unique endophenotypes

Posted on Friday 19 November 2010

Biological Consequences and Transgenerational Impact of Violence and Abuse
Understanding the Risks Associated With Early Life Stress
Psychiatric Times
By Gretchen N. Neigh, PhD, Lorie A. Ritschel, PhD, and Charles B. Nemeroff, MD, PhD
November 17, 2010
My obsession with Dr. Charles Nemeroff, defrocked Chairman of Psychiatry at Emory now Chairman of Psychiatry at the Miller School of Medicine in Miami did not disappear. There just haven’t been any recent developments. Today, I received a Google alert that Dr. Nemeroff had an article published in the Psychiatric Times – a free Psychiatric Publication that still comes to my mailbox even though I’ve been retired for seven years. The article itself is something of a review article similar to many that have Dr. Nemeroff’s name attached. The topic is two-fold. First, people who have had early life trauma tend to develop adult mental illnesses. A variable number of such people have abnormal stress hormone responses that persist into adulthood. Moreover, the offspring of traumatized people likewise may show the same predisposition to mentalillness and abnormal stress hormone responses [transgenerational transmission]. Obviously, this raises fascinating questions and is the focus of many studies in both humans and laboratory animals. You may recall that one of Dr. Nemeroff’s presentations this Summer was on this topic [August 7th]:
He believes that the response to various medications in Depression varies with genetic types and that "non-responders" may be genetically predestined. I had my say about one of his studies that he uses to support this hypothesis earlier [how’s your life…]. I have no idea if what he thinks is true or not. I kind of doubt it. But I feel confident that the studies he’s basing his thoughts on don’t come close to justifying his conclusions.

The article published above runs on the same lines, proposing various possible mechanisms for the transmission of vulnerability to mental illness from childhood ELS [early life stress] to adulthood and to offspring. He assumes that the passage is biological and focuses on the pituitary/adrenal axis [stress hormones] as the culprit – a mechanism under investigation for decades. Millions of research dollars have been spent chasing this theory yielding a lot of tempting but not yet definitive data.

But there’s another piece in this recurrent line of thinking in his publications, that there’s a genetic piece to this puzzle – that some as yet undefined genetic factor predisposes some people to pass on this vulnerability. Where he’s headed is the same direction as the paper this summer – that someday, patients will be sent to a genetics lab and that treatment will be determined by the outcome. If that’s true, the proof will come later, because it’s not in the studies I read in his references. Obviously, I’m a doubting Thomas on this point. But my reason for bringing it up is to point out certain jumps on logic that are in this paper that don’t pass muster.
Numerous biological theories have been proposed to explain the potent and robust effects of ELS on mental and physical health outcomes. One such theory, the diathesis-stress model, posits that:
    • Excess reactivity of certain neural and endocrine systems increases individual vulnerability to stress-related disease
    • Exposure to stress during developmentally critical periods results in persisting hyperreactivity of the physiological response to stress
Thus, genetically susceptible individuals are at increased risk for stress-related disease.
It’s a theory, not a fact. It doesn’t deserve a "Thus." It calls for a "Thus, if this theory is proven." But then we read:
Regardless of the developmental stage during which it occurs, exposure to violence and trauma alone does not produce adverse effects in all exposed women. Thus, the risk of PTSD and/or depression is, in part, heritable.
Now there’s a "Thus" that’s indefensible. There are a blue jillion other possible reasons that all exposed women don’t become vulnerable to future illness. He might as well say that "All soldiers shot in battle don’t die. Thus, the risk of dying from a gunshot is, in part, heritable." And then later we read:
The data described in this review indicate that patients with MDD or PTSD and a history of ELS may constitute unique endophenotypes with respect to course of illness. In addition, such patients may also require a unique treatment protocol.
There’s nothing in this paper or the case presented that leads to this conclusion except as a speculation that I’m sure antedated the paper [or the many other papers that preceded this one]. It’s something he and his colleagues want to be true – a dream.

My point here is that there’s a series of hypotheses that range from "possibly" to "maybe" through "kind of" on the way to "far fetched" that are linked to a recurrent conclusion – that the fuzzy mental illnesses we work with are actually discrete biological entities, treatable with specific medicines, with responses determined by genetic make-up. That’s way beyond the research findings – a speculative conclusion in search of a proof rather than a reasonable hypothesis arising from the data itself. And even more to the point, it’s a lucrative idea – doing genetic testing, treating with expensive drugs, etc. And it leaves out the possibility that the "mind" is involved in mental illness. eg the disclosures:

My bias is clearly on the mind side of the equation, though some of the biological treatments are quite helpful and the speculative genetic/ biological hypotheses are intriguing. So I’m not arguing against the hypotheses themselves. What I’m arguing against is messy speculative science being mispresented and wildly extrapolated. And as always with Dr. Nemeroff, I’m arguing that there’s a profit motif in the background of his hypotheses. Note the disclosures:
… Dr Nemeroff reports that he has received research grants NIH MH 039415, MH 42088, MH 058922, MH 069056, MH 077083; he is on the scientific advisory boards of CeNeRx, NovaDel Pharma, Inc, PharmaNeuroBoost, American Foundation for Suicide Prevention (AFSP), NARSAD, Takeda; he has stock/equity in Corcept; Revaax; NovaDel Pharma, Inc, CeNeRx, PharmaNeuroBoost; he is on the board of directors of the AFSP, NovaDel Pharma, Inc; and he holds the following patents: (1) Method and devices for transdermal delivery of lithium (US 6,375,990B1); (2)Method of assessing antidepressant drug therapy via transport inhibition of mono-amine neurotransmitters by ex vivo assay (US 7,148,027B2).
I’m curious about the mechanisms of transmission of vulnerability too. I wonder about the biology of it myself. I’m less curious about all this business about "non-responders" to medications being based on some genetic factor. Most of the people I see who don’t respond to antidepressants have a perfectly good reason not to respond – and it’s in their history, their personality, or in their life situation, not in their DNA…
    Ivan the Terrible
    November 19, 2010 | 1:59 AM

    Good work deconstructing yet another Nemeroff pastiche, Mickey.

    Nemeroff by now is beyond derision. Who cares what nonsense he places in a low tier publication like Psychiatric Times? It’s the scientific equivalent of borderline functioning – the as if mode of speculation. Only the ifs don’t hold water.

    Then he packages it with preposterous terms like preeminent (as in my ideas), burgeoning (as in evidence), concatenation (of evidence), and intriguing (as in wild speculation for which there is no evidence beyond wishful thinking).

    Fuhgeddaboudit already.

    November 19, 2010 | 7:34 AM

    It’s not much of an offering, granted. But it reminds me of his earlier stream of “intriguing” productions, no more scientific than this one, that made it to the big time – like the “promising” vagus nerve zapper.

    Then there’s this:
    Likely 1: “Thus, minimizing ELS would likely reduce the risk and severity of multiple mental and physical illnesses and stop the transgenerational cycle of abuse-related pathology.” Somehow, this perfectly obvious conclusion has lead to any number of successful grant applications.

    Likely 2: “In addition, a better understanding of the mechanisms that underlie the pervasive effects of ELS will likely lead to improved behavioral and pharmacological treatment strategies.” Like RU-486? or what?

    I remain awed that this kind of thinking has had such an impact on Psychiatry, one that continues to exert its influence in these days of late paradigm exhaustion. I would hope that even the Psychiatric Times could move from preeminent, burgeoning, concatenation, and intriguing to remotely scientific.

    Mostly, I feel guilty for not screaming about him 25 years ago. I think I was intimidated by… I don’t know how to end that. Maybe it was that my own branch of things had oversold itself for the 25 years before

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