Nine hundred people from 24 countries turned up in Pittsburgh in June 2001 for the Fourth International Conference on Bipolar Disorder, hosted by the Western Psychiatric Institute, part of the University of Pittsburgh Medical Center Health System. Many of the best minds were there to inform and enlighten, but the unintended overall theme was brick walls and molasses - either we have hit various cul-de-sacs which require abrupt changes in direction or we have found ourselves bogged down in the slow lane of scientific discovery.

It didn’t take long to run into the brick wall phenomenon. Suddenly, it seems, the lights have switched on to the fact that the experts have been wrongly emphasizing the manic as opposed to the depressive side of this illness. As Robert Post MD of the Stanley Foundation reported, bipolar patients are depressed 33 percent of days of the year as opposed to being manic 10 percent of days of the year. The experts have compounded their error by treating the depressive phase of our illness with the usual array of antidepressants, with not a high degree of success, and at the risk of flipping a patient into mania or rapid cycling. Alan Metz MD, Vice President for Neuroscience of GlaxoSmithKline, noted we can make a case for distinguishing between bipolar depression and unipolar depression, with the need for different regulations and different drugs. But does GSK or its competitors have a bipolar antidepressant in development? Don’t count on it.

As for mood stabilizers, Dr Robert Post observed that this class of drugs essentially turns bipolar Is into bipolar IIs. According to Stanley Foundation research, one quarter of bipolar patients were sick for more than one fourth of the year. Bipolar, he acknowledged, is more recalcitrant to treatment than we thought. Mark Bauer MD of Brown University, spelled it out: Thirty to 50 percent of bipolar patients remain chronically ill.

But don’t expect the pharmaceutical companies to rush in with a mood stabilizer that is not a recycled antipsychotic or anticonvulsant. As Fouzia Laghrissi-Thode MD from Hoffman-La Roche explained, the industry would have to leap over three times as many regulatory hurdles than for a simple antidepressant, involving two successful trials each for acute mania, depression, and the prevention of reoccurrence. In the meantime, the new anticonvulsants that are being pressed into service have not been proven effective as mood stabilizers, according to Dr Giller. Call it the molasses side of the equation.

One would have expected Steven Hyman MD, Director of the NIMH, to be talking up a bright future, as people charged with securing larger slices of the budgetary pie are want to do. But the genetic puzzle for bipolar, with its many complex pieces, is problematical, he let the Conference know in so many words. By contrast, based on genetic discoveries in the field of Alzheimer’s, we are on the verge of stopping this illness in its tracks. In animal models, we can evoke fear, but "it is very hard to interview an animal on their emotional state." We can do a circuit diagram of vision, but "what is the neural representation of hopelessness [or] grandiosity?"

Yes, we have neuroimaging and other tools, but Dr Hyman does not seem impressed by a picture of the frontal lobes lighting up: "It is 2001, and there is not a good theory of mood regulation in the brain."

So where does that leave us, with a disorder that seems to confound science, treated with hand-me-down drugs designed for other illnesses, with the pharmaceutical companies sitting on their hands, and no breakthroughs on the horizon?

For one, the onus is on us as patients to make do with what we’ve got. As imperfect as these medications are, the consequences of being noncompliant can be enormous. Jan Scott MD, FRC Psych of Gartnavel Royal Hospital, Scotland, found that of those who were partially adherent to their mood stabilizers, only 40 percent managed to avoid hospitalization over a 16 month period. This stood in stark contrast to the 85 percent avoidance rate amongst those who were compliant. That same study also found just under fifty percent of bipolar patients acknowledged medications noncompliance in the last two years. Would we be better patients if the drugs proved more satisfactory? We don’t have the answer to that.

The immediate focus of bipolar treatment research is for smarter ways to use the same drugs, which is what STAR*D and STEP-BD are mainly all about, two NIMH-funded projects involving thousands of patients being treated at dozens of centers. In the meantime, many of us will be looking outside the medical-scientific establishment for answers, as some of us already are, to complementary and alternative therapies. Brick walls and molasses will likely remain the order of the day for some time, well past the next Bipolar Conference two years from now. It’s one more thing we have to live with. Somehow, we’ll manage.

Hope Floats

When it comes to medical science sitting up and paying attention to our needs, we have been placed on the equivalent of hold. We have yet to catch the eye of the waiter, the guy behind the counter has not said, "next," and the person in the front door seems oblivious to our open trick or treat bag, to serve up just a few metaphors.

As Dennis Charney MD, who has recently joined the NIMH to head up their new mood and anxiety disorders research program, explained at the national NAMI Conference held in July 2001 in Washington DC, the DSM-IV is based on symptoms rather than biology. The depression you suffer from may have a different physiology entirely than the depression of the person next to you, but the treatments available to us do not recognize this fact of life.

Then Dr Charney said: "Our goal is to get to a diagnostic system based on biology and genes ...We have a plan of how we can get there, a five or 10 year plan."

Do we detect a major sea change? Here’s a brief glimpse into the future, according to Dr Charney:

Depression is not just a deficiency of serotonin. In some patients it may be parts of the serotonin system that break down. Prozac and its chemical cousins operate on the serotonin transport site, but there are also 15 or so different serotonin receptors. The serotonin 1A receptor, when not working right, for instance, appears to result in low serotonin in one half of depressed patients in the hippocampus and amygdala (the seat of emotion) of the brain, according to PET imaging done at the NIMH. This work needs to be replicated, Dr Chaney cautions, "but it shows what we can do," and suggests the possibility of developing a "serotonin agonist" to treat the problem.

Here’s where it really gets interesting: If SSRIs work by blocking the serotonin transport site, there may be something wrong with the site to begin with. SPEC imaging indicates that one half of depressed patients may be affected this way. According to Dr Chaney, we are learning a lot more about the genetics of this site, and the next step would be to see if the genetic coding of this site corresponds with the imaging. Three studies are in progress.

Speaking of genes: The day of genetic blood screening appears right around the corner. For instance, if a particular gene says you will respond to Paxil, your doctor will say let’s try Paxil.

Back to biology, there is the HPA axis, which produces CRH which secretes the stress hormone cortisol, which is to mental tranquility what Saddam Hussein is to world peace. Four different companies now have a CRH drug in development. Three or four companies are also working on a substance P agonist (substance P is a neurotransmitter implicated in mood). Work is also being done on the glutamate system (glutamate is an excitatory amino acid that may be responsible for the loss of neurons in the brain), and in looking at how the growth or lack of growth of neurons can affect mood (some antidepressants increase neuron growth).

Just to show how fast things are moving, a month prior to Dr Charney's address, a new peptide was discovered that reduces anxiety (appropriately named stresscopin).

Lest we get carried away, one only has to recall the words of Dr Charney’s boss, Steven Hyman MD, Director of the NIMH, speaking at the previous month’s Fourth International Conference on Bipolar Disorder in Pittsburgh. "It is 2001," he told that gathering, "and there is not a good theory of mood regulation in the brain." But this time, speaking to the NAMI Conference, he sounded decisively more upbeat. Schizophrenia and bipolar are far more complicated than Alzheimer’s (which medical science seems on the brink of solving), he acknowledged, yet "it is a time of optimism ... ultimately, we have hope."

Which seems to be an affirmation of our existence, at long last - that human voice on the other end of the line, the eye contact with the waiter, the "next" from behind the counter, the person in the door at long last spotting our open trick or treat bag ...

For three free online issues of McMan's Depression and Bipolar Weekly, email me and put "Sample" in the heading and your email address in the body.

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Mary-Anne (Oct 10, 2002): Your article is brilliant!!! I'm getting some wonderful insight on my as of yet undiagnosed bipolar depression. I'm sure this is my problem. I live in a smaller city in Ontario where help is limited. I'm working on it. YOU are helping to carry me through. thanks.

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Dennis Charney: "We have a plan..."