1	Psychiatric Drugs Training Lecture #1 Grace E. Jackson, MD (last revised: 7/18/10)
2	Outline of Lecture Major Classes of Psychiatric Drugs America’s Drug Problem III. Killing the Mentally Ill IV. Psychiatric Drug Toxicity
3	"I" I. Types of Psychiatric Drugs
4	5 Major Classes of Psych Drugs Antidepressants Antipsychotics Mood Stabilizers Sedative Hypnotics / Anxiolytics Stimulants
5	"II" II. America’s Drug Problem
6	Question #1
7	Question #1 Most Common Disease (point prevalence) asthma Alzheimer’s diabetes arthritis
8	Question #1 Most Common Disease d) arthritis þ
9	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%
10	Question #2
11	Question #2 Top Selling Drug Class in the U.S.A. cancer medicines insulin asthma inhalers antipsychotics
12	Question #2 Top Selling Drug Class in the U.S.A. d) antipsychotics þ
13	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
14	# 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
15	U.S. = 4.5 % of world population 90% of stimulant sales 63% of AP sales 51% of AD sales 41% of AED sales
16	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
17	Question #3
18	Question #3 Leading Cause of Death in the U.S.A. heart disease HIV/AIDS stroke cancer
19	"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
20	Question #3 Leading Cause of Death in the U.S.A. heart disease þ but . . . this is only part of the story…
21	Institute of Medicine (1999) 44,000 to 98,000 dead from errors
22	JAMA (2000) N ADVERSE EFFECTS N 106,000 inpatient deaths 199,000 outpatient deaths ---------------------------------- 305,000 deaths from Rx
23	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
24	"III" III. What’s Killing the Mentally Ill
25	Morbidity and Mortality in Public MH Patients [Sources: 2006 - Colton & Manderscheid & NASMHPD 13^th Technical Report] annual death rates SMI 1 - 3.5% non-SMI 0.5 - 0.8%
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27	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:
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29	Swedish SMR Trends
30	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
31	High Rate of Health Disorders SMI Compared to Non-SMI Groups Maine Medicaid – 2004
32	Burden of Medical Illness: Maine Medicaid 2004
33	"IV" IV. Psychiatric Drug Toxicity
34	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
35	Dementia defined: From Latin de mens / de mentis out of (away from) one’s mind
36	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
37	"≥ 65 with dementia" ≥ 65 with dementia 2.3% in 2000 è 4.5% in 2040 7.6 million 18.3 million
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39	≥ 65 years of age 12% to 18% to 21%
40	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…”
41	A perfect crime…
42	Antipsychotic Timeline timeline = year that the drug was invented or first used 1^st generation drugs 1950 to 1960s Thorazine, Haldol, Clozaril 2^nd generation drugs 1970 to 1990s Risperdal, Zyprexa, Seroquel, Geodon 3^rd 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.
43	U.S. Drug Sales – 2009 ($ billions) 9.9
44	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
45	"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
46	"Other folks started to notice..." Other folks started to notice the same trend in different patients…
47	Black Box Warnings “not for dementia-related psychosis”
48	"In England" In England, some physicians began to wonder --- what would happen to dementia patients if they stopped taking antipsychotic drugs ?
49	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
50	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
51	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
52	Antipsychotic drugs are deadly for dementia patients… what about giving them to the non-demented ?
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57	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
58	Postmortem Pathology
59	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…
60	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
61	"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
62	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
63	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 (1^st generation and clozapine)
64	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)
65	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)
66	University of Pittsburgh (2005, 2007, 2008) Do lab techniques (specimen processing) affect the structure of the brain? As an aside: What about drugs?
67	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
68	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
69	f/u Studies of Parietal Lobe
70	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%
71	Biomarkers in Humans
72	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
73	Neuroimaging (brain scans)
74	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
75	What about children ?
76	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)
77	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.
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79	Gray Matter Loss Due to “Disease” Thompson et al (2001) – multiple scans of teens (aged 13.9 to 18.6) UCLA & NIMH
80	Reduced Exposure to APs no gray matter deficit in temporal lobe
81	Recap of Lecture Major Classes of Psychiatric Drugs America’s Drug Problem III. Killing the Mentally Ill IV. Psychiatric Drug Toxicity