Scientists may not know exactly why, but antidepressants work

by | Sep 22, 2022

Antidepressants work. Antidepressants don’t work. Which is it? Let’s check-in with two academic psychiatrists who believe they do, even if scientists don’t know exactly why.

…psychiatrists have never explained clinical depression solely in terms of reduced serotonin or any specific neurotransmitter.

Here we are, smack-dab in the middle of the “Do antidepressants work?” donnybrook.

Two weeks ago I posted “Serotonin and Depression: Is there really a relationship?.”

It’s a discussion of a recent University College London (UCL) news release entitled “No evidence that depression is caused by low serotonin levels, finds comprehensive review.”

That comprehensive review was conducted by a team of UCL researchers and published in Molecular Psychiatry.

Not serotonin, not a chemical imbalance

The team’s bottom-line is summed up in the title of the release. And we can add depression isn’t likely caused by a chemical imbalance.

That’s right, so why bother with antidepressants?

I didn’t question the accuracy of the data used in the review. However, I sensed an “agenda-driven bias” and “unyielding bite” that made me uneasy.

For the record, two of the team members published a follow up article in which they more directly attacked antidepressants.

Up front, this is a long article. But it has to be, given the abundance of interesting and need-to-know information.

So get comfy, take breaks, read it over a couple of days, whatever – you don’t want to miss this.

Serotonin or not, antidepressants work

Seems I wasn’t the only one uncomfortable with the review.

Bumped into an article on Psychiatric Times entitled, “Serotonin or Not, Antidepressants Work,” written by academic psychiatrists and psychopharmacologists Ronald W. Pies, MD and George Dawson, MD.

The byline: “The latest claim that antidepressants don’t work: refuted.”

Dr. Pies and Dr. Dawson get right down to it…

In our view, the credulous, media-driven narrative generated by the review and the follow-up article amounts to well-worn rhetoric – and the review itself is little more than old wine in new bottles.

Furthermore, we find at least 7 serious problems with the review’s claims, each of which undermine the review’s thesis, as we will elaborate.

We’re going to dig in to those “serious problems.” And to bring them to you I’ve had to do some pretty intense condensing and editing. The docs were on a mission.

7 serious problems with the review’s claims

  1. “Psychiatry” has never proposed a theory of depression asserting it’s caused by one or more neurotransmitters. Dr. Dawson conducted a detailed review and found no references to a “chemical imbalance theory” of mental illness in any standard psychopharmacology textbook or peer-reviewed literature over the past 30 years.
  2. Psychiatrists have known for decades that the cause of depression and other mood disorders can’t be explained solely in terms of a single neurotransmitter. Furthermore, in the period of 1990 to 2010, psychiatrists and neuroscientists proposed at least 17 other hypotheses regarding depression, with eight additional ideas since then.
  3. The complexity of serotonergic (having to do with serotonin) systems and signaling in the brain is not captured in the review. Recent work in this area reveals that although serotonin systems are now much better characterized, additional work needs to be done. The review’s claim that psychiatric research on serotonin has yielded no useful information – and that this whole area of research should be brought to a close – does not accurately reflect the current scientific research program.
  4. Information in the review wasn’t news to psychiatrists. At least four investigations of the 5-HT (serotonin) hypothesis found inconclusive or inconsistent evidence. The most recent review (2017) concluded that additional evidence was needed to support the model and resolve inconsistencies. These authors also proposed several new 5-HT receptor-based hypotheses.
  5. The brain contains about 50 to 100 neurotransmitters. Hypotheses regarding depression have extended far beyond serotonin – indeed, far beyond biogenic amines (e.g., the monoamine neurotransmitters: norepinephrine, histamine, dopamine, etc.). The review is focused narrowly on serotonin and does not address other small molecule or neuropeptide neurotransmitters (e.g., galanin) that may figure in antidepressant action. Furthermore, the review does not address effective nonserotonergic antidepressants like bupropion (Wellbutrin) or antidepressants like vortioxetine (Trintellix), which have very complex serotonergic effects.
  6. In the area of drug development, there has been active debate about whether a specific mechanism of action and/or drug target is necessary for a medication to be approved. Dr. Dawson recently reviewed the package inserts of drugs that were FDA approved as disease-modifying drugs for multiple sclerosis. Eighteen drugs have been approved since 1993, yet the mechanism of action for 17 of the 18 medications is listed as unknown.
  7. The techniques described in the review were not designed to determine antidepressant efficacy, which is determined by randomized controlled clinical trials. Thus, no conclusions can be drawn from the review regarding antidepressant efficacy, or the “good versus harm” associated with antidepressant treatment.

Told you they were on a mission.

Clinical approach to depression  

antidepressants work

“Okay, I’ve examined both sides. Now I can work on an informed decision.”

Pies and Dawson weren’t finished.

They go on to say that in response to the UCL review, several neuroscientists and researchers have pointed out that the role of serotonin in mood disorders isn’t settled science.

There may well be some role for it in some types of depression.

They quote psychiatrist and researcher Michael Bloomfield, MD…

I don’t think I’ve met any serious scientists or psychiatrists who think that all [cases] of depression are caused by a simple chemical imbalance in serotonin. What remains possible is that for some people with certain types of depression…changes in the serotonin system may be contributing to their symptoms. The problem with the review is that…it has lumped together depression as if it is a single disorder, which from a biological perspective does not make any sense.

Pies and Dawson point out that the review doesn’t in any way impugn the overall safety and effectiveness of serotonergic antidepressants in the acute treatment of moderate-to-severe major depression. They’re concerned the public may be led to believe otherwise.

That said, they believe antidepressant treatment should be undertaken conservatively, monitored closely, and regarded as only a single component of a comprehensive, biopsychosocial approach to depression, generally including talk therapy.

As such, patients should be educated regarding all three components of mood disorders: biological, psychological, and sociocultural.

Finally, the risk/benefit discussion concerning antidepressants (and other biological treatments in psychiatry) should be approached in the same way as the physician would approach any other serious medical intervention.

Dr. Pies and Dr. Dawson conclude

Dr. Pies and Dr. Dawson wrap up their article by referring to depression as a complex, heterogeneous disorder with biological, psychological, and sociocultural determinants and risk factors.

They go on to submit that few, if any, US psychopharmacologists and academic psychiatrists have ever endorsed a sweeping chemical imbalance theory of mood disorders.

Historically, psychiatrists have never explained clinical depression solely in terms of reduced serotonin or any specific neurotransmitter.

Perhaps most important of all, Pies and Dawson hope that patients and clinicians are not deterred from the use of antidepressants by the review, or by the fact that the SSRIs’ mechanism of action is complex and not completely understood.

An informed decision

Antidepressants work. Antidepressants don’t work. Which is it? Well, you’ve gotten a full dose of “they do.” Two weeks ago you got “they don’t.”

And now you can work on an informed decision.

Take the time to read “Serotonin or Not, Antidepressants Work” on Psychiatric Times. You’ll find lots of info and tables I couldn’t possibly include.

And be sure to read the “they don’t” point of view: “Serotonin and Depression: Is there really a relationship?

More Chipur mood and anxiety disorder info and inspiration articles? Here ya’ go

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