Evidence That Serotonin Failure Does Not Cause Depression

Most of the available anti-depressant drugs do one thing: They selectively block reuptake. That is why they are called selective reuptake inhibitors. A drug that is a selective serotonin reuptake inhibitor is called an SSRI.

However, does the effectiveness of these SSRIs depend upon their ability to block serotonin reuptake? To answer that question, consider what happens immediately after you swallow your first pill containing an SSRI. After about 30 minutes, it has entered your brain. It immediately starts blocking the reuptake of serotonin. Do you feel better? No. You must keep taking these drugs for many weeks, and then, maybe, if this is the correct drug therapy for you, you might begin to feel a little better.

Notice that the blockade of reuptake does not coincide with a reduction in the symptoms of depression. Recovery, if it occurs, involves a series of molecular and genetic changes. Whether these modifications are directly responsible for any clinical benefits remains unknown.

More importantly, are these selective reuptake inhibitors effective? Currently available treatments for depression are modestly effective, while treatment resistance and recurrence of symptoms remain a significant problem for most depressed people who take these medications.

Why are SSRIs not effective? The answer lies in the design of experiments conducted over a quarter-century ago. Scientists were trying to understand the function of serotonin by depleting the brain of serotonin. Essentially, laboratory animals or humans were fed a diet high in large neutral amino acids; this diet effectively reduced the availability of tryptophan to the brain and greatly reduced the production of serotonin in the brain leading to symptoms of depression, sometimes within only a few hours.

The scientists concluded that since the depletion of serotonin could produce the symptoms of depression, then it should be possible to treat depression by enhancing serotonin function. Sounds like a sensible conclusion.

The problem with the conclusions drawn from the tryptophan depletion model is that it explains nothing about the neural mechanisms that underlie the development of depression in people who are not tryptophan-depleted, which is virtually everyone.

Simply because the abrupt depletion of serotonin in the brain can reproduce some of the symptoms of clinical depression is not proof that this is what occurs in the brains of depressed humans. A recent study has confirmed that depression is not due to low serotonin levels in the brain.

Today, neuroscientists realize that brain inflammation plays a far more critical role in the development of depression. In addition, some anti-inflammatory medications are effective anti-depressants. Inflammatory illnesses are associated with greater rates of depression than non-inflammatory illnesses.

Finally, higher baseline inflammation levels are associated with a lack of response to anti-depressant treatment. For example, obesity is associated with elevated levels of pro-inflammatory proteins; depression in obese people does not respond well to anti-depressant drugs.

Given the complexity of these changes and our limited understanding of what they mean, it is naïve to assume that the changes in serotonin, or any specific neurotransmitter, are the only ones involved.

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