Placebos for depression:

How could placebos have an effect on the deep anguish of depression?

One reason, according to a study in the American Journal of Psychiatry [1], is because Prozac and placebos for Prozac have very similar effects on the brain:

Both INcrease activity in these 5 areas of the brain (hover to enlarge):

And both Prozac and placebo DEcrease in activity in these 5 areas of the brain:

Isn't that a bit of a stretch -- that placebos could do all that?

Yes and no:

No, it's not a stretch that placebos for Prozac result in a change in many areas of the brain (above) that are affected by Prozac, but --

Yes, it's a stretch if it's assumed that placebos (for any condition) are a cure-all. Prozac affects areas of the brain in addition to those which it's placebo-standin is capable of affecting. In other words, Prozac is more potent than placebo, as I'm sure you suspected, but it's more potent both in relieving symptoms and in creating the side effects that placebos don't have [1].

5 Caveats:

1. If the sufferer knows it's a placebo rather than the 'real' thing, it won't have an effect. A placebo only 'works' if the person believes it's the 'real' medication, because it's the assumption of potency that triggers a beneficial change in the chemistry of the brain. In other words, the anticipation of benefit is essential. [31]

2. Even if believed, the placebo usually works only if it mimics a treatment that has 'worked' for that person previously. In other words, the potency of a pill that's successful in relieving symptoms conditions the body to unconsciously respond favorably to any pill that appears to be that same medicine. Placebos piggy-back on that conditioning. [4] [27]

3. People who are not able to respond to a placebo for a given illness are often not able to respond to the 'active' treament as well.

4. The effect of a placebo treatment often isn't as long-lasting as the 'real' treatment it replaces, and often is not as potent. (On the other hand, neither does it --usually-- have the negative side effects of the 'real' treatment.) As an example, a placebo injection of morphine is equivalent in effect to about 1mg of actual morphine [15].

5. Even when all the other conditions are met, placebo still may never work for some diseases (such as Alzheimer's), and particularly may not work for advanced cases of diseases that respond to placebos in their early stages (just as is true with many 'active' medications).

Do placebos for depression have anything in common, anatomically, with placebos for Parkinson's or for pain ?

Dopamine and the reward pathway [31] which it fuels, are involved in placebos for both depression and Parkinson's [3] [27], but placebos for depression and pain have more in common with each other. Both show increased activity during anticipation of relief in the Dorso-Lateral PreFrontal Cortex (DLPFC) and the Anterior Cingulate Cortex (ACC) and both show decreased activity in the thalamus whenever patients report an experience of relief. (Is it possible that physical pain and psychic pain have more in common with each other than we had thought?)

Of course, one way that the placebo response for depression differs from that of the response for pain or for Parkinson's Disease is that depressive illness sometimes subsides after a period of time whether treatment is received or not. So the purported placebo response to depression could conceivably be just a disguised 'spontaneous remission'. More research is needed to separate out these two, but the point of the findings [1] [and later research by the same author] that highlights these areas of the brain is that symptom improvement in depression by any means involves changes in specific areas of the brain, and those specific areas are pretty much the same no matter what means provide the relief.


[1] Mayberg HS et. al.: The functional neuroanatomy of the placebo effect: Am J Psychiatry 2002; 159:728-737

[3] de la Fuente-Fernandez R, Stoessl AJ: The placebo effect in Parkinson's disease. Trends in Neuroscience 2002; 25(6):302-306

[4] Benedetti F et. al.: Conscious expectation and unconscious conditioning in analgesia, motor, and hormonal placebo/nocebo responses. J Neuroscience 2003; 23(10): 4315-4323

[15] Petrovic P Placebo and opioid analgesia: imaging a shared neuronal network. Science 2002; 295(5560): 1737-1740

[27] de la Fuente-Fernandez et. al.: Placebo mechanisms and reward circuitry; clues from Parkinson's disease. Biological Psychiatry, in press as of Mar 2004.

[31] de la Fuente-Fernandez R, Stossel J: The Biochemical Bases for reward: Implications for the Placebo Effect. Evaluation and the Health Professions, Dec 2002, 25(4) 387-398

Thanks to Nathan Smith for the CSS for image enlargement upon hover.
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