The Newest Treatments for Treatment-Resistant Bipolar Depression: Part I, The Pharmaceuticals

by on June 30, 2013

According to the World Health Organization, bipolar disorder is the sixth leading cause of disability in the world. The illness is characterized by periods of overexcitement, or mania, followed by depression, with its reduced functioning. The National Alliance for the Mentally Ill adds the shocking statistic that approximately 25-50% of those with bipolar disorder (BD) attempt suicide at least once, one of the highest rates for any psychiatric disorder.  One study found that, over a 12-month period, bipolar disorder was associated with 65.6 lost days per sick worker; annual human capital loss per worker was averaged at $9619 for BD--and annual projections to the US labor force were $14.1 billion for BD [Kessler 2006]).16733826_s

Yet one of the most challenging things when dealing with bipolar disorder is its resistance to treatment, for it's a disease that raises its ugly head again and again. Nearly 1 out of every 2 patients with BD will suffer a recurrence within their lifetimes--often within two years of their last episode (Chou, 2011).

Although the manic phase gets much of the ‘play,’ the majority of the bipolar patient’s disturbed time is spent in the depressed state. It’s a state of serious concerns for the patients functions more—more personal problems, more functional impairment, more comorbid physical problems, and—treaters’ biggest fear—more suicide attempts.  (That’s before we add in costs to society with in-hospitalization and disability costs as well as occupational impairment expenditures.)

Fifteen years ago a depression was considered refractory (or treatment-resistant) after two 6-week trials of antidepressants.  How things have changed. Perhaps you thought, like so many others, that a good dose of Paxil, or, failing that, perhaps Wellbutrin, was just what the doctor ordered. Not here. Turns out antidepressants are out. Back in 2007 researchers ran a study comparing subjects on mood stabilizer plus antidepressants versus mood stabilizer plus placebo. And the results were pretty disappointing: 23.5% of those on the antidepressants recovered--as did 27.3% on placebo (Sachs 2007). AND antidepressants run the danger of throwing  bipolar patients into a manic episode, so they're really uncool. Rather inconvenient if you're trying desperately to treat depressed people--but the reality nonetheless.

Failures of patients with bipolar depression to respond to mood stabilizers—in addition to antidepressants—added to the discouragement of doctors and suffering patients.  Doctors who had tired the mood stabilzers, givein the antipsychotics a whirl, desperately thought about the antidepressants. . .  but then thought better of it--well, they need something else to try.

And the FDA offers them. . .two choices.

That's right.  There are precisely two FDA-approved treatments for bipolar depression: a drug called Symbyax, which is a combination of Zyprexa, an antipsychotic, and Prozac, an (need I really say this?) antidepressant, that Eli Lilly kindly mixes together, approved since 2004.  Then Seroquel, another antipsychotic, approved 3 years later.

It doesn't exactly leave doctors with a large bag of tricks. So researchers have been studying drugs to treat bipolar depression people never thought they'd never see in the mental health field at all. Traveling the road less traveled by, they've looked far and wide--at Parkinson's, narcolepsy (of course!), Lou Gehrig's disease, and-- even a date rape drug. Here's a starting list of what's cutting edge in treating refractory bipolar depression:

Riluzole: Researchers continue to explore riluzole (Rilutek as marketed by Sanofi-Aventis), currently FDA-approved to treat the paralyzing disorder ALS, or Lou Gehrig's Disease. Recent studies in bipolar disorder have discovered that glutamate, an excitatory neurotransmittor found in abundance in the body, might possibly play a more significant role than seratonin in mood regulation. Bipolar depression (along with ALS) is correlated with higher levels of glutamate activity in the brain.

Riluzole researchers were quite familiar with how the neurotransmitter worked, not from ALS--but from spending quality time with rats.  In rat brains, riluzole both inhibits the release of glutamate while simultaneously significantly increasing glutamate uptake. And when researchres left the rat lab and headed to humans, results were promising, as well.

The best-known study--admittedly a small one—gave riluzole to 14 subjects with bipolar depression for 6-12 weeks. Sure enough, the drug decreased glutamate release and --as theorized--subjects had "a significant reduction in depression symptoms” (Brennan et al, 2006).

Celecoxib: Known quite well as Celebrex, the arthritis drug made by Pfizer and used by millions to treat their pain, celecoxib is an acknowledged "long shot" in the treatment of bipolar depression--but it's still in the game.

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID)-- like Advil. Both drugs work by reducing compounds known as prostaglandins, which contribute to inflammation in the body, causing anything from pain and fever to chronic peptic ulcer to Crohn's disease, hepatitis--arthritis--and more.

Enter our hero celecoxib.  It blocks the enzyme that makes prostaglandins, yielding, ultimately, lower inflammation and pain. And it seems that, although we didn't know this for years, depressed patients (both those with unipolar and bipolar depression) have levels of prostaglandins that are abnormal over time.

The major study included both the psychiatrist of the "long shot" fame and 28 bipolar patients currently experiencing either a mixed or depressive episode. Patients stayed on their medicine regimen, but were randomized to receive placebo or Celebrex for a 6-week trial.

Results were both positive and fast. The patients taking Celebrex had lower scores on a depression rating scale starting in the first week of treatment. Conclude the authors, "Our findings suggest that adjunctive treatment with celecoxib may produce a rapid-onset antidepressant effect in BD patients experiencing depressive or mixed episodes" (Nery et al., 2008).


Pramipexole, (Mirapex) has been used to treat Parkinson's disease since 1997. It’s what’s called a dopamine 'agonist,' which mobilizes the brain's dopamine receptors, helping to balance the amount of dopamine in the brain.

For those of you still in the early stages of neurotransmitter familiarity, let me encourage you to add this one to your repertoire. Dopamine affects satisfaction, enjoyment and motivation--and that wonderful sense of achievement you feel when you've done something well. [It probably comes as no surprise that both food and sex release dopamine (Imran Siddiqui 2005)]. In other words, it's the brain's "pleasure chemical."

Nor surprisingly, then, dopamine also controls motivation, something we only recently discovered.  It doesn't just sit back and help us 'feel good' once we've, say, eaten that pack of M&Ms--it actually causes us to initiate an action (to hop in the car to drive to CVS)--and then to persevere, to keep at it (to wait in that never-ending line, while the woman at the front pulls out 32 coupons, some out of date--but she's negotiating their use), until we achieve what we want-- M&Ms!

As recently as January of this year researchers explained, "It was believed that dopamine regulated pleasure and reward and that we release it when we obtain something that satisfies us, but in fact the latest scientific evidence shows that this neurotransmitter acts before that, it actually encourages us to act. In other words, dopamine is released in order to achieve something good or to avoid something evil" (Asociación RUVID 2013).

And such a view of dopamine clearly suggests possible treatments of depression and bipolar depression, so researchers were right on it.   Mirapex could do its 'agonist' thing with dopamine and make a difference in the lives of those suffering from bipolar depression. Always used as an adjunct to a mood stabilizer or antipsychotics or both, results were still good. In 2000, Sporn and colleagues found that 50% of those on pramipexole improved (based on their scales), in 2004 a study "showed marked responses that were sustained at least through 12 week follow-up" (Goldberg et al, 2004). As recently as 2010, researchers found that "[f]or all patients, . . . the total profile of depressive symptoms improved significantly within 4 weeks and remained significantly improved for as long as 36 weeks” (El-Mallakh et al).

Not too shabby, I'd say. And sure makes dopamine look like a major player.


Modafinil As someone who's been a sleepy-head her whole life, I'm truly intrigued by this one. It's better known by its brand name, Provigil, which treats shift sleep work disorder, and  sleepiness due to obstructive sleep apnea and to narcolepsy. It does so effectively enough that maker Cephalon has made a pretty penny off of its use. I can only begin to imagine how happy the company is now that some psychiatrists are using the drug for unipolar and bipolar depression, also.

I must say that I appreciate honestly, so when I went to ferret out how modafinil worked, and I checked in with Mark Frye, who did some of the groundbreaking work on modafinil and bipolar depression, I wasn’t disappointed when I turned up this: "Modafinil's wakefulness-promoting mechamism of action is unknown" (Frye et al 2007).  Simple enough. And it looks like we haven't come too far in the past few years either, but what I can tell you is that modafinil seems to (we're not all sure here), assist in releasing dopamine, and also acts kind of like a psychostimulant, like, say, amphetamine--but a lot less powerful (CPA 2008).

There's a fair amount of evidence that modafinil can make a difference in other forms of depression--but it's mostly the kind of evidence that scientists sneer at--the studies might be open-label, or not double-blinded. The major, most rigorous study of the drug to date (yes, it's Dr. Frye's), published in 2007 after studying 85 patients for 6 weeks, did observe a clear antidepressant effect, although, interestingly enough, the subjects had no reduction in their level of sleepiness, often a diagnostic of depression (Frye et al 2007).

However, researchers wondered if they had under-dosed the drug, and perhaps with higher doses would have come greater wakefulness. Either way, they felt they had something that might very well "improve symptoms of bipolar depression without mood destabilization."

Although there are more compounds being looked at for treatment-refractory bipolar depression seemingly all the time, and the suffering should hold out hope, I close my piece with perhaps the oddest of the ideas out there (and keep in mind that I haven't dealt with Aricept, used to treat Alzheimer's, tamoxifen (yes, for breast cancer--and I haven't even started with anything that has the word 'magnet' in its treatment formulation), so you know researchers and doctors are really looking everywhere.



Ketamine Okay, let's face it, you’d think that any med that's also known as a date rate drug wouldn’t have people standing in line to take it. Except that this club drug is different from almost any other treatment for bipolar depression: when administered properly, ketamine alleviates the depression within minutes.

It really is worth a look. A dissociative anesthetic (and we'll come back to that, because people don't necessarily like disassociating), it was developed in the 1960s, and mainly used as a veterinary anesthetic.

But it hasn't spent its whole life innocently putting rabbits to sleep. Sneaking out of the veterinary OR, it's found a home on the street and in clubs, reinventing itself as "K," "Special K"," or "cat Valium," and inducing out-of-body sensations in those who take it--and doing triple-duty as a date-rape drug.  It has the perfect profile for such--it's odorless, tasteless, and causes amnesia in the one who takes it. But wouldn’t it be nice if it had a fourth use, one that could change people's lives within minutes?

It just might. The idea of using ketamine for depression is fairly new. First came a study in 2000 on 'regular' depression, one with only 7 subjects, but it strongly indicated that ketamine had anti-depressant effects.  More small-scale studies followed, but there were no results of any rigorous (you remember from above, one with all the words scientists love: "randomized,” placebo-controlled,” “double-blind crossover") studies on ketamine's effect on bipolar depression until as late as 2010. In that year we met a research team led by Dr. Carlos A. Zarate Jr, Chief, Section on the Neurobiology and Treatment of Mood Disorders and Chief of Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health.  I'd tell you some more of his jobs, but I imagine you're getting restless.

We return to the study with the intriguing title "A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.” (Don't be thrown by all that "N-methyl-D-aspartate antagonist" stuff--it just means that ketamine is an anesthetic that works to inhibit [that's the 'antagonize'] the action of N-methyl-D-aspartate receptors, which are types of glutamate receptors. Apparently blocking these receptors improves the brain’s electrical flow, which, in turn, reduces depression.)  Here, researchers found that, within 40 minutes of administering ketamine to their subjects, depressive symptoms significantly improved--for 71% of those given the drug.

The clearest downside of ketamine--well-known to doctors and researchers?  The improvement lasts a only days.

As expected, the most common adverse effect was dissociation. This can be distressing to people, as it includes vivid and wild dreams, visual hallucinations, delirium, disorientation, and confusion--but such symptoms do usually pass within an hour.

Just last year the journal Biological Psychiatry published an article once again establishing ketamine's efficacy in bipolar depression--and, this time, in suicide.  Dr. Zarate and his fellow researchers declared that they found a "rapid and robust antidepressant response" (2012), and, beyond that, they found the drug "rapidly improved suicidal ideation"

Despite the fact that a number of areas of concern remain in using ketamine to regularly treat those with bipolar depression (there's the dissociative 'trip,' the drug can lead to dependence, and long-term use can cause abnormalities in the brain), Dr. Zarate seems pretty sure he's onto a good thing: he's applied for patent for the use of ketamine in major depression.

In a 1989 issue Psychological Review, the authors develop an entire theory of depression that is based on hopelessness-—and it is a lot to ask someone in the depths of despair to hold out hope for a treatment so new it’s still in clinical trials. But there really is cause for hope for the person with treatment refractory bipolar depression. Researchers have new ideas all the time for ways to treat bipolar depression, and they’re putting them to the test. More cutting-edge psychiatrists are already using a number of the treatments in this post—and for some, as they travel “the road less traveled by”, they bring their patients along with them—and that can “make all the difference.”


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  1. Aleida Hawkins

    I have had mixed bipolar for over thirty years and have tried countless medication with only short term results. Medical Dr recently prescribe Celeoxib, not knowing much about it, I decided to research it, and boy I'm I glad I did !!!! I learned more about bipolar then I have from all the Dr.s i have seen over the years. So I just Wanted To say Thank You.

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