For all this frustrating uncertainty, for all the limitations of baby steps you aren’t even sure are in the right direction until a bunch of other people have taken those same steps, she seems to me remarkably zen. And quite certain: “I absolutely think [depression] is a disease of the brain based on neurobiological dysfunction….On a neurobiological basis, something is not working.”
* * *
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THE NEXT BRAINS I seek out are in Canada. I head north of the border to Quebec, where Gustavo Turecki probes preserved brains—some flash-frozen and some pickled—in Montreal’s Douglas Mental Health University Institute. He’s focused on tracking strands of RNA and comparing differences between people who are sick and who are well; people who killed themselves who suffered childhood trauma and those who killed themselves and did not.
Gustavo Turecki acquired his own brain bank almost by happy accident: he wanted to work with colleagues who had a small collection of brains, maybe a dozen, from people who’d killed themselves, which they were planning to study for biochemical research. A commercial deal fell through, the colleagues who’d owned the brain bank went on to do other things—and he had a collection on his hands. Now his Montreal bank boasts about three thousand brains. Brains of people who’ve killed themselves, of people who’ve had Parkinson’s or Alzheimer’s, and of controls who had none of those.7
Turecki decided to zero in on suicide because it struck him as an urgent problem that remained maddeningly intractable. “Suicide is a fascinating issue, from a clinical point of view; not only because it’s the only condition of psychiatry that is lethal…it’s difficult to understand. And this is what we all try to prevent constantly, yet we have no objective means of doing so.” He is sitting across from me in his office, a glass coffee table between us and the grassy campus quad in west Montreal outside the window. It’s August and I can taste the warmth behind the air conditioning and in the dust motes at the window. As recently as the 1990s, he says, the mere suggestion there could be biological underpinnings to self-obliteration was anathema. “There were some people that were in shock to think you could study the biology of suicide. They were viscerally against it….They [would say] it’s reductionistic to think that suicide is something happening in the brain. They think that it’s social. But the issue is that it’s not one or the other. If you are very sad, to the point that you can’t see any way out, so that you’re so severely hopeless that everything in reality changes from how it was before, it is in your brain….We don’t know exactly where it’s broken, but we know it’s broken.”
That brokenness is what Gustavo Turecki and his colleagues are looking for. They haven’t found it yet. In many ways they don’t really know what they’re chasing or how to go about chasing it. But for now he’s banking on epigenetics.
Futuristic gene editing notwithstanding, your DNA doesn’t change: the blueprint you’re born with is the blueprint you keep as you mature, age and die. What does change is the way that blueprint’s interpreted. Your RNA acts as messenger, translator, photocopier. Different forms of RNA tell every cell in your body what to do and when to do it. Their instructions differ depending what’s going on in your life. That’s epigenetics. It means “on top of,” or “above,” genetics, and it’s become an increasingly sexy field in our efforts to explain things not revealed by genetics alone.
Gustavo Turecki thinks the secret to suicidality lies in epigenetics. The way your RNA uses some instructions but not others, if it transcribes some genes too much or too little, is implicated in your mood disorder. That doesn’t imply causation. But just being able to differentiate between the genetic interpretation of a depressed or suicidal person and the genetic interpretation of a healthy person would be huge.
How can inspecting a dead brain give you insights into what was going on when it was alive?
He characterizes the dead brain as more like a fossil fixed in time than a computer gone irretrievably dark, taking its hard drive and activity with it. “Dead,” he says, “means, basically, the book was left open at one particular time, on one particular page. So you can read what was going on at that particular time when the person died.”
In his lab I barge in on a young woman extracting RNA proteins from tiny snatches of different brains to compare their activity levels and check any changes in the transcription rate of particular genes. She introduces herself as Meghan. “The brain is flash-frozen, so we’re hoping the proteins will still be active,” she murmurs. If she’s annoyed at my barging she doesn’t show it, and seems happy to explain to me what she’s doing. Meghan takes about twenty milligrams of brain tissue, puts it into a tiny tube and grinds it up until “it becomes a brain pulp, in a sense.” Add some buffers, spin it down, boom: isolated protein at the bottom.
Turecki has seen pathophysiological distinctions at play, he says, in the brains of people who’ve been through childhood trauma. They have trouble regulating their emotions, dealing with what others would encounter as everyday adversity. And there’s molecular evidence of that—fewer hippocampus receptors that detect levels of the stress hormone cortisol, which hampers what’s supposed to be a negative feedback loop. So your fight-or-flight mode never switches off. “Which is, if you think about it, an adaptive mechanism for someone who was exposed to adversity….The message these people get is that the environment is sort of unreliable. So they cannot sort of be quiet and rest and relax because they never know when they’re going to get it….[The mechanism] becomes maladaptive.”
Brains are intensely, mind-meltingly complicated. To the point that we’re only just beginning to comprehend their complexity, much less alter their functioning with precision. Even knowing the way trauma is expressed epigenetically has done little to change clinical practice. I am bad at delayed gratification and for all our huge advances the future of mental health care still seems decades down the road behind the doors of these labs, stacked frozen or placed pickled in high-tech freezers.
What is there for those of us unwilling or unable to wait?
15
A Dry Pharma Pipeline
Much to the chagrin of anyone stuck on a crazy medication merry-go-round, there’s not much new in the pharma pipeline.
It’s psychiatry’s curse of serendipity: the major breakthroughs on which virtually all pharmacologic depression treatment is based were lucky flukes, stumbled upon while scientists were trying to fix something else.
Iproniazid didn’t cure tuberculosis, as researchers of the early 1950s hoped it would. But doctors noticed that it did make depressed tubercular patients a lot happier. Eventually researchers figured out that iproniazid was disrupting the work of an enzymatic system called monoamine oxidase (remember that guy?), whose job normally involves breaking down neurotransmitters that could then spend more time bouncing around, available. This was around the same time physicians figured out that monoamine oxidase is present just about everywhere in the body, and inhibiting it in the brain meant inhibiting all the other stuff it’s supposed to do. This is a recurring theme: pharmacological treatment of mental disorders has all the precision of surgery conducted with a chainsaw.
Imipramine, a couple of generations removed from a failed nineteenth-century textile dye, was used as an experimental treatment for psychotic patients in a Swiss clinic. It didn’t fix anyone’s psychosis. But it turned out to be a wicked antidepressant—one that launched a thousand copycat drugs and a $20 billion antidepressant industry.1
Decades of R&D followed, replicating the same couple of lucky breaks. But treatment development is running out of pixie dust. Steven Hyman attributes the half-century of less-than-innovative, extremely lucrative psychiatric pharmaceutical creation to “the false hope created by the first serendipitous discoveries.”2
Steven Hyman heads the Harvard-MIT Broad Institute’s Stanley Center for Psychiatric Research, is a former Harvard provost and former head of the National Institute of Mental Health. He was among the first people I talked to after embarking o
n this harebrained project. At first, he tells me by phone, everyone thought “these drugs would just be the beginning—that if you reverse-engineered what the drugs were doing, they would teach us about the mechanism of depression. And that kind of giddy hope wasn’t really out of place in the 1950s.”
Things didn’t work out that way.
Instead, pharma companies spent decades developing “me-too” drugs—drugs with near-identical mechanisms of action as other drugs but with a small change allowing for a lucrative patent—based on those initial lucky breaks, using the original drugs’ medical mechanisms as starting points to such a degree that initial animal tests for antidepressants were designed and evaluated based on whether the drug acted like existing antidepressants, not whether it actually quelled depressive symptoms. The drugs they created became more tolerable in terms of side effects and less dangerous in case of overdose, which is a plus when you’re prescribing them to seriously serially suicidal patients like me. But they never got any better at doing what they were supposed to do: alleviate depression.3
If anything, the early flukes gave way to a skewed understanding of the disease itself: the idea that depression must be caused by some kind of neurotransmitter imbalance—wonky levels of the chemical messengers that regulate mood, among other things.
We know now it’s far more complicated. And we’re nowhere close to breakthroughs in terms of how depression actually works. While even cancer lets you take a biopsy and peer closely at a small slice of tumour, good luck hacking off a chunk of someone’s brain. And even if you could, it wouldn’t help. Whatever’s messing with your brain isn’t confined to one small fold of grey matter, a single snip of neurons. The screw-up involves a multifactorial maze within an organ we haven’t begun to understand.
Drug R&D probably would have continued churning out near-identical versions of the same 1950s discoveries if buyers and regulators hadn’t wised up and started requiring new psychiatric drugs to actually be demonstrably better than what was out there. Europe made the first move in 2013, requiring all new drugs for treatment-resistant depression to perform not only better than placebos, but better than existing, pharmacologically similar drugs already on the market.4 Why didn’t this happen earlier? “Payers were dumb,” Hyman says, then corrects himself. “That’s not a nice thing to say. It’s because marketing works. But the payers really should have known better.” And once the rules changed, the party was over. “I think that really, in some ways, started the exit….There are still a few companies who are in this business but most of them, even the ones that still have a reasonable number of projects…are actually investing much less money per project.”5
Truth is, pharma companies don’t know how to make new and more efficacious depression meds because nobody does. And it’s hard to make money when you don’t know how your secret ingredients work.
So, many are getting out of the biz and closing psychiatric R&D units altogether: Research and development is expensive and slow; the availability of animal subjects with brains similar to humans essentially nonexistent; the metrics of success increasingly slippery and tough to quantify. Any real, profit-making progress is a decade away. GlaxoSmithKline closed its neuroscience research facility in 2010, as did AstraZeneca; Novartis shuttered its brain research facility in 2011. “Progress based on neurotransmitters has become small and incremental,” Mark Fishman, then president of the Novartis Institutes of BioMedical Research, told Nature at the time.6 Pfizer, Merck and Sanofi also retrenched their research and development in psychiatric drugs around the same time.7
Richard Friedman, the director of psychopharmacology at Weill Cornell Medicine in New York, recommended to me by Andrew Solomon, paints the same picture. “In the last couple of years [pharmaceutical companies] have really begun to shut down, if not totally shut down, their brain research science, because developing psychotropic drugs is extremely risky, expensive, unlikely to yield effective agents for all kinds of complicated reasons. So the drug companies play it safe….It’s not that it happened suddenly—it’s a drip, drip, drip. But it’s been going on for quite a while and they decided to cut their losses.” After doing the same thing for so long with so few new insights or results, “developing a new compound with a new target is daunting.” 8
And, he adds, “Behavioural measurements, while they can be valid and reliable, to a lot of people are ‘squishy.’” Uncertainty-averse people in the business of making money are not fans of measures that require someone to tell you about the kinds of deep-seated emotions and soul-destroying self-conceptions the patient has spent ages trying to suppress or hide or ignore.
Okay, but what do pharma companies themselves have to say about this neglected and unattractive field? I reached out to some of the biggest players to get their takes on why depression gets no love.
Lilly, maker of Prozac, the drug that’s become synonymous with depression pharmacotherapy, as well as big-name newbies such as Cymbalta, declined my request to chat. “Thank you for reaching out to us. We’re not able to grant an interview at this time, but I know there are many external resources on this subject. You can also visit Lilly.com for a timeline of discoveries if that’s helpful,” Lilly’s spokesperson wrote in an email.9
Pfizer, maker of Effexor and Zoloft, the latter one of the most popular drugs in the United States as recently as 2013 and whose generic version I popped for years, did not want to be interviewed either. “That is not an area of focus for us now. Thanks for the offer, but we’ll pass,” a spokesman wrote back.10
Sanofi declined to speak with me when I asked, because “treatment of depression and suicide is not an area Sanofi concentrates [its] efforts.”11 Ditto Merck. “Depression is not an area that Merck currently has compounds in development, per our corporate pipeline chart. I would refer you to others in the field involved in this area of research.”12
Allergan, which is one of the few major companies making new depression treatments, initially responded to an email request for an interview but then, when I followed up, did not get back to me.13
“If you are the CEO of a drug company and your job depends on your revenue and your profits,” Steven Hyman points out, “it’s pretty obvious the brain seems too hard, too risky….I was trying to convince…some companies to stay involved with schizophrenia, and the head of discovery said, ‘Look—this might help my successor’s successor, but how will it help me?’”14
The pharmaceutical industry’s commercial imperatives are not kind to depression drug research. Shareholders know that. “They look at the portfolio of the company,” says Ken Kaitin, head of the Tufts Center for the Study of Drug Development, who I turned to for clarity in sorting out why there’s so little new on the depression treatment horizon, “and if they see the company is focusing on antidepressants, they’re going to say, ‘Sell. I don’t want this stock anymore, because I’m not interested in a company that’s developing drugs that are not going to be big sellers.’”15
The smart pharma money right now is on cancer: cancer is way ahead and advancing faster; there are actual genes to target. Huge public support has been tremendously effective in raising money and awareness. And new cancer drugs can command a very high price.
The one thing depression drugs have going for them is market potential: there’s a big unmet need, and a higher disease burden, overall, than for cancer. But need is not enough—the millions of people who will buy your novel new depression drug for years, if not decades, are not themselves adequate incentive for anyone to want to invest the time and money required to make that drug.
When it comes to drug research the deck is stacked against psychiatric conditions in general and depression in particular, Ken Kaitin says. To drive pharmaceutical R&D in a particular disease area you need scientific knowledge, an economic environment that makes for a strong business case, a market demand and a risk level that allows you a degree of confidence that your new compound is going to succeed, and depression drugs face a real challenge in all th
ose areas. “Bottom line is, the competitive landscape, scientific knowledge and technical risks, all those negatives outweigh the positives of a positive market environment.” And prospective psych drugs take longer to go through clinical testing than others—about nine years, on average, compared to five or six. That means added hassle and cost but it also shortens the amount of time you have exclusive dibs on the product. And that’s assuming you get approval. Psych drugs fail at a higher rate than any other drug type out there, he says—their success rate is about half the industry average.
Richard Friedman argues it’s time to rip up the existing model for depression drug development and start over. Instead of waiting for pharma companies to come up with something fun and new, he would like to see publicly subsidized researchers identify novel compounds and take those to corporations to turn them into marketable drugs. But not everyone is on board: Ken Kaitin is skeptical about getting government and other publicly funded bodies too deeply involved in what he sees as commercial drug development. He’d like to see multi-party partnerships whose aim is to devise new treatments for conditions where the public interest in breakthroughs outweighs the private-sector appetite for risk. There’s a multi-party Alzheimer’s Disease Neuroimaging Initiative in Japan, Australia and Brazil. And America’s National Institutes of Health has started an accelerated medicines partnership targeting drugs to treat lupus, rheumatoid arthritis, diabetes and Alzheimer’s.
None of this exists for depression.
“The emotional toll,” Kaitin says, “of something like Alzheimer’s disease or cancer, that drives a lot of passion. And it drives a lot of fear among people [which] they fall prey to. You don’t see that in areas like depression.
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