Coming soon – the SSRA antidepressant

No, this isn’t a joke, rather a new spin on the serotonin fairy tale (that presupposes that ANYONE can me exactly how an SSRI like Seroxat works – and by the way, Glaxo doesn’t know):

A type of drug has been found that starts working much faster against depression than current medications. Behavioural and molecular tests in rats show that the compounds kick into action in days, rather than weeks.

But the drugs — called serotonin receptor agonists — won’t be replacing Paxil (paroxetine) soon. None has yet been approved for treating depression in humans, and some have been scrapped because of concerns over side effects.

But researchers are still keen to pursue them, because the most popular type of antidepressant, called selective serotonin reuptake inhibitors (SSRI), can take up to two months to start easing symptoms. And for one-third of people with depression, they don’t work at all.

“This is a very good first step in identifying and potentially having a rapidly acting antidepressant,” says Ronald Duman, a drug expert at Yale University in New Haven, Connecticut. “But there’s a lot of work to done.”

Serotonin sponges

SSRIs such as Prozac have become a household name over the past three decades, garnering many millions of prescriptions every year in adults, children and even pets. The drugs work by stopping neurons from greedily keeping hold of a neurotransmitter called serotonin, so allowing more of the pleasure-providing molecule to reach protein receptors in nearby brain cells.

But in most patients, the drugs take weeks to work, says Guillaume Lucas, who did the work as a graduate student at McGill University in Montreal, Canada. “In major depression you have a real risk of suicide,” he says.

This lag is caused by specialized proteins called autoreceptors, which sop up the extra serotonin. After several weeks these receptors get used to the extra serotonin and release the molecule, allowing it to spread to where it is needed to lift mood.

Super recognition

Lucas and his supervisor Guy Debonnel, who died last year, reasoned that serotonin’s action could be increased by activating the proteins that recognize it, rather than by boosting the amount circulating between neurons. This could circumvent the early counteraction of autoreceptors, and speed up the effect.

The team found two compounds that did the job — one from a chemical supply company and the other from an abandoned clinical trial for irritable bowel syndrome.

In one test, rats were exposed to stress such as water deprivation, flashing lights and crowding for several weeks, while some received an antidepressant. The researchers then tested them for sugar consumption. Depressed rats, the researchers knew from previous studies, are less likely to partake in sweet treats. The rodents that received an antidepressant were less sugar-shy than controls, and the ones that got the new serotonin receptor agonists regained their sweet tooth a week earlier than those given an SSRI.

Two other behavioural tests in rats showed that the drugs were fast-acting, as did several molecular studies. After three days, rats receiving serotonin receptor agonists showed signs of new neuron growth — another indicator of antidepressant action — whereas the SSRI-treated rats did not. The results are reported in Neuron1.

Challenges ahead

Although the studies were done in rats, the researchers suggest that serotonin receptor agonists might also be speedier than SSRIs in humans. “We can expect therapeutic benefits to appear four to five times more rapidly,” says Lucas, who is now at the University of Montreal.

Lucas, who has patented the idea of melding serotonin receptor agonists with SSRI’s, hopes to see clinical trials start as soon as compounds are found that are safe in humans. Sanofi-Aventis, a pharmaceutical company based in Paris, is testing another serotonin receptor agonist as a treatment for dementia, he says.

The study stands out because it looked at several different ways of monitoring depression in rats and found the same answer, says Duman. But he cautions: “It really has to be taken with a grain of salt because these are rodent models, and they’re a long way from what could happen in human studies of depression.”

I’ll just run that by you again shall I…Depressed rats, the researchers knew from previous studies, are less likely to partake in sweet treats. The rodents that received an antidepressant were less sugar-shy than controls, and the ones that got the new serotonin receptor agonists regained their sweet tooth a week earlier than those given an SSRI”. All sounds a bit thin to me. Post-rationalisation anyone?

And from this guesswork, Lucas is able to leap straight to “We can expect therapeutic benefits to appear four to five times more rapidly…”

I wonder if any drug companies are pouring funding into the University of Montreal…

The article is here.

10 Responses to “Coming soon – the SSRA antidepressant”

  1. squirrel Says:

    WTF ! How can someone tell if a rat is depressed!
    And thats probably why these drugs don’t have withdrawl problems, because the rats never reported any!!

  2. Matthew Holford Says:

    “…And for one-third of people with depression, they don’t work at all…”

    Hang on! I need to do some arithmetic… OK, so, two thirds of SSRI prescriptions are for mild depression. Now, NICE’s guidance is that:

    “Antidepressants are not usually recommended
    for people with mild depression. But they may
    help you in certain circumstances – for example,
    if your depression has lasted a long time, or if
    you have had severe depression before and now
    have milder symptoms.” (CG23 Depression: Information for the Public (amended), page 22)

    Nope, I’m struggling. Quacks routinely prescribe SSRIs for mild depression, even though they’re not recommended, as a general rule. If we assume that the one third for whom SSRIs are inefficacious are mildly depressed, then we have to draw the conclusion that the rest of the mild depressives, and all of the moderately and severely depressed people enjoy success.

    So, half of the people who ought not to be prescribed SSRIs aren’t helped by them? Oh, fuck it! What a fucking useless statistic – why even bother?

    Matt

  3. experimental chimp Says:

    Don’t mistake the PR for the research. Criticising a scientific paper’s methodology based on what some marketing guy wrote about it is completely pointless.

    Fortunately the abstract is easy to find:

    “Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin4 (5-HT4) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2–3 week treatments with classical molecules: desensitization of 5-HT1A autoreceptors, increased tonus on hippocampal postsynaptic 5-HT1A receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT4 agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT4 receptor agonists as a putative class of antidepressants with a rapid onset of action.”

    The funding came from CIHR, the Canadian Institutes of Health Research – a federal agency. In other words, this was publicly funded research.

  4. truthman30 Says:

    I think you will find chimp, that actually the CIHR is not an independent agency at all…

    http://www.cihr-irsc.gc.ca/e/28293.html

    As you can see from the above article CIHR is affiliated with pharma… GSK

    http://www.cihr-irsc.gc.ca/e/28114.html

    CIHR/Rx&D Research Program
    In partnership with
    GlaxoSmithKline Inc.

    The goal of the program is to create two clinical research fellowships that will provide training in general endocrinology as well as elements specific to the management of patients with type 2 diabetes.

    Funds Available:

    CIHR’s contribution to the amount available for this initiative is subject to availability of funds voted annually to CIHR by parliamentary appropriations, and the conditions that may be attached to them.

    Per award: Up to $55,000/year.
    2 or more applications will be funded through this opportunity.
    Duration of projects:
    Up to 1 year

    I wonder was this study done on Avandia?..
    Hmmmm..
    We all know how that turned out don’t we…

    I have friends who work in labs , doing PhD’s in neuroscience and biology. I know of one of their colleagues who is testing prozac on rats ( to treat social anxiety) for Eli Lilly. They have ways and methods of making the rats stressed and anxious and depressed. It is also my understanding from talking to my friends who are scientists that a lot of academics add their names to papers in labs. This happens often, even in cases where the scientist has played no part in the research. They heklp each other out. This adds to their portfolio of research (basically it looks good on the CV) . The influence of Pharma is huge in all universities, labs etc. Most PhD students studying science get sponsored by pharmaceutucal companies. And it isn’t difficult to imagine just how easy it would be for the sponsor to manipulate and influence an eager and naive student hungry for their doctorate. Their is no truly independent scientific research lab in the world. Thats a fact.

  5. Matthew Holford Says:

    “Don’t mistake the PR for the research. Criticising a scientific paper’s methodology based on what some marketing guy wrote about it is completely pointless.”

    Ah, but we already know that the whole thing is BS: if it wasn’t the PR and “science” would be completely congruent. If it’s not, then there’s a flaw in the reasoning, it’s just a question of taking a look to find out where, exactly, and then presenting that flaw to those who are in a position to do something about it. If they choose to do nothing, we know where we stand.

    Matt

  6. experimental chimp Says:

    truthman: There are important concerns about the independence of academic research, yes. I think you’re overstating the case somewhat, though. It’s absolutely unsurprising that a federal organisation would enter into co-funding arrangements with industry and I’m unsure what point you’re trying to make.

    Matthew: That’s not how PR works, unfortunately. Most people who do PR don’t have a scientific background. Most journalists who interpret the PR don’t either. In this case, it seems fairly clear that the PR person in question has selected the bits that they do understand (ie. the simple bit with rats and stuff) and ignored the bits that they, and the journalists who have to read an interpret this stuff, don’t (ie. the complicated stuff involving specific receptors, phosphorylation and neurogenesis).

    To put it another way, criticising a scientific paper based on the PR is like deciding you don’t like the food at a new restaurant because their adverts sucked, without ever going there.

    And, maybe I’m not quite up to speed on this, but what exactly do you think “those who are in a position to do something about it” should do about it? It’s published research in a scientific journal. Its net effect will be to add a few bits of knowledge to the discourse. I’m failing to see how that’s a cause for a call to action.

  7. Matthew Holford Says:

    “That’s not how PR works…”

    Well, when the product isn’t good enough to sell itself on its merits, I imagine that the PR machine will kick in with some “truths” of its own. Those who are paying attention will note that this doesn’t match what the science actually said, and will maybe delve into the reasons for this.

    If one finds a flaw in the scientific reasoning that suggests that the product is not all one has been told it is, then one presents one’s findings to those appropriately positioned (eg, the amusing tale of Martin Keller). One may have one’s own ideas as to what should be done, but it’s always interesting to see what others would do, first.

    Matt

  8. experimental chimp Says:

    Matthew: I think we’re talking past each other here. At least I hope so. In these situations, the scientist doesn’t generally care about the PR: Their paper’s been published in a good journal, which is the important (and career enhancing) thing. The people who care about the PR are generally the university administrators and the journal. The university administrators want to raise the profile of their university and be seen to be home to Important Research. The journal wants to raise its profile (or keep its profile high) for similar reasons.

    In this case, the press release came from the journal. You can read it here. You’ll notice the media contact has a cell.com email address. Cell Press publish the journal Neuron. So the product in this case isn’t the research. The research is being used to sell Neuron.

    The reason that the press release doesn’t match the science on a one-to-one basis is that the science is fairly technical. The original press release has more detail than the article on the Nature website; Nature is a general science journal. Most of their readers aren’t neurologists, so getting technical in a press release would be pointless. The report isn’t bad, but its intention is to summarise in an interesting way.

    I take your point regarding Keller’s study, but there’s a big difference between publishing some interesting findings that highlight a promising area of research and publishing something that has real-world effects on which medications get prescribed.

    You seem to be suggesting that a scientist’s integrity should be called into question on the basis of a slightly inaccurate report based on a press release written by a third party. To me, this doesn’t seem a remotely adequate reason to doubt anyone’s integrity.

  9. Matthew Holford Says:

    Well, obviously, if somebody thinks that they’ve spotted something, during the course of their research, then they should say so. However, per Marty Keller, there’s a big difference between the presentation of one’s findings (which might be characterized as disinterested, aside from the enhancement of one’s personal reputation), and a paper which it is claimed supports the licensing of a drug. The regulators aren’t scrutinizing these claims (based on “trust”, according to Breckenridge, lest we forget), despite the conflicted nature of most of the academics concerned…

    Regrettably, nobody’s “integrity” is above question, in this field. Otherwise, we are reduced to believing everything that we are told by a given person, solely on the basis of that person’s standing. I can’t accept the validity of that proposition. “Experts” are as capable of corruption and malfeasance as anybody else, I would hold – their position in society doesn’t exempt them from that possibility, not in my eyes, anyway. In fact, given that most people do bow before others’ “greater knowledge”, I should have thought that those whose word is taken at face value on a regular basis are the ones most likely to abuse that situation.

    I’ve been talking to the MHRA long enough to know that it is unwilling to give a straight answer. Its replies are largely evasive, and when pressed on issues such as the withholding of data, assessment procedures, and so on, things go very quiet.

    Something’s wrong. Something’s wrong, because people are complaining, and those with the facility to address those issues are putting up the shutters. If there’s nothing to hide, why is that necessary?

    Matt


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