Solving Psychiatry

Psychiatric suffering cries out for understanding: state of the art management predicts an effective treatment in a meager 30% of cases: another third will respond to a later trial and the last third will remain treatment resistant in both psychosis and depression. 

In an attempt to clarify, psychiatry has subdivided diagnoses (schizoaffective disorder vs. schizophrenia, schizophrenia subtypes) and medications (SSRI vs. SNRI), but neither has proved helpful. New treatments are often represented as being part of a new drug class, further fragmenting the psychotropic landscape.

In contrast, symptoms and treatment responses are clearly connected. Like a Rubik's cube, bluntly solving one side can create problems on another side (changing mania into depression or psychosis into metabolic syndrome). 

What if we could understand medications in the way that the body understands them? Not as a first or second-generation antipsychotic (the body can't tell when a drug was patented), but as a chemical with structural similarities that predict function.

Comparing psychotropics, including drugs of abuse and physical symptom-causing molecules can help create a cohesive understanding of psychiatry, allowing for improved prediction and nuance in untangling knots of symptoms.

Purines are a group of signaling molecules fundamental to life. A subgroup of purines are DNA building blocks but purines also have many effects including as receptor modulators and ligands, second messengers, and biochemical co-factors.

Purine metabolism changes one purine to another via complicated cyclical pathways with multiple rate-limiting steps, susceptible to a variety of logjams. In the brain, purine metabolism enzymes are spread out among multiple cell types requiring coordination for basic cell functions. Purines can be subdivided into two categories: (top-half) adenosine-derivatives and (bottom-half) non-adenosine oxopurines, with just a few enzymes that convert between the two categories.

Increasing reliance on reclaimed purines (dotted lines return to the MP column or within the column to IMP) during maturation coincides with the timeline of typical emergence of severe psychiatric illness.

Disrupted purine metabolism is present in a variety of psychiatric disorders including bipolar, depression, psychosis/ schizophrenia, substance use, autism, and dementia. Purines affect the neurotransmitters typically associated with psychiatric disorders: serotonin, dopamine, GABA, etc. Some proposed psychiatric treatments target purine metabolism: some accepted treatments are also known to strongly affect purine metabolism.

Interruptions in the purine cycle create compensatory imbalances: decreased metabolism at one point will tend to result in excesses before that point and deficits after. This may mirror the observation of multiple symptoms that can resolve simultaneously. Purine imbalance could be the "chemical imbalance" of common parlance.

For over 100 years, bipolar mania has been known to alter purine metabolism, causing purine wasting. Recent research affirms that degree of purine wasting correlates with degree of severity (length of hospitlalization) and that purine wasting resolves when mania resolves. Lack of purine wasting resolution predicts lack of psychiatric stability. Since the simplest explanation is also the most likely, we should consider the possibility that mania symptoms are the result of disrupted purine metabolism.

Mania brings together a variety of otherwise disparate symptoms: decreased need for sleep, grandiose delusions, hyper-religiosity, hypersexuality. These symptoms also share strong ties to purines. Need for sleep is modulated by the purine adenosine. Grandiose delusions and hyper-religiosity can be caused in isolation by mimics of the purine guanosine. Purine metabolism is the accepted target of sexual dysfunction treatments (PDE5 inhibitors increase the purine cGMP). Notice that these correlations move in directions that are consistent with compensatory changes in a closed loop system: decreased adenosine and increased oxopurines (guanosine, cGMP, and uric acid).

In lab-based research, mania is associated with decreased ATP signaling. Increased ATP is increasingly recognized as the therapeutic mechanism of non-pharmaceutical mania treatment ECT. Lithium and valproate, two first-line mania treatments, increase ATP by reducing ATP conversion to adenosine-derivatives cAMP and SAM, respectively. Decreases in cAMP and SAM are widely recognized as contributing to side-effects of these agents. The simplest explanation for therapeutic effect is compensatory increase in ATP. 

Downstream increases in adenosine should follow increased ATP, restoring need-for-sleep signaling. If other purine metabolism pathways are unrestricted, excess guanosine and other non-adenosine derivatives (oxopurines) can be metabolized to restore ATP adequacy, simultaneously resolving multiple mania symptoms and purine wasting.

Connections with epilepsy, which has broader acceptance of purine-based pathophysiology and treatment, allowed for a robust examination of this original theory to be published PMID 37820933.

Some purines are psychoactive and available as dietary supplements, including s-adenosyl-methionine (SAM), which has promising early evidence in depression. Some recreational substances are purine-similar, including caffeine (trimethyl xanthine), the world's most popular psychoactive drug. Some prescription medications are purine-similar and notably psychoactive: allopurinol has fairly robust evidence for antipsychotic augmentation and reliable evidence in mania prevention but is under-utilized by psychiatry. 

By considering psychoactive compounds, recreational and therapeutic, as purine-mimics, patterns emerge. Clinical use correlates more closely with chemical structures than disparate drug classes or other descriptors. Connections emerge between otherwise separate realms of medications for physical symptoms, medical causes of psychiatric symptoms, and side-effects. And these connections can be translated back from needed interventions to apparent underlying physiology to find new applications for accepted knowledge.

Although purine profile testing is not available, certain psychiatric and physical symptoms correlate with specific purines. These can be used to formulate an individualized purine metabolism disruption hypothesis, which can be matched with purine-mimic treatments to create a treatment plan that holistically targets both psychiatric and physical symptoms, including chronic medical disorders. Commercially available genetic testing may also identify purine metabolism enzyme variation.

Targeting apparent purine imbalances can simultaneously treat psychiatric and physical symptoms and gradually decrease the need for psychiatric intervention, restoring robust psychiatric and physical health.

With a purine framework, treatment experience (effects and side-effects) can do more than simply include or exclude one agent: it can refine the working hypothesis, provide potential explanations for treatment resistance, and guide selection of the next agent. 

Very few medical disorders/ symptoms are currently attributed to purine imbalances. But purines are evolutionarily ancient and therefore ubiquitous. Psychiatric medications can have a broad range of side-effects, including endocrine (hormone) and immune-system changes. Purine-related disorders may be similarly broad. Understanding purine metabolism may provide guidance for a variety of clinical problems.

This website provides a place to put together what is known about purine metabolism (medical literature and original summary charts) with what is known about a variety of clinical problems and treatments. These theories provide ways to repurpose already-approved medications to provide nuanced treatment beyond what is broadly available. Where possible, I share incidental clinical observations. Detailed understanding of a single symptom may provide some ideas, but the ability to consider the entire pattern of purine metabolism may allow targeted treatments to address multiple disorders simultaneously.

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