Psychiatry in Boston (and the East Coast) is such a funny mix of psychoanalysts and rigidly conservative psychopharmacologists. Apparently on the West Coast things are a little different, with more acceptance of polypharmacy and supplements. But from the center of the most conservative bastion of psychiatry from the 1930s-60s and some of the busiest depression and bipolar pharmaceutical clinical researchers on the planet comes some really cool work with supplements and alternative treatments. I'm a big fan of Neirenberg and Fava over at MGH and their work with alternative therapies. They have open minds and scientific eyes.
Tame Impala: Feels Like We Only Go Backwards
Let's get to it. Bipolar disorder can be difficult to diagnose and more difficult to treat. I try not to judge too much when someone comes to my office with a "bipolar II" diagnosis on the newest, most expensive antipsychotic and a mood stabilizer when they really have depression plus ADHD and/or anxiety symptoms and/or a history of being traumatized. All the diagnoses in the DSM are from the symptom level up, not from the brain pathology down, so things are messy. But despite all that there are plenty of honest-to-goodness bipolar folk who benefit from mood stabilizers� but 54-68% of appropriately treated folks continue to experience subthreshold symptoms, and side effects continue to be a major problem.
Omega 3 fatty acid supplementation may be useful not only for brain health but for physical health. (Of course I personally prefer limiting the omega 6 consumption and eating a nominal amount of cold water oily fish weekly�[practical aside here] one trick is to make tuna salad with 2 cans of light tuna, one can of sardines, celery, pickles, carrot, onion, spices, and your own olive oil mayonnaise (I use the olive oil recipe from Well Fed which is still my favorite "paleo" cookbook, though Eat Like A Dinosaur is great for kid-friendly meals and Primal Blueprint Quick and Easy Meals is also a staple).
Individuals with bipolar disorder are more likely to be obese, less likely to cook their own meals, and more likely to eat sugary foods. And, according to a recent paper (1) looking at the nutrient intake of people with bipolar disorder, they tend to consume food with lower levels of thiamin, riboflavin, folate, phosphorous, zinc, vitamin B6, and vitamin B12 compared to the population norms.
Omega 3 fatty acids work by increasing membrane fluidity and normalizing signal transduction, reducing inflammation, and activate nuclear receptor effects. In bipolar disorder, the first studies were done by Andy Stoll of high doses (around 10g), and over a period of 4 months, there was significantly less depression and higher levels of global functioning. EPA + DHA has the most data, and the amount used in various studies� vary a great deal. ALA (flax oil) was not found to be useful, nor was DHA alone. Mania doesn't seem to be affected, only depression and general functioning symptoms, and the effect sizes are not strong enough and the intervention not studied enough to take in lieu of regular pharmacologic treatment for bipolar disorder. However, as an adjunct, the risks may be very low compared to possible benefits.
Inositol has also been studied several times (but all small sample sizes) in bipolar depression. (See my earlier post for the mechanism.) Again, as an adjunct, it seems to have some promise for depression, but we need larger sample sizes.
Choline might be helpful by improving and increasing the efficiency of brain energetics. The brain is hungry for ATP (the energy currency of the cells), and in many neuropsychiatric disorders including bipolar disorder, energetics seem to be impaired, possibly by inflammation and oxidative damage. Choline is the main reason (along with all those delectable B vitamins and general yummyness) that I think advice to toss out the egg yolks is idiocy. All the randomized controlled studies of choline supplementation in bipolar disorder are small, and of complicated patients (for example, rapid cycling bipolar and cocaine dependence). One small open label trial by Stoll did demonstrate some benefit for mood.
Magnesium deficiency, as I've discussed in the past, is quite common in the general population. Signs of deficiency include irritability, fatigue, insomnia, loss of appetite, mental confusion, and a vulnerability to stress. Magnesium also has some effects on neurotransmission that are similar to mood stabilizers lithium, valproate, and lamotrigine. There are some small studies of manic patients doing much better with adjunctive magnesium added (one was oral magnesium oxide, the other injected magnesium in severely manic patients). There is only onse study of magnesium as a monotherapy, and 40 meq daily did reduce mania in rapid cycling patients.
Chromium (I haven't written anything on chromium yet� should get on that) seems to improve insulin sensitivty in the hypothalamus and affects the monoamine neurotransmitter systems. Enhanced hypothalamic function may increase the release of serotonin, norepinephrine, and melatonin. There are a few studies showing efficacy in unipolar depression, but not atypical depression, and in the one study of bipolar disorder, there were lots of drop outs.
Folic acid has been studied only once in bipolar disorder, in conjunction with valproate (which interferes with folate metabolism). It seemed to be helpful, particularly for cognitive symptoms. There are more positive studies in unipolar depression, and there's no reason to think it wouldn't be helfpul in bipolar depression (though there are reasons to think folic acid might be an inferior supplement to l-methylfolate, they have not had head to head studies in depression as far as I know).
Rapid tryptophan depletion will decrease serotonin levels in the brain. It can be achieved fairly readily using a tryptophan-depleted drink (see this post for more details). In Canada, it is actually approved as adjunctive therapy to lithium in acute mania, and another study of manic patients showed it might be helpful, but 23% of patients couldn't tolerate the drink. L-tryptophan itself also looked like a promising antimanic agent in a small study of 24 patients (12 grams daily, looks like, for two weeks). However, after it was banned by the FDA in 1989, further studies have been lacking.
In general, nutritional supplementation to current therapies may work synergistically with the therapies (such as folate and valproate), and for many therapies (excepting perhaps chromium and rapid tryptophan depletion), the side effects and risks seem lower compared to the conventional therapies or combining conventional therapies, which is often done with resistant cases now. More larger studies of some of these combination effects would be great to help us clinicians in the field have a larger tool kit from which to work. In addition, the nutritional therapies haven't been tested with consistent dosing or in consistent populations to really give us a sense of optimal amounts or usage. Their potential coud be fantastic.
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