The Frontal Cortex

Prozac and Plasticity

Prozac (aka fluoxetine) is one of the most successful drugs of all time. Since its introduction as an antidepressant more than 20 years ago, Prozac has been prescribed to more than 80 million people around the world. Currently, approximately one in ten Americans are on an anti-depressant, with the vast majority taking SSRI’s like Prozac.

How does Prozac work? At first, the answer seemed simple: the drug is supposed to increase the brain’s supply of serotonin, a neurotransmitter, by blocking its reuptake. This inspired an elegant theory, known as the chemical hypothesis: Sadness is simply a lack of chemical happiness. The little blue pills cheer us up because they give the brain what it has been missing, which is a sufficient amount of serotonin. Here, for instance, is a Zoloft ad that summarizes this hypothesis.

Unfortunately, the serotonergic hypothesis is mostly wrong. After all, within hours of swallowing an antidepressant, the brain is flushed with excess serotonin. Yet nothing happens; the patient is no less depressed. Weeks pass drearily by. Finally, after a month or two of this agony, the torpor begins to lift.

But why the delay? If depression is simply a lack of serotonin, shouldn’t the effect of antidepressants be immediate? This is known as the Prozac lag, and it first led researchers to question the model of action behind SSRI’s.

A few years ago, I wrote about recent attempts to better understand what’s happening in the depressed brain, and why anti-depressants can sometimes reverse it. (Let’s not forget that, in cases of mild and moderate depression, the drugs barely outperform placebo.) It turns out that serotonin is only indirectly involved. Instead, the drug seems to promote plasticity, leading to younger neurons and an increase in neurogenesis:

Rather than seeing the disease as the result of a chemical imbalance, these researchers argue that the brain’s cells are shrinking and dying, as our response to stress spirals out of control. The effectiveness of Prozac, these scientists say, has little to do with the amount of serotonin in the brain. Rather, the drug works because it helps heal our neurons, allowing them to grow and thrive again.

In this sense, Prozac is simply a bottled version of other activities that have a similar effect, such as physical exercise. They aren’t happy pills, but healing pills.

These discoveries are causing scientists to fundamentally reimagine depression. While the mental illness is often defined in terms of its emotional symptoms – this led a generation of researchers to search for the chemicals, like serotonin, that might trigger such distorted moods – researchers are now focusing on more systematic changes in the depressed brain.

“The best way to think about depression is as a mild neurodegenerative disorder,” says Ronald Duman, a professor of psychiatry and pharmacology at Yale. “Your brain cells atrophy, just like in other diseases [such as Alzheimer's and Parkinson's]. The only difference with depression is that it’s reversible. The brain can recover.”

Consider, for instance, a 2008 paper by Italian researchers, published in the journal Science. The scientists were interested in seeing if fluoxetine, the active ingredient of Prozac, could increase the plasticity of brain cells in the adult rat. They studied animals with severe cases of “lazy eye,” a condition characterized by poor vision in one eye due to underdevelopment of the visual cortex. The scientists showed that fluoxetine gave brain cells the ability to take on new roles and form new connections, which erased the symptoms of the visual disorder.

A brand new paper by Japanese researchers extends this hypothesis, by looking at the response of mouse neurons to fluoxetine. Essentially, the antidepressant seemed to reverse the “maturation” of our hippocampal neurons:

Serotonergic antidepressant drugs have been commonly used to treat mood and anxiety disorders, and increasing evidence suggests potential use of these drugs beyond current antidepressant therapeutics. Facilitation of adult neurogenesis in the hippocampal dentate gyrus has been suggested to be a candidate mechanism of action of antidepressant drugs, but this mechanism may be only one of the broad effects of antidepressants. Here we show a distinct unique action of the serotonergic antidepressant fluoxetine in transforming the phenotype of mature dentate granule cells. Chronic treatments of adult mice with fluoxetine strongly reduced expression of the mature granule cell marker calbindin. The fluoxetine treatment induced active somatic membrane properties resembling immature granule cells and markedly reduced synaptic facilitation that characterizes the mature dentate-to-CA3 signal transmission. These changes cannot be explained simply by an increase in newly generated immature neurons, but best characterized as “dematuration” of mature granule cells. This granule cell dematuration developed along with increases in the efficacy of serotonin in 5-HT4 receptor-dependent neuromodulation and was attenuated in mice lacking the 5-HT4 receptor. Our results suggest that serotonergic antidepressants can reverse the established state of neuronal maturation in the adult hippocampus, and up-regulation of 5-HT4 receptor-mediated signaling may play a critical role in this distinct action of antidepressants.

In other words, the drugs do up-regulate serotonin, but that up-regulation is less important than the newfound youth and suppleness of our neurons, which (and this is the mostly speculative part) might help compensate for the damage caused by chronic stress.

Comments

  1. #1 Zoasterboy
    April 22, 2010

    So perhaps does this mean that taking a supplement of 5-HTP would have the same effective as an anti-depressant, in the long run?

  2. #2 Texas Reader
    April 22, 2010

    I took Prozac years ago, but had to switch to another med as it destroyed my appetite and I lost a dangerous amount of weight.

    One weird benefit when I was on it was to my coordination. We had a work bowling event and I’m not athletic and have rarely gone bowling. I scored several spares that day – and was shocked.

  3. #3 NeuroK├╝z
    April 22, 2010

    The neurogenesis/plasticity hypothesis of antidepressant action could indeed explain why exercise has been demonstrated as effective in treating depression in many cases. Exercise is pretty much the most reliable way to generate neurogenesis in mice. Consider this study in press that compares the neurogenic effects of exercise and Prozac.

  4. #4 Mike
    April 22, 2010

    What might the newer serotonergic hypothesis imply regarding the action of other chemicals believed to act on serotonin, such as MDMA?

  5. #5 nick
    April 22, 2010

    If it all boils down to stress, which is probably due to inflammation in the neurons. Wouldn’t an anti inflammatory agent have similar effects? If not, then is increase in serotonin may important for the dematuration?

  6. #6 Pietr Hitzig, MD
    April 22, 2010

    Zoasterboy and Mike,

    Combined precursors (5-HTP and levodopa) of dopamine and serotonin, when used together and with a specific protocol usually stop affective disorders and addictive cravings in minutes.

    Dopamine and serotonin are antipodal regulators of the adaptive immune system. Serotonin is a neuroprotectant and presumptively this protocol stops microglial activation, tryptophan degradation and neuronal apoptosis even if these processes are initiated by severe allostatic stress. The PURSORTM protocol is a very effective therapeutic immunomodulator and may be restoring Th1/Th2 balance.

    PURSORTM is a far more effective anxiolytic and antidepressant than anything on the market. In the last decade PHARMA has grossed $1009 on psychotropics. I spent half the decade in federal prison as a “drug dealer.”

    If you still believe in the Federal Judicial system, God Bless! I will let others argue on that score.

  7. #7 David
    April 22, 2010

    So what about for disorders other than depression? I’m being pressured to take an SSRI (either Zoloft or Luvox) for mild but pervasive OCD. I’ve diligently tried other methods that deal with brain plasticity (Dr. Schwartz’ four-step method, meditation, diet, exercise), and they have provided relief but no “cure.” I should note that I’m not a depressed person, nor can I, at 40, remember any significant periods of depression more than the usual temporary melancholy.

  8. #8 Texas Reader
    April 22, 2010

    David – is there any particularly reason you are hesitant to try an SSRI for your OCD?

    Personal SSRI experience: Prozac – must take in the a.m. as if taken at night will keep you awake. Made me lose weight. Remeron – made me want to eat CONSTANTLY, had to get off it. Zoloft – made me feel a little disconnected from everything and people noticed at work. Effexor – made me so warm that one winter I never put on a jacket or sweater. Had to switch to another type when summer arrived. Lexapro – some weight gain, no other issues for me.

  9. #9 David
    April 22, 2010

    Texas Reader –

    I don’t like taking any medications, but especially not any that adjust my personality. Further, if there’s proof that SSRI’s work no better than a placebo for OCD — like it has been proven for depression — than why take it? I would rather put the hard work in doing some other, natural methods. I’m trying to understand if the theory behind why SSRI’s ease depression (the promotion of plasticity versus the incorrect theory of additional serotonin) is the same reason they’re supposed to work for OCD. If so, I’ll get the plasticity some other way. If not — if they do something different and uniquely effective in the case of OCD – than I’ll take the medication.

  10. #10 Rob
    April 22, 2010

    This idea of SSRIs serving as plasticity-inducing agents is exciting and was well reviewed in a Pittenger & Duman 2008 neurophsychopharm article. However, I’m not sure why so much attention & resources are being spent on a drug that, when a meta-analysis was published in the NEJM, is as effective as placebo? Time to move on to a paradigm shift rather than dressing SSRIs up in a new outfit. I think Nick is right, the smart money is on neuroinflammation.

  11. #11 Eric
    April 22, 2010

    The post mentions the placebo effect as well as the millions of people consuming anti-depressants. Anti-depressants are way over prescribed and because of the placebo effect, millions of people don’t need them.

  12. #12 Zoasterboy
    April 23, 2010

    @Pietr Hitzig (6)

    Thanks for the info and insight!

    @Mike (3)

    I doubt amphetamines such as MDMA or any of the other variations would have similar effects, as they also block the re-uptake of stress hormones such as norepinephrine, which probably weakens or neutralizes any increase in neurogenisis. Then again I don’t really know.

  13. #13 Buttmop Gonzo
    April 23, 2010

    I was depressed too – then I told my boss what I thought of him and now I feel great.

  14. #14 anon
    April 23, 2010

    @Zoasterboy

    Hitzig. The bio page on his website is curiously blank,so I googled him. It ain’t pretty. Lost license for sexual misconduct with patients, did jail time for prescribing phenfen over the internet… Maybe he is on to something with his latest scheme, or maybe he’s just a quack. I don’t know, but I’d be careful before jumping on his bandwagon, as a “patient” or otherwise.

    Either way, his comment is self-promotion and should be considered spam. Jonah, maybe some comment moderation is in order here.

  15. #15 Jamie
    April 23, 2010

    This also points to why it is helpful, sometimes even necessary, to engage in effective psychotherapy aimed at identifying how the depressed person (perhaps unknowingly) is actually maintaining stressors in their environment / interpersonal surround. Neurogenesis is undoubtedly a good thing. But there are some interpersonal choreographies that are so stressful, and some intrapsychic choreographies that are so stressful, that no amount of neurogenesis can keep up. In those cases having a skilled psychotherapist (hard to find) help identify ways to change one’s life will save one’s life.

  16. #16 Zoasterboy
    April 23, 2010

    @anon (14)

    I assumed something along those lines with all the TMs, ramblings about being imprisoned, and high concentration of technobabble. I was just being nice hah, but thanks for the heads up.

  17. #17 Sara
    April 23, 2010

    Well I don’t buy that Prozac makes neurons “young and supple” I’m afraid. Far from it, people on SSRIs often get premature dementia and big gaping holes in their gray matter (See Joseph Glenmullen’s book Prozac Backlash). And neurogenesis often follows traumatic injuries to the brain and although it sounds good, no one has actually proven that this type of neurogenesis is really leading to a healthy improvements in brain function. If and when antidepressants reverse depression, it’s pretty darn short-lived and comes from some stimulant effect. In the long run, antidepressants probably damage the brain and lead to reduced prospects for true healing and ever worsening chronic depression.

  18. #18 Ben
    April 23, 2010

    Have you read any of the studies about myo-Inositol as a treatment for depression and anxiety? If so, have you reached any conclusions?

    As for whether or not inositol actually facilitates the same healing processes as SSRI’s or not, the abstract says, “…inositol is reported to reverse desensitization of serotonin receptors.”

    http://www.biopsychiatry.com/inositol.htm

    http://www.biopsychiatry.com/inositol-5ht2.htm

  19. #19 orion
    April 27, 2010

    if you’re interested in how prozac works on the brain,
    get a phd

  20. #20 gramsci
    April 29, 2010

    @Ben
    We have had our daughter, who suffers from anxiety and depression, on both an SSRI and Inositol. She was on the SSRI for a while, and when we added the Inositol we saw really good results. The doctor who recommended Inositol said it is not a replacement for an SSRI, but a possible complement that is worth at least trying. So far that’s what it has seemed like.

    As for plasticity, this would seem to reinforce the idea that meds and therapy (CBT or otherwise) should work in tandem. At a crude level (I have to do more reading to substantiate the idea), plasticity would make the brain more able to capitalize on the work of therapy, creating conceptual connections and scripts that could help on a conscious level to combat depressive trains of thought.

  21. #21 JC
    May 2, 2010

    If depression causes neuronal cell loss, I should have no neurons left 4 times over.

    This is another sexy theory that isn’t going to amount to squat. The body is exquisitely designed to regulate the cell cycle and genesis of any cell in the body in ways that we still don’t fully understand. Are these new neurons histologically normal and functional?

    It would be nice if sri’s made the brain “youthful” and “supple” (what a shallow, culture-bound value) but I think the fact is that most people know sri’s clinically dull your emotions. They make you feel very little. To the point where you don’t even know your feelings are dulled, because, well, you have no feelings about it either way. That is why they are similarly effective in eliminating the sex drive of 80+ % of men who take them.

    If sri’s made your neurons sexy, cool supple, fresh, youthful, tanned, taught, Botoxed — whatever — would you expect that to result in emotional dulling clinically?

    Sri’s are one of the biggest frauds ever perpetuated on the public and that some people are helped by them and subjectively experience them as wonderful bears little meaning to anything else considering the vast number of confounding variables involved in this research.

  22. #22 hugger-mugger
    May 2, 2010

    I’ve had severe depression for many years and was able to heal myself by eating more raw foods and practicing yoga. The real problem is that most people are unwilling to do what it takes to be healthy even if deep down they very well know. Of course who wouldn’t rather pop a pill than put daily effort in adopting a healthier lifestyle?

    I find it amusing that i have very little scientific knowledge and yet was able to heal myself simply by listening to my body’s reaction to the food I ingest… and by respecting what it has communicated. Eat local and organic, lots of greens and fruits and some vegetables. Try to eat real foods (not packaged) in their raw state more often than not. Food that have been sitting on a shelf for over a month is not something that should realistically be eaten. Pesticides are obviously and logically not good for you… Stop lying to yourself! If you love eating something that leaves you feeling depressed or tired, something needs to be done about your bad habits.

    Change your relationship with food! Ironically, if food is your only source of pleasure in life, you will be drawn to foods which make you depressed. And if you are able to develop a healthy relationship with food, you will naturally be more often drawn to healthier food which in turn will make you a happier person.

    Be both your own scientist and guinea pig, conduct experiments on yourself and notice your body’s reactions to different food. It is both fun and educational.

  23. #23 rainmoon
    November 19, 2010

    I tried Prozac in the morning (maybe 10 or 11 am) and I felt a huge increased amount of energy all day. Nighttime came and I still felt like I was on crack cocaine. Couldn’t sleep or relax until 6 am. I only took 10 mg.

  24. #24 Autism SSRI's
    February 5, 2011

    I have an autistic daughter who self abuses. Prozac was not very helpful for self abuse (she didn’t scratch herself as much, but still had episodes) But it did stop her from yelling and screaming all day. And that was worth it. And by the way, for all you hippi dippy folks who think medication is for people who just won’t do YOGA or eat RAW foods, or stare at the trees, or WHATEVER, well, wake up to other people’s reality okay? Have U considered there are families dealing with children with serious issues like autism? Sure thing you flower power people, I’ll just bring on down my autistic daughter to the latest HOT yoga center, where she’ll most likely wander the room, touching the wall, pounding on anything that sparkles (including those cyrstal necklaces you all love to wear). See ya there! Oh, and we’ll make sure she’s not taking PROZAC that day, and eating only RAW food, so she’ll SCREAM the entire time you’re trying to MEDITATE and get in touch with your inner child COEXIST mammalian brain.

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