Back in December, I had a shot at responding to a question about Melancholia. I had recently seen a case and it was fresh on my mind [melancholia…, as precisely as possible…]. Although it’s a term from antiquity, the disease is still with us just like it has always been. It’s not all that common. It got removed from the DSM-III for reasons that still make little sense to me, reasons discussed in those earlier posts. It makes little sense because the condition hasn’t gone away. Of all the failings of the DSM-III, DSM-IV, and the coming DSM-5, none seem so absurd as removing this unique clinical syndrome. It is as distinctive as an Acute Schizophrenic Decompensation – once seen, it’s never forgotten.
When I posted about my case [as precisely as possible…], Dr. Bernard Carroll, former Duke Chairman and noted Biological Psychiatrist commented, confirming the diagnosis. He’s the expert on Melancholia, not me. Today, I got two notes. The first was a thank you note from the afflicted person I mentioned. We found him a psychiatrist near where he now lives and he responded to appropriate treatment. The second was a heads up that Dr. Carroll has an editorial that just came out in Bipolar Disorders this week entitled, Bringing Back Melancholia. It’s not available full text online, but the first page is posted here. He’s included a poem that describes the syndrome. The poem shows on the sample page and has annotations pointing to the corresponding clinical symptoms and signs.
The February 2012 edition of World Psychiatry contains a special article on a related theme: Wakefield&First conclude that there is simply not the empirical evidence to support the proposal to eliminate the bereavement exclusion to major depression in DSM-V. It’s worth a read.
I’ve just read Dr. Carroll’s editorial in Bipolar Disorders and have a few questions,
For a diagnosis of Melancholia, does one have to have all the cardinal features? If not, how many of the cardinal features does one have to have?
I don’t mean to turn this into a numbers game — I’m interested in whether one could still have this type of depression absent, for example, feelings or guilt or self-devaluation. Or if one only had a few of the cardinal features. Any feedback would be appreciated.
My son has a type of recurring endogenous depression that isn’t really captured by the criteria listed in the DSM-IV or proposed DSM 5, or by Dr. Carroll’s description of Melancholia either (at least if one has to have all/most of the cardinal features).
Thank you for your question, Jackie. We did not stipulate an exact number of symptoms. One reason for that is because mild and early cases may not express the full picture. Another reason is because the underlying process may be patchy, giving rise to some cardinal symptoms and accessory symptoms but not all of them. For that matter, DSM-IV does not require all the defining symptoms to be present, either. So, the scenario you describe is certainly possible, Jackie.
We may think about melancholia in the way neurologists think about Parkinson’s disease. PD has patchy underlying pathology and variable symptoms. PD has 4 cardinal symptoms (rigidity, slowness, resting tremor, gait disturbance). Not every patient has all of these, and the expression of PD varies from one patient to another, just as the expression of melancholia does. One patient with melancholia may be markedly agitated and guilty whereas another may be profoundly psychomotor retarded and anhedonic.
What determines the clinical diagnosis in PD and melancholia is the overall pattern of signs and symptoms, along with the past history and the family background. Over time, as more clinical data come in and as we see how the person responds to treatments, then the certainty of the clinical diagnosis may increase. However, clinicians are taught to tolerate some uncertainty, so in the beginning the treatment threshold is usually set at a diagnostic probability level of 80%.
The clinical diagnosis of PD, by the way, is not a slam dunk in every case, and quite a few turn out eventually to be PD look-alikes. We need to keep that in mind when we think about melancholia. I like to use the term Kraepelin’s disease for the classical, familial, prototype mood disorder, while recognizing that there are look-alikes such as late onset vascular based melancholic episodes.
What a thoughtful set of questions and responses! Apropos of perhaps, wild speculation, I ran across some studies demonstrating a fairly robust linear association between constitutional hypotension and depression+anxiety, followed by depression, then anxiety. It leads me to wonder if there isn’t some impairment in cerebral blood flow as a result which then instigates that fretful anxiety response, along with the cognitive and attentional impairments so often attendant. I also read that there is an almost perfect correlation with increased cortical stimulation and prolonged wakeful periods. The insomnia associated with depression might also be a result of an under-perfused brain trying to raise an alarm, if not blood pressure, with self-stimulation. Has anyone treated the underlying hypotension and gotten decent antidepressant results? I asked a neuroscience blogger, and she posted a thought-provoking review of a few of the recent biologic processes studies. Neither of us found any clinical treatment and patient outcome studies.
Yeah but Dr. Carroll, (and I have great respect for you), since you invoke the model of PD, what is the “patchy underlying pathophysiology” of melancholia?
Good question, Tom. The short answer is, we don’t know. There are some reasonable leads, however, and these are being worked on. In general terms, I think of PD as a monoamine disconnection disorder: when the dopamine producing neurons in the midbrain die then the forebrain targets that are normally inhibited by dopamine become overactive and the cardinal motor signs of PD appear. In the emotion circuits of the brain, the corresponding monoamines are mainly norepinephrine and serotonin which, like dopamine, also are mainly inhibitory on their forebrain targets. Interruption of norepinephrine and/or serotonin projections from brainstem to forebrain areas like anterior cingulate cortex and prefrontal cortex would lead to functional changes in emotion circuits that resemble the functional changes that occur in motor circuits in PD.
How might these key projections be interrupted? Here are several ways. Sustained stress results in degeneration/retraction of terminal arborizations of norepinephrine neurons in the forebrain projection fields, with consequent loss of synaptic contact. A second way is genetic vulnerability. One candidate for that is the Val66Met polymorphism of the gene for BDNF (brain derived neurotrophic factor). Maintenance of synaptic connections (such as between projecting norepinephrine neurons and prefrontal cortex) depends in part on BDNF, so this loss of function polymorphism sets the person up for stress-related disconnection. Remember, too, that all antidepressant treatments induce activity of BDNF with a lag time and that this is now considered a key step in antidepressant treatment action (that includes ECT, by the way). A third way is for the ascending monoamine neuron projections to be damaged by vascular lesions, especially in the anterior limb of the internal capsule. This quite likely is the basis of so-called vascular depressions. A fourth way is for the brainstem monoamine neurons to die, which they do in Huntington disease, Parkinson disease, and Alzheimer disease. The resulting disconnections of forebrain sites would then be considered a prime factor in the secondary depressions associated with each of these degenerative conditions. Finally, certain drugs that are well known to cause depressions resembling melancholia produce a pharmacological disconnection. Exhibit A is reserpine, which blocks the vesicular monoamine transporter (VMAT) and thus depletes monoamine terminals of stored neurotransmitter.
Back to the idea of patchy underlying pathology: the classic example of patchy pathology is PD, where symptoms for the first years may be strictly unilateral. It is not unreasonable to think that the factors described above also may be patchy. The symptom repertoire of a given patient with melancholia then may depend on his/her unique distribution of lesions in the emotion circuits.
Sorry if this is a long winded answer, but you asked for it.
Thanks! I learned a lot.
Dr. Carroll,
That you for your long and considered response to my questions, although I’m disappointed that you didn’t have any easy answers/quick fixes for me! Kidding, of course.
After 10 years of various types of treatment, my son can still be debilitated (as he is now) by depression — but he has never been on a TCA. As maybe he has Melancholia, and would benefit from TCAs, I am definitely going to do some research on this.
Thank you again.
aek,
Once again, you’ve come up with things that make us go hmm …
In response to your post above, it seems to me that anyone doing research in this area would cite the Nord-Trondelag Health Study (HUNT).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2465598/
Perhaps you could find some answers by looking at who is citing HUNT in their work? Hope so …
@ Jackie: Yeppers – that’s the largest set of studies (there are two) that I’ve run across. But no one is citing them, nor it seems, is pursuing this line of research. So far. That’s why I contacted the neurosci folks to see if rat/mouse/other species studies had been done. I was hoping to gather best evidence and make a case to present selfishly for my own treatment as I am used to being an N=1 guinea pig, but I don’t think it will go anywhere. The only interesting clinical tidbit I ran across is that apparently in Europe (not the UK, though), hypotension is not treated as a benign condition and is viewed as aberrant in the absence of optimal athletic conditioning.
Today’s field trip is attending a Harvard Law School lecture titled: Clinical Trials: Is Corporate Sponsorship Compatible With Credibility?. Harvard should really consider introducing its right hand to its left sometime. But it makes for interesting times…
@ Dr Carroll:
I’ve read and re-read the poem accompanying your listing of clinical features. Selfishly, I am grateful for its ability to hone in with unerring accuracy to get at the gist of the experience. It is incredibly on target. Is what is published on the first page the poem in its entirety? And are you the author? What was the process in writing it?
It comes across as having experienced all of it, rather than simply diagnosing the clinical features and applying the poetic descriptors. After the first sense of relief that someone understands, reading it makes me feel rather sad that the poem came to fruition as a result of that suffering.
And finally, it leads me question what can be done to lessen the distress – especially when all of the “standard” treatments fail, and the distress just goes on without end…
@ aek: Thank you for the compliment. I am happy that you report the poem rings true. Two other veterans of melancholia have told me the same thing in recent days.
The poem does not arise from my personal experience, rather from 45 years of listening to patients and teaching. As to process, it began as a contribution to another journal that was calling for 100-word commentaries on current psychiatric issues. When they declined I added the surrounding text, and the journal Bipolar Disorders was kind enough to publish it as an invited editorial.
I wish you well in seeking relief.
@aek
Here is a link to a 22-year follow-up paper for the HUNT study (which you probably have already!) published in Mid 2011:
http://www.biomedcentral.com/1471-2458/11/601
A few of the papers in the references section look interesting … and the lead author leaves a link to his email address.
If I see anything else on the hypotension/depression link, I’ll pass it along it to you via your own website.
Thanks so much, Jackie. I had read that, and I continue to mosey around the literature. Challenge is finding a clinician who might be interested, though…