Beyond ‘Beyond Lithium’–Treament-Resistant Bipolar Maintenance, Or Not Staying Put, Part II

This may be shameful to admit, but I trust you’ll forgive me. As far as I could remember when I first came across it in my research on this topic, my familiarity with chromium came from Billy Joel’s “Allentown.” Remember?


“So the graduations hang on the wall/but they never really helped us at all./No they never taught us what was real/Iron and coke, chromium steel./And we’re waiting here in Allentown.”

This is, I promise, directly related to the topic at hand.

To review: we’ve determined in Part I that you’re one of those bipolar people who just won’t stay put. Each time you achieve a modicum of mood stability, and your psychiatrist is ready to dance a jig, you’re off to the races again, flipping from pole to pole. It’s a serious issue, and one that’s hard to treat.

And for whatever reason, you won’t be using or haven’t responded to clozapine, maintenance ECT, or levothyroxine. Just where does that leave us?

Crazy as it sounds, there is evidence that chromium may help alleviate bipolar depression, and, additionally, stabilize mood. Golden & McLeod [all references below] studied the effects of chromium on 8 patients with refractory mood disorders. Here’s where the ‘random-controlled trial’ fanatics, those who hold to the gold standard of research, may have something, though, because, according to the researchers,  “All of the patients experienced clinical remissions, which enabled them to return to more productive levels of functioning without any significant depressive symptoms.” That would officially register as a miracle cure if it wasn’t just a collection of case studies–and not a very large collection, at that.Somewhere close to Allentown, I guess. Because one of the new approaches for treatment-resistant bipolar maintenance is none other than–you guessed it–chromium. Turns out, since I did take high school and college chemistry, that I must have met chromium before–it just didn’t leave a lasting impression like, say, hydrogen, or even helium, did. It can’t be blamed for that, though. It is, indeed, a trace element (atomic number 24, for those of you who are interested), actually a hard metal.

So Amman et al ran a 2-year study–once again, no random-controlled trial standards in place, I’m sorry to inform you, but it has length on its side, at least.

They only took patients who had not stabilized for at least 6 months on treatment that included mood stabilizers, antipsychotics, and antidepressants. The researchers did not cut the medications, rather they used chromium as an add-on therapy.

The patients did well: 6 out of 7 more or less stabilized, and their number of mood episodes decreased over the course of a year. However, the researchers note, in a brutally honest statement, chromium is “too weak to keep most of the patients in our study.”

So they recommend, of course [what am I going to say?], a randomized controlled trial, and also suggest using less severely debilitated subjects.  Despite these two missing factors in their study, though, the author conclude that there may very well be a role for chromium to play in treating bipolar disorder.

But it doesn’t exactly inspire full confidence, really, does it? So where does that leave us now?

Well, perhaps in the same boat as your elderly grandmother who’s been insisting she’s been having a heart attack for years, and finally got her doctor to take notice. It’s no heart attack she’s got–it’s an arrhythmia, or irregular heartbeat.

Let me introduce you to mexiletine, trade name Mexitil

Schaffer et al  ran a study–and I regret to inform you it was not a randomized controlled trial, so if Mexitil helps you, quoting the pioneer study will get no scientist up in arms in excitement–on 20 rapid cyclers (bipolar patients rapidly switching between depression and mania) who had failed (or couldn’t tolerate) the “Big 3” of mood stability: Lithium, Depakote, and Tegretol.

The rapid cyclers were treated with Mexitil for 6 weeks, and, by the end, 46% of the remaining subjects had a full response and 15% had a partial response. Sounds pretty good, I must say, but what do the researchers conclude, being scientists themselves? Well, that Mexitil may be effective for treatment-resistant bipolar patients, but–you guess it here. What’s wrong with their study, which they must point out to everyone?

Aha–the Return of the Random Controlled Trial Standard. This one wasn’t. So–the drug might help, but (and let me quote this): “Randomized, controlled trials are required to confirm the current results.” And as far as I can tell, that was that, until 2007.

When the self-same group ran a study I assume they considered more self-respecting, as it was, indeed, a double-blind, placeb0-controlled study. The only downside? The scales they used to assess improvement seemed to indicate that Mexitil helped–but the numbers didn’t reach statistical significance.  Sometimes you can’t count on those randomized controlled trials.

However, James Chou, in his 2011 “Treatment-resistant bipolar disorder: A review of treatment approaches” still lists it as an option for treatment-resistant bipolar maintenance, as he does chromium–AND vagus nerve stimulation.

Now, I generally have a poor association with the word ‘nerve,’ recalling an unnamed parent saying ‘you’re getting on my very last nerve,’ associating it with the ‘nervous breakdown,’ and having heard the horrible phrase ‘nerve degeneration.’ But I had to do an about-face here, because vagus nerve stimulation has shown promise in maintaining stability for the bipolar suffer.

Vagus nerve stimulation is becoming progressively more common in the treatment of bipolar disorder. Interestingly I could find only one study in a peer-reviewed journal, “A 1-year pilot study of vagus nerve stimulation (VNS) in treatment-resistant rapid-cycling bipolar disorder.” 9 rapid-cycling bipolar patients were treated and assessed for a year with VNS. During the 12-month study, VNS was correlated with a 38.1% mean improvement in overall illness, plus significant reduction in symptoms.In the  most simple terms, vagus nerve (sometimes called ‘vagal nerve’) stimulation, a pulse generator is (and I’m not a big fan of the following words either, although I guess I could come to terms with them, if I had to) surgically implanted in your chest. A wire threaded under your skin connects the pulse generator to the vagus nerve on the left side of your neck. The pulse generator sends out electrical signals along the nerve to your brain, and it’s believed that these signals affect the mood centers of the brain.

And here the side effect profile should get a round of applause, because major complaints were (ready?): voice alteration during stimulation and hoarseness. [If I had to pick that, serious weight gain, osteoporosis, dangerously low white blood count, or potential seizures, it just wouldn’t be that hard of a decision.]

Researchers are a cautious group. What was their conclusion from their results? “These data suggest that VNS may be an efficacious and well-tolerated treatment option for patients with treatment-resistant RCBD [rapid cycling bipolar disorder].”

But I’ve trained you well enough to know what they’re going to say as a caveat, right? And here it is: “Larger randomized trials are needed to verify these findings.”

But in my literature search I wasn’t able to locate larger randomized controlled trials for VNS, so it remains somewhat of an experimental treatment for treatment-resistant bipolar maintenance.

But I bring to you the somewhat unorthodox approaches of clozapine, maintenance ECT, levothyroxine, Mexitil, chromium, and VNS so that you, if you do indeed suffer from the inability to just stay put, once your mood has leveled off, know the following: 1) you have other options beyond unsupplemented mood stabilizers and antidepressants, and 2) new research is being conducted all the time to find a better way to treat you and keep you balanced. There is hope for a stable future–it may lie in the periodical table or Allentown, or it might be in your grandmother’s medicine cabinet, but it’s there, waiting for you.



Amman BL et al. A 2-year, open-label pilot study of adjunctive chromium in patients with treatment-resistant rapid-cycling bipolar disorder.  Journal of Clinical Psychopharmacology 2007; 27(1):104-6.

Chou James. Treatment-resistant bipolar disorder: A review of treatment approaches. Psychiatric Times 2011; 27(7):58-62.

Marangell LB, Suppes T, Zboyan HA, et al. A 1-year pilot study of vagus nerve stimulation in treatment-resistant rapid-cycling bipolar disorder. Journal of Clinical Psychiatry 2008; 69:183-189.

McLeod Malcolm, Golden Robert. Chromium treatment of depression. International Journal of Neuropsychopharmacology 2000; 3:311-314.

Muzina David, Calabrese Joseph. Rapid-cycling bipolar disorder: Which therapies are most effective?  The Journal of Family Practice 2002; 1(3).

Schaffer A, Levitt AJ, Joffe RT. Mexiletine in treatment-resistant bipolar disorder. Journal of Affective Disorders 2000; 57(1-3):249-53.

Schaffer A, Levitt AJ. Double-blind, placebo-controlled pilot study of mexiletine for acute mania or hypomania. Journal of Clinical Psychopharmacology 2005; 25(5):507-8.

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