I Hate Homocysteine (Also It Is Elevated in Schizophrenia and Bipolar Disorder)

There are some biochemical reactions that are just gorgeous. Poetry. Glycolysis and the citric acid cycle, for example. I used to be able to draw out the whole process, and there was always something very pleasing about doing so. Enter glucose and oxygen and a few other things, and exit energy in the form of ATP, flying off the citric acid cycle like sparkling droplets of water off a spinning wheel.

The folate cycle, on the other hand, is ugly. It plays a starring role in Evolutionary Psychiatry, however, and I have to come to terms with it. There are a zillion components, an army of vitamins, and end-products going every which way - amino acids, neurotransmitters, membrane lipids, and whatever the heck homocysteine is. (seriously - my anchor article for this post calls homocysteine a "non-protein amino acid". What does that even mean?)

Image from Wikipedia

Homocysteine is a by-product of the folate cycle. It is supposed to be recycled back into methionine, but if you are low in certain B vitamins (or, like 10% of people, genetically deficient in certain enzymes that work to recycle homocysteine), you end up with too much of it hanging around. And when that happens, you happen to have a higher risk of all sorts of nasty things, such as heart disease, stroke, hip fractures, and dementia. Turns out that homocysteine likes to cleave the disulfide bridges in cysteine molecules. That doesn't sound so bad, but it affects things you might need, like collagen, for example, which plays a major part in holding bones together and keeping your arteries nice and elastic. High homocysteine *sometimes* goes hand in hand with high triglycerides, high blood pressure (from those stiff, inelastic arteries, one would presume), low HDL, high fasting glucose, and abdominal obesity. All those signs together (or three of them at least, anyway) make up the so-called metabolic syndrome which plagues our Western populations.

The good news is that abnormally high blood levels of homocysteine can rather easily be lowered by B vitamin supplementation. Almost any B vitamin will do the trick - B6, B12, folate, even betaine. That's rather exciting, one would think. Plausible biologic mechanism for a big, big problem. Cheap and simple fix. The bad news is that lowering homocysteine with B vitamin supplementation doesn't seem to make one whit of difference in cardiovascular disease, or at least it didn't in the 3700 Norwegian heart attack survivors who were followed for two years in the last decade (3) or seem help 5500 folks with known vascular disease or diabetes (4).

I don't really care about your hearts or bones. That's not true. I care. But your brains interest me a lot more. A new paper came out this month in Psychiatry Research from researchers in Croatia about high blood levels of homocysteine in patients with bipolar disorder and schizophrenia. And you will not be surprised to know that metabolic syndrome and obesity (and diabetes and heart disease) are more common in these patients than in the general population. While some of the medications used to treat these conditions cause obesity and impaired glucose tolerance, when you really parse the data, there appears to be an increased risk of metabolic syndrome just from having the illnesses, apart from any medication contribution.

(A rather unrelated aside - antipsychotic medications are well known for some pretty disturbing side effects. One of the scariest ones is called "neuroleptic malignant syndrome" where you get a high fever, stiffness, blood pressure spikes, and it can lead to kidney failure and death from muscle injury. One of the fastest treatments for NMS is electroshock therapy, believe it or not. What many people don't know is that schizophrenics institutionalized in the years prior to the invention of medication would suffer high fevers, stiffness, and death (it was called "malignant catatonia"). Now there is no question that the medicines cause NMS, but there is also an additional issue with the dopamine regulation in schizophrenia that could lead to autonomic dysfunction in a serious and fatal way. Just some food for thought.)

Right. Homocysteine. Not only does it degrade important things like bones and arteries, but it also might be able to antagonize the NMDA receptor in the brain (1), which could be a mechanism by which homocysteine itself could cause psychosis directly. It has been suggested that high homocysteine and low folate and B12 are independent risk factors for the development of schizophrenia and bipolar disorder (2).

The Croatians did a pretty simple study. They measured the fasting homocysteine and other signs of metabolic syndrome in patients admitted to their hospital ward with schizophrenia and bipolar disorder. They did not measure serum folate and B12, which is unfortunate, because that would be interesting to know. Oh well. The results? 34.2% of the sample of 60-odd patients had metabolic syndrome. And 67% of those with metabolic syndrome had high homocysteine. Only 23% of participants without high homocysteine had metabolic syndrome. In addition, high blood pressure also independently correlated with high homocysteine, which at least makes biologic sense.

One more little interesting tidbit from the paper - high homocysteine has also been found to be correlated with high omega 6 fatty acid levels in patients with major depression.

The take home? As I said in the Zombieland 2 post, I tend to connect high homocysteine levels with poor nutrition in general. Also, high homocysteine can be caused by a number of drugs and supplements, including niacin, metformin, insulin, corticosteroids, NSAIDs, and some anticonvulsants cause high homocysteine levels too. Chronic high intensity exercise and smoking are also related to high homocysteine. What do we do about it? Having all the B vitamin players on the team can help, so it can be properly recycled. The Norwegians were heart attack survivors - the damage had already been done. Maybe (comparable to omega 3s for mild cognitive impairment = possibly useful vs omega 3s and Alzheimers = a disappointment) homocysteine is something to keep low in the long term as a preventative strategy. Lowering homocysteine did seem to reduce stroke incidence by 25% in the HOPE2 trial. But who knows? We'll have to wait for more studies.

The brain is on the front lines, and metabolic syndrome (or the inflammation behind it) has psychiatric components as well. It is all linked in ways that we only barely understand.