This presentation has four goals:

1) to introduce the major families of psychiatric medications

2) to explain current trends in the USA’s consumption of pharmaceuticals

3) to describe the kinds of medical conditions which commonly affect patients                                       who receive mental health care from publicly funded sources (e.g., Medicaid)

and

4) to explain the serious health risks which are associated with psychiatric drug treatments.

Although chemicals have long been used throughout history to alter cognition, mood, and behavior, the so-called “psychopharmaceutical era” originated in the late 19th and mid-20 centuries.

The Food and Drug Administration is the U.S. governmental agency which approves and regulates medications.  Currently, there are more than 100 different pharmaceuticals which have received FDA “approval” for the treatment of psychiatric conditions. 

Excluding the chemicals which are specifically used to treat nicotine (varenicline), alcohol (disulfiram, acamprosate) and opioid dependence (naltrexone, methadone, buprenorphine), there are five major categories of psychotropic drugs:

antidepressants

antipsychotics (sometimes called “major” tranquilizers)

mood stabilizers (anticonvulsants and lithium)

sedatives/anxiolytics (sometimes called “minor” tranquilizers)

stimulants

In any given year, which of the aforementioned medical conditions afflicts the greatest number of people within the U.S.A.?

This answer may be surprising to many readers.   However, according to the Centers for Disease Control (CDC), arthritic conditions affect approximately

46 million (1 in 5) residents within the U.S.A.   [Source: CDC  2009]

This statistic, drawn from the “National Health Interview Survey,” reflects

the following prevalence rates for a variety of rheumatological / skeletal

conditions  [Source:  Arthritis and Rheumatism, 2008]

This slide compares the lifetime prevalence rates for various diseases of the human body (somatic conditions) versus the prevalence rates for various phenomena which affect the mind or soul (psychiatric conditions).

The key point to be made is that chronically or recurrently psychotic states – such as those which result in the diagnosis of “schizophrenia” or “bipolar disorder” – affect a strikingly small percent of the population.

According to *IMS Health, U.S. sales of antipsychotics (AP) totaled 14.6 billion dollars in 2009.  Antidepressant (AD) sales in the United States amounted to 9.9 billion dollars.  Sales of stimulants (e.g., drugs used to treat the symptoms of childhood hyperactivity and inattention) and anti-seizure drugs accounted for 5.8 billion dollars and 5.3 billion dollars, respectively.

Key:

AD = antidepressants

ACEi = ACE inhibitors (a class of drugs which lower blood pressure)

AED = antiepileptic drugs (anticonvulsants)

benzos = benzodiazepines (e.g., diazepam, clonazepam, alprazolam)

In terms of U.S. prescription volumes in 2009, lipid lowering drugs

(e.g., statins) and codeine or codeine combinations (synthetic painkillers) were the dominant drugs.  

Interestingly, three families of neuropsychiatric medications were commonly prescribed.  Antidepressants were the third most dominant drug class in terms of # of prescriptions dispensed (168.7 million prescriptions).  AED (anti-epileptic drugs, which are used not only for seizure disorders, but increasingly for control of mood swings, aggression, and misbehavior) placed seventh (104.5 million prescriptions).  Benzodiazepines (so-called “minor tranquilizers” or anti-anxiety drugs) finished eleventh.

Although the U.S. population comprises only 4.5% of the planet’s human inhabitants, Americans account for a disproportionate share of the world’s pharmaceutical sales:

             90% of the world’s stimulants

63% of the world’s antipsychotics

51% of the world’s antidepressants

41% of the world’s anti-epileptics

In 1999, the Institute of Medicine stunned many medical professionals and policy makers with an analysis of America’s healthcare system.  In its report entitled To Err Is Human, the Institute of Medicine estimated that at least 44,000 and as many as 98,000 people die in America’s hospitals each year as a result of preventable errors.

Included in this analysis of hospital-related errors were wrong or delayed diagnoses, errors in drug doses or method of drug delivery, inadequate monitoring, and avoidable delays in responding to abnormal tests.

The following year, the prestigious Journal of the American Medical Association (aka, JAMA) featured an article by Johns Hopkins University professor, Dr. Barbara Starfield.   The article expanded upon the Institute of Medicine’s theme of iatrogenic (treatment-related) death.

Using data culled from a variety of inpatient and outpatient investigations,     Starfield’s analysis estimated that adverse effects of medication (i.e., “therapeutic” doses of prescription drugs taken exactly as prescribed) account for approximately 305,000 deaths per year.

106,000 inpatient deaths due to pharmaceuticals

199,000 outpatient deaths due to pharmaceuticals

[Note:  Given the fact that “adverse drug reactions” are rarely reported, and given the fact that drug-related heart attacks, strokes, pneumonias, and cancers are seldom attributed by physicians or governmental agencies to pharmaceuticals, these estimates were absurdly conservative.]

If one integrates the aforementioned statistics within the previous governmental listing of America’s top causes of death, the results are striking:

This slide (drawn from the aforementioned study) depicts the average age of death among public mental healthcare recipients diagnosed with Serious Mental Illness.

The column on the far right depicts the mean number of  “Years of Potential Life Lost” per mental health patient.

On average, recipients of public mental healthcare in the U.S.A. were dying in the late 1990s approximately 13 to 30 years earlier than expected.

Although these data are now dated (1997 to 2000), they quite likely underestimate the scope of existing mortality among Americans with SMI.  The reasons for this continuing crisis include factors which will be discussed below.

Many medical professionals and laypersons have been educated to believe that great progress has occurred in the treatment of patients diagnosed with Serious Mental Illnesses, such as schizophrenia.  However, the research evidence suggests otherwise.

One popular research strategy for evaluating the effectiveness of healthcare compares changes in SMRs (standardized mortality ratios) over time.  For those who are unfamiliar with the term, the Standardized Mortality Ratio divides the death rate of patients with a certain condition by the death rate of age-matched, unaffected controls.

An interesting analysis performed for residents of Stockholm County (Sweden) evaluated changes in the SMRs of patients diagnosed with schizophrenia between the years 1976 and 1995.

This slide depicts the changes in mortality for Stockholm County patients diagnosed with schizophrenia.

For women, SMRs increased from 2.1 in the period of 1976-1980 to 3.6 in the period 1991 to 1995.  [In other words, by 1991-1995, women with schizophrenia were 3.6 times more likely to die than age-matched healthy controls.]

For men, the changes in mortality ratio were even worse.  SMRs for males diagnosed with schizophrenia increased steadily from 2.6 in the time period of 1976-1980, to  9.4 in the time period of 1991-1995.  

These and other “longitudinal” investigations of mortality rates for patients with Serious Mental Illness have revealed a progressive deterioration of longevity in industrialized nations, despite so-called advances in the quality and delivery of pharmaceuticals.

According to the National Association of State Mental Health Program Directors in 2005, almost 6 million people are served by the public mental health system each year.

Compared to people without Serious Mental Illness, public health care recipients with SMI:

die in greater numbers each year (1-3.5% vs. 0.5-0.8%)

die 10 to 30 years earlier than expected

and

experience higher rates of somatic (non-mental) disease

The Maine Medicaid Study also found that patients diagnosed with SMI not only experienced higher rates of specific illnesses, but also experienced higher rates of combined (multiple) and serious diseases.

This slide compares the 2004 prevalence of medical conditions among the Seriously Mentally Ill (SMI with and without substance abuse) vs. non-SMI [Medicaid recipients without mental health conditions or substance abuse]: 

SMI non-SMI

1 plus conditions 69%   51%

2 plus conditions 46%   27%

3 or more conditions 28%   15%

Key Point:      
Among recipients of Medicaid, SMI is associated with higher rates of physical (somatic) medical disease.

The purpose of this section is to consider the role of medications in the overall disease burden of patients receiving treatment for mental illness.

This slide depicts the “odds” (likelihood) of developing heart disease, diabetes, pneumonia, suicide, stroke, or dementia for mentally ill patients based upon exposure to antidepressant (AD) or antipsychotic (AP) drugs. 

Numerous investigations, performed in a variety of age groups, have demonstrated the potential of pharmaceuticals to accelerate the risks of disease and death.  Even when compared to similarly diagnosed patients who have avoided antidepressant or antipsychotic drugs, consumers of these medications have been two to fifteen times more likely to attempt or complete suicide, and two to seven times more likely to develop pneumonia, diabetes, heart disease, or stroke.

Equally important -- but seldom discussed by health care professionals – the use of antidepressant or antipsychotic drugs has been repeatedly associated with a two- to fourteen-fold higher likelihood of dementia.

 

The word “dementia” is derived from the Latin terms

                de mens / de mentis

meaning           “out of (or away from) one’s mind”

In the year 2000, the prevalence of dementia among Americans age 65 or older was 7.6 million people – roughly 2.3% of the entire U.S. population.  This number is projected to increase to 4.5% of the U.S. population by the year 2040 (18.3 million people).

The box on the left depicts the age-related rates of dementia:

ages 40-65 0.1% of this group will be diagnosed with dementia

ages 65-70 2% of this group will be diagnosed with dementia

age 70-80 5% of this group will be diagnosed with dementia

80+ 20% of this group will be diagnosed with dementia

The pie chart on the right depicts the prevalence of the major diseases which give rise to dementia:

           70% of dementias  are associated with Alzheimer’s disease

           17% of dementias are associated with vascular disease (e.g., stroke)

           13% of dementias are associated with other medical conditions

This slide depicts the number of people in the U.S. population of retirement age (light gray: 65 and above; dark gray: 85 and above).

In the early 1900s, the U.S.A. was populated by a relatively small number of older people.  This situation changed drastically after 1920:

 # of U.S. residents aged 65 or older

1900 3.1 million people

1920 4.9 million people

1940 9 million people

1960 16.7 million people

1980 25.7 million people

1990 31.2 million people

2000 35 million people

With the end of World War II came the return of soldiers to the U.S. mainland, and with their return came an explosion in the birth of babies.  The so-called “Baby Boom Generation” refers to this population subgroup whose members were born between 1945 and 1964.

As the “Baby Boomers” approach their retirement years (red bars in the slides above), the overall structure of the U.S. population will change from a pyramid shape (2000) to a rectangle shape (2040) – a phenomenon which some researchers have called “The Squaring of the Population Pyramid.”

These demographic shifts have important implications for economic and healthcare policy, because the number of retirees (aged 65 and older) will reach an historical high point:

  12% of the population in 2000

18% of the population in 2020

21% of the population in 2040

Given the fact that the prevalence and costs of dementia are expected to rise in conjunction with America’s changing demographics, there is an urgent need for health care providers and policy makers to prevent the fundamental causes of brain disease.

It is within this context that many health care providers will need to revise their approach to medicating patients.

Even though the construct is seldom mentioned by physicians in their clinical work, it is nevertheless significant that the American Psychiatric Association’s own diagnostic handbook (the DSM) has long recognized the fact that drugs of any kind may induce or enhance long-lasting, cognitive limitations.

To the extent that psychopharmaceuticals contribute to brain dysfunction and dementia (i.e., substance-induced persisting dementia), they are perpetrators of a perfect crime.

In the novel, Murder on the Orient Express – Agatha Christie’s famous fictional detective, Hercule Poirot, must determine the identity of the person who has killed a fellow train passenger.  The case is never definitively solved because there are twelve different suspects for the murder, each of whom has strong motives for the crime.

In the Academy Award winning film, Michael Clayton, an attorney who represents a large chemical company becomes a whistle blower after he discovers that his client has knowingly concealed the deadly effects of a farm product.  In an act of corporate retaliation, the attorney is cleverly killed by hit men so that his death appears to be a suicide.

Recall from slide #13 that antipsychotics were the top selling drugs in the United States in 2009 (14.6 billion dollars).   The history of antipsychotic drugs dates back to the early 1950s when physicians in France hypothesized that sedating chemicals might be valuable in “taming” the residents of the world’s asylums.

There are two major ways of describing the evolution of antipsychotic drugs.   As shown above, it is possible to describe this history in terms of  “when” the drugs entered clinical use. A second method refers to the molecular and physiological effects of each agent. 

According to this latter approach, the “first” generation drugs (typical or conventional antipsychotics) are associated with the blockade of dopamine receptors and specific kinds of adverse effects.  The so-called “second” generation drugs (atypical antipsychotics) are distinguished by the blockade of dopamine and serotonin receptors, along with an “allegedly” more benign side effect profile.  The so-called “third generation” drugs (such as Abilify) is characterized by its affinity for specific states of the dopamine receptor (partial agonism).

Unfortunately, the myth of “atypicality” has not held up.  Many consumers of 2nd and 3rd generation drugs have developed Parkinson’s disease, tardive dyskinesia, and diabetes.  Astute clinicians have openly questioned the classification of the newer products, such as Risperdal (risperidone), after finding that recommended doses have induced toxicities identical to those which are commonly inflicted by the older drugs.

In 2007, investigators affiliated with the Department of Veterans Affairs reported the 12-month mortality rates for all retired veterans who received a diagnosis of dementia in fiscal year 2002 or 2003.

The study identified dementia patients from a national database of veterans (23,436 individuals) who were 65 years of age or older.

Excluded from the investigation:  

any patient who had used psychiatric drugs in the 6 months              preceding the diagnosis of dementia

any patient who had previous or new diagnoses of a seizure disorder

  any patient who received treatment with lithium

The research team compared the death rates of demented veterans based upon new outpatient exposures to various classes of psychiatric drugs.

Of the 12,821 patients who avoided exposure to psychiatric drugs, 18% died within one year.

Of the 10,615 patients who experienced treatment with antipsychotic drugs, death rates were consistently higher:

On April 11, 2005, the Food and Drug Administration issued a Public Health

Advisory to inform healthcare professionals about a 1.6 to 1.7x  higher risk of

mortality for elderly demented patients following exposure to the “2nd

generation” antipsychotic drugs.  This alert reflected the detection of higher

death rates – mostly cardiac or pulmonary – in the FDA’s “Randomized

Controlled Trial” database for olanzapine (Zyprexa), risperidone (Rispderdal),

and quetiapine (Seroquel).

Two years later, this warning was revised and expanded because of further

research discoveries.   On June 16, 2008, the FDA alerted physicians that the

risk of premature death in elderly demented patients was elevated by both

the “new” and “old” (1st generation) antipsychotic drugs.

In 2009, Ballard et al reported the results of the Dementia Antipsychotic Reduction Trial (DART-AD) – a novel study performed among dementia patients in four different regions of the U.K.

At the time of entry into the study, all of the patients had been diagnosed with possible or probable Alzheimer’s disease, and all of them had consumed an antipsychotic drug for at least three months.

Mean duration of drug use: 25 months

The researchers randomly assigned 165 patients to two groups:  in one group, 83 patients were continued on antipsychotic drug therapy;  in the second group, 82 patients were switched to placebo (inert pill).

The investigators carefully monitored the patients for compliance with the new treatments.

Primary outcome:      1-year mortality

Researchers were able to compare outcomes (mortality and survival rates) over a follow-up period of 1 to 3 ½ years.

Regardless of the duration of follow-up, the highest mortality rates occurred among the chronic users of antipsychotics:  25% were dead within 1 year,

74% were dead within 3 ½ years.

In contrast, the cessation of antipsychotic drug therapy was associated with significantly higher rates of survival:  79% surviving at 1 year, 47% surviving after 3 ½ years.

The withdrawal of antipsychotic drug therapy from demented patients was associated with significantly higher rates of extended survival. 

In order to appreciate the effects of chemicals upon the human brain, it is important to understand the structure of that remarkable organ.  As a method of simplifying the anatomy for the non-scientist or layperson, it may be helpful to think about the brain in comparison to a Tootsie Roll Lollipop.  Just as the lollipop has three discrete sections (an outside candy coating, a chocolate center, and a stick), the human brain can be divided into three sections (shown above).

Historically, scientists have attributed different functions to these various brain zones:

cortex uniquely human functions of higher thought/planning/creating

subcortex animal functions (appetite, sex, emotions)

brainstem vegetative functions (asleep/awake, breathing, heart beat)

When the human brain is examined under a microscope,  it is possible to detect two basic types of cells.  These are known as neurons and glia.

Neurons (shown here in yellow) have traditionally been regarded as the key  actors which control brain activity.   In contrast, glia (shown above in black, gray, and tan) have traditionally been relegated to secondary roles, such as nourishment and infection response.  [Interestingly, these concepts are now overly simplistic and outdated].

For the purpose of this lecture, it will suffice to appreciate the fact that human behavior and intelligence depend upon the proper functioning and survival of neurons.  In fact, the death of neurons is a common feature of all disease processes which result in dementia.

Recall from slide #38 that 70% of all dementias in the U.S.A. are attributed to Alzheimer’s disease (AD).

These pictures show the locations of abnormal tissue in the human brain as Alzheimer’s disease begins (top) and progresses (bottom).

Top: pathology begins within the hippocampus of the temporal lobe

Bottom: in advanced disease, Alzheimer’s pathology extends well beyond the temporal lobe.   The hippocampus undergoes profound degeneration.  Fluid-filled spaces of the  brain (known as ventricles) become enlarged.

The defining features of Alzheimer’s disease include (but are not limited to):

1)abnormal deposits inside neurons (composed of a protein known as “tau”, these are sometimes referred to as neurofibrillary tangles]

2)

2)abnormal deposits outside neurons (composed of a protein known a

      beta-amyloid, these deposits are referred to as amyloid plaques)

1)

3)  the disintegration and death of neurons

This slide depicts Alzheimer’s abnormalities as they would appear through the

lens of a microscope.  The pink cells (top center, lower right) are neurons.  An

amyloid plaque can be seen in the lower left.  Tau tangles appear inside the

large neuron (dark blue).  Disintegrating cell parts (microtubules) appear in

white.

Because dementia is a syndrome which arises from many possible medical conditions, doctors must work methodically to identify the root cause of a patient’s cognitive and behavioral limitations.

Even though the structural features of Alzheimer’s disease have been recognized for many decades,  there remains no definitive way to confirm the presence of these changes in living patients.   Since brain samples (biopsies) are not generally obtained for this purpose -- due to the fact that brain surgery is invasive, expensive, and potentially hazardous – physicians render the diagnosis of Alzheimer’s by evaluating the quality and progression of symptoms, and by ruling out other potential causes of disablity.

Many researchers are now working to identify “biomarkers” which will permit the accurate determination of Alzheimer’s disease, based upon non-invasive tests of biological samples (blood, urine, cerebrospinal fluid) or via brain scan techniques.  For now, however, the gold standard for determining Alzheimer’s disease remains the postmortem examination of brain tissue – otherwise known as autopsy.

Historically, pathologists have devised a variety of chemical methods for preserving and examining brain tissue.   Accompanying these changes have been several revisions in the classification schemes (thresholds) used to decide if a specimen demonstrates “probable” vs. “definite” signs of
Alzheimer’s disease.

In light of the complexity of these revisions, there is a compelling record in the  medical literature which suggests a positive association between antipsychotic drugs and the appearance of Alzheimer’s pathology within the human brain.

 

If antipsychotic drugs are causally related to Alzheimer’s pathology, it would be important for medical doctors and researchers to discern which anatomic abnormalities they potentially induce.

It is in this context that a recent discovery in neuroscience is most pertinent.  Using electron microscopy to investigate the smallest components of brain cells, a team of investigators at the University of Pittsburgh (Desai et al, 2005)  identified apolipoprotein D as a core component within the beta-amyloid deposits (plaques) which distinguish Alzheimer’s disease.

In a postmortem investigation of psychiatric patients who had received treatment with various kinds of antipsychotic drugs, researchers evaluated the levels of apoD in two different regions of the brain.

Brain Region Tootsie Pop Equivalent

DLPFC = dorsolateral prefrontal cortex candy coating

caudate = region of the subcortex tootsie roll center

The study compared two groups of medicated subjects (20 diagnosed with schizophrenia, 8 diagnosed with bipolar disorder) and one group of mentally healthy controls.  75-90% of the psychiatric patients had received treatment with antipsychotic drugs, consisting of 1st generation drugs or clozapine.

When compared to drug-naive controls, patients exposed to antipsychotics had apoD levels that were two times higher in the cortical and subcortical zones of the brain.

Similar investigations have been performed in non-human animals.  In studies involving mice and rats, exposures to clinically relevant doses of antipsychotic drugs (olanzapine, risperidone, or clozapine) have resulted in higher protein levels of apoD in the cortical and subcortical regions of the brain.

To reiterate, the relevance of this finding pertains to the fact that apoD is a core component of the amyloid plaques which are found in Alzheimer’s disease.

Recall that one of the key features of Alzheimer’s disease and other diseases which cause dementia is the death and disintegration of brain cells.

The purpose of this slide is to call attention to the existence of more than a dozen early experiments in lab animals which were performed between the late 1950s and 1975.  Common to all of these investigations of drug effects were the discoveries that brief (2 week) and extended (up to 1 year) exposures to the first-generation antipsychotics resulted in diffuse damage throughout the brain.

Regrettably, textbooks of medicine and medical training programs have excluded this legacy.  For professionals and laypersons who are interested in this well concealed history, the publications of the Austrian neuropathologist, Dr. Kurt Jellinger, are invaluable.

The fact that the first-generation drugs were diffusely neurotoxic was not regarded as a problem when antipsychotics arrived on the market in the 1950s.  Ironically, the destructive capacity of these pharmaceuticals was initially celebrated as a necessary component of drug therapy, because psychiatrists mistakenly believed that psychosis could be “cured” via chemical lobotomy.

In this context, a recent series of publications prepared by scientists at the University of Pittsburgh have produced dramatic results.  Motivated by a desire to understand the cellular effects of lab techniques (do the sequential steps involved in the preparation or storage of brain tissue alter the tissue in any way), the investigators made several vital discoveries.

 

The experiment exposed 18 adult male macaques (4.5 to 5.3 years of age) to clinically relevant, oral doses of haloperidol (Haldol), olanzapine (Zyprexa), or placebo (sucrose pellets).

Animals received treatment for approximately 1.5 to 2 years.

Medications were administered once a day, in order to produce serum drug levels equivalent to those which occur in human patients at clinically recommended doses.

At the end of the experiment, the animals were sacrificed.  The brains of the medicated animals were compared to the brains of the drug-free controls.

Several important behavioral and anatomical effects were observed.

First, all of the animals appeared to develop an aversion to the taste and/or subjective effects of the medications.

Second, a significant number of monkeys became aggressive during the study

(2/3 of the olanzapine recipients, 1/3 of the haloperidol recipients).

Third, chronic exposure to haloperidol and olanzapine resulted in comparable and diffuse reductions in brain volume and brain weight.

Curious to know why the monkey brains had become progressively smaller in weight and volume, the Pittsburgh scientists conducted several follow-up investigations.

In the next studies, they performed meticulous inspections of brain tissue, focusing upon changes in the parietal lobe. 

Brain region Tootsie Roll lollipop equivalent

parietal lobe = cortical region candy coating

The slide above demonstrates the comparable region as it appears in the human brain.

Throughout the history of allopathic medicine, the diagnosis of many diseases has been based upon the characteristics of cells and chemicals collected from body fluids, such as venous blood (left), urine (top right: specimen jar), or cerebrospinal fluid (bottom right - spinal tap).  

The term “biomarker” refers to any chemical or cell component which can be measured before death, in order to provide an accurate signal that a disease is present.

What physicians desperately need at this time is an objective test to confirm the presence of dementia-causing conditions (such as Alzheimer’s, Parkinson’s, or Lewy body disease) prior to death, but without the need for surgical brain biopsy.

Researchers around the world have been working to establish an accurate but non-invasive test for the diagnosis of Alzheimer’s disease.   Several biomarkers have been suggested for this purpose, including spinal fluid levels of specific proteins (tissue transglutaminase and tau) and blood levels of apoD.

tTG = tissue tranglutaminase

an enzyme which cross-links proteins, including components of tangles and plaques.  Some scientists have speculated that tTG is a cause of, or marker for, programmed cell death.

tau = component of intracellular (neuronal) neurofibrillary tangles

apoD = component of compact beta-amyloid plaques

Neuroimaging techniques provide another tool for diagnosing dementia-related diseases in living subjects.

Various forms of equipment have been developed, all of which rely upon the properties of chemistry and physics to reproduce two-dimensional images of brain structures.  Within the field of neuropsychiatry, radioactive (CT,  PET, and SPECT) and non-radioactive (MRI, MRA) methods are commonly employed in order to track changes in the appearance of the brain.

Using MRI technology, scientists are able to discern the features of different components within the brain (e.g., white matter vs. gray matter, fluid vs. solid tissue).   The goal of anatomical studies is to take “snapshots” of the brain in order to identify normal or abnormal structures.  So-called “functional” brain scans (fMRI) compare changes in blood flow which accompany specific activities or states of mentation.

Over the past 20 years, numerous brain scan studies (CT and MRI) have evaluated the anatomy of patients following new exposures to antipsychotic drugs.

Without exception, study designs that have compared anatomical changes

“before” and “after” the use of these pharmaceuticals have revealed shrinkage of the brain under the influence of conventional (old) and/or newer (so-called “atypical”) drugs.

[That the drugs are the cause of these changes, rather than an underlying disease process, is strongly implied by the research involving animals.  Recall the University of Pittsburgh investigation, where monkeys exposed to Haldol or Zyprexa for 1 ½ to 2 years experienced a 10% reduction in brain volume and brain weight.]

Given the fact that antipsychotic drugs are no longer used only for psychosis (indeed, academic psychiatrists have been touting the drugs for control of aggression, irritability, and insomnia), and given the fact that their use in American children has increased *five-fold over the past two decades, one might reasonably expect that the toxicities of these drugs would become a central focus of concern and debate.

As far as this writer has been able to discern, however, neither the U.S. medical establishment, nor the various leaders of government, have seriously questioned the legitimacy of a national health policy which accepts and extends the use of antipsychotic drugs in preschoolers, children, and teens.

*from 0.2% of non-institutionalized youths in 1996-1997 to approximately 1% of non-institutionalized youths in 2004-2005

The previous point is well illustrated by the work of researchers affiliated with the National Institute of Mental Health and UCLA (University of California, Los Angeles).

Using a sophisticated neuroimaging technique known as 3-dimensional cortical mapping, the investigators performed a series of MRI brain scans in an effort to track changes in anatomy over time.  

Children received brain scans at entry into the study (baseline), and again at repeated intervals of approximately 2 and 5 years.

The study compared the neurodevelopment of three groups of children as they matured from the ages of 13.5 to 18 years.  

In this specific protocol, individual brain scan changes were “pooled” to create a database for each group.   Computer software was used to create colorful graphics which reflected shrinkage (atrophy) of the cortical surface of the brain.   [Recall the Tootsie Roll lollipop candy coating = cortical surface].

Group One:   12 children with Childhood Onset Schizophrenia --                        all of these children had histories of negative responses to at   least two conventional (first generation) antipsychotics

Group Two:   12 age-matched, gender-matched non-psychiatric controls

Group Three: 10 children with Psychosis Not Otherwise Specified --    these children displayed mood and/or behavioral problems but   never met the DSM criteria for schizophrenia; these children   had also failed at least 2 trials of first-generation drugs

When compared to the normal controls, the teenagers exposed to antipsychotic drugs experienced accelerated reductions in cortical surface area (2 to 3.5% per year).   The red zones (above, right) demonstrate the brain regions where gray matter loss was advanced.

Although normal teenagers also experienced some reduction in surface area (green), their rate of change was 2-3x less than the medicated children with schizophrenia, and was consistent with *expected (normal) development.

                          cortical gray matter loss per year

Schizophrenia         2 to 3.5% per year

Normal Controls         0.9 to 1.4% per year

•normal development = as neurons become myelinated during and beyond puberty, the ratios of white to gray matter increase; at the cortical surface, this results in the apparent “thinning” of gray matter

This slide depicts the progression of gray matter deficits (cortex) of the schizophrenia group over a period of five years.  Red and pink zones (frontal, parietal, and temporal lobes) show the greatest areas of shrinkage, relative to normal controls.

Although the researchers were quick to attribute these findings to the patients’ “underlying” condition (schizophrenia), it is important to appreciate the study design.   All of these teenagers had failed at least two previous trials of antipsychotics prior to the first brain scan.  In their publication, Thompson et al did not divulge details about the age-of-onset, duration, or doses of past pharmaceuticals.  Nevertheless, the fact that these exposures had occurred prior to age 14 makes it difficult to accept the researchers’ conclusion that the observed abnormalities were not the result of prepubertal exposures to neurotoxins.

In an attempt to discern which “brain abnormalities” might be attributable to schizophrenia (mental condition) rather than drug-treatment, the researchers compared changes in the Schizophrenia Group relative to a group of children with transient psychosis (Psychosis Not Otherwise Specified).

It is significant that the published paper by Thompson et al (PNAS, 2001)

reveals that 20% (2 of 10) of the Psychiatric Control Group remained

drug-free throughout the study.   However, the authors did not confirm that an equal number of patients in the Schizophrenia Group avoided antipsychotic drugs.

Thus, when the researchers discovered less severe deficits in the Psychiatric Controls after five years (7.5% reduction in frontal gray matter relative to normal children, versus 13% reduction for the Schizophrenia Group), it is far from clear that these between-group differences were due to different “underlying” mental illnesses.

This presentation has focused on four major themes.

I.Excluding chemicals which are used to treat addiction (e.g., Antabuse, methadone), there are five major classes of psychiatric drugs: antidepressants, antipsychotics, anti-anxiety (sedative/hypnotics), mood stabilizers, and stimulants.

II.Americans account for 5% of the world’s population yet they consume the majority of the world’s prescription drugs.  Even when taken precisely as recommended and prescribed, pharmaceuticals are the third leading cause of death in the U.S.A. each year.

III.Compared to mentally healthy individuals of the same age, patients who receive treatment within America’s public mental health system die 10 to 30 years earlier than expected; die in higher numbers each year; and experience higher rates and combinations of disabling medical conditions.

IV.Psychiatric drugs elevate the risks of early death and serious medical disease.  Evidence from animal experiments, human autopsies, brain scans, and biomarkers converge on the finding that antipsychotic drugs  – America’s top-selling drugs in 2009 – damage the brain by killing neurons. Recent evidence also suggests that antipsychotic drugs promote the defining features of Alzheimer’s disease.

I.