Manufacturing depression (28 page)

It’s not that Americans don’t like to cheat nature—consider, for example, the Interstate Highway System, which renders mountains nearly irrelevant. But when it comes to changing our inner landscape, our destiny isn’t quite so manifest.

On the one hand, Americans have always enjoyed a good buzz.
Even the Puritans,
the same people who once outlawed the celebration of Christmas on the grounds that it was sacrilegious, kept their larders stocked with rum and ale. Indeed, while John Winthrop was giving his shipboard sermons about a life of hard work consecrated to God, barrels of booze were rolling around in the hold and one of his shipmates was no doubt figuring out where to put the pubs in the City upon a Hill.

On the other hand, Americans have also always been suspicious of getting high. They once amended the Constitution to outlaw drinking and currently spend something like
$14 billion a year
on a “war” to keep the country drug free and to round up those who would cheat in the pursuit of happiness.

But there is a third hand, which becomes obvious when you realize that
$14 billion is only a little more
than the national expenditure on antidepressants, and if you throw in tranquilizers like Valium and the uncountable volume of opioid analgesics like Vicodin that are used long after the pain from surgery wears off, you’ve dwarfed the war-on-some-drugs budget by an order of magnitude. Apparently, some ways of getting high are acceptable after all.

Confused? Well, Gerald Klerman, a Harvard psychiatrist who was an early antidepressant researcher, has a concept for you: pharmacological Calvinism.
*
According to this doctrine, Klerman wrote in 1972 (at just about the time that it seemed like the whole country
was teetering on the brink of turning on, tuning in, and dropping out),
“If a drug makes you feel good,
it must be morally bad.” “Psychotropic hedonism,” as he called this something-for-nothing degeneracy, is bad because you haven’t
earned
your happiness.

But there is an exception to the rule. “The dominant American value system,” Klerman continued, “condones and sanctions drug use only for therapeutic purposes and then only under professional supervision by physicians and pharmacists.” Make the drug a medicine, get it from a pharmacy on the advice of a doctor, turn feeling good into feeling well (and feeling not-so-good into a disease), and you’ve found the way to steer your drug-laden camel through the eye of a just-say-no needle. So long as you’re sick, you’re not cheating if you take drugs. That’s what all those pep-pill poppers, and their doctors and druggists, were guilty of—seeking the “quick pill,” as Everett Dirksen put it, when they weren’t really sick in the first place.

This was Nate Kline’s big mistake: failing to reckon with pharmacological Calvinism, he forgot to make “ordinary performance” into a disease.

Iproniazid’s demise was not by any stretch the end of Nate Kline’s career. He went on to win the Lasker Award in 1964 for his role in developing antidepressants, to grace the cover of
Fortune,
and eventually to become
THE ULTIMATE SPECIALIST ON DEPRESSION
—or so the cover of his best-selling
From Sad to Glad
: Kline on Depression
shouted. Even as iproniazid was crashing and burning, imipramine and a host of related compounds were on a slow and steady ascent. And as Kline and other doctors began to advance the claim that, as
From Sad to Glad
promised, “You can conquer depression without analysis”—i.e., with drugs—they were also creating the means of redemption, the scientific works that, by tying the drugs to a biochemical disease, would save those drug users from the sulfurous pit of psychotropic hedonism.

I’ve already mentioned Kline’s first foray into explaining what was going on with these drugs—his experiments with reserpine, which supported the hypothesis that serotonin imbalances caused mental illness. According to David Healy, the 1955
Science
article that publicized this result was
the “inaugural article” of the antidepressant era.
“A bridge had been built from neurochemistry to behavior, and it remained for other researchers to cross this bridge and establish a beachhead on the other side.”

And pour over they did. Leading the charge were scientists wielding their knowledge that iproniazid blocked the action of monoamine oxidase (MAO), an enzyme that broke down a group of brain chemicals that included serotonin, known collectively as monoamines. If iproniazid was a monoamine oxidase inhibitor (MAOI), and if at least one monoamine—serotonin—had been implicated in mental illness, then it stood to reason that iproniazid worked because it stopped the destruction of serotonin, thus increasing its presence in the brain. The reserpine experiments, the ones that showed less serotonin activity in the brains of animals that had suffered a reserpine-induced “depression,” gave credence to this emerging hypothesis about how iproniazid worked, and, in the bargain, to the serotonin theory of mental illness.

War soon broke out among the troops, however. A young Swedish researcher, Arvid Carlsson, soon proved that Kline, and Carlsson’s own bosses at NIH, were wrong about reserpine. He put serotonin back in the brains of the reserpine-treated rabbits, but they remained lethargic—the opposite of what should have happened if reserpine’s depressant effects were due to serotonin depletion. Only when he treated the rabbits with L-dopa—a chemical that in the body became dopamine, another newly discovered monoamine—did the rabbits become frisky again. This led Carlsson to theorize that dopamine, not serotonin, was the culprit in the rabbits’ torpor. He wasn’t interested so much in the psychiatry of this finding as in its implications for Parkinson’s disease—the rabbits were suffering from motor problems, he thought. Soon he
had demonstrated that the reserpine effect was indeed caused by a depletion not of serotonin but of dopamine—work that led to a treatment for Parkinson’s disease and a Nobel Prize for Carlsson.

By the late 1950s, the biological psychiatrists had decamped for a new neurochemical territory: not just dopamine but its cousins in a subgroup of monoamines, the catecholamines—which did not include serotonin. In particular, interest focused on norepinephrine, a chemical related to adrenaline, whose role in the fight-or-flight response had been known since the early twentieth century. Norepinephrine had recently been discovered in the brain. It was known to be depleted by reserpine. MAOI drugs like iproniazid, on the other hand, countered the reserpine effect and raised levels of norepinephrine. These observations led scientists to conclude that antidepressants worked by boosting levels of norepinephrine, providing some kind of stimulation that worked against depression.

There were at least two problems with the
catecholamine hypothesis,
as this theory came to be known. First of all, in 1955, two British scientists did what no one else had done.
They ran a controlled clinical trial
of a prospective antidepressant, one in which all variables were eliminated except the treatment. The trial was a success, but the drug was reserpine, which, according to the theory should have been anything but an antidepressant. Second, imipramine does not block the action of monoamine oxidase, and yet it still has an antidepressant effect.

Scientists never even tried to explain the first problem. The reserpine study was simply ignored, probably because it ran counter to the increasingly prevailing wisdom. The second problem, on the other hand, yielded an answer much more amenable to the emerging story about how antidepressants worked. There is
an excellent account
of how the imipramine mystery was unraveled between 1959 and 1963 in David Healy’s book
The Antidepressant Era.
I’d love to tell that story here because it involves some of my favorite things: dyes (both William Perkin’s old friend aniline and newfangled radioactive reagents), many dangerous drugs and a
host of dead lab animals (no coincidence there), basic discoveries about such things as how the liver works, serendipitous drug company bonanzas (the research led to the invention of Tylenol), and scientists fighting over a Nobel Prize. But it would require a digression too long and rambling even for me. Suffice to say that the result was the uncovering of a second way that the brain conserves the chemicals secreted by nerve endings. In addition to being broken down by enzymes like MAO, those chemicals are also reabsorbed whole by the same nerve endings that released them. Julius Axelrod, the doctor who eventually won the fight for the Nobel, called this a
reuptake mechanism
, and soon neuroscientists had two ways to make a brain chemical more available: stop its destruction by inhibiting an enzyme or prevent its reabsorption. And when Axelrod showed that imipramine worked the latter way, blocking the reuptake of norepinephrine, it was easy to believe that the catecholamine hypothesis was correct.

Or so thought Joseph Schildkraut, an NIH scientist. In 1965, he reviewed all the evidence—the reserpine research, the clinical trials with drugs like imipramine and iproniazid, the studies showing evidence of increased catecholamines in the blood and urine of people taking antidepressants, the discoveries of enzyme and reuptake inhibition—and concluded,
“There is good evidence
to support the thesis that the antidepressant effects of both the monoamine oxidase inhibitors and the imipramine-like drugs are mediated through the catecholamines.” So much for serotonin, at least until it returned with a vengeance twenty years later.

But Schildkraut wasn’t only interested in settling some parochial argument about which brain chemical was being influenced by which pharmaceutical chemical. If he had been, he probably would have called his paper, which appeared in the
American Journal of Psychiatry,
something like “The Catecholamine
Hypothesis of Antidepressant Action.” Instead, however, he called it “The Catecholamine Hypothesis of
Affective Disorders
” (emphasis mine), as if all this scientific work was somehow about the cause of depression rather than the effects of drugs—and as if figuring out how antidepressants worked was the same thing as figuring out how depression worked.

But the paper never addressed the obvious scientific and logical problem: just because you know that a drug makes you feel better, and that feeling better is correlated with a change in brain chemistry, you can’t claim that the problem was a lack of those brain chemicals in the first place. All you’ve explained is how the drug affects the chemicals you’re looking at. For all you know, by tweaking the metabolism of one chemical, you’ve changed something else, something you haven’t even examined.

But even if your explanation turns out to be correct, scientifically speaking, you still haven’t proved that you’ve repaired an underlying problem, let alone explained how that alleged chemical deficiency creates the experience we call depression. You may have explained antidepression, but not depression itself.

Schildkraut acknowledged as much. The catecholamine hypothesis, he wrote, was
“at best, a reductionistic oversimplification
of a very complex biological state.” But that didn’t stop him from making the claim anyway. He even had a justification for his overreaching. The catecholamine hypothesis, simplistic and speculative as it was, still had
“considerable heuristic value,
providing the investigator and the clinician with a frame of reference integrating much of our experience with those pharmacological agents which produce alterations in human affective states.” So long as scientists framed their investigations of drugs as investigations of the biochemistry of our affective states, they couldn’t help but generate knowledge about their causes. To put it another way, although probably not the way Schildkraut would have, if you know what you’re looking for, you’re bound to find it.

In this case, what scientists were looking for was that single target, the one that they reckoned their bullets must be hitting. Their conviction that such a target must exist got an enormous boost
from another scientific development of the early 1960s. The debates about catecholamines and other monoamines were skirmishes in a larger scientific war—over the hypothesis, first advanced by Betty Twarog, that the brain, like the peripheral nervous system, worked by means of neurochemical transmission. The leading neuroscientists of the day refused to accept the concept, preferring to cling to the old idea that sparks flew in the brain, perhaps because it preserved some semblance of the ethereal, of the spirit, amid the gathering knowledge of just how carnal humans are.

Caught in the crossfire between
the “soups” and the “sparks,”
as the factions came to be known, most of the depression doctors hedged their bets: those monoamines might be neurotransmitters, but it was also possible that they were toxins, or antitoxins, or hormones, or fluids that, like Hippocrates’ humors, somehow maintained the proper ambience in the brain. But then scientists started to find ways to catch the monoamines at work within the brain. In 1958,
a British team
inserted recording electrodes directly into a small group of neurons, introduced various alleged neurotransmitters, and listened in as the firing rates of the nerve cells increased in the presence of the chemicals. Three years later,
John Gaddum figured out
how to inject a saline solution into a cluster of neurons and then withdraw it after stimulation so that the resulting changes in the cells’ chemistry could be assayed. And then in 1962 Arvid Carlsson and a colleague used fluorescent dyes that reacted differently with different monoamines to show that dopamine, norepinephrine, and serotonin each had their own pathways in the brain’s tangle of cells and fibers. The
brilliant, beautiful photos
(along with images, captured a few years later, of chemical activity at the synapse) did not prove the principle of chemical neurotransmission, and a few dead-enders held out until the end of the 1960s. But once scientists could hear those recordings and hold those pictures in their hands, once they had visual and auditory evidence that what goes on in the brain is no different from what happens elsewhere in the nervous system—that the inner life is the life of carbon, oxygen,
nitrogen, and hydrogen mixing and colliding and recombining—the war was all but over.