Major Depression After Recent Loss Is Major Depression - Until Proved Otherwise

Suppose your new patient, Mr. Jones, tells you he is feeling “really down.” He meets all DSMIV symptomatic and duration criteria for a major depressive episode (MDE) after having lost his wife to cancer 2 weeks ago. Should you diagnose major depressive disorder?

I’m guessing most psychiatrists would be reluctant to do so. Indeed, DSM-IV permits a “bereavement exclusion” in such circumstances, provided the patient lacks “certain symptoms that are not characteristic of a ‘normal’ grief reaction.”

But, say, another week has gone by. Mr Jones tells you tearfully, “Doc, I caused my wife’s cancer. I’m thinking of driving my car into a tree. I’m just not worth keeping around.” He shows marked psychomotor retardation and has missed work this past week. Is this just “normal grief”? Maybe not so much, now that Mr Jones has those “certain symptoms” that would override the bereavement exclusion. These vexing issues are nicely discussed in a recent editorial by Maj.¹

In the November issue of Psychiatric Times, we ran a commentary² by Professors Alan V. Horwitz, PhD and Jerome C. Wakefield, PhD, authors of The Loss of Sadness: How Psychiatry Transformed Normal Sorrow into Depressive Disorder.³ Essentially, the Horwitz-Wakefield (H-W) thesis holds that the “decontextualized” criteria for MDE set forth in DSM-III (1980) and DSM-IV have created a “seeming epidemic of depression” and spuriously high depression prevalence rates. By “decontextualized,” Horwitz and Wakefield mean without considering the context of loss or bereavement that makes the person’s depressive symptoms “normal” or understandable. The second linchpin in the H-W thesis is the claim that psychiatrists can-and should- determine how “proportionate” the depressed person’s response is to the recent loss-based on so-called evolutionarily derived criteria.^3(p221)

The Loss of Sadness is a thoughtful book with honorable intentions. But I believe the H-W thesis puts the conceptual “cart” many years before the evidentiary “horse,” and that its practical effect could be to undermine our care of some bereaved patients who also meet MDE criteria. I should note here that despite a collegial email exchange with Professor Wakefield, I remain deeply skeptical of the H-W thesis.

What is at issue here?
Let me be clear: after a major loss, many people experience intense sadness and isolated depressive symptoms (e.g., tearfulness, insomnia, poor appetite) that may not constitute “disease” or “mental disorder.” Many will feel better with simple support and “tincture of time,” after 1 to 2 months. As Maj notes, “Adepressive state is an expectable and culturally sanctioned response to the death of a loved one and . . . does not represent a mental disorder.” ¹This much is not in dispute.

Rather, the controversies arising from the H-W thesis are these:
• Are there controlled, prospective data showing that recent loss or bereavement per se predicts a benign, self-limited course when the patient meets all symptomatic and duration criteria for an MDE?
• Are there controlled data showing that major depressive symptoms after recent loss or bereavement differ in fundamental ways, including treatment response, from typical depressive symptoms without loss or bereavement?
• Do we have any clinically validated instruments, based on “evolutionarily derived” criteria, by which to judge how “proportionate” a patient’s depressive reaction is to a putative stressor?

In our present state of very limited evidence, I believe the answer to these questions is no.^1,4

Common sense or theoretical bias?
Horwitz and Wakefield make much of “common sense” in their book. Thus, they believe “a wealth of evidence supports the commonsense judgment that many people who develop symptoms of depression after a loss, even when they meet DSM criteria for a disorder, are not disordered, but are experiencing a biologically designed response.” ^{3(p51, italics added)} First, we would do well to recall Einstein’s well-known dictum: “Common sense is the collection of prejudices acquired by age 18.” As for the supposed “wealth of evidence,” a careful search for controlled, prospective studies reveals only poverty.

Now consider the following “commonsense” view of depressive symptoms in the context of bereavement. Common sense tells us that bereavement-related depression (BRD) will abate on its own within a few weeks or months as the patient copes with the loss. Common sense tells us that BRD symptoms will more closely resemble those of “normal sadness” than those of nonbereaved (“standard”) major depression. And, because BRD is precipitated by a unique loss, common sense tells us the depression is not likely to recur, all other things being equal. Finally, common sense might tell us that BRD is a normal, “adaptive” response to loss, whose “biology” and response to antidepressants would differ considerably from that of standard major depression.

This is all quite commonsensical- and all quite without convincing controlled evidence. For example, Brent and colleagues⁵ studied depressive reactions in youths exposed to a friend’s suicide. The exposed subjects developed symptoms most consistent with major depressive episodes-not uncomplicated bereavement-on the basis of both course and risk of recurrence. The median duration of depression in the 37 subjects who became depressed was 8 months! Compared with controls, the exposed subjects also had a higher rate of depressive recurrence during the follow-up period, even after adjusting for previous history of depression and other risk factors.

Similarly, Karam and associates⁶ compared features of bereavementrelated and non–bereavement-related major depression in a prospective community study (N = 685). The global “symptom profile” of depressed persons and their risk for depressive recurrence was similar in bereaved and non-bereaved subjects. Moreover, the duration of illness was actually longer in the bereaved group. The authors concluded that “the descriptive and etiologically neutral approach the DSM presumes in reaching a diagnosis should be applied in the case of [major depression] until more convincing data point to the contrary.”

We have very limited data on the neurobiology of BRD versus “standard” major depression. However, Zisook and Kendler⁷ found that, in general, BRD has biological features that resemble those of “standard” major depression, including impaired immune function and excessive adrenocortical function. And it is far from clear that these abnormalities represent merely an “adaptive” response to loss.

Some features may distinguish BRD from depression triggered by other losses or stressors. These include lower rates of seeking professional treatment⁸ and less interference with life activities in BRD.⁹ However, there are deep clinical and epistemological problems in the notion of a unique “trigger” for a depressive episode; for example, chronological distortions in a patient’s recollection of depression onset^1,4 and the presence of underlying medical factors.⁴ Indeed, I believe the construct of a depressive “trigger” is nebulous and empirically unverifiable, except perhaps in highly unusual scenarios (for instance, a euthymic subject is injected with a powerful, short-acting biogenic amine-depleting agent; severe depressive symptoms develop within 2 hours and then spontaneously remit over the next 12 hours).

The appeal to “tradition”
Horwitz and Wakefield repeatedly invoke what they call the “2500-year history of psychiatric medicine”^2,3 in defending their depression “with cause versus without cause” distinction. Citing Aristotle, Felix Platter, and Emil Kraepelin, they argue that only depressive syndromes “without cause” were considered “mental disorders” throughout most of medical history.^3(p58) Our modern diagnostic schema, they maintain, “radically diverges from what has traditionally been considered appropriate.”^3(p53)

Let us put aside the suspicion that this argument is essentially an appeal to “eminence-based medicine.” We must still ask whether the “with cause versus without cause” distinction is really representative of how most physicians actually thought and acted during the entire 2500-year history of medicine. H. C. Erik Midelfort, professor of history at the University of Virginia, and author of the book, A History of Madness in Sixteenth-Century Germany (Stanford University Press), comments on this as follows: “. . . for ancient and early modern physicians, there was no clear, bright line between disease and health. They did not, generally, decide that someone was suffering an understandable and proportionate sadness and was not therefore ‘ill.’They generally decided that if one were suffering, for whatever reason and whether proportionate or disproportionate, they would do what they could to help . . . [and their remedies] did not depend upon a strict decision that so-and-so was fundamentally ‘ill’ while someone else was merely sad for good, sufficient, and proportionate reasons” (personal communication, October 2008; italics added).

Indeed, the physician’s primary role has always been to relieve suffering and incapacity-not to act as an amateur evolutionary biologist and sit in lofty judgment, as regards how “proportionate” a patient’s response is to some putative stressor.

Is there really an “epidemic” of depression?
Epidemiological data from the 1980s indeed suggested that the incidence of depressive disorders in cohorts born since WWII has been increasing in some countries, such as the US, Sweden, and Germany.¹⁰ However, recent, multi-decade epidemiological data from both the Baltimore ECA (epidemiological catchment area) Study¹¹ and the Lundby Study¹² from Sweden strongly suggest that the incidence of depression over the past 30 to 50 years has remained more or less the same, with the possible exception of rising rates in women. Both of these studies employed criteria similar to the “precipitant-neutral” criteria of DSM-III and IV.

To be sure, Horwitz and Wakefield do not claim that that there has been an “actual increase” in rates of depressive illness.^3(p4) Rather, they point to “the recent pandemic of seeming depressive disorder,” which they unambiguously attribute to “changes in the psychiatric diagnostic system presented in DSM III.” ² Furthermore, they believe that virtually all community-based epidemiological studies of depression since the late 1970s are contaminated by “false-positive” diagnoses of depression, owing to their decontextualized DSM criteria.³

But this notion of false positives is troubling on several levels. First, we do not have a veridical “test” for depression- akin to, say, detecting Treponema pallidum in syphilis-that would demonstrate that subjects have been “falsely” diagnosed as depressed, by DSM criteria. Nor, as healers, should we insist on such a test. Furthermore, the claim that epidemiological studies of depression produce many “false positives” assumes as true precisely what Horwitz and Wakefield have yet to prove: namely, that we should not “count” cases of BRD as depression. This would be analogous to a cancer researcher arguing that we should exclude mesothelioma cases that appear to be “provoked” by environmental exposure, without first demonstrating that such “precipitated” cases differ in their pathophysiology, course, outcome, response to treatment, etc, compared with spontaneous cases.

As for reports of rising rates of “depression” as a psychiatric diagnosis and increased antidepressant prescribing rates in recent years,^3(p187) these trends are probably driven by numerous factors. These include increased public awareness of depression; increased help-seeking; exposure of both patients and physicians to “Big Pharma” advertising; and pressure exerted by third-party payers to provide “reimbursable” diagnoses. These trends are certainly worrisome, but they cannot confidently be attributed to changes in our diagnostic criteria for depression. Indeed, I believe that overdiagnosis of depression-to the extent it occurs-often results from a failure to apply DSM criteria stringently, rather than to their use. This, however, is a conundrum that requires much more study. In my experience, I have observed what I call the “twin peaks” phenomenon: ie, underdiagnosis of depression in some clinical settings and overdiagnosis in others.

My objections to the H-W thesis should not be misconstrued as an endorsement of current DSM-IV criteria for major depression. Among several other problems,¹³ the 2-week duration criterion may be too brief (S. Zisook, personal communication, November, 2008). Extending it to 3 to 4 weeks might slightly decrease sensitivity but could increase specificity. Only carefully conducted longitudinal studies of depression outcome will decide the matter. But extending the duration criterion for MDE has nothing to do with attributing “special properties” to depression in the context of loss. It simply reflects the clinical observation that depression of only 1 to 2 weeks’ duration may spontaneously remit in some patients, given another 2 to 3 weeks.

Neither do I mean to suggest that the DSM’s categorical system of diagnosis represents the pinnacle of psychiatric wisdom. I and many others have long believed that a “dimensional,” psychodynamic, spiritual, and phenomenological understanding of grief and depression should complement and enrich the DSM categories.^14-18

A heart attack is a heart attack
Dr Zisook has observed that when someone has a myocardial infarction (MI), physicians regard it as an instantiation of cardiac disease, regardless of its “context.” The MI may have occurred in the context of the patient’s poor diet, smoking, and high levels of psychic stress-but it is still an expression of disease. We do not try to “normalize” the MI by saying, “Well, you’d have a heart attack, too, if you had been exposed to that much stress!” (This is a version of what I call the “Fallacy of Misplaced Empathy.”¹⁹) To be sure, knowing the medical and psychosocial context helps us counsel and treat the post-MI patient, just as knowing the experiential and sociocultural context of a patient’s depression facilitates holistic treatment, as Dr Zisook observes (personal communication, November, 2008). And, in so far as Horwitz and Wakefield have shown us the importance of “context” in these respects, they have performed a valuable service. One hopes their book may also spark some much-needed research.

Nevertheless, as Maj¹ concludes, “At the present state of knowledge, it may be . . . unwise to disallow the diagnosis of major depression in a person meeting the severity, duration, and impairment criteria for that diagnosis just because the depressive state occurs in the context of a significant life event.” Depression is a potentially lethal condition. It would be tragic if we inadvertently discouraged recently bereaved persons from seeking professional help, on the dubious presupposition that their depressive symptoms are merely “normal adaptations” to loss.

References:

1. Maj M. Depression, bereavement, and “understandable” intense sadness: should the DSM-IV approach be revised? Am J Psychiatry. 2008;165:1373-1375
2. Horwitz AV,Wakefield JC. An epidemic of depression. Major depressive disorder or normal sadness? Psychiatric Times. 2008;25:44-45.
3. Horwitz AV, Wakefield JC. The Loss of Sadness. New York: Oxford University Press; 2007.
4. Pies R. Depression and the pitfalls of causality: implications for DSM-V. J Affect Disord. In press.
5. Brent DA, Perper JA, Moritz G, et al. Major depression or uncomplicated bereavement? A follow-up of youth exposed to suicide. J Am Acad Child Adolesc Psychiatry. 1994;33:231-239.
6. Karam EG,Tabet CC,Alam D, et al. Bereavement related and non-bereavement related depressions: a comparative field study. J Affect Disord. 2008 May 29. Epub ahead of print.
7. Zisook S, Kendler KS. Is bereavement-related depression different than non–bereavement-related depression? Psychol Med. 2007;37:779-794.
8. Kendler KS, Myers J, Zisook S. Does bereavementrelated major depression differ from major depression associated with other stressful life events? Am J Psychiatry. 2008;165:1449-1455.
9. Wakefield JC, Schmitz MF, First MB, Horwitz AV. Extending the bereavement exclusion for major depression to other losses: evidence from the National Comorbidity Survey. Arch Gen Psychiatry. 2007;64: 433-440.
10. Klerman GL,Weissman MM. Increasing rates of depression. JAMA. 1989;261:2229-2235.
11. Eaton WW, Kalaydjian A, Scharfstein DO, et al. Prevalence and incidence of depressive disorder: the Baltimore ECA follow-up, 1981-2004. Acta Psychiatr Scand. 2007;116:182-188.
12. Mattisson C, Bogren M, Nettelbladt, et al. First incidence depression in the Lundby Study: a comparison of the two time periods 1947-72 and 1972-1997. J Affect Disord. 2005;87:151-160.
13. Zisook S. Commentary on chapter 1, “diagnosis of depressive disorders.” In: Herrman H, Maj M, Sartorius N, eds. Depressive Disorders. 3rd ed. Vol 9. Hoboken, NJ: John Wiley & Sons. In press.
14. Geppert C. The value of nothing. Psychiatric Times. In press.
15. Genova P. Dump the DSM! Psychiatric Times. http://www.psychiatrictimes.com/display/article/ 10168/47316. Published April 1, 2003.Accessed November 11, 2008.
16. Pies R. The anatomy of sorrow: a spiritual, phenomenological, and neurological perspective. http:// www.peh-med.com/content/3/1/17. Published June 17, 2008. Accessed November 12, 2008.
17. Schwartz MA,Wiggins O. Science, humanism, and the nature of medical practice: a phenomenological view. Perspect Biol Med. 1985;28:331-366.
18. Ghaemi SN. Feeling and time: the phenomenology of mood disorders, depressive realism, and existential psychotherapy. Schizophr Bull. 2007;33:122- 130.
19. Pies R. Is grief a mental disorder? No, but it may become one. http://psychcentral.com/blog/archives/2008/10/04/is-grief-a-mental-disorder-nobut-it-may-become-one/. Published October 4, 2008. Accessed November 11, 2008.

Further Reading
kiskal HS, Bitar AH,Puzantian VR, et al.The nosological status of neurotic depression:a prospective three to four-year follow-up examination in light of the primary- secondary and unipolar-bipolar dichotomies. Arch Gen Psychiatry.1978;35:756-766.
Almeida DM,Wethington E, Kessler RC. The daily inventory of stressful events: an interview-based approach for measuring daily stressors. Assessment. 2002;9:41-55.
Brown GW. Life events and affective disorder: replications and limitations. Psychosom Med. 1993;55:248- 259.
Clayton PJ, Herjanic M, Murphy GE, Woodruff R Jr. Mourning and depression:their similarities and differences. Can Psychiatr Assoc J. 1974;19:309-312.
Karam EG. The nosological status of bereavementrelated depressions.Br J Psychiatry.1994;165:48-52.
Kramer PD. Bereavement-related-depression is depression. http://blogs.psychologytoday.com/blog/in-practice/200809/bereavement-related-depressionis-depression. Published September 16, 2008. Accessed November 12,2008