The Frontal Cortex

How Prozac Really Works

I’ve got an article in the Boston Globe Ideas section on the new science of depression:

Prozac 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 54 million people around the world, and prevented untold amounts of suffering.

But the success of Prozac hasn’t simply transformed the treatment of depression: it has also transformed the science of depression. For decades, researchers struggled to identify the underlying cause of depression, and patients were forced to endure a series of ineffective treatments. But then came Prozac. Like many other antidepressants, Prozac increases the brain’s supply of serotonin, a neurotransmitter. The drug’s effectiveness 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.

There’s only one problem with this theory of depression: it’s almost certainly wrong, or at the very least woefully incomplete. Experiments have since shown that lowering people’s serotonin levels does not make them depressed, nor does it significantly worsen their symptoms if they are already depressed.

In recent years, scientists have developed a novel theory of what falters in the depressed brain. Instead of seeing the disease as the result of a chemical imbalance, these researchers argue that the brain’s cells are shrinking and dying. This theory has gained momentum in the past few months, with the publication of several high profile scientific papers. 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.

And yet, if you go to the official Eli Lilly Prozac website, the company is still peddling a cartoon version of the chemical hypothesis…

Comments

  1. #1 Left_Wing_Fox
    July 6, 2008

    I’m curious about the role of ECT in this new hypothesis. In the past year, I’ve seen three separate stories about electro-convulsive therapy therapy for depression; One from a TED talk, and two through Canada’s “Quirks and Quarks” science show, one featured a segment attempting to rebut the hollywood image of Electroshock Therapy, and the other talking about “Deep ECT”, where the electrodes are planted surgically in deeper parts of the brain as a cure for some of the worst-case scenarios of depression.

  2. #2 OftenWrongTed
    July 7, 2008

    In light of this new information, I wonder what happens when a person stops taking prozac after a period of sustained use.

  3. #3 Morris
    July 7, 2008

    The point is that -somehow- Prozac DOES work.

  4. #4 Emily
    July 7, 2008

    They also say that antidepressants are not addictive and do not cause real chemical changes in the brain. I was on Prozac from the ages of eight to nine, but discontinued because I couldn’t swallow pills and couldn’t tolerate the taste of the crushed pill. I didn’t take antidepressants again until I was fourteen and put on Lexapro. The first week I went into a deeper depression with severe anxiety attacks which put me into the adolescent psych ward for three days. I started therapy again and two years later, my doctor decided that I could be weaned off the medication if I wanted to. So, I followed his instructions perfectly and I still had withdrawal symptoms. A day after my last half dose I started shaking. I was freezing and had terrible headaches. I couldn’t sleep for over three days. It was terrible. I haven’t had a reoccurrence of my depression since, though, and I’ve started painting and writing again. There is a theory that antidepressants take a week or two to work because it takes that long to heal enough neurons. I wonder what happened in my brain when I stopped.

  5. #5 Milt Lee
    July 8, 2008

    Prozac is really a terrible drug, but of course it’s only one of many SSRI’s on the market – all of which have caused amazing damage to folks. One person asked what happens if you quit after long term use – the answer is that people suffer terrible withdrawal. But the continued use is even worse. People who have used Prozac for years often suffer from tardive dyskinesia, a disorder that causes ticks, and a cudding chewing motion. You can see folks who look like they are chewing on something all the time, but in reality they are have this nervous response to prozac.

    We can only hope that it is taken off the market, but it makes so much money for Lily that it will be around for a very long time.

  6. #6 Felipe
    July 8, 2008

    And they keep inventing new explanations before resorcing to scientific tests… *sigh*

  7. #7 Josh
    July 8, 2008

    This is a very cool theory. But, how does it account for the fact that some people who take Prozac become MORE depressed and/or suicidal, etc.? Right now, the “new novel theory” doesn’t seem to be answering any questions. But I guess it’s nice that scientists are pursuing research under a wholly different paradigm.

  8. #8 hmmm
    July 8, 2008

    It’s easy to call Prozac toxic or harmful if you’ve never been depressed before. Depression is like a living death–and guess what, I’ll take any poison big pharma will throw at me to loosen the horrible yoke of depression from my neck.

  9. #9 Crusty Dem
    July 8, 2008

    Milt Lee – scientologist much? For some patients with severe depression, these drugs are a real wonder, withdrawal symptoms or not.

    One problem with this theory is the location and type of the new neurons produced with SSRIs. While it’s interesting that these drugs are important in the development of progenitor cells, I’m more than a little skeptical of the conclusions of the Hen Science paper (no offense to the good people at Columbia). There’s no other evidence that the dentate gyrus is involved in regulating mood, and there’s a huge gap between irradiation of ~1/3 of the brain (including all the dopaminergic neurons in the midbrain!!) and the “requirement” of DG neurogenesis in stopping depression.

    Maybe I’m missing something important, it’s not really my field, but it seems a bit of a reach.

  10. #10 scicurious
    July 9, 2008

    Milt Lee: There is no association whatsoever with SSRIs and tardive dyskenesia. Tardive dyskenesia is a side effect associated with long term use of antipsychotics, such as chlorpromazine. Antipsychotics have a different mechanism of action from SSRIs. Antipsychotics block dopamine receptors to decrease amounts of dopamine in the brain, while SSRIs decrease serotonin reuptake to INCREASE the amounts of serotonin (as well as some dopamine and norepinephrine) in the spaces between neurons.

    Most of the people in my field today agree that Prozac and other SSRIs work eventually by changes in neurogenesis in certain areas of the brain, which has led to a lot of new research on brain growth factors.

    Crusty Dem: it’s true that the dentate gyrus doesn’t seem to be directly involved in mood. Most of the people I’ve talked to about this think that changes in neuronal generation and connections in the dentate gyrus are responsible for changes in memory formation associated with negative though patterns. There’s a theory that decreases in neurons in the dentate gyrus will produce negative processing of memories and events, which will then produce increased negative thought cycles. However, none of this is proven.

    (shameless plug) If anyone is interested, I’m hoping to do a several part explanation series on depression over at my site. (end shameless plug)

  11. #11 Bob
    July 9, 2008

    Milt Lee: I call shenanigans. I was on prozac, a fairly high dose but I forget the mg, and quit it cold turkey with no withdrawal symptoms at all. Same with Celexa and Zoloft, which does seem to be helping. And I had no side effects at all. The only thing I noticed was that I couldn’t start taking the maximum dose at once; I really did have to acclimate myself a little, although not as slowly as the dr. suggested.

    My wife has been on Celexa for almost 8 years and has no major side effects. And it has really helped her anxiety. I can’t begin to describe the positive change in her behavior since she started anti-depressants.

  12. #12 arkadaşlık
    July 9, 2008

    thanks

  13. #13 natural cynic
    July 9, 2008

    More experiences:
    I have been on both SSRIs & SNRIs [serotonin-norepinephrine reuptake inhibitors] and I hava found that the SNRI that I am taking now – Cymbalta – works the best. What it seems to do for me is keep me from getting into a downward hopeless-helpless spiral. It really doesn’t seem to have much effect on positive feelings, it certainly doesn’t make me happy all the time.

    Withdrawal from both SSRIs & SNRIs is tolerable, with the main symptom of “brain shivers”. The feelings that occur seem to be like brief periods of disorientation – lasting about 1 sec. every 1-5 minutes – where it almost feels like the brain is shaking like a jello mold.

  14. #14 Greg Laden
    July 9, 2008

    I have not read any of this new literature. So, I have two questions and a comment coming from relative ignorance:

    Q1: Is prozac still thought to inhibit uptake enzymes?
    Q2: Is the inhibition of uptake revitalizing these dying off cells?

    Comment: The discussion in the globe uses the overall chemical balance metaphor, but the whole point of prozac is really more aligned with the “magic bullet” metaphor .. as an uptake inhibitor Prozac keeps more serotonin where the brain is already producing it.

  15. #15 Mike
    July 13, 2008

    Why not consult us anthropologists? Perhaps depression is more the result of outside cultural forces placing stress on a person’s stability or a subconscious reaction against Durkheim-ian social facts. It would be interesting to see which nations/cultures produce the largest depressed populations and compare with those that have the smallest to discern some sort of pattern.

  16. #16 Joe
    July 15, 2008

    Jonah, you were incorrect when you made the following statement: “The drug’s effectiveness inspired an elegant theory, known as the chemical hypothesis…” Prozac did not do that. There were a number of antidepressants before Prozac that inspired the chemical hypothesis: drugs like Elavil, which inhibits the reuptake of Norepinephrine and Serotonin, and the MAO Inhibitors, which inhibit the enzyme that breaks down these neurotransmitters. Prozac was unique because of its selectivity for Serotonin, not because it was the first drug associated with a “chemical” effect.

  17. #17 jonathan leo
    July 20, 2008

    There is a subtle difference in this discussion that I think needs calirification. Part and parcel of the Serotonin Theory of Depression is the idea that a serotonin imbalance caused the depression not that it was correlated with psychological stress. The difference between causation and correlation has enormous implications for the classification and treatment of mental disorders. On one hand, if depression is caused by a chemical imbalance, or other biological defect, then we are treating an organic brain disease. On the other hand, if it is just a correlation then you are treating a symptom (the imbalance) but not the cause (the stress). Studies shwoing that chronic stress damages the brain by suppressing the release of trophic factors is not an example of an underlying biological defect as the cause of a disorder, but is an example of a biological response to a problematic environment. Here is a real world example. Our current method of dealing with children in foster care is to medicate them. According to the traditional view, this is justified because they have a disease an underlying organic brain defect is the cause of their illness. However, according to Dumans experiment, and probably just good old fashion common sense, their problems, or atrophied neurons, are directly linked to stress in this case we are treating a correlation between depression and a problematic environment. At this point in time, the current medical dogma is based on the view that mental illnesses are caused by faulty biology. Dumans experiment not only shows that serotonin is not the culprit, it also complicates the idea the disease concept of mental illness. Is mental illness caused by sudden neuronal atrophy or stress?

  18. #18 acmegirl
    July 23, 2008

    I’m not an expert here, but I don’t quite see the problem as laid out above. If a child in foster care is not functioning well due to depression, and a medication can help fix that by healing the neurons, what difference does it make if the damage was caused by stress or an underlying preexisting imbalance?

    In other words, I think the symptom is the depression, no matter how you look at it. The cause is the chemical imbalance. But then you can ask what triggered the chemical imbalance. Some people become depressed in spite of everything, and no amount of looking for a “cause” such as stress, abuse, mommy not loving them enough, etc. will yield any signigicant fruit. And some people become depressed for a “reason”. I suspect that both feel equally bad, and if there is some biological process that is occuring in both cases, they both should begin with the same treatment.

    Of course the “reason” should be sorted out if there is one, but often a depressed person cannot handle this effectively until they have some improvement in their symptoms.

    Now that I think of it, jonathan, your argument seems like just another version of the “snap yourself out of it” approach to depression that just drives me nuts.

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    June 4, 2009

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    June 25, 2009

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    July 23, 2009

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  22. #22 luckyone
    July 25, 2009

    JUST BE POSITIVE – PEOPLE – Smoke some weed and relax, do what you want to do, It is just in your freaking mind – YOU CAN CONTROL YOU SELF AND YOU MIND, LEARN YOUR SELF, LEARN THE PROBLEM – KNOWLEDGE IS A POWER!!! THE WORLD IS GREAT !!!

  23. #23 Prozac Withdrawal
    January 31, 2010

    Good recommendation of books. The book has a nice cover… I like ice cream.

  24. #24 john doe
    August 13, 2011

    I find this hard to believe. I was suicidally depressed and I ran everyday 10 miles. So I doubt lack of exercise was the cause but once I started taking fluxetine my life got back on track.

  25. #25 Feeling good
    December 10, 2011

    Prozac makes me feel better; I really notice a difference in my mood. I sleep better, I eat better, and not sure if this has anything to do with the drug, but my lower backache is gone. I don’t feel a “happy high” or anything but just feel right.

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