Twenty-five years ago a depressed patient told researchers at Columbia University College of Physicians and Surgeons, "You know those people who run around the park with lead weights? I feel like that all the time. I feel so heavy and leaden [that] I can’t get out of a chair."
The statement graphically portrayed a symptom peculiar to a subset of depressed patients first described by English psychiatrists a generation earlier as "atypical." The Columbia researchers, seeking to define the group more rigorously, incorporated that symptom—which they called "leaden paralysis"—into the criteria that currently serve as the basis for a diagnosis of "depression with atypical features."
That diagnosis depends on the presence of "mood reactivity"—depressed mood that can brighten readily at a positive turn of events—in conjunction with any two of the following: hypersomnia, hyperphagia, leaden paralysis, and interpersonal rejection sensitivity.
But while experts agree that the definition roughly describes a subgroup of people who are different from those with classic melancholic depression, much about the description, including the centrality of mood reactivity, is debated.
Even researchers involved in developing the original Columbia University criteria agree that the diagnosis requires refinement.
"There is something out there that we can call atypical depression, but the problem is that the DSM criteria are too broad," said Jonathan Stewart, M.D., a professor of clinical psychiatry at Columbia and a research psychiatrist at the New York State Psychiatric Institute.
"It’s clear to me that even though it captures most of the people who have the disorder—whatever it is—it probably captures a lot who have something else."
As Stewart recounted, almost 50 years ago the English psychiatrists West and Dally first described a subset of patients who were depressed but whose clinical symptoms differed from those of classic melancholic depression. Moreover, while this group did not respond to tricyclic antidepressants, it did respond to monoamine oxidase inhibitors (MAOIs).
Stewart said the Columbia research in the 1980s confirmed the latter, identifying a group of depressed patients who preferentially responded to the MAOI phenelzine sulfate. The treatment studies also validated criteria for atypical depression that originated with published observations by the English group and by the American Donald F. Klein, M.D., with reactivity of mood as the basic distinguishing characteristic.
"If you are depressed and something nice happens, you feel better for a while," Stewart explained. "In contrast, the quintessential melancholic is an emotional rock. The melancholic is not going to have any reaction at all."
Stewart and colleagues also found the opposite to be true of the patients with atypical depression—that they had an extreme reaction to negative events, particularly interpersonal rejection that others might just brush off. In contrast to the insomnia and loss of appetite usually seen in patients with melancholic depression, the patients with atypical depression were prone to overeating and oversleeping.
Since the development of the Columbia criteria, however, the uncertainty about how exactly to characterize these patients has become apparent, with some researchers and clinicians emphasizing some aspects over others.
Linda Carpenter, M.D.: "As we learn more about the biology of depression—not just the phenomenology, but the biological markers—we will be able to lump less and split more."
"The original criteria were adopted on the basis of nonresponse to tricyclic antidepressants, not on the basis of a biological or genetic finding," said Linda Carpenter, M.D., chief of the mood disorders program at Butler Hospital in Providence, R.I., and an assistant professor of psychiatry at Brown University School of Medicine.
In this way, she said, people with atypical depression are a subgroup that has been defined by researchers—and the definition is still in the making. Carpenter added that the picture is complicated by the fact that patients with bipolar disorder, anxious depression, and personality disorders share some of the features of atypical depression.
So, even a reasonable estimate of prevalence is elusive, depending on what criteria are used to identify the atypical patient.
"The term atypical depression makes it sound like some rare thing," said Frederick E. Miller, M.D., Ph.D., chair of the department of psychiatry at Evanston Northwestern Healthcare in Evanston, Ill.
"Of the patients I see, it’s a common minority, depending on how much you stress the requirements in the DSM criteria. But it is not uncommon to see someone whose chief complaint is lethargy, who says [he or she] can sleep a thousand hours, but who also doesn’t eat a lot.
"Are we making rational distinctions?" Miller wonders. "Or are we just sort of splitting certain symptoms that are part of a more general condition?"
A recent analysis of depressed patients with atypical features emphasizing the reverse vegetative symptoms—overeating and oversleeping—suggest that those two symptoms alone might serve as important markers of atypical depression for primary care physicians who might not otherwise look for the disorder.
The study, appearing in the September Archives of General Psychiatry, used the two symptoms to identify 836 patients with major depression, 304 of whom had atypical features and 532 who did not, in the National Comorbidity Survey.
Study author Louis S. Matza, Ph.D., told Psychiatric News that the analysis suggests that the simpler criteria emphasizing overeating and oversleeping could be readily used by primary care physicians to identify depressed patients who are liable to have a different clinical course and possibly a different response to treatment.
He noted that the study found that the patients who fit the criteria had an earlier onset of illness. They also reported higher rates of depressive symptoms, suicidal thoughts and attempts, psychiatric comorbidity, drug dependence, and a history of paternal depression, childhood neglect, and sexual abuse.
Matza is with MEDTAP International of Bethesda, Md. MEDTAP is a research organization specializing in health outcomes research.
Stewart, a co-author of the study, noted that the earlier age of onset found among the patients identified by the NCS is "exactly what we see in patients with atypical depression as diagnosed according to the full DSM-IV criteria."
Experts who reviewed the study for Psychiatric News found compelling the use of the reverse vegetative symptoms to identify atypical depression in such a large national sample.
Carpenter agreed that hypersomnia and hyperphagia are prominent. "A person with atypical depression is usually slowed down, as opposed to agitated and moving around a lot," she said. "They will tell you they are oversleeping and overeating—that is sort of a classic characteristic. If you had to say what jumps out when you see these patients, that would be it."
But she and others expressed surprise, and some skepticism, about the finding of an increased-risk profile for suicide and comorbid psychiatric disorders among people with atypical depression.
"There have been plenty of typically melancholic depressed patients who are significantly ill," said Mark Frye, M.D., director of the bipolar research program at the University of California, Los Angeles. "The idea that [atypical patients] have more drug use is remarkable as well. I am not sure I have seen that. It makes me think that many of these patients are covert bipolars."
Miller, too, expressed surprise at the finding and—underscoring the complicated picture of atypical depression—wondered whether the increased risk found among the sample could reflect the confluence of personality disorders.
All the clinicians interviewed by Psychiatric News agreed that reverse vegetative symptoms cannot be used as criteria to start patients on MAOIs as a first-line treatment.
"Why force someone into following an MAOI regimen with its side-effect problems until you have demonstrated that less problematic treatments are not going to work?," Stewart asked.
Stewart told Psychiatric News that he and colleagues have refined their definition of atypical depression, focusing on early onset and chronic course as critical features.
"If you sort the patients who meet the criteria [for atypical depression] into those who have early-onset chronic illness and those who have later-onset or nonchronic illness, those two groups look entirely different," he said.
Moreover, the "true" atypical patients with early onset and chronic course differ from both late-onset nonchronic patients and from patients with classic melancholic depression on cortisol testing and auditory perceptual processing, as well as on their response to tricyclic antidepressants.
"The patients with melancholic depression and late-onset atypical depression lie on the same side of normal controls on cortisol testing and perceptual processing, while these early-onset chronic patients lie on the opposite side of normal controls," Stewart said. "This demonstrates to me that they have biologically different disorders. It argues against the notion of depression as a continuum and in favor of the idea that these categorical distinctions make some sense, that they are biologically distinct disorders."
More generally, experts said, the stubborn existence of a subgroup of atypical depressed patients—distinguishable in terms of symptoms, drug response, and possibly even underlying neurobiology—points to the possibility that "depression" itself is less a disease than a description, encompassing a variety of subtypes.
"As we learn more about the biology of depression—not just the phenomenology, but the biological markers—we will be able to lump less and split more," Carpenter said. "The nosology will reflect more subtypes as we have greater understanding of the biological, genetic, and psychosocial contributions."
An abstract of the study, "Depression With Atypical Features in the National Comorbidity Survey: Classification, Description, and Consequences," is posted on the Web at http://archpsyc.ama-assn.org/cgi/content/abstract/60/8/817?. ▪
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