Posted by Phillipa on September 19, 2015, at 20:19:21
After the article are sources & then doc comments P
Serotonin: How Psychiatry Got Over Its High School CrushSerotonin: How Psychiatry Got Over Its High School Crush
September 15, 2015 | Couch in Crisis
By Ronald W. Pies, MD
©aleisha/shutterstock.com
©aleisha/shutterstock.com
Weve had 6 or 7 decades with this paradigm, what I call the high school crush on serotonin.
--Roger S. McIntyreI owe the cheeky title of this piece to Roger McIntyre, MD, Professor of Psychiatry and Pharmacology at the University of Toronto, who was interviewed at the recent American Psychiatric Association (APA) meeting in Toronto. But before providing some context for Dr McIntyres quip, I invite you to consider 2 claims relating to mental illness:
Psychiatrists think that most mental illnesses are caused by a chemical imbalance.
Psychiatrists think that some mood disorders are associated with abnormal serotonergic neurotransmission, among other functional or structural brain abnormalities, which may or may not be the cause of the disorder.
Since there are light years of conceptual space between these 2 claims, you might imagine, or naively hope, that psychiatrys most strident critics would be able to distinguish claim 1 from claim 2. Alas, antipsychiatry bloggers continue to bang away at the notion that Psychiatry (that sinister, monolithic corporate entity) deliberately duped the public by promoting a bogus chemical imbalance theory, in cahoots with Big Pharma. Suffice it to say that this line of argumentation is itself bogus, for reasons I have reiterated at length in several venues.2,3 For example, in 2005, on a publicly available website, the APA clearly stated, The exact causes of mental disorders are unknown . . . [but] we can say that certain inherited dispositions interact with triggering environmental factors.4 At that time, the same APA website also indicated that several factors can play a role in the onset of depression, including biochemistry (abnormalities in brain chemicals or brain networks), genetics, personality, and environmental factors. To my knowledge, no professional psychiatric organization has ever publicly promoted a chemical imbalance theory of mental illness in general. (And, no, the original biogenic amine hypothesis was not a theorythe scientific distinction is important.5) That antipsychiatry bloggers assiduously comb the Internet and find a handful of celebrity psychiatrist quotes to the contrary neither surprises nor impresses me.
But there is a sense in which some of psychiatrys critics have a point, and this brings us back to Dr McIntyre and our old friend (or frenemy?), serotonin. It was not hard for the general publicand, alas, some doctorsto pick up the skein of serotonin and weave an entire tapestry with it, ultimately producing the threadbare chemical imbalance theory. No doubt, this was abetted by drug company illustrations of serotonergic synapses, complete with little packets of neurotransmitters whose reuptake is inhibited by the companys ace antidepressant.6 Even today, some non-pharma websites continue to post misleading diagrams that attribute depression to a chemical imbalance, as Dr John Grohol recently discovered.7
So, to be clear: to establish, for a particular patient, a bona fide imbalance of neurotransmitters, we would need a Gods-eye view, in real time, of the dozens (hundreds?) of neurotransmitters in her brain; their relative concentrations in relation to well-validated norms; and their deviations from the patients normal baseline. Clearly, we have no such divine insight into the brains chemical constituents, even though we have learned a great deal about the brains circuitry and neural networks in recent years.8
Furthermore, all this focus on serotoninwhile heuristically useful in some respectsmay have delayed more fruitful inquiries into the biological bases of depression. Indeed, when asked about the role of serotonin in depression, Dr McIntyre replied:
"I think theres been inertia in the field insofar as we had a paradigm based on serotonin. Weve had 6 or 7 decades with this paradigm, what I call the 'high school crush' on serotonin, and weve had treatments that fit into that paradigm, such as the Prozac-type drugs, the serotonin agents, etc. Although that paradigm/treatment applies to a subset of around 10% to 20% of patients remarkably well, we need to think of ways to reach other subpopulations of patients."1
I agree with Dr McIntyre. And, as I recently stated:
"There is little question that the role of serotonin in depression was over-emphasized and over-marketed in the 1990s, though most psychopharmacologists understood that the neurobiology of depression was much more complicated. Indeed, the term 'SSRI' is itself a misnomer, since some of these agents also affect other brain chemicals (eg, sertraline has mild effects on dopamine)."9
The neurobiology of depression is, of course, far more complicated than a simple deficiency of one or more neurotransmitters. In this regard, Dr McIntyre went on to elaborate an intriguing hypothesis that links some forms of depression to immune dysfunction, inflammation, and glucose dysregulationwhat he calls the immune inflammatory metabolic model.1 But it turns out that this model may link up with the serotonin hypothesis. Dr McIntyre notes, for example, that inflammation reduces serotonin in the brain. In principle, pharmacologic agents (eg, cytokine antagonists) that alleviate certain inflammatory conditions might amplify serotonergic function and reduce some types of depression.10 All this is just to say that, while the serotonin story has been greatly overblown, there are still reasons to retain some role for serotonin in at least a subset of persons with mood disorders.
No, this does not necessarily mean that mood disorders are caused by an imbalance of serotoninor any other brain chemical. Over 50 years ago, the fathers of the biogenic amine hypothesis, Drs Joseph Schildkraut and Seymour Kety, recognized the complexities of sorting out psychosocial causes from biological effectswhich can in turn become new causes or predispositions. They wrote:
". . . it is . . . conceivable that early experiences of the infant or child may cause enduring biochemical changes, and that these may predispose some individuals to depressions in adulthood. It is not likely that changes in the metabolism of the biogenic amines [dopamine, norepinephrine, and serotonin] alone will account for the complex phenomena of normal or pathological affect."11
The causal chain in the genesis of major depression is almost certainly long and complexprobably beginning with a genetic predisposition to depression, exacerbated by psychosocial stressors and losses, and worsened by dysfunctional personality traits and poor social supports. And while the self-defeating cognitions posited by cognitive theorists may not be a proximal cause of depression, their presence may deepen or prolong the persons depression.12 Recently, psychiatrists have also focused on socio-economic, educational, and cultural factors that contribute to the risk, and perhaps the onset, of clinical depression. In their recently released book, The Social Determinants of Mental Health,13 psychiatrists Michael T. Compton, MD, and Ruth S. Shim, MD, cite the following risk factors for depression: racial discrimination, poverty, unemployment, lack of social skills, reduced frustration tolerance and self-regulation, and food insecurity.14
All this is nothing radically newits really an elaboration of the biopsychosocial model that has dominated academic psychiatry since the 1980s. Clearly, this multi-level model bears little resemblance to a simplistic chemical imbalance theory. And it gives the lie to those who claim that psychiatry has become reductionistic, hostile to the role of the mind, or void of psychodynamic understanding. On the contrary, this expanded biopsychosocial model opens the possibility for therapeutic interventions at several links in the causal chain. Thus, antidepressantsand perhaps, someday, anti-inflammatory agentsmay ameliorate the biological components of depression, while psychotherapy reduces the experiential aspects of the illness, such as pathological guilt and self-loathing.
In short, if serotonin was once American psychiatrys high school crush, the field now appears wedded to a more mature model of biological and psychosocial understanding.
REFERENCES
1. LeBano L. Inflammation, mood disorders, and disease model convergence. Psych Congress Network (interview with Dr Roger McIntyre). Accessed September 11, 2015.
2. Pies R. Doctor, is my mood disorder due to a chemical imbalance? Psych Central. Accessed September 11, 2015.
3. Pies R. Nuances, narratives, and the chemical imbalance debate. Psychiatric Times. April 11, 2014.
4. American Psychiatric Association. Lets talk facts: what is mental illness? 2005. Accessed September 11, 2015.
5. Understanding Science: How Science Really Works. Accessed September 11, 2015.
6. Healy D. Serotonin and depression. BMJ. April 21, 2015. Accessed September 11, 2015.
7. Grohol JM. The problem with Googles health knowledge graphs. Psych Central. Accessed September 11, 2015.
8. Gong Q, He Y. Depression, neuroimaging and connectomics: a selective overview. Biol Psychiatry. 2015;77:223-235.
9. Borchard T. Is the link between serotonin and depression a myth? Psych Central. Accessed September 11, 2015.
10. Raison CL, Miller AH. Role of inflammation in depression: implications for phenomenology, pathophysiology and treatment. Mod Trends Pharmacopsychiatri. 2013;28:33-48.
11. Schildkraut JJ, Kety SS. Biogenic amines and emotion. Science. 1967;156:21-37.
12. Ellis A, Harper RA. A Guide to Rational Living. Los Angeles: Wilshire Book Co; 1961.
13. Compton MT, Shim RS. The Social Determinants of Mental Health. Washington, DC: American Psychiatric Association Publishing; 2015.
14. Bailey RK. Book Forum. Review of The Social Determinants of Mental Health. Am J Psychiatry. 2015;172:913-914.
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As a practicing psychiatrist who after forty years actually found his way back to the lovely lady who was once his "high school crush," I'd like to say a few positive words for those whose lives have changed for the better in association with serotonin. Dr. Pies "high school crush" title seems to demean serotonergic medications, but for those who read his essay it is clear that the medications are not his target at all. He doesn't deny that many people have and will continue to benefit from antidepressants that increase serotonergic neurotransmission.We liked SSRIs when we first met them in the late '80's because side-effect profiles made them more appealing than their predecessors. The real problem has been blind affection for invalid theoretical models. As I've said elsewhere, "Treating depression as if it were a unitary syndrome robs patients of the chance to be perceived by prescribing professionals as individuals deserving of...treatments tailored to their needs." (1)
We can renew our appreciation for many familiar treatments -- both psychotherapeutic and pharmacological -- if we accept them for all their strengths and weaknesses without pretending to know more about how they work than we do.
Thank you, Dr. Pies for making that point in your essay, if not its title.
Richard J. Metzner, M.D.
Clinical Professor
Department of Psychiatry & Biobehavioral Sciences
Semel Institute for Neuroscience & Human Behavior, UCLAMetzner, RJ "The unfriending of serotonin," http://depressionconsultant.com/index.php/home/the-unfriending-of-serotonin. Accessed 9/19/2015.
replyRichard @ Sat, 2015-09-19 18:03
Thanks for the thoughtful note, Dr. Metzner. Of course, you are right--many of our (and my own) patients have benefitted greatly from serotonergic antidepressants, which were not in any way a "target" of my essay. (That said, the "selective" part of "selective serotonin reuptake inhibitor" is a bit misleading for several of the so-called SSRIs, as you know; e.g., sertraline has modest dopaminergic effects, paroxetine has modest noradrenergic effects, etc.). Psychiatry's critics often confuse the issue of how our medications work with whether they work--and I would argue that, indeed, our antidepressants do work (better than placebo) in properly selected, vigorously treated, and carefully monitored patients [1]. After all, it was decades before we understood how aspirin works, yet few have doubted that aspirin is good at relieving a tension headache! (Subsequent controlled studies verified this commonly held view).I fully agree with you that, "Treating depression as if it were a unitary syndrome robs patients of the chance to be perceived by prescribing professionals as individuals deserving of...treatments tailored to their needs." Just as Bleuler described "the schizophrenias" (plural), we should probably speak of
"the depressions". And, as I think we would both agree, "treatment" should often include--and perhaps begin with--some form of evidence-based psychotherapy. Indeed, for milder cases of major depression, "talk therapy" is, in my book, the treatment of first choice.Best regards,
Ron Pies MD1. Pies R: Are Antidepressants Effective in the Acute and Long-term Treatment of Depression? Sic et Non. Accessed at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398684/
replyRonald @ Sat, 2015-09-19 20:23
depress |diˈpres|
verb [ with obj. ]
reduce the level or strength of activityThere in lies the problem. The word "depressed" was the obvious choice because Psychiatry, through the DSM, defined mental illness only by overt manifestations. If, from the beginning, the underlying brain activity had been investigated the word "depressed" would not have been chosen since in fact the brain is hyper active in those who are "depressed": the "chemical imbalance" being just a part of a complex neurological impairment.
Barry Stanley
Barry Stanleyreplybarry @ Sat, 2015-09-19 16:16
Thanks for the note, Dr. Stanley. Yes, I agree that sometimes our language can be our prison house! If we name a syndrome "melancholia" (literally, "black bile"), we look hard for evidence of black bile. If we call a syndrome "Borderline", we look for conditions at some hypothetical "border." The term "depression" can be misleading in that respect, based on some (though not all) brain metabolic studies--depending on the brain region and the task being examined; e.g., some patients with major depression show abnormally reduced activity in lateral prefrontal cortices during explicit voluntary control of emotional experience [Rive et al, Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 2):2529-53].Perhaps it might have been more productive if we had simply defined "Syndrome X" as consisting of, e.g., profound and constant sadness; excessive guilt; change in appetite, psychomotor retardation or agitation; sleep disturbance, etc., and then searched for neurophysiological markers and endophenotypes. But we humans tend to like "names"--it often gives us a sense of control or understanding, even when it leads us astray, as you suggest.
Best regards,
RonRonald Pies MD
replyRonald @ Sat, 2015-09-19 20:07
What an appropriate title of High School crush! I have watched as well as participated in this side-show since my graduation from medical school in 1962. All this high drama is quite understandable. Psychiatry has emptied the old mental hospitals in reliance on psycho-pharmaceuticals, so we think we have got the key to unravel the secrets of the mind. We got carried away and lost our common sense, the skill to listen. Psychiatrists have, for the most part, become sophisticated pill pushers.I have written a book, having joined the bandwagon on pharmaceutical wild goose chases early in my career only to learn that the miracles of psycho-pharmacology has naturally their limitations. The books Engaging Multiple Personalities, volumes 1 and 2, are about how I missed the correct diagnosis in case after case until I learned that we needed to go back to the fundamentals of simple listening to the patient, putting some common sense back to the psychiatric practice.
In Chapter 5 of EMP volume 1 discusses the treatment of Ruth, diagnosed as suffering from psychotic depression confirmed by numerous subsequent consultations. She was given high doses of antidepressants and kept in the psychiatric ward in a general hospital continuously for 5 months as a result of repeated suicidal attempts, one of which almost bled her to death, from a severed blood vessel. The treatment focused exclusively on the abnormal serotonergic neurotransmission alone. Many tens of thousands of dollars were wasted on keeping her confined to the hospital.
Her children had been taken away from her to be prepared for adoption, she was forced by her family and church to return to her abusive psychopathic husband, and yet no psychiatrist would even listen to why she was depressed. Surprise upon surprise, depression in her case is a normal emotion under such circumstances. In brief, I merely listened to her story, engaged her dissociative fragmented self, stopped all her medications, and helped her to heal. She has remained well and without any further need for treatment in the intervening 20 years, as is documented in Volume 1 of Engaging Multiple Personalities. Createspace (2014)
David Yeung MB BS. FRCPC (retired)
replydavid @ Sat, 2015-09-19 15:15
Thanks for your interesting comment, Dr. Yeung. Your experience with this patient reminds us of the critical importance of careful listening and diagnosis--contrary to the "anti-diagnostic" rhetoric of, for example, the British Psychological Society, which seems to regard all psychiatric diagnoses as meaningless or "stigmatizing" labels [1]. Your letter also reminds us that while randomized, controlled, studies may be the "gold standard" of evidence, we can learn a great deal from the well-founded, single case study--particularly when the patient is followed for 20 years. Finally, your letter brings to mind the importance of what Theodor Reik wisely called, "listening with the third ear"!--Best regards, Ron Pies MD
1. http://www.psychiatrictimes.com/blogs/war-psychiatric-diagnosis/page/0/2
replyRonald @ Sat, 2015-09-19 17:00
Dr Pies has hit the nail right on it's head, One can sum up his blog by saying that depression is not so much a disorder as it is a symptom, like for example fever, which may have a number of root causes.replyLaura @ Sat, 2015-09-19 10:40
I agree that the term "depression"--like "anxiety"--is best understood as a symptom, in search of a diagnosis. It's a bit like saying that your car has "engine trouble"--not terribly helpful! That said, there have been some strong arguments put forth by several highly regarded clinicians, arguing that "melancholia" possesses "...a distinctive biological homogeneity in clinical experience and laboratory test markers...is differentially responsive to specific treatment interventions...[and therefore deserves recognition as a separate identifiable mood disorder." [1]. This may indeed be the case, and reinforces the point that the term "depression"--and even "major depression"-- is not very meaningful (and is widely misrepresented in the popular press as a sort of "bad hair day"!).My essay's main point, though, is just that, in general, American psychiatry has put forward a broad-based, biopsychosocial model of major depression and other psychiatric disorders, notwithstanding the unfortunate "high school crush" on serotonin. By the way, I'd like to thank Dr. Barney Carroll for sending me his classic 1971 paper, which already saw the problems inherent in any simplistic "chemical imbalance theory" of mood disorders, and stated this very clearly:
"...no clinical studies have revealed unequivocal, consistent and unique physiologic abnormalities in
depressives" that clearly supported the then still developing monoamine hypothesis. [2]Finally, to Laura and other readers, please do sign your notes with your full name and profession--thank you!
Best regards,
Ron PiesRonald Pies MD
1. Parker G, Fink M, Shorter E, Taylor MA, Akiskal H, Berrios G, Bolwig T, Brown WA, Carroll B, Healy D, Klein DF, Koukopoulos A, Michels R, Paris J, Rubin RT, Spitzer R, Swartz C. Issues for DSM-5: whither melancholia? The case for its classification as a distinct mood disorder. Am J Psychiatry. 2010 Jul;167(7):745-7. doi: 10.1176/appi.ajp.2010.09101525
2. Carroll BJ: Monoamine precursors in the treatment of depression. Clinical Pharmacology & Therapeutics. 1971; 12:743-61
replyRonald @ Sat, 2015-09-19 12:54
I do not believe it was Dr. Pies intent to indicate that Depression is a symptom and not a disorder.The problem is the use of "depression " as both a noun and an adjective.The article above which expresses the difficulty in establishing an etiology and underlying physiological mechanisms for, "Depression", reflects a problem created by the well intentioned authors of the DSM III-V series to create a common language to be spoken by researcher in the field.Those of us old enough to have treated patients with Involutional Melancholia, realize that it is not the same "depression"as others which also meet criteria for Major Depressive Disorder.
That being so, it is not possible to establish one set of contributing factors and underlying physiological mechanisms for the current diagnosis, Major Depression which
now includes more than one illness..We must first establish criteria for each of them. Having done so, would permit a more successful effort to establish contributing factors and physiological mechanisms.Don Kornfeld
replyDonald @ Sat, 2015-09-19 13:20
Many thanks, Dr. Kornfeld, and I agree with your analysis of the problem, vis-ą-vis developing criteria for the various subsets and subtypes of illness now lumped under the term "Major Depression." Your comments on involutional melancholia are consistent with what Max Fink and others have written re: melancholia per se, as a distinct subtype. You are right that before we can speak confidently about contributing factors or precipitants of "depression"--or, for that matter, of the "neurobiology" of depression-- we need better validated-criteria for the individual subtypes. A very rough analogy would be to try to develop a list of "contributing factors" to "anemia", without first understanding the difference between, say, microcytic and macrocytic anemia, anemia due to B12 deficiency vs. bone marrow disease, etc. Thanks again for your note!Best regards,
Ron Pies MDP.S. Psychiatric Times readers will enjoy reading the "bio" for Dr. Kornfeld, describing his many and varied contributions to the psychiatric literature, over so many years!
http://asp.cumc.columbia.edu/facdb/profile_list.asp?uni=dsk3&DepAffil=Ps...
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