April 25, 2015
Background This post is about a set of expert reactions to an editorial by David Healy, So Long and Thanks for All the Serotonin. The editorial was published in the British Medical Journal as Serotonin and Depression: The Marketing of a Myth, and re-posted here and there under the more fanciful name.
The editorial was quickly circulated among Thought Leaders and a squad of experts assembled to produce pull-quotes for the inevitable media coverage that would follow the somewhat damning thought-piece. Each expert penned a few hundred words, some of them almost certainly still in pajamas.It’s not clear that they’d all had enough sleep to get their BACs down to the safe-typing level of 0.0 The collection of essays is marvellous, a reputation-tainting hall-of-famer that could be called: Misfires, mistakes, meltdowns and monkey business: A case of apparent ethanol-potentiated mass hysteria in after Someone published Something something that might upset the apple cart.
[The links open in new windows. The links to the editorial and the expert panel’s reactions appear again at the bottom of this page, for your convenience.]
David Healy’s So Long and Thanks for All the Serotonin is not just another take-down of antidepressants, academic log-rollers and drug-making malefactors. Healy’s point is not that the serotonin theory was a non-starter; that’s old news in science. It’s that the news didn’t reach the public. What did get through was a very good pill-selling message couched in scientific terms but endorsed by no scientist or lab, namely that depression is caused by low serotonin, and that although no one knows exactly how they work, SSRIs somehow relieve depression by boosting the availability of serotonin in the brain. Researchers did toy with a low serotonin theory of depression in the 1960s but found it wanting. One might be tempted to say: The reason no one knows how SSRIs alleviate depression is that they don’t.
Over the years the serotonin theory shed specifics and settled into “chemical imbalance,” which means nothing and therefore can’t be disproved. Whatever it is called, it influenced the marketing, prescribing, and swallowing of SSRI drugs and, in Healy’s view, was a costly distraction:
“SSRIs pushed older tricyclic antidepressants out of the market. This is a problem because SSRIs have never been shown to work for the depressions associated with a greatly increased risk of suicide (melancholia).”
A British thing called the Science Media Centre kindly offered a handful of prominent apothecaries a chance to react to Healy’s editorial. They reacted as though Healy had written an attack on SSRIs. They disputed things he hadn’t said with things they shouldn’t have said. Each of them did make a point – the same point, as it turned out. Not having a leg among them to stand on, they can be forgiven for sharing a crutch.
Sir Simon Wessely led the charge, apparently having shot his wad long before reaching the fray. Not one to skip a gunfight for lack of ammunition, he gave it his paltry all with “antidepressants are helpful in depression” which he modestly qualified with “…together with psychological treatments.” (We’ll take your word for it, soldier.) There’s something that should bother Wessely, if he meant what he said. SSRIs are prescribed by psychiatrists and GPs all over the world for mild anxiety, low mood, and the heebie-jeebies (ailments for which a new pair of shoes and a roll in the hay should be considered first-line), and occasionally for unrelenting major depressive disorder. According to The Health Foundation, a British non-profit, the psychological treatments Wessely mentioned are only rarely undertaken in conjunction with antidepressants. If antidepressants are helpful when paired with “psychological treatments,” and those treatments are rare, then antidepressants are rarely helpful.
Yo, Science Media Center, I hear ya. Give it a rest. I’m just trying to clarify things for the lay audience.
True, a lethal dose of a tricyclic can be as low as five pills, whereas it might take bottles and bottles of an SSRI to do the trick. If someone on TCAs intends to commit suicide, enough TCAs are probably on hand. The problem with SSRIs is their sometimes paradoxical effects, which can send someone who didn’t intend to commit suicide into suicidal despondency. When that happens, the low toxicity of SSRIs confers no safety; another method of suicide is found. Further, the most notorious RCT scandal to date, Study 329 (Keller et al., 2001), minimized to the point of concealment a suicidality rate in children on Paxil that was more than three times the rate seen in the tricyclic and placebo control groups. The conclusion stated in Study 329’s abstract was “Paroxetine is generally well tolerated and effective for major depression in adolescents.”
David Taylor opened with a serpentine statement that turned out to be a snakeskin minus the snake: “Professor Healy makes a forceful but poorly supported argument against something which doesn’t and has never really existed: the idea that SSRIs ‘correct’ an ‘imbalance’ of serotonin in the brain.”
How forceful can a poorly supported argument (that wasn’t made) really be, when (not made) against something that doesn’t exist? Surely more forceful than Taylor’s subsequent lapse into word salad:
“Researchers and psychiatrists alike know that SSRIs are effective in a number of disorders but no one is sure exactly how they work. [Oh, good.] Their readily demonstrable effect is on serotonin [You mean low serotonin does cause depression?] but they have many indirect secondary effects in the brain [which we call akathisia, anorgasmia, and weight gain]. Professor Healy also ignores very strong evidence that tryptophan depletion (which reduces serotonin production) reverses the beneficial effects of antidepressants with a variety of modes of action [So low serotonin does cause depression. Thanks!]”
Taylor made the most of the shopworn reminder about TCA side effects by shoe-horning the word “conspiracy” into it, claiming that the TCAs were supplanted because of their high toxicity rather than “any conspiracy concerning a theory of serotonin’s involvement in depression.” Zing! That’ll be Healy’s conspiracy theory obliterated. It would be, that is, if he had one.
Note to David Taylor: Say, doc, as long as we’re just free-associating, do you know ifTrintellixzw has a novel mechanisim of action in the brain, or does it work by provoking violent and protracted bouts of emesis? Such bouts do tend to improve one’s outlook once they’re over, but do they correct a chemical imbalance in the gut, or merely relieve a symptom, the debilitating nausea that’s earned Trintellix its devoted following? [Taylor is a consultant and researcher for the e that makes Brintellix.]
Paul Keedwell chided Healy for saying antidepressants cause dependence and provoke suicide, as if there were no documentation of either phenomenon, as if taking a drug that makes your brain grow new neurons would not lead to some interesting phenomena once the drug is withdrawn; as if GSK hadn’t been fined billions of dollars for data about Paxil and suicide. This is appalling. Someone of his prominence has a duty to warn. There are people who would like him to take Paxil for exactly six months, so he might learn that akathisia is to anxiety what Datura is to Darvon. He did not get around to refuting Healy’s claim that as many as nine out of ten prescriptions for SSRIs are written only because patients can’t manage to get off the drugs. Instead, Keedwell thought you should know that SSRIs have fewer troublesome side-effects than their predecessors. Oy.
Clare Stanford pulled a Taylor, attacking positions Healy had not taken and transcending the bulk of her flummoxed flailings with a head-scratcher: “In short, SSRIs probably switch-on anti-depression, rather than switch-off depression (which could explain the rapid efficacy of ketamine).” It’s impressively esoteric; no one understands it. Healy wrote about it in a blog post he called “Switch on Anti Depression Today.” He doesn’t know what it means; he asked his friends, and they don’t either. I tried scholar.google.com and got a 404 error. Maybe Stanford picked it up on Erowid. Of course, she reminded us that tricyclics “are so dangerous in overdose.” La la la…
Australia’s own Science Media Center thing posted an enhanced edition of the reactions, making space among the padded sell-outs for Ma-Li Wong, who was mainly wrong. She did choke out an admission that SSRIs “may not be more efficacious than older tricyclic antidepressants,” but, but, but … “they have more a tolerable side effect profile.” ([Ed.: The Australian thing is down during a transition to a new site, which is not very sciencey. The entry containing Dr. Wong’s contribution was not included on a transitional site located at scimex.org.]
She wheeled out her own vintage research, requiring us to our minds back to a distant era, the years 1998 through 2002. During that four-year span, suicide rates decreased while SSRI prescribing rates rose. It would be a credit to SSRIs if the trend had persisted, but it didn’t. After that little blip, antidepressant prescriptions and suicides began to rise in lockstep, continuing least through 2013. You know, like these charts show:
Graph of CDC suicide statistics including 2000 to 2013: Suicide Facts and Figures
NCHS finding of near-quadrupled antidepressant use between 1988 and 2011: Steep Rise in Anti-depressant Use
Like Stanford, Wong went off half-cocked, but at least managed to cite a correlation, spurious though it was, to support her polemic. The poor thing, by then possibly losing awareness of her surroundings, went on to assail Healy as biased, and his writings inflammatory and harmful. As her tawdry exegesis wound down, she blurted, “the research referenced in my comments was not sponsored by the pharmaceutical industry.” But her habit of being married to her husband, Julio Licinio, puts her in bed, so to speak, with an accused (but not convincingly, other than here, where he admitted it) toyboy of Eli Lilly’s. Lilly has blood on its hands; I hope the sheets are not a mess.
I don’t have anything else to say.
So Long and Thanks for All the Serotonin, by David Healy.
Expert reaction to editorial on serotonin and depression from Science Media Center
Meet the experts:
Sir Simon Wessely, President of the Royal College of Psychiatrists
David Taylor, Director of Pharmacy and Pathology and Head of Pharmaceutical Sciences Clinical Academic Group, King’s Health Partners, South London and Maudsley
Paul Keedwell, Consultant Psychiatrist and Specialist in Mood Disorders
Clare Stanford, Reader in Experimental Psychopharmacology, UCL
Ma-Li Wong, MD, Adjunct Professor, John Curtin School of Medical Research, Australian National University.