the brain - a mindless obsession

The Wilson Quarterly | To this day, no one knows exactly how psychoactive drugs work. The etiology of depression remains an enduring scientific mystery, with entirely new ways of understanding the disease—or diseases, since what we think of as “depression” now is probably dozens of discrete disease entities—constantly emerging. Indeed, the basic tenet of biological psychiatry, that depression is a result of a deficit in serotonin, has proven to be one that was too eagerly embraced. When this “monoamine” theory of depression emerged in the 1960s, it gave the biologically minded practitioners of psychiatry what they had long been craving—a clean, decisive scientific theory to help bring the field in line with the rest of medicine. For patients, too, the serotonin hypothesis was enormously appealing. It not only provided the soothing clarity of a physical explanation for their maladies, it absolved them of responsibility for their illness, and to some degree, their behavior. Because, after all, who’s responsible for a chemical imbalance?

Unfortunately, from the very start there was a massive contradiction at the heart of the monoamine theory. Whatever it is that Prozac and the other members of the widely used class of drugs called selective serotonin reuptake inhibitors (SSRIs) do to change brain chemistry, it happens almost immediately after they are ingested. The neurochemical changes are quick. However, SSRIs typically take weeks, even months, to have any therapeutic influence. Why the delay? No one had any explanation until the late 1990s, when Ronald Duman, a researcher at Yale, showed that antidepressants actually grow brain cells in the hippocampus, a part of the brain associated with memory and mood regulation. Such a finding would have been viewed as preposterous even a decade earlier; one of the central dogmas of brain science for more than a century has been that the adult brain is incapable of producing new neurons. Duman showed that the dogma is false. He believes that the therapeutic effects of SSRIs are delayed because it takes weeks or months to build up a critical mass of the new brain cells sufficient to initiate a healing process in the brain.

While Duman’s explanation for the mechanism of action of the SSRIs remains controversial, a consensus is building that SSRIs most likely initiate a series of complex changes, involving many neurotransmitters, that alter the functioning of the brain at the cellular and molecular levels. It appears that SSRIs may only be the necessary first step of a “cascade” of brain changes that occur long after and well “downstream” of serotonin alterations. The frustrating truth is that depression, like all mental illnesses, is an incredibly complicated and poorly understood disease, involving many neurotransmitters, many genes, and an intricate, infinite, dialectical dance between experience and biology. One of the leading serotonin researchers, Jeffrey Meyer of the University of Toronto, summed up the misplaced logic of the monoamine hypothesis: “There is a common misunderstanding that serotonin is low during clinical depression. It mostly comes from the fact that many antidepressants raise serotonin. This is a bit like saying pneumonia is an illness of low antibiotics because we treat pneumonia with antibiotics.”

The flimsiness of the entire enterprise was brought home to me in devastating fashion in a conversation with Elliot Valenstein, a leading neuroscientist at the University of Michigan, and the author of three highly regarded and influential books on psychopharmacology and the history of psychiatry. I was talking to Valenstein about why today’s psychiatric drugs address only a very small proportion of the neurotransmitters that are thought to exist. Virtually all these drugs deal with only four neurotransmitters: dopamine and serotonin, most commonly, and also norepinephrine and GABA (technically known as gamma-aminobutyric acid). While no one knows exactly how many neurotransmitters there are in the human ­brain—­indeed, even how a neurotransmitter is defined exactly can be a matter of ­debate—­there are at least ­100.

So I asked Valenstein, “Why do all the drugs deal with the same brain chemicals? Is it because those four neurotransmitters are the ones understood to be most implicated with mood and thought ­regulation—­that is, the stuff of psychiatric disorders?”

“It’s entirely a historical accident,” he said. “The first psychiatric drugs were stumbled upon in the dark, completely serendipitously. No one, least of all the people who discovered them, had any idea how they worked. It was only later that the science caught up and provided evidence that those drugs influence those particular neurotransmitters. After that, all subsequent drugs were ‘copycats’ of the ­originals—­and all of them regulated only those same four neurotransmitters. There have not been any new radically different paradigms of drug action that have been developed.” Indeed, while 100 drugs have been designed to treat schizophrenia, all of them resemble the original, Thorazine, in their mechanism of action. “So,” I asked Valenstein, “if the first drugs that were discovered had dealt with a different group of neurotransmitters, then all the drugs in use today would involve an entirely different set of neurotransmitters?”

“Yes,” he ­said.

“In other words, there are more than a hundred neurotransmitters, some of which could have vital impact on psychiatric syndromes, yet to be explored?” I ­asked.

“Absolutely,” Valenstein said. “It’s all completely arbitrary.”