Metabolic Syndrome

Metabolic syndrome is a co-occurring cluster of what had previously been separately measured and separately treated symptoms: insulin resistance (antihyperglycemics), dyslipidemia (statins), and hypertension (blood pressure medications), and excess white adipose tissue (weight loss), contributing to excess cardiovascular morbidity and mortality via stroke, heart attack, and renal failure.

Metabolism is much more complex than calories in, calories out: e.g. ketogenic diet modifies metabolism such that high-fat diet increases lipolysis.

Metabolic syndrome is particularly important to psychiatry due to the unfortunate propensity of some psychiatric medications to causing severe metabolic syndrome.

Metabolic syndrome is also important as a correlate of depression XXXX, autoimmune disorders, etc.

Antipsychotics are known for causing metabolic syndrome 33686614, with some of the best all-purpose antipsychotics correspond to the worst Metabolic Syndrome: 33800403.

Metabolic syndrome agents are also known to have neuropsychiatric effects: verapamil may have clinical use in bipolar disorder XXXX, withdrawal from anti-HTN meds causes anxiety and insomnia 15857353.

Agents used in treatment of metabolic syndrome may also have psychiatric effects: e.g. statins, metformin has antidepressant effects.

HCTZ causes both depression XXXX and clinically relevant insulin resistance/ impaired glucose tolerance: 3243177, chronic Metabolic Syndrome: 18326972, with worsening cholesterol profile: 7669481, Compared to other BP medications, HCTZ, indapamide, chlorthalidone lowers BP more, but NOT risk of Metabolic Syndrome complications (e.g. cardiac arrest, etc.) 12479763. These medications also increase uric acid production, worsen insulin resistance, and increase cholesterol 6869207, HCTZ + verapamil is without additional benefit 2643413 (both activate PNP) 

Methyldopa is a BP medicine that is known to cause depression XXXX and suicidal ideation: decreases endogenous L-DOPA production, but independently acts as a PNP activator, like verapamil.

We knew that some agents had broader impact than addressing the traditionally recognized pathway: for instance, ACEi improve insulin sensitivity XXXX, metformin contributes to weight loss XXXX, hydralazine lowers uric acid 6627763, correlated with metabolic syndrome severity, and also decreases dyslipidemia 6869207 etc.

Biochemically, metabolic syndrome severity is correlated with serum uric acid 26395162. 

Gout is correlated with metabolic syndrome 36415898

Allopurinol augments antimetabolic syndrome effects of ACEi without reference to gout: XXXX

Xanthine’s structure was used as a basis to design treatments for insulin resistance 24900744, 27560285, resulting in DPP-4 inhibitors, with linagliptin including the xanthine-similar structures.  It is easy to imagine xanthine similarities identifying receptors of interest while appendages prevent activation.

Bromocriptine, which shares a xanthine-similar structure, has been repurposed as a treatment for insulin resistance: PMID 20977575.

In both linagliptin (a DPP-4 inhibitor) and bromocriptine, an 8-amino (N) xanthine structure may inhibit purine nucleoside phosphorylase (PNP) similar to 8-amino guanosine and 8-amino guanine analogues.

A variety of phenylethylamines have historically been used for weight loss: phentermine, fenfluramine, aminorex, dexamphetamine, but their use is limited by adverse cardiac and psychiatric effects. It is readily apparent that use of illicit methamphetamine causes significant weight loss.

Recent evaluation of mirabegron, a phenylethylamine that has limited ability to cross the blood brain barrier 24703195, shows simultaneous improvement in insulin sensitivity, lipid balance, and weight loss 31961826.

Caffeine: causes temporary insulin resistance: PMID 11815511, including worse glycemic control in diabetics: PMID 28935543.

Nicotine: association with caffeine in psychotic patients 36470161

In the purine theory of psychosis, antipsychotics act to reduce production of G-derivatives and/or block their action at the D2/D3 receptor.

The final step in production of G-derivatives is conversion of XMP into GMP by GMP synthase. Antipsychotics that directly block this conversion may be expected to be all-around effective at reducing psychosis, but will cause XMP build up.

Antipsychotics that have less PNP inhibition/ more PNP activation are doubly likely to cause metabolic syndrome.

L-dopa: diuresis 10367596, impact on furosemide 8450472, not effective for renal failure 11094464,  Dopamine diuresis/ sodium diuresis 14085064

Purine signaling and metabolic syndrome: i, not x associated with obesity, 

Antipsychotic medications can cause Metabolic Syndrome  (severe weight gain, insulin resistance, worsening cholesterol profile, etc.) to varying degrees: PMID 33686614, but some of the best all-purpose antipsychotics correspond to the worst Metabolic Syndrome: PMID 33800403.

Serum uric acid levels correspond to the severity of Metabolic Syndrome: PMID 26395162, suggesting a purine connection.

In the purine theory of psychosis, antipsychotics act to reduce production of G-derivatives and/or block their action at the D2/D3 receptor.

The final step in production of G-derivatives is conversion of XMP into GMP by GMP synthase. Antipsychotics that directly block this conversion may be expected to be all-around effective at reducing psychosis, but will cause XMP build up.

Xanthine is metabolized into uric acid. Increased X-derivatives (blocked from conversion to GMP) would be predicted to increase uric acid production. Uric acid levels are correlated with Metabolic Syndrome: PMID 26395162.

The physiologic response to excess xanthines may include Metabolic Syndrome changes. For example, caffeine, a xanthine, causes temporary insulin resistance: PMID 11815511, including worse glycemic control in diabetics: PMID 28935543.

Clinically relevant insulin resistance/ impaired glucose tolerance: PMID 3243177 followed by progression to chronic Metabolic Syndrome: PMID 18326972, complete with worsening cholesterol profile: PMID 7669481 is an effect of some xanthine-similar blood pressure (BP) medications, providing additional evidence of a direct relationship between xanthine, BP, and insulin resistance in Metabolic Syndrome. Compared to other BP medications this drug class lowers BP more, but risk of Metabolic Syndrome complications (e.g. cardiac arrest, etc.) less, consistent with xanthine similarity: PMID 12479763 (analysis).

HCTZ + verapamil is without additional benefit 2643413 (both activate PNP) 

Phenytoin, an anticonvulsant, has been shown to decrease insulin secretion in response to glucose load 16527842

Xanthine’s structure was used as a basis to design treatments for insulin resistance, resulting in the class of medications called DPP-4 inhibitors, some of which include xanthine-similar structures: PMID 24900744, 27560285.  It is easy to imagine xanthine similarities identifying receptors of interest while appendages prevent activation.

Sitagliptin, a DPP-4 inhibitor, blocked aspects of olanzapine-induced metabolic syndrome in a short-term RCT: PMID 32701903, suggesting that xanthine mediates antipsychotic-induced Metabolic Syndrome.

Bromocriptine, which shares a xanthine-similar structure, has been repurposed as a treatment for insulin resistance: PMID 20977575.

In both linagliptin (a DPP-4 inhibitor) and bromocriptine, an 8-amino (N) xanthine structure may inhibit purine nucleoside phosphorylase (PNP) similar to 8-amino guanosine and 8-amino guanine analogues. Bromocriptine’s PNP inhibition is also consistent with its limited role in (guanine deficient) Parkinson’s: PMID 3901046.

The 8-amino xanthine structure is shared among a variety of anti-insulin resistance therapies, spanning DPP-4 inhibitors (linagliptin, alogliptin), sulfonylureas (glipizide, glyburide), PPAR-gamma agonists (pio/rosiglitazone), and bromocriptine (above).

It may be that each of these medications acts directly to prevent xanthine production via PNP inhibition (above), in addition to the other named pathways, each of which may have xanthine as its physiologic ligand (agonist/antagonist).

The most recent class of anti-insulin resistance treatments, SGLT2 inhibitors, are xanthosine-similar. It is easy to imagine these agents similarly impairing purine nucleoside phosphorylase-mediated conversion of xanthosine to xanthine.

Canagliflozin is a SGLT2 inhibitor that has two MTPT-similar structures, providing for ample PNP inhibition.

Metformin is the only current member of the biguanine class of anti-insulin resistance agents that remains in use. An alternative member of the same class is phenformin, which was withdrawn due to excess risk of lactic acidosis. Phenformin structure suggests guanosine, indicative of PNP inhibition.

As a guanine analogue, metformin may inhibit PNP: cases of metformin-induced dystonia are reported 21063324, 27193328, but PNP inhibition might be expected to worsen Parkinson's (like statins below) whereas metformin is being repurposed to treat Parkinson's disease: PMID 35008822, suggesting that PNP inhibition is outweighed in some patients by guanine-similarity.

Metformin: PMID 34588212 is commonly used to treat antipsychotic-induced weight gain. Acetazolamide also has been noted to cause weight loss: PMID 30397500 (unknown mechanism) and has a minimal enough side-effect profile that it is a proposed treatment for antipsychotic-induced metabolic syndrome: PMID 30192255. Both may act by product inhibition, reducing conversion of xanthosine into xanthine. Allopurinol PMID 23588856 and ACE inhibitors PMID 19696478 including captopril have also been shown to be protective against metabolic syndrome or helpful in reversing metabolic syndrome.

I recently attended a case that presented with catatonia and unexplained severe hyperglycemia > 400. 

Home medications included olanzapine: diagnoses included Metabolic Syndrome, A1c <6 treated with metformin (discontinued in ED). Elevated CK had recently been attributed to a statin (discontinued) and treated with a prednisone taper: unknown compliance, limited response, continued/completed on admission. Olanzapine was briefly continued, later retrialed, then stopped with worsening CK. Suspected paranoia spontaneously resolved. Insulin (lispro) was given per BG/carbs, then discontinued. No other antihyperglycemic agents were given.

By purine theory, treating catatonia (guanine deficiency) replenishes G-derivatives via conversion of compensatory excess xanthine, simultaneously resolving both catatonia and acute insulin resistance.

Ondansetron was used in this case and shows evidence in animal models of improving metabolic sydrome PMID 26188166.

Statins reduce risk of cardiac mortality, although the risk reduction is not necessarily commensurate with cholesterol reduction or HMG-CoA inhibition, suggesting the need for an alternative hypothesis.

One of the strongest statins, rosuvastatin, shares significant chemical structure with hydrochlorothiazide, which causes increased cholesterol (above). By comparing statins to SLGT inhibitors and their apparent function as a xanthosine-analogue inhibitor of PNP, we might hypothesize that statins are also PNP inhibitors, and that the reduction in xanthine (root cause of metabolic syndrome) is responsible for the reduction in cholesterol and cardiac risk.

Statins have been increasingly associated with psychological wellbeing PMID 12932603 and demonstrate efficacy as an intervention decreasing predilection to depression PMID 35606186 and improving interpretation of stimuli PMID 34872404, and have even shown promise as an adjunct for depressive symptoms: PMID 27148902. This is consistent with similar proposed mechanism to duloxetine. IMG

Consistent with the hypothesis of dystonias (including Parkinson's and catatonia) as a guanine deficiency, and with statins as PNP inhibitors, statin use is correlated with worse Parkinson's symptoms: PMID 27304858. Duloxetine has also been associated with Parkinsonism: PMID 28058376.

While statin use has not been correlated with catatonia per se, there is a recognized statin-induced dystonia which progresses to rhabdomyolysis termed statin-induced myositis.

I recently attended a case previously diagnosed with statin-induced myositis whose dystonia did not respond to treatment for statin-induced myositis, but did respond to treatment for catatonia. IMG

We should avoid glibly assuming that antipsychotic-induced metabolic syndrome can be safely and adequately treated by adding statins and insulin-resistance agents to antipsychotics. Instead, attempt to prevent metabolic syndrome by utilizing other agents whenever possible and trending BP as an early indicator of unsustainable drug regimens.

Several stimulants have been associated with weight loss. Although alternative explanations exist, PNP inhibition by a stimulant, resulting in decreased xanthine and therefor anti-metabolic syndrome may be the simplest hypothesis. Bupropion-induced lack of appetite is blocked by adding xanthine-similar agents PMID 23894096. IMG

Schizophrenia-like symptoms may be induced by various xanthine-similar compounds, which are also implicated in metabolic syndrome. But there is evidence that patients with schizophrenia have some level of (xanthine-mediated?) insulin resistance even prior to initiation of antipsychotics: PMID 19407273.

Sacharine is xanthine-similar, often mixed with cyclamate, which is also xanthine-similar.

Increases brown fat PMID 31961826, which is known to be dependent on inosine-signaling PMID 35790189, reverses dyslipidemia, and increases insulin sensitivity. 

Some ACEi cross the blood-brain barrier (captopril, fosinopril, lisinopril, perindopril, ramipril, trandolapril); some do not cross the blood-brain barrier (benazepril, enalapril, moexipril, quinapril): 22465175

HCTZ is found in CSF 29982257, and is associated with depression, but listed as not crossing the blood-brain barrier in rats 25691927 despite contributing to rat seizures, furosemide does cross the blood-brain barrier.

Xanthine-analogue decreases athlerosclerosis IMG

Xanthosine decreases gluconeogenesis PMID 36627075

Fructose increases hypoxanthine and guanine concentrations, consistent with hgPRT, aPRT, and xPRT inhibition as a PRPP synthetase inhibitor, also increases de novo purine synthesis PMID 36601078. Review of fructose/ua 36230882