Whither Melancholia?

After formulating and signing “Melancholia: A Declaration of Independence,” an international cadre of psychiatrists recently launched a campaign to have the upcoming DSM-V recognize melancholia as a distinct syndrome rather than as a specifier for the mood disorders of major depression and bipolar disorder.

Australian psychiatrist Gordon Parker, MD, PhD, sent a position paper, “Whither Melancholia? The Case for Its Classification as a Distinct Mood Disorder,” written by 17 experts^a in the field, to David J. Kupfer, MD, chair of the DSM-V Task Force, and to members of the DSM-V Mood Disorders Work Group.

Jan Fawcett, MD, work group chair, explained to Psychiatric Times that the work group has 4 major subgroups: major depression, bipolar disorder, suicide risk assessment dimension, and anxiety dimension. He gave the “Whither Melancholia?” position paper to the major depression subgroup to let them “chew on it.”

William Coryell, MD, head of the major depression subgroup and the George Winokur Professor of Psychiatry at the University of Iowa’s Carver College of Medicine, has communicated with Parker, lead author of the position paper, Fawcett said. Parker, who is executive director of the nonprofit Black Dog Institute at the Prince of Wales Hospital in Australia and who has conducted extensive research on melancholia and other mood disorders for more than 2 decades, was asked to provide additional evidence. Parker is also Scientia Professor of Psychiatry at the University of New South Wales.

The concept of melancholia is centuries old, said Max Fink, MD, one of the paper’s coauthors and professor emeritus of psychiatry and neurology at Stony Brook University, Stony Brook, NY. Melancholia was encapsulated into Emil Kraepelin’s concept of manic-depressive illness and accepted as such for decades, he added. In DSM-IV, it became a specifier for mood disorders.

“Rush and Weissenburger¹ reviewed the literature on melancholia and its implications for DSM-IV, and concluded that melancholia should be a specifier but not a separate entity,” Fink said. “Yet when Michael Taylor [University of Michigan psychiatrist] and I read the paper, it clearly presented good evidence for melancholia as a separate entity.”

Taylor and Fink² compiled and analyzed studies about melancholia and published their book, Melancholia: The Diagnosis, Pathophysiology, and Treatment of Depressive Illness in 2006. That same year in May, Fink with Parker joined Edward Shorter, MD, of the University of Toronto, and Tom Bolwig, MD, of Copenhagen University, to launch the Copenhagen conference, “Melancholia: Beyond DSM, Beyond Neurotransmitters.”

“The participants of that conference agreed that the syndrome was best separated from the amorphous descriptions of ‘major depression’ and ‘bipolar disorder’ and recommended it be a separate entity in the DSM-V,” said Fink.

The reports on the study of melancholia and current research were published in a 2007 supplement to Acta Psychiatrica Scandinavica.³

“The DSM-V work group members,” Fink said, “will describe major depression according to formulated criteria. We urge their consideration of melancholic depression as a specific type of depression that should be identified separately. It should have its own classification number and be considered a distinct entity, because it is an identifiable syndrome with recognizable clinical signs, verifying laboratory tests, and validating treatment responses.”

Melancholic depression is a severe illness. Most of those affected end up in hospital settings, Fink said, adding that some 60% of the patients with depression referred for electroconvulsive therapy (ECT) have melancholia.

The current melancholia specifier in DSM-IV does not properly demarcate melancholia, Fink contended.

The position paper authors stated that many of the specifier’s symptoms (eg, anhedonia, psychomotor agitation or retardation, weight loss, excessive or inappropriate guilt) are also criteria for major depression. Thus, they compromise attempts to distinguish melancholia and to clarify its etiological and treatment differences.

Proper identification

The proper identification of melancholia as outlined in the position paper requires the presence of prototypic signs across all or most of the following domains:

• Disturbance in affect, usually disproportionate to any stressor and marked by unremitting apprehension, morbid thoughts, and blunted emotional response: so that clear reactivity of mood is generally inconsistent with a diagnosis of melancholia

• Psychomotor retardation that may be expressed in reduced facial and vocal reactivity, as well as by anergia or, in severe instances, torpor

• Psychomotor agitation that may manifest the painful melancholic mood by profound apprehension, anguish, bewilderment, perplexity, and motor agitation (eg, hand-wringing and pacing) or in severe instances, by pathologic guilt, importuning themes, and stereotypic movements

• Cognitive impairment with distinctly impaired concentration

• Vegetative dysfunction displayed by loss of sleep (most commonly early morning wakening), appetite, and weight, as well as diurnal variation (with mood and energy generally worse in the morning)

• Psychosis (in some patients) expressed as delusions and/or hallucinations; nihilistic convictions of hopelessness, guilt, sin, ruin, or disease are common preoccupations

Patients with melancholia are very likely to have disorders in endocrine metabolism that can be identified through laboratory tests, Fink said.

Three tests help define melancholia, Fink said: the dexamethasone suppression test (DST), with measurement of cortisol levels; the thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH); and a sleep electroencephalogram (EEG).

“The TSH response to TRH test is more often abnormal in melancholic depression than in other forms of illness, but this test is not as sensitive as the DST. The DST is a measure of the severity of melancholia. Results normalize with remission of the illness and become abnormal again with relapse. The sleep EEG is abnormal in many patients who have melancholia, but it is not an easy test, and it is best used to better define the syndrome,” Fink said.

While lacking absolute sensitivity and specificity for diagnosing melancholia, the tests could be helpful, Parker said, noting that further clarification studies are needed.

Treatment considerations

Patients with melancholic depression generally respond well to tricyclic antidepressants (TCAs) or ECT, Fink said. Remission rates for effective ECT are on the order of 80%.

“Studies of melancholic depression do not show a benefit from psychotherapy,” Fink said. “Among melancholic depressed patients treated with psychotherapy only, there is a high incidence of suicide.”

Parker reported that there is a 10% response to placebo, a 30% to 40% response to SSRIs, a 40% to 50% response to dual-action antidepressants, a higher response to TCAs, and possibly a slightly higher again response to monoamine oxidase inhibitors (MAOIs).

“Adding low-dose atypical antipsychotic drugs (or lithium) to the antidepressant can further advance a response in some patients, due to true augmentation effects,” he said. “Melancholia responds well to ECT, although it is rarely required. The age of the patient has a distinct effect on treatment outcome (ie, as patients become older, their response to narrow-action drugs (eg, SSRIs) diminishes.”

Parker told Psychiatric Times that at the Black Dog Institute, they are using a computer-based algorithm of 32 clinical features to identify patients with melancholia.⁴ “Clinically, we also weigh the presence of a family history, and episodes that are more severe and persistent than might be expected by any (if any) antecedent stressors,” he said.

Recently, Black Dog Institute began a clinical trial for melancholic depression. The 12-week trial consists of 3 separate treatments involving patients with melancholic depression in each group. The treatments are individual cognitive behavioral therapy (CBT), an SSRI, and a broad-action antidepressant drug approach. Patients in the third group will start therapy with a dual-action antidepressant. If no response occurs with the dual-action drug, a progressive broadening strategy of medication (ie, antipsychotic, TCA, MAOI) will be followed.

“Clearly, the hypothesis is that medication is superior to CBT and that broad-action approaches are superior to an SSRI,” Parker said. “The study is powered on relevant data (ie, a meta-analysis showing that TCAs are 3 times more effective than SSRIs), and we anticipate that we will need a sample size in excess of 100.”

Mood Disorders Work Group

Fawcett was asked about the work group’s process for considering changes.

“People proposing changes to the DSM are thinking of the positives of what they are proposing, but we have to be sure that if we make the change, it is going to result in clarification for clinicians, usability for clinicians, and better treatments for patients,” he said.

The work group, he added, has to consider not only the positives but also the negatives and the implications of making changes.

“We are trying to change things where there are good arguments for the change and good evidence. The question is whether the evidence from Dr Parker, Dr Fink, and their colleagues is at the highest level to create a new diagnosis. It is the same issue with premenstrual dysphoric disorder and extended grief, among others,” he said.

Stability over time is an important validator of a diagnosis, Fawcett said. Parker has been asked to provide follow-up data on this issue, along with data on the specificity of laboratory tests for melancholia.

Unintended consequences are also a consideration. “The major depression criteria have been used in research for years, and there is a huge body of research on major depression,” Fawcett said. “If you change the criteria to accommodate melancholia as a separate entity, what are the unintended consequences?”

More generally, the work group is exploring the possibility of adding external dimensions to diagnoses rather than changing diagnostic criteria, Fawcett said. “Dimensional specifications carry more information, but we are stuck with categories to line up with medicine,” he said.

Kupfer in a recent American Psychiatric Association (APA) press statement noted that draft changes to DSM will be posted on the DSM-V Web site in January 2010. Comments will be accepted for 2 months and reviewed by the relevant DSM-V work groups in each diagnostic category. Field trials for testing proposed changes will be conducted in 3 phases.

To allow more time for public review, field trials, and revisions, APA president Alan Schatzberg, MD, just announced that the anticipated release date for the DSM-V has been moved from 2012 to May 2013. The extension will also permit DSM-V to better link with the US implementation of the ICD-10-CM codes for all Medicare or Medicaid claims reporting, scheduled for October 1, 2013, he added.

References:

References

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Rush AJ, Weissenburger JE. Melancholic symptom features and

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2.

Taylor MA, Fink M.

Melancholia: The Diagnosis, Pathophysiology, and Treatment of Depressive Illness.

Cambridge, UK: Cambridge University Press; 2006.

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Melancholia: Beyond

DSM,

Beyond Neurotransmitters. Proceedings of a conference, May 2006, Copenhagen, Denmark.

Acta Psychiatr Scand Suppl.

2007;115(433):4-183.

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Parker G, Fletcher K, Hyett M, et al. Measuring melancholia: the utility of a prototypic symptom approach.

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