Psychiatry, Medications and the Brain-Nov-4-2011.ppt...• Discuss some of the possible future...

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.



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



The history of psychiatric drugdiscovery and our earliestpsychiatric medications:

a case of serendipity

The history of psychiatric drugdiscovery and our earliestpsychiatric medications:

a case of serendipity

Antipsychotics - ThorazineAntipsychotics - Thorazine

• 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.

• 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.



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



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.”

Year# of in-patientsinstitutionalized

in NH State Hospital

1963 2,700

2013 120

Mood Stabilizer - Lithium:our oldest psychiatric medication


• Reportedly used in spring water to treatmania in the Roman and Greek eras.

• 19th century used to treat gout.

• 1870s used to treat mania in USA andDenmark.

• 1900 lithium abandoned as a medicationbecause pharmaceutical companies couldnot patent it.

• Reportedly used in spring water to treatmania in the Roman and Greek eras.

• 19th century used to treat gout.

• 1870s used to treat mania in USA andDenmark.

• 1900 lithium abandoned as a medicationbecause pharmaceutical companies couldnot patent it.





• 1949 Australian psychiatrist John Caderediscovered the effectiveness of Li salts inthe treatment of mania.

• 1970 FDA approved for mania.

• 1974 FDA approved for the prevention ofmanic-depressive disorder.

• 1949 Australian psychiatrist John Caderediscovered the effectiveness of Li salts inthe treatment of mania.

• 1970 FDA approved for mania.

• 1974 FDA approved for the prevention ofmanic-depressive disorder.

Clue about depression - Reserpine:an antihypertensive that lowers

blood pressure by depleting norepinephrine

Clue about depression - Reserpine:an antihypertensive that lowers

blood pressure by depleting norepinephrine

• 1952 Indian snakeroot (Rauwolfia serpentina)was found to contain reserpine.

• 1954 reserpine was introduced in the USA.

• Norepinephrine depletion was associated withincreased depression.

• Contributed significantly to the “monoaminedepletion hypothesis of depression”(norepinephrine, dopamine and serotonin).

• 1952 Indian snakeroot (Rauwolfia serpentina)was found to contain reserpine.

• 1954 reserpine was introduced in the USA.

• Norepinephrine depletion was associated withincreased depression.

• Contributed significantly to the “monoaminedepletion hypothesis of depression”(norepinephrine, dopamine and serotonin).



First Antidepressant - IproniazidFirst Antidepressant - Iproniazid

• 1952 researchers observed that patients treated withisoniazid for tuberculosis became “inappropriately happy”.

• Structure was modified, and in 1958 iproniazid was FDAapproved as the first antidepressant.

• 1961 withdrawn from the US market due to liver toxicity.

• Mechanism of action is that of a monoamine oxidaseinhibitor (MAOI). Raises levels of norepinephrine,dopamine and serotonin.

• Followed by the MAOIs Nardil and Parnate.

• 1952 researchers observed that patients treated withisoniazid for tuberculosis became “inappropriately happy”.

• Structure was modified, and in 1958 iproniazid was FDAapproved as the first antidepressant.

• 1961 withdrawn from the US market due to liver toxicity.

• Mechanism of action is that of a monoamine oxidaseinhibitor (MAOI). Raises levels of norepinephrine,dopamine and serotonin.

• Followed by the MAOIs Nardil and Parnate.

Psychiatric Medications TodayPsychiatric Medications Today

From Serendipity:

To Molecular “fingerprinting”

From Serendipity:

To Molecular “fingerprinting”



AntipsychoticsAntipsychotics

“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).



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



*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



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

• Lithium (Eskalith, Lithobid)

• Divalproex (Depakote)

• Carbamazepine (Equetro)

• Chlorpromazine (Thorazine)

• Risperidone (Risperdal)

• Olanzapine (Zyprexa)

• Quetiapine (Seroquel)

• Ziprasidone (Geodon)

• Aripiprazole (Abilify)

• Asenapine (Saphris)

• Lithium (Eskalith, Lithobid)

• Divalproex (Depakote)

• Carbamazepine (Equetro)

• Chlorpromazine (Thorazine)

• Risperidone (Risperdal)

• Olanzapine (Zyprexa)

• Quetiapine (Seroquel)

• Ziprasidone (Geodon)

• Aripiprazole (Abilify)

• Asenapine (Saphris)



AntidepressantsAntidepressants

• Classes:

– Monoamine oxidase inhibitors (3)

– Tricyclic Antidepressants (10)

– Selective Serotonin Reuptake Inhibitors (6)

– Serotonin Norepinephrine ReuptakeInhibitors (4)

– Other (6)

• Classes:

– Monoamine oxidase inhibitors (3)

– Tricyclic Antidepressants (10)

– Selective Serotonin Reuptake Inhibitors (6)

– Serotonin Norepinephrine ReuptakeInhibitors (4)

– Other (6)


• Classes:

– Monoamine oxidase inhibitors

• Nardil

• Parnate

• Emsam (transdermal patch)

• Classes:

– Monoamine oxidase inhibitors

• Nardil

• Parnate

• Emsam (transdermal patch)




• Classes:

– Tricyclic Antidepressants

• Classes:

– Tricyclic Antidepressants

• Doxepin

• Amoxapine

• Trimipramine

• Protriptyline

• Maprotiline• tetracyclic

• Doxepin

• Amoxapine

• Trimipramine

• Protriptyline

• Maprotiline• tetracyclic

• Amitriptyline

• Imipramine

• Nortriptyline

• Desipramine

• Clomipramine

• Amitriptyline

• Imipramine

• Nortriptyline

• Desipramine

• Clomipramine


• Classes:

– Selective Serotonin Reuptake Inhibitors

• Prozac

• Zoloft

• Paxil

• Luvox

• Celexa

• Lexapro

• Classes:

– Selective Serotonin Reuptake Inhibitors

• Prozac

• Zoloft

• Paxil

• Luvox

• Celexa

• Lexapro




• Classes:

– Serotonin Norepinephrine ReuptakeInhibitors

• Effexor

• Cymbalta

• Pristiq

• Fetzima

• Classes:

– Serotonin Norepinephrine ReuptakeInhibitors

• Effexor

• Cymbalta

• Pristiq

• Fetzima


• Classes:

– Other

• Trazodone

• Serzone

• Remeron

• Wellbutrin

• Viibryd

• Brintellix

• Classes:

– Other

• Trazodone

• Serzone

• Remeron

• Wellbutrin

• Viibryd

• Brintellix



Our evolving understanding ofhow psychiatric medications

work:

mechanism of action at thecellular level

Our evolving understanding ofhow psychiatric medications

work:

mechanism of action at thecellular level

Affective and Psychotic Disorders:Three important monoamine

neurotramsmitters

Affective and Psychotic Disorders:Three important monoamine

neurotramsmitters

• Serotonin

• Dopamine

• Norepinephrine

• Serotonin

• Dopamine

• Norepinephrine



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



Receptor Antagonist

Cell Membrane

Intra-cellular

Extra-cellular

Target receptorX

Receptor –Agonist

Cell Membrane

Intra-cellular

Extra-cellular

Target receptor



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.



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.



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)



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



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)

aa

b

ge

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

+ ++ + + ++ + + ++ + + + ++ + + ++ + + + + ++

= GABA binding site

= benzo binding site

= ETOH binding site

= barbit binding site

Na = sodium (1+)Cl = chloride (1-)

Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl

Na Na Na Na Na Na Na Na Na Na Na Na Na Na Na

Cl Cl Cl Cl Cl Cl

Influx of negative chargehyperpolarizes the neuron –

decreasing excitability



G-Protein Coupled Receptor

a b g

G-protein

Cell Membrane

Effectors inactive

Intra-cellular

S = serotonin

Extra-cellular

Adenylyl cyclase

K+ ion channel

GDP


b gCell Membrane

Intra-cellular

S = serotonin

Extra-cellular

Adenylyl cyclase

aGTP

K+

K+

ATP cAMP

Activates Protein Kinase A

Activates CREB – a transcription factor




a b gCell Membrane

Effectors inactive

Intra-cellular

S = serotonin

Extra-cellular

Adenylyl cyclase

K+ ion channel

GDP

P

GTPase

From receptors . . .

To . . .

Circuits

From receptors . . .

To . . .

Circuits



SerotoninNeuron

DopamineNeuron

= Serotonin Neuron

= Dopamine Neuron

S = SerotoninD = Dopamine

D DD

D

V = 5HT-2A Serotonin Receptor

SerotoninNeuron

DopamineNeuron

= Serotonin Neuron

= Dopamine Neuron

S = SerotoninD = Dopamine

DD D DD D DD DD DD D

D D D DDDD D D




DopamineNeuron

SerotoninNeuron

GABANeuron

= Serotonin Neuron

= GABA Neuron

= Dopamine Neuron

S = Serotonin

G = GABA

D = Dopamine

D DD DD D


y = GABA Receptor

DopamineNeuron

SerotoninNeuron

GABANeuron

= Serotonin Neuron

= GABA Neuron

= Dopamine Neuron

S = Serotonin

G = GABA

D = Dopamine

DDD DD DDD DD D DDD D

DD DD D DD D DDD D DD D



A close up view of a

synapse

A close up view of a

synapse

SSSSSSSSSSSSSSSSSS

S SS S SS S SS S SS S

S S SS S

S S

SS SS S

Neuronal TransmissionInformation Flow


Pre-synapticNeuron

Post-SynapticNeuron

X

5HT-1

S SS S SSSS S S

SS S S SS SS S SS S SS

S S



SSSSSSSSSSSSSSSSSS

SS SS S



Pre-synapticNeuron

Post-SynapticNeuron

XS SS S S

S S SSS S

S SS S SSSS S S

SS S S S


S S SS S

S S

X

X

Celada P, et al. J Psychiatry Neurosci 2004; 29 (4): 252-65.

SSSSSSSSSSSSSSSSSS

SS SS S



Pre-synapticNeuron

Post-SynapticNeuron

XS SS S S

S S SSS S

S SS S SSSS S S

SS S S S


S S SS S

S S

X

X

X

Celada P, et al. J Psychiatry Neurosci 2004; 29 (4): 252-65.



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.



Cholinergic nicotinic agonistsCholinergic nicotinic agonists

• Cognitive enhancers for conditions likeAlzheimers.

• Treat adult attention deficit hyperactivitydisorder.

• Add on drug for antidepressantimprovement.

• Improve the negative and positivesymptoms of schizophrenia.

• Cognitive enhancers for conditions likeAlzheimers.

• Treat adult attention deficit hyperactivitydisorder.

• Add on drug for antidepressantimprovement.

• Improve the negative and positivesymptoms of schizophrenia.

Serotonin receptor modulatorsSerotonin receptor modulators

• 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.



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)

Questions??Questions??

Psychiatry, Medications and the Brain-Nov-4-2011.ppt...• Discuss some of the possible future...

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