How Everyone Became Depressed (19 page)

It is possible that mixed depression-anxiety is in fact the natural form of mood disorder—or that the nervous syndrome of which mixed anxiety-depression is a part—is the natural form. Mixed anxiety-depression seems to have a genetics of its own. In a 1996 study of 1029 female twin pairs, Kenneth Kendler and co-workers at the Medical College of Virginia found that twins with severe depression were almost always anxious: “More than 75 percent of twins with severe typical depression had, at the same time, an anxiety syndrome diagnosable as either GAD [general anxiety disorder] or panic disorder. In this epidemiologic sample of women, severe depression rarely occurred without major symptoms of anxiety.”
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(If both twins have the same illness, particularly both from the same egg, the odds increase that it is genetically determined.) Around the same time, in a study of 446 adult twin pairs, Gavin Andrews and team at the University of New South Wales in Sydney were not able to isolate genes specific for either anxiety or depressive neurosis, but did identify “a genetic contribution to neuroticism,” meaning a mixture of the two.
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In 1996, Andrews described a genetically based “general neurotic syndrome,”
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which is tantamount to the nervous syndrome. In 2002 Assen Jablensky and Robert Kendell, two leading psychopathologists, concluded “that the genetic basis of generalized anxiety disorder is indistinguishable from that of major depression.”
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In genetic terms, mixed anxiety-depression was a single disorder, not two separate entities that happened to be “comorbid.”

Thus, mixed depression-anxiety was unquestionably the commonest form of either depression or anxiety and is, in fact, the diagnosis that corresponds to the “nerves” of yesteryear. (In a study in 1988 in a Virginia clinic of 47 patients with “nerves” compared to controls, the nerves patients had more anxiety and depression than the controls, and more somatic symptoms as well; they also reported fatigue twice as often.
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)

Historically, just as nerves were sliding into yesteryear, we find clinicians commenting on the frequency of mixed-depression anxiety. Kraepelin himself never endorsed anxiety as a disease, but acknowledged its frequency in manic-depressive illness, saying in 1909: “We find anxiety most frequently in the depressive phases of circular insanity [manic-depressive illness].”
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Edward Mapother, superintendent of the Maudsley Hospital in London, seconded this in 1926: “Anxiety neurosis has achieved a persistent acceptance even among the large majority who reject Freud’s views as to its causation. There seems no particular objection to isolating it if it be regarded as merely one of the numerous subdivisions of the manic-depressive group.”
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Thus, anxiety was considered part of manic-depression.

In England there certainly were community physicians with upper-middle-class practices who described mixed anxiety-depression without using the term. In 1933 J. W. Astley Cooper, with a practice in Middleton St. George in Durham County, who frequently sent his patients to expensive private nervous clinics, called the profession’s attention to “rest in the treatment of neuroses.” He considered many patients “neurotics of the anxiety type.” But what else did they have? They presented with “all the indications of mental and physical exhaustion—namely, tremors, loss of appetite, loss of weight, restlessness, insomnia, loss of interest (in everything but their own troubles).” He considered them cases of “mental and physical exhaustion,” but another analysis might have called it mixed anxiety-depression. (In any event, they responded wonderfully to the enforced inactivity of the Weir–Mitchell rest cure.)
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Likewise, Thomas Ross did not use the term mixed anxiety-depression. Yet of the 45 patients with symptoms of depression admitted to the Cassel Hospital for Functional Nervous Disorders in 1927–1928, 69% had symptoms of anxiety.
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The foundation stone of the modern doctrine of depression and anxiety as a single illness was laid by Aubrey Lewis in 1934. Lewis, then an assistant medical officer at the Maudsley, had studied carefully in 1928–1929—not with rating scales but with close personal observation—some 61 patients with melancholia. The paper on the subject that he wrote in 1931, and published 3 years later, is one of the most influential in the history of mood disorders. Notable was Lewis’s declaration that “The relation of depression to anxiety is intimate.”
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Given that Lewis went on to become arguably the most influential psychiatrist in the world—the more so after the destruction of German psychiatry following 1933, and after Kraepelin’s death in 1926 and Freud’s in 1939—this was an opinion of enormous weight.

We are not going to follow the depression wars that took place in the mid-twentieth century, the endless squabbling over how to classify depression. Yet from these debates several clinical realities emerged. One was that mixed anxiety-depression was a meaningful type of depression. This is important because it shows the survival of the nervous syndrome at some kind of gut level, even though diagnostic officialdom was, in 1980 with DSM-III, about to separate anxiety and depression completely. Fridolin Sulser, a psychopharmacologist at Vanderbilt University, was of Swiss origin and had graduated in Basel in 1955. At a conference on the role of serotonin in psychiatry in the 1990s, he professed himself puzzled: “I was taught by Manfred Bleuler [in Zurich] 30 years ago that anxiety is a core symptom of depression. If this is true … how can fluoxetine [Prozac] be a good antidepressant if from animal data it is thought to increase anxiety.”
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The point was a delicious one, given that Prozac is not a very good antidepressant. But Sulser put anxiety squarely in the center of the depression table.

Bleuler and Sulser were part of a powerful European tradition of seeing anxiety as central to depression, although there were other kinds of depressions as well. Parisian psychiatrist Jacques Launay, who with Henri Baruk created in 1958 the first French psychopharmacological association, the Soci é t é Moreau de Tours, gave anxiety pride of place in his typology of depressions in 1965. He postulated, “depressive states with a predominance of anxiety and neuropsychic irritability [éré thisme],” the main characteristic of which was “a more or less permanent feeling of malaise, with interior tension, emotional incontinence, affective hypersensibility, physical anguish such as feelings of tightening of the throat … ”
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Even though in these years American psychiatry was taking the baton from Europe, this continental stream remained influential.

In England, Max Hamilton at Leeds, creator of depression and anxiety scales named after him, was probably the most influential thinker in disease classification (especially after Aubrey Lewis died in 1975); Hamilton believed that there were really two kinds of depressions: endogenous (meaning melancholic) and anxious. He told a conference in 1973, “I myself am very skeptical about all these pseudo categories of psychotic versus neurotic; endogenous versus reactive, and so on. Most of these terms, when carefully examined, turn out to have very little clear meaning and I tend to avoid them. But in the rating scale, the factor analysis … clearly groups the symptoms of what is sometimes called endogenous depression, such as guilt, suicide, [psychomotor] retardation, loss of insight, on one side, and on the other it puts anxiety, agitation, somatic anxiety and so on.”
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Across the Atlantic, John Overall, a psychologist in the Department of Psychiatry at the University of Texas Medical School at Houston, figured prominently among American psychopharmacologists and disease classifiers. Overall was particularly interested in depression, and in his own subtyping, anxious depression was the most numerous “phenomenological class,” ahead of agitated, retarded, and hostile depression.
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These are really just snapshots from a much larger clinical literature showing that mixed depression-anxiety, the descendant of the nervous syndrome, was very much alive in international psychiatry in the 1960s and 1970s.

But there was some pushback. Several influential psychiatrists believed that anxiety and depression were in fact quite different disorders, and their voices contributed to the fateful decision in 1980 to tear apart the conjoined twins.

In England during the 1960s and 1970s a tremendous battle was fought over whether anxiety and depression were the same illness or separate (a battle muddled by the failure of the participants to exempt melancholic depression from the discussion). The main protagonist of the view of the separateness of anxiety and depression was Martin Roth. Born in 1917 and trained at the Maudsley, in the 1950s Roth became the virtual founder of the field of geriatric psychiatry.
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In 1956 he took the chair of psychiatry at Newcastle on Tyne, and in 1959 launched a diagnosis that he rather clunkily entitled “the phobic anxiety-depersonalization syndrome,” a combination of phobic anxiety and depersonalization that eventuated upon a personal calamity or severe illness and became known as “Roth’s calamity syndrome.”
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At Newcastle, Roth and colleagues became involved in factor analyses, trying to sort out what symptom overlap existed between anxiety and depression. There was little, they argued. There was “a significant negative correlation between anxiety and a diagnosis of endogenous depression.”
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Quite so. Yet this did not respond to the issue of an overlap between nonendogenous depression and anxiety. That lay ahead. In 1972 the investigators factor-analyzed depression and anxiety broadly conceived: The anxiety symptoms clustered at one pole of the analysis and the depressive symptoms at the other pole, “confirming that within an affective material there are two distinct syndromes corresponding to anxiety and depression.”
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Roth was knighted in 1972 and became professor of psychiatry at Cambridge in 1977. In the years ahead, his views, enunciated from the towering heights of psychiatry, would be highly influential, although they remained largely unreplicated. Some workers, such as Hagop Akiskal, then at Tennessee and later at the University of California at San Diego, affirmed them
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; others, such as Frank Fish at Liverpool, threw cold water on the supposed differentiation as artifacts of suggestion.
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Despite Roth’s prestige it is fair to say that a majority of clinical opinion supported the view that mixed anxiety-depression was a disease of its own quite distinct from pure anxiety and pure depression.
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For insiders, the supposed difference between anxiety and depression became largely a matter of convenience. Ross Baldessarini at the McLean Hospital wryly recalls that when he first came to work at McLean, “There was a young colleague here running an outpatient psychopharmacology clinic. Within about a one-month period, he had two site visits on two grants projects. It turned out that a couple of the visitors came to both visits. At lunch on the second visit one of them called the PI [principal investigator] aside, and said, ‘I’ve been scribbling some numbers on the back of an envelope about the patient flow through your clinic,’ and he said, ‘the numbers don’t add up. Can you explain them? Last time we visited, you had a project on major depression, today we’re talking about anxiety disorders. How come?’ The PI blushed and said, ‘Some of them are the same people. You can move them one way or the other, depending on the needs.’”
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U ntil DSM-III in 1980, the supposed difference between anxiety and depression lived on mainly in the world of pharmaceutical advertising, where diseases were found to fit the compounds on hand, rather than the other way around. The benzodiazepines, launched in 1960 with Librium, are actually quite suitable agents for mixed anxiety-depression. But they would be spun either toward anxiety or depression, depending on the needs of commerce. The Upjohn Company, for example, wanted to introduce its benzodiazepine alprazolam (Xanax) in 1981 as an antidepressant and was blocked from doing so only by the absence of an inpatient study.
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So they ended up with a marketing hit for panic disorder! (more on this in Chapter 9). Big bucks were riding on the question of whether anxiety was a separate disease: If separate, different agents would be needed to treat it. If the same, the patient could be spared one prescription. The entire issue became degraded by commercial considerations.*

*A fter the disaster of DSM-III’s major depression in 1980, a campaign began to insert “mixed-anxiety-depression,” called “cothymia” by Peter Tyrer,
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in the official diagnostic roster; and the campaign seemed to have succeeded in an early draft of DSM-5 in 2012. Yet, incredibly, in May 2012, the DSM-5 Task Force elected to delete the historic diagnosis on the grounds that not quite enough was known about it.
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C arried aloft by the two great wings of neurotic depression and mixed anxiety-depression, from the 1920s on the frequency of diagnosed depression soared.

A red light: It is unlikely that the frequency of serious depression, which has deep genetic roots in brain biology, ever changes over time. Why would it? Genetic influences shift very slowly, if at all, and there is no reason to think that patients who would have had a positive dexamethasone suppression test—which identifies organicity in melancholia—would be more numerous today than in 1790. A number of clinical observers believe this too, and view claims of an increase in depression with skepticism (although they did not always say this loudly in public, as the pharmaceutical industry had a great deal invested in the idea of an increasing epidemic of depression enveloping us all). Paul Kielholz, professor of psychiatry in Basel who, with his powerful personality, had a great deal to do with spreading the notion of epidemic depression (in forming the International Committee for Prevention and Treatment of Depressive Illness in 1975), was privately of the opinion that serious depression did not change historically. His friend and colleague Raymond Battegay recalled in an interview with David Healy, “Kielholz was always of the opinion that the major depressions remain constant over time because they are predominantly hereditary diseases. What increased were the depressions resulting from a more and more stressful human environment.”
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Gerald Klerman’s article in 1986 in a volume edited by Munich psychiatry professor Hanns Hippius firmly implanted in the profession the idea that the incidence of depression was increasing (although all he had to go on was the diagnosis of depression.
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) Yet ever since the eighteenth century, people have believed that they lived in a stressful environment, and the idea that increasing stress causes increased depression would be comparable to the notion that rising stress in the nineteenth century caused increased nervousness: Certainly doctors were impressed that nerves and stress were always on the rise. But this is meaningless.