Posted on Tuesday 21 June 2011

The other day, I encountered two things almost simultaneously. The first was a 2007 Journal Supplement on Melancholia that I found compelling. As I was reading through the articles, someone sent me a link to an abstract I hadn’t seen from Drs. Rush and Trivedi – a policy piece about Measurement Based Care. There was a striking contrast between articles in the Supplement and the later Abstract, and they lingered in my mind together through several busy days.

The 2007 Supplement in the Acta Psychiatrica Scandinavica was called Melancholia: Beyond DSM, Beyond Neurotransmitters [I liked both "beyonds"]. It was from a conference in Copenhagen in 2006. I felt nostalgia as I read through the various articles. They were like journals used to be before they got filled up with clinical trials. The Preface set the stage for the conference:

    There has been rising unhappiness within psychiatry and psychopharmacology over the heterogeneous nature of ‘major depression,’ over the poverty of current patent-protected offerings in the treatment of mood disorders, and over the lack of innovative new approaches in drug discovery. In May 2006 a group of specialists in the biology, history and clinical care of mood disorders met in Copenhagen to consider one of the principal illness entities within the category ‘major depression’– melancholia. The point of the conference was to identify new directions in the biological understanding and clinical care of melancholic illness, a robust historical diagnosis that now seems ripe for revival…

    Melancholia represents a disease in itself on the basis of psychopathology, biology, and response to treatment. MMD is characterized clinically by psychomotor change and symptoms of severe mood disturbance; biologically, it demonstrates distinctive neuroimaging features, a characteristic response to the dexamethasone suppression test, and shows rapid eye movement sleep latency; in therapeutic terms, melancholia responds preferentially to electroconvulsive therapy and to certain psychopharmacologic approaches. Non-melancholic mood disorder, by contrast, demonstrates few of these characteristics and represents a mixture of anxiety, character disturbance, and situational reactions that requires further elucidation…
There was a clear description of the syndrome of Melancholia:
Resurrecting melancholia
by M. Fink & M. A. Taylor
Acta Psychiatrica Scandinavica 115[s433]:14–20, 2007.

Objective: To define melancholia as a distinct mood disorder, identified by unremitting depressed mood, vegetative dysfunction, and psychomotor disturbances, verifiable by neuroendocrine tests, and treatable by electroconvulsive therapy and tricyclic antidepressants.
Method: A review of the literature of two centuries finds descriptions of severe mood disorders, either depression or mania or circular, defined as ‘melancholia.’ In the 1980 diagnostic revision (DSM-III), melancholia was relegated to a features specifier only.
Results: DSM classification criteria develop heterogeneous patient samples that are neither guides to prognosis nor to treatment response, and confound studies of pathophysiology. Within the large population of mood disorders, a syndrome of melancholia is identifiable by specific behaviors, vegetative signs, and validated by neuroendocrine abnormalities (cortisolemia). Populations so identified are clinically homogeneous and have improved treatment responses. Patients meeting criteria for melancholia are now identified as psychotic depressed, geriatric depressed, postpartum psychosis, and pharmacotherapy resistant.
Conclusion: The review supports the establishment of melancholia by empirically derived criteria rather than by a checklist is an alternative to the major depression choice and offers an improved model for psychiatric classification.
Fink and Taylor even gave us some [DSM-III sounding] criteria for melancholia:
Dr. Bernard Carroll [et al] was there [out of his watchdog mode and in his researcher role] with a sophisticated study of cortisol dynamics in Melancholia.
Pathophysiology of hypercortisolism in depression
by B. J. Carroll, F. Cassidy, D. Naftolowitz, N. E. Tatham, W. H. Wilson, A. Iranmanesh, P. Y. Liu, and J. D. Veldhuis
Acta Psychiatrica Scandinavica 115[s433]:90–103,2007.

Objective: The mechanisms mediating hypercortisolemia in depression remain controversial. Adopting the biomarker strategy, we studied adrenocorticotropin (ACTH) and cortisol dynamics in hypercortisolemic and non-hypercortisolemic depressed in-patients, and in normal volunteers.
Method: Deconvolution analysis of 24-h pulsatile secretion, approximate entropy (ApEn) estimation of secretory regularity, cross-ApEn quantitation of forward and reverse ACTH–cortisol synchrony, and cosine regression of 24-h rhythmicity.
Results: Hypercortisolemia was strongly associated with melancholic and psychotic depressive subtypes. Hypercortisolemic patients had elevated ACTH and cortisol secretion, mediated chiefly by increased burst masses. Basal ACTH secretion was increased, ACTH half-life was reduced, and mean 24-h ACTH concentration was normal. Cortisol secretion was increased in a highly irregular pattern (high ApEn), with high ACTH → cortisol cross-ApEn (impaired feedforward coupling). Cortisol-mediated feedback on the secretory pattern of ACTH was normal. Hypercortisolemic depressed patients had normal programming of the central hypothalamo–pituitary–adrenal (HPA) axis pulse generator: ACTH pulse frequency, cortisol pulse frequency, circadian acrophases, and ApEn of ACTH secretion were normal. Responsiveness of the adrenal cortex to endogenous ACTH was normal. Non-hypercortisolemic patients resembled hypercortisolemic patients on ACTH regulatory parameters but had low total cortisol secretion.
Conclusion: Increased ACTH secretion occurs in depressed in-patients regardless of cortisolemic status, confirming central HPA axis overdrive in severe depression. Depressive hypercortisolemia results from an additional change in the adrenal cortex that causes ACTH-independent, disorderly basal cortisol release, a sign of physiological stress in melancholic/psychotic depression.
But the article that I found myself rereading was this one:
The doctrine of the two depressions in historical perspective
by E. Shorter
Acta Psychiatrica Scandinavica 115[s433]:5–13,2007.

Objective: To determine if the concept of two separate depressions – melancholia and non-melancholia – has existed in writings of the main previous thinkers about mood disorders.
Method: Representative contributions to writing on mood disorders over the past hundred years have been systematically evaluated.
Results: The concept of two separate depressions does indeed emerge in the psychiatric literature from the very beginning of modern writing about the concept of ‘melancholia’. For the principal nosologists of psychiatry, melancholic depression has always meant something quite different from non-melancholic depression. Exceptions to this include Aubrey Lewis and Karl Leonhard. Yet the balance of opinion among the chief theorists overwhelmingly favors the existence of two quite different illnesses.
Conclusion: The concept of ‘major depression’ popularized in DSM-III in 1980 is a historical anomaly. It mixes together psychopathologic entities that previous generations of experienced clinicians and thoughtful nosologists had been at pains to keep separate. Recently, there has been a tendency to return to the concept of two depressions: melancholic and non-melancholic illness. ‘Major depression’ is coming into increasing disfavor. In the next edition of DSM (DSM-V), major depression should be abolished; melancholic mood disorder (MMD) and non-melancholic mood disorder (NMMD) should become two of the principle entities in the mood disorder section.
I first encountered Dr. Shorter through his book Before Prozac: The Troubled History of Mood Disorders in Psychiatry which was an invaluable resource in looking back at the genesis of the DSM-III. The abstract doesn’t do justice to this article which reviews the history of clinical depression classifications. He makes the point that the collective clinical intuition throughout history is that there are two kinds of depression [except for the last thirty years]. He goes on to discuss how modern science confirms the distinction, and concludes the obvious:
    This argument of the two depressions has two important practical implications. If one accepts the notion that there are two depressions, then major depression of the DSM has no longer exists. As an amalgam of the two depressions, major depression should be removed from the next edition of the Manual.

In those early days of the DSM-III, one frequently heard the argument against "n = 1" science. It was, of course, aimed at psychoanalysis which focused on one case at a time, then generalized to groups. They were saying that was backwards, it should be group findings generalized to individuals. The point has been duly noted and taken. But there’s another way to think about that discussion. For clinicians, it’s always an "n = 1" situation – the one case before you at the moment. It’s how all of medicine is practiced. As such, a meeting of a clinician and a patient should be an encounter between a person with "ill-ness" and the history of medicine’s experience – with an eye on diagnosis, treatment, and management.

I thought all three of these articles would inform my meeting with a depressed patient. Drs. Fink and Taylor offer a set of criteria to separate out a kind of depression that directs treatment and management. Dr. Carroll et al furthers the understanding of the only thing close to a biologic marker in psychiatry [an abnormality in cortisol metabolism] with a graph that demonstrates the obvious difference between the two kinds of depressed patient:

And finally, a historian who focuses on psychiatry reviews the history of medical views of depression, including exceptions to the prevailing view, and argues that separating out Melancholia remains clinically relevant. He says, " major depression should be removed from the next edition of the Manual."

Besides the fact that I’m sympathetic to the conclusions in these articles, the things that struck me were their transparency and the fact that they seemed to be written to be read by colleagues. I’ve been reading clinical trial articles for months, and I’m always looking for what’s being buried and what spin is being put on the results – where I’m being lead. I found these articles a refreshing change of pace.

Then this abstract popped up in the middle of my reading:

Measurement-based care in psychiatric practice: a policy framework for implementation.
by Harding KJ, Rush AJ, Arbuckle M, Trivedi MH, Pincus HA.
Journal of Clinical Psychiatry. Jan 11, 2011 [Epub ahead of print]

This article describes the need for measurement-based care (MBC) in psychiatric practice and defines a policy framework for implementation. Although measurement in psychiatric treatment is not new, it is not standard clinical practice. Thus a gap exists between research and practice outcomes. The current standards of psychiatric clinical care are reviewed and illustrated by a case example, along with MBC improvements. Measurement-based care is defined for clinical practice along with limitations and recommendations. This article provides a policy top 10 list for implementing MBC into standard practice, including establishing clear expectations and guidelines, fostering practice-based implementation capacities, altering financial incentives, helping practicing doctors adapt to MBC, developing and expanding the MBC science base, and engaging consumers and their families. Measurement-based care as the standard of care could transform psychiatric practice, move psychiatry into the mainstream of medicine, and improve the quality of care for patients with psychiatric illness.
The contrast was jarring. These are the authors that brought us the algorithm studies: TMAP, STAR*D, IMPACT and CO-MED. The algorithms in each case were not based on science or actual studies, they’re based on questionnaires sent to experts of various kinds. The original Expert Guidelines came from researchers, clinicians, mental health officials, and advocacy groups.  TMAP was built largely from those guidelines and their revisions. It cost a mint, had no real outcome advantage, was an ethical nightmare, and seems to have evaporated with little trace. As seen in my recent posts [detestable…, a long awaited corner…], the pharmaceutical industry was the key background player in both sets of algorithms. Then came the $35 M NIMH STAR*D, again with an arbitrary algorithm of drugs all of which were conflicts of interest for Rush and Trivedi [algorithmic psychiatry – the algorithms…]. STAR*D brought us confusion more than anything else [The STAR*D trial: the 300 lb gorilla is in the room, but does it block all the light?]. IMPACT was heavily advertised but actually never even occurred [algorithmic psychiatry – the fall…]. And CO-MED was a spectacularly negative outing [another “dud”…]. So  I thought it was a bit presumptuous for the authors of this string of psychopharmacological mis-adventures to be suggesting policies to get us all to follow in their footsteps. It reminded me of the saying, "Insanity is doing the same thing over and over again, expecting different results."

But beyond their presumptuousness, I’ve realized that it’s the way they write. They’re not writing to colleagues, they’re selling a product. In this offering, they’re thinking up ways to get us all to do their measurement-based care thing and proposing a campaign to bring us around – including "financial incentives." Their track record is so lackluster that it’s hard to see why they think we’d want to follow their lead. The last time they did this was TMAP, the now defunct program that was mostly oriented towards getting people to use expensive in patent drugs – drugs made by companies that financed their initiatives and paid them to be consultants and speakers.They haven’t figured out that we read their articles with one eye trained on "what are they trying to get us to do this time?"

They would do well to read the Symposium that I began with. It models what medical researchers and "Key Opinion Leaders" actually ought to be doing. We don’t need people like Trivedi and Rush who are heavily contaminated by industry influences telling us how to practice medicine. I doubt many of us think they know much more than the rest of us. We need scientists and thinkers who are trying to help clinicians broaden our understanding of the patients we see and their diseases…
    Melon Collie
    June 22, 2011 | 5:48 AM

    ]’m going to show this to my doctor – there’s no telling how differently treatment and outcomes could be…I am one of the terminally stressed.

    Bernard Carroll
    June 22, 2011 | 5:58 PM

    Thanks for noticing our Supplement on melancholia.

    The sad thing about much of current clinical research is that it has an agenda, which may be promoting a drug (like experimercials for second generation antipsychotic drugs in depression) or showcasing a programmatic initiative (STAR*D and its cousins) or undisciplined but profitable blue skying (hyperbole about translational research, as in the pitifully unproductive Emory-GlaxoSmithKline-NIMH Mood Disorders Initiative) or data mining for evidence, any evidence, to support a favored theoretical model (combined psychosocial and drug treatment of disorder X).

    The price paid for such agenda driven research is steep: The really hard clinical research questions don’t get asked; precious infrastructure resources are squandered in support of misbegotten studies; and young investigators see their mentors preoccupied with scoring points in the grants game instead of dispassionately addressing the important questions.

    NIMH under its recent Directors has been an enabler of these perverse trends.

    June 22, 2011 | 9:15 PM

    “perverse trends” is a perfect name for it. It’s like the Myth of Sisyphus on purpose. They don’t seem to notice that they never move up the hill…

    June 22, 2011 | 10:18 PM

    Despite the impressive scientific EVIDENCE supporting the classification of melancholia as a distinct mood disorder, my read is that the DSM-V committee (AKA the Council of Nicaea) will VOTE to maintain the staus quo as to the major depression classification. In so doing, the conflict of interest-ridden committee will vote the interests of Big Pharma and unethical biological psychiatrists (note I did not say all biological psychiatrists) so as to continue the “push product at all costs to the masses” mind set of current psychiatry. I am just waiting for the inclusion of a “prodromal major depression” category to surface soon.

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