April 25, 2015 (All links open in new windows.)
1. Please begin with a least a skim of a sensible article about the orphaned serotonin hypothesis, So Long and Thanks for All the Serotonin, by David Healy. It was published as an editorial this week by the British Medical Journal.
2. Then, please savor this professional-reputation-damaging hall-of-famer: Misfires, mistakes, meltdowns and illogic: A case of apparent ethanol-potentiated mass hysteria in psychiatrists confronted with written material they dislike but cannot refute. (It’s actually called Expert reaction to editorial on serotonin and depression.)
I’ll start by saying that David Healy’s “So Long and Thanks for All the Serotonin” is deep and subtle. It is not just another take-down of antidepressants and academic log-rolling and drugmaker malfeasance. Healy’s point is not that the serotonin theory of depression was a non-starter; that’s old news. It’s that “low serotonin” as the root of depression nonetheless flavored public discourse for decades, shedding specifics and eventually settling into “chemical imbalance” after considering and rejecting “nothing.” It influenced the marketing, prescribing, and use of SSRI drugs and their successors and, in Healy’s view, was a costly distraction:
“[they] 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 Center kindly offered a handful of prominent apothecaries a chance to react to Healy’s editorial. They reacted as though Healy’s had written an attack on SSRIs, disputing things he didn’t say 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.
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, together with psychological treatments.” (We’ll take your word for it, soldier.) There’s something that should bother Wessely, if he means what he said. SSRIs are prescribed by 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 can also be quite helpful), and occasionally for unrelenting major depressive disorder. But the psychological treatments Wessely mentioned are only rarely undertaken in conjunction. If antidepressants are helpful, but rarely combined with therapy, they’re rarely helpful. And that comes from Wessely, not me.
True, a lethal dose of a tricyclic can be as low as five pills, whereas it would take bottles and bottles of an SSRI to do the trick. If someone on TCAs intends to commit suicide, enough TCAs are probably at hand. The problem with SSRIs is their sometimes paradoxical effects, which can send someone who didn’t intend to commit suicide into suicidal despair. When that happens, the low toxicity of SSRIs confers no safety; another method of suicide is found. Further, perhaps the most notorious RCT scandal to date, Study 329 (Keller et al., 2001), concealed a suicidality rate in children on Paxil that was more than three times the rate seen in the tricyclic and placebo control groups.
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 was not made) really be, when (not made) against something that does not 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 [Also known as akathisia, inorgasmia, 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 really 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 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. I mean it would be, if it he had one.
Note to Taylor: Say, doc, as long as we’re just free-associating, do you know if Brintellix 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 relieve the debilitating nausea that’s earned Brintellix its devoted following? [Taylor is a consultant and researcher for the company that makes Brintellix.]
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 had never suppressed data about Paxil and suicide. This is appalling coming from someone of his notoriety. He has a duty to warn. There are people who would very much like to feed him Paxil for 6 months and not a day more, 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 SSRI prescriptions are written for only because patients can’t manage to get off them.
Oh, and Keedwell thought you should know that SSRIs have fewer troublesome side-effects than their predecessors. Oy.
Stanford pulled a Taylor, attacking positions Healy had not taken, and transcending the bulk of her reactionary reactings 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 on his blog in a post he called “Switch on Anti Depression Today.” He doesn’t know what it means; he asked his friends, and they don’t know either. I asked scholar.google.com, and it hadn’t a clue. Maybe Stanford picked it up on Erowid.
And of course, Stanford reminds 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 the admission that SSRIs “may not be more efficacious than older tricyclic antidepressants,” but, but, but … “they have more a tolerable side effect profile.”
She wheeled out her vintage research, turning 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 certainly 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 figures including 2000 to 2013: https://www.afsp.org/understanding-suicide/facts-and-figures
Reports the NCHS finding of near-quadrupled antidepressant use between 1988 and 2011 http://www.health.harvard.edu/blog/astounding-increase-in-antidepressant-use-by-americans-201110203624
Like Stanford, Wong went off half-cocked, but at least managed to cite a correlation, spurious as it was, to support her views. Poor thing, probably losing awareness of her surroundings by then, 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 toyboy of Eli Lilly’s. Lilly has blood on its hands; the sheets must be a mess.
I don’t have anything else to say.
Meet the experts:
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 Dr
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.