The damaged brain: How drugs cause dementia

Dementia of all varieties, including Alzheimer’s disease, is now epidemic, approaching an incidence similar to that of the major killers: for instance, seven million Americans aged over 65 are currently diagnosed with dementia compared with 10 million of all ages with cancer. 

Furthermore, the incidence rates of dementia are sharply on the increase. Predictions suggest that the disorder will increase fourfold among the elderly within the next 40 years, and escalate across all age groups.

Nevertheless, the raw statistics fail to reveal the most insidious aspect of the disease—namely, that the chances that any one of us will suffer from dementia sharply increases with every decade. According to one team of researchers, who tracked the incidence of the disorder over time, after the age of 60, your risk of developing dementia doubles every five years. This means that, by the time you reach your mid-80s, you face a one-in-four risk of having dementia and, by the time you reach 90, the odds increase to one chance in three (Alzheimer Dis Assoc Dis, 2003; 17: 63–7).

One reason for the prevalence is simply due to the ambiguous nature of the term. Virtually every form of cognitive decline is now classified as dementia, including memory loss, and impairment in planning, judg-ment, reasoning and ordinary thought processes.

However, modern medicine must take the greatest blame for the mental decline seen among the elderly. Even though they represent only one-seventh of the population, the over-65s take one-third of all prescription drugs—and usually a cocktail of them. The average senior is taking six drugs at a time, many of which affect the brain.   
Evidence is emerging that a large coterie of drugs given for other conditions, such as high cholesterol, depression, inflammation, insomnia, anxiety, heart disease and arthritis—in short, most of the drugs given to us as we grow older—can all bring on dementia. 

Many of these drugs cause actual damage to the structure of the brain, including shrinking brain volume and destroying the crucial fatty struct-ures of brain cells, thus leading to the abnormal accumulation of tissue in vital brain structures.  
Given the fact that some 90 per cent of Americans from their mid-50s onwards are taking at least one drug regularly and nearly one-third are taking five or more drugs, it may well be—as American psychiatrist Grace E. Jackson claims in her brilliant and damning self-published study—that dementia is, in many cases, a drug-induced disease (Jackson GE. Drug-Induced Dementia. AuthorHouse, 2009). Of the 36 million Americans who now take statins, for instance, an estimated 162,000 people could be severely cognitively impaired because of these drugs in the US alone.  

The chicken or egg dilemma

Although used as an all-purpose catch phrase, dementia could be defined as any condition in which there is an observable abnormality involving neurons or glial cells. On the basis of such a description, it could be said that there are four types of true dementia:

•    Lewy body dementia, in which patients have movement disorders much like those seen in Parkin-son’s disease, with abnormal deposits of ‘Lewy body’ proteins, named after the German neurol-ogist who first observed them, throughout the neurons of the brain;
•    vascular dementia, where the brain’s blood supply has become cut off or interrupted, usually as a result of large or small strokes, causing the death of neurons;
•    frontotemporal dementia, usually diagnosed in patients aged under 65, where the frontal or temporal lobes (including the hippocam-pus) of the brain shrink; and
•    Alzheimer’s disease.
According to Jackson, Alzheimer’s victims all share three specific abnormalities:
•    senile plaques, abnormal clumps of amyloid and other sorts of proteins that form outside of cells in the gray matter of the brain; 
•    neurofibrillary tangles, abnormal, twisted bundles of fibres within brain neurons mostly made up of tau proteins that impair the formation of tubulin, a protein necessary for healthy connective nerve tissue, the result of which
is that messages in the brain aren’t transmitted properly; and
•    granulovacuolar degeneration (GVD), where neurons in the brain have abnormal ‘holes’ (vacuoles), each of which contains a small, dense protein.

The problem is that researchers cannot agree on whether these characteristic findings are the cause or the effect of an abnormal process in the body. The evidence from studies of the effects of aluminium and mercury on the brain suggest that they are the result of toxicity rather than being a true cause of dementia. In test-tube studies using human brain cells, for instance, minute doses of mercury produced changes identical to those seen in Alzheimer’s disease (J Neurochem, 2000; 74: 231–6).

In other, animal studies, professor of medical biochemistry Boyd Haley and colleagues at the University of Kentucky fed rats aluminium, but observed no changes in tubulin levels, whereas mercury-fed rats displayed diminished tubulin levels similar to those seen in typical Alzheimer’s patients. Furthermore, some researchers suggest that the vacuoles seen in GVD are filled with toxic materials, such as aluminium, which the neuron has ‘fenced in’ to keep the rest of the brain safe (Am J Pathol, 1999; 155: 1163–72).

Research at the University of Pittsburgh has discovered that a fat-binding agent known as ‘apolipo-protein D’ (or apoD in medico-speak) is present in the brain plaques seen in patients with Alzheimer’s disease.
However, apoD is also found in other kinds of pathology, and many animal and human studies have shown that antipsychotic drugs induce the production of apoD. Furthermore, scientists have found this type of lipoprotein in fat and brain cells following injury, which suggests that it plays a role in cell renewal and repair.  
Nevertheless, the evidence in general suggests that toxicity—a form of insult to the brain—rather than natural cellular degeneration is the cause of dementia.  

Antidepressants

There is no doubt that certain drugs cause damage to the structure of the brain, thereby impairing its function. Among the chief offenders are antidepressants, which appear to target the white matter of the brain.
The white matter is the part of the brain that contains bundles of nerve fibres covered with myelin, a white fatty substance that forms an insu-lating sheath around each fibre. It is through these neural bundles that messages are passed between different areas of gray matter, which is made up of unmyelinated nerve cells, within the nervous system.
This means that the white matter is rather like a telephone network, responsible for the rapid transmis-sion of nerve impulses and cell-to-cell communication.

One natural aspect of ageing is losing neural connections. Each of us begins adulthood with some 176,000 km of white matter, but we all should expect to lose around 10 per cent of these connections with every decade of life.  
However, antidepressants clearly hasten this process. In 2008, a US study carried out by Duke University Medical Center in Durham, NC, published the results of the 10-year study, which examined the magnetic resonance imaging (MRI) scans of more than 1800 patients performed over two periods of time—first, from 1991 to 1994, and then, from 1997 to 1999. The authors compared the findings for the 163 patients who had begun taking antidepressants between the first and second scans with those for patients who were not using any such drugs.

They found similar incidences between the two groups of virtually every condition looked at—diabetes, stroke, heart attacks, hypertension—save one. Those taking the anti-depressant drugs experienced more ‘bright spots’ in the white matter on MRI. This sort of appearance on a scan is thought to indicate damage to blood vessels, impaired blood flow, demyelination (degeneration of the myelin sheath of nerve cells), disintegration of the blood–brain barrier and even damage to the nerve cells in the gray matter of the brain (Stroke, 2008; 39: 857–62).

Indeed, those taking the drugs suffered a 36-per-cent incidence of white-matter damage compared with 27 per cent in those who had been drug-free over the decade. In addition, all types of antidepressants —be they old or new—hastened the decline. What’s more, although the worst offenders were the old-style tricyclic antidepressants, adverse effects were observed with all of the newer types of drugs that inhibit the uptake of serotonin. Overall, 60 per cent of the patients who used either type of antidepressants showed increased damage to white matter that was above the norm.
Antidepressants also appear to shrink the hippocampus, part of the limbic system of the brain that is involved in long-term memory, spatial navigation, learning and mood. There is solid scientific evidence that patients who are chronic users of antidepressants, particularly SSRIs (selective seroto-nin reuptake inhibitors) such as Prozac (fluoxetine), have smaller hippocampal structures compared with controls. 

In one fascinating study, the hippocampi of long-time depressed patients who were taking long-term medication were compared with those of two other patient groups: those who’d just been diagnosed with the illness and had not yet begun taking any drugs; and a group of non-depressed controls. There was no difference in brain size between the just-diagnosed depress-ed patients and the controls, whereas the long-time medicated showed a hippocampus that was 12 per cent smaller, on average, than those of the others (Proc Natl Acad Sci USA, 2003; 100: 1387–92). 

The importance of this study is that it demonstrates that it’s the drugs themselves, and not the depression on its own, that causes the brain to shrink.

Autopsies of cavaders have also revealed brain damage in those who’d been long-term users of anti-depressants. In one Dutch study, of patients who’d been taking anti-depressants, 73 per cent showed evidence of brain cell death (apoptosis) compared with 33 per cent in patients using long-term steroids and 6 per cent of their matched controls (Am J Pathol, 2001; 158: 453–68).

In addition, epidemiological studies have also shown a greater incidence of dementia among populations using antidepressants. Researchers in Copenhagen carried out a sweeping study, involving nearly a third of the entire Danish popu-lation, focused on patients aged over 40 who’d taken antidepressants, even if just one single time. The risk of developing dementia was two to five times higher in those who’d used antidepressants compared with non-users (J Affect Disord, 2009: 117: 24–9).
However, Jackson believes that this population study may have underestimated the risk, as one-fifth of those using antidepressants died during the study follow-up period.

Statins

Statins, those ‘miracle’ cholesterol-lowering drugs, also appear to lead to progressive cognitive decline. This is particularly ironic, as medicine has been under the illusion that cutting down on cholesterol in the elderly is desirable particularly for the brain (see box, page 11) and, consequently, that statins can keep Alzheimer’s at bay.   
It is true that statins can cross the blood–brain barrier and alter cholesterol metabolism in the brain, but this has no bearing on Alzheimer’s disease. Earlier this year, Harvard University researchers, in conjunction with a number of other centres in the US, Germany and Spain, gave statins for 12 weeks to patients with mild Alzheimer’s disease or mild memory loss.  
During the course of this study, they found a “modest but signifi-cant” inhibition of brain cholesterol biosynthesis. Nevertheless, although the drugs lowered cholesterol in the brain, this had no alleviating effects on Alzheimer’s disease whatsoever (Alzheimer Dis Assoc Disord, 2010 May 13 doi: 10.1097/WAD.0b013e3181d61fea).

In fact, the lack of effectiveness of statins as a treatment for Alzheimer’s disease was finally estab-lished last year, when two reviewers independently analyzed two large-scale randomized controlled trials, involving a total of 26,340 patients as part of the HPS 2002 and PROSPER 2002 studies, and reached an agree-ment after discussing their results. Their conclusion was that statins given late in life to individuals at risk of vascular disease have no effect in preventing either Alzheimer’s disease or dementia (Cochrane Database Syst Rev, 2009; 2: CD003160).

Indeed, far from helping memory and cognitive function, statins can cause sudden and complete memory loss.
This evidence emerged when flight surgeon Duane Graveline suffered global amnesia when taking atorva-statin (Lipitor) for the first time. When his family doctor Jay S. Cohen took up his case with Pfizer, the drug’s manufacturer, he was sent clinical evidence gathered before the drug’s release showing that there were 4.5 cases of severe cognitive disturbance out of every 100 patients given the drug.

This included cases of impaired, worsening or general lapses of memory, general forgetfulness and short-term memory loss. Pfizer’s own studies had also discovered instances in which patients had difficulty concentrating, or suffered abnormally slow or difficulty in thinking, slowed or decreased mental activity, impaired intellect or judgment and even irrational thinking.
Graveline and Cohen then con-ducted an online literature search of MedWatch, the US Food and Drug Association (FDA) database of reported drug side-effects, for reports of severe cognitive impairment or serious amnesia associated with Lipitor. They found 662 such reports, including 399 cases of amnesia and 236 cases of memory impairment. The investigating pair also found that, over time, the complaints had become more frequent (Townsend Lett Docs, 2009; 311: 64–70).
MedWatch, which is thought to be notified of only 2.5 to 5 per cent of all drug side-effects, therefore suffers from vast underreporting, so the true incidence of memory problems from statins is probably closer to 66,000
or more. In fact, Graveline and Cohen believe that virtually every patient taking the drug suffers from cognitive damage in one form or another that may be too mild to be initially detected. This is perhaps because all statins lower levels of coenzyme Q10, known to be vital for brain function (see box, page 12).

Graveline and Cohen’s detective work has also been vindicated by a meta-analysis carried out by Duke University in Durham, NC, which uncovered 60 patients with memory loss attributable to statins. Half the patients had noticed cognitive decline within just two months of starting the drugs; of these, more than half found that their memory improved as soon as they stopped taking the drugs. Furthermore, all of the four patients who started taking the drugs again suffered a recurrence of their memory problems. 

As a further nail in the coffin, not one single experimental study could find any evidence to support any benefit with statins in delaying cognitive decline (Pharmacotherapy, 2003; 23: 871–80).

Antipsychotic agents


Another major culprit causing dementia is that broad class of drugs called ‘antipsychotics’. The first so-called ‘neuroleptic’ medications were developed in the 1950s to relieve patients suffering from hallucina-tions, paranoid schizophrenia and other psychoses. Unfortunately, these drugs brought with them unwanted extrapyramidal (brain motor system) side-effects such as tardive dyskinesia, characterized by muscle stiffness, tics, tremors and other awkward movements.

The arrival of clozapine (Clozaril) introduced the next generation of neuroleptics—which also includes olanzapine (Zyprexa), quetiapine (Seroquel) and risperidone (Risper-dal)—that were dubbed ‘atypical antipsychotics’ to distinguish them from their older and supposedly more dangerous cousins. These drugs are supposed to suppress the psychotic and antisocial aspects of schizo-phrenia without all the antipyramidal effects (World J Biol Psychiatry, 2000; 1: 204–14).

However, this newer generation of drugs comes with its own laundry list of dangerous, even life-threatening, side-effects, including serious mental deterioration.

There is no doubt that the so-called ‘antipsychotic drugs’ can cause or speed up the development of dementia (J Neurol Neurosurg Psychiatry, 2007; 78: 233–9). This is ironic because these drugs are often given to sedate or calm patients with dementia, whereas it appears that they are also speeding up and worsening the process of cognitive decline.

Nevertheless, the most compelling evidence comes from autopsy studies that have compared patients using antipsychotic drugs with those who did not. In one study by the Wolfson Centre for Age-Related Diseases at King’s College London, those who’d been given neuroleptics had a 30-per-cent greater density of amyloid plaques and 65- to 367-per-cent more neurofibrillary tangles than those who were free of neuroleptic drugs (Int J Geriatr Psychiatry, 2005; 20: 872–5).

Moreover, in a similar US study, 102 patients with schizophrenia showed evidence on autopsy of brain deterioration that was suggestive of Alzheimer’s or some other form of dementia. The signs were present in 74 per cent of those who’d been given antipsychotic drugs, but in only 36 per cent of those who’d died prior to the advent of these drugs (Alzheimer Dis Assoc Disord, 1994; 8: 211–27).

In other words, taking anti-psychotics more than doubled the patients’ chances of developing dementia.

The worst combination of all is taking an antipsychotic together with an antidepressant, which appears to quadruple the speed at which the disease develops (J Neurol Neurosurg Psychiatry, 2007; 78: 233–9).

What’s more, Alzheimer’s patients who are given an antipsychotic—a common practice, usually to sedate them—have double the usual risk of death. In a major study involving various centres across the UK—the first independent study of its kind not paid for by a drug company—less than half the patients (46 per cent) taking an antipsychotic were still alive at the two-year follow-up. After three years, only 30 per cent of those taking antipsychotics were alive compared with 59 per cent taking a placebo (Lancet Neurol, 2009; 8: 151–7; doi: 10.1016/S1474-4422(08)70295-3).

In another UK study that was focused on care facilities in the North East of England, the London-based researchers compared the efficacy of the antipsychotic quetia-pine, the cholinesterase inhibitor rivastigmine and a placebo in calming institutionalized patients with dementia. Neither of the patients in the active-treatment groups were any calmer than those who were simply taking sugar pills, although there was one significant difference with quetiapine—it was associated with significantly greater cognitive decline (BMJ, 2005; 330: 874).

Antipsychotics also appear to shrink the volume of the frontal lobes of the brain by 0.2 per cent per year, according to a University of Iowa study (Arch Gen Psychiatry, 2003; 60: 585–94). Other studies have shown size reductions in a variety of areas of the brain with both older (halo-peridol) and newer (olanzapine) antipsychotic medications (Arch Gen Psychiatry, 2003; 60: 585–94).

What is coming to light is a clear association between antipsychotic drugs and cognitive decline. In a painstaking English survey, every case of dementia recorded on a dementia register during 1993–1994 was examined. Researchers studied the patients’ diagnoses and treat-ments from their various medical carers and interviewed their next of kin, then matched these patients to a similar group of elderly people living in Southeast London.

Of the patients on the register, 13 per cent had a past history of psychiatric treatment, and the use of psychiatric drugs was three to four times higher among those who’d gone on to develop dementia (Age Ageing, 1998; 27: 181–8).

Benzodiazepines

In addition to the major anti-psychotic drugs, benzodiazepine tranquillizers and sleeping pills are also responsible for cognitive decline. One Argentinian study noted evidence that sleeping pills, which are often handed out without a prescription in that country, led to severe memory and cognitive impairment, and delirium (Vertex, 2001; 12: 272–5). 

Newer studies now show that this effect has to do with an effect on gangliosides in the brain. These molecules, which contain fat and sugar, are present to a large extent in brain lipids and on the surface of every neuron. They are essential for regulating cell growth, maintaining the integrity of the material con-tained within cells, and responding to foreign invasion by toxins and bacteria. Without these gangliosides, we lose myelin and entire neurons, and may even die.

A series of studies by the Institute for Medical Research in Belgrade, Yugoslavia, has demonstrated that, at least in rats—so it may not apply to humans—chronic doses of Valium (diazepam) led to the loss of 46 per cent of gangliosides in the cere-bellum within six months. After a short period of total drug withdrawal, the rat brain still had not fully recovered (Physiol Res, 1999; 48: 143–8).

When the researchers repeated the study in 2002, focusing especially on the effects of the drug on various regions of the brain, they found significant reductions of gangliosides in the hippocampus, cerebral cortex and cerebellum, as well as increases of simple gangliosides in other areas (Neurol Sci, 2002; 23: 69–74). These findings are consistent with those of many human neurological diseases, including Alzheimer’s.

Indeed, in a 1993 British study, researchers took computed tomog-raphy (CT) brain scans of long-term benzodiazepine users and compared them with those of drug-free controls. The scans revealed that the drug users had a reduction of brain tissue in their frontal and occipital lobes, as well as in the left caudate nucleus—areas that are crucial for cognitive function (Psychiatry Res, 1993; 48: 135–44).

At present, in the US alone, six million patients are being treated for dementia at a cost of $90 billion, or one-third of all Medicare bills. This means that 1 per cent of the entire gross domestic product of the US is being spent on a mostly iatrogenic (doctor-induced) condition.

Medicine has reached the point where it is chasing its own tail, attempting to mop up with yet more drugs and treatments a vast and costly problem that it has itself caused in the first place.

Evidence is mounting that one of the major toxic insults to the brain is the mercury from amalgam fillings, but this effect may be eclipsed by the dangers we face from the modern medical response to ageing.

Keeping bright and alert in old age requires a few simple practices: regular exercise; eating an anti-oxidant-rich wholefood diet along with good fats; minimizing toxic exposure to heavy metals; engaging in regular brain workouts (crossword puzzles or reading); and staying connected through a social network. However, now there is one more simple homily to add to the list: avoid as many prescription drugs as you can.

Lynne McTaggart

Why the brain needs fats

Although medicine used to believe that the master conductor of brain activity was the neurons, or nerve cells, that create and release neurotransmitters and electrical signals, this view has been revised by a more holistic view of the brain. This concept appreciates that the brain works in its entirety through a web of activity between neurons and four varieties of glial cells. Glial cells, which surround the neurons, keep them in place, provide them with nutrients, and destroy and mop up pathogens. They also insulate one neuron from another and modulate the transmission of signals. One major function of glial cells is to form myelin—the insulating sheath that covers every tentacle of a nerve cell—which is largely made up of lipid (fatty) tissue.  
Yeon-Kyun Shin, a professor of biophysics at Iowa State University, recently went on record to say that high cholesterol is vital for good brain function, and a lack of cholesterol impairs the brain’s thinking ability and memory.

“If you deprive the brain of cholesterol, then you directly affect the machinery that triggers the release of neurotransmitters. Neurotransmitters affect the data-processing and memory functions; in other words, how smart you are and how well you remember things,” he said (Proc Natl Acad Sci USA, 2009; 106: 5141–6).

The role of coenzyme Q10

It is well known that patients taking statins lose coenzyme Q10 (CoQ10) in a dose-related manner. The drugs block production of both cholesterol and CoQ10 by inhibiting the enzyme precursor of not only cholesterol, but also that of CoQ10.

CoQ10 participates in chemical reactions, particularly those that involve cellular energy production, and helps to make cell membranes more resis-tant to oxygen damage. It is found abundantly in the heart mostly because of the huge energy requirements of cardiac cells.

In fact, studies have shown that a deficiency of CoQ10 is linked with heart failure and impaired heart function. Of 15 published studies in the literature, nine have confirmed that statins can significantly lower CoQ10 levels (Arzneim Forsch, 1999; 49: 324–9).

Critics of statins believe that the widespread use of these drugs has caused an increase in ‘statin cardiomyopathy’, where the heart loses its ability to pump blood or heart rhythm is disturbed, leading to irregular heartbeats. Drug manufacturers tacitly acknowledge this effect by offering several drug formulations that combine a statin with CoQ10.

But a less well-known problem with blocking CoQ10 is that it interferes with cognitive performance, resulting in memory loss and muddled thinking. In an elderly person, this sort of side-effect is almost invariably passed off as age-related dementia, requiring yet another coterie of ‘wonder drugs’.

Other researchers have been discovering that statins also inhibit and cause mutations in mitrochondria cells, the energy power packs of the body. Scientists now suspect that an array of neurodegenerative diseases are due to mutated or altered mitochondria.

WDDTY VOL. 21 ISSUE 6