a monophosphate-analogue and a phenyl ring with only one halide as a ribose analogue.

Sertraline: Dopaminergic Effects

Increasing adenosine without blocking adenosine deaminase is expected to increase inosine and hypoxanthine (as well as guanosine and guanine among other oxopurines), rather than acting as a direct inosine mimic.

Consistent with our guanosine and guanine correlations with dopamine, sertraline PMID 20816814 is recognized as dopaminergic. Chemically similar lamotrigine has been shown to be dopaminergic/ helpful in low-dopamine Parkinson's PMID XXXX. These correlations suggest that sertraline and lamotrigine can be helpful in patients with tremor/dyskinesia (guanosine deficit) and delirium/ dystonia/ catatonia/ Parkinson's disease (guanine deficit). Analogously, these agents may contribute to psychosis in patients with schizophrenia or depression with psychotic features.*

Purine metabolism connects these symptoms with the treatment's chemical structure, creating a nuanced picture of potential benefits and problems: this medication is no longer a mysterious black-box or a slice on a spinning carnival wheel. We can now paint a picture of the ideal candidate as well as candidates likely to experience problematic effects.

*All antidepressants are contraindicated in mania. Lamotrigine has a weeks-long titration that limits feasibility of use in mania. A case of SAM-e supplement resulting in mania PMID 2183633 suggests that lamotrigine may be more problematic than therapeutic in acute treatment of grandiose delusions.

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