1 Boring Old Man

Insight: Antidepressants give drugmakers the blues
Reuters
By Kate Kelland and Ben Hirschler
March 23, 2012

The development of a novel antidepressant ground to a halt this week when researchers found it did not make patients feel any better than the pills they were already taking. The drug firms took the hit, with shares tumbling in Targacept, while AstraZeneca wrote off a total of $146.5 million for the drug’s failure. It was bad news for investors and bad news for patients – and a depressingly familiar tale for drugmakers seeking to develop new treatments for brain illnesses.

Data from Thomson Reuters Pharma shows returns for pharmaceutical companies in the antidepressant market are collapsing – despite widespread use of pills like Prozac – as patents expire and new drugs fail to make it to market. Some Big Pharma firms are quitting the field altogether. Others are hacking back investment and shedding jobs. These might seem like prudent decisions in an increasingly expensive and frustrating field. Other diseases such as cancer and diabetes are reckoned to be better areas to be in these days. Yet some scientists say the timing could hardly be worse.

Researchers who study the brain believe they are finally figuring out the basic mechanics of depression and other mental disorders, discoveries that should open the door to far more effective ways to tackle illnesses that can cripple society. "It’s a great time for brain science, but at the same time a poor time for drug discovery for brain disorders," says David Nutt, professor of neuropsychopharmacology at Imperial College London. "That’s an amazing paradox which we need to do something about."

The numbers say it all. Major depression affects around 20 percent of people at some point in their lives. The World Health Organization predicts that by 2020, depression will rival heart disease as the health disorder with the highest disease burden in the world. Around a third of all Americans and 40 percent of all Europeans could be classified as mentally ill, with a European study last year finding that almost 165 million people in the region suffer each year from a brain disorder of some kind. The study covered more than 100 illnesses from insomnia through depression to schizophrenia.

In the developed world, at least, we are popping more pills than ever. One in five adults in the United States is now taking at least one psychiatric drug, according to data from Medco Health Solutions, a pharmacy benefit manager. But the drugs only work in some of the people some of the time, and there is an urgent need for new, more effective therapies. "The burden of these diseases is huge, and the costs are enormous — and it’s only going to get worse with increasing life expectancy," said Colin Blakemore, professor of Neuroscience at Britain’s Oxford University. It is a human tragedy that should, in theory, also be a major market opportunity for drugmakers. The problem is that realizing the potential gains is proving extremely hard…

"You can have depression medicines that in absolute numbers may show a 5 percent difference versus placebo because there was a placebo response of 50 percent and a drug response of 55 percent," he told Reuters. "Even with approved drugs sometimes you achieve the endpoint and sometimes you miss it." As a result, in the absence of compelling new science, GSK decided two years ago to throw in the towel on depression and some other areas of neuroscience. Others cutting neuroscience work in recent years include Merck, Sanofi, Novartis and AstraZeneca, with the latter deciding in 2010 to stop discovery work in depression even as it continued with development of TC-5214…

The commercial impact is stark. Across the industry, sales are sliding fast as popular selective serotonin re-uptake inhibitors (SSRIs) like Eli Lilly’s Prozac and GSK’s Paxil are dispensed as cheap generics and new medicines of a similar type, such as Viibryd from Forest Laboratories, fail to bridge the revenue gap. Worldwide sales of antidepressants, which peaked at $15 billion in 2003, are now expected to fall to under $6 billion by 2016, according to Thomson Reuters Pharma projections, based on consensus forecasts from analysts…

"‘The burden of these diseases is huge, and the costs are enormous — and it’s only going to get worse with increasing life expectancy,’ said Colin Blakemore, professor of Neuroscience at Britain’s Oxford University. It is a human tragedy that should, in theory, also be a major market opportunity for drugmakers." That brings up the second point. You’d have to believe that whatever the cause of the epidemic, the treatment would be some kind of as yet undiscovered medication. What would it be? Our current antidepressants are being taken like candy, and yet this scourge is increasing untouched. So we need some other kind of new drug? That’s a bizarre premise.

My personal take is that this whole line of thinking is a market-creation scheme. I don’t believe any of it anymore. The last decade’s wonder drugs are this decade’s losers? requiring replacement by something new? Why do we only hear about this international spread of the depression virus in articles that go on to talk about the sales figures for antidepressant drugs? pipelines? patents? The logic works better backwards than forwards – a conclusion-driven argument. It starts with drug-profits-are-down and ends with the-depression-epidemic – not vice versa. Which brings us to the third point – why is this being brought up by academic research psychiatrists? They’re like a greek chorus on the side of the stage whining to the drug company gods to give them something else to talk and write about. And a new twist:

^{BRAIN SCANS
Brain scientists say it is time for some fresh approaches. "What we want to do is start from understanding the illness," says Nutt. And he and others are increasingly confident they are starting to do that. Nutt points to work by psychiatrist Catherine Harmer at Oxford University, who published what one expert commentator called a "paradigm-changing" study in the American Journal of Psychiatry in 2009. It showed that, counter to previous thinking, antidepressants actually start working instantly even though patients may not notice the effects for months because it takes time for small changes to build up and alter their world view.}

^{In separate research using functional magnetic resonance imaging (fMRI) brain scans, Harmer’s team showed that activation of the amygdala – the brain’s emotional hub – is blunted by antidepressants even after the first few doses. Since emotional disorders such as depression and anxiety are linked with hyperactivity of the amygdala, this is thought to have an almost immediate but subconscious effect on reducing patients’ negative responses. "So now we have this new theory – and it has quite a bit of evidence now – that what antidepressants do is to change cognitive bias so that people start to see the world as a more positive place," said Nutt.>}

The Dram of Eale
Posted: 23 Mar 2012 02:01 AM PDT

They told me the 80 year old man who’d had a stroke must be depressed – he wasn’t rehabilitating properly. Could I see him and look at whether the citalopram he’d been started on a week before needed tweaking? Jeff was solidly middle class, professional. He had never been ill before his stroke and never ever been mentally ill. He had a large loving close-knit family who came to see him every day. He didn’t seem depressed to me. I stopped his SSRI and said I would come back in a week to see how things looked – perhaps his depression would be more obvious then.

A week later, Jeff seemed much better than he had been on citalopram. He clearly didn’t need an antidepressant – if he wasn’t rehabilitating it was because of where his stroke had struck. I got up to leave just as his family came in. He grabbed my arm. ‘I’ve something to tell you before you go. You see the man across the room’. There was another older man confined to his bed. ‘Well while on those pills you know I had a terrible urge to get up from my bed in the night and go over and strangle him. I don’t know why. I’ve never seen him before. Those feelings have gone since you stopped my pills.’

This makes it about as Evident as you can get that SSRIs cause violence. The only thing possibly more convincing would be data from healthy volunteer studies where aggressive episodes have been relatively common [see Mystery in Leeds].

^{MAGIC MUSHROOMS
In research published in January, Nutt and colleagues scanned the brains of people tripping on psychedelic magic mushrooms and found, counter-intuitively, that the active ingredient psilocybin does not increase but rather suppresses activity in key areas of the brain. Because the dampening effect of just one small dose of psilocybin was rapid and similar to that prompted by other depression treatments including drugs like Prozac, as well as cognitive behavioral therapy [CBT] and deep brain stimulation, the findings suggest magic mushrooms and other psychedelics could in future also be used to treat depression.}

These are findings about the function of the amygdala – how drugs effect it and what it does. They’re the findings of basic science, deserving intense study. Is this why some people get homicidal, suicidal, agitated? Is this related to antidepressant properties? Does this tell us anything about depression itself? or what the amygdala does? We’re in way to big a hurry to make some practical profitable application out of every little finding. That’s not the business of neuroscientists.