Saturday, December 15, 2012

Alternative Therapies and Bipolar Disorder

I will get back to OCD. In the mean time a new paper came out called Nutrient-Based Therapies for Bipolar Disorder, A Systemic Review. And this paper is not written by some press agent working out of the basement of a supplement company. It's the Massachusetts General Hospital bipolar research clinic. I've been in meetings with some of these folks and heard them speak.

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.


  1. Excellent and helpful, thanks!

  2. L-Valine supplementation is thought to deplete serotonin: see second paragraph in Discussion of this very interesting case study:

  3. One of my favorite omega 3 FA delivery tool snack is to buy smoked salmon and eat it with marscapone cream as a cheese rollup. Not only good for the omega 3 but it also enforces ketosis.

    When I make salmon I always buy skin on as this delivers a lot of fat. Salmon steaks have a lot more fat than skinless boneless fillets. They also taste a lot better.

    Trader joes sells chunk salmon that is very flavorful; unlike canned fish it is dry not water packed, which allows the chunks to add to salad as people traditionally do chicken. I also eat them alone with salt because they are very tasty IMO.

    Though flax seed is widely considered worthless I have observed benefits eating it, and I also bake a "bread" of flax seed meal (the other components being ground almonds, eggs, butter/coconut oil, and some protein powder, leavening, erythritol/sucralose and cinnamon). It feels like a hearty bread and eat with marscapone/granular erythritol. Again, dual function omega 3 delivery tool + ketosis enforcer.

    Since fixing my omega 3 problem I not only observe progressively diminishing mood symptoms, but all other aspects of physical health have improved such as a tendency to acne and odd dry/scaly skin, and general mental functions like memory and over all level of calmness.

    It should be first line that all people presenting to crazy doctor start on high dose fish oil in addition to drugs, unless of course they have bleeding disorder (which almost no one has unless genetically abnormal, hypercoaguable diseases/trauma is far more epidemic in our o3 deficient society).

    1. I've seen some interesting thing about flax and some good anecdotes, but research is lacking because no one wants to waste time on non-converters mucking up the mix, I guess.Andy Stoll used to dose people so high they would get fishy-smelling.

  4. Re: l-tryptophan...

    If tryptophan depletion resolves acute mania, why would l-tryptophan be an antimanic agent? Perhaps downregulating enzymatic conversion process to serotonin, or perhaps by excessive metabolism into antiserotonin metabolites? I tend to err toward the latter. You can shut off serotonin by completely ablating tryptophan supply, *or* by grossly overdosing it, which accomplishes the same thing as metabolism shunts it into serotonin antagonism.

    5-htp is widely available which is the same thing as l-tryptophan except more potent, requiring smaller doses for similar effects. Just a few mgs of 5-htp equals a few thousand mg of l-tryptophan in terms of impact on serotonin metabolism.

    My experience with 5-htp is that it is generally a depressant. It definitely affects my mood powerfully, although how depends on season and light availability; in darkness/coldness 5-htp is depressant and can worsen if not outright induce symptoms of atypical/winter depression (if trending that way). In peak sunlight and high temps it can promote insomnia, hyperactivity and excessive mental stimulation... suggesting to me something is quite wrong with how light/temp regulates my serotonin metabolism. Taking 5-htp usually does little to help and actively worsens such a condition, although melatonin directly can help. When my mood/energy is more typical 5-htp is a helpful sedative and seems to promote a lazy, hazy, pleasant outlook the next day...but I do not take it every day because it tends to cause depression when excessive.

    Historically taking melatonin is identical to taking 5-htp (in terms of depressant ability of the substance) except melatonin is more powerful to cause depression, whereas 5-htp requires more time on it/more days of use before I get those symptoms. I am pretty much afraid of melatonin as it has in the past induced negative emotionality/depression like symptoms the next day even after a single dose.

    Although, as stated, I suspect my serotonin metabolism is rather abnormal for whatever reason. Light/seasonal changes are huge triggers for my mood and energy, I virtually expect them and resign myself to them and I only hope to modulate severity/endurance of symptoms.

    Srry for WOT, discard this if more appropriate.

    1. 5-htp makes me nervous, lots of peripheral conversion to serotonin and ? phen-fen or meridia like effects on the valves.

    2. Is there a study showing phen-fen like effects on the valves? SSRIs don't have such effects. I'm nervous, as I take 400 mg daily of 5-HTP. Helps me with anxiety. I am supposedly bipolar II, but could be unipolar w/ ADHD and anxiety.

  5. Hi, this is my first time posting on your blog although I've been lurking for some time. I fully agree with your comment that bipolar type 2 can be hard to distinguish from its differential diagnoses, and to the list (depression + ADHD etc.) perhaps I'd add covert substance abuse as well.

    I wonder if you could tell me what your favourite resources are (textbooks, journal articles) with regards to distinguishing these conditions? It is of interest to me as I'm in the same profession but practising in an Asian country where diagnosing adult ADHD is rarely done.

    1. Hi Nur,

      I don't find most psychiatry textbooks too helpful. They are usually rehashes of the DSM, excrutiatingly boring, and filled with sentences such as "Between 14-70% of patients with anxiety disorder respond favorably to behavioral interventions."

      That said, Goodwin's textbook on bipolar is very good (latest edition was 2007)

      For practical and evidence-based advice, I really like The Carlat Report. I'm a subscriber, but there are many free articles on the website, and you can get the newsletter "a la carte" with CME if you don't want to subscribe for the whole year. I was just doing some CME a couple days ago, and their newsletter on ADHD had a lot of useful tips for diagnosing adult ADHD, including links to free/validated scales.

      Hope that helps! Agree re: covert substance abuse.

  6. Emily - I've specialized in treating bipolar disorder for about 8 years, and have seen a number of my clients improve a great deal - even without meds, on EmPower Plus - vitamin/mineral/amino acid supplement from a Canadian company called TrueHope. There is one psychiatrist I've met in the SF Bay Area who prescribes it regularly to many of her patients, but most doctors wont even consider it. Wondering if you've had any experience with this.

  7. "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 "

    Great idea to mix sardines and tuna! I went in the kitchen and made it straight away with Spectrum Omega 3 mayo w/flax oil. But, good idea to make your own.

    It'sTheWoo, also a good idea to have smoked salmon with mascarpone cheese. Agree that salmon steaks are superior to the fillets. Will check out the chunk salmon from TJ's.

    I'm not bipolar but several people close to me are, so I'm researching as much as I can. Anyway, the food tips are good for me too, of course.

  8. Hi,
    Wondering about the relationship between Schizophrenia and bipolar. A family member suffered for many years from schizophrenia, but recovered 40 years ago by following Dr Abram Hoffer's regimen of large doses of Niacin and Vit C. His hallucinations ended in two weeks, as the Dr said they would. He had lingering depression, which was recently found to be caused by gluten.
    One of his sisters was bipolar. Another sister had mental illness and discovered she can't have dairy.
    It leads me to wonder about dietary causes of bipolar. Has that been studied?


  9. Thank you for posting this interesting and very well researched post. Didn't know there was a connection, will have it in my mind .


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