1 Boring Old Man

I think you nailed it, Dr. Mickey. The heterogeneity of what DSM called major depression created noise sufficient to mask any signal from the really good studies, such as the one by Wayne Drevets and colleagues in 1992. Back in the day, we talked about selecting patients for such studies very carefully. We thought it best to enroll only clear-cut cases for a first look with new technologies like PET or fMRI scans. We also did our best to apply plausible clinical distinctions such as melancholic versus nonmelancholic versus atypical cases. We did that even while recognizing that the reliability of such distinctions was not perfect for all cases. But by contrasting patients at the ends of the spectrum we might learn something, while leaving it for later to resolve issues in the less-clear middle group.

The story told in this review article underlines the futility of studies that ignore clinical heterogeneity among depressed patients. You could add waste to futility, too – waste of time, waste of funding, waste of clinical research resources and infrastructure. Robert Spitzer and the DSM-III crowd have a lot to answer for.

It is a waste. Reading through this article and its supplements, one has the sense of some solid scientists who put some real sweat equity into doing it right. While some of their statistical comparisons are beyond any place I’ve been or am likely to go, they did a good job of making it apparent how much this kind of research needs standardization – and the thrust of their recommendations had to do with improving this methodology. But as to their topic of the brain in Unipolar Depression – how many different ways do we have to be shown that the category is not an entity, not a disease, not really even a disorder? It’s a large group of people with similar symptoms who have been inappropriately “lumped” together.

“By using the revised activation likelihood estimation algorithm, different meta-analyses were calculated.”

I would not put any more faith in meta-analyses that the spreadsheet analyses and selection of variables that preceded them.

Does any clinical psychiatrist need a meta-analysis of research imaging results to tell them that depression is a heterogenous group of disorders? The only factor that I have ever seen produce better results was depression severity (HAM-D scores >30). The trade-off for most researchers is that it would take years to accumulate a large enough group of those folks who were also not severely personality disordered.

I would also not agree that major depression has not played out as an entity. It plays out every time I see somebody who is severely depressed, depressed and psychotic, or depressed and suicidal. I am counting on that literature and inductive reasoning to come up with a strategy to treat that person. Much more often than not I am correct. The severely depressed are not great placebo responders and they generally have failed multiple treatments and providers before I see them. The only logical conclusion is that there is something there in that literature despite the noise of polygenes and epigenetic effects.

George, I recognize what you say but I would caution that severity and typology (subgroup) are not the same constructs. But you are right to say that when you encounter a patient with severe symptoms that include mood-congruent psychotic features and who is incapacitated then you pretty much know what ballpark you are in.

Barney, I recognize the focus on constructs that are used to differentiate the idea of depression. I don’t know if you read Kendler’s paper earlier this year in the Am J Psychiatry on diagnoses as an indexing effort rather than something more specific. Being interested in human consciousness and the computational ability of the human brain – is there a factor in the conscious state of the psychiatrist that is not explicit in making these diagnoses and treating the problem? We do have the qualifier that reading the criteria are not enough. But it is clear that psychiatrists vary in their diagnoses and treatment practices.

I think that Kendler is correct. Criteria in a manual get us into the ballpark. After that – experience treating thousands of people in that ballpark lead to refined diagnostic and treatment procedures. Severity just makes things clearer.

Nobody really adequately discusses that process. I posed the following question to an expert in epidemiology and statistics: “In your review critical of antidepressants I have treated many times the number of patients in these studies with much better results. At what point can we say that meta-analyses do not really reflect the treatment condition or psychiatric expertise?”

He never responded to me. As far as I know – nobody ever addresses this obvious point. Psychiatrists and Big Pharma are lumped together as ineffective based on highly biased studies and meta-analyses that have nothing to do with clinical practice

A big part of that variance is that a diagnosis by a real psychiatrist in not an indexing procedure and treatment in not a clinical trial. And more importantly – the difference between my much larger and better results and some clinical trial or meta-analysis is more than the placebo effect.

George, I agree with your emphasis on idiographic versus nomothetic approaches to diagnosis. What you say about skilled clinicians reflects their capacity for pattern recognition, which is essential if we are to avoid diagnosis by checklist. And, of course, clinicians vary greatly in their ability to discern clinical patterns. I have long taught that the proper use of formal diagnostic criteria is to verify that the idiographic diagnoses made by clinicians conform to a minimum nomothetic data set. But the clinical diagnosis comes first, and it can be influenced by factors that are outside the diagnostic criteria – like family psychiatric history or the course of past episodes. Such “external” factors can change the Bayesian prior probabilities of competing diagnoses. Good clinicians are attuned to such “external” factors.

It’s important as well to keep clearly in mind the distinction between defining a disorder and diagnosing a case. Those are not coterminous operations, and that’s what Kendler was getting at with his comments about indexing. When there is disagreement between the clinician’s idiographic diagnosis and the checklist criteria then a clinical override may be contemplated. That should not happen very often, and it always raises the specter of a goofy clinician (yes, they do live among us). In such cases, deferral of the diagnosis may be preferable or a second opinion could be requested. Needless to say, none of these nuances are captured by the brute force of EHRs.