Psychiatric Drugs
|
|
|
Training Lecture #1 |
|
Grace E. Jackson, MD |
|
|
|
|
|
(last revised: 7/18/10) |
|
|
|
|
Outline of Lecture
|
|
|
|
|
|
|
Major Classes of Psychiatric
Drugs |
|
America’s Drug Problem |
|
III. Killing the Mentally Ill |
|
IV. Psychiatric Drug Toxicity |
"I"
|
|
|
|
|
|
|
|
|
I. Types of Psychiatric Drugs |
|
|
5 Major Classes of Psych
Drugs
|
|
|
Antidepressants |
|
Antipsychotics |
|
Mood Stabilizers |
|
Sedative Hypnotics /
Anxiolytics |
|
Stimulants |
"II"
|
|
|
|
|
|
|
II. America’s Drug Problem |
Question #1
Question #1
Most Common Disease (point prevalence)
|
|
|
|
|
asthma |
|
Alzheimer’s |
|
diabetes |
|
arthritis |
|
|
|
|
Question #1
Most Common Disease
Somatic vs.
Psychiatric
Lifetime Prevalence - USA
|
|
|
depression 16% |
|
specific phobia 9% |
|
ADHD 5% |
|
PTSD 3.5% |
|
bipolar 3% |
|
panic 3% |
|
OCD 1% |
|
schizophrenia
1% |
|
|
|
|
|
cancer 30-50% |
|
arthritis ~ 20% |
|
asthma 12% |
|
diabetes 9% |
|
MI/angina 7% |
|
stroke 3% |
|
epilepsy 3% |
|
dementia 2% |
|
|
Question #2
Question #2
Top Selling Drug Class in the U.S.A.
|
|
|
|
|
cancer medicines |
|
insulin |
|
asthma inhalers |
|
antipsychotics |
|
|
Question #2
Top Selling Drug Class in the U.S.A.
U.S. Drug Sales 2009
[IMS Health]
|
|
|
Total Drug Sales 300.3
billion |
|
|
|
APs #1 14.6 billion |
|
lipid #2 14.3 billion |
|
PPI #3 13.6 billion |
|
ADs #4
9.9 billion |
|
insulin #9 6.3 billion |
|
stimulants #11 5.8 billion |
|
seizure
#13 5.3 billion |
|
|
|
APs = antipsychotics |
|
ADs = antidepressants |
# of U.S. Prescriptions -
2009
[IMS Health]
|
|
|
Total Prescriptions 3.9 billion |
|
|
|
lipid #1 210.5 million |
|
codeine #2 200.2 million |
|
ADs #3 168.7 million |
|
ACEi #4 162.8 million |
|
AEDs #7 104.5 million |
|
benzos #11
87.9 million |
|
arthritis #13
77.9 million |
U.S. = 4.5 % of world
population
|
|
|
|
|
90% of stimulant sales |
|
63% of AP sales |
|
51% of AD sales |
|
41% of AED sales |
|
|
U.S.A.: Psychiatric Drugs 2009
[Source: Express Scripts 2009 Drug Trend Report]
|
|
|
|
|
|
|
|
|
|
|
antidepressants 9.9% 31,000,000 |
|
anticonvulsants 4.0% 12,300,000 |
|
stimulants 2.2% 6,754,000 |
|
*antipsychotics 1.8%
5,526,000 |
|
|
|
|
|
*part of Express Scripts’
“mental/neurological” class: |
|
includes lithium, dementia drugs, sub. abuse |
Question #3
Question #3
Leading Cause of Death in the U.S.A.
|
|
|
|
|
heart disease |
|
HIV/AIDS |
|
stroke |
|
cancer |
|
|
|
|
"1"
|
|
|
|
|
|
|
1) cardiac disease |
|
2) cancer |
|
3) stroke |
|
4) chronic lower respiratory |
|
5) accidents (unintentional
injuries) |
|
6) Alzheimer’s disease |
|
7) diabetes mellitus |
|
8) influenza and pneumonia |
|
9) kidney disease |
|
10) septicemia |
|
|
Question #3
Leading Cause of Death in the U.S.A.
|
|
|
|
|
heart disease þ |
|
|
|
|
|
|
|
|
|
but . . . this is only part of
the story… |
|
|
|
|
Institute of Medicine
(1999)
44,000 to 98,000 dead from errors
JAMA (2000)
|
|
|
N ADVERSE EFFECTS N |
|
|
|
106,000 inpatient deaths |
|
199,000 outpatient deaths |
|
---------------------------------- |
|
305,000 deaths from Rx |
|
|
|
|
|
|
|
|
Reality Check: # of deaths (2006)
|
|
|
1. cardiac disease 629,191 |
|
2. cancer 560.102 |
|
3. adverse drug reactions 305,000 |
|
4. stroke 137,265 |
|
5. accidents 124,614 |
|
6. medical errors 98,000 |
|
7. Alzheimer’s disease 73,177 |
|
8. diabetes mellitus 72,507 |
|
9. flu & pneumonia 56,247 |
|
10. septicemia 44,791 |
|
|
"III"
|
|
|
|
|
|
|
III. What’s Killing the Mentally Ill |
Morbidity and Mortality in Public MH Patients
[Sources: 2006 - Colton & Manderscheid &
NASMHPD 13th Technical Report]
|
|
|
annual death rates |
|
SMI
1 - 3.5% |
|
non-SMI
0.5 - 0.8% |
Slide 26
Causes of death
1997-2000…
|
|
|
non-SMI % of deaths |
|
|
|
|
|
cardiac 21-30% |
|
cancer 18-22% |
|
stroke 5% |
|
chronic respiratory 2-4% |
|
diabetes 2% |
|
suicide 0.3-1% |
|
|
|
|
|
dementia |
|
SMI % of deaths |
|
|
|
|
|
cardiac 17-31% |
|
cancer 5-10% |
|
suicide 5-9% |
|
chronic respiratory 4-5% |
|
stroke 2-5% |
|
diabetes 1-3% |
|
|
|
|
|
Missing from the discussion: |
|
|
Slide 28
Swedish SMR Trends
Public MH patients = 5.9
million per year
|
|
|
Compared to non-SMI, those with
SMI: |
|
|
|
|
|
die in greater numbers each year |
|
die earlier than expected |
|
experience more illnesses than non-SMI |
High Rate of Health
Disorders
SMI Compared to Non-SMI Groups
Maine Medicaid – 2004
Burden of Medical
Illness:
Maine Medicaid 2004
"IV"
|
|
|
|
|
|
|
|
|
IV. Psychiatric Drug Toxicity |
Psychiatric Drugs á the Odds of Disease
|
|
|
AD AP |
|
á 1.4-2x á 2-3x |
|
unclear á 1.2-7x |
|
á 1.6x á 1.9x |
|
á 2-15x unclear |
|
á 1.3-1.6x á 1.4-6x |
|
á 2-5x á 2-14x |
|
Risk of heart disease |
|
Risk of diabetes |
|
Risk of pneumonia |
|
Risk of suicidality |
|
Risk of stroke |
|
Risk of dementia |
Dementia defined:
|
|
|
From Latin de mens / de mentis |
|
|
|
|
|
out of (away from) one’s mind |
|
|
|
|
|
|
Features of Dementia
|
|
|
|
Memory impairment |
|
Aphasia (impaired language) |
|
Apraxia (impaired ability to carry out motor
activities) |
|
Agnosia (failure to recognize objects) |
|
Executive functioning deficits |
|
planning, organizing,
sequencing, abstracting |
"≥ 65 with
dementia"
|
|
|
≥ 65 with dementia |
|
|
|
2.3% in 2000 è 4.5% in 2040 |
|
7.6 million 18.3 million |
Slide 38
≥ 65 years of
age
12% to 18% to 21%
Drug-Induced Dementia
|
|
|
DSM-IV, Text Revision (2000) |
|
Substance-Induced Persisting
Dementia |
|
|
|
“Features are those associated
with |
|
dementias generally…can occur
in |
|
association with…alcohol,
sedatives, |
|
hypnotics and anxiolytics, or
other or |
|
unknown substances…” |
A perfect crime…
Antipsychotic Timeline
|
|
|
*timeline = year that the drug was invented or first
used |
|
|
|
1st generation
drugs 1950 to 1960s |
|
Thorazine, Haldol, *Clozaril |
|
2nd generation
drugs 1970 to 1990s |
|
Risperdal, Zyprexa, Seroquel,
Geodon |
|
3rd generation
drugs 2000 to 2010 |
|
Abilify |
|
|
|
*Invented in 1958, clozapine
was introduced in Europe in the early |
|
1960s. It did not gain FDA approval in the U.S.A.
until 1989. Partly for this |
|
reason, American physicians
refer to it as a “second generation” drug. |
|
|
|
|
|
|
|
|
|
|
U.S. Drug Sales – 2009 ($
billions)
Dept. of Veterans
Affairs
Kales et al (2007)
|
|
|
23,436 patients (national
database) |
|
|
|
≥ 65 years of age |
|
|
|
diagnosis of dementia in 2002
or 2003 |
|
|
|
12-month mortality risk after
starting a |
|
psychiatric drug |
|
|
"12,821 avoided
psychiatric drugs"
|
|
|
|
|
12,821 avoided psychiatric
drugs |
|
18% died within one year |
|
|
|
10,615 started psychiatric
drugs |
|
23% using newer APs died |
|
25% using old
(“conventional”) APs died |
|
29% using both kinds of APs died |
|
|
"Other folks started
to notice..."
|
|
|
|
|
Other folks started to notice
the same |
|
trend in different patients… |
|
|
Black Box
Warnings
“not for dementia-related psychosis”
"In England"
|
|
|
|
|
In England, some physicians
began to |
|
wonder --- |
|
|
|
what would happen to dementia
patients |
|
if they stopped taking
antipsychotic drugs ? |
|
|
|
|
|
|
U.K. - DART-AD
Dementia AP Reduction Trial
|
|
|
Enrolled residents of nursing
or residential homes in four |
|
areas (2001-2004); followed
patients to April 2006 |
|
|
|
All patients had been diagnosed
with possible or |
|
probable Alzheimer’s and all
had taken APs for |
|
≥ 3 months (APs =
risperidone, thioridazine, haloperidol, |
|
trifluoperazine, or chlorpromazine) |
|
|
|
Mean duration of drug use: 25
months |
|
|
DART-AD
Ballard et al (2009)
|
|
|
165 patients were randomly assigned to |
|
antipsychotic (83) or placebo
(82) |
|
|
|
Assessed patients according to treatment |
|
fidelity (compliance) and
outcome… |
|
|
|
Primary outcome: 12-month mortality |
|
|
|
|
Outcomes Based Upon
Continuing
Use of Drugs vs. Placebo
|
|
|
APs PBO |
|
% surviving |
|
1 year 75% 79% |
|
2 year 46% 71% |
|
3 year 30% 59% |
|
3 ½ years 26% 53% |
|
|
|
|
|
APs = antipsychotic drugs |
|
PBO = placebo |
Antipsychotic drugs are
deadly for
dementia patients…
|
|
|
what about giving them to the
non-demented ? |
|
|
|
|
|
|
Slide 53
Slide 54
Slide 55
Slide 56
How Do Doctors Diagnose
Alzheimer’s Disease?
|
|
|
No way to know for sure while a
patient is |
|
still living… |
|
|
|
look at symptoms and how they
evolve |
|
“biomarkers” are in development |
|
3) gold standard = autopsy pathology |
|
|
Postmortem Pathology
Do Antipsychotic Drugs
Cause Alzheimer’s Disease ?
|
|
|
|
|
If they do, we should expect to
see evidence |
|
of Alzheimer’s pathology
(abnormal |
|
anatomy) among patients who
have |
|
received antipsychotic drugs… |
|
|
Postmortem Studies of
Humans
|
|
|
|
1988 Buhl and Bojsen-Moller –
100 patients (consecutive autopsies) |
|
schizophrenia 35% Alz.
pathology |
|
non-psych controls 0% Alz. pathology |
|
|
|
|
|
Soustek – 225 pts with chronic schizophrenia
(dying in 1975-85) |
|
41% showed Alz. pathology |
|
6x higher rate than general
population |
|
|
|
1994 Wisniewski – 102 patients
with history of schizophrenia |
|
41 died prior to antipsychotic
era 46% had tangles |
|
62 died after antipsychotic
era 74% had tangles |
|
|
"2002 Bozikas – 18
schizophrenia..."
|
|
|
2002 Bozikas – 18 schizophrenia
patients vs. 14 age-matched controls |
|
patients had 400% á tangle density in cortex (layer II of EC) |
|
patients had á plaque density
(throughout the brain) |
|
|
|
2005 Ballard et al – studied 40
patients with Lewy body dementia |
|
23 patients avoided
antipsychotic drugs |
|
17 patients received
antipsychotics |
|
when compared to the other
patients, the 17 drug-consumers exhibited: |
|
30% higher density of cortical plaques |
|
65-367% higher density of tangles |
|
|
|
|
apoD is marker of
neuropathology
|
|
|
University of Pittsburgh (Desai et al,
2005) |
|
|
|
apoD is key a feature of Alzheimer’s
disease |
|
63% of the beta-amyloid plaques contained
apoD |
|
|
Thomas et al (2001)
autopsy study of brain levels of apoD (ug/mg)
|
|
|
|
|
|
|
|
|
schiz bipolar controls |
|
n=20 n=8
n=19 |
|
% using APs 90% (18) 75% (6) 0 |
|
|
|
DLPFC 0.244 0.233 0.115 |
|
caudate 0.132 0.112 0.059 |
|
|
|
|
|
|
|
|
|
|
|
|
|
apoD levels were 2X higher in users of
APs |
|
|
|
|
|
|
|
|
|
APs = antipsychotic drugs (1st
generation and clozapine) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
apoD in Animals
|
|
|
mice and rats (multiple
investigations) >> |
|
|
|
14 to 45 days of OLZ, RISP, or
CLZ |
|
|
|
all three drugs resulted in
higher mRNA and |
|
higher protein levels of apoD
in cortical and |
|
subcortical regions of brain |
|
|
|
mRNA = messenger RNA (a
molecular precursor for protein synthesis) |
|
|
|
|
Other Postmortem Studies
rabbits, rats, monkeys, guinea pigs
|
|
|
1958 – 1975 |
|
|
|
all showed damage to |
|
cortex, subcortex, and |
|
brainstem following |
|
brief (2 wks) or chronic |
|
exposure (up to 1 yr) |
University of Pittsburgh
(2005, 2007, 2008)
|
|
|
|
|
Do lab techniques |
|
(specimen processing) |
|
affect the structure of |
|
the brain? |
|
|
|
As an aside: |
|
What about drugs? |
Experiment
|
|
|
18 adult male macaques (4.5 to
5.3 yrs old) |
|
|
|
oral doses of haloperidol or
placebo (27 months) |
|
oral doses of olanzapine (17 months) |
|
|
|
relevant doses of drugs
vis-à-vis human therapy |
|
1-1.5 ng/mL for HAL |
|
10-25 ng/mL for OLZ |
|
|
Changes in Behavior and
Brain
|
|
|
4 of 6 monkeys on OLZ >>
aggressive |
|
2 of 6 monkeys on HAL >>
aggressive |
|
|
|
atrophy of cortex/cerebellum/brainstem |
|
|
|
HAL 9% lower volume of brain |
|
9% decreased brain weight |
|
|
|
OLZ 10.5% lower volume of
brain |
|
11% decreased brain weight |
|
|
|
|
f/u Studies of Parietal
Lobe
Parietal Lobe Cell Loss
|
|
|
Reductions in Cell Number After Drug
Treatment |
|
haloperidol olanzapine |
|
|
|
total cells 10.6%
7.4% |
|
neurons 6.3% 5.5% |
|
oligodendrocytes 13.9% 11.8% |
|
astrocytes 20.4% 20.5% |
Biomarkers in Humans
Old and new
antipsychotics
all increase Alzheimer’s proteins…
|
|
|
Protein changes in
antipsychotic recipients, |
|
relative to drug-free controls: |
|
|
|
source biomarker change |
|
Austria 2005 (CSF)
tTG ↑ 200-400% |
|
Italy 2005
(CSF) tau ↑ 24% |
|
USA 2002
(blood) apoD ↑ 58% |
|
|
|
|
|
CSF = cerebrospinal fluid |
|
|
|
|
Neuroimaging
(brain scans)
Numerous studies…
|
|
|
|
|
Without exception, “before and
after” |
|
brain scans have revealed
shrinkage |
|
(atrophy) of the brain under
the influence of |
|
old or new antipsychotic drugs |
|
|
|
|
|
In some cases, patients have
experienced |
|
a 4-9% reduction in volume in
< 3 years |
|
|
|
|
|
|
|
|
|
|
What about children ?
NIMH / UCLA study
child onset schizophrenia
|
|
|
|
|
Using sophisticated
neuroimaging methods (3D “cortical mapping”), longitudinal studies were
performed on three groups of adolescents |
|
|
|
Goal: check changes in brain
anatomy |
|
over time (baseline, 2.3 years,
4.6 years) |
|
|
Multiple brain scans >
age 13.5 to 18
|
|
|
Study Design: |
|
12 children with Childhood
Onset Schizophrenia |
|
(onset of symptoms before age
12) |
|
all had histories of poor
response to / intolerance |
|
of at least two typical
antipsychotic |
|
|
|
10 children with transient
psychosis |
|
mood and behavioral problems |
|
|
|
12 age & gender
matched “normal” controls |
|
|
|
Psychiatric patients received
treatment with the following antipsychotic |
|
drugs: risperidone, olanzapine, or clozapine. |
Slide 78
Gray Matter Loss Due to “Disease”
Thompson et al (2001) – multiple scans of teens (aged 13.9 to 18.6)
UCLA & NIMH
Reduced Exposure to
APs
no gray matter deficit in temporal lobe
Recap of Lecture
|
|
|
|
|
|
|
Major Classes of Psychiatric
Drugs |
|
America’s Drug Problem |
|
III. Killing the Mentally Ill |
|
IV. Psychiatric Drug Toxicity |