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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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March 9, 2005

Rewiring the Brain?

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Posted by Derek

Just how do antidepressant drugs work? The answer you get (and the confidence with which it's delivered) will vary according to the experience of the person giving it: the more experienced and knowledgeable they are, the more tentative and uncertain the answer. I worked on central nervous system drugs for eight years, and I can confidently state that we know just slightly more than jack.

Well, the more, um, standard answer is that antidepressants act by changing the concentrations of key neurotransmitters like serotonin or noradrenaline. That's certainly what they're designed to do, by shutting off metabolic and clearance pathways and allowing serotonin, say, to build up. Underlying all this is a larger hypothesis, one so large that we usually don't even think about it: that depressio is indeed a disorder of those neurotransmitters, a chemical imbalance that could in theory be righted if we just studied the relevant pathways hard enough.

There's been a feeling, though, that we've been a bit too reductionist about this. This view is well stated in a new article in Nature Reviews Neuroscience (6, 241) by Eero Castren. It's a proposal that will appeal to software engineers in particular:

"This new hypothesis, the network hypothesis, proposes that problems in activity-dependent neuronal communication might underlie depression, and that antidepressants might work by improving information processing in the affected neural networks. A key aspect of the network view is the recognition that the principal role of the nervous system is not to handle chemicals but to store and process information. . .Although chemical neurotransmitters are crucial for the transfer of information between neurons, information in the brain is not stored in a chemical form but is thought to be processed by the complex interactions of neurons in neural networks. These networks develop through interactions with the environment, and the neuronal structure of, and neurotransmission in these networks are constantly being refined. . ."

That makes the difference between the two approaches sound bigger than it really is, as Castren goes on to point out:

"It should be noted that the chemical and network hypotheses are not mutually exclusive, but are complementary. As the synthesis and release of several important signaling molecules are regulated by neuronal activity, changes in the activity of neural networks produce changes in the concentration of these signaling molecules. Therefore, although the initial effects of antidepressants are obviously chemical. . .the ensuing adaptive changes in the concentrations of those signaling molecules are tightly linked to the structure of the neural network, and might be a consequence of the altered information processing rather than its cause. According to this view, antidepressants initiate a 'self-repair' process, whereby plasticity in neural networks and chemical neurotransmission indivisibly cooperate and gradually bring about mood elevation."

Rodent studies have shown that antidepressants stimulate the growth of new neurons, and that this correlates with their mood-elevating effects. Brain-derived neurotrophic factor (BDNF), which has long been known as a key signal for neuronal sprouting, might be the player here, as several lines of evidence have begun to implicate it in changes in mood. All this, if true, points to a combination of drug and behavior therapy as the best combination to take advantage of the brain network remodeling, and I think that this is considered the best clinical practice as well.

The author is honest about some of the evidence against the hypothesis, such as the several factors that can bring on rapid (albeit temporary) mood changes in depressed patients. Rewiring a neural network isn't going to be rapid. But these observations don't have to invalidate the hypothesis (although they could), and there are others that support it. For example, antidepressant drugs have a very slow onset of action, an effect that's been noted for decades, and many people have suspected that there must be some sort of slow reorganization going on.

So where does that leave drug discovery folks like me? We're used to going after defined targets, and "Loosening up the synapses" doesn't sound like one. Here's Castren again, and I hope that he's right:

"The hypothesis that mood represents a functional state of neural networks might sound incompatible with the efforts of rational drug development. However, the data reviewed above indicate that the antidepressant drugs that have been used successfully for several decades might function by initiating such plastic processes, apparently indirectly, by influencing monoamine metabolism. It is possible that a similar process could also be initiated through other pharmacological mechanisms, which might become the targets of new antidepressants. . ."

Comments (7) + TrackBacks (0) | Category: The Central Nervous System


COMMENTS

1. Alex Chernavsky on March 10, 2005 12:21 AM writes...

Antidepressants are gloried placebos.  Roughly two-thirds of depressed people show a positive response to antidepressant therapy.  This is about the same proportion of people who respond to a placebo.

Studies on antidepressants are bit like experiments on ESP -- the more rigorous the experimental design, the smaller the effect becomes.

See, for example:

http://www.psychiatrictimes.com/p020906.html

And then, of course, there's the whole question of antidepressants and their possible link to suicide (a subject much in the news lately).

My advice for alleviating depression?

  • Consider a short-term therapy, like cognitive-behavioral therapy, or interpersonal therapy.
  • In severe cases of depression, consider electroconvulsive therapy.
  • If you abuse alcohol or other chemicals, stop.
  • If you're stuck in an unhappy romantic relationship, either get couples'-counseling or get out of the relationship.
  • If you currently have no "significant other", place an advertisement on Match.com or attend some singles events.
  • Do aerobic exercise at least half an hour a day, five days a week.
  • Make sure you get enough sleep.
  • Watch less TV.
  • If your work situation is making you unhappy, come up with a specific plan for addressing the problem(s).
  • Don't isolate yourself. Get involved in social activities. Rekindle old friendships, or make new ones.
  • Do volunteer work. Feed the homeless, walk dogs at your local animal shelter, or read to the blind. This step is amazingly effective at giving you some much-needed perspective in life.
  • If you used to engage in a satisfying hobby that you have since neglected, resume your interest. Pick up your old guitar, go out and plant some tomatoes, or dust-off your camera.
  • Throw out your bags of Doritos and Chips Ahoy cookies. Resolve to improve your eating habits.
Permalink to Comment

2. GasPundit on March 10, 2005 12:42 AM writes...

Long time reader, shy on commentating. Your blog rocks. But I digress...

How then would ECT play into this theory? It certainly works. It's slightly less specific than...well, it defines ill-sensitivity. Amnesia, seizures, electricity, sleepiness...a good chunk of the psychiatric spectrum to boot.

Your point on the more someone knows about the drugs, the less convincing their explanation is right on. Imagine how many more questions crop up when you ask, "What are the effects on a developing brain?" I should specify early development in childhoo. It scares the hair right off my head, if I mull over it too long. Parents scared to have their kids vaccinated for fear of mercury, but all too willing to scramble a developing neural net.

Permalink to Comment

3. GasPundit on March 10, 2005 12:42 AM writes...

Long time reader, shy on commentating. Your blog rocks. But I digress...

How then would ECT play into this theory? It certainly works. It's slightly less specific than...well, it defines ill-sensitivity. Amnesia, seizures, electricity, sleepiness...a good chunk of the psychiatric spectrum to boot.

Your point on the more someone knows about the drugs, the less convincing their explanation is right on. Imagine how many more questions crop up when you ask, "What are the effects on a developing brain?" I should specify early development in childhood. It scares the hair right off my head, if I mull over it too long. Parents scared to have their kids vaccinated for fear of mercury, but all too willing to scramble a developing neural net.

Permalink to Comment

4. Daniel Newby on March 10, 2005 3:33 PM writes...

Alex Chernavsky said "Antidepressants are gloried placebos. Roughly two-thirds of depressed people show a positive response to antidepressant therapy. This is about the same proportion of people who respond to a placebo."

Which demonstrates the efficacy of suggestion in mild depression, not the lack of efficacy of antidepressants. If you want a scientific test of standalone efficacy, you have to administer the antidepressant without the patients' knowledge. In the 1950s (if I remember right), this was done accidentally with an anti-tuberculosis drug that just happened to be a monoamine oxidase inhibitor (which increases levels of neurotransmitters like serotonin). The sanitarium patients inexplicably got a lot happier and more active. It took some investigation to figure out what was going on, and the antidepressants were born.

It is lucky that such a crude approach works in depression. Migraine too could probably benefit by up- or down-regulating a small population of neurons, but the existing prophylactic drugs are a random collection of drugs developed for other purposes that have rather low efficacy.

Permalink to Comment

5. Rick on March 11, 2005 3:20 PM writes...

Alex Chernavsky's comments reflect the typical proliferation of "experts" in poorly undersood areas of science and medicine, and bear more than a hint of chemophobia. His suggestions for getting over depression are about as helpful as saying "Get right with God" or "just get over it".
To the extent that a placebo effect is operating, a long course of Prozac treatment is much cheaper than even a short course of cognitive therapy, which he recommends.
The bottom line is that, while they are not a panacea, SSRI's are much more than a placebo.

Permalink to Comment

6. NoFreeLunchMD on March 15, 2005 5:47 PM writes...

Given the timescales, it's likely that whatever is going on involves changes on a transcriptional level.

Permalink to Comment

7. godelbach on March 17, 2005 6:23 AM writes...

Interesting -- do you have a reference for the claim that antidepressants stimulate neurogenisis in rodents? Would be interesting to follow that up.

Permalink to Comment


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