The Newest Treatments for Treatment-Resistant Bipolar Depression: Part II, The More Natural Route

by on June 30, 2013

So we know from last post that bipolar sufferers spend more time depressed than manic (in a three-to-one ratio), and that with that depression comes lost days per sick worker, a loss to the U.S. labor force in the billions—and the highest suicide rate for any psychiatric disorder.

On the other hand, as we also saw, there are numerous compounds in clinical trials—and some of which are already in use by certain, more experimental psychiatrists.8243497_s

But what’s most unfortunate about many of the medications used to treat bipolar depression (as is true of so of the medications used to treat so many diseases), is that their side effect profiles are plain lousy. Remember Zyprexa, part of the package (one of only two) approved to treat bipolar depression? Weight gain is so common that up to 22.2% of adults experience it when taking the drug. The other approved med, Seroquel? Up to 52% have reported experiencing sedation or somnolence on it. That’s not to get into a whole slew of other symptoms dealing with the metabolic, endocrine, respiratory, or musculoskeletal systems.

So it’s no surprise that researchers would look to more natural substances in their fight against resistant depression that’s so resistant to remitting. And here’s what they’ve found.


N-acetyl-cysteine (NAC): You'd think writing about N-acetyl-cysteine (NAC) would have been fairly easy, given how many people are familiar with it—or already taking it as a supplement.  Well--you'd have thought wrong.

Medscape--usually my friend in these situations--failed me here.  It illuminated the matter this way, "NAC is a cysteine analogue shown to effectively raise plasma levels of the primary antioxidant, glutathione. NAC also modulates cytokines, glutamates neurotransmission, and enhances neurogenesis" (Brauser 2011). Aaah. There you have it.

But it really isn't that bad. Let's start at the very beginning (a very good place to start). A cysteine is just an amino acid (remember those? the building blocks of proteins?) --and not even an essential one (and for our purposes the word 'analogue' isn't that informative here--it means our NAC is still working hard to raise those plasma levels).

Glutathione is a biggie--but I'm really hoping glutamate rings a bell here (hint--perhaps from our discussion of riluzole last time?).

At any rate glutathione is a tripeptide  (I hesitate to state the obvious but a tripeptide is a peptide made of--no guessing here—three) amino acids: cysteine, glycine, and glutamate, joined by peptide bonds, made by your liver--and also sold in dietary supplement form, as what isn't today?

The tripeptide glutathione (gamma-glutamylcysteinylglycine, referred to as GSH) is the primary endogenous free radical scavenger in the human body. When GSH levels are reduced there is an increased potential for cellular oxidative stress (Whoa--sounds bad, but all that phrase means is when extra stress is put on an organism by the increase of. . .[you could guess this here; who's always the bad guy, in all body adventures?].  . .free radicals [to, be short, the lousy characters who cause cell damage]).

Researchers point out that when GSH levels drop there is a greater possibility for oxidative stress. Fairly recently, it seems, they’ve also discovered that increased oxidative stress has been implicated in the pathology of bipolar disorder.

However, all is not lost on the GSH front. It turns out that NAC is, as researchers put it, "a safe, orally bioavailable precursor" (Berk 2008) of GHS. So the hypothesis was simple enough: Give subjects NAC--see if it replenishes the GHS in their bodies--and if that makes enough of a difference in mood and symptomatology in those with bipolar depression.

Professor Michael Berk (Deakin University in Australia) believes enough in the power of NAC that he's run full-scale studies--twice. In 2008, looking at 75 subjects, he found that "benefit was evident by 8 weeks," which I guess encouraged him enough to round up everyone again (a number of the same authors appear, although about 7 more show up on the 2nd research paper, which, I'm hoping is a good sign), get together 149 depressed folks with bipolar, give half of them NAC, half of them placebo, and to find that "Improvements in functioning and quality of life were similarly evident" (Berk 2011), the second time-round. Sounds pretty good.


Agomelatine: Known variously as Voldoxan, Melitor, or Thymanax, agomelatine was developed by the French pharmaceutical company Servier, with Novartis having acquired the rights to further develop and market it in the U.S.

Although this may not mean much to the average layperson, researchers were quite excited when they discovered that they had on their hands the very first "melatonergic antidepressant.” That means it interacts with both subtypes of melatonin receptors, MT1 and MT2--and, for extra fun—it also operates as a 5-HT2C antagonist. This all sounds more complex than it is (kind of).

Available as a dietary supplement since the 90s, melatonin’s link to sleep has been recogniezed by researchers since the 50’s. Given that sleep disruption is one of the major symptoms in depressive disorders (Srinivisan 2012), scientists continually look for an antidepressant to manage the sleep-wake cycle.  Enter melatonin, a hormone whose major job is just such regulation of the cycle. Sometimes our bodies need a little boost in production, or we need--since we're talking fancy science talk--a melatonin receptor agonist--which just means something that will bind to and encourage the melatonin receptors (recall our friends MT1 and MT2) to take their jobs more seriously and make some more melatonin.

That's basically the first part of what agomelatine does.  Now to the 'antagonist' component, which sounds rather unfriendly, put turns out to be fairly helpful for those suffering from depression. 5-HT2C receptors regulate mood, appetite, anxiety  and endocrine secretion--all of which have been linked with depression (Millan 2005). These receptors release two well-known neurotransmitters: dopamine and norepinephrine, the feel-good transmitters. Apparently that 'antagonism' by agomelatine of the 5-HT2C receptors yields an increase in production of dopamine and norepinephrine (particularly in the frontal cortex, in case you didn't feel this was all technical enough), and. . .viola. . .relief from depressive symptoms.

As recently as 2013 (granted, with no placebo or double-blinds) a study has been published supporting  in 'real life' all this complicated theory: In it 82.4% depressed bipolar patients on mood stabilizer Depakote and 90.9% of those on lithium showed a clinical improvement when given agomelatine as an adjunct (Fornaro 2013). 


Inositol also known as Vitamin B8, is a sugar alcohol with 9 varieties--of which myo-inositol is by far the most abundant--found mostly within cell membranes.  It's a big deal in the body, kind of like the most popular kid when it comes to relaying messages, as every one of the major neurotransmitters (aren't you glad you're an expert in neurotransmitters now?) uses it to get their messages across. Those are some important messages, too, as they play a role in balancing body chemicals in order manage conditions as variable as polycystic ovary syndrome to panic disorder--and, of course, bipolar depression.

So far so good--but, notably, depressed people have been found to have lower than normal levels of inositol in their spinal fluids, and autopsies of brains of bipolar suicides consistently indicate decreased myo-inositol levels. One theory is that manic episodes actually cause the brain to wear itself out of the compound. But, came the obvious question, would supplementing inositol levels help?

It seemed worth a try, so in 2000, researchers assigned half of 24 depressed bipolar subjects to receive either 12 g of inositol or placebo for 6 weeks, during which time they stayed on their mood stabilizers. On a major depression rating scale, 67% of the patients who took inositol had a 50% or greater decrease from their depressed baseline scores--as opposed to 33% who took placebo.

The numbers were hardly overwhelming, and initial researchers were just cautiously optimistic. However, they were particularly pleased with the drug's tolerability and the fact that it was a 'natural substance' (Chengappa 2000).  But tepid as the initial data may have been, later studies  were downright disappointing, with two studies from 2006  hardly serving as cheerleaders for the compound. Evins et al found that "on average, inositol was not more effective than placebo as an adjunct for bipolar depression" (2006), and a second trial that year was also underwhelming, finding that lamotrigine (Lamictal) basically whipped inositol on all accounts: recovery rates, functioning levels--even more patients stayed in the study if they were on Lamictal as opposed to inositol (Nierenberg 2006).

It would be enough to make you despair completely that doctors will ever use the supplement, but I leave you with a quote from a 2010 case study of inositol, where the researchers --either quite bravely, or in desperation--discontinued a bipolar woman's mood stabilizer and just used inositol to mange her illness. They concluded (ready?), "we consider . . . the 4 years of follow up assessments of this patient as a satisfactory time period for concluding that inositol has been a very effective treatment, replacing lithium, for mood stabilization. . ." (Kontoangelos 2010).

You never know.


Levothyrhoxine  Most people get their thyroid levels checked every so often, when they get around to their "yearly" physical, and that's enough ado about that. Except--and this knowledge built itself bit by bit over years, until we finally know what we know today--that if you're suffering from bipolar (or even unipolar) depression, someone better be taking an awful close look at those levels.

Low thyroid, called hypothyroidism, is correlated with fatigue, weight gain, memory problems--and depression. As far back as 1942 the British Medical Journal published a piece correlating low thyroid with "madness" in general, but also, specifically, with depression. And then, in 1980, in the Indian Journal of Psychiatry, researchers stated that "while considering the results . . .of 31 depressives in comparison to 31 controls it was observed that the levels of T8 and T4 were significantly lower and that of TSH significantly higher in the depressives" (Boral et al).

More letters and numbers. They're just fancy abbreviations for very manageable concepta. Like TSH? Stands for thyroid stimulating hormone--and guess what it does? We're not going to deal much with the T8 for now, but the T3, or triiodothyronine, and the T4 basically regulate your metabolism.  T4 is called thyroxine, and levothyroxine (or Synthroid) is the medication supplement that stimulates the thyroid to make more if it.

Back to our walk down memory lane: In 1999 researchers found if depressed bipolar patients didn’t have enough thyroxine, it was bad news. They found an . . .well, here's their title: "Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients" (Frye et al, 1999).  Got it? Three years later researchers showed their hands again with the title  "Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function" (Cole et al, 2002). And--to make matters even worse--if you were bipolar and stabilized and really doing alright, studies found that a drop in your thyroid function "can exacerbate bipolar symptoms even in euthyroid subjects” (Frye et al 2009). That's seriously bad news.

So. . .we’ve got people with bipolar depression less likely to get better if they have low thyroid levels. This doesn't take a genius: researchers began looking at what would happen if they were to augment the regimen of bipolar patients with levothyroxine. Research takes time, but by the 5th European Stanley Conference on Bipolar Disorder in Spain in 2005, Dr. T. Stamme presented the initial results of a large study comparing the addition of levothyroxine with placebo. Although incomplete, findings were still quite promising, in that "many patients in the acute phase improved significantly, and then in open continuation for 6 months most patients showed further improvement, suggesting the possibility that this drug will be effective in bipolar depression. . .[Additionally,]  doses of levothyroxine were very well tolerated and few patients dropped out early due to side effects" (Bipolar News Network, 2007).


And that is one of the selling points of the “doing it naturally” treatments—they are well-tolerated. So it’s worth looking further into them. So I’d like to give an honorable mention to three additional supplements—and a cheer for some plain old vitamins. These supplements have not been rigorously studied in the context of  bipolar disorder, so they haven’t really earned a spot in the body of the post—but the word on the street is pretty positive, and they’ve each undergone at least some official study, perhaps for unipolar depression, perhaps for mood in general. T 5-hydroxytryptophan (5-HTP) is worth a look when it comes to treating bipolar depression (it’s basically a precursor to serotonin itself, so you can take that and run with it), and early studies on depression look good.  Some suggest tyrosine, an amino acid which is a precursor to dopamine and norepinephrine, two neurotransmitters we’re intimately familiar with—and which are involved with mood. And researchers have just completed collecting research for their study, “A Trial of SAMe for Treatment-Resistant Bipolar Depression.” SAMe, or S-adenosyl methionine, has shown itself well in trials of unipolar depression—although nobody seems particularly clear on its mechanism of action.

And then, some of the more cutting-edge psychiatrists supplement with vitamins. They might use a whole host, but the ones that appear most commonly are the omega-3 fatty acids, particularly EPA, which, if researchers are right (as they hope they are), can change brain signal pathways in in ways similar to mood stabilizers, and the B-s, which generally energize and help build up the immune system (in a neat pattern, doctors recommend B-1, B-6, and B-12).

There’s still hard work to be done before there is a critical mass of published clinical trails firmly establishing the roles of vitamins and supplements in treatment-resistant bipolar depression, although a lot of doctors seem pretty convinced about the vitamins already.  Additionally, psychiatrists today regularly test the thyroids of those with BD and are quick to supplement with levothyroxine; and a number of them utilize NAC, even if only as an adjunct. We’ve really gotten somewhere, using natural means.  It reminds me of old Annie, in “Annie, Get Your Gun:”

“Still we’ve gone from A to Z/

Doin’ what comes naturally.”


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