John J. Miller, M.D. November 2013 Brain Health – Exeter, NH 1 Psychiatry, Medications and the Brain: Past, Present and Future Psychiatry, Medications and the Brain: Past, Present and Future John J. Miller, M.D. Medical Director, Brain Health Staff Psychiatrist, Seacoast Mental Health Center Consultant, Exeter Hospital Exeter, NH Consultant, Insight Meditation Society Barre, MA John J. Miller, M.D. Medical Director, Brain Health Staff Psychiatrist, Seacoast Mental Health Center Consultant, Exeter Hospital Exeter, NH Consultant, Insight Meditation Society Barre, MA OBJECTIVES OBJECTIVES • Briefly review the history of psychiatric medication discovery and our earliest psychiatric medications. • Review and appreciate the impressive tool box of psychiatric medications that are currently FDA approved, with a focus on antipsychotics, mood stabilizers and antidepressants. • Understand the basic mechanism of action of some of our current commonly prescribed psychiatric medications. • Discuss some of the possible future psychiatric drugs currently in development by the pharmaceutical industry. • Briefly review the history of psychiatric medication discovery and our earliest psychiatric medications. • Review and appreciate the impressive tool box of psychiatric medications that are currently FDA approved, with a focus on antipsychotics, mood stabilizers and antidepressants. • Understand the basic mechanism of action of some of our current commonly prescribed psychiatric medications. • Discuss some of the possible future psychiatric drugs currently in development by the pharmaceutical industry.
31
Embed
Psychiatry, Medications and the Brain-Nov-4-2011.ppt · Psychiatry, Medications and the Brain: Past, ... • Discuss some of the possible future psychiatric drugs ... 80% Antipsychotic/antimanic
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 1
Psychiatry, Medications and the Brain:Past, Present and Future
Psychiatry, Medications and the Brain:Past, Present and Future
John J. Miller, M.D.
Medical Director, Brain Health
Staff Psychiatrist, Seacoast Mental Health Center
Consultant, Exeter Hospital
Exeter, NH
Consultant, Insight Meditation Society
Barre, MA
John J. Miller, M.D.
Medical Director, Brain Health
Staff Psychiatrist, Seacoast Mental Health Center
Consultant, Exeter Hospital
Exeter, NH
Consultant, Insight Meditation Society
Barre, MA
OBJECTIVESOBJECTIVES
• Briefly review the history of psychiatric medicationdiscovery and our earliest psychiatric medications.
• Review and appreciate the impressive tool box ofpsychiatric medications that are currently FDAapproved, with a focus on antipsychotics, moodstabilizers and antidepressants.
• Understand the basic mechanism of action of some ofour current commonly prescribed psychiatricmedications.
• Discuss some of the possible future psychiatric drugscurrently in development by the pharmaceuticalindustry.
• Briefly review the history of psychiatric medicationdiscovery and our earliest psychiatric medications.
• Review and appreciate the impressive tool box ofpsychiatric medications that are currently FDAapproved, with a focus on antipsychotics, moodstabilizers and antidepressants.
• Understand the basic mechanism of action of some ofour current commonly prescribed psychiatricmedications.
• Discuss some of the possible future psychiatric drugscurrently in development by the pharmaceuticalindustry.
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 2
The “Black Box”The “Black Box”
Hi!! I’m your brain. I’m ablack box and nobodyunderstands me.
Circa 1980sCirca 1980s
The Wiring of the BrainThe Wiring of the Brain
• There are approximately 100 billion neurons in thehuman brain
• There are on average 1,000 synapses/neuron
• Hence, there are approximately 100 trillion synapses inthe human brain
• There are approximately 100 billion neurons in thehuman brain
• There are on average 1,000 synapses/neuron
• Hence, there are approximately 100 trillion synapses inthe human brain
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 3
The history of psychiatric drugdiscovery and our earliestpsychiatric medications:
a case of serendipity
The history of psychiatric drugdiscovery and our earliestpsychiatric medications:
• Antipsychotic efficacy discovered by a Frenchphysician in 1952 who observed that agitatedpsychotic patients with nausea, had theirnausea, agitation and psychosis improve withchlorpromazine.
• Shifted the focus of treatment to the “positivesymptoms” of schizophrenia.
• Chlorpromazine (Thorazine) – FDA approved1954
• Antipsychotic efficacy discovered by a Frenchphysician in 1952 who observed that agitatedpsychotic patients with nausea, had theirnausea, agitation and psychosis improve withchlorpromazine.
• Shifted the focus of treatment to the “positivesymptoms” of schizophrenia.
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 4
Introduction of Chlorpromazine(Thorazine) to the United StatesIntroduction of Chlorpromazine(Thorazine) to the United States
• ECT (electroconvulsive therapy)
• Psychosurgery
• Insulin shock therapy
• Provided a treatment which facilitated thedeinstitutionalization movement
• ECT (electroconvulsive therapy)
• Psychosurgery
• Insulin shock therapy
• Provided a treatment which facilitated thedeinstitutionalization movement
Significantly decreased use of:Significantly decreased use of:
Consequence of the introduction ofChlorpromazine to the US MarketConsequence of the introduction ofChlorpromazine to the US Market
McKenzie, James F.; Pinger, R. R.; Kotecki, Jerome Edward (2008). Anintroduction to community health. Boston: Jones and Bartlett PublishersMcKenzie, James F.; Pinger, R. R.; Kotecki, Jerome Edward (2008). Anintroduction to community health. Boston: Jones and Bartlett Publishers
Year# of in-patients in state and
county psychiatric hospitals inthe USA
1955 558,922
1970 337,619
1980 150,000
1990 115,000
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 5
October 31, 1963 President John F. Kennedy signedthe Community Mental Health Act into law.
“The time has come for a bold new approach, … If weapply our medical knowledge and social insights fully, all
but a small portion of the mentally ill can eventually achievea wholesome and constructive social adjustment.”
October 31, 1963 President John F. Kennedy signedthe Community Mental Health Act into law.
“The time has come for a bold new approach, … If weapply our medical knowledge and social insights fully, all
but a small portion of the mentally ill can eventually achievea wholesome and constructive social adjustment.”
“Typical” versus “Atypical”“Typical” versus “Atypical”
Medications from Thorazine to pre-Clozaril (1989)are all classified as “Typical”.
These medications block the Dopamine-2 receptortighter than the Serotonin 5HT-2A receptor.
Medications from Thorazine to pre-Clozaril (1989)are all classified as “Typical”.
These medications block the Dopamine-2 receptortighter than the Serotonin 5HT-2A receptor.
AntipsychoticsAntipsychotics
“Typical” versus “Atypical”“Typical” versus “Atypical”
Medications from Clozapine (1989) to Latuda (2011)are all classified as “Atypical”.
These medications block the Serotonin 5HT-2Areceptor tighter than the Dopamine-2 receptor, withthe exception of Abilify which has an entirelydifferent mechanism of action (antagonist-partialagonist at Dopamine D-2).
Medications from Clozapine (1989) to Latuda (2011)are all classified as “Atypical”.
These medications block the Serotonin 5HT-2Areceptor tighter than the Dopamine-2 receptor, withthe exception of Abilify which has an entirelydifferent mechanism of action (antagonist-partialagonist at Dopamine D-2).
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 9
Antipsychotics - TypicalAntipsychotics - Typical
• Thorazine
• Serentil
• Mellaril
• Loxitane
• Moban
• Orap
• Thorazine
• Serentil
• Mellaril
• Loxitane
• Moban
• Orap
• Trilafon
• Stelazine
• Navane
• Haldol
• Prolixin
• Trilafon
• Stelazine
• Navane
• Haldol
• Prolixin
(Incomplete list)(Incomplete list)
Antipsychotics – Atypical(in the order of market entry)
Antipsychotics – Atypical(in the order of market entry)
• Clozaril
• Risperdal
• Zyprexa
• Seroquel
• Geodon
• Clozaril
• Risperdal
• Zyprexa
• Seroquel
• Geodon
• Abilify
• Invega
• Fanapt
• Saphris
• Latuda
• Abilify
• Invega
• Fanapt
• Saphris
• Latuda
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 10
*Roth BL, Sheffler DJ and Kroeze WK. Nat Rev Drug Discov. 2004 Apr;3(4):353-9
53receptors
Medications for Bipolar DisorderMedications for Bipolar Disorder
Simple salt Anticonvulsants Antipsychotics
Lithium Depakote Typical
Tegretol(Equetro)
Atypical
Lamictal
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 11
Agents Approved forBipolar Disorder in the U.S.
Agents Approved forBipolar Disorder in the U.S.
Acute Mania
Year Drug
1970 Lithium
1973 Chlorpromazine
1994 Divalproex
2000 Olanzapine*
2003 Risperidone*
2004 Quetiapine*
2004 Ziprasidone
2004 Aripiprazole
2004 Carbamazepine
2009 Asenapine
Acute Mania
Year Drug
1970 Lithium
1973 Chlorpromazine
1994 Divalproex
2000 Olanzapine*
2003 Risperidone*
2004 Quetiapine*
2004 Ziprasidone
2004 Aripiprazole
2004 Carbamazepine
2009 Asenapine
Acute Depression
Year Drug
2003 Olanzapine-
fluoxetine
combination
2006 Quetiapine
2013 Lurasidone
Acute Depression
Year Drug
2003 Olanzapine-
fluoxetine
combination
2006 Quetiapine
2013 Lurasidone
FDA-Approved Medicationfor treating Bipolar I ManiaFDA-Approved Medicationfor treating Bipolar I Mania
Affective and Psychotic Disorders:Three important monoamine
neurotramsmitters
Affective and Psychotic Disorders:Three important monoamine
neurotramsmitters
• Serotonin
• Dopamine
• Norepinephrine
• Serotonin
• Dopamine
• Norepinephrine
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 16
Current pharmacological agentsfor the treatment of schizophreniaCurrent pharmacological agents
for the treatment of schizophrenia
• All FDA approved medications that treatthe postitive symptoms of schizophreniashare the property of blocking thedopamine D-2 receptor.
• All FDA approved medications that treatthe postitive symptoms of schizophreniashare the property of blocking thedopamine D-2 receptor.
Receptor –EndogenousNeurotransmitter
Cell Membrane
Intra-cellular
Extra-cellular
Target receptor
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 17
Receptor Antagonist
Cell Membrane
Intra-cellular
Extra-cellular
Target receptorX
Receptor –Agonist
Cell Membrane
Intra-cellular
Extra-cellular
Target receptor
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 18
ReceptorAntagonist/Partial Agonist
Cell Membrane
Intra-cellular
Extra-cellular
Target receptor
hypothalamus
d
c
Nucleusaccumbens
Tegmentum
bSubstantianigra
BasalGanglia
a
DOPAMINE PATHWAYSDOPAMINE PATHWAYS
Stahl S. Essential Psychopharmacology. Second Edition. 2000; 375.Stahl S. Essential Psychopharmacology. Second Edition. 2000; 375.
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 19
Adapted from: Stahl S. Essential Psychopharmacology. Second Edition. 2000; 403-407.Adapted from: Stahl S. Essential Psychopharmacology. Second Edition. 2000; 403-407.
Consequences of D-2 antagonism at the 4 dopamine circuitsConsequences of D-2 antagonism at the 4 dopamine circuits
ExtrapyramidalSymptoms
Decreasedpsychosis
Cognitive dysfunction&
Worsening negativesymptoms
Prolactinelevation
Consequences of increasingoccupancy of D-2 receptorsConsequences of increasingoccupancy of D-2 receptors
% Occupancy of D-2
receptors
Clinical Consequences
< 60% minimal
60 – 80% Antipsychotic/antimanic
> 70% Elevation of prolactin
> 80% Increasing EPS
Kapur S. Mol Psychiatry. 1998 Mar; 3(2):135-40.Tauscher J, et al. Psychopharmacology. 2002 Jun; 162(1):42-9.Grunder G, et al. Arch Gen Psychiatry. 2003 Oct; 60(10):974-7.Seeman P. Can J Psychiatry. 2002 Feb; 47(1):27-38.
Kapur S. Mol Psychiatry. 1998 Mar; 3(2):135-40.Tauscher J, et al. Psychopharmacology. 2002 Jun; 162(1):42-9.Grunder G, et al. Arch Gen Psychiatry. 2003 Oct; 60(10):974-7.Seeman P. Can J Psychiatry. 2002 Feb; 47(1):27-38.
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 20
Social andOccupationalDysfunction
Social andOccupationalDysfunction
Negative Symptoms:Flat affect
Social withdrawalEmotional withdrawal
Symptoms of schizophreniaSymptoms of schizophrenia
Black DW et al. Introductory Textbook of Psychiatry. 2001;204-228.Siris SG. Schizophrenia. 1995;128-145.Harvey PD et al. Am J Psych. 2001;158:176-184.Stahl SM. Essential Psychopharmacology. 2nd ed. 2000;385-386.
Black DW et al. Introductory Textbook of Psychiatry. 2001;204-228.Siris SG. Schizophrenia. 1995;128-145.Harvey PD et al. Am J Psych. 2001;158:176-184.Stahl SM. Essential Psychopharmacology. 2nd ed. 2000;385-386.
Mood Disturbances:Dysphoria
Depression
Cognitive Changes:AttentionMemory
Executive functioningDecision making
Positive Symptoms:Delusions
HallucinationsUnusual behavior
Animal models of schizophreniaAnimal models of schizophrenia
• NMDA-glutamate antagonists induceboth positive and negative schizophrenia-like symptoms in animal models:
– Ketamine
– Phencyclidine (PCP)
• NMDA-glutamate antagonists induceboth positive and negative schizophrenia-like symptoms in animal models:
– Ketamine
– Phencyclidine (PCP)
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 21
Cell Membrane
Intra-cellular
Extra-cellular
NMDA-glutamateion channel
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ + + + + + + + + + + + + + + + +
Mg Mg
Mg = magnesium (2+)
Ca = calcium (2+)
Na = sodium (1+)
K = potassium (1+)
- Glutamate binding site
- Glycine binding site
Cl = chloride (1-)
K Cl K K Cl Cl K Cl Cl K Cl K CL Cl K Cl K Cl K Cl Cl
Na Na Na Ca Na Ca NaNa Na Na Ca Na
Ca Ca CaNa Na
Influx of postitive chargewill depolarize the neuron -resulting in an action potential
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 22
Cell Membrane
Intra-cellular
Extra-cellular
NMDA-glutamateion channel
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ + + + + + + + + + + + + +
Ca Ca Ca
Mg Mg
AMPA-glutamateIon channel
Ca Ca Ca
Glycine Neuron
Ca CaCa Ca
MajorDepolarization
MinorDepolarization
MgMg
Cell Membrane
Intra-cellular
Extra-cellular
GABA-A chloride ion channel(heteropentameric glycoprotein)
Where do we go from here?Where do we go from here?
The evolving drug pipeline withnew mechanisms of action
The evolving drug pipeline withnew mechanisms of action
Glutamate modulatorsGlutamate modulators
• Drugs that fine tune the glutamate system showeffectiveness in treating the psychotic symptoms ofschizophrenia as well as our current dopaminereceptor blockers, but without the dopamine sideeffects on the muscles, cognition and prolactin.
• Ketamine and ketamine analogues seem highlyeffective in treating refractory depression.
• Drugs that fine tune the glutamate system showeffectiveness in treating the psychotic symptoms ofschizophrenia as well as our current dopaminereceptor blockers, but without the dopamine sideeffects on the muscles, cognition and prolactin.
• Ketamine and ketamine analogues seem highlyeffective in treating refractory depression.
• There are at least 20 different types ofserotonin receptors, all with very differentfunctions.
• Develop drugs that stimulate someserotonin receptors and block others, tomore finely tune a healthy serotoninbalance.
• There are at least 20 different types ofserotonin receptors, all with very differentfunctions.
• Develop drugs that stimulate someserotonin receptors and block others, tomore finely tune a healthy serotoninbalance.
John J. Miller, M.D. November 2013
Brain Health – Exeter, NH 31
The histamine H3 receptor: from genecloning to H3 receptor drugs
The histamine H3 receptor: from genecloning to H3 receptor drugs
Rob Leurs, Remko A. Bakker, Henk Timmerman & Iwan J. P. de Esch
Abstract
Since the cloning of the histamine H3 receptor cDNA in 1999 byLovenberg and co-workers, this histamine receptor has gained the
interest of many pharmaceutical companies as a potential drugtarget for the treatment of various important disorders,including obesity, attention-deficit hyperactivity disorder,Alzheimer's disease, schizophrenia, as well as for myocardialischaemia, migraine and inflammatory diseases. Here, we discussrelevant information on this target protein and describe thedevelopment of various H3 receptor agonists and antagonists, andtheir effects in preclinical animal models.
Rob Leurs, Remko A. Bakker, Henk Timmerman & Iwan J. P. de Esch
Abstract
Since the cloning of the histamine H3 receptor cDNA in 1999 byLovenberg and co-workers, this histamine receptor has gained the
interest of many pharmaceutical companies as a potential drugtarget for the treatment of various important disorders,including obesity, attention-deficit hyperactivity disorder,Alzheimer's disease, schizophrenia, as well as for myocardialischaemia, migraine and inflammatory diseases. Here, we discussrelevant information on this target protein and describe thedevelopment of various H3 receptor agonists and antagonists, andtheir effects in preclinical animal models.
Nature Reviews Drug Discovery 4, 107-120 (February 2005)Nature Reviews Drug Discovery 4, 107-120 (February 2005)