Making medicines safer for all of us

Adverse drug events are now the fourth leading cause of death in hospitals.

It’s a reasonable bet they are an even greater cause of death in non-hospital settings where there is no one to monitor things going wrong and no one to intervene to save a life. In mental health, for instance, drug-induced problems are the leading cause of death — and these deaths happen in community rather than hospital settings.

There is also another drug crisis — we are failing to discover new drugs. [Read more...]

Archive for August 2012

RxISK Stories – Azathioprine Withdrawal

Crohn's Disease

This post was written by Ken Spriggs and comes from his DIYEHR (do it yourself electronic health record) site, and has first been published on the RxISK.org website. If you would like to comment on this post, please do so using this link. It brings out nicely how some people are only aware of the problems their drug causes when they stop. This is particularly true for people taking statins, but can be found taking anything from aspirin to azathioprine. Poison is an emotive word but all drugs are poisons which taken chronically will poison. Think arsenic; when taken in the short-term it clears skin and eyes but long-term not so good.

I found myself browsing the second or third page of azathioprine related google results and an abstract about withdrawing from azathioprine when Crohn’s is in remission. It’s personal because I’m someone who stopped taking azathioprine against the advice of my physician. I ended the drug about 15 months ago and I’ve not only remained in remission but I no longer have to deal with the side effects. There’s a lot I’d like to discuss about the article because I disagree with the conclusion and would like to question their process as well.

Title: A Randomized, Double-Blind, Controlled Withdrawal Trial in Crohn’s Disease Patients in Long-term Remission on Azathioprine Source: Gastroenterology – June 2005 (Vol. 128, Issue 7, Pages 1812-1818, DOI: 10.1053/j.gastro.2005.03.031)

Here’s a link to the full article and below is the abstract in its entirety. See what you think:

Background & Aims: An open study reported that patients with Crohn’s disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is discontinued. To confirm this observation, we performed a multicenter, double-blind, non-inferiority withdrawal study. Methods: Patients who were in clinical remission on azathioprine for ≥42 months were randomized to continue azathioprine or to receive an equivalent placebo for 18 months. The primary end point was clinical relapse at 18 months. Results: Forty patients were randomly assigned to receive azathioprine and 43 to receive placebo. Characteristics of patients at entry were similar in the 2 study groups. At 18 months, 3 patients had a relapse in the azathioprine group, and 9 had a relapse in the placebo group. Kaplan-Meier estimates of the relapse rate at 18 months were 8% ± 4% and 21% ± 6%, respectively. The hypothesis that placebo was inferior to azathioprine was not rejected (P = .195). Among the baseline variables, C-reactive protein level >20 mg/L, time without steroids <50 months, and hemoglobin level <12 g/dL were found to be predictive of relapse in the multivariate analysis. Conclusions: This study shows that azathioprine withdrawal is not equivalent to continued therapy with azathioprine for maintenance of remission in patients with Crohn’s disease who have been in remission on azathioprine for ≥3.5 years. Thus, azathioprine maintenance therapy should be continued beyond 3.5 years.

Ok so I had to read that last sentence twice because it doesn’t seem to go with the rest of the abstract. To me it looks like in the placebo group there were 34 out of 43 which didn’t relapse. That’s phenomenal! That means 79% don’t need azathioprine! Yeah! No more achy joints, nausea, fatigue, diarrhea, trips to the pharmacy, money spent, blood tests, not to mention azathioprine is listed as a carcinogen.

Let’s look at the azathioprine group, they experienced 3 relapses out of 40. If you apply that knowledge to the placebo group it implies that not 9 people relapsed because of azathioprine withdrawal but only 6 relapsed. Three, we expect, would have relapsed anyway. This means we should expect 37 out of 43 to remain in remission. That changes the 79% to 86%! Even better!

Based on the evidence here’s the conclusion I would think is more responsible to give a Crohn’s patient: There was as trial done which included a fairly small number of patients and it showed that if you’ve been in remission (a Crohn’s Disease Activity Index  score of less than 150) for at least 42 months and are still taking azathioprine then you can consider stopping. You stand an absolute chance of 9 out of 43 (21%) of coming out of remission but only a 6 out of 43 chance (14%) of coming out of remission because you stopped azathioprine.

Contrast this with their conclusion: “Thus, azathioprine maintenance therapy should be continued beyond 3.5 years.”

If you didn’t get my point think about it this way. Suppose you had a treatment which worked for 79% of patients and it had no side effects to speak of. Would this not be a wonder drug? Of course it would! Call the marketing department, this one’s gonna be an easy sell! In this case the “wonder drug” is NOT taking the azathioprine and, unfortunately, there is no marketing department to call for that.

Further consider you’re one of the 34 patients in the placebo group who remained in remission for 18 months and then your doctor tells you that you were in the placebo group but to start taking your azathioprine again. What? Would this seem like reasonable advice? There’s no possible way I’d start the medication again. Why would anyone in remission want the side effects? It’s a senseless conclusion for the vast majority of the placebo group.

To turn their conclusion on its head again, we can say that staying on azathioprine only helps about 14% of patients stay in remission.

This brings me to questions about methodology and resourcefulness. The paper acknowledges that azathioprine has side effects but it makes no attempt to quantify them. What they could have done is to ask the study participants at the end of the trial if they thought they were in the placebo group or not. It’s crazy to me the researchers overlook this. Participants could also be asked if their quality of life improved during the trial. That’s actually the most important thing of all! Suppose 79% of participants in the placebo group said their quality of life improved while no one in the azathioprine group did. (It’s also possible, though unlikely, for someone who did relapse to report that their quality of life improved. This would happen if the side effects were worse than the relapse.) But alas, this information is MIA. But why? Quantifying side effects should mean a lot to a study about a drug. It could always turn out that side effects are worse than treatment. These researchers completely ignore this possibility. Bad science.

To shore up this massive design flaw in the study participants should be asked questions about the side effects of azathioprine before the study begins, during the study, and also after.

I’m reminded of a quote by David Healy from Pharmageddon:  There is no evidence based approach to determining whether treatments have injured a patient or what to do when it happens. Why ever not?

(RxISK.org is a patient oriented organization dedicated to researching and reporting side effects.)

There’s another important issue I’d like to touch on. When I went through my simple analysis I didn’t once mention statistical significance. In order to disagree with the conclusion there was no need to think about statistical significance, we just had to count.

Now I’d like to question that perhaps the entire design of the experiment was amiss. Bare with me cause this is gonna get simple. The first sentence of the abstract says: “…patients with Crohn’s disease in remission who have taken azathioprine for longer than 3.5 years are at low risk of relapse when azathioprine is discontinued.” Why do you need statistical significance to answer this? You don’t. Instead what you do is gather a bunch of people who meet the criteria and tell them to stop taking their azathioprine. Then count the number of relapses over the next 18 months. That’s it. Really. You can then report that X% of patients relapse when they withdrew from azathioprine. If you wanted to say how many relapsed because of azathioprine withdrawal then you’d have to have one group stay on the medication and count the number of relapses. My take on the second step is to say it might be interesting to try and predict who will relapse based on bloodwork results or genetics or something related to lifestyle and diet. I’d guess the sample size of participants needed probably renders the idea prohibitive. And if a study like that isn’t plausible then the added knowledge is academic since it’s not possible to have any idea who will relapse. I think the study wasted half the participants, the entire control group isn’t necessary.

Ok so now you’re wondering why these authors with their PhD’s and MD’s did what they did. Well, they followed “This method universally used in non-inferiority trials…”. When I read something like that I’m reminded of the Sokal affair and Fashionable Nonsense. As these ideas apply to medicine Healy sums it up with this quote from Pharmageddon:

Explaining why Fisher’s ideas have such traction within medicine is not easy. Regulators have followed this line because the definition of statistical significance offers them a rule of thumb, an almost mechanical procedure that takes the place of a judgment call. For pharmaceutical companies, the issue is simple; Fisher’s ideas mean that positive effects in a minority of clinical trials can transform a weak and inessential drug into one apparently certified by science, while at the same time airbrushing its hazards out of existence.

But why do doctors follow this line? A number of medical academics have attempted to grapple with this, pointing out that current dependence on statistical significance testing has created a “junk epidemiology” in the domain of therapeutics. So Louis Lasagna, the first professor of clinical pharmacology in the United States, and later dean of medicine at Tufts University, who introduced randomized controlled trials into drug development, described the approach outlined above as “p-value madness”. For Sandor Greenland, professor of epidemiology and statistics at UCLA, “statical thinking [of this type] has produced a chronic psychosis” – by which he means that researchers relying on Fisher’s idea have lost touch with reality. Ezra Hauer, a professor of civil engineering from the University of Toronto and authority on analyzing road traffic accidents, explains that “in this manner good data are drained of real content. The direction of the empirical conclusions is reversed and ordinary human and scientific reasoning is turned on its head.” For Charlie Poole, professor of statistics and epidemiology at the University of North Carolina, “Statistical significance should be abandoned immediately and universally.” Ironically when faced with this issue in 2011, with investors’ dollars at stake, the US Supreme Court argued that statistical significance cannot be the arbiter of what an investor might deem as significant risk. But patients it seems do not have the same rights as investors.

The differences between much of clinical practice and other branches of science were starkly framed by Kenneth Rothman, professor of epidemiology at Harvard and editor of the journal Epidemiology, in a note about submissions to the journal:

“When writing for Epidemiology, you can . . . enhance your prospects if you omit tests of statistical significance… We would like to see the interpretation of a study based not on statistical significance, or lack of it, for one or more study variables, but rather a careful quantitative consideration of the data in the light of competing explanations… Misleading signals occur when a trivial effect is found to be ‘significant,’ as often happens in large studies, or when a strong relation is found ‘non-significant,’ as often happens in small studies.”

At the beginning of this post I mentioned I stopped taking azathioprine. It was about 3 and a half years after surgery and I’d been in remission the entire time. It’s been about 15 months since I stopped talking it and I haven’t felt this good since I was 17 and Crohn’s was years away from wrecking me. So here’s what makes me upset: Azathioprine has serious side effects. When I was on it I suffered diarrhea, chronic fatigue and my knees often ached as if I had arthritis. After I stopped taking the drug these symptoms cleared up in about 3 weeks with the exception of the diarrhea. I was like a new person. I went and took tennis lessons, joined a league, and started getting out of bed much easier and an hour earlier. The researchers never even tried to quantitate the effects of the drug. It was passively acknowledged at most. Side effects weren’t even considered in the conclusion. There’s probably physicians who have read this paper and they go on prescribing azathioprine even though someone’s been in remission for years. It’s sad and it’s irresponsible. Patients should demand an exit strategy from their physicians but that’s a different issue.

Lastly a few more questions to ask: What was the financial role of GlaxoSmithKline? The company was mentioned as providing the azathioprine in the form of their brand name Imuran but that’s it. Was the paper ghostwritten? Do the researchers have financial ties to GSK?

RxISK Stories: Withdrawal from Antidepressants – V’s Story

withdrawal symptoms

For the next few weeks, this blog will take a feed from RxISK.org. If you would like to comment on this post please do so on the RxISK website using this link. RxISK is open to stories from anyone on drugs who have adverse events and are in need of answers or from doctors managing adverse events on any medical drugs.

Question from V

This is what V wrote on filing a RxISK report.

I quit taking Prozac using a step-down method. Started in Sept. 2011 and finally off in January 2012. I experienced severe loss of balance early on, which progressed into full-blown ataxia & parasthesia. Have had extensive blood-testing & MRIs of brain & cervical spine, all negative! I have to believe this is a result of coming off Prozac, although most sites say the withdrawal side effects don’t last this long.

Quite frankly, I am terrified that I may never get well. I am very ADHD now, tired always, and uninterested in performing normal daily activities (I guess because everything too hard!). My family doctor is a good guy, but he (like many other docs) is clueless re SSRIs and the dangers of taking them. I am pretty much on my own with this. Any help, recommendations, or hope would be so welcome!

Response to V

The single commonest question to RxISK.org has been about dependence on and withdrawal from treatments, such as anticonvulsants, statins, diuretics, and others. (See Medicine Induced Stress Syndromes, Dependence and Withdrawal, Halting Antidepressants, clopidogrel withdrawal and withdrawal from azathiopine).

On completing the RxISK Terminator Algorithm V scored 10. A score of 9 makes it highly likely this is a withdrawal syndrome. Our hope is that printing out a RxISK report will give people something to take to their doctor that will engage the doctor. There are an astonishing number of doctors still who do not recognize that antidepressants cause dependence and withdrawal, even though many people give convincing stories of how these drugs can be more difficult to stop than heroin, speed or other illegal drugs.

The companies knew dependence and withdrawal were a risk even before these drugs were marketed. Studies in healthy volunteers had shown convincing evidence of dependence and withdrawal in normal people after they had been exposed to the drugs for a little as two weeks. The main symptoms these healthy volunteers had on stopping were anxiety, and depression, along with dizziness and fatigue. The data from these studies is buried.

So the first thing to say to V is this is not in your mind – you need to hold on to this point during what may be a trying time. Second, not getting help for your doctor even if he is a good doctor is par for the course.

There are three key questions for each person having the problems V outlines. First what is it? Second how long can this go on for. Third what can be done to help.

On the what is it question, there are a few things that can happen other than simple withdrawal. The obvious condition in most cases will be enduring withdrawal. This almost by definition should stop at some point. But another option is a stress syndrome and no-one really knows how long these might go on for. Finally there are legacy effects.

As regards how long this can last for, I hear from many people for whom this problem has continued for some years. It may be that these people are the exception – I don’t hear from people when things clear up. What we all need is some estimate of how long these problems last on average. A complicating factor is that some of those with enduring problems slip seamlessly from withdrawal to a stress syndrome.

Based on my experience there appear to be a number of things that might help. These ideally need to be targeted at the condition they are most likely to help – withdrawal or stress syndrome. A graded program of physical and mental activity is helpful for withdrawal, stress syndromes and legacy effects. It’s almost impossible to know how helpful the various supplements sold as part of withdrawal management strategies are. They all sound like they should be doing the right thing but it is by no means sure they are.

As regards drugs treatments, it is important to get the taper right in the first instance – using liquids and taking it gradually. Tapering slowly does not guarantee success. Many people who taper extraordinarily slowly still have problems.

One option aside from taping is to switch to a low potency serotonin reuptake inhibitor, such as the anti-histamine chlorpheniramine, a serotonin reuptake inhibiting antihistamine that comes in liquid form.

Second, a triptan such as sumatriptan appears in some cases to relieve features such as dizziness and anxiety almost instantly but the relief is only temporary – while the drug lasts in the body. Restarting Prozac (fluoxetine) or another SSRI rarely does this, which is why the triptan effect is interesting. Getting a few hours benefit like this however may make it easier to carry on.

Another treatment is donepezil. This acts on the cholinergic system. Varenicline, the smoking cessation agent, also acts on the cholinergic system and may be helpful. It may be a mistake to think that these treatments help by acting on the brain. In the case of the triptans, they likely help by acting on blood vessels and on the middle ear rather than in the brain.

In the case of drugs like these, your doctor may object that this use is off-label. He may ask where’s the evidence? If this happens, you may need to find a doctor who is prepared to explore some of these issues with you.

Another source of help out there are all the people who have been on antidepressants who may have coincidentally been put on donepezil, varenicline, sumatriptan or other drugs and found that when they take these treatments their problem clears up. We need to hear from such people. The example of Anne-Marie in Out of My Mind shows what can be done.

This post with a question from V and response shows how little is actually known. RxISK would love to hear from people out there who may be able to explain just what is happening in these withdrawal and stress-states and what can be done to help. There are many programs out there offering to detoxify people. At present we have no reliable knowledge of anything that would detoxify in the sense of remove drugs that may have accumulated in bodily systems, in particular in nerve endings.

As regards supportive therapy, we are working on putting together a cognitive-behavioral approach that may be of some help. If one can be developed, this will be made available.

Finally we are interested to get other accounts of dependence on and withdrawal from antidepressants or other drugs.

In the next few weeks there will be an update covering issues such as detoxification, how your doctor is likely to react to being presented with withdrawal problems and what you can do about it.

RxISK Stories – Withdrawal from Clopidogrel

blood cells

For the next few weeks, this blog will take a feed from RxISK.org of RxISK stories, alternating with posts challenging Barack and Mitt to get to grips with healthcare costs. RxISK is open to stories from anyone on drugs who have adverse events and are in need of answers or from doctors managing adverse events on any medical drugs.

Query from Fiona Barton

Dr Healy, a friend suggested I email you. I am desperate to get some support with my story.

I had a heart attack two years ago and was prescribed Clopidogrel and low dose Aspirin as my after care. Several months ago it was decided that I should come off the Clopidogrel. I was keen to do so as I had begun to get tinnitus and my research suggested that aspirin-like drugs could cause this. As I was told I would have no side effects, I stopped it dead. Three times that week I was admitted by ambulance to hospital with numbness down my left side and headaches. I had an emergency brain scan – all normal. I asked if it could be withdrawal from the Clopidogrel. They said no.

I went back on it. I then started to wean myself slower. As I did the tinnitus stopped. But then I was admitted to hospital again. Worse I had acute anxiety, suicidal thoughts and hallucinations. My doctor told me to go back on Clopidogrel and when I did the symptoms stopped but the tinnitus came back. I then tried an even slower withdrawal. Again I was admitted to hospital – this time with sweats, agitation, anxiety, pain, and headaches. I was told this is in my head and is anxiety in case I have another heart attack – absolute rubbish. This is following a pattern. I know it’s this drug.

The combination of Clopidogrel and aspirin I was told could cause gut problems and has caused me gut problems. But every time I try lansoprazole or omeprazole I get anxiety, hallucinations and numbness.

Can you offer me any advice or where to get help? I know I am chemically dependent on this drug. I don’t want to be on this for the rest of my life as was suggested by the cardiologist. You don’t have a problem on it so keep taking it, he said. What happens if the drug manufacture changes or I become tolerant and need more? What happens if I need surgery and have to stop it in case I have a bleed? I know my body would not take the shock of it stopping suddenly.

I was addicted to the benzodiazepines in the 1980s. It took me 3 years of hell to come off them so I know what withdrawal feels like and this is it. Please can you help? I don’t know who else to ask that will believe me.

RxISK response

The first point to make is that the options are to agree that this is a withdrawal syndrome or else to disbelieve FB. For FB, the stakes are high, including death and significant disability. For the doctors there are no bad consequences of disbelieving her. Indeed one of the consequences of believing her might be to start doubting the standard line about Clopidogrel and other drugs.

Second, FB presents a compelling case for a withdrawal syndrome from clopidogrel. The problems emerge on stopping a drug she had no reason to think could cause a problem, clear up on going back on the drug and reappear on reducing again, and this happens more than once. This is as compelling as it gets.

The first defense for those who don’t want to believe is to say that we cannot see how it could be happening and therefore the problems are not what they might appear to be. Taking this approach requires an alternate explanation – and in this case there is a temptation to pick on the anxiety symptoms and perhaps even the prior history of dependence on benzodiazepines. Someone with less inner conviction than FB may even be persuadable that this is all in her mind.

But there are ways to explain what is happening. Among the types of withdrawal is one that is sometimes termed rebound (DBM Medicine Induced Stress Syndromes; DBM Dependence and Withdrawal). This can lead to rebound heart rate increases in drugs like beta-blockers that slow heart rate and rebound clotting in drugs that reduce clotting. And in fact rebound clotting is well recognized on drugs like aspirin. Another that might fit the bill here is a legacy effect – an enduring effect after a drug is stopped.

Searching in RxISK under Clopidogrel shows that a withdrawal syndrome has been reported on a number of occasions (7 – in FDA’s database these reports come from Europe). European regulators may have many more reports. This frequency is so low that its proportional reporting ratio is close to 0. There is in other words no signal. On the basis of this we are faced with a choice between a compelling description of a withdrawal problem and the data which says no signal. I’m inclined to go with the compelling description. Part of the reason we likely have no signal is that the people affected by problems like this are not doing the reporting; it is doctors who find something like this close to inconceivable who are still the primary reporters of adverse events.

My inclination on reading FB’s report was to believe her. But more research on RxISK throws up further reasons to go with FB. There is a condition that is usually thought of as rare called thrombotic thrombocytopenic purpura (TTP). In TTP, platelets in the blood form micro-clots (thrombosis) which can cause problems. But the micro-clots also remove platelets from blood which leads to bleeding (purpura). There are 169 reports of TTP on clopidogrel to FDA. This is a whopping signal – PRR = 22.2. (if the PRR is over 2.0, this is taken as evidence of a signal). We don’t know whether these have happened on withdrawal or not – FDA reporting systems don’t make these distinctions. But there is every chance that a significant number have happened on withdrawal. If recoded as part of a withdrawal syndrome, the signal for withdrawal would be much more salient. There is fact a great deal of evidence that stopping clopidogrel is linked to problems. Michael Ho and colleagues in JAMA (2008), 299: 532-539 have shown a doubling of mortality and in particular heart attacks in the 90 days after stopping clopidogrel.

TTP or related problems could readily give rise to just the clinical features FB reports, including anxiety, numbness down her arm, hallucinations and the rest.

RxISK also shows 108 reports of hemorrhagic stroke on clopidogrel. Again the signal for this (PRR = 13.6) suggests strongly that clopidogrel may be causing the problem. These strokes may be TTP related cases. The problem may be happening on the drug or on withdrawal – we just don’t know from the way the data is collected at the moment.

Finally another feature of FB’s case is her reaction to lansoprazole and omeprazole. European regulators have advised against combining clopidogrel with proton pump inhibiting drugs like these. Eliminating acid from the gut likely interferes with a range of different drugs, but in this case PPIs and clopidogrel also interact in the liver, causing FB to slip into withdrawal.

If you are a doctor you can put FB’s difficulties down to problems on the drug and not withdrawal but if you do this, then you cannot also say to FB that staying on clopidogrel is risk-free. Who moreover should make the choice as to whether she dies of a heart attack, or stroke, FB or her doctor? For many suffering a stroke is close to the ultimate horror.

Staying on the drug is not an easy way-out for other reasons. The risks FB outlines are very real – needing surgery, having the drug discontinued, or accidentally ending up without a supply. But in addition, staying on the drug itself cannot be assumed to be without consequences. We think of drugs like aspirin or the statins as acting simply on platelets or cholesterol levels and as a result wonder where the problem might be in staying on them.

But in fact just as the SSRIs do not work solely or even primarily on brain serotonin levels but even more so on blood system serotonin where just like aspirin they reduce platelet adhesiveness, leading to rebound clotting when stopped and cases of TTP and stroke, so also aspirin and statins can lead to extensive changes through the body that affect the brain and other organs. This can include change of personality, or might lead to other conditions improving or getting worse. We know a great deal about what happens soon after we start taking many drugs but know little about what the longer term effects are, and FB is right to be concerned.

Solutions

It will need great skill to come up an answer. FB may need input from a haematologist rather than a cardiologist. In other cases of withdrawal, I advocate using liquid forms of a drug to wean off very slowly, but Clopidogrel permanently blocks some receptors and so this approach is of no use. She would likely to better stopping Clopidogrel while taking warfarin or a heparin analogue, until her entire supply of platelets have turned over.

FB’s case challenges us to recognize that problems like this may be a manifestation of dependence and withdrawal, and that for instance many aspects of SSRI withdrawal may be intensely physical in origin rather than mental as people sometimes assume. We do not in this case know for instance if the permanent changes Clopidogrel causes in platelets might also happen in brain.

This is a case where patients need a doctor to work closely with them as a team. FB has filled a RxISK report and has taken a copy of this to her doctor.

Clopidogrel – Plavix

It seemed to be by chance that the first post on this RxISK blog is on Clopidogrel. But maybe not.

The Tree Must Go

tree in the countryside

Crusoe had a chance to view the new facility – the brainchild of one of the world’s wealthiest men, who had made his name in a race to sequence the genetic code. He had famously used his own DNA in the process. He later went on to create synthetic life and it was from synthetic biology He made his fortune.

The inspiration to recreate Eden came from watching an old movie, The Truman Show, in which Truman Burbank, played by JC, is cocooned in a world in which everyone else is an extra in his life and everything is stage-managed.

Why not do it properly with real people? They could be designed free of genetic disorders. Their main use for drugs would then be for psychedelic or hallucinogen purposes where every dose produces a different outcome in contrast to the numbing uniformity of twenty-first century drugs.

A range of projects in a number of different countries had shown how to create self-contained environments. Curiosity’s trip to Mars in 2012 had confirmed the presence of extensive subterranean water, making all else possible. The new facility was set up. Unlike the Truman Show, its occupants were unlikely to come into contact with outsiders for several centuries, perhaps millennia.

Synthetic biology had made it possible to design species to fit the new ecosystem. No-one of course could know beforehand what in fact would happen when these species began to interact. In other words, the place would almost instantly begin to have a history, and slip out of control. Whether He realized this or not was less clear. Maybe He had a fantasy about being able to intervene.

The most important moment was designing the woman to take control of the Garden. The man came from stem cells retrieved from the marrow in one of her ribs.The first couple were just about to be woken up in the Garden, when Crusoe arrived. She was in time to see the final check that everything was in order. One last round for Health and Safety. It was then they noticed the tree, growing on a slope. A firstborn son out climbing who slipped could have a dangerous drop on the downhill side. The tree must go they said.

The New World had a history. Ultra-short story writing became its dominant art form. The form developed when someone dreamt one night of the following: “For sale, baby shoes, never worn“. The shortest was “Crusoe, we say, was saved”.

The Oedipus Effect

Crusoe was called to see the woman. It all began she said when on the way home after a successful board meeting, taking shelter from a sudden downpour, he stepped into an empty building. There he saw something. Perhaps it was the nutmeg with the meal or the mushrooms that did it. A bunch of children, he said, sitting looking at a stockmarket ticker tape. Many of them appeared limbless, had cleft palates or clubfeet or were otherwise deformed. Others had the scar of some operation down their breastbone or elsewhere, some with the stitches still in.

All hail the Thane of Delaware one sang, as the ticker tape showed a share-price rise. All hail the Thane of Pennsylvania another said as the share-price rose further. All hail Mr. President the last one said as the share-price rose yet higher.

He came home astonished. He couldn’t see what she could. But she said, tearfully turning to Crusoe, things had not worked out. The treatments coming through had been nothing like the breakthrough treatments of a few decades before. Far from getting people well, more were dying earlier. Younger and younger children were being put on some of the foulest drugs on earth. She had thought no-one in their right mind would prescribe such drugs to children or pregnant women but there seemed to be nothing that could stop it happening. The last years of a person’s life, the years of sere and yellow leaf, became the most profitable years for the company. Few of the elderly went to their graves on less than 30-40 pills per day. The country was in thrall.

There was wailing across the land but no-one seemed to have an idea how to bring about change. Some broke into and occupied buildings, but what good could this do when it was impossible for doctors to do anything other than what the evidence said. A series of traitors leaked documents but these resulted in no more than minor embarrassments.

When the Thane of Indiana’s wife became depressed in the midst of all this, she was put on treatment and committed suicide.

She sometimes wondered if he was on something he had become so unfeeling. Never more so than when one of his closest friends on the way up suggested they needed to change course, and soon after was terminated. The man she married would never have done this. Not to someone who had been through so much with him, without whose help he would never have made it.

There was no option he said. As long as the clinical trial data pointed the one way, there was no other rational option for the country but to follow it. Unless someone was to show the entire body of clinical trials was worthless marketing copy, there was no way to undo the system – and what chaos would ensue then. He had even mockingly on one occasion said no-one born of man could bring the system down.

The security around him recently had become total. She was sure they had profiled her and knew she posed no threat. Or else thought her death would make no difference. They knew she was infertile.

“But I had a test-tube baby before I met him and gave him up for adoption”. “Has he just contacted you?” Crusoe asked.

For The Oedipus Effect – see The Antidepressant Era. Re parable, a startling number of US Senators, Governors, Secretaries of State, and even Presidents have had senior roles within the pharmaceutical industry, which is based in Delaware, Indiana, Pennsylvania and New Jersey.

Suffer The Little Children

Illustration of sick child in hospital

This post was written by Dr Irene Campbell-Taylor, a former Clinical Neuroscientist and Assistant Professor of Medicine at the University of Toronto.

This phrase means, of course, to allow the little children but today I want to write about children who are suffering in the other sense. The word “patient” comes from the Latin patire, to suffer or to endure. The children I write of here are suffering what I can only call medical abuse. Anyone interested however marginally in controlling what Big Pharma is doing should watch the PBS program “The Medicated Child”.

We become outraged at the actions of pharmaceutical manufacturers that negatively affect young adults, the middle aged and the elderly but when one sees the pharmaceutical abuse of children, outrage takes on a whole new meaning.

They “make me more like I’m supposed to be”

The most striking thing about this program is, of course, the number of antidepressants and antipsychotics these children are given, often from toddler age. It is deeply disturbing to hear parents declare that they have become convinced that their child needs to be constantly drugged and will probably continue to need these medications for life. When one mother expresses concern about the effect these may be having on her child’s development, she is, politely but definitely, dismissed. It is even more distressing to hear a thirteen year old say that she has to take several medications because they “make me more like I’m supposed to be.” Who decides how she’s “supposed to be”? It is to weep.

Having worked for many years with children and adults who have developmental and/or cognitive impairments, I couldn’t help but be amazed at the physical signs and behavioural aspects that, in this film, are repeatedly missed by pediatricians and psychiatrists. In several of the children in the program, I would want to investigate the possibility of a genetic condition, the physical aspects are so clear.

The parents are brainwashed

The parents are, in a word, brainwashed. Over and over we hear that “if we stop the medications his behaviour returns, sometimes worse.” Have none of these physicians ever heard of withdrawal syndrome? To illustrate just how far this propaganda has spread, we hear that the schoolteachers are suggesting medications. And being listened to by parents.

The “tantrums”, aggression and self-harm that lead to this appalling medication cascade don’t seem to be examined for what they might actually represent. There are genetic conditions in which these are prevalent behaviours and require specific approaches, depending on the particular disorder. But let’s imagine we are three years old again and are afraid of something real or anticipate fear or feel pain that we can’t express. What are we going to do to get the message across? What if you’re three years old and have been abused? How might you react? I’m not suggesting that this is the case with any of the children in the program but I have seen a sufficient number of children who have been physically and sexually abused, at ages you probably wouldn’t believe, to keep it in the forefront as a possible explanation for behaviours that have been described as “oppositional”, “aggressive”, “violent” and so on but now are…BIPOLAR.

I hardly know where to begin. Bipolar disorder in adults is extremely rare and to have the arrogance to assert, on the basis of no evidence whatsoever, that it is common in children is staggering. It is probably possible to do as Dr Biedermann has done, to take the signs of several disorders, overlap them, pick out those that occur in common and create a whole new disease.

Biederman and the drug companies

It is important to note that Massachusetts General Hospital disclosed sanctions against Drs. Joseph Biederman, Thomas Spencer and Timothy Wilens for violating hospital ethics guidelines by failing to adequately report, internally, seven-figure payments they received from drug companies. The disciplinary actions include:

  • They must refrain from “all industry-sponsored outside activities” for one year.
  • For two years after the ban ends, they must obtain permission from Mass. General and Harvard Medical School before engaging in any industry-sponsored, paid outside activities and then must report back afterward.
  • They must undergo certain training (type not specified).
  • They face delays before being considered for “promotion or advancement.”

Each disclosed previously undeclared payments of over $1M each from pharmaceutical companies. It is inevitable that the integrity of their work has become, at best, questionable yet many psychiatrists and other physicians cling to the conviction that juvenile bipolar disorder is a real disorder probably because it gives them something to do about it – treat it with the same drugs they give to adults.

This is medical battery

To proceed, with no supporting evidence, to prescribe ever-increasing dosages of powerful  drugs, never intended for children is, in my opinion, malpractice including medical battery because who is capable of giving informed consent? Certainly not the child and the parents are not told that there’s no scientific evidence for any of this and we really don’t know what we’re doing. Informed consent is, I submit, impossible.

I am not even going to touch the theories around “abnormal amygdala”. It may very well be the case that there is an influence but even if there is, we are far from knowing what it means. Courchesne, many years ago, identified children who have what I insist on calling “true autism” as opposed to the “autistic spectrum disorders” now prevalent. He found that they were born with a part of the brain called the cerebellum smaller than normal. Similarly, persons with Down syndrome have abnormally sized parts of the cerebellum, but in different areas than in the person with autism. This is all very well but so far hasn’t led to effective treatment although in the future we may have some sort of breakthrough based on these initial findings.

There is, however, a growing reliance on MRI and PET scanning as though these were diagnostic instead of mere tools to aid in diagnosis. This month, in the American Journal of Psychiatry, we find a chilling report of the evaluation of “92 children who were at high risk for developing autism, because they had older siblings with the disorder. At age six months, the children underwent (MRI) imaging. Additional imaging data was obtained from most of the children at 12 months and/or 24 months old. Behavioral assessments were also performed at 24 months. Twenty-eight of the 92 children met the criteria for autism spectrum disorders at 24 months.” There are literally dozens of genetic abnormalities that carry the label of “susceptibility to autism” but from this report, I can’t see that any genetic investigation was conducted. The researchers apparently made the assumption that if an older sibling had one of the “autistic spectrum disorders”, the infant was at risk and, lo and behold, by age two, they were so diagnosed. Well, when you’re a hammer, everything looks like nail and, if you can increase the numbers of MRIs and, in turn, massively increase the probability of selling drugs on a scale never seen before, so much the better – except for the children, of course.

Now, let’s consider lithium as a treatment for bipolar disorder. When swallowed, lithium becomes widely distributed in the central nervous system and interacts with a number of substances. Lithium is known to be responsible for significant amounts of weight gain as do several of the antipsychotics such as olanzapine. Lithium also increases water output into the urine, a condition called nephrogenic diabetes insipidus. It increases appetite and thirst, and reduces the activity of thyroid hormone (hypothyroidism). And we give this to children. The recent discussion about mercury and arsenic as medications seems somehow connected. I hope that one day soon we will come to regard lithium given to children as a treatment with same disbelief that we now consider mercury, white lead and arsenic.

Can we talk about Jacob

The adverse reactions to antipsychotics, antidepressants and similar medications are very clear in the young fellow called Jacob in the program. By age nine he was showing an unusual neck and head movement. The narrator refers to these movement disorders as “tics” and, while not accurate, serves as well as anything to describe abnormal muscle movement as a result of the drugs he was taking. In Jacob, the neck muscles are the ones most involved in that involuntary contraction of the muscles at the side, back and front of his neck cause his head to roll. Apparently, no-one has introduced a simple method of controlling this when it starts and that is to touch the chin or the back of the head gently when it is about to happen. This breaks the cycle. Of course, it should never have occurred in the first place and is entirely due to the antipsychotics he is ingesting like candy. The other effect the medications have had, is on his speech. He is dysarthric, that is unclear in articulation, a common side effect of antipsychotic medications. He is at increased risk of choking because of disruption of the muscles used for speaking and swallowing and this is something I find patients and parents are never told.

Why go to see a doctor?

Fewer and fewer health professionals seem to learn about the multiplicity of ways in which one can identify and treat the behaviours that are identified in these children as “pathologic”. No-one seems to care about treating the child and not the “disease” or getting entire families into programs that will examine what factors, environmental, familial or genetic may be causing or maintaining the perceived problems. But, of course, as one pediatrician says,” When you see a new child every fifteen minutes….” We have allowed a very wrong turn in the assessment and treatment of all of us, at all ages for conditions that are too often misidentified and then, for want of knowing about anything else, dismissed with drugs that have unknown and untold effects on DNA, physical functioning and mood.

The prescription pad is the only thing doctors now have. As the little fellow in the film, asked why he is going to see Dr X, reply gleefully and accurately, “To get medicine!”

Krystallized

BBC Radio Four’s Today program ran a piece on August 2 in response to an NHS report showing a startling 500% rise in prescriptions for antidepressants since the advent of SSRIs and a 9% rise last year. Close to 47m prescriptions were dispensed in the NHS in 2011 for anti-depressants and sleeping pills. There has been a rise year on year for the last two decades.

“Antidepressants work” and “antidepressants save lives”

In response to questioning on Today, Professor Clare Gerada, of the Royal College of General Practitioners, trotted out the standard lines “antidepressants work” and “antidepressants save lives”. Would we be worried if there was a rise in the use of statins or anti-cancer drugs?

The UK twittersphere exploded with tweeters taking sides. When challenged on the issue of antidepressants working Dr. Gerada insisted they do. There were predictable tweets from individuals who stated antidepressants saved my life – although as is often the case with such comments the person will often add that it was only on the fourth or fifth antidepressant that they were helped.

Claims that antidepressants work and save lives are not evidence based

Claims that antidepressants work and antidepressants save lives are not evidence based. There is no question that antidepressants do things and in this sense “work” (DBM position paper on antidepressants). If the trials had undertaken to demonstrate SSRIs have an acute onset anxiolytic effect this could have been conclusively demonstrated. But the clinical trials that were done were undertaken to see if antidepressants “work” for depression and this has not been shown. They haven’t even been shown to “work” marginally better than placebo, as is often claimed.

What has been shown is that these drugs have “effects” on rating scales that regulators such as FDA can interpret as evidence they “might” work. This is quite different to demonstrating that the drugs get people back to work or save lives. It is indeed a moot point whether the law has been broken in the licensing of antidepressants in that the 1962 FDA statutes state that the agency will approve drugs that have been shown to be effective.

The rating scales moreover have been rating scales completed by doctors where some of the benefits may stem from sedative, anxiolytic or appetite enhancing side effects of antidepressants. On rating scales completed by patients, or scales less sensitive to the side effects of the medication, there is no evidence even for a rating scale benefit.

Pharmaceutical companies will sue

Pharmaceutical companies will quickly sue anyone who says things that the company believes it can prove in court are unsupported or injurious to the reputation of its product, as happened to Prescrire. (See also Welcome to Data Based Medicine). It is against this background that I am saying that antidepressants such as Cymbalta or Pristiq or Zoloft have not been shown in clinical trials to work.

Having made this point, I also have to say that I use antidepressants. They can have clear therapeutic effects. These effects are typically concealed by trials. If used judiciously I hope I can sometimes put such effects to good use. Whether on balance I do more good than harm is something neither I nor any other doctor can know, in the way we can know when we give an antibiotic for a life-threatening infection or a benzodiazepine for catatonia. Appealing to the literature won’t do it, as this is largely marketing copy and the better the marketing copy the more misleading it is likely to be.

More deaths on antidepressants

The second statement that antidepressants save lives has simply got no evidence base. In 2006, the FDA in the USA got all (or most) placebo controlled antidepressant trials from companies (FDA 2006). In 2004, the MHRA in the UK got all (or most) placebo controlled trials for some antidepressants from companies (MHRA 2004). There were large discrepancies between the two datasets. But a common finding was that there were more deaths in the antidepressant arm of these trials compared to the placebo arm.

So what is happening in the case of those who tweet that an “antidepressant saved me”? There are two options. One is that they are wrong. The other is that they are right but there are a slightly greater number of voices who might have tweeted an “antidepressant killed me”. All anyone hears though are the voices saying the pills saved me.

“Antidepressants saved my life” are like the wonderful stories of people whose lives were saved when their religious medal or medal for valor deflected the bullet away from their heart. We never get to hear the stories of those who die when the medal deflects the bullet the wrong way.

It’s the same with those who swear a statin or other medical drug saved them when trials show an excess of deaths on these also. The evidence base comes back to bite us in the case of treatment induced death – Pharmacosis – which has become at least the fourth leading cause of death. Some drug must be responsible for this, but everyone – psychiatrists, cardiologists, primary care doctors and others – look the other way and say “not me”.

Why are prescriptions rising so relentlessly

If antidepressants don’t work very well, why are prescriptions rising so relentlessly? A great part of the rise stems from the fact that an ever greater number of people are stuck on these drugs permanently. There is likely no more people being put on an antidepressant for the first time each year now than there was 10 or 15 years ago, but the total on treatment continues to build because of the people who cannot stop.

Freudian slip

A year ago in the New York Review of Books Marcia Angell wrote a two-part review of recent books including Bob Whitaker’s Mad in America, Irving Kirsch’s The Emperor’s New Drugs, and Daniel Carlat’s Unhinged that, based largely on the issue of do antidepressants work and save lives, asked the question are Americans in the middle of a raging epidemic of mental illness.

A year later organized psychiatry is still fuming. The latest response is from John Krystal, the President of the American College of Neuropsychopharmacology. After the usual arguments which amount to the claim that the evidence is not what it appears to be, that only we guardians of the flame can interpret it, and that the media should stop alarming people, he comes to an extraordinary conclusion:

“By stigmatizing a field progressing toward a scientific foundation and by disparaging treatments that show signs of efficacy, Dr. Angell’s facile criticism of psychiatry could do harm.”

This is astonishing on a few levels? Herbalism and a range of other fields could be characterized as progressing toward a scientific foundation with treatments that show signs of efficacy. Put a sufficiently large number of people in a trial and choose your measures carefully and even snake oil will show efficacy. Dr. Krystal seems to have consigned psychiatry to a lower level in the pecking order than physiotherapy and other paramedical disciplines. Many in other branches of medicine will likely smile wryly.

If psychiatry is only progressing toward a scientific foundation and its treatments only show signs of efficacy, the harm lies in the fact it has sold itself as a fully scientific discipline with treatments that work and save lives. If this isn’t the case, people need to be told.