

Fearless Youth: Prozac Extinguishes Anxiety by Rejuvenating the Brain - tokenadult
http://www.scientificamerican.com/article.cfm?id=prozac-extinguishes-anxiety-rejuvenating-brain

======
Construct
Interesting behavioral study. However, the Scientific American authors make
the conclusions appear a lot more concrete than they actually are.

Previously, researches have found that fluoxetine (Prozac) actually suppresses
neuronal growth in vitro:

<http://www.ncbi.nlm.nih.gov/pubmed/20377614>

Fluoxetine treatment is often associated with an increase in BDNF (Brain-
derived neurotrophic factor), a protein which encourages the development of
new synapses in the brain areas responsible for higher-order thinking and
other functions. At first glance this sounds great, as the Scientific American
authors concluded. However, other researches, such as those in the study I
linked above, hypothesize that this increase in BDNF and neuronal growth may
actually be due to neuronal insult from fluoxetine. In other words, the
increase in plasticity and new cell growth might be a healing response from
the brain following damage caused by fluoxetine.

Furthermore, fluoxetine is an older SSRI with effects and receptor affinities
that extend beyond the serotonin system. When using fluoxetine for research,
caution must be taken to separate the effects on the serotonin system from the
effects of other functions of fluoxetine. Without further study, we can't know
if these effects apply to all SSRIs, or just fluoxetine.

I should also note: All of this is great for future R&D of next-generation
anti-depressants, but it should not be used by anyone when determining a
treatment path. Despite the study I linked above, to my knowledge we haven't
seen any deleterious effects on memory or cognition due to SSRI treatment in
the general population. The bottom line is that we don't know why or how SSRIs
work (despite what the drug company marketing department wants you to
believe), but they are effective for many people. And combined with therapy,
the rate of remission improves even more.

~~~
Alex3917
"Previously, researches have found that fluoxetine (Prozac) actually
suppresses neuronal growth in vitro"

Neurogenesis is only one type of plasticity, and it doesn't sound like the
type they're talking about in this article. (Albeit I didn't read the study.)

~~~
kevinalexbrown
While they didn't measure neurogenesis directly in the study, they _did_
measure BDNF (Brain-derived neurotrophic factor) which can induce neuron
growth[1]. Essentially they took two groups of mice: regular mice, and mice
whose BDNF levels are believed to not respond to Prozac (Flx). They found that
in regular mice, Prozac plus retraining reduced anxiety. In those mice in
which Prozac doesn't increase BDNF, the Prozac effect went away.[2]

I know it's hard to read the actual study all the time, but sometimes it
helps. :)

[1] [http://en.wikipedia.org/wiki/Brain-
derived_neurotrophic_fact...](http://en.wikipedia.org/wiki/Brain-
derived_neurotrophic_factor)

[2] _Because mice heterozygous for the BDNF null allele (BDNF+/−) are
insensitive to Flx treatment in behavioral models of depression and anxiety
(3, 26), we tested whether BDNF+/− mice (C57Bl/6J background) responded
differentially to Flx in the fear-conditioning paradigm. Flx again prevented
fear renewal in the wild-type mice, but in BDNF+/− littermates trained to
fully extinguish the fear response, the Flx effect was absent as indicated by
elevated levels of freezing 1 week after extinction (Fig. 4B and fig. S7). To
test whether BDNF was acting predominately in the amygdala, we used
doxycycline-regulatable lentiviral infection to overexpress BDNF locally in
the BLA from the end of extinction onward (figs. S8 and S9). BDNF-
overexpressing mice did not show fear renewal, whereas control mice did (Fig.
4C)._

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tokenadult
Supporting online material for the related article in Science:

<http://www.sciencemag.org/content/334/6063/1731/suppl/DC1>

Abstract of the article, including link to a related resource:

<http://www.sciencemag.org/content/334/6063/1731.short>

The research finding here was surprising to me, so I submitted it even though
it will eventually need more replication.

<http://norvig.com/experiment-design.html>

The research group involved in the research

<http://www.helsinki.fi/neurosci/groups/castren_group.html>

has an appropriate background for conducting this kind of research.

This preliminary finding about a serotonin reuptake inhibitor helping brain
cells stay healthy is consistent with earlier findings I have read about in
relation to lithium, another drug used to treat depression. Animal necropsy
studies appear to show that lithium preserves nerve cells in the brains of
animals treated with it as compared to controls. The references to this can be
found in the standard medical textbook about mood disorders by Frederick
Goodwin and Kay Redfield Jamison.

[http://www.amazon.com/Manic-Depressive-Illness-Disorders-
Rec...](http://www.amazon.com/Manic-Depressive-Illness-Disorders-Recurrent-
Depression/dp/0195135792/)

So perhaps the findings generalize to the idea that preserving youthfulness
("plasticity," that is adaptability) of the brain helps people suffering from
depressed mood develop new thought patterns, perhaps with additional help from
talk therapy such as cognitive behavioral therapy.

~~~
Alex3917
Meh, this is just pro-pharma propaganda. Dozens of drugs increase brain
plasticity, but you don't hear Eli Lilly funding journal articles saying that
everyone should smoke weed or drop acid in combination with therapy. What
exactly is so special about Prozac? Absolutely nothing.

~~~
kevinalexbrown
It's not the Prozac that's the key in the study, despite the Scientific
American angle:

What's significant here is that they were able to study the plasticity
directly, and found that the reduced anxiety depended _both_ on the Prozac
(insert your favorite chemical here) _and_ the re-training. And it compares it
to a physiological difference in the two cases. That's novel, regardless of
the drug. Prozac is a natural choice 1) because it's well studied, and 2) it
has the well-documented clinical property of working best when combined with
treatment (edit: therapy treatment).

How does this happen? Addressing this latter question is exactly what makes
the study so cool: they identified physiological mechanisms that might cause
this behavior, pending further research. Sure, they could ask the same
questions with weed, or acid, or mushrooms, or caffeine. They happened to use
Prozac.

Disclaimer: I do neuroscience, but not in this field.

~~~
Alex3917
Makes sense. The research is cool, I just take issue with the writeup that was
submitted.

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epochwolf
If prozac increases brain plasticity, I wonder if it could be used to enhance
retraining of adults. For example, if you go back to college to learn a
completely new field of work (say medicine or law), you could take prozac to
make the process easier.

I swear I've seen a similar drug in a science fiction novel.

~~~
pkghost
From what little I understand, you're absolutely right. Brain plasticity is
simply your brain's potential to make lasting changes in its own physical
structure.

The study cited by tokenadult says: "Fluoxetine treatment increased synaptic
plasticity.. acted through local brain-derived neurotrophic factor." Brain-
derived neurotrophic factor is a protein that facilitates plasticity, and
there are a number of natural methods for boosting production of BDNF:

eat less; eat even less; fast once in a while; exercise regularly; eat
turmeric; eat fish (or take a DHA supplement); do stuff with your brain.

I wish I had studies top of mind to cite, but most of this is summarized in a
book called Power Up Your Brain: The Neuroscience of Englightenment (written
by a neuroanatomist and a shaman). I read it after going on a 10-day Vipassana
retreat and thinking that meditation is noninvasive neurosurgery. Effects
differ depending on the style of meditation, but they all strengthen a
fundamental pattern of brain activity, be it attentional control, physical
awareness, emotional nonreactivity, compassion, etc, and there's plenty of
studies documenting the neuroanatomical changes that result.

If you're interested in brain plasticity, look up Michael Merzenich, the UCSF
research who coined the term neuroplasticity, on YouTube or TED.

~~~
tfb
_eat less; eat even less; fast once in a while; exercise regularly_

I've recognized the effects this has on my own brain, and you're absolutely
right (for me, at least). And it makes me wonder about the origins of this
particular chemical pattern, and how it came to be.

Perhaps it's some kind of evolutionary mechanism: back in the hunter/gatherer
days, when food was scarce, those who had the particular genome to trigger the
production of just the right set of chemicals for brain plasticity on an empty
stomach were better able to form the neural pathways required for hunting and
gathering food, thus able to survive.

~~~
Dn_Ab
This is a very good hypothesis. The underlying mechanisms may be older. The
main culprits I have read are due to a reduction of insulin levels and an
upregulation of stress/heat shock proteins.

------
hack_edu
With Prozac being one of the more mild antidepressants, one must imagine the
results from even more refined drugs produced in recent decades. I also wonder
how the mood stabilizers with antidepressant effects would intersect here.

But, remember that anxiety is one of the most common side effects of Prozac
and similar drugs. Perhaps for every patient positively affected you have
another who's anxiety is actually amplified.

Edit: Why downvote? This is both factual and informed by my anecdotal
experience...

~~~
Construct
Be careful. Anxiety is a common side effect only at the beginning of SSRI
treatment. Once serotonin receptors down-regulate to accommodate the new
levels of extra-cellular serotonin, steady-state is reached and the anxiety
usually abates.

Unfortunately, this causes many patients to abandon treatment before the the
therapeutic value is apparent. This is one of the biggest obstacles in
treating depression.

Of course, there are always exceptions. However, most of the time you will
find that those who complain about SSRIs inducing anxiety did not actually
wait long enough for the effects to become apparent.

Also, your suggestion that Prozac is one of the more mild SSRIs is completely
backwards. Prozac is one of the earliest SSRIs and has a rather broad spectrum
of receptor affinities. Newer SSRIs are more selective and have better side-
effect profiles. Escitalopram is the gold standard here.

~~~
hack_edu
I guess we must agree to disagree that its only a side effect in the
beginning. My clinicians experience and mine (personal and experiences I've
heard in Group Therapy) differ, though I'm happily on another anti-depressant
that works for me. For what its worth, Prozac's effects were negligible for
me. I still recommend it as a first treatment for those with symptoms.

The same goes for my statement that Prozac is one of the more mild anti-
depressants in terms in side effects. Its often the first prescribed,
specifically for the reason that its effects (side and primary) are more mild,
thus a safer place to baseline to start from.

------
loceng
"Antidepressants may prime the adult brain to rewire faulty circuits during
therapy."

Considered faulty circuits because stimuli was repeatedly presented with
pain/an electric shock?

This article also doesn't tell us why it's seemingly plastic.

Also, it was only once the mice were removed the painful environment that ...
so how about just remove people from a negative environment?

What happens to the mice if you put them on Prozac, and the pain is still
there? Do they learn to fear it even greater/stronger?

Try this with MDMA along with therapy and you'll desensitize the mice/people
too; <http://www.maps.org/mdma/protocol/>

~~~
warfangle
Let me give you an example of 'painful environment,' something many people can
probably relate to.

There's a kid. They're outgoing, talk to everyone, and adults constantly tell
their parents what a smart kid they have.

Kid grows up a bit, and during puberty is constantly ridiculed in social
environments. Eventually the kid withdraws into themselves - a shell of their
former, outgoing self.

In their twenties, even though they aren't in the negative environment of
getting ridiculed for every single last thing anymore, the mere act of talking
to someone new induces feer and anxiety.

They know they need to be more social. That they aren't depresses them. They
find alcohol a decent enough social lubricant, but it doesn't work as well as
they hoped. So they use more of it. They may add a couple more drugs into the
mix - a line of cocaine in the john will help liven them up, surely - and end
in a flat-out spiral of drug and alcohol abuse coupled with crippling
depression and social anxiety.

Their learned response to the stimulus of the social is emotional pain.

They go on prozac; they go into therapy; the increased brain plasticity helps
the therapy hold; their response to social interaction is no longer flight-or-
fight.

Get it, now?

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thisrod
This is a neat story. I'm a bit too eager to believe it. If I knew some
neurology, I'd surely think of reasons to be sceptical.

What are they? Apart from the obvious one, that no one has repeated the
experiment yet.

------
ikirill
So the idea is to use Prozac to make it easier for therapy to reprogram a
brain's responses to social situations that induce anxiety. I'd be curious to
know what this says, if anything, about the kinds of problems that have less
to do with fear/anxiety than something else, like autistic spectrum disorders.
Would using antidepressants to help rewire a brain be effective then? It's a
very cool idea regardless.

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code_duck
I've observed that flouxetine lowers ones inhibitions drastically, more like a
stimulant than like alcohol. Interesting results, as they basically confirm
this.

