In Practice

A practicing doctor's views on psychiatry and contemporary culture.

The "Chemical Imbalance" Theory: Dead or Alive?

That Zoloft ovoid: not so dumb after all.

Is there such a thing as a “chemical imbalance,” a dysregulation of neurotransmitters in the brain that can be linked to mood disorders? A scientific overview this year in the New England Journal of Medicine attests to the vitality of a theory prematurely declared dead.

“Chemical imbalance” is a popular translation of the “monoamine” or “biogenic amine” theory of depression. That hypothesis has it that mood disorder is due to a relative lack of certain transmitters, notably norepinephrine and serotonin. In Listening to Prozac in 1993, I warned that “the amine theory is perhaps false and at least incomplete.” No one had been able to demonstrate a consistent deficit in depressed patients. Overall, the pertinent evidence was full of contradictions.

In terms of perception, the low point for the “chemical imbalance” came in 20005, with the accusation that Big Pharma was misleading patients by implying that medications correct a deficit in the brain. The prime target was the Zoloft television commercial starring the “miserably depressed ovoid.” Soon, the media was filled with articles debunking the amine theory.

In retrospect, this hoopla seems contentious and naïve. (Frankly, it did not look much better at the time.) While it is clear that serotonin changes do not fully explain depression, the evidence that amines play a role in mood disorder was always substantial.

Since 1993, other biochemical contributors to depression have claimed their roles, especially “stress hormones” and factors that influence nerve cell growth. The new overarching biological model of depression (I outline it in Against Depression) integrates all three factors—monoamines, stress, and cell growth—but serotonin dysregulation remains very much on the table as a contributor to depression.

This persistent role of the “chemical imbalance” is evident in the new major overview, a Journal article titled “Mechanisms of Disease: Major Depressive Disorder.” The authors, R. H. Belmaker and Galila Agam of Ben Gurion University of the Negev, in Beersheba, Israel, devote a substantial section to the monoamine hypothesis.

Belmaker and Agam cite studies that may explain why older work was equivocal. Recently, researchers have subtyped monoamine-modulating enzymes and found a form that is specific to the brain. (Older studies looked at enzymes that also exist in the rest of the body, making it harder to detect brain-based abnormalities.) A PET scan study has shown that depressed patients have more of the enzyme — it breaks down serotonin and its relatives — than do non-depressed subjects. In the depressed patients studied, monoamine metabolism was, in fact, different.

Other studies have found that serotonin receptors function less efficiently in depressed patients. A protein named P11 is implicated; depressed patients have less of it in the brain. (P11 research is hot just now. Expect to read a good deal about this protein in the science press.) Some downstream messenger substances are also reduced in the brains of depressives.

Going far back upstream, the genes that confer liability to depression seem to code for molecules that handle serotonin. This research is in its infancy; still it has helped keep researchers’ attention on the amines.

The New England Journal article notes that a third of depressed patients do not respond to antidepressants. In those who do respond, what the authors call “the monoamine-deficiency hypothesis extended” remains the most powerful explanation of the drugs’ mechanism of action.

Like psychotherapists, the neuroscientist authors warn against “premature closure.” As was true in 1993, the neurotransmitter theory is incomplete and not fully proven. All the same, the evidence for it has grown steadily stronger with time. I am no fan of Big Pharma’s advertising. Still, that Zoloft ovoid may have been smarter than the critics made him or her out to be.

Peter D. Kramer is a psychiatrist and author. His books include Against Depression and Listening to Prozac.

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