The Noonday Demon (61 page)

Antidepressants were discovered in the early 1950s. The most
charming version of the story is that a group of patients isolated with tuberculosis and put on iproniazid, a new compound that was supposed to help their lungs, became curiously exultant. Before long the substance was being used for nontubercular patients (it did little for TB), and so its discovery preceded the discovery of its mode of action. In fact, whether the big insights came first from Nathan Kline (who, in the United States, discovered iproniazid, an MAO inhibitor) or from Lurie and Salzer (who, also in the United States, showed early good results with isoniazid, again without knowing its mechanism) or from Roland Kuhn (who, working in Germany, discovered imipramine, a tricyclic) has been the subject of extensive nationalist, ego-driven debate. Since iproniazid caused jaundice, its manufacturer withdrew it relatively soon after it went into distribution. Isoniazid was never widely distributed. Imipramine, on the other hand, is today the official antidepressant of the World Health Organization, and until Prozac it was the world’s first-line antidepressant medication. Kuhn’s interest in these drugs was classification-based; he thought they could be used in the cataloging that had obsessed German psychiatric researchers since Kraepelin. Kline, on the other hand, had started from psychoanalysis and discovered his drug while he was attempting to prove a theory about the location of ego energy. Lurie and Salzer were pragmatists. Though Kuhn’s drug became the most successful, his agenda failed: there was no apparent logic governing responsiveness to his drug, and so it did not define categories of depression. Kline, on the other hand, who had wanted to help patients cope with their past traumas, was surprised to find that many of them ceased to care about their past traumas. Lurie and Salzer, who just wanted to make depressed people less depressed, came close to their goal.

Discovering antidepressants was exciting, but figuring out how or why they worked was an entirely different matter. Neurotransmitter theory had been introduced in 1905; acetylcholine was isolated in 1914; and in 1921 the function of acetylcholine was demonstrated. In 1933, serotonin was isolated, and in 1954, researchers proposed that brain serotonin might be linked to emotional functions. In 1955, an article published in
Science
stated that behavior was in some instances the immediate result of biology. Drugs that apparently
lowered
the level of serotonin in the brain caused animals to be sedated or to spasm. Later that year, another researcher found that the same drug caused levels of another neurotransmitter, norepinephrine, to drop as well. Attempts to boost norepinephrine appeared to normalize the animals’ behavior—but had no effect on norepinephrine, which remained depleted. It turned out that
the boosting drug was acting on dopamine, yet another transmitter. Norepinephrine, epinephrine, dopamine, and serotonin are all chemical “monoamines” (so called because they have a single amine ring as part of their chemical structure), and the new drugs beginning to come into use were monoamine oxidase inhibitors (MAO inhibitors), which effectively raised the levels of the monoamines in the bloodstream (oxidation breaks down the monoamines; MAOIs prevent oxidation).

The tricyclics, whose efficacy had been demonstrated, should have performed the same function; but tests showed that they
lowered
the level of norepinephrine in the bloodstream. Further experimentation showed that norepinephrine, though not flowing freely in the bloodstream, was still present in the body, and eventually Julius Axelrod, a U.S. scientist working at the newly formed National Institute of Mental Health, proposed the idea of reuptake. The norepinephrine got released; it did something in a no-man’s-land called the “synaptic cleft” (some of it even fell out of the cleft and got metabolized); and it was then reabsorbed into the same nerve through which it had been released. Axelrod, who won a Nobel Prize in 1970, later said that if he’d known more, he would never have arrived at such a far-fetched hypothesis. And yet it worked. It was soon demonstrated that the tricyclics blocked the reuptake mechanism, increasing norepinephrine in the synaptic cleft without raising the overall body and bloodstream level of it.

Over the next twenty years, scientists debated which neurotransmitters were the really important ones. The original idea that serotonin mattered the most was replaced by new insight showing that mood was strongly affected by norepinephrine. Joseph Schildkraut’s 1965 article in
The American Journal of Psychiatry
put together all this information and proposed a coherent theory: that emotion was regulated by norepinephrine, epinephrine, and dopamine (a group collectively called the catecholamines); that the MAO inhibitors prevented the breakdown of these substances and so raised the quantity of them in the brain and, therefore, in the synaptic cleft; and that the tricyclics, by inhibiting reuptake, also increased the catecholamines in the synaptic cleft.

The publication of this theory marked the definitive split between psychoanalysts and neurobiologists. Though the synaptic-cleft theories were actually not totally incompatible with the ego-sublimation ones, they were so different that it seemed to most people who were close to either of them that they could not both be true. Recent scholarship persuasively questions most of our assumptions about the action of antidepressant medications and looks at the holes in Schildkraut’s influential argument. Many new arguments are elaborate and technical, but the gist of them is that though it is true that some compounds affect catecholamine
levels and are effective antidepressants, it is not clear how these two facts are linked; and more extensive study shows that many substances that affect the level of catecholamine in the brain do
not
have antidepressant effects.

The direct derivative of Schildkraut’s thought is the serotonin theory, which is much the same but with a different neurotransmitter. Reuptake theories about the amount of transmitter in the synaptic cleft spawned receptor theories, which are about the transmitters’ destination rather than about the transmitters themselves. These theories suggest that if the receptor is not functioning correctly, the brain may act as though it has depleted neurotransmitters even when it has an ample supply. It has since turned out that high levels of neurotransmitters can cause receptors to desensitize. First articulated by a group of Scottish scientists in 1972, receptor theories have almost as many holes as the reuptake theories did: some substances that bond with receptors have no antidepressant qualities, and some drugs that are highly effective antidepressants (mianserin and iprindole, for example) do not bond with receptors or affect transmitter levels. Further, receptors are not steady entities, ports to which vessels return time and time again. They are constantly changing, and the number of them in the brain can be altered easily. Within half an hour of taking a medication, you can alter both the level of neurotransmitters in the synaptic clefts and the number and location of receptors.

A theory published in 1976 held that the delay in response to early antidepressants was due to one group of receptors, the beta-adrenergic receptors, which were desensitized by most antidepressants after a few weeks. This is another theory that has been neither proved nor disproved; it has, in fact, been mostly ignored since the advent of the SSRIs and the attempt to redefine depression as a problem in the serotonin system. As early as 1969, Arvid Carlsson suggested that the effectiveness of the existing antidepressants might be due to their peripheral effects on serotonin, rather than their primary effects on norepinephrine, epinephrine, and dopamine. He took that idea to Geigy, one of the major manufacturers of antidepressants, but they said that the idea of an antidepressant that targeted the serotonin system was uninteresting to them. Meanwhile, in Sweden, a group of scientists began to experiment with altering the structure of the existing antidepressants, and they developed the first serotonin drug in 1971. After nine years of testing, it was released in Europe in 1980. Unfortunately, like several promising drugs before it, it had serious side effects, and despite clinical successes, it was soon taken off the market. Carlsson was working with Danish researchers, and they released citalopram (Celexa), the first usable serotonin drug and still the most popular one in Europe, in 1986. While more theories about the mode of action of
these drugs went in and out of circulation, the American scientist David Wong, working at Eli Lilly, had in 1972 developed another serotonin drug, called fluoxetine. Lilly wanted to use this drug as an antihypertensive, but it was not particularly effective, and in the early 1980s they began looking at its possibilities as an antidepressant. In 1987, it was launched as Prozac. Other SSRIs followed fast. Fluvoxamine (Luvox/Faverin) was already out in Europe and soon became available in the United States. Sertraline (Zoloft/Lustral), paroxetine (Paxil/Seroxat), and venlafaxine (Effexor/Efexor) were all launched within ten years. These compounds, all of which block the reuptake of serotonin, are structurally diverse and are all multifunctional.

The latest science on depression echoes Hippocrates’ suggestion that depression is an illness of the brain that may be treated with oral remedies; scientists of the twenty-first century
A.D.
are better at formulating the remedies than were those of the fifth century
B.C.
, but the basic perceptions have in essence come full circle. Social theories, in the meanwhile, conform to an Aristotelian mode of thought, though the development of specific kinds of psychotherapy is more sophisticated than its distant antecedents. What is most distressing is that these two kinds of insight are still being argued as though truth lay elsewhere than between them.

D
epression cuts across class boundaries, but depression treatments do not. This means that most people who are poor and depressed stay poor and depressed; in fact, the longer they stay poor and depressed, the more poor and depressed they become. Poverty is depressing and depression is impoverishing, leading as it does to dysfunction and isolation. Poverty’s humility is a passive relationship to fate, a condition that in people of greater ostensible empowerment would require immediate treatment. The poor depressed perceive themselves to be supremely helpless, so helpless that they neither seek nor embrace support. The rest of the world dissociates from the poor depressed, and they dissociate themselves: they lose that most human quality of free will.

When depression hits someone in the middle classes, it’s relatively easy to recognize. You’re going about your essentially okay life and suddenly you begin feeling bad all the time. You can’t function at a high level; you don’t have the will to get to work; you have no sense of control over your life; it seems to you that you will never accomplish anything and that experience itself is without meaning. As you become increasingly withdrawn, as you approach catatonia, you begin to attract the notice of friends and coworkers and family, who cannot understand why you are giving up on so much of what has always given you pleasure. Your depression is inconsistent with your private reality and inexplicable in your public reality.

If you’re way down at the bottom of the social ladder, however, the signs may be less immediately visible. For the miserable and oppressed poor, life has always been lousy and they’ve never felt great about it; they’ve never been able to get or hold a decent job; they’ve never expected to accomplish anything much; and they’ve certainly never entertained the idea that they have control over what happens to them. The normal condition of such people has a great deal in common with
depression, and so there’s an attribution problem with their symptoms. What is symptomatic? What is rational and not symptomatic? There is a vast difference between simply having a difficult life and having a mood disorder, and though it is common to assume that depression is the natural result of such a life, the reality is frequently just the other way around. Afflicted by disabling depression, you fail to make anything of your life and remain stranded at the lowest echelon, overwhelmed by the very thought of helping yourself. Treating the depression of the depressed indigent often allows them to discover within themselves ambition, competence, and pleasure.

Depression is a big field full of subcategories, many of which have been studied at length: depression among women; depression among artists; depression among athletes; depression among alcoholics. The list goes on and on. And yet—indicatively—little work has been done on depression among the poor. This is curious, because depression occurs more often among people living below the poverty line than in an average population; indeed, welfare recipients have a rate of depression approximately three times as high as the general population. It has been fashionable to talk about depression in isolation from life events. In fact, most of the poor depressed fit several profiles for initial onset of depression. Their economic hardship is only the beginning of their problems. They are often in bad relationships with parents, children, boyfriends, girlfriends, husbands, or wives. They are not well educated. They do not have easy distractions from their sorrow or suffering, such as satisfying jobs or interesting travel. They do not have the fundamental expectation of good feelings. In our rage to medicalize depression, we have tended to suggest that “real” depression occurs without reference to external materiality. This is simply not true. Lots of poor people in America suffer from depression—not just the hangdog, low-down feeling of being at the bottom, but the clinical illness whose symptoms include social withdrawal, inability to get out of bed, disruptions of appetite, excessive fear or anxiety, intense irritability, erratic aggression, and inability to care for the self or others. Virtually all of America’s indigent are, for obvious reasons, displeased with their situation; but many of them are, additionally, paralyzed by it, physiologically unable to conceive of or undertake measures to improve their lot. In this era of welfare reform, we are asking that the poor pull themselves up by their bootstraps, but the indigent who suffer from major depression have no bootstraps and cannot pull themselves up. Once they have become symptomatic, neither reeducation programs nor civic citizenship initiatives can help them. What they require is psychiatric intervention with medication and with therapy. It is being amply demonstrated in several
independent studies across the country that such intervention is relatively inexpensive and highly effective, and that most of the indigent depressed, liberated from their depression, are keen to better themselves.