- Written by Dr Ken Gillman
These accounts are from people with whom I have recently interacted via my web site. This first gentleman’s account illustrates vividly how rapidly Parnate can be effective, despite treatment failure of, among many things:
- The usual ‘guideline recommended’ regimes with various additions and combinations
- ‘38 ECT treatments
- six weeks of daily transcranial magnetic stimulation treatments
- multiple (and very expensive) IV ketamine doses’.
Understanding, or justifying, the pathological avoidance of Parnate by psychiatrists is quite beyond my understanding — as illustrated by the above prolonged and extraordinary measures, before Parnate was tried. [see my AD algorithm]
This account may be found a little upsetting by some people, so to ease the suspense for readers, I will quote his comment about the ‘result’, from near the end of this long story, right now: “The change seemed to occur overnight, almost exactly 3 weeks in; one morning I woke up and knew — with some certainty — that something was different and that, for want of a better phrase, the nightmare was over; really, actually, over”.
In my ‘Guidelines’ commentary I discuss why RCTs and statistics bamboozle researchers and doctors. These RCTs are all about a few rating-scale-points improvement — not complete remission of a prolonged illness in 3 or 4 weeks. When you have seen a number of examples of responses such as these below (I have seen a great many) you may be inclined to re-assess your evaluation of RCT data and use Parnate more often, and sooner, in the course of the illness.
Just think about the suffering this man endured, never mind the wasted time and money. I hope that will pain you as much as it pains me, and may make you wish you could ‘turn-down’ your capacity for empathy. And, ‘lest we forget’, for every story like this, there are the ones we will never know of, because those people did commit suicide. Remind yourself of that, Doctors, next time you are blathering like a blithering idiot about some trivial SE, like low or elevated blood pressure, or whatever***.
I should also repeat that this story is not exceptional: I am contacted by large numbers of patients with not dissimilar stories, many of whom respond dramatically and quickly to tranylcypromine.
*** One can ‘blather’, or ‘blither’, but only properly be a ‘blithering idiot’: the vagaries of English are so delightfully quixotic. That may be because the vowel order is jarring; one says ‘tic, tac, toc, or tick-tock (sound of a clock). To say ‘toc, tic’ just sounds wrong — native English speakers follow this ‘rule’ without even being conscious of it. Perhaps that is why ‘blathering idiot’ never came into use?
Not everybody either wants to, or finds it easy to, revisit such traumatic experiences and write an account of them. Indeed, this gentleman took some months to do it because it was a process that aroused powerful memories and emotions.
In so far as this story is not exceptional, and one cannot say that without thinking of Dr Osheroff, recently deceased, and his legal case against the infamous ‘Chestnut Lodge’ hospital around 1980. Osheroffhas an uncanny number of parallels to this first story. I will not go into the case in detail, comment is plastered all over the Internet, and it is often a part of the teaching of doctors in training. For those who are interested, I suggest using the search terms: Osheroff, Chestnut Lodge, Bernard Carroll, Gerald Klerman, and Mickey Nardo (also recently deceased).
The first story
One of the clinics where he was an inpatient, having psychological treatment, as well as medication, was a famous institution the name of which would be known to every psychiatrist in America. Incredibly — he obtained his own clinical notes subsequently — when they failed to improve him with their medication treatment, they blamed him for being uncooperative, and ‘sabotaging his own therapy’, and invoked the same kinds of judgemental comments concerning his personality, as Chestnut Lodge had done with Dr Osheroff. In this day and age, I find that almost unbelievable, but that is the extraordinary psychological attitude that is commonly invoked by doctors, who deny their own therapeutic incompetence, and project their failure on the patient (Freud’s egregious legacy dies hard).
NB. I advised this gentleman to increase the Parnate unusually rapidly because I could tell, from the other side of the world, that he was quite likely to succeed in killing himself if he did not improve ‘PDQ’ [pretty damned quickly].
His own story
‘I am a working professional in my forties, and completed several years of postgraduate education. I experienced my first episode of incapacitating clinical depression in my 20s which resulted in about 3 weeks of inpatient treatment, followed about 10 years later with another episode lasting almost a year, for which I took 6 months off work. This second episode rather miraculously (at the time) responded to a short course of ECT.
Now, another decade after that, I had relapsed into yet another agitated clinical depression, and after a year or so of various intense and wholly unsuccessful treatments I felt I’d reached the end of the line. Agoraphobic and practically housebound, I’d spend all of each waking day in frenzied pacing back and forth between my dining room and kitchen, my mind clouded in a nonfunctioning fog of regret, indecision, and self-deprecation. I was unable to read, listen to music, watch TV, or even sit still for that matter; I was consumed with how productive and functional I once was, and how it seemed things would never be that way again.
It seemed like I’d tried everything the psychiatric establishment had to offer for the treatment of depression. During the year, I’d had 3 separate rounds of ECT, which had been curative in an agitated depression 10 years prior, but failed to have any positive effect this time around despite 38 sessions total of mostly bilateral ECT, which seemed to have wreaked havoc on my memory and cognition. I’d also undergone 40+ sessions of repetitive Transcranial Magnetic Stimulation (rTMS), 5 sessions of IV ketamine, and dozens of medication trials. I’d taken, for various lengths of time, duloxetine, venlafaxine, aripiprazole, olanzapine, clonazepam, escitalopram, quetiapine, Lyrica, lamotrigine, triazolam, risperidone, Pristiq, Brintellix, methylphenidate ER, mirtazapine, citalopram, diazepam, alprazolam, loxapine, lurasidone, EMSAM patch, clonidine, chlorpromazine, clomipramine, hydroxyzine, tizanidine, nefazodone, buprenorphine, bupropion, temazapam, Phenibut, and cannabis in various forms.
Each medication in turn brought worse anxiety, agitation, or mental clouding, or simply didn’t work. I did take small doses of benzodiazepines (clonazepam, lorazepam, etc.) once or twice a day, which might help the anxiety somewhat for 2-4 hours; higher doses would merely leave me dazed and drowsy and I was terrified of dependence; it only added to my discouragement that I was probably already dependent anyway after all the months of taking it.
Between January and April of 2016 I’d also been hospitalized at 4 different facilities, once for a high-end 6-week program where each day was filled with group therapy, dialectical behavioral therapy, various other group activities, meditation, yoga, and individualized psychiatry and psychotherapy visits, none of which resulted in much improvement, culminating in fact in a transfer to an actual hospital where 2 weeks of ECT were performed. There was actually some improvement after these sessions, but I quickly and fully relapsed within 7-10 days afterwards.
By April I’d had several months of self-destructive impulses to go along with the increasing agitation and despondency; I’d made many attempts with a noose I’d fashioned out of an electrical cord but found I was just unable to let go completely … and my final thoughts just before losing consciousness seemed to always be of my parents, whereupon I would release the pressure and inhale deeply. Sometimes I’d spend 30-45 minutes repeating this process, each time with the same result. Finally, I drove to the local firearms store and even in my completely flat, depressed, suicidal state, discovered that obtaining a gun was shockingly easy. In a daze, I bought a pistol and later returned to pick it up after the waiting period, and early one morning at home prior to a scheduled ECT (it was ~5AM) I loaded it and played around with it and aimed it at myself from various angles and then, without thinking, cocked it; as soon as I did that I decided I wasn’t going to go through with it then and there but that I had no idea how to un-cock the gun … I stood up and placed it on the bed and suddenly it fired loudly in a cloud of black smoke and light, fortunately in a direction away from me and toward the sliding glass door, leaving a clean round bullet hole in a vertical blind. I heard my friend, who had arrived to bring me to ECT, frantically running up the stairs toward my room, calling out my name, and I quickly put the gun in the nightstand drawer. When she reached me, she later said, what she saw was entirely not what she expected to see: me standing at the side of the bed, looking distraught, but alive.
In a trembling voice she asked what happened, to which I could only reply that I didn’t know. Pushing aside the vertical blind with the bullet hole revealed a large spider’s web of cracked glass with pieces randomly falling off; suddenly the entire section crumbled to the ground, followed by an inflow of crisp early morning air. She asked me where the gun was, and said I needed to give it to her; I told her I wasn’t sure, and that I wanted to keep it. I pleaded with her not to tell anyone about it; she said she wasn’t sure what she was going to do, as she was still in a state of shock. Needless to say, we did not make it to ECT that day, and it’s hard to believe but I did do two more outpatient ECT sessions later that week before finally ending the ECT as it obviously was not helping.
I struggled along, barely hanging on for the next two weeks with my only social interaction being my friend who would come often to see me and keep me company for limited periods of time, as she had throughout my illness. We decided that I really ought to tell my outpatient psychiatrist about the recent incident, and so at my next visit with him, in my deeply despondent state I told him about accidentally shooting the gun off in my room, whereupon he said I needed to give the gun to somebody immediately or he would call the police, citing legal obligations and saying I was mentally unstable and a danger. I told him I would give the gun to my friend and she would call him to confirm; after I got home I was deciding how to proceed when my cellphone rang - it was the police and they were outside my place.
As soon as I went outside they handcuffed me and explained that my psychiatrist had called them and told them I had a gun and was potentially suicidal, but reassured me that I was not under arrest. I was brought back upstairs to my room where I showed them where the gun and ammunition were; these were both confiscated. They then looked through my drawers and shelves and while there was nothing else to find, I was told that I would be brought to a yet another psychiatric facility as a 5150-involuntary patient, to which I expressed my sincere belief that this would only probably make things worse, to no avail.
So, that night I was driven in handcuffs in the back of police car to a locked ward at a mental health facility about 3-4 miles away; my experience there, while better than at the previous facility in March, was mostly unpleasant and filled with anxiety and despondency; the psychiatrists there were no less baffled than anyone else as to what I could try next and at some point there I was even on a trial of Saphris (asenapine), an atypical antipsychotic, as monotherapy for my suicidal agitated depression, which, looking back, would never, ever have worked. But regardless I stopped after two days due to severe worsened anxiety and insomnia, after which they tried giving me Vyvanse, paroxetine, and finally Brintellix (vortioxetine), on which I was discharged after two weeks in the hospital, on May 6, 2016.
I tried my best to tolerate the Brintellix and took it for almost two weeks, with questionable change in depression, but constant and increasing nausea, belching, brain fog; my body felt like it was on fire when I tried to lie down, and my body kept twitching furiously. I just couldn’t continue it, and stopped around May 20. The next week consisted of me desperately trying to self-medicate with 2 other antidepressants, literally spending 2-4 hours each morning deciding between taking venlafaxine again or a small dose of escitalopram, but with increased anxiety either way; I also tried taking some Concerta, a long-acting form of Ritalin, which I had been prescribed earlier in the year but had never taken. This did help the mood one day but the next day the despondency seemed even worse. Then, I saw on an internet message board that some people had anecdotal improvement in their depressions with Suboxone, and went to see my psychiatrist, who said he would be willing for me to try a tiny dose of buprenorphine, which is the opiate portion of suboxone, with the knowledge that opiate addiction was a possible outcome, if I were to stay on it for more than a couple of weeks or so.
So, he gave me a prescription for buprenorphine buccal formulation, which was one patch to the inner cheek twice a day; not only was it not covered by my insurance, it was not carried in stock by any of the pharmacies in the area so it had to be ordered; i picked it up several days later at $300 for 50 doses and started with the first cheek dose before I got home from the pharmacy. No effect whatsoever. The next 2-3 doses had no effect either, other than giving me the feeling that I was heading down the road to opiate addiction. My psychiatrist suggested I increase the dose up from 1 dose twice a day to 2 doses twice a day, and I took that once I believe.
It was at this time that my friend told me she had scheduled a consultation for me with a psychiatrist in Beverly Hills, one she had been referred to because “he’s not afraid of treatment-resistant depression.” I was sure there was no point in going to this since 1) it was unlikely there was anything left to try, 2) this was at least an hour away with traffic and it seemed absurd that I would be able to follow up with a psychiatrist so far away, and 3) the initial consultation was a week away and it was doubtful I would make it that long anyway. But I did and when the morning of the appointment arrived my friend gave me a final chance to decline going, and finally with great reluctance I agreed to at least to go see what he had to say. So she drove us there through the sludge of traffic (with a terrible head cold she’d had for several days, I might add) and as we waited in the psychiatrist’s waiting room I stood, sat, got up, paced, sat, paced, in my usual agitated fashion. Finally, he called us into his room and invited me to tell my story; after I had spoken for about 10 minutes he suddenly stated that what I would need to do would be to stop the buprenorphine immediately, and begin a dopaminergic antidepressant like Wellbutrin or nortryptiline. I explained I’d taken the Wellbutrin before, with severe anxiety as a result, but he said he thought that instead of Wellbutrin (bupropion hydrochloride) I should take a newer form called Aplenzin (bupropion hydrobromide), as it had less associated anxiety due to the bromide group. Finally, if this didn’t help, the next step, he said, would be another MAO inhibitor. I had used the EMSAM patch in the past, but he felt strongly that I would benefit from one I had never heard of, called Parnate.
Aplenzin turned out to be impossible to find at any pharmacy anywhere, and no pharmacy was interested in ordering it unless I committed to paying for it - a reasonable request except it wasn’t covered by insurance and would cost $1200 for a 2-week supply! And the likelihood it would be tolerable for more than a few doses seemed low given my previous reaction to Wellbutrin. Plus I had just spent $300 on the buprenorphine, of which I only took 3 days-worth of before stopping. So, after speaking to the psychiatrist I started another trial of regular Wellbutrin instead of the Aplenzin. This lasted one day as I was overcome by severe nausea and headache in addition to the increased agitation and anxiety I’d previously had with it.
I called the psychiatrist again and he said it was time for an MAO inhibitor, “a real one, not EMSAM,” and again recommended Parnate, saying it would probably work faster than the other option, Nardil. “Two or three weeks,” he said.
So, I set upon the internet to research Parnate and what little information was available suggested it was rarely used anymore due to the typical MAO-I concerns (food and drug interactions), and was felt to likely increase agitation and anxiety due to its amphetamine-like structure; furthermore I discovered that it is currently FDA approved only for “Depression Without Melancholic Features,” characterized by things like sleeping too much, weight gain, and ability to be ‘cheered up’ by positive events - none of which I had. In fact, for my “subtype” of depression - “melancholic” depression, characterized by complete inability to find pleasure in things, lack of mood reactivity to positive events, agitation, guilt, etc. — Parnate appeared to be contraindicated.
Other than this, there appeared to be practically no useful or encouraging information available. While researching, however, I happened upon an intriguing website called psychotropical.com, where an entire section was devoted to dispelling many of the prevailing notions regarding MAO-I usage; the author, an Australian psychiatrist named Dr. Ken Gillman, felt strongly that not only are MAOIs quite safe and effective for all kinds of depression - whether “atypical” or “melancholic” or “psychotic” etc. — but also that they are vastly underused for reasons borne out neither by the available research nor by his clinical experience, which included many hundreds of patients he had treated through the years. Also, there were several essays providing evidence that the “modern” pharmacologic framework for depression treatment is extremely flawed, especially in its reliance on medications such as the SSRIs and Remeron (mirtazapine).
Finally, there was a portion of the website where he described depression as a sort of “mental anemia,” akin to, say, an iron-deficiency anemia, where tactics such as increasing one’s physical activity, going running, thinking more positively, etc, were likely to be counterproductive if not impossible as they did not address the underlying biochemical issues at root - a description I could definitely relate to.
Along with the website’s informational resources, Dr. Gillman also included his contact information, including how to reach him via Skype if requested. Soon enough I was videoconferencing with him, from my location in USA to his in Australia; he listened patiently to my tale of woe and my numerous questions and hesitations about MAO-I’s, and stated that he did feel that Parnate would likely be helpful, although the dosage would need to be increased as quickly as tolerated to a level that would produce the desired biochemical effect (inhibition of monoamine oxidase) - and he related that the majority of psychiatrists nowadays, whether in the U.S., Australia, or elsewhere, likely did not have enough experience with the MAOI’s to properly escalate the dosage as a result of the focus on “newer” therapies such as SSRI’s, SNRI’s, etc. during their training. But he encouraged me nonetheless to obtain a prescription from my psychiatrist and if needed he could help titrate the dosage, which he felt would need to be at least 40-50mg a day to be effective.
He also agreed to speak separately with my friend and with my family, and offered them encouragement that there was a good chance the Parnate would be beneficial, probably within two or three weeks if I could hang on a while longer.
So, I returned to my psychiatrist and discussed the possibility of trying Parnate, of which he was willing (as we had tried just about everything else), though he did think it would merely worsen the agitation and thereby be intolerable; with this in mind he prescribed 5mg twice a day, to be increased every 2 weeks as tolerated.
Dr. Gillman checked in with me via Skype nearly every day at first, and reiterated that the dosage needed to be higher and also increased faster, and to this end suggested fairly rapidly titrating the dosage to 40mg a day over the course of about a week — in fact, he had found in his experience that when the correct dosage was reached, a particular pattern of blood pressure readings would occur, and at 40mg a day my blood pressure readings, as he predicted, were indicative of having reached this point.
At that time, after the first week, I would say that I felt something positive and different, and though the anxiety and agitation were not necessarily that much improved, they were definitely not any worse; in addition, the suicidal ideations seemed to be decreased. However, my blood pressure readings were quite labile, with systolic readings in the 180-200 range followed by 80-90 range readings; in addition, there was a distinct sensation of feeling quite cold, which was odd as this was in June and during fairly hot weather. Splitting the 40 mg into two or three doses during the day helped to some extent, though there remained a very noticeable “chest agitation” that had been present for several months and remained severely limiting.
After several days of feeling somewhat better, it suddenly seemed to wear off; as a result, Dr. Gillman suggested going up to 50 mg a day, which I did in 3 split doses as the blood pressure readings continued to be quite labile. On this dose, the previous positive trend returned, and the sensation of chest agitation even seemed blunted until later in the day; and though I was still fairly incapacitated especially having been sick for so long, I did manage to go out to dinner with some friends one evening, something I hadn’t done in many months - it didn’t feel quite normal, and the chest sensation returned with a vengeance halfway through, but it was tolerable and something of an encouraging sign for what it was worth.
Still, I repeatedly voiced my doubts and ambivalence about the Parnate to Dr. Gillman during those initial 2-3 weeks, and each time he reiterated that I just needed to hold on a bit longer, and that probably after 3 weeks I would notice a significant difference. He had also connected me with another person he had been talking with over Skype who was in a similar situation as mine and who had also just started Parnate; that individual also offered support and encouragement and persuaded me to hold on a bit longer.
The change seemed to occur overnight, almost exactly 3 weeks in; one morning I woke up and knew — with some certainty — that something was different and that, for want of a better phrase, the nightmare was over; really, actually, over.
That day I went to Target, which, while seemingly a simple task, had been something I had avoided for at least 8 months due to unrelenting and unexplainable anxiety - and yet there I was, walking around, surrounded by people, completely unfazed. I called my family, who were shocked at how different I sounded - in fact, almost everyone who had spent any time with me during the months prior conveyed the same sense of amazement, often using the same words - shocking, miracle, amazing, unbelievable. The next day I went to Costco, always a chaotic mess of people of all ages, carts and tempers colliding, and cacophonous noise - and yet I felt confident I’d be able to handle it just fine and I did - and as with Target, it had been at least 8-9 months since I’d last even felt close to being able to go there.
My friend noticed with relief and gratification that I’d begun referring to the depression in the past tense; she had unconditionally helped me through months and months of a dark, suicidal illness and was ultimately the person that had set me on the path to try Parnate - for which I will always be beyond grateful.
Gone was the chest anxiety and agitation and constant panic and envy; gone, too, of course, were the suicidal thoughts. My blood pressure was still labile but within reasonable limits, and the sensation of coldness, while still present, would slowly resolve. There have been various side effects of varying duration - mid-afternoon drowsiness seems to be a particularly persistent one - but they are far better than the incapacitation and desolation of severe clinical depression.
My diet has generally been fairly liberal, though I’ve never been a fan of aged cheeses and there are usually alternatives to things like draught beer and fermented foods like kimchi. The need to avoid cold medications with dextromethorphan and pseudoephedrine was probably my biggest concern but has turned out to be not as difficult as imagined, as cold symptoms go away on their own anyway. There has been only one episode that I’d attribute to an MAO-I interaction - Costco sells frozen yakisoba noodles that have edamame mixed in, to which I developed a very severe headache starting in the occipital region about 45 min after consuming, with blood pressures over 210 systolic and nausea, and which resolved within about 60-90 min. There may have been an issue with the freshness of that batch of noodles as well.
But all in all, after an ordeal which included the failure of 38 ECT treatments, six weeks of daily transcranial magnetic stimulation treatments, multiple (and very expensive) IV ketamine doses, dozens of medications, 4 hospitalizations, and several very serious suicide attempts, it took three weeks of Parnate (with Dr. Gillman’s dosing recommendations) to completely eradicate a very severe, agitated clinical depression. I am very lucky of course, to have had unwavering support in general (and in particular the dedication of my friend who never gave up despite how bleak it was for a long time), as well as the good fortune to happen upon Dr. Gillman's website, without which, at best, I would have been on 5-10 mg of Parnate for two weeks before possibly increasing it - and would have stopped it by then for sure, with literally no hope of recovery. A sobering thought, indeed!
APA textbook update: MAOIs
- Written by Dr Ken Gillman
APA textbook — serious errors
In August of 2016, I posted some observations about serious errors in the APA textbook of psychopharmacology (4th ed.). I communicated my concerns to the editor, Dr Nemeroff, and associates, in view of their importance. I received an assurance that appropriate alterations would be considered in the up-coming 5th edition.
The text of the fifth edition is now available and I have looked at the MAOI chapter to see if it is usefully updated and improved: it is not (I dare say the TCA chapter, and others, are just as bad — but I am not prepared to waste my time looking); it contains the much same inconsistent and erroneous information as before, which demonstrates the authors’inability to understand drug interactions (Dr K. Ranga Rama Krishnan***).For a text produced in the second decade of the third millennium it can only be described as being of a poor academic standard. There are many seminal references, that are essential to an up-to-date understanding, that they have completely failed to take note of or cite (some of them mine).
*** Krishnan’s supposed ‘expertise’ in this field is predicated on his ‘authorship’ of one 3rd-rate review article on MAOIs (1). I say ‘authorship’ because this article was published in a Journal supplement; these are usually not peer-reviewed, and are usually ghost-authored. There is an acknowledgement to a lady who provided ‘writing/editorial’ assistance. We can safely assume this was a ghost-written article and that Dr Krishnan had next-to-nothing to do with it.
I wonder if that is the case with the book chapter also? It certainly reads like that.
The blurb says ‘A work of uncommon scientific rigor and clinical utility … side effects and toxicology, and drug–drug interactions are addressed for each agent’.
One struggles to find the words needed to convey how outrageously inaccurate that description is. To claim this book represents ‘Uncommon scientific rigor’ is to be party to a stupendous deceit. If, by ‘uncommon scientific rigor’, they mean an uncritical recitation of every half-baked ‘RCT’ ever done, which proves drug A is better than B > C > A, in a meaningless circle, then yes.
If readers are hoping for a mature interpretation of the morass of biased information and poor trials, tempered with a bit of clinical wisdom, they will be mortally disillusioned.
As far as ‘drug–drug interactions are addressed for each agent’, this area is very poor, inaccurate and way out of date.
It is pointless to waste time discussing the errors in detail because, with access to the literature of the last decade or two, anyone of any perspicacity will be able to see how poor this chapter is.
It is appropriate that anyone who is inclined to assume that the APA book is a useful text, which they can rely on in relation to, among other things, MAOIs, TCAs, and serotonin toxicity, should be aware that many experts in the field would strongly advise them against such reliance.
Bearing in mind that, as a recognised world expert in ST, I specifically alerted them to significant and potentially fatal mistakes in the previous text (4th edition) it seems they have dealt with the production and amendment of this latest edition with a carelessness and disdainful insouciance that is a breathtaking insult to prospective readers.
Students and doctors in the early stages of their career, or indeed, anyone intending to improve their knowledge, have my sympathy concerning the difficulties they must have trying to decide which texts to trust; but this is not, by any conceivable measure, one of them.
My previous comment remains applicable, almost in its entirety, as a criticism of the ‘updated’ fifth edition. Therefore, I shall not expend any further time or energy on further comment.
There is a much better bang-for-your-buck to be had by subscribing to the material from the British Assoc. for Psychopharmacology
Previous text from my 2016 comment
In the latest round of writing updates relating to MAOIs I tripped across the American Psychiatric Association’s textbook of psychopharmacology 4th ed. (1). I am not sure what the readership of such texts is outside of those in training, but it certainly is not a book that I would pay to have on my shelf. Like the curates’ egg, ‘Parts of it are excellent’, but are spoiled by the parts that are not.
That is an ironic and esoteric joke now, I suppose: to understand it (if you do not already) see:
The chapters I looked at were those on MAOIs and TCAs — people send me things like this because of my expertise in these fields. Sometimes they are hostile and demand to know how I can so heretically contradict a sacred text.
The answer is, because I know better, and not only do I say it is wrong, but it gives advice which, if followed would put you on the wrong end of an expensive law suit (is there any other sort?). The chapter on MAOIs is appalling, that on TCAs is somewhat iffy, and in need of significant updating in quite a few respects.
Since one can be certain that a fifth edition is due soon, I thought I would flag these errors and make a brief comment. I sincerely hope they do manage to correct these errors, that could, indeed should, have been corrected long ago. Let us be clear, I am not quibbling about the fact that they do not include references from last year or two (like my reviews!), I am talking about important facts that have been established in the literature for a couple of decades; not to have assimilated those into a textbook of the standing one imagines most people would suppose this book to have is absolutely reprehensible. They seem to be treating the people who pay for book with derisory insouciance.
Life-threatening and serious errors and omissions
The errors and omissions of serious and life-threatening importance are in relation to explaining or elucidating the major interactions of serotonin toxicity and the tyramine pressor response. In essence, it is fair to say that the author(s) of this chapter show little or no understanding of the serious interactions of MAOIs. It is unnecessary to go into it in detail here, because all the information is already in published reviews, not just mine, and on the website. One only has to compare the table (18.4) with that information to see how serious many of the mistakes are.
The section on drug interactions (with table 18.4) is a swamp of hopeless misinformation which completely fails to recognise the essence of serotonin toxicity and the modern data on which drugs can and cannot elevate serotonin, and thus constitute a risk. It is appallingly bad (not corrected in 5th ed.).
The comments concerning the interaction of moclobemide with SSRIs surely must border on criminal negligence. Firstly, there is a complete failure to recognise the entirely predictable interaction of combining an MAOI, even a selective reversible one like moclobemide, with any SRI. To compound this serious error, it then goes on to state specifically that no interactions have been reported when that is manifestly incorrect (partly corrected in 5th ed.).
‘Several studies have examined potential drug–drug interactions with moclobemide (Amrein et al. 1992). No drug interaction with lithium or in combination with TCAs has been reported. Moclobemide has also been combined with fluoxetine and other SSRIs with no significant interaction.’
Many fatal interactions had been reported (well before this 4th edition was published), exactly as would be predicted. It is blindingly obvious that the writers of this chapter have lamentably poor knowledge of psychopharmacology and drug interactions and one wonders how they can have been selected for the job, or, indeed, who refereed the chapter. Surely a book like this must be refereed? There can hardly be a more serious error than failing to know about and emphasise an established proven fatal interaction.
And re Tranylcypromine:
This is grossly inaccurate information.
“Tranylcypromine, a non-hydrazine reversible (corrected in 5th ed.) MAOI, increases the concentration of NE, epinephrine, and 5-HT in the CNS. When tranylcypromine is discontinued, about 5 days are needed for recovery of MAO function. Tranylcypromine has a mild stimulant effect.”
‘Reversible’, really, that is a new one!
I see, ‘increases the concentration of NE, epinephrine, and 5-HT’: ah, so it does not affect dopamine then? Really.
And ‘5 days are needed for recovery of MAO function’: I have seen and heard of quite a few severely serotonin toxic patients who would disagree with that, then there is the published research (not corrected in 5th ed.).
These authors & editors are Bozos, Wallies, Twits, Prats; pick your favourite insult and use it liberally because these authors jolly well deserve to be publically shamed.
Why? Because advice like that above will f---ing kill people. Dead (well, at least the correction re moclobemide/SRI has been sort of corrected in 5th ed. So, the advice given makes it unlikely anyone will be killed).
1. Krishnan, KR, Revisiting monoamine oxidase inhibitors. J Clin Psychiatry, 2007. 68 Suppl 8: p. 35-41.
Guidelines: problems aplenty
- Written by Dr Ken Gillman
Guidelines: problems aplenty
They fuck you up, the bloody guidelines.
They weren’t designed to, but they do.
They’re filled with faults, then add
egregious extras, just for you.
A parody: my apologies to Philip Larkin – Original here
In a time of universal deceit, telling the truth is a revolutionary act.
George Orwell 1984
Guidelines are the ‘final common pathway’ communicating data, that are generated by randomised controlled trials (RCTs), to practicing doctors. This commentary assembles the evidence that most RCTs, and therefore guidelines, are seriously flawed, and are a negative influence on good clinical practice (1, 2). First and foremost, this is because so many RCTs are based on corrupted data and corrupted methodology, which emanates from the systematic errors, manipulations, and distortions, of clinical trial processes (mostly by ‘big pharma’), and the resulting ‘evidence’. A great majority of all trials published are paid for by ‘big pharma’ (3), so that distorts the greater part of all published, and unpublished, medical science.
As the Lancet editor, Richard Horton, so scathingly put it: ‘much published drug-trial research is McScience’; it is advertising — not science. He is among a number of journal editors and prominent researchers who have commented in relation to this, along with other ex-editors of leading medical journals (4-10). Horton has reviewed Kassirer’s (ex-NEJM editor) just-published book (11) and comments that ‘The best editors get fired’ [because making money and publishing good science are antithetical enterprises]. All these editors came to the realisation that they were being duped, manipulated and blackmailed into publishing misleading science, through the prestigious publications they were in charge of, which had been turned into cash-cows and, [Horton] ‘little more than information-laundering operations for industry’, and [Smith] ‘extensions of the marketing-arm of pharmaceutical companies’ (7, 12).
Another facet is the erosion of the fundamental pillar of the independence of medical editors. This erosion has resulted from commercial pressures, either directly from the publisher, or via withdrawal of advertising by pharmaceutical companies, or threatening not to purchase ‘reprints’ (13). There have been instances of the direct blocking of publication of research which was unfavourable to particular drugs (14).
Doctors, and other health-care professionals, generally have an insufficient appreciation of just how comprehensively corrupted are the data that are subjected to ‘meta-analysis’ (M-A) and ‘systematic review’, which are the back-bone of evidence-based medicine (EBM), and therefore how corrupted are the guidelines themselves — as Prof Ioannidis recently expressed it: ‘Few systematic reviews and meta-analyses [there are now hundreds of thousands] are both non-misleading and useful’ (15). The crazy position is that there are more systematic reviews and meta-analysespublished annually, than actual original trials.
They are all merely ‘re-digesting’ the same material, which is sometimes execrably poor, usually producing different ‘results’ and interpretations.
Almost none of these data, relied on by reviews, M-As and guidelines***, have been independently replicated. That which is not replicated is not science.
*** In this commentary, one can generally think of the terms, systematic-review, meta-analysis, EBM, and guidelines, as synonymous.
Big Pharma has played a major part in creating and steering both diagnostic practice and guidelines, which are the coup de grace in this sorry saga of the mutilation and abuse of science.
There has been, quite rightly, a fuss, and much writing, about the various issues relating to the deceit, fraud, bias etc. detailed and discussed in this commentary. On a web site called ‘International Network for the History of Neuropsychopharmacology’, some of the most famous names in the field from the last 60 years have aired opinions agreeing with what I say in this commentary.
However, right from the start, I want to emphasise how little difference this has made to the continuation and dominance of those very same improper and dishonest practices.
Many of the apparent improvements that have been claimed, concerning the probity of science research and publishing, constitute a charade and are no more than a splash of new paint on the facade of a decrepit building.
Guidelines magnify these mis-truths and imbalances and promote a narrow perspective on health-care which puts excessive emphasis on drugs over other non-drug interventions, or no intervention at all.
Independent replication is the corner-stone of all science: if you cannot inspect the original ‘raw’ data (see below), you cannot know if it is sound data, nor whether anyone has replicated it. Most medical research is not independently replicated, ergo, it is not science. It is that simple. No rationalisations or excuses can alter that.
Either you are doing science, or you are not.
Epidemic of meta-analyses: RCTs & ‘coprophagia’
Guidelines have proliferated like rabbits over recent decades, and they are the dominant influence over the treatments chosen by practicing doctors. The ‘meta-analyses’ and ‘systematic reviews’ on which they are based have proliferated even more than guidelines, and proliferated to a farcical extent, rabbits (coprophages) cannot compete — in a recent paper, ‘The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses’, Professor Ioannidis has detailed how more systematic reviews of trials are published annually than actual new randomized trials. For antidepressant drugs alone there have been 185 meta-analyses published between 2007 and 2014 (15). Professor Ioannidis concludes:
‘The production of systematic reviews and meta-analyses has reached epidemic proportions. Possibly, the large majority of produced systematic reviews and meta-analyses are unnecessary, misleading, and/or conflicted’.
Many meta-analyses are indeed industry initiated, organised, sponsored, and conflicted (16).
How better to describe this activity than as ‘intellectual coprophagia’?
The meetings of senior doctors, to craft both the Diagnostic & Statistical Manual (DSM)*** and most guidelines, have been heavily funded by drug companies. Large numbers of eminent American doctors were handsomely remunerated to attend resorts in Palm Springs and like venues, to thrash out guidelines for the use of SSRIs, Xanax, Risperdal, Seroquel … you name it.
*** The DSM is the very profitable product of the ‘American Psychiatric Association’: I have to say that most of my colleagues in USA, those who have retained their probity, regard the APA as a corrupted organisation.
Guidelines now unjustifiably impose themselves on doctors who may not agree with them. That is ‘intellectual imperialism’ (17). I suggest ‘intellectual fascism’ is a more accurate term.
By the way, there are multiple guides to guidelines — honestly (18-22).
Which set of guidelines do you then choose to follow? One might facetiously ask, ‘is there an evidence base for deciding which guideline has the best evidence base’?
Guidelines are contaminated by having expert panel-members who have financial ties to drug companies, even though the Institute of medicine long ago recommended that no such people should be on the guideline-panels (23, 24). Even if panel-members are truly independent, their main currency is still corrupted RCT data, and no-one can overcome that problem, any more than can the statistical legerdemain of meta-analysis — garbage in, garbage out (see below).
There are other good reasons, in addition to the problems with RCTs, to suppose that the evidence-based medicine (EBM) enterprise is diseased from the roots to the shoots (17, 25-28).
Guidelines have morphed. They may well have been intended by some proponents, as exactly that, guides: the sort of kind advice that a senior colleague might give about a difficult case. But they have been seized on by the simple-minded, the lazy, the authoritarian, the managers, the media, and even politicians, as if they were diktats — and that is how one sees them being applied to many patients.
This is a complex topic to deal with and understand. It involves an understanding of history, how businesses work, how medicine works (I refer particularly to the vested interests of specialists and experts), and much else besides. That understanding can only be attained through wide-ranging experience of medicine and life, and extensive reading. Few doctors have the time to do that, except for those like me who are enjoying a comfortable retirement in the sun, which is setting on the age of the polymath.
The books I have listed are in my view the indispensable background to enabling people to see and understand the big picture. I will simply add that as a pharmacologist with a sceptical attitude, I am absolutely certain that vast numbers of people are being treated with expensive drugs that produce little or no benefit, but have many poorly documented and unpublicised ill effects.
Do we need to be reminded that adverse reactions to drugs, and drug-drug interactions, are among the leading causes of hospital admissions and deaths (29-33)?
I am reminded of Shaw’s words:
‘When a stupid man is doing something he is ashamed of, he always declares that it is his duty.’
I expect my readers can translate that into ‘guideline-speak’.
This is a good point at which to recommend books relevant to this subject: I recommend these because they are all written by scientists giving an informed view of the subject. These individuals continue to attract a considerable degree of opprobrium: powerful groups do not like the truth being told.
Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients’’ (Faber and Faber, 2013) Ben Goldacre; Senior Clinical Research Fellow, Centre for Evidence-Based Medicine, University of Oxford.
Pharmageddon. Professor David Healy. Hergest Unit, Bangor, Wales(the best pun title I can remember).
Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare Professor Peter C. Gøtzsche. Danish physician, medical researcher, and leader of the Nordic Cochrane Center at Rigshospitalet in Copenhagen, Denmark. He co-founded, and has written numerous reviews in, the Cochrane collaboration.
Psychiatry Under the Influence: A Case Study of Institutional Corruption. Professor Lisa Cosgrove and Mr. Robert Whitaker (a medical writer, director of publications at Harvard Medical School), both are fellows at Edmond J. Safra Center for Ethics, Harvard.
The Truth About the Drug Companies: How They Deceive Us and What to Do About It (Random House, 2005) by Marcia Angell, M.D., (former editor of the New England Journal of Medicine). Marcia Angell, M. D., is a Corresponding Member of the Faculty of Global Health and Social Medicine at Harvard Medical School and Faculty Associate in the Center for Bioethics. She stepped down as Editor-in-Chief of the New England Journal of Medicine on June 30, 2000. The only one of this list that I have not read myself.
Merchants of Doubt: How a Handful of Scientists Obscured the Truth on Issues from Tobacco Smoke to Global Warming. Professor Naomi Oreskes, Erik M. Conway. This is a more general historical overview covering tobacco and climate denial etc. which gives a better impression of the enormity and persistence of these big-business tactics.
I do not make a habit of reading books like this, since I have already made most of these points myself. And continuing to read literature which simply agrees with what you already think is not a priority, reading material which disagrees with what you think is what good scientists do. However, when I decided I would write a commentary about guidelines it was necessary to read or re-read these texts.
Seriously corrupted data — a core problem
The serious persistent problems surrounding confliction and evidence relating to guidelines are undeniable, as evidenced by many recent reviews (20, 34-36), which indicate, as suggested above, that little has changed over the last decade or two, despite all the kerfuffle.
These problems are related to, first and foremost, the appropriation, hiding and distorting of patient data by ‘big-pharma’ (see below), as well as the conflicted handling, and then mis-used third-rate science, that underpins most of the clinical-trial base, and thus of the ‘evidence-based medicine’ enterprise.
This has been fuelled by the massive financial power imbalance in the medical system (pharmaceutical companies have all the money). It has been powerfully catalysed by the weak acquiescence of the medical profession in allowing drug companies to take over the whole trial process, including the actual data — that is, incidentally, a glaring ethical betrayal of patients: but few seem to have commented on that, or even noticed it.
Allowing the partisan drug industry to sequester the data, and refuse to let (even their own) expert ‘authors’ examine it, was a serious tactical error (possession is 9/10 of the law).
It is hard to respect the medical professionals who have colluded in this process, a proportion of whom are undoubtedly wicked, greedy, self-aggrandising and dishonest, even if they convince themselves otherwise.
What do I mean by seriously corrupted data? The concise answer is this: data that any seasoned observer has good reason to suspect are unreliable, and which are not subject to examination and checking by others, nor reproducible (see e.g. Pharmageddon).
If I report that a patient I have assessed was ‘suicidal’ this means little if I do not record exactly what I asked the patient, and what they replied. Needless to say, it means even less if I refuse to show my case records to anybody else, and simply justify my opinion by saying ‘because I say so’. But that is what big Pharma is still getting away with.
There is rather more to it than that: for instance, if the patient does not have a relationship with me, and does not trust me, then they are unlikely to answer truthfully about suicide, for fear of being locked-up.
I am going to have to give a few examples relating to corrupted data here, because, although endless examples and details are in the references and books cited, many will not get around to looking at them. Since these are crucial evidential material, I will give details on one or two, because I can hear some of my colleagues saying, ‘come on Ken, surely you are overstating the case here, it's only a few bad apples etc.’ If only …
Blumsohn was the doctor at Sheffield who lost his job for attempting to insist on seeing the raw data for the tables in the ghost-written paper he was presented with as ‘author’. He was not prepared, like most are, to just ‘sign-off’ on it. His Dean, Eastwell, another co-author, did sign-off on it, and subsequently appeared before the General Medical Council because he said he had seen the ‘raw data’ when he had not*** (37); The reference has all the details.
***An explanatory comment on this is mandatory. Eastwell’s (successful) defence was that he had seen the data, but what he was referring to was the coded data, not the original ‘raw data’. Let us assume that he was not being disingenuous (which may be the case), that still leaves him guilty of being a naive and bad scientist. If scientists did not insist on dealing with original ‘raw’ data then we would all believe in ghosts.It all goes to show how many doctors do not understand science.
Documents revealed in another court case showed a senior company executive commenting on the [established fact of] hiding of adverse-event data from a drug trial, saying in an internal company email, ‘if this comes out I don't know how I will be able to face my wife and children’ — one imagines this was a rather superficial and self-serving mea culpa, but no less revealing for that.
It seems that many companies have been keeping research documentation ‘offshore’, which impedes accesses to them by legal processes — but such data could only be incriminating if they revealed ‘misrepresentation’, lying, cheating, whatever. It is an instance of ‘excusatio non petita accusatio manifesta’ [he who excuses himself, accuses himself].
I have previously commented on the chicanery involved in the Risperdal trials, and would only repeat here that the much-cited meta-analysis by Leucht (38) failed to cite the classic Huston paper that dissected the deceit pervading Risperdal trials (39): I asked Leucht why he had not cited Huston and he replied that they simply did not know about it. How hard did they look? If I can find it, in my disadvantaged and isolated situation here in tropical North Queensland, how come a professor at a major European University cannot find it. You see what you want to see, and forget what you do not want to remember.
Anyway, the extensive dishonesty involved with Risperdal (and, of course, many other drugs (40)) is well documented elsewhere and I have lost track of the number of successful legal actions against them in relation to this. They must have paid out more than a billion, by now. Ah well, it's just the cost of doing business. Google it, it will astonish you.
Look at the references for a myriad of further examples: when commenting on this sort of thing one feels like a hawk attacking a flock of starlings, there are so many targets that there is a danger of not killing any of them. I have to add here the observation that those are precisely the tactics Big Pharma sometimes uses. Flood the literature with ‘your stuff’ and the contrary view simply gets snowed-under and lost — that is exactly how they dealt with Barry Marshall (Heliobacter, Nobel prize, remember?) in order to maintain sales of the billion-dollar block-buster anti-ulcer drugs that still had a while to run under patent. Eventually the more effective, life-saving, long-term cure, anti-biotics, displaced them: eventually, after many more deaths — it seems co-lateral damage is acceptable not only in the military.
RCT: gold-standard or fools-gold?
‘Where the outcome at issue is at all substantial then not only is randomisation unnecessary, so also is the use of any formal statistical test of significance’.
Sir Austin Bradford Hill 1965.
Control RCTs. Control clinical practice
Control RCTs and the data they generate, keep it to yourself (preferably off-shore along with your tax shelf-companies) and you control clinical guidelines and clinical practice: talk about a fait accompli.
The dogma of RCTs as the gold standard has been made to over-shadow other forms of evidence: therefore, controlling clinical practice*** has become, pretty much, a one-step process.
*** In case there is anyone who does not get it — controlling clinical practice means drug companies can make sure all the new expensive drugs are featured prominently as first-line treatment recommendations in the guidelines, and thus maximise their profits.
Therefore, key questions for the incisive analyst become: do RCTs have any special epistemic validity, excellence, or superiority? how much value should we place in RCTs? how are their results demonstrably relevant and beneficial to the typical patient? do they translate into reliable and meaningful short-term or long-term treatment decisions?
These are crucial questions which have never been well addressed, even though they were raised by eminent statisticians right at the start of the whole EBM/RCT endeavour. As Worrall discusses (41), proponents of EBM advance an exaggerated view of the epistemic virtues of RCTs — here, we might note that Hill himself made a point of endorsing Claude Bernard's view that there is ‘no qualitative epistemic difference between experiment and (properly scientific) observation’ [i.e. clinical experience].
The eminent Australian professor, Gordon Parker, argued, some time ago, that there are major ‘limitations to ‘level 1’ evidence derived from randomised controlled trials … which are no longer producing meaningful clinical results’ (42), and that paper, and others (43-47), are entirely consonant with the major points raised herein.
One could make more of the epistemological, methodological, and statistical faults and problems concerning RCTs (1, 45, 48) [see especially Feinstein, 1997], but that is not the prime purpose of this commentary, other than to raise awareness and persuade readers that there are indeed very serious problems which should have a major influence on how ordinary doctors regard the results of RCTs, and therefore, guidelines.
No lesser authority than Hill himself pointed out that you need neither randomisation, nor statistics to analyse the results, unless the treatment effect is very small (49). Remember that.
Anti-depressant — a meaningless term
There is another point to be borne in mind. The degree of symptom improvement that a drug must exhibit, in order to be approved and officially labelled as an ‘antidepressant’, is minimal. Bearing in mind that such drugs are assessed for effectiveness using the poor and antiquated ‘Hamilton rating scale for depression’, one can easily see how small changes of symptoms, that have nothing to do with the core pathology of depressive illness (anergia and anhedonia), are sufficient to get almost any drug with sedative or anxiolytic properties over that hurdle (e.g. see my commentary on quetiapine), even if it has absolutely no effectiveness on the core changes that constitute the illness .
Look at this online version of the HRSD to see what I mean. Qs 4, 9,10,11 & 12 might all be improved by any anxiolytic/sedative — a one gradation change in each of those produces a 5-point improvement of your score, more than double that needed to get a drug approved by the FDA as an AD. Yes, incredible as that may seem to outside observers, it really is that silly (50).
Also, note there is not one single question in HRSD assessing the key core symptom of anhedonia, and precious little for anergia either — absurd, totally absurd.
That is not science.
Deliberately dishonest coding
The data gathered in clinical trials are inevitably subject to interpretation and uncertainty. Responses to a series of questions, artificially and rigidly constructed, asked by someone (unknown to the patient), paid for by a drug company, to go around asking questions from a clipboard!
For the purposes of analysis, they are coded by someone. Doctors have abrogated the responsibility for their lead-role in trials, so this someone is rarely the doctor who had responsibility for clinical care of the patient, but a technician at drug company central office — in fact, they pay separate ‘clinical trials’ companies, set up specially to manage these things, to do this. Having an arm's-length-separation facilitates plausible deniability. A recent painstaking re-analysis of the infamous paroxetine study 329 illustrates many of these points (51).
Furthermore, we know that coding sometimes has been incorrect (or deliberately dishonest), so that suicidal thoughts and feelings and intentions were coded, during the analysis of results, as something different (51-55) — and read ‘Pharmageddon’ for further details and references. Therefore, when the results were presented, and written-up for publication by ‘ghost-writers’, who had nothing at all to do with the actual drug trial — they were probably not even on the same continent — no one at these meetings, neither the presenters nor the attendees, had any idea what had really happened to actual patients.
Such practices have nothing to do with good science and the many doctors that associate themselves with such practices have either been duped, or are dishonest, and are traitors to science.
The medical colleges and authorities have abandoned their ethical principles. That is highlighted by the fact that the ‘famous’ KOL doctors who have allowed their names to be used as authors (front-men) of these kinds of papers have not been struck off the medical register for dishonesty or corruption.Are we so inured to such behaviour that we have lost our capacity to be outraged by it?
It is routine practice for the doctors, who participate in these trials from various different centres, to be refused access to the original aggregated data, they only get to see the data after its coded by somebody else. There are now numerous documented examples that this is done misleadingly, erroneously, or dishonestly, and that the practice continues (56, 57). What has recently been put on the Internet in the name of ‘transparency’ is a token: because the data shared is not the original data, it is the coded data. Not the same thing.
That is a mockery of science.
The way the pharmaceutical industry presented the benefits and side effects of SSRIs is an illustration of several of the above points concerning misleading manipulation of data and misclassification of side-effects. A major therapeutic effect (it is not a ‘side effect’) of all SSRIs is to inhibit the pathways that lead to sexual climax (no RCT needed there. cf. Hill). The minor effects on anxiety and mood are small by comparison (barely a 2-point difference between drug and placebo on the HDRS).
See my note on citalopram from nearly twenty years ago. [it has been on the site, but not attached to a menu — it is now: which is a reminder to use the search facility]. There are a number of bullet points at the end, one of which points out that the average practitioner would not have been able to discern the difference between those on placebo, vs those on citalopram, at 'endpoint'.
Anyway, the trials of these drugs claimed that inhibition of sexual climax was an uncommon occurrence — well, I was using clomipramine to help premature ejaculation in the 1980s, before ‘Prozac’ even existed. That is how well-know the SRI-effect on ejaculation was. I shall not dwell on this here, but if there is anybody out there who still doubts how the relative prominence of SEs vs benefits has been turned on its head, they might be persuaded if they read the relevant section of Prof Healy’s book Pharmageddon.
That exemplifies well the methodology that was developed for maximising the trivial effects on ‘mood’, by using large numbers of patients to get a marginally significant statistical result (cf. citalopram, above, and more recently of course see Kirsch (58, 59)) whilst at the same time failing to ask appropriate questions to elicit side-effects, or ‘mis-coding’ them (51, 60).
And long-term side effects — not our problem, it is licenced now, up to someone else to do all that.
That is bad science and it is deceitful science; it simply does not, and cannot get more, how can one put it: incorrect, erroneous, false, fallacious, duplicitous, mistaken, inaccurate, shoddy, corrupt, double-dealing, deceptive, deceitful, crooked, untrustworthy, fraudulent, misleading.
In short: it is as wrong as the parrot was dead. For those interested in rhetoric that is an amusing example of ‘pleonasm’.
The adage: ‘lies, dammed lies, and statistics’ has a long history going back to at least the 19th century. In, The Life and Letters of Thomas Henry Huxley, is his account of a meeting of the X Club, which was a gathering of eminent thinkers who aimed to advance the cause of science, especially Darwinism: ‘Talked politics, scandal, and the three classes of witnesses — liars, damned liars, and experts’. Even more apposite for our time.
I start with this old adage because it has withstood the test of time, which is telling, and because modern information-laundering, in this post-truth world, has re-invigorated its potency and influence.
Here is a tiny sample of many references I could give, by eminent researchers, discussing misuse of statistics in a great proportion of medical studies. Hardly surprising then that almost all published medical studies turn out to be wrong, as history indisputably demonstrates (61-67). One recent review by a group of eminent statisticians (68) stated [of the use of such tests] ‘definitions and interpretations that are simply wrong, sometimes disastrously so — and yet these misinterpretations dominate much of the scientific literature’.
The ASA has commented ‘Statisticians and others have been sounding the alarm about these matters for decades, to little avail’ (69).
I am not a statistician, so I will merely content myself with pointing out the above references and mentioning that two of the prominent culprits are p-values and the procedure called meta-analysis, which is invariably applied in a pseudo-scientific manner. I have previously described meta-analysis as ‘the phrenology of the third millennium’. I have recently become aware that an eminent researcher from Yale pre-empted me by decades, with a better analogy. He compared it to alchemy, and his detailed criticism of it remains essential reading, two decades later (1, 70). [The 1997 ref is an exemplar of prescience and a ‘must-read’].
Meta-analysis forms the backbone of guidelines, where it reaches its pseudo-scientific zenith. Elsewhere I have quoted Charles Babbage on this subject (GIGO — garbage in, garbage out).
A researcher, whose name is well-known in this field, recently said to me in a private email:
‘I have rather gone off 'meta-analysis' as it is mostly selective/rubbish data in - spurious certainty or continuing uncertainty out, whatever the sophistication of the statistical methods. I include myself in this criticism by the way’.
The trials included in M-A have multiple problems (71, 72), they exclude most of the patients that we treat in every-day practice — e.g. the young, the old, those with mild, or particularly serious illness, those with multiple conditions, and those on multiple drugs, and, craziest of all, patients who are suicidal. They may solicit subjects by advertisement, and now many of them are conducted in totally different cultures and settings in China, India, Asia and Africa (some 80% of Chinese trials are thought to be ‘fabricated’). Shi-min Fang (73) exposed scientific misconduct in his native China, for which he won the inaugural Maddox prize in 2012.
RCTs represent an atypical fraction of the real-world treatment population (20).
Methodology and heterogeneity
But, as if all that was not enough, it is not valid to extrapolate from the averaged result of a non-homogeneous group (70), and then apply it to individuals not from that group, but who share a somewhat arbitrary descriptive similarity (a score on a rating scale).
I defy anybody to produce even a skerrick of evidence that the group of patients, defined as MDD by DSM, is at all likely to represent a patho-physiologically homogenous group.
Drawing conclusions from, or extrapolating from, RCTs involving groups that, prima facie, cannot be assumed to be, or demonstrated to be, patho-physiologically homogeneous, is incorrect. It is invalid science. Black and white. End of story. No argument.
This is such a fundamentally important scientific fact, that an understandable analogy is required.
Lots of people enjoy gardening: so, let us pretend that the patients are represented by the vegetables (non-homogeneous) in your garden; root vegetables? green vegetables? ‘fruity’ vegetables? etc. (define a vegetable, define depression — there is much mileage in this analogy).
Now then, you have got some super new fertiliser from the garden-centre (organic and terribly expensive) and you want to know if it improves the yield of your vegetable garden — for aficionados of statistics, that is exactly why the famous statistician Fischer, of ‘Fisher's-exact-test’ fame, developed his analysis of variance test. It was to help measure the effect of fertilisers on crops at the Rothamsted agricultural research station in the UK — would you just scatter it around the garden, then see if your basket of mixed vegetables was a little heavier than before? or would you test the fertiliser on each separate type of plant, even though some of them look almost the same?
I hope it is obvious that, if the weight of your basket of mixed vegetables was only slightly greater on the new fertiliser, that would not prove all the plants were improving. It might well be only one of them was being helped a lot, and the rest not at all. Indeed, it might be that one or two were poisoned by it, because it was the wrong balance of nitrogen and phosphorus, or too concentrated. Whatever.
I trust that makes the point clear. No qualifications in rocket-science are needed here.
RCTs, as they are generally conceived and executed, represent science at an astonishingly incompetent level, yet that is what dominates drug research in psychiatry (and much of medicine), and ‘informs’ guidelines. It is hardly any better than the evidence for ‘Alt-Med’.
Presentation is the key: ghost authorship the solution
Despite all the fuss, ghost authorship in industry-initiated trials (i.e. most trials) is still common, perhaps even the rule (74-78).
The commissioning, timing, and placement of these ‘papers’ is orchestrated by …
… the marketing and sales divisions.
Because? Timing, presentation, and placement (key journals) are the sine qua non to optimal marketing and sales.
The medical-writing companies ghost-write and orchestrate it all, lastly, they get key authors on board, and presto …
PLoS Med and the NY Times got a raft of such documents [to do with medical-writing companies] made public (see here), in a court case: Ginny Barbour, editor in chief of PloS Medicine, said she was taken aback by the systematic approach [to generating ghost-written papers] of the [medical writing] agency. ‘I found these documents quite shocking, … They lay out in a very methodical and detailed way how publication was planned’ [before the ‘authors’ ever got involved] (79).
Many doctors routinely take the credit for articles written this way.
Such doctors, let us not mince words, are frauds, cheats, and liars.
But let us start this most serious of issues with something amusing.
A real ghost-author!
In the revealing Wilmshurst-case-saga — a man of probity — made well-known because of Simon Singh and the UK libel-tourism story, it was revealed, when he withdrew from authorship because they refused to give him the original data, that, included in the official list of authors of the published paper, was Anthony Rickards.
Anthony Rickards had died before the research was even conducted.
These unprincipled and unpleasant people then sued Wilmshurst for remarks he had made in academic good faith, about the limitations of the conclusions in the paper. This gives everyone a bit of insight into the threatening and bullying which has a major spill-over effect on the willingness of most academics to take on these kinds of people. It is a very insidious influence and totally antithetical to the scientific endeavour.One can see the power of the self-censorship and self-selection effect here: why would a decent, mild-mannered, industrious, conscientious researcher want to get involved in that kind of thing? those who do get involved may be a ‘different sort’ of person.
At the end of the day, all of the details substantiating the frequency, poor quality and dishonestly, of ghost-written material, are contained in references given herein.
What I would highlight is this, ‘the big picture’: one only has to look at the blossoming of these specialist medical-writing companies, to whom the pharmaceutical companies farm-out their ghost-writing tasks, in order to understand the mega-dollars involved and how common it must thus be, in order to sustain so many profitable enterprises.
Next, look at the number of papers published under the name of doctors (KOLs (80)***) associated with these drugs. You will find there are many academics who have been publishing papers ridiculously frequently (dozens per year), over prolonged periods of time. You cannot possibly write ‘proper’ scientific papers at that rate — so that tells anyone of perspicacity that these people are making a minimal, possibly negligible, contribution to either the research work, or the papers, that bear their prostituted imprimatur.
It is simple. You do not have to be Einstein to work it out.
*** From Moyinihan (80): quoting a drug company source ‘Key opinion leaders were salespeople for us, and we would routinely measure the return on our investment, by tracking prescriptions before and after their presentations, … If that speaker didn’t make the impact the company was looking for, then you wouldn’t invite them back.’
The medical establishment has done nothing to call ghost-writing doctors to account. This is the most astonishing ethical failure, and betrayal of patients, perpetrated by my generation of doctors — we should be profoundly ashamed.
The next step
Another step in this deceitfully orchestrated enterprise is the unscientific manipulation of data using the statistical metric of the p-value and other statistical peregrinations. I will not here describe what that means for non-scientists. Many prominent names in science agree with me (66, 81-83), I could have inserted one hundred references there, just from the last decade. Yet, unbelievably, doctors have colluded with it and swallowed all this in an uncritical and naïve manner.
It is also relevant to remind ourselves that statistical analysis is only really needed to ‘show’ a difference when the treatment effect is small; we did not need statistics to realise that penicillin and chlorpromazine were effective drugs. If complex statistics, and conflation of trials via M-A, are needed to show small treatment-effects of drugs — that covers all drugs in psychiatry in recent times — then the effects are of minimal significance or usefulness, no matter what blandishments may be offered to contradict this. Again, it is that simple.***
Lest anyone think I am going beyond my expertise in asserting this (being ultracrepidarian), I would refer them to the paper by Sir Austin Bradford Hill — he of the smoking-lung-cancer fame, and also the instigator of the first RCT ever carried out — who said of RCTs (49): ‘Where the outcome at issue is at all substantial then not only is randomisation unnecessary, so also is the use of any formal statistical test of significance’.
Do RCTs translate usefully to everyday practice?
Contrary to what is strongly contended by many, there is no sound reproducible science that would allow reliable conclusions that RCTs usefully predict everyday efficacy or long-term outcomes (84). They most certainly do not predict long-term side effects.
The EBM approach, based on an insufficiently critical assessment of RCTs, promotes unjustified over-generalization by accepting that the outcomes of RCTs apply generally — unless there is a compelling reason to believe otherwise (71, 72, 85). However, that is turning science on its head, and would certainly not have been accepted by Popper (86).
RCT evidence does not allow us to predict which particular small percentage of patients will experience these slight benefits — revisit the vegetable analogy above.
Generalizations (i.e. guidelines) that certain drugs ‘should be used’ in a large but ill-defined target population are an invitation for poor clinical practice and over-prescribing (2, 84).
Algorithm-guidelines, nurse practitioners
If doctors are pressured and constrained to practice within these guidelines, as they increasingly are, by their colleagues, health service managers and insurance companies, and fear of litigation, then why have doctors at all? Is all you need is managers and nurse practitioners checking that everyone is given the computer-generated-algorithm-guidelines that dictate treatment: in no time at all you will be able to dispense even with the nurse practitioners and get your treatment ‘instructions’ online and take your algorithm-generated script straight to the pharmacist.After all, most people only get a 10-minute ‘medication-management’ appointment anyway.
Incidentally, a bit of history: this is not a revolutionary idea, but a return to the past. The concept of prescription-only drugs is relatively new in the history of medicine.
And perhaps most sinister of all is the fact that patients worry that, if they did not accept the guideline recommended treatment, they will be refused reimbursement for any other treatment — now that really is medical fascism.
Bye-by, it was nice meeting you. May I leave you in the care of ‘Siri’ for psych —anyone remember ‘Eliza’.
My personal experience
My personal experience, my understanding of common practice, the published literature, and the requests I get for opinions on treatment from around the world, all lead me to the opinion that doctors continue to become more proscriptive and prescriptive. Proscriptive (i.e. dogmatic about following guidelines) and prescriptive (authoritarian and unwilling to consider the preferences of patients). It is as if they have come to regard themselves bound to guidelines —slaves to them, or guardians of them? A bit of both perhaps.
There is a disturbingly prominent vein of authoritarianism present that is in no way justified by the quality or certainty of the evidence and which does not admit discussion, options, choice, preferences, and flexibility (87, 88).
This is abhorrent ‘medical fascism’ and good doctors should have no truck with it, but some will lose their jobs because they try to stand up to it.
The very existence and prominence of guidelines magnifies this authoritarianism because guidelines provide a deceptive aura of authority and certainty. This is mediated by a fundamentally flawed system of narrowly focussed ‘pseudo-evidence’ (sponsored clinical trials and their associated methodological flaws) digested via the non-scientific medium of the statistical procedure that agrandifies itself with the epithet ‘meta-analysis’. Armoured with this false shield, our shining-medical-knights sally forth to do battle with mythical disease-dragons — many have shunned DSM, and the disease-mongering that has accompanied it (89-91).
I referred above to the fact that this was an immense and complex topic. I must indicate what I mean by ‘mythical disease-dragons’. Many informed commentators have noted how the internationally influential American Psychiatric Association manual, called DSM, has over the last few decades served to expand the definition of mental illness to encompass a very substantial proportion of the population, thus legitimising and enabling the ‘medicalisation’ and insurance-remunerated administration of drugs to vast numbers of people (for instance, I think recent figures indicate something like 10% of all American children are on medication for ADHD).
Issue of long-term therapy
A doubtful inference that is made from RCTs (and amplified via guidelines) is that modest short-term treatment effects over a few weeks, even if you accept those are meaningful, extend to long-term treatment and meaningful real-life outcomes (like a reduction in the suicide rate) — as opposed to a small change on a rating scale, which is merely an interim proxy measure. Indeed, if anything, the evidence points in the opposite direction: for instance, lithium has the least effect on short-term scores on the HRSD, but the greatest long-term reduction of suicide and hospitalisation (92-94).
These drugs are almost always given over a period of many months, often years. Indeed, other types of evidence, and this speaks to the almost complete lack of external validity of guidelines, suggests that long-term treatment with most antidepressants (and antipsychotics) does not reduce long-term illness manifestations. Statistics concerning such questions are complex, not always reliable, and much disputed. Disability, the hospital readmission rate, the suicide rate, may be reduced, little, if at all (95-102). All those things are fairly powerful evidence that the drugs have questionable long-term benefit for patients. The long-term side-effects are not in doubt though. It seems reasonable to suppose that there are substantive benefits for carefully selected severely ill patients: however widespread use of these drugs probably means that a large proportion of people who are being given them, are being exposed to risks without benefit.
One should note here that this not to say that ‘antidepressant’ drugs are ineffective for everyone. Experience clearly demonstrates that severely depressed patients experience major benefits from various particular antidepressants. And, even if SSRIs are not really ‘antidepressants’, that is not to say they do not benefit some symptoms in some people.
It is difficult to construct a sound argument that the evidence strengthens the case for using RCTs to guide treatment for the general population. Much evidence supports the opposite point of view.
To listen and advise
Doctors are there to listen and advise, not to dictate and direct with insufficient real evidence, explanation, and discussion. For me at least, it is a fundamental precept of medical practice that we listen and advise and resort to paternalism and authoritarianism as little as possible.
There are few circumstances in clinical medicine in which the underlying science is sufficiently good to confidently dictate one particular form of treatment over another. In psychiatry, there are no circumstances in which the underlying science is sufficiently good to dictate one particular treatment over another.
Guidelines are furthering and fostering medical rigidity and authoritarianism. They must avoid being prescriptive, and their creators need to accept responsibility for how they are used and abused. Then there are other issues, like their period of validity, a clear statement about when they are due for revision (sometimes missing) and what kinds of new evidence might invalidate them. There is no established mechanism for questions and discussions with those who promulgate such ‘edicts’, nor criteria for judging who has valid authority and expertise to participate in issuing such edicts (1).My inner atheist is smiling as it contemplates the myriad of parallels between religious texts and guidelines: who decides which texts become an accepted part of the holy book? who are the anointed priests who determine these things? and should we hold a ‘council of Trent’? The parallels just go on and on, but we must leave it there, despite the rich comic and satirical possibilities.
The creators of guidelines have a clear obligation to get out there and engage in dialogue with the people who are actually expected to use them. At the moment, the whole process bears too close a resemblance to a papal edict. The world of guidelines is rife with schisms, just like the world of religions.
The various churches have generally adopted the wisdom of claiming that their redemptive truths can only be verified in the [anticipated] afterlife.
Summary and conclusion
This commentary has looked at the various problems plaguing RCTs & M-A & EBM & guidelines. The foremost of these problems, that practicing doctors will benefit from an awareness of, are that the data behind RCTs/guidelines are seriously contaminated by secrecy, corruption, distortion, bias, and misapplied and poor science.
Major problems, of a directly science-related nature — epistemological, methodological, and statistical — are flagged, but not analysed in detail: to do that would require a book. A prominent one is the invalidity of extrapolating from patho-physiologically non-homogeneous trial groups: this afflicts almost all RCTs and it hugely diminishes their value.
A rather doubtful inference is made from RCTs (and amplified via guidelines): that modest short-term treatment effects over a few weeks, often only estimated by proxy measures, extend to long-term treatment and meaningful real-life outcomes.
Guidelines are a gift to the intellectually lazy, and are increasingly treated as inerrant texts with a quasi-religious authority that relieves doctors of their duty for personal thought, judgement, responsibility, and individual consideration — follow the guidelines, and that will relieve you of necessity to make decisions for yourself.
Despite clear statements in the introductions to many guidelines about their ‘advisory’ nature, and the responsibility of the individual doctor to assess and treat each patient on their merits, this frequently just does not happen: intellectually laziness supervenes. Guideline creators should be obligated to take full responsibility for all aspects and problems created by their ‘product’: how they are presented, promulgated, and updated, and how they are abused and misused, and more.
Furthermore, those who now have an increasing influence on the delivery of health care, be they politicians, or managers of health care delivery organisations, or insurance companies etc. make simplistic assumptions and interpretations in relation to what guidelines actually recommend, and use them for their own ends. That can mean not giving treatment-cost re-imbursement to patients, or sacking a doctor, for not following ‘the guidelines’. Even if that is infrequent, that does not alter the fact that many doctors who contact me justify not using particular drugs on the basis that ‘it is not recommended in the guidelines, and I will get in trouble’.
Add all these factors together and you have a considerable potential, much of it already realised, for misapplication and patient harm.
We already have a generation of doctors who have not developed clinical experience and expertise in utilising non-standard treatments. Therein lies a downside for progress in clinical practice, because so many advances actually come from observations quite unrelated to clinical trials and purpose-directed research.
However good the intentions might have been, in those who initiated the notion of guidelines, it is well to remember that, as the old saying goes, 'The road to hell is paved with good intentions'.
The ‘gold-standard’ of RCT guideline evidence, when assayed, is found to contain a disconcerting percentage of fools-gold.
We might end by reminding ourselves of one or two simple observations, discussed above, which suggest that these expensive new treatments have achieved little. The expenditure on drugs for psychiatric illnesses has increased exponentially, by close to 100 times over the course of my career. The suicide rate has decreased little, if all at, and the number of psychiatric patients on disability benefit is much increased in most western countries. The number of patients hospitalised and harmed, by adverse drug reactions, is now among the leading causes of morbidity and mortality.
Massive expenditure, minimal if any advance, much harm.
Assigning greater weight to other possible research methodologies, and to experience and clinical judgement (2), as opposed to ‘RCTs’, is of great, but presently neglected, importance.
A final point to emphasise for those not familiar with scientific literature is that a majority of the references below are authors who are eminent. The papers have been published in the most prestigious journals, like Nature, BMJ, Lancet, JAMA, PLoS Medicine etc. We are not talking about authors on the fringe of medicine publishing in dubious and obscure journals.
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Valproate for acute mania
- Written by Dr Ken Gillman
Valproate for acute mania — under-dosing endemic
Is valproate under-dosed, in acute mania? Good evidence indicates that is the case; I am not alone in that view (1): I will proffer my opinion to explain why this is so.
When I was in practice I was an early adopter of high-dose valproate. The valproate regime I used was informed by my friend Professor Mervyn Eadie, a neurologist who was doing research on valproate around that time (2-8), and it was aimed at using the maximum tolerable dose. I therefore started with the objective of using 20 – 60 mg/kg per day, aiming at an initial dose in the middle of that range of 40 – 50 mg/kg, which is a daily dose of 2,500 mg for smaller persons (50 kg body wt.), and 5,000 mg for larger persons (100 kg body wt.).
I quickly settled on an initial dose of 1 g on admission (in the non-slow-release form in which it was then available, ‘Epilim’ tabs), followed by a further 1 g 4 to 6 hours later, usually escalating to 3 or 4 g the following day — most patients were able to tolerate 3 to 4 g daily without difficulty.
The T max is 1-2 hrs, T1/2 11-20 hrs (steady-state 3-4 days).
Vajda et al. (9) found human brain valproate levels were only a fraction of serum & CSF levels (6.8% to 27.9%).
Most ‘TDM’ serum level requests are inappropriate, and many are not taken at the correct time — at least eight hours after the last dose, and before a morning dose (10).
Using blood levels to guide dose is of uncertain value for several reasons, summarised by Eadie (5, 7, 11):
‘Therapeutic ranges of plasma concentrations of antiepileptic drugs are good servants in the management of epilepsy, but can become bad masters. The therapeutic range for valproate is rather wide, and some authors believe there is little correlation between plasma concentrations and antiepileptic effects of the drug (12).
In a recent review from the epilepsy field Patsalos et al. (13) highlight the value of ‘individual therapeutic concentration’, as opposed to reference ranges which, as Eadie said long ago, can become bad masters.
Patsalos et al. also, like Eadie, conclude that the evidence validating a useful predictable dose-effect relationship is poor (see also ‘toxicology’ below), and that due to individual variation many patients require concentrations outside the reference ranges. Management is best guided, at least for epilepsy, by determination of the ‘individual therapeutic concentration’ (the concentration needed for seizure freedom in a particular individual).
One possible explanation for the poor correlation between therapeutic benefit and serum levels in epilepsy is that different types of epilepsy have different sensitivities to the effects of valproate. I know of no analysis of the literature that has looked at this question, which was drawn to my attention by Prof Eadie. That point makes it even more relevant to assess the levels at which it is effective in mania separately, and not to rely only on pre-existing epilepsy data — see comment re Allen (14) below.
Twice daily administration of the standard preparation is a reasonable way to start therapy, and if blood tests are felt to be absolutely necessary they should be done before the morning dose.
Note that some Valproate SEs are not concentration-related (see toxicology below).
Until I undertook the research for this commentary I was unaware that the vast majority of trials, and other published accounts, of valproate in acute mania had utilised such low doses (viz. a maximum of 10 – 20 mg/kg). Despite this, they demonstrated a modest degree of efficacy, more or less equivalent to lithium and APs in most studies. The Cochrane review tabulates the details of the trials that were included (15), of which none used in excess of 20 mg/kg except Freeman (16), who used up to 3,000 mg, but only in a small number of patients, and Tohen (17) who used a max of 2,500 and used blood levels in a target range of 50 to 125 µg/ml.
In Druschky’s more recent European data (18) the mean dose was 1,500 mg daily.
A review by Vasudev et al. underlines the under-dosing problem (1).They found the mean valproate dose being given after the first week was 1,000 mg. The maximum, after one whole month, was only 1,500 mg. They concluded, understandably, that inadequate initial dosing and inadequate dose increments indicated that current practice is not evidence-based.
A small digression is relevant here, because this is an excellent example of how guidelines are a powerful negative self-fulfilling and circular exercise. Trials are often designed to show equivalent effectiveness to existing treatment, but with less side effects. The trials with the lowest doses demonstrating equi-effectiveness get published. Others get lost. Since no trials have utilised higher doses the guidelines will inevitably conclude that there is no evidence that higher doses are better — and they will therefore entrench and perpetuate that unfounded misconception, especially because more and more doctors now are unwilling to use non-guideline drugs and doses. This is exemplified by the UK NICE guidelines which are unhelpful, in more ways than one.
Therefore, few doctors gain the experience that would contradict that, because they feel constrained to follow the guidelines. Furthermore, so few psychiatrists have knowledge of the pharmacology and toxicology of valproate, that they do not have the confidence to try higher doses.
In this instance, that is despite scientific evidence that under dosing is occurring, and that higher doses are safe and more effective (see below).
Vasudev’s paper leaves me profoundlyperplexed regarding the kind of difficulty in thinking and decision-making that allows a clinician to take a month to do something so simple, like to adjust the dose of the drug above the minimum effective dose. This is especially so because it is being given for an acute condition which carries significant morbidity.
This frequent failure of ‘good-clinical-management’ of treatment, in relation to dose-escalation, duration, and response, is a theme which permeates most of psychiatric therapeutics, and is given insufficient attention in guidelines, if it is mentioned at all (see the comments in my AD algorithm). This seems to relate to several factors: the poor critical-thinking skills of psychiatrists, the inattention to teaching competent decision-making during their training, and poor confidence, resulting largely from poor pharmacological knowledge.
Rapid control of acute/severe mania
Valproate is relatively unusual in that the intravenous and oral doses are equivalent (i.e. bio-availability is 100%): therefore, blood levels and effectiveness are similar when equivalent IV/oral doses are administered (19). Generally speaking, in manic patients, it will be easier to give drugs orally, than attempt to manage intravenous infusions, which would in any case have no advantages.
Valproate has now been in use for over 50 years, and it has become clear that doses of up to 140 mg per kilogram (per day) are safe. Trials in epilepsy indicate that doses of 40 to 60 mg per kilogram well-tolerated and many patients have little by way of side-effects or significant adverse effects even when levels are above 100 mg/kg (see also ‘toxicology’).
Typical guidelines for the treatment of epilepsy advise doses up to a maximum of 60 mg/kg.
The above information helps to put the low doses of around 10 mg per kilogram, which are typically used in mania, into perspective.
A conservative dose range was simply adopted from pre-existing common practice in epilepsy patients. It is unlike most other psychiatric drugs, which gained approval specifically for a treatment indication in psychiatry: those were subjected to dose response studies, prior to the clinical-trial phase of experimentation.
It is worth noting that no proper dose-ranging study has ever been done concerning the use of valproate in acute mania, or any other psychiatric condition — but see Allen (14) regarding evidence that higher levels are better. They produced evidence of a pronounced and clear improvement in benefit showing a linear trend that did not plateau-out even at serum levels of > 100 μg/ml.
Carlat sums it up as ‘very effective for acute mania, and rapidly so, usually quelling manic symptoms within a week’. ‘Trials’, and hence guidelines, suggest it is equally effective as lithium and APs; I take Carlat’s above comment to infer the opinion that it is better, much better. That is the view I propound.
However, it seems to be used in only a proportion of cases, like about 50% (18): although this frequency of usage will inevitably vary from place to place and is probably often in combination with the so-called’ ‘atypical’ APs.
Incidentally, it appears lamotrigine is used surprisingly frequently in acute mania despite complete lack of evidence for its effectiveness.
Relative safety vs AEDs and APs
Druschky’s review (18) indicates, as previous reports and data suggest, that valproate is the safest of all the AEDs, and it is safer and much more ‘patient-friendly’ than APs. It has the lowest rate of adverse drug reactions rated as severe, compared to other AEDs (18).
It has low day-to-day mild side-effects compared to alternatives, and the lowest rate of treatment cessation from all causes, including SEs (a contrast to quetiapine where in some studies up to 50% of recipients cease it within 4 weeks).
Dose-related SEs most frequently seen appear to be: asthenia, diarrhoea, vomiting anorexia, but even in patients on high doses these rarely required treatment discontinuation (20). Note other SEs are not dose-related.
It has a wide margin of safety as the toxicology data demonstrates.
Recent papers relating to higher doses of valproate
Trinka (21):Efficacy and safety of intravenous valproate for status epilepticus: a systematic review. … 15 and 45 mg/kg in bolus (6 mg/kg/min) followed by 1-3 mg/kg/h infusion. Safety studies of intravenous VPA administration in patients with status epilepticus showed a low incidence of adverse events overall (<10%), mainly dizziness, thrombocytopenia, and mild hypotension, which was independent of infusion rates. Of note, good cardiovascular and respiratory tolerability was observed in these studies, even at high doses and fast infusion rates (up to 30 mg/kg at 10 mg/kg/min), despite multiple morbidities or other antiepileptic drugs.
Georgoff (22): The maximum tolerated dose of intravenous valproate in healthy subjects was 140 mg/kg; significantly higher than the previously established maximum tolerated dose of 60-75 mg/kg. Adverse events were mild and no drug-related abnormalities were seen in clinical laboratory tests, ECG, and cognitive testing.
Case reports of interactions and toxicity can be highly misleading, as they are in my field of serotonin toxicity. The same, unsurprisingly, applies to valproate, which has, as a result of misleading case-reports, unjustifiably gained a reputation for high toxicity and a narrow therapeutic index.
More comprehensive data from large series of carefully observed overdoses from toxicology units strongly contradicts that impression (23, 24). In a nutshell, valproate is relatively benign in overdose: mostly producing only drowsiness, tachycardia, and gastrointestinal effects (vomiting). In Isbister’s series ‘in 8 of the 15 valproate alone poisonings, greater than 200 mg kg-1 (14 g) was ingested, none of these had any major abnormalities except drowsiness in two cases ingesting 20 g and 25 g.’ Just as there is little correlation between SEs and serum levels at therapeutic doses, so Isbister found there is no correlation in ODs between serum levels and severity: they concluded, ‘more than half of the valproate-alone overdoses ingested greater than 200 mg kg-1 with little effect. Drowsiness was seen in two patients ingesting 300– 400 mg kg-1.
These data are from Prof Whyte’s prospective toxicology database, that I have a connection with, because that is where most of the ST data have come from. It is high-quality data from a top research group. Lastly, they also noted how much more toxic was carbamazepine.
Only limited, and poor quality, evidence supports the efficacy of valproate in the long-term treatment of bipolar disorder. As Ciprianiet al. state (25): ‘Clinicians and patients should consider acceptability and tolerability profile when choosing between lithium and valproate, their combination, or other agents, as long-term treatment for bipolar disorder’.
Valproate is under-used and greatly under-dosed in acute mania. Mono-therapy with high-dose valproate is the first-choice preference by a wide margin.
It has less side effects and a wider margin of safety than any of the other relevant drugs. It is much less expensive than almost any other option.
If adequately dosed, is almost certainly much more effective, despite the paucity of evidence for this from RCTs. That simply speaks to the fact that RCTs are frequently unhelpful, and as Parker has said (26), they ‘produce clinically meaningless results’.
It is therefore important for clinicians to develop and trust their clinical judgement, and stop deferring too readily and too often to the sometimes mis-informed conclusions promulgated by the committees that produce these guidelines — for a discussion of the extensive problems with guidelines see my recent commentary.
It reminds me of one of the factors that speeded my departure from the National Health Service in the UK many years ago. The more competent a clinician you were, the more of the actual work you finished up doing, whilst the people who were less capable sat on committees telling you how you should be doing the work! I was not very tolerant of being told how to do my job by a bunch of grannies.
There has been little useful new basic research on valproate for some years now — all the money is in new APs! But there is more data on dosing and toxicology, showing valproate has a substantially better profile than any other AEDs.
No dose ranging study has been done concerning the use of valproate in acute mania, a rather conservative dose-range was simply adopted uncritically from then-current epilepsy practice. The re-examination of those data above supports the safety, and theoretical rationale, and effectiveness, for administering much larger doses.
Accordingly, I would urge clinicians to give careful consideration to higher dosages of valproate in acute mania (30 – 60 mg/kg/day, or more): that means, even for a little (50 kg) patient a minimum dose of 1,500 mg per day (30 mg/kg) and for a larger person (100 kg) a minimum dose of 3,000 mg per day.
It is probable that the immense amount of money put into the marketing of new so-called ‘atypical’ antipsychotic drugs for the treatment of mania has obscured the profile and usefulness of valproate. As if it were needed, this is yet another example of the distorting effect on good clinical practice, produced by the huge dollar influence in sales and marketing from big Pharma, acting on the rather half-hearted and hesitant profession of psychiatry.
1. Vasudev, K, Mead, A, Macritchie, K, and Young, AH, Valproate in acute mania: is our practice evidence based? Int. J. Health Care Qual. Assur., 2012. 25(1): p. 41-52.
2. Eadie, MJ, Plasma level monitoring of anticonvulsants. Clin Pharmacokinet, 1976. 1(1): p. 52-66.
3. Eadie, MJ, Heazlewood, V, McKauge, L, and Tyrer, JH, Steady-state valproate pharmacokinetics during long term therapy. Clin. Exp. Neurol., 1983. 19: p. 183-91.
4. Eadie, MJ, Hooper, WD, and Dickinson, RG, Valproate-associated hepatotoxicity and its biochemical mechanisms. Med. Toxicol. Adverse Drug Exp., 1988. 3(2): p. 85-106.
5. Dickinson, RG, Hooper, WD, Dunstan, PR, and Eadie, MJ, Urinary excretion of valproate and some metabolites in chronically treated patients. Ther. Drug Monit., 1989. 11(2): p. 127-33.
6. Eadie, MJ, McKinnon, GE, Dunstan, PR, MacLaughlin, D, et al., Valproate metabolism during hepatotoxicity associated with the drug. Q. J. Med., 1990. 77(284): p. 1229-40.
7. Eadie, MJ, Formation of active metabolites of anticonvulsant drugs. A review of their pharmacokinetic and therapeutic significance. Clin Pharmacokinet, 1991. 21(1): p. 27-41.
8. Eadie, MJ, Drug therapy in Neurology, in Drug therapy in Neurology, MJ Eadie, Editor. 1992, Churchill Livingstone: Edinburgh. p. 115.
9. Vajda, FJ, Donnan, GA, Phillips, J, and Bladin, PF, Human brain, plasma, and cerebrospinal fluid concentration of sodium valproate after 72 hours of therapy. Neurology, 1981. 31(4): p. 486-7.
10. Perucca, E, Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs, 2002. 16(10): p. 695-714.
11. Ariyoshi, N, Miyazaki, M, Toide, K, Sawamura, Y, et al., A single nucleotide polymorphism of CYP2b6 found in Japanese enhances catalytic activity by autoactivation. Biochem. Biophys. Res. Commun., 2001. 281(5): p. 1256-60.
12. Kilpatrick, CJ, Bury, RW, Fullinfaw, RO, and Moulds, RF, Plasma concentrations of unbound valproate and the management of epilepsy. Aust. N. Z. J. Med., 1987. 17(6): p. 574-9.
13. Patsalos, PN, Berry, DJ, Bourgeois, BF, Cloyd, JC, et al., Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia, 2008. 49(7): p. 1239-76.
14. Allen, MH, Hirschfeld, RM, Wozniak, PJ, Baker, JD, et al., Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry, 2006. 163(2): p. 272-5.
15. Macritchie, K, Geddes, JR, Scott, J, Haslam, D, et al., Valproate for acute mood episodes in bipolar disorder (Cochrane Review). Cochrane Database Syst Rev, 2003(1): p. CD004052.
16. Freeman, TW, Clothier, JL, Pazzaglia, P, Lesem, MD, et al., A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry, 1992. 149(1): p. 108-11.
17. Tohen, M, Baker, R, Altshuler, L, Zarate, C, et al., Olanzapine versus divalproex for ther treatment of acute mania. . Stanley Foundation Conference on Bipolar Disorder September 21-22 2000 Amsterdam., 2000.
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19. Ghaleiha, A, Haghighi, M, Sharifmehr, M, Jahangard, L, et al., Oral loading of sodium valproate compared to intravenous loading and oral maintenance in acutely manic bipolar patients. Neuropsychobiology, 2014. 70(1): p. 29-35.
20. Beydoun, A, Sackellares, JC, and Shu, V, Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a double-blind, concentration-response design clinical trial. Depakote Monotherapy for Partial Seizures Study Group. Neurology, 1997. 48(1): p. 182-8.
21. Trinka, E, Hofler, J, Zerbs, A, and Brigo, F, Efficacy and safety of intravenous valproate for status epilepticus: a systematic review. CNS Drugs, 2014. 28(7): p. 623-39.
22. Georgoff, PE, Nikolian, VC, Bonham, T, Pai, MP, et al., Safety and Tolerability of Intravenous Valproic Acid in Healthy Subjects: A Phase I Dose-Escalation Trial. Clin Pharmacokinet, 2017.
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Lithium levels in tap-water & suicide
- Written by Dr Ken Gillman
There are many papers, over the last 15 years, reporting that violence and suicide is lower in areas where the natural lithium intake from municipal reticulated tap-water supplies is higher.
However, there is no credible evidence of a correlation between the very low levels of lithium ingested in tap-water and the level of lithium in people’s blood. Indeed, quite the reverse is the case, because serum lithium — like sodium — does not vary much with intake: they are both tightly regulated physiologically. Even if there was a relationship between normal low-level total dietary lithium intake, and serum levels, that would have little to do with tap-water, because most ingested lithium does not come from tap-water. Therefore, any attempt to correlate the lithium level in tap-water with the serum level, in people from different regions, with different water supplies, can be confidently predicted to be a failure. Research published so far ignores that lack of relationship and, with no rational basis, attempts to link tap-water directly to suicide: that is not only, a priori, misguided, but, worse than that, it is so utterly ill-conceived that it is a good example of the third-rate science that continues to erode confidence in the medical literature.
There have been repeated claims, for some years, that the suicide rate and violence is lower in areas where the natural lithium intake from municipal reticulated tap-water supplies is higher. There are a number of papers on this topic (1-12).
For reasons that will be mystifying to any scientist, none of the above papers have seen fit to measure the serum levels of lithium in subjects, in the different areas where they have assessed the rate of suicide, in order to establish that they are in fact different.That is the essential and obvious first step in the scientific investigation of such a question.Yet, none of these researchers have done anything except to measure the lithium level in the municipal water supply, they have not accounted for lithium from any other source.
The established facts about lithium levels detailed in this commentary indicate that speculative associative epidemiology, attempting to link tap-water with suicide and violence is, a priori, highly unlikely to be correct, and even less likely to reveal any actual cause-effect relationship.
Let us look at the evidence.
Endogenous serum lithium
The best replicated and latest data indicate that typical endogenous serum lithium levels are around 0.0003 mmol/L and that levels show low variation (~ 0.0001 -0.0005) in relation to typical dietary ingestion amounts (which are < 1 mg/day).
It may be noted that the measurement of nano-gram levels of endogenous lithium (and other trace metals) in biological tissues and fluids involves technical challenges and difficulties (13-16) and some reported measurements require replication before one can have confidence in them.
Lithium intakes above 1 mg per day probably overcome the physiological control mechanisms (see below) and lead to an increase in serum levels, exhibiting linear pharmaco-kinetics, as we see with therapeutic doses.
The most recent large samples (thousands of subjects) of endogenous serum lithium levels in humans are from Bochud et al. (17) and Seidlerova et al. (18).
The first step
The first logical step in any such research must necessarily be to demonstrate that a representative sample of people, ingesting water with a substantially different lithium concentration, actually do have serum lithium levels that are reliably and reproducibly different, compared to people in other areas where the water has a different lithium concentration. Simple.
Not to establish that before proceeding with detailed research, ignores logic and scientific methodology. Current evidence contradicts the proposition that tap-water is a determinant of total dietary lithium intake, and therefore, on the face of it (i.e. ‘a priori’) that makes a complete nonsense of all this kind of research.
Tap-water: less than one tenth of daily intake
The data indicating that tap-water constitutes less than one tenth of typical daily dietary lithium intake is clear and relevant, because these researchers have sought to link the varying amount of lithium in the municipal tap-water supply, in different districts, to suicide rates and violence etc. Our best current estimation of lithium intake, from the French ‘Total diet study’, is an average of 0.5 mg per day (19): the amount of tap-water which would have to be consumed, to reach just one 10th of that level, using the mean figure from a recent large survey of European water sources (20), would be 20 L per day (i.e. 0.002 mg/L x20 = 0.04 which is about 1/10 of the daily total of 0.5 mg). That is clearly absurd.That is a conservative estimate, for a large proportion of people in many areas where tap-water has even less lithium, the proportion of lithium ingested from tap-water would be more like 1% of the total lithium intake.
Municipal reticulated water supply (tap-water) and serum levels
The key step, missing in all the papers published so far, is to elucidate the relationship between tap-water and serum lithium. The data of Bochud et. al. (17), and Seidlerova et al. (18)has never been cited by any psychiatric publication on lithium. They both measured serum lithium concentrations & 24-hr. urinary excretion, in a couple of thousand subjects, and also in the tap-water they consumed.
The average concentration of lithium in tap-water in the Belgium cohort (Bochud) was 0.01 mg/L (high for tap-water), & in South Africa was 0.00021 mg/L (pretty low) — a fifty-fold difference — the serum lithium levels in the two cohorts were identical. The mean 24-hour urinary lithium excretion was higher in the Belgian sample (0.055 mg vs 0.021 mg per 24 hours) and more variable.
Serum lithium levels were almost identical: Belgium 0.0022 mg/L vs. South Africa = 0.0023 mg/L. And that in relation to a fifty-fold difference in tap-water lithium concentration.
Seidlerova et al. (18) measured serum Lithium in more than one thousand subjects (from northern Belgium) with similar results — average Lithium level was 0.18 µmol/L (0.0013 mg/L), with low variance.
That demonstrates unequivocally that serum lithium is tightly regulated even when there are variations in dietary intake (at these trace-intake levels from natural dietary sources of < 1 mg/day). Lithium and sodium are both alkali metals and sodium is tightly regulated, in such a manner that increases in sodium intake do not cause much variation in the plasma level: it is hardly surprising that same is true for lithium.
Micro-doses of lithium
de Roos et al. (21) used a lithium ‘supplement’ as a marker in a diet study: their 78 subjects had baseline levels of 0.0064 mg/L on normal diet (somewhat high compared to other results herein, but in the right ball-park)and on the supplement of 1.75 mg lithium daily themean lithium level was 0.046 mg/L (steady state, 24 hrs. post-dose).
Likewise, with similar results, Donahoo et al. (22) also using a ‘supplement’ dose of 1.75 mg, in 7 subjects, found a serum level of 0.035 mg/L (9 hrs. post-dose).
Shiotsuki et al. (23) looked at serum lithium levels in 43 subjects visiting a health spa and found they were much elevated after drinking the lithium-rich spa-water, the estimated lithium intake in these people was between 10 mg and 70 mg over a few hours. Serum levels rose from 0.026 mmol/L (not a true ‘baseline’ measurement) to 0.073 mmol/L (0.5 mg/L), the therapeutic range is around 0.4 up to 1.0 mmol/L.
Nunes et al. (24) did a study over many months giving a dose of only 0.3 mg daily of lithium to patients with dementia. The information in this commentary reveals why this study was of doubtful utility: they are barely getting any more than a typical daily intake, which as we have seen above, does not increase lithium levels. Furthermore, they did not measure serum lithium levels. Therefore, just like all the silly studies on suicide and tap water, this study falls into the same trap. Future studies need to measure serum lithium levels and use doses that actually are demonstrated to elevate serum lithium above the tightly regulated ‘endogenous background level’.
The above results suggest that intakes above around 0.5 – 1 mg per day saturate the physiological control mechanisms regulating lithium and lead to a progressive increase in serum levels exhibiting near-linear pharmaco-kinetics, as we see with therapeutic doses.
At the 1000 times higher therapeutic intake levels, of ~ 1,000 mg/d, serum lithium is determined by glomerular filtration rate and alters in direct proportion to daily dose: so, if 500 mg gives a steady state level of 0.3 mmol/L then 1,000 mg will give 0.6 mmol/L.
Other results for ‘endogenous’ lithium levels — for the record, but all are smaller sample sizes compared to Bochud & Seidlerova — Miller found serum lithium levels around 0.00016 mmol/L for normal subjects dwelling in the Denver metropolitan area, and the mean 24-hr excretion rate was 0.005 mmol/day (25). Folkerd (26) healthy volunteers (n = 25), mean 0.00027 +/- 0.02 mmol/L (range 0.00013-0.00055 mmol/L). Lehmann, small sample, maximum of 0.06 mg/L (0.009 mmol/L) (27). However, older assays may be inaccurate.
Endogenous lithium levels and suicide
In Bayesian terms, the above indicates that the prior probability of there being any relationship between low levels of lithium ingestion and any human behaviour is exceedingly small. Strange and tortuous assumptions and arguments would need to be adduced for any such hypothesis to be entertained, even fleetingly, by the most simple-minded reductionist.
There have been repeated claims, over the last 15 years, that violence, and the suicide rate, is lower in areas where the natural lithium intake from municipal reticulated tap-water supplies is higher. There are now a large number of papers touching on this topic (1-12).
Note, the recent Knudsen (28) and Kessing (29) studies were negative.However, they involved a lot of time and resources which this analysis indicates were a completely pointless effort.
The ‘Kapusta’ paper
An examination of the paper by Kapusta et al. (5), published in the British J of Psychiatry, a prestigious journal, and a follow up effort (4), will illustrate the kind of nonsensical material that is being published, even in supposedly first division journals. Kapusta’s paper seeks to make a correlation between population suicide rates and the differing concentrations of lithium in tap-water between different districts in Austria. The majority of the sample reported were exposed to low levels of lithium in the tap-water in their districts, and all within a relatively narrow range of concentrations (0.002-0.01 mg/L): since the established range in fresh water is 0.000005 to 0.3 mg/L, that constitutes a small window into the possible range.
The most recent best estimate of dietary lithium intake is, as above, around 0.5 mg per day (19, 30, 31). Intake from tap-water must represent less than one tenth of total daily intake — if typical tap-water is 0.002mg/L then drinking 2L per day is barely 1% of the total 0.5 mg estimated total daily intake. Lithium in food probably contributes ten times as much as tap-water. Not only that, but many of the foods (especially sea-food) and vegetables, and particularly bottled water, in peoples’ diet have come from different districts and different countries: which indicates that the locality in which one lives has nothing to do with lithium intake.
The consumption of bottled spring-water supports a multi-billion-dollar industry and bottled waters have, on average, a five times higher lithium concentration: viz. median level of bottled waters is 0.010 mg/L vs. 002 mg/L for tap water (20). In Europe, the EU average consumption, for 2015, was 110 L per capita per year, Austrian data indicates around 90 l per year.
Source: European Federation of Bottled Waters. http://www.efbw.org/index.php?id=90
Bearing in mind that children, and the financially less-advantaged, and geriatrics, are unlikely to drink mineral water (all this is so silly that it is difficult not to be facetious about it), we can estimate the typical adult is drinking about 150 L per year, or 3 L per week. That is equivalent to 15 L of ordinary tap water in terms of lithium content — based on the assumption from the data above, that the average difference between mineral water and tap water is five-fold.
That indicates a substantial proportion of Kapusta’s sample (or any other sample) will have been ingesting more lithium from bottled spring-water than from tap-water, certainly enough to make complete and utter nonsense of their data.
Lastly, Kapusta did not measure serum levels of lithium of a sample of people in areas exposed to different levels of lithium in their tap-water in order to demonstrate a correlation between the tap-water level and the serum level: that is the essential and simple requirement needed to establish a relationship between those two variables. Not to do that represents an epic fail — if there is no relationship between the lithium level in tap water in the different areas, and the average lithium level in the people living in those areas, then the principle behind such research is invalidated (cf. Bochud et al.), never mind the issue of lithium from other sources.
Remember, two huge studies of large samples ingesting water with a fifty-fold concentration difference found identical serum levels: they therefore concluded that, at those levels of intake, serum levels are tightly regulated and vary little with intake.
Without the correlation between serum levels and lithium concentration in tap-water (which the currently available data indicates is simply not present) it is obvious the paper is of no value. It is just silly and unscientific, I feel a sorry for them wasting their time. What is more of a concern is the ‘expert referees’ who decided to waste money by giving them a research grant, and also the journal’s referees who missed these obvious and major mistakes, which should have caused the paper to be rejected.
Lastly, in regard to not having accounted for the consumption of lithium either in bottled water, or in the diet, Kapusta et al. blithely state: ‘For obvious reasons, data for both of these factors are not available at aggregate levels; hence we were unable to consider these factors.’ That statement is glaringly incorrect: TDS1 had already been published (30) and estimates of bottled water sales/consumption are readily available. How facile is that? to so blithely dismiss a failure to address a key assumption at the heart of the paper. Perhaps we should not be surprised, since I have just noticed (in the small-print) that this gentleman comes from the Department of psychoanalysis at Vienna! Now then, which well-known fraud sprouted from there a hundred or so years ago?
Research attempting to link lithium in tap-water with suicide, violence etc. represents a wildly misguided misallocation of research resources.
Such studies do not deserve to be published, they devalue science, and they exemplify the truth of Ioannidis proposition: ‘Why most published research findings are false’ (32-34).
I hope the data and reasoning above persuade my readers that Kapusta et al. (and all the other silly papers seeking to establish such links) are quite obviously incorrect, and that all such similar efforts to correlate lithium in tap-water with suicide, violence, or in-growing toenails, are fundamentally and fatally flawed.
Please, stop wasting your time and our time.
As ever, caveat lector.
Before leaving this subject, it may be noted that the above criticisms do not preclude the possibility that at some point, at a very low level of lithium intake, the above evidence suggests at around 1 mg per day, the body's ability to regulate lithium may be overwhelmed, and levels start to go up. At that point, one might suppose that levels would be proportional to dose, as they are with therapeutic levels, even though those are 500 - 1000 times higher.
Thus, it remains entirely possible that in areas with an unusually high lithium level, and some (especially bottled mineral) drinking water gets up to a few milligrams per litre, enough lithium may be ingested by some people to affect physiology, and even illness processes.
However, the kind of research above is not going to throw light on that. Someone needs to do endogenous serum lithium levels in populations where there are very large variations in the lithium concentrations in water (cf. Bochud), and look at how ‘micro-dose’ supplements of a few mg per day, affect serum lithium levels (see above).
Finally, remember that we still do not understand what the relationship is between serum lithium, and the level in various nervous tissues. Improved scanning techniques may allow accurate estimations in humans at these very low concentrations, and may inform us about the degree to which lithium is concentrated in different tissues and brain regions; cf. thyroid tissue — where it is concentrated quite considerably — caveat, most of these studies are old and un-replicated! Time for some real science to be done? Or am I getting over-optimistic and silly in my old age.
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