Coyne project

Hi colleagues, 

Facts be damned!? Over the long haul, science, as for most things involving our species, is about community consensus. I believe this is called "epistemological community." 

"Mon griefs" article is a "smoke and mirrors" production. Why so... why so?

There's little question from their biochemical pharmacology that most known classes of drugs termed "antidepressants" block or alter many 5-HT receptor type functions dose- dependently, or biphasically, at many anatomical locations within multiple organisms including the human. 

"MyGrief" tries very hard to make the case that altered serotonin functions are not tightly associated with "depression" in any stage, or with its pharmacological treatment.    Conflated with this is her well-documented crusade to persuade all those in ear shot that antidepressants are ineffective, and perhaps risky treatments. This is bordering on criminal science. 

For a moment let's remove the conflating factor and concentrate on the recent review. The umbrella review suffers from too little rainfall. No matter how well constructed the umbrella, it is not necessary when it's not raining.  The review required, but had to omit, according to the rules of Prospero "Hoyle", the serious depression of bipolar disorder.   (If there were not enough data - then screw the review.) While quibbling about the outcome measures - HRSD versus the categorical responder rates - the review nevertheless relied on DSM definitions of depression, while apparently taking baseline HRSD severity scores as a given.  And in this regard covariance It is exceedingly important to add that baseline covariance does nothing to solve the issue separating out responders from non-responders however defined,  

What is required here is more of a SIPHON than an UMBRELLA analysis. This is not so much to get at the "truth" as it is to get at hypotheses to be tested. My question would be "of those studies in which 5HT functionality or its metabolites were measured whether or not outcomes could be post-hoc analyzed based on baseline severity within each study itself." I suspect that the numbers of patients per study are too small to be persuasive. But, if such post-hocs were replicated from study to study, we would be on to something quite practical. 

I hope all here realize that most anti-depressant data post 1984 or so is garbage - as patients have become more and more professional and suffer a false depression compared to those institutionalized before SSRIs,  no matter how to find, depression as his exist in the FDA database of approved any depressants is a hodgepodge of garbage. Even so diluted, a small efficacy signal shines through all the garbage... The argument that this is due to un-blinding is likely BS just as analyzed in a paper I authored in 2004, In which the opposite is observed.  

I have already illustrated my data-filled reasoning on "depression", its severity, and treatment response, including most persuasively replicated dose response curves within studies on baseline severity. This appears in my 50+ page response to Professor Barry Blackwell.   

So, where to go from here? 

There are enough data to support antidepressant prescription in people who qualify in whatever way as seriously depressed. I would say that withholding such treatment in such patients, is nothing short of criminal malpractice. In this I am not saying that psychotherapies cannot be very helpful. But as I have remarked, the control groups of psychotherapy research - although creative, are science window dressing. 

Taking a cue from current events surrounding abortion, I would say that Moncrieff and her adherents, could be considered accomplices warranting designation as criminals for spreading their "sheep in wolfskin science." It is most unfortunate that scientific consensus in medicine would need to rely on lawyers. But that is where we are given some of the uncertainties in medicine.  The once trusted BMJ – well-meaning possibly – is an embarrassment. 

The most serious issue to my small brain is that serotonin norepinephrine and dopamine (their blockades, amplifications) are involved intimately with most bodily functions and at the most granular level of molecular pathways of general energy metabolism and immune reparative response. Because they have an effect on a state of human and animal behavior we term depression, we must be compelled to understand how to obtain pristine small clinical subtypes, and exhaustively follow these at the most granular level in terms of known and unknown biochemical pharmacology - which now includes location specific genetic molecular pathways. This is not going to be easy because earliest studies have shown that 1/3 of any pristine population will fail to respond to anything. 

I do believe that the key to understanding antidepressant actions is within the body's response to acute and chronic threat, the immune response in all of those tissue compartments that are well protected or not -- and in acute, chronic and what becomes chronic disease.  I feel once as we get closer, we will see exactly how psychotherapies might be efficacious in some cases and how not in others. and to be very clear I am saying that among the few probes we have are existing antidepressants. 

To be clear, I am saying that it is important not to withhold treatments that may seem to be only marginally effective statistically. This is after all within the realm of clinical practice. This requires longitudinal individual patient assessment of risk versus benefit. There is no umbrella or other review in the world that can substitute for such clinical wisdom. And this wisdom is evidence-based in the reality of a patient - an individual patient, despite what detractors say.  

What are the actual motivations of the Healys, Moncrieffs, and Kirschs of the world to publish their stuff? We know they are smart – so what the hell are they doing that is constructive for humanity? I feel what they are doing is self-serving which is okay if it were beneficial! 

As I reread this, I see that what I'm saying maybe taken as impractical. But if so, let it be a humbling moment for us all.  In 2022 we are only at the very beginning of the evolving science of psychopharmacology / neuropharmacology. As I have opined previously, the biggest changed in medical science are likely to come through the field of physics that is why – as a hobby – I follow that field more than any other. 

Best regards, 

Mark Kramer

October 6, 2022