![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 12 to 36 of 36. Go back in thread:
Posted by Squiggles on July 28, 2007, at 13:14:22
In reply to Re: Should all drugs be generic? » Squiggles, posted by Larry Hoover on July 28, 2007, at 12:51:03
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11999908
>
> LarI can find many articles and recent researches on this (see LITHIUM IN NEUROPSYCHIATRY - Bauer, Grof, and Mu[..]ller-Oerlignhausen) that say the contrary.
In the majority of cases, lithium inhibits thyroid hormone secretion rate by an increase in TSH concentration. Sometimes goiter and enlargement of the thyroid results. In some interesting, rare case there is the phenomenon of hyperthyroidism-- but that is a clinical oddity; is this what you are referring to by toxicity?
Also, let me remind you that patients on lithium are regularly checked for TSH function.
And in my case, i have been on lithium since i think about 1986, and have a steady level of creatine clearance, and TSH, with the TSH lowered in the first couple of years and remaining at a level where Synthroid was required, and the dose changed 2 or 3 x since. Therefore, you could say I am stable.
Furthermore, if i did try to get off lithium, given a stable state which others might envy on other drugs, it is not a certain that the thyroid gland could be reversed to its initial natural state.
P.S. Could you please approach a milder tone with me; you seem irritated by my posts or me.
Squiggles
Posted by Klavot on July 28, 2007, at 15:26:23
In reply to Re: Should all drugs be generic? » Larry Hoover, posted by Squiggles on July 28, 2007, at 12:06:04
> That's interesting. So, some companies make generics for the poor, and they are bioequivalent to non-generics? Do you now of such a company?
Hi Squiggles
To paraphrase Shakespeare, a molecule by any name is still the same molecule. Generally speaking, generics are not of inferior quality, and they are not targeted at poor people. By law, they need to be bioequivalent to within a certain margin with the brand-name drug. So you're getting pretty much the same chemicals but at a much lower price.
Klavot
Posted by Squiggles on July 28, 2007, at 15:31:10
In reply to Re: Should all drugs be generic? » Squiggles, posted by Klavot on July 28, 2007, at 15:26:23
> > That's interesting. So, some companies make generics for the poor, and they are bioequivalent to non-generics? Do you now of such a company?
>
> Hi Squiggles
>
> To paraphrase Shakespeare, a molecule by any name is still the same molecule. Generally speaking, generics are not of inferior quality, and they are not targeted at poor people. By law, they need to be bioequivalent to within a certain margin with the brand-name drug. So you're getting pretty much the same chemicals but at a much lower price.
>
> Klavot
So, if they are bioequivalent, as the FDA assures us, and they are not targeted at poor people, then why make them at all?Squiggles
p.s. it takes more than a molecule to make a drug in most cases i would think;
Posted by Klavot on July 28, 2007, at 15:51:49
In reply to Re: Should all drugs be generic? » Klavot, posted by Squiggles on July 28, 2007, at 15:31:10
Hi Squiggles
> So, if they are bioequivalent, as the FDA assures us, and they are not targeted at poor people, then why make them at all?
Once the patent to a drug expires, other pharmaceutical companies are able to profit by selling a generic version of that drug at a cheaper price.
> p.s. it takes more than a molecule to make a drug in most cases i would think;
Yes, but the active molecule is where most of the innovation lies.
Klavot
Posted by Squiggles on July 28, 2007, at 16:01:23
In reply to Re: Should all drugs be generic?, posted by Klavot on July 28, 2007, at 15:51:49
> Hi Squiggles
>
> > So, if they are bioequivalent, as the FDA assures us, and they are not targeted at poor people, then why make them at all?
>
> Once the patent to a drug expires, other pharmaceutical companies are able to profit by selling a generic version of that drug at a cheaper price.
>
> > p.s. it takes more than a molecule to make a drug in most cases i would think;
>
> Yes, but the active molecule is where most of the innovation lies.
>
> Klavot
Can't help it but my mind turns to biology and
parisitic opportunism. I wonder if there is a concept for that in Marketing Management.Squiggles
Posted by Larry Hoover on July 29, 2007, at 10:33:01
In reply to Re: Should all drugs be generic? » Larry Hoover, posted by Squiggles on July 28, 2007, at 13:14:22
> http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11999908
> >
> > Lar
>
> I can find many articles and recent researches on this (see LITHIUM IN NEUROPSYCHIATRY - Bauer, Grof, and Mu[..]ller-Oerlignhausen) that say the contrary.??
I presented empirical evidence of kidney function disturbance by lithium, which took me less than 10 seconds to find. It is irrelevant that others exclude data to reach contrary conclusions.
Moreover, I showed one of many kidney disturbances from lithium intake. I've already shown your supposition to be false.
> > Time flies like an arrow. Fruit flies like a banana.
> I'm not sure how profound that is.
It's not meant to be profound. It's a simple word play. The first statement primes the mind into considering one option, whereas the second statement is about something else entirely. It is not that 'fruit (collective noun)' 'flies (verb intransitive)', but that 'fruit flies (noun plural)' 'like (verb intransitive)'.....
> P.S. Could you please approach a milder tone with me; you seem irritated by my posts or me.
>
> SquigglesI think that's your perception.
Lar
Posted by Larry Hoover on July 29, 2007, at 10:36:08
In reply to Re: Should all drugs be generic? » Squiggles, posted by Larry Hoover on July 29, 2007, at 10:33:01
> It's not meant to be profound. It's a simple word play. The first statement primes the mind into considering one option, whereas the second statement is about something else entirely. It is not that 'fruit (collective noun)' 'flies (verb intransitive)', but that 'fruit flies (noun plural)' 'like (verb intransitive)'.....
Ooops. I meant the latter was transitive, or I'd not have included the descriptor.
Lar
Posted by Squiggles on July 29, 2007, at 10:49:58
In reply to Re: Should all drugs be generic? » Squiggles, posted by Larry Hoover on July 29, 2007, at 10:33:01
> > http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11999908
> > >
> > > Lar
> >
> > I can find many articles and recent researches on this (see LITHIUM IN NEUROPSYCHIATRY - Bauer, Grof, and Mu[..]ller-Oerlignhausen) that say the contrary.
>
> ??
>
> I presented empirical evidence of kidney function disturbance by lithium, which took me less than 10 seconds to find. It is irrelevant that others exclude data to reach contrary conclusions.
>
> Moreover, I showed one of many kidney disturbances from lithium intake. I've already shown your supposition to be false.
REPLY:
Is it "disturbance" or is it "toxicity" or both--
you seem to be wavering.http://www.emedicine.com/med/topic1313.htm
"The role of lithium in the production of acute renal failure is well accepted. The cause is generally due to severe dehydration and volume depletion due to the combination of natriuresis and water diuresis accompanied by elevated lithium levels, altered mental status, and subsequent poor oral intake. Acute renal failure has also been described as a result of lithium-induced neuroleptic malignant syndrome. However, controversy still exists over its role in chronic renal failure. Boton et al estimated (from an analysis of more than 1000 patients) that 85% of patients on long-term lithium therapy had normal glomerular filtration rates (GFRs); the remaining 15% had GFRs of more than 2 standard deviations below the age-corrected normal values, but very few patients had values less than 60 mL/min.
Extensive reviews in 1988 and 1989 suggested that monitored long-term lithium treatment does not adversely affect the GFR, despite other reports of concurrent histological damage. Prospective studies of patients taking stable lithium also failed to show a decline in GFR in the absence of acute lithium intoxication. Although a minimal increase in the protein excretion rate has been reported in some patients who were taking lithium for at least 2 years, overt proteinuria is not a common complication. A rare association between minimal-change nephrotic syndrome and lithium administration has also been described.
Lithium does not appear to adversely affect proximal tubular function."
-----
Please not Larry, that if you are referring to
nephrogenic diabetes insipidus, i have been tested for that. I am monitored. And, my voiding is almost clockwork regular. See the conditions which may lead to renal failure above.
And keep in mind that other psychiatric drugs also lead to "toxic" effects, under certain conditions; for example cardiac arrest due to prolonged or large dose of some tricyclics.Squiggles
Posted by Larry Hoover on July 29, 2007, at 11:29:18
In reply to Re: Should all drugs be generic? » Larry Hoover, posted by Squiggles on July 28, 2007, at 12:06:04
> > Your beloved lithium could not pass current clinical trial requirements, IMHO. Just be thankful it got approved before the lawyers could sue the makers for thyroid toxicosis and kidney damage. Just consider how we accept *these* toxic effects without batting an eye, but we howl if one of the mose effective anti-inflammatory drugs in existence shows a correlation with heart attack. The causative link has never been demonstrated (unlike with lithium salts), as there are a number of possible alternative explanations for the statistical finding (e.g. subject selection bias), yet Vioxx is toast. And the lawyers get rich.
> >
>
> I don't understand the thyrotoxicosis point-- lithium lowers the thyroid hormone not elevates it. Infact, lithium is used to thyrotoxicosis.Here we go again, with the jargon issue. I apologize for not being 100% rigorous with my semantics, but I did not ever mention thyrotoxicosis. I mentioned thyroid toxicosis, whereby what I meant was "lithium-induced toxicosis of the thyroid", i.e. that the thyroid was the specific organ affected by toxic lithium exposure.
Thyrotoxicosis is a specific effect of hyperthyroidism. That is not what I meant at all, and I apologize for opening the door on that misinterpretation of my words.
Lithium influences iodine uptake and storage in the thyroid. Goiter is a common result of lithium therapy (about 1 in 4 users). Frank hypothyroidism is far more common among lithium users than in the broader population. I dispute that TSH influences the thyroid, but that TSH is a result of thyroid defects caused by lithium. In the end, the argument is moot, IMHO, as I intended the broadest possible interpretation of the thyro-toxic effects of lithium. Mechanisms were not my concern.
Lar
Posted by Larry Hoover on July 29, 2007, at 12:00:52
In reply to Re: Should all drugs be generic? » Larry Hoover, posted by Squiggles on July 29, 2007, at 10:49:58
> > I presented empirical evidence of kidney function disturbance by lithium, which took me less than 10 seconds to find. It is irrelevant that others exclude data to reach contrary conclusions.
> >
> > Moreover, I showed one of many kidney disturbances from lithium intake. I've already shown your supposition to be false.
>
>
> REPLY:
>
>
> Is it "disturbance" or is it "toxicity" or both--
> you seem to be wavering.I am not wavering in the least.
>
> http://www.emedicine.com/med/topic1313.htm
>
> "The role of lithium in the production of acute renal failure is well accepted...."Let's stop right there. For a moment, and let that sink in. Your reference, right?
As I stated in the quoted portion of my prior post, above, "It is irrelevant that others exclude data to reach contrary conclusions."
The segment of the article you reference was cherry-picked, and it thus is out of context. It is common in the introduction to a review article to lay out the pros and cons of an argument. You have quoted only one side of the story.
If you were to only review the referenced articles for this one piece (rather than the entire body of medical literature), this, in part, is what you would find:
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=3314489
Am J Kidney Dis. 1987 Nov;10(5):329-45.
Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy.
Boton R, Gaviria M, Batlle DC.
Department of Psychiatry, University of Illinois at Chicago."...The most prevalent renal effect of lithium is impairment of concentrating ability, which we estimated to be present in at least 54% of 1,105 unselected patients on chronic lithium therapy. This defect translated into overt polyuria in only 19% of unselected cases. A renal lesion confined to the collecting tubule has been described in humans who have taken lithium for short periods of time. This lesion may represent the collecting tubule's response to the intracellular accumulation of lithium, which interferes with cAMP formation and results in an early and probably reversible inhibition of antidiuretic hormone (ADH)-mediated water transport. However, long-term lithium therapy may induce a progressive and partly irreversible defect in concentrating ability...."
So, in 1987, they presume a partly irreversible defect, but by 2005, that changes to "CONCLUSION: ...Long-term treatment with lithium seemed to result in irreversible NDI."
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=15806465
Am J Kidney Dis. 2005 Apr;45(4):626-37.
Causes of reversible nephrogenic diabetes insipidus: a systematic review.
Garofeanu CG, Weir M, Rosas-Arellano MP, Henson G, Garg AX, Clark WF.
Division of Nephrology, Walkerton Health Study, London Health Science Centre, Westminster Campus, Canada.BACKGROUND: In nephrogenic diabetes insipidus (NDI), the kidney is unable to produce concentrated urine because of the insensitivity of the distal nephron to antidiuretic hormone (arginine vasopressin). In settings in which fluid intake cannot be maintained, this may result in severe dehydration and electrolyte imbalances. The risk for conversion of reversible to irreversible NDI seems to be a potential complication. This review summarizes the reversible causes of acquired NDI to facilitate earlier recognition and more effective treatment by clinicians. METHODS: Two reviewers independently searched MEDLINE, Experta Medica (EMBASE), and ISI bibliographic databases. Human studies that described NDI caused by drugs, substances, or metabolic disturbances were included. To evaluate the causal role of the risk factor, data were abstracted according to Koch's postulates. RESULTS: One hundred fifty-five studies published between 1957 and March 2004 described 30 risk factors. Of 155 studies, 58 studies provided a "definite" diagnosis of NDI; 83 studies, a "probable" diagnosis; and 14 studies, a "possible" diagnosis. Nine factors were considered "definite" causes of NDI; 15 factors, "probable" causes; and 6 factors, "possible" causes. The most reported risk factors were lithium (84 studies), antibiotics (16 studies), antifungals (11 studies), antineoplastic agents (9 studies), antivirals (8 studies), and metabolic disturbances (8 studies). Duration of NDI reversal, as well as conversion to irreversible symptoms, seemed to depend on the duration of exposure. CONCLUSION: Most risk factors for reversible NDI were medications, and their identification and removal resulted in resolution of the condition. Long-term treatment with lithium seemed to result in irreversible NDI.
Nota bene that last sentence. Remember, this was your reference. I didn't even have to show you the ones I found.
And about thyrotoxicosis, there is a significant increase over baseline in lithium-exposed patients:
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11678833
Clin Endocrinol (Oxf). 2001 Oct;55(4):501-8.
Association between lithium use and thyrotoxicosis caused by silent thyroiditis.
Miller KK, Daniels GH.
Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.OBJECTIVE: To determine the incidence of silent thyroiditis in lithium users and characterize lithium-associated thyrotoxicosis. DESIGN: Retrospective record review. PATIENTS: 400 consecutive patients (300 with Graves' disease and 100 with silent thyroiditis) who underwent radioiodine scanning of the thyroid. MEASUREMENTS: Odds of lithium exposure. RESULTS: The odds of lithium exposure were increased 4.7-fold in patients with silent thyroiditis compared with those with Graves' disease (95% CI: 1.3, 17). Lithium-associated silent thyroiditis occurred with an incidence rate of approximately 1.3 cases per 1000 person-years, and lithium-associated thyrotoxicosis occurred with an incidence rate of approximately 2.7 cases per 1000 person-years, higher than the reported incidence rates of silent thyroiditis (< 0.03-0.28 cases per 1000 person-years) and of thyrotoxicosis (0.8-1.2 cases per 1000 person-years) in the general population. CONCLUSION: Thyrotoxicosis caused by silent thyroiditis might be associated with lithium use.
The thing is, Squiggles, a valid theory must account for all empirical findings. I'm trying to account for the evidence that is available for consideration. The Garofeanu et al study is a meta-analysis. That's not cherry-picking. Although the title of the review is about reversible NDI, they yet conclude that lithium causes irreversible NDI.Lar
Posted by Squiggles on July 29, 2007, at 12:10:36
In reply to Re: lithium » Squiggles, posted by Larry Hoover on July 29, 2007, at 12:00:52
I think you cherry-pick too. You're bright
alright, and you have been in the clinical
settings, but i think you have an agenda.Squiggles
Posted by Larry Hoover on July 29, 2007, at 12:31:52
In reply to Re: lithium » Larry Hoover, posted by Squiggles on July 29, 2007, at 12:10:36
> I think you cherry-pick too. You're bright
> alright, and you have been in the clinical
> settings, but i think you have an agenda.
>
> SquigglesHow so?
There are some basic scientific principles at play, here. It is impossible to prove a negative. It appears that your premise is that lithium doesn't do certain things. Yet, significant findings are abundant which are inconsistent with the null hypothesis.
I don't think that I'm the one with the agenda.
Lar
Posted by Squiggles on July 29, 2007, at 13:41:12
In reply to Re: lithium » Squiggles, posted by Larry Hoover on July 29, 2007, at 12:31:52
> I don't think that I'm the one with the agenda.
>
> Lar
>
>If not agenda, at least a question of interpretation to support your questionable
certainty that lithium IS AND MUST do serious
renal damage. All drugs do damage after a chronic period of use. Lithium should be
weighed against them, and see if it does not
infact come up as one of the best for lifelong treatment.
---------------------------------------------
1: Drug Saf. 1999 Mar;20(3):231-43.Links
Lithium and the kidney: an updated review.
Gitlin M.University of California, Los Angeles, Department of Psychiatry, USA. MGitlin@NPIH.medsch.ucla.edu
Despite the availability of alternative agents, lithium continues to be the standard against which all mood stabilisers, prescribed for acute and maintenance treatment of bipolar (and, to a lesser extent, unipolar) mood disorders, are compared. As a medication often used on a maintenance basis for a lifelong disorder, the potential for lithium to cause long term organ toxicity has generated appropriate concern. Foremost among these concerns are its renal effects. Lithium adversely affects renal tubular function, causing polyuria secondary to a deficit in urine concentrating ability. This effect is probably progressive for the first decade of lithium therapy, i.e. it correlates with duration of lithium therapy. Although this effect of lithium is probably functional and reversible early in treatment, it may become structural and irreversible over time. In contrast, the effect of lithium on glomerular function is not progressive. Conclusions in this area are hampered by the evidence that patients with psychiatric disorders who are not receiving lithium also show defects in certain aspects of renal function. Despite the generally sanguine data on glomerular function, a very small group of patients may develop renal insufficiency due to lithium (possibly in conjunction with other somatic factors) in the form of interstitial nephritis. However, for the vast majority of patients, the renal effects of lithium are benign. Current strategies for minimising the renal effects of lithium include: (i) assiduously avoiding episodes of renal toxicity; (ii) monitoring serum lithium concentrations in order to achieve optimal efficacy at the lowest possible concentration; (iii) monitoring serum creatinine levels on a yearly basis, getting further medical evaluation when the serum creatinine level consistently rises above 140 mmol/L (1.6 mg/dl); and (iv) possibly administering lithium once a day.
------------------------------------------------
PMID: 10221853 [PubMed - indexed for MEDLINE]
Posted by Larry Hoover on July 29, 2007, at 14:15:04
In reply to Re: lithium » Larry Hoover, posted by Squiggles on July 29, 2007, at 13:41:12
>
> > I don't think that I'm the one with the agenda.
> >
> > Lar
> >
> >
>
> If not agenda, at least a question of interpretation to support your questionable
> certainty that lithium IS AND MUST do serious
> renal damage.I did not say anything of the sort. I would never use such language.
From your referenced piece: "Although this effect of lithium is probably functional and reversible early in treatment, it may become structural and irreversible over time."
Let's recap the sequence of debated issues.
You initially questioned the sociological value of patented drugs, arguing that generics would be of greater value to society.
You then questioned if lithium could have been patented, and suggested that drugs (such as lithium) from the 1950's were somehow both cheaper and superior to later developments.
I then entered the discussion, suggesting that doing away with drug patents would destroy drug research and development as it is presently conducted. Furthermore, I declared that lithium would never be approved under current drug testing guidelines. Although a minor point in what I had written, you chose to focus on that one issue.
I won't re-argue the presentation of evidence, but I believe that the null hypothesis is inconsistent with the body of evidence. I reserve my conclusions until after studying the data, to avoid confirmation bias. (However, I also accept that to believe that might also demonstrate bias. I am reminded of Escher, but I digress....)
What is most interesting to me is that, despite your protestations that lithium is safe to the thyroid and the kidney, your own doctor routinely tests these functions. You seem to derive some comfort from this. I suggest that you have simply been lucky, both in having the doctor you have (only about 1/3 of lithium-treated patients even get routine thyroid testing), and in the negative results therefrom.
Generalizing from your experience, one might conclude that lithium is safe. However, the experience of others is also relevant to the issue of safety.
Lar
Posted by Squiggles on July 30, 2007, at 8:08:13
In reply to Re: lithium » Squiggles, posted by Larry Hoover on July 29, 2007, at 14:15:04
Hi,
Sorry i didn't get back to this yesterday.
> From your referenced piece: "Although this effect of lithium is probably functional and reversible early in treatment, it may become structural and irreversible over time."
>
> Let's recap the sequence of debated issues.
>
> You initially questioned the sociological value of patented drugs, arguing that generics would be of greater value to society.Actually, i questioned the motive of the manufacture of generics. The sociological value could easily be got by making all drugs cheaper.
>
> You then questioned if lithium could have been patented, and suggested that drugs (such as lithium) from the 1950's were somehow both cheaper and superior to later developments.
>
> I then entered the discussion, suggesting that doing away with drug patents would destroy drug research and development as it is presently conducted. Furthermore, I declared that lithium would never be approved under current drug testing guidelines. Although a minor point in what I had written, you chose to focus on that one issue.Two different issues here: i don't know if it's true that patent protection has in any way delivered great strides in medication, in comparison to the old days. Second issue: could you tell me why you think that lithium would never pass testing guidelines today?
>
> I won't re-argue the presentation of evidence, but I believe that the null hypothesis is inconsistent with the body of evidence. I reserve my conclusions until after studying the data, to avoid confirmation bias. (However, I also accept that to believe that might also demonstrate bias. I am reminded of Escher, but I digress....)
Yeah, you digress-- i don't understand what your point is here.
>
> What is most interesting to me is that, despite your protestations that lithium is safe to the thyroid and the kidney, your own doctor routinely tests these functions. You seem to derive some comfort from this. I suggest that you have simply been lucky, both in having the doctor you have (only about 1/3 of lithium-treated patients even get routine thyroid testing), and in the negative results therefrom.There are many drugs given today (e.g. some heart drugs, diebets drugs, which require regular monitoring. This should not be an argument against the efficacy or safety of a drug, except perhaps for economic reasons to the hospital.
>
> Generalizing from your experience, one might conclude that lithium is safe. However, the experience of others is also relevant to the issue of safety.
>The experience of others? Well, last night i went to one of the most meticulous psychiatrists in the United States, and read what he had to say
about lithium neurotoxicity. That would Dr. Sheldon Preskorn.From what i recall, he points to the dangers of neurotoxicity, not on lithium alone, unless it is a dose related problem (that is mostly over 1.5 blood level leads to brain and acute renal toxity-- apparently the two are related).
The combination of drugs such as Haldol and lithium or tricyclics and lithium, and other well-known factors such as electrolyte imbalances, diet, dehydration, diuretics, NSAIDs, ibuprofin (which by the way i took through many yrs. of my life and noticed i felt sick-- stupid monograph didnt't tell me then), --it hought it was the ibuprofin, but it was the interaction).
Also, the absence of benzos which are commonly used with lithium for bipolar disorder. I found this interesting, because when i was withdrawing from benzos, i got a seizure, which may not have been withdrawal but actually NMS, or both.
Dr. Preskorn also mentions something found in Dr. Schou's works, that clinical testing in lithium should take into account the picture between blood serum levels and brain toxicity-- something which I am sure is rarely done. Dr. Schou had pointed out that a lithium holiday would be appropriate for chronic users because of the accumulation of lithium in the brain. I think that probably is the case for many other drugs as well. But this kind of clinical care is way beyond the means and economics of present mental health resources.
Age is another factor he mentions.
But all these factors are common to many psychiatric drugs, and with the new ones, who knows what we will discover in a decade or two after the population has been exposed to them.
So lithium is not a drug to be excluded but to be monitored.
Here are some interesting hits:
http://psychservices.psychiatryonline.org/cgi/content/full/52/2/229
http://www.preskorn.com/columns.html
http://www.clinchem.org/cgi/content/full/44/5/1073
Squiggles
Posted by Larry Hoover on July 30, 2007, at 9:45:45
In reply to Re: lithium » Larry Hoover, posted by Squiggles on July 30, 2007, at 8:08:13
> > Let's recap the sequence of debated issues.
> >
> > You initially questioned the sociological value of patented drugs, arguing that generics would be of greater value to society.
>
> Actually, i questioned the motive of the manufacture of generics. The sociological value could easily be got by making all drugs cheaper.Whatever.
> > I then entered the discussion, suggesting that doing away with drug patents would destroy drug research and development as it is presently conducted. Furthermore, I declared that lithium would never be approved under current drug testing guidelines. Although a minor point in what I had written, you chose to focus on that one issue.
>
> Two different issues here:Thanks for picking that up.
> i don't know if it's true that patent protection has in any way delivered great strides in medication, in comparison to the old days.
There are no old days or new days, vis a vis patent protection. The only new difference is the requirement for stringent clinical trials.
> Second issue: could you tell me why you think that lithium would never pass testing guidelines today?
Okay. I feel like you didn't read anything I posted, but.....Animal testing shows that lithium impedes iodine uptake at the thyroid, and impairs both thyroid hormone and reproductive hormone status. Thus, lithium would fail at Phase 1. However, if it got past that hurdle, lithium shows immediate adverse effects on kidney function in a substantial proportion of healthy subjects. It thus could not get past Phase 2, even if the thyroid function effect was not judged to be an issue. There would be no Phase 3 efficacy trials, so the putative superiority of lithium in bipolar disorder would never be known.
> >
> > I won't re-argue the presentation of evidence, but I believe that the null hypothesis is inconsistent with the body of evidence. I reserve my conclusions until after studying the data, to avoid confirmation bias. (However, I also accept that to believe that might also demonstrate bias. I am reminded of Escher, but I digress....)
>
>
> Yeah, you digress-- i don't understand what your point is here.http://en.wikipedia.org/wiki/Confirmation_bias
Recursion of bias. Escher.> >
> > What is most interesting to me is that, despite your protestations that lithium is safe to the thyroid and the kidney, your own doctor routinely tests these functions. You seem to derive some comfort from this. I suggest that you have simply been lucky, both in having the doctor you have (only about 1/3 of lithium-treated patients even get routine thyroid testing), and in the negative results therefrom.
>
> There are many drugs given today (e.g. some heart drugs, diebets drugs, which require regular monitoring.For efficacy. Or for uncontrolled sequelae of the underlying disorder. Seldom for toxic effects. And those disorders are literally life threatening, which puts them in a different light.
> This should not be an argument against the efficacy or safety of a drug, except perhaps for economic reasons to the hospital.
The issue *is* the safety of the drug. And, as I have repeatedly stated, the change in perception of risk over time. Lithium is in use today because it was grandfathered into the current regulatory regime. Not because it is safe, according to current guidleines.
> > Generalizing from your experience, one might conclude that lithium is safe. However, the experience of others is also relevant to the issue of safety.
> >
>
> The experience of others?Yes, all those other people who take lithium and get thyroid and kidney problems. Or other problems, which I've simply not bothered to mention. Consider that you yourself raise the issue of neurotoxicity: "Dr. Schou had pointed out that a lithium holiday would be appropriate for chronic users because of the accumulation of lithium in the brain. "
If you shop around long enough, you can always find an authority whose opinion you like. You name drop all the time (such as the infamous Thomas Szazs, author of The Myth of Mental Illness). It's a logical fallacy, though: argumentum ad verecundiam, an appeal to authority. Which goes back to confirmation bias. If you're not going to look at the evidence, then there is no point in discussing this further.
Lar
Posted by Squiggles on July 30, 2007, at 10:00:15
In reply to Re: lithium » Squiggles, posted by Larry Hoover on July 30, 2007, at 9:45:45
OK - show me the evidence--- because every time
I post an article regarding chronic lithium treatment with no renal failure, or cardiac disease, or thyroid damage (assuming you get the supplement) you say I cherry pick. So, cherry pick your own statistics, and I would like to see them and compare them to the sources I have read.Squiggles
> If you shop around long enough, you can always find an authority whose opinion you like. You name drop all the time (such as the infamous Thomas Szazs, author of The Myth of Mental Illness). It's a logical fallacy, though: argumentum ad verecundiam, an appeal to authority. Which goes back to confirmation bias. If you're not going to look at the evidence, then there is no point in discussing this further.
>
> Lar
Posted by Larry Hoover on July 30, 2007, at 11:08:37
In reply to Re: lithium » Larry Hoover, posted by Squiggles on July 30, 2007, at 10:00:15
> OK - show me the evidence---
Already did. Read the thread.
Posted by Squiggles on July 30, 2007, at 22:24:10
In reply to Re: lithium » Squiggles, posted by Larry Hoover on July 30, 2007, at 11:08:37
> > OK - show me the evidence---
>
> Already did. Read the thread.That's grossly insufficient. OK - it looks
like i'll have to do some heavy homework and
post it. I need some more time. There are
many articles on this issue, and the evolution of lithium research is tilting towards its favour,
not against.Later
Squiggles
Posted by Larry Hoover on July 31, 2007, at 8:01:39
In reply to Re: lithium » Larry Hoover, posted by Squiggles on July 30, 2007, at 22:24:10
> > > OK - show me the evidence---
> >
> > Already did. Read the thread.
>
> That's grossly insufficient. OK - it looks
> like i'll have to do some heavy homework and
> post it. I need some more time. There are
> many articles on this issue, and the evolution of lithium research is tilting towards its favour,
> not against.
>
> Later
>
> SquigglesIt is not relevant that you might find a stack of opinions on the subject. The issue is incorporating the body of evidence into a cogent understanding of the phenomenon itself.
Issues before you are:
1. You can't prove a negative. Which case, unfortunately, you seem set on demonstrating.
2. Every one (I think it was every one) of the references you have provided so far has actually stated that irreversible kidney damage follows long term lithium therapy. Not always does lithium do this, of course, but sometimes. And I found these statements within references which you provided as evidence of lithium's safety.
3. I am not addressing popularity or efficacy. The issue I raised is toxicity. Opinions, no matter how numerous, will not erase the clear evidence of lithium's toxic effects.
4. You must avoid confirmation bias. A valid summary of this issue must incorporate the contrary evidence, and afford it some explanation. For example, it must provide some rationale for the nearly 5-fold increase in relative risk of thyroiditis over those with Grave's disease, and the roughly 10-fold increase over the general population. Similar, but lesser, risks for thyrotoxicosis. Empirical evidence of this, I gave to you. Offering up an opinion that it doesn't matter doesn't cut it. Think CSI. Let the evidence speak. Then, and only then, theorize.
5. Explain your own consumption of medical resources with respect to medical tests. If lithium is without risk, then why do you permit your doctor to waste resources monitoring your condition? BTW, that the toxic risk can be managed is not now, nor ever was, the issue. The issue raised was that lithium could not pass present-day drug testing protocols.
6. And, since you brought it up, please demonstrate the overall safety of lithium neurotoxicity.Lar
Posted by Squiggles on July 31, 2007, at 8:47:25
In reply to Re: lithium » Squiggles, posted by Larry Hoover on July 31, 2007, at 8:01:39
I'll get back to you - busy now; at first
glance many of the things you say are false,
you use equivocation and interpretation in
a sophistical manner.I *am* interested in long-term studies because
that is what the relevant clinical evidence is
in the case of renal effects of lithium. And
as you must know, there is a wide range between
acute renal failure, nephrogenic diabetes insipidus, globular changes, hormonal failures, and kidney shrinking. As for toxicity--- that
is about as broad a concept as addiction and carries the same linguistic wars; like how many angels can dance on the head of a pin.Later
Squiggles
Posted by Squiggles on August 1, 2007, at 9:15:25
In reply to Re: lithium » Larry Hoover, posted by Squiggles on July 31, 2007, at 8:47:25
> I'll get back to you - busy now; at first
> glance many of the things you say are false,
> you use equivocation and interpretation in
> a sophistical manner.
>
> I *am* interested in long-term studies because
> that is what the relevant clinical evidence is
> in the case of renal effects of lithium. And
> as you must know, there is a wide range between
> acute renal failure, nephrogenic diabetes insipidus, globular changes, hormonal failures, and kidney shrinking. As for toxicity--- that
> is about as broad a concept as addiction and carries the same linguistic wars; like how many angels can dance on the head of a pin.
>
> Later
>
> Squiggles
--------------------------- August 1, 2007I tried to post the texts but there were too many unacceptable characters, so here are the url's:
Some articles on renal effects and lithium:
http://sunzi1.lib.hku.hk/hkjo/view/21/2100155.pdf
http://archpsyc.ama-assn.org/cgi/content/abstract/54/1/9
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=424553
http://grande.nal.usda.gov/ibids/index.php?mode2=detail&origin=ibids_references&therow=239687
http://www.emedicine.com/med/topic1313.htm
http://www.healthieryou.com/mhexpert/exp1120103e.html
http://www.antenna.nl/lithium/english/postgrad/vasopressin_ep.htm
http://jpet.aspetjournals.org/cgi/content/full/289/1/443
I think I will stop here now. You can go on with the appropriate key words, and you may already
have. Obviously, the research shows that as far as renal effects go, there is substantial evidence
that the kidneys are affected. This is just one of the effects that lithium has. Personally, I would be
more concerned with the bradycardia that is induced by lithium and does not receive as lengthy
study (as far as i have seen on the net). I have had periods of such an occurrence and neither clinics
nor doctors considered it as significant enough as renal checks.
Regarding renal clearance and kidney changes, my question would be, to what extent this is
a serious pathology enough to change from lithium to say depakote, wich has its own can of worms,
raising weight about 3 to 4 times than lithium and affecting the liver, and causing neurological damage
upon withdrawal. At least with lithium it is possible to have a clearance by stopping it for some time.Also, the effects of lithium toxicity are detectable both personally and through lab tests, and therefore
easy to monitor. In seniors or women, the dose may be lowered, or an adjunct given.Given the incomparable specificity, mental clarity, and suicide prevention that this drug can provide,
the physiological effects should be compared and weighed against other drugs, which can be researched
for more severe side effects.-------------------------
Squiggles
LITHIUM POSTER GIRL
http://www.scripophily.net/secomi.html
Posted by Larry Hoover on August 1, 2007, at 11:00:02
In reply to Re: lithium, posted by Squiggles on August 1, 2007, at 9:15:25
> I tried to post the texts but there were too many unacceptable characters,
Just cut and paste into a program like Notepad. It gets rid of all the formatting.
> so here are the url's:
>
> Some articles on renal effects and lithium:
>
> http://sunzi1.lib.hku.hk/hkjo/view/21/2100155.pdfFrom 1986.
> http://archpsyc.ama-assn.org/cgi/content/abstract/54/1/9
Personal opionion, with no evidence presented. There is nothing to consider.
> http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=424553
Rabbits, from 1986.
> http://grande.nal.usda.gov/ibids/index.php?mode2=detail&origin=ibids_references&therow=239687
1987 paper, about diabetes mellitus, a different disorder altogether.
> http://www.emedicine.com/med/topic1313.htm
This paper I already critiqued. It was the one you cherry-picked from. And you've never addressed the findings of the referenced Garofeanu et al meta-analysis.
> http://www.healthieryou.com/mhexpert/exp1120103e.html
This article references Bendz et al:
Nephrol Dial Transplant (1994) 9: 1250-1254
© 1994 European Renal Association-European Dialysis and Transplant Association
Kidney damage in long-term lithium patients: A cross-sectional study of patients with 15 years or more on lithium
H. Bendz1, M. Aurell2,, J. Balldin3, A. A. Mathé4 and I. Sjödin5
1Department of Psychiatry, University of Lund Lund 2Nephrology, University of Göteborg Göteborg 3Psychiatry and Neurochemistry, University of Göteborg Göteborg 4Department of Psychiatry, Karolinska Institute Stockholm 5Department of Psychiatry, University of Linköping Linköping, SwedenCorrespondence and offprint requests to: Correspondence and offprint requests to: Dr M. Aurell, Njurkliniken Göteborg liniversitet, Sahlgrenska Sjukhuset, 41345 Goteborg, Sweden
The renal risks associated with long-term lithium treatment are a growing concern. We have therefore studied renal function by means of glomerular filtration rate (GFR) and maximum urinary concentrating capacity (Umax) in 142 of 215 patients with more than 15 years of lithium treatment in nine psychiatric clinics. Data on psychiatric and somatic diseases, hospital admissions, cumulative lithium doses, and other psychotropic treatments were extracted from the medical records. The patients were investigated according to a standardized protocol. GFR was measured as 51Cr EDTA clearance and Umax using the DDAVP test. Thirteen patients had had signs of lithium intoxication. GFR was reduced in 21% of the patients and Umax in 44%. Nephrogenic diabetes insipidus was present in 12%. Umax but not GFR was inversely correlated to the cumulative lithium dose. Kidney function was more reduced in patients on lithium combined with psychotropic treatment and/or concomitant treatment for somatic disorders. Thirst was a complaint of 53% of the patients, predominantly those with additional psychotropics. We conclude that kidney damage is common in patients on long-term lithium treatment and that both glomerular and tubular function are affected.
You really ought to read everything Bendz has published.
> http://www.antenna.nl/lithium/english/postgrad/vasopressin_ep.htm
Neither evidence nor arguments provided, unless you think "further research required" is noteworthy.
> http://jpet.aspetjournals.org/cgi/content/full/289/1/443
The article is really about another drug, amiloride, and the subjects are rats. We already knew that lithium affected aldosterone responsiveness.
> I think I will stop here now.
Where is your argument? What have you shown?
> You can go on with the appropriate key words, and you may already
> have. Obviously, the research shows that as far as renal effects go, there is substantial evidence
> that the kidneys are affected.I think that's *my* argument.
> This is just one of the effects that lithium has.
I recall making that argument myself, also.
> Personally, I would be
> more concerned with the bradycardia that is induced by lithium and does not receive as lengthy
> study (as far as i have seen on the net).I also mentioned that there were other adverse effects, which I had yet to list or consider.
> I have had periods of such an occurrence and neither clinics
> nor doctors considered it as significant enough as renal checks.Okay.
> Regarding renal clearance and kidney changes, my question would be, to what extent this is
> a serious pathology enough to change from lithium to say depakote, wich has its own can of worms,
> raising weight about 3 to 4 times than lithium and affecting the liver, and causing neurological damage
> upon withdrawal.Usually when the kidneys are so damaged as they can no longer tolerate continued lithium exposures.
> At least with lithium it is possible to have a clearance by stopping it for some time.
Only to re-expose to the toxin, thereafter?
> Also, the effects of lithium toxicity are detectable both personally and through lab tests, and therefore
> easy to monitor.So you acknowledge lithium toxicosis is real?
> In seniors or women, the dose may be lowered, or an adjunct given.
>
> Given the incomparable specificity, mental clarity, and suicide prevention that this drug can provide,
> the physiological effects should be compared and weighed against other drugs, which can be researched
> for more severe side effects.Oh, really? Cochrane disagrees with your conclusions.
Cochrane Database Syst Rev. 2001;(3):CD003013
Lithium for maintenance treatment of mood disorders.Burgess S, Geddes J, Hawton K, Townsend E, Jamison K, Goodwin G.
Department of Psychiatry, University of Oxford, Oxford, UK, OX3 7JX. john.geddes@psychiatry.oxford.ac.ukBACKGROUND: Mood disorders are common, disabling and tend to be recurrent. They carry a high risk of suicide. Maintenance treatment, aimed at the prevention of relapse, is therefore of vital importance. Lithium has been used for some years as the mainstay of maintenance treatment in bipolar affective disorder, and to a lesser extent in unipolar disorder. However, the efficacy and effectiveness of prophylactic lithium therapy has been disputed. Low suicide rates in lithium-treated patients have led to claims that lithium has a specific anti-suicidal effect. If so, this is of considerable importance as treatments for mental disorders in general have not been shown convincingly to be effective in suicide prevention. OBJECTIVES: 1. To investigate the efficacy of lithium treatment in the prevention of relapse in recurrent mood disorders. 2. To examine the effect of lithium treatment on consumers' general health and social functioning, its acceptability to consumers, and the side-effects of treatment. 3. To investigate the hypothesis that lithium has a specific effect in reducing the incidence of suicide and deliberate self-harm in persons with mood disorders. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and The Cochrane Controlled Clinical Trials Register (CCTR) were searched. Reference lists of relevant papers and major text books of mood disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished. Specialist journals concerning lithium were hand searched. SELECTION CRITERIA: Randomised controlled trials comparing lithium with placebo, where the stated intent of treatment was maintenance or prophylaxis. Participants were males and females of all ages with diagnoses of mood disorder. Discontinuation studies (in which all participants had been stable on lithium for some time before being randomised to either continued lithium treatment or placebo substitution) were excluded. DATA COLLECTION AND ANALYSIS: Data were extracted from the original reports independently by two reviewers. The main outcomes studied were related to the objectives stated above. Data were analysed for all diagnoses of mood disorder and for bipolar and unipolar disorder separately. Data were analysed using Review Manager version 4.0. MAIN RESULTS: Nine studies were included in the review, reporting on 825 participants randomly allocated to lithium or placebo. Lithium was found to be more effective than placebo in preventing relapse in mood disorder overall, and in bipolar disorder. The most consistent effect was found in bipolar disorder (random effects OR 0.29; 95% CI 0.09 to 0.93 ). In unipolar disorder, the direction of effect was in favour of lithium, but the result (when heterogeneity between studies was allowed for) did not reach statistical significance. Considerable heterogeneity was found between studies in all groups of patients. The direction of effect was the same in all studies; no study found a negative effect for lithium. Heterogeneity may have been due to differences in selection of participants, and to differing exposures to lithium in the pre-study phase resulting in variable influence of a discontinuation effect. There was little reported data on overall health and social functioning of participants under the different treatment conditions, or on the participants' own views of their treatment. Descriptive analysis showed that assessments of general health and social functioning generally favoured lithium. Small absolute numbers of deaths and suicides, and the absence of data on non-fatal suicidal behaviours, made it impossible to draw meaningful conclusions about the place of lithium therapy in suicide prevention. REVIEWER'S CONCLUSIONS: This systematic review indicates that lithium is an efficacious maintenance treatment for bipolar disorder. In unipolar disorder the evidence of efficacy is less robust. This review does not cover the relative efficacy of lithium compared with other maintenance treatments, which is at present unclear. There is no definitive evidence from this review as to whether or not lithium has an anti-suicidal effect. Systematic reviews and large scale randomised studies comparing lithium with other maintenance treatments (e.g. anti-convulsants, antidepressants) are necessary. Outcomes relating to death and suicidal behaviour should be included in all future maintenance studies of mood disorder.
In fact, lithium is the most poorly studied common psych medication in use today. Oh, there's been a lot written *about* it, but it has not been subjected to rigourous controlled studies of good quality.We view lithium differently because it was grandfathered into use. Just like ECT. Neither one would stand a hope of being approved as a treatment under today's perceptions of acceptable medical risk.
I would argue that medical complications arising from lithium are vastly under-reported. Doctors "know" that lithium messes with the heart and brain and kidney and thyroid and parathyroid etc., so what's there to report? They just go on to treat the problem as best they can. And there's no big pharma big wallet to get sued, either.
Lar
Posted by Larry Hoover on August 1, 2007, at 11:09:11
In reply to Re: lithium » Squiggles, posted by Larry Hoover on August 1, 2007, at 11:00:02
> We view lithium differently because it was grandfathered into use. Just like ECT. Neither one would stand a hope of being approved as a treatment under today's perceptions of acceptable medical risk.
I should add that I have no problem with either one being used, under full informed consent. Each is a tool, which hopefully is employed within the parameters within which each tool is best suited. I am happy for those who obtain benefit from these tools, but I will not ignore empirical findings if I perceive bias in the discussions surrounding them.
Lar
Posted by Squiggles on August 1, 2007, at 15:09:48
In reply to Re: lithium (addendum), posted by Larry Hoover on August 1, 2007, at 11:09:11
You don't think money might have something driving
the current epiphanies in pharmacopeia in lithium treatment, that were eclipsed in the Dark Ages prior to new treatments?http://psychservices.psychiatryonline.org/cgi/content/full/54/8/1076
This is the end of the thread.
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