Editor’s Note: Over the next several months, Mad in America is publishing a serialized version of Peter Gøtzsche’s book, Critical Psychiatry Textbook. In this blog, he critiques the use of drugs to treat dementia. Each Monday, a new section of the book is published, and all chapters are archived here.
As noted earlier, an editor of one of the textbooks,18 Poul Videbech, wrote in 2014 that depression doubles the risk of dementia,408 but the meta-analysis he cited did not mention with one word which treatments the patients had received.407 Other studies suggest that it is depression pills and other psychiatric drugs that make people demented.557,558
The information about treatment of dementia was highly misleading. In one book, the chapter about Alzheimer’s disease was written by two psychologists20:341 who went into detail about the drugs, even though this is none of their business, as psychologists are not allowed to prescribe drugs in Denmark. They claimed that acetylcholinesterase inhibitors can dampen the development of symptoms20:351 but none of their 19 references were to research documenting this.
Two other psychologists wrote that the drugs have a better effect on Lewy body dementia and dementia in Parkinson’s disease than in Alzheimer’s disease on cognitive functions, apathy, visual hallucinations, delusions, and other neuropsychiatric symptoms.20:375 These finger-tip sensations are far-fetched for drugs that don’t work (see below), and none of their 38 references were about drug effects whereas several were about psychotherapy and other therapies, e.g. a meta-analysis of the effect of dancing in patients with Parkinson’s disease. Very strange, indeed.
Another book claimed that drugs can inhibit the progression of Alzheimer ‘s disease for months to a few years, and that donepezil, galantamine, and rivastigmine have equal effect.18:48
A third book mentioned that acetylcholinesterase inhibitors may delay the decline in functional level and behaviour.17:243 This became more concrete 424 pages later: Drugs, primarily acetyl-cholinesterase inhibitors, may to some extent re-establish lost cognitive skills as well as postpone further deterioration. The progression in Alzheimer’s can be delayed for 6-12 months.17:667
A fourth book did not pull any punches either.16:127 It claimed that, in a minority, a clear improvement of cognitive functions is experienced, with resumption of earlier activities and possible disappearance of hallucinations or other neuropsychiatric symptoms. The authors also claimed that acetylcholinesterase inhibitors may have a beneficial effect on behavioural and psychological symptoms of dementia and may delay their onset.
Dementia was of course not an issue in the textbook about child and adolescent psychiatry.19
All these statements are totally wrong. There wasn’t a single reference to placebo-controlled trials or meta-analyses, which would have told a story of drugs that don’t work and are harmful.7:197
The small subjective effects registered in drug trials are likely spurious, as they can easily have been caused by unblinding bias because of the drugs’ conspicuous adverse effects.
A 2006 Cochrane review of donepezil, galantamine, and rivastigmine didn’t pay attention to this problem and concluded that, “The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer’s disease.”559 Even without considering the unblinding problem, this conclusion was unwarranted. The improvement in cognitive function was 2.7 points, in the midrange of a 70-point scale. This is less than the 4 points the FDA considers the minimally relevant clinical change.560 We may also compare with the smallest effect that can be perceived on the Hamilton scale for depression, which is 5-6, although the maximum is only 52.267
The author of the Cochrane review wrote that “donepezil appears to have no serious or common side effects.” This is so egregiously false that I don’t think Pfizer would have dared claim this in one of their advertisements for Aricept (donepezil).
The harms are both common and serious, which the author of the Cochrane review actually demonstrated herself, as 29% of the patients dropped out of the drug groups, as compared to only 18% in the placebo groups, partly because of more adverse events.559 The most common harms of donepezil are nausea, diarrhoea, insomnia, vomiting, muscle cramps, fatigue, and anorexia.561 This is not what we would want for an old person who might already have problems with bad sleep, feeling tired, and eating too little.
The list of frequent adverse effects in Pfizer’s product information for Aricept is very long.561 The drug causes syncope in 1% of the patients and when old people fall, there is a considerable risk that they break their hip and die. A large Canadian cohort study showed that if people with dementia took dementia drugs, they had almost a doubled risk of hospitalisation for syncope, and they had more pacemakers inserted and more hip fractures.562 More than half of the patients who were admitted to hospital for bradycardia were retreated with the same type of drug after discharge.562 This is yet another proof that doctors cannot handle psychotropic drugs safely.
A 2014 study, of 5,406 nursing home residents in the United States with advanced dementia, found that one-third received cholinesterase inhibitors and one-fourth memantine, another dementia drug.563 The title of the paper was appropriate: “Use of Medications of Questionable Benefit in Advanced Dementia.”
It is interesting that no benefits for society have been found,564 as we so often hear about the economic burden of dementia and how important it is to intervene with drugs.
The political sales pitches—which tend to coincide with general elections—are vacuous. A long-term trial of 565 patients with mild to moderate Alzheimer’s disease that compared donepezil with placebo found no meaningful effects, and the authors concluded that donepezil isn’t cost-effective, with benefits below minimally relevant thresholds.565
In contrast to other trials, this trial was publicly funded. It was excluded from the Cochrane review,559 and the author used 511 words on explaining why. The main reasons appeared in a table: “Results for the 5 and 10 mg/day groups were not reported separately. Complex design and high numbers of dropouts made analysis and interpretation difficult.”
It is not acceptable to exclude a study because it combines two dose groups in the results. And that the design was complex is not a valid reason either for its exclusion. Furthermore, as it was a long-term trial, where more people drop out than in short-term trials, the high drop-out rate was also an invalid reason for exclusion.
The outcome after three years was similar on drug and placebo for institutionalisation, progression of disability, and behavioural and psychological symptoms.565
Extremely few trials in psychiatry run for three years but such trials are exactly those we need instead of the thousands of short-term trials we have, which are useless for an assessment of drug effects, as very few patients are treated for only a few weeks.
Six years after the trial was published, TV commercials for Aricept implied that the patients’ cognitive and daily functioning, including attention, focus, orientation, communication, social interaction and engagement, will be restored to normal; “Don’t wait. Talk to your doctor about Aricept.”566 The FDA told the company that—with these huge lies—it had broken the law.
You should not talk to your doctor about dementia drugs because, as the textbooks so clearly showed, your doctor is highly likely to mislead and harm you. These drugs should not be used by anyone to prevent or treat dementia.
Three critical comments have been published on the 2006 Cochrane review, including mine.559 Unfortunately, contrary to good scientific practice, they are undated. The author apologised for an error, which she said would be corrected in the next version, and she replied to me that another error had “also now been corrected.” It has not been corrected. In 2015, I was told that “An update of the review … is in preparation.”559 The review has not been updated. It stands as a gravestone over a once magnificent organisation, which is currently facing big financial trouble because it has not lived up to the expectations of its major funder, the UK National Health Service.146
There are other Cochrane reviews of these drugs, e.g. one in vascular dementia, which is not encouraging either.567 The authors concluded that donepezil and galantamine have a small effect on cognition but that it is unlikely to be clinically important.
One of the textbooks noted that psychosis pills cause considerable harms, e.g. an increased risk of thrombosis in the heart and brain and an increased risk of death.16:127 It claimed that risperidone and olanzapine have a documented minor effect in dementia.16:127 This was in a chapter about dementia written by two doctors who work with these patients. In another chapter, about psychopharmacology, the author contradicted this, as she noted that psychosis pills should be avoided in elderly people with dementia and behavioural disorders due to the lack of evidence for an effect, increased sensitivity to harms, and an increased risk of stroke.16:561 She did not mention the most important reason to avoid these drugs: To avoid killing patients in large numbers (see Chapter 7).
This demonstrated a general issue. People who treat patients become carried away by their “clinical experience” and other biases and are much too positive towards the effects of psychiatric drugs. They are therefore not the most trustworthy textbook authors. They have many vested interests, too, very often financial ones related to the drug industry.
Even people who should know better can be disappointing. A clinical pharmacologist acknowledged at a public meeting that the drugs don’t work but he recommended that they should be tried, as they work better in some people than in others. I asked him if he had never heard about statistical variation. With his argument, we could use whatever we pleased that doesn’t work.
The perspective is chilling. Doctors are like children. They cannot keep their fingers away from dangerous toys, which is why we should take all the ineffective and dangerous psychiatric drugs off the market. I suggested this in a newspaper article in 2014.189
As I doubted it could be true that risperidone and olanzapine work for dementia,16:127 which no drugs do, I browsed the Internet and found a trial of olanzapine.568 I had been duped again. It was not about having an effect on dementia but about calming down disturbing Alzheimer patients with a major tranquilliser, and the patients became somnolent and developed gait disturbances. I also found a Cochrane review, but this was also not about treating dementia but about treating aggression and psychosis in people with dementia. Everything I found was about this.
This book noted that the effect of depression pills is very limited and added that a minority without depression develop depression after discontinuation.16:131 This is interesting because it is an iatrogenic harm, an abstinence depression (see Chapter 8, Part Twelve).
Yet again, this was not about treating dementia, it was about treating depression in people with dementia. I found a Cochrane review, which was also discouraging.569 It noted that the data were of variable quality and unsupportive: “On the only measure of efficacy for which we had high‐quality evidence (depression rating scale scores), antidepressants showed little or no effect.”
As noted earlier, it is likely that all psychotropic drugs can cause chronic brain damage,5,135 which may be permanent. A hallmark of this is impaired cognitive function. Chronic brain damage is related to the length of drug exposure and often worsens when the dose is increased, whereas it will usually improve considerably when drugs are tapered off. If it had been the disease that caused the problems, the patients should have become worse when the drugging was reduced.135 A 17-year follow up of the Framingham Heart Study found that use of depression pills increased the risk of developing dementia by about 50%,570 and benzodiazepines seem to double the risk of dementia.571
We should avoid drugging demented people. We should care for them. A systematic review of 33 trials of agitated demented people showed pretty large effects of care, e.g. communication skills training, activities, music, touch, massage and talking to people.572
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To see the list of all references cited, click here.