Receptor pharmacology in depression treatment
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Receptor Pharmacology in Depression Treatment. Rakesh Jain, MD, MPH. Let’s Not Underestimate Our Enemy: Depression is THE Leading Cause of Disability.

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Receptor pharmacology in depression treatment

Receptor Pharmacologyin Depression Treatment

Rakesh Jain, MD, MPH


Let s not underestimate our enemy depression is the leading cause of disability

Let’s Not Underestimate Our Enemy: Depression is THE Leading Cause of Disability

*DALYs represent the total number of years lost to illness, disability, or premature death within a given population. They are calculated by adding the number of years of life lost to the number of years lived with disability for a certain disease or disorder.

National Institute of Mental Health. Leading individual diseases/disorders. www.nimh.nih.gov/statistics/2LIDD.shtml. Accessed April 17, 2012.


The king is dead long live the king beyond the monoamine hypothesis of depression

“The King is Dead – Long Live the King”: Beyond the Monoamine Hypothesis of Depression

Gene Transcription Cascades

Neurotrophins

Systems Circuitry

Neuronal Circuitry

Intracellular Pathways

Monoamine Neurotransmitter-level View

Marsden WN. Med Hypotheses. 2011;77(4):508-528.


Neurotransmitter receptor intracellular gene transcription interactions

Neurotransmitter – Receptor – Intracellular – Gene Transcription Interactions

Glutamate

5-HT/NE

BDNF

5-HT/NE

TrkB

alpha2,beta-R,5-HT1A/7

alpha1

5-HT2

beta-R,5-HT4,7

NMDA

SoS

Ras

SHC

Gs

AC

Raf

CaM-kinase IV

cAMP

MEK

Akt

CaM-kinase II

ERK1/2

GSK-3b

PKA

GluR1

BDNF

RSK2

Fos

P

P

CREM

CREB CREB

CREB CREB

ARC

Modulation ofgenetranscription

P

P

Racagni G et al. World J Biol Psychiatry. 2011;12(8):574-587.


Receptors examining the role they play in mood regulation

Receptors – Examining the Role They Play in Mood Regulation


What is a receptor

What is a Receptor?

The term “receptor” specifically refers to proteins that participate in intracellular communication via chemical signals

Upon recognition of an appropriate chemical signaling molecule (ligand), receptor proteins transmit the signal into a biochemical change in the target cell

Ligands include drugs as well as endogenous signaling molecules such as hormones and neurotransmitters

The beneficial therapeutic effects and unwanted toxic effects of drugs are elicited through interactions with proteins

Enzymes (aspirin + cyclooxygenase)

Transporters/Carriers (fluoxetine + serotonin reuptake transporter)

Ion channels (local anesthetics + Na+ channels)

Receptor proteins (cimetidine + histamine receptor)

Shoichet BK, Kobilka BK. Trends Pharmacol Sci. 2012 Apr 13;[Epub ahead of print]; Brunton L et al. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. McGraw-Hill Professional; 2008.


Major classes of receptors

Major Classes of Receptors

Ligand-Gated Ion Channels

Tyrosine Kinase-Linked Receptors

G-Protein Coupled Receptors

Ligand-Activated Transcription Factors

Connolly CN, Wafford KA. Biochem Soc Trans. 2004;32(Pt 3):529-534; Samartzis N et al. ReprodBiolEndocrinol. 2012;10(1):30; Philippidou P et al. Proc NatlAcadSci U S A. 2011;108(2):852-857; Maurice P et al. Adv Pharmacol. 2011;62:349-380.


Receptor pharmacology in depression treatment

G-protein coupled

receptors

Ligand-gated ion channels

Tyrosine kinase-linked receptors

Ligand-activated transcription factors

ions

Change in

membrane potential

or

ionic concentration

Protein phosphorylation

Intracellular 2o messenger (eg, cAMP)

nucleus

mRNA

protein

Cellular effect

Cellular effect

Cellular effect

Cellular effect

Nicotinic acetylcholine

receptor

(milliseconds)

Insulin

receptor

(seconds-minutes)

β-adrenergic

receptor

(seconds-minutes)

Estrogen

receptor

(hours)

Samartzis N et al. ReprodBiolEndocrinol. 2012;10(1):30; Philippidou P et al. Proc NatlAcadSci U S A. 2011;108(2):852-857


The lock and key model of ligand receptor interaction

The Lock and Key Model of Ligand-Receptor Interaction

RECEPTOR

Hormone or Neurotransmitter

AGONIST

ANTAGONIST

?#@&%$!

Brunton L et al. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. McGraw-Hill Professional; 2008.


What does a receptor look like serotonin 5 ht7 as an example

What Does a Receptor Look Like? Serotonin 5-HT7 as an Example

There is a considerable amount of evidence supporting a role for the 5-HT7 receptor in depression

Both blockade and inactivation of the receptor have resulted in an antidepressant-like profile in models of depression

Supporting evidence has also been obtained in sleep studies

Especially interesting are the augmented effects achieved by combining antidepressants and 5-HT7 receptor antagonists

Hedlund PB. Psychopharmacology (Berl). 2009;206(3):345-354.


Exploring the concept of ic50 and ki values

Exploring the Concept of IC50 and Ki values

  • What is IC50?

    • This quantitative measure indicates how much of a drug is needed to inhibit a given biological process by half. According to the FDA, IC50 represents the concentration of a drug that is required for 50% inhibition in vitro

  • What is Kivalue?

    • Ki is the binding affinity of the inhibitor. It’s also called the Equilibrium Constant

  • Calculation is done as follows:


  • Receptor pharmacology in depression treatment

    Receptors Are So Important to Our Fundamental Understanding of Medications, the FDA Uses Receptor Pharmacology to Label Most, But Not All Antidepressants

    Examples

    SSRIs – selective serotonin reuptake inhibitors

    SNRIs – serotonin-norepinephrine reuptake inhibitors

    NDRIs – norepinephrine-dopamine reuptake inhibitors

    SARIs – serotonin antagonist and reuptake inhibitors

    NaSSA – noradrenergic and specific serotonergic antidepressants

    Exceptions – TCAs (structure-based classification), MAOIs (enzyme-based classification)

    TCAs, tricyclic antidepressants; MAOIs, monoamine oxidase inhibitors.


    Examining the classification of receptors

    Examining the Classification of Receptors

    Focus on the Serotonin System


    The serotonin receptor system

    The Serotonin Receptor System

    5-HT1A

    5-HT2A

    5-HT1B

    5-HT1C

    5-HT2B

    5-HT2C

    5-HT1

    5-HT2

    5-HT3

    5-HT receptors

    5-HT4

    5-HT5

    Based on biochemical and pharmacological criteria, serotonin receptors are classified into 7 main receptor subtypes, 5-HT1-7. Of major pharmacotherapeutic importance are those designated 5-HT1, 5-HT2, 5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the 5-HT3 subtype represents a ligand-gated ion channel.

    5-HT6

    5-HT7


    Drugs acting on serotonergic neurotransmisson

    Drugs Acting on SerotonergicNeurotransmisson

    TCAs

    SSRIs

    SNRIs

    Amphetamine Methylphenidate Modafinil

    MAOIs

    Reuptake inhibitors

    Storage inhibitors

    Degradation inhibitors

    Presynaptic agents

    Serotonin (5-HT) pharmacology


    Serotonin agonists

    Serotonin Agonists

    5-HT1B and 5-HT1D agonist

    5-HT1A agonist

    Buspirone

    5-HT2 antagonist

    Triptans

    Trazodone

    5-HT4 agonist

    Cisapride

    Ergotamine

    LSD

    Selective

    5-HT receptor agonists

    Non-selective


    Serotonin antagonists

    Serotonin Antagonists

    Methysergide

    Ketanserin

    Atypical antipsychotics

    5-HT2A/2C antagonist

    5-HT receptor antagonists

    5-HT3 antagonist


    Focus on 5 ht1a 5 ht2a 5 ht3a receptors

    Focus on 5-HT1A, 5-HT2A, & 5-HT3A Receptors

    3A

    3A

    The most abundant serotonin receptors in the PFC, 5-HT1A, 5-HT2A, and 5-HT3A receptors, are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons, and play a critical role in modulating cortical activity and neural oscillations.

    1A

    2A

    1A

    1A

    2A

    1A

    2A

    1A

    1A

    2A

    1A

    1A

    2A

    Puig MV, Gulledge AT. Mol Neurobiol. 2011;44(3):449-464.


    5 ht1a its importance in antidepressant action

    5-HT1A: Its Importance in Antidepressant Action

    Fluoxetine

    K+

    5HT

    5HT

    5-HT1A

    5-HTX

    GIRK

    GFR

    P13K

    G1α

    G1β

    G1γ

    PDK

    AC

    Akt

    PKA

    cAMP

    GSK3

    Immobility

    Context Fear

     5-HT1A receptors regulate phosphorylation of GSK3 in the hippocampus.  PI3K/Akt signaling pathway mediates regulation of GSK3 by 5-HT1A receptors.  5-HT1A receptor-induced inhibition of contextual fear learning is GSK3β-dependent. Fluoxetine regulates phosphorylation of GSK3 in the hippocampus.  Regulation of GSK3 is an intermediate of fluoxetine’s anti-immobility effect.

    Polter AM et al. Cell Signal. 2012;24(1):265-271.


    How norepinephrine interacts with serotonin role of receptors

    How Norepinephrine Interacts With Serotonin: Role of Receptors

    Presynaptic Alpha 2 Autoreceptor

    5-HT Neuron

    Postsynaptic Alpha 2 Hetero Receptor

    Release the5-HT brake

    Alpha 1 Receptor

    Alpha 2 Antagonist

    5-HT

    NE

    Step on 5-HT Accelerator

    NE Neuron

    Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd Edition. 2000:254.


    Receptor pharmacology in depression treatment

    Functional Connectivity Across the “Big Three” Monoamine Systems:Serotonin, Norepinephrine, and Dopamine

    5-HT

    α1

    +

    D2

    5-HT1A

    +

    -

    DA

    NE

    α2

    D2

    -

    -

    5-HT1B

    α2

    α2

    Interneuron5-HT2A for NE neurons5-HT2C for DA neurons

    D2

    PostsynapticNeuron

    Kennedy SH et al. J Affect Disord. 2011;132(Suppl 1):S21-S23; Trivedi MH et al. J Clin Psychiatry. 2008;69(2):246-258.


    Where do receptors live in our brains how does depression change their distribution

    Where Do Receptors “Live” in Our Brains?How Does Depression Change Their Distribution?

    Focus on Serotonin Receptor Subtypes


    5 ht1a receptor distribution changes in depression

    5-HT1A Receptor Distribution Changes in Depression


    5 ht2 alterations in depression

    5-HT2 Alterations in Depression


    5 ht3 receptor distribution in depression

    5-HT3 Receptor Distribution in Depression


    5 ht6 and 5 ht7 receptor changes in depression

    5-HT6 and 5-HT7 Receptor Changes in Depression


    Beyond receptors projections serotonin norepinephrine gaba and glutamate projections

    Beyond Receptors: Projections (Serotonin, Norepinephrine, GABA, and Glutamate Projections)

    Serotonin

    Norepinephrine

    GABA

    Glutamate


    What does the future of receptor pharmacology receptor modulation hold for us

    What Does the Future of Receptor Pharmacology & Receptor Modulation Hold for Us?


    Receptor modulation examining opportunities vs risks

    Receptor Modulation: Examining Opportunities vs Risks


    Beneficial versus toxic drug effects

    Beneficial versus Toxic Drug Effects

    “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.”

    Paracelsus

    (1493 – 1541) German-Swiss physician, botanist, alchemist, astrologer, and occultist


    Serotonin receptors their central role in the pharmacological treatment of depression

    Serotonin ReceptorsTheir Central Role in the Pharmacological Treatment of Depression

    5-HT1A

    X

    X

    X

    X

    X

    Presynaptic region

    SRE

    SSRISNRI

    MAOInhibitors

    Synapse

    5-HT

    MAO

    5-HIAA & othermetabolites

    SARI

    NaSSA

    5-HT1B/1D

    5-HT2A/2C

    5-HT3

    5-HT6

    5-HT7

    5-HT

    Postsynaptic region

    X

    5-HT in vesicles

    5-HT Transporter

    Postsynaptic 5-HT receptor

    Somatodendritic 5-HT receptor

    Inhibition

    Rajkumar R, Mahesh R. CurrNeuropharmacol. 2008;6(3):215-234.


    Effects of interacting with different neurotransmitter receptors by antipsychotics

    Effects of Interacting With Different Neurotransmitter Receptors by Antipsychotics

    Sagud M et al. Psychiatr Danub. 2011;23(3):302-307.


    Antidepressant side effects

    Antidepressant Side Effects

    Central

    Nervous

    System

    Sexual

    Dysfunction

    Antidepressant

    Side Effects

    Gastrointestinal

    Weight Gain

    Ferguson JM. Prim Care Companion J Clin Psychiatry. 2001;3(1):22-27.


    Side effects at the basal ganglia

    Side Effects at the Basal Ganglia

    Akathisia

    Psychomotor retardation

    Parkinsonism

    Dystonic movements

    +

    5-HT2AR

    Poyurovsky M et al. J ClinPsychopharmacol. 2003;23(3):305-308; Lane RM. J Psychopharmacol. 1998;12(2):192-214.


    Nausea and vomiting

    Nausea and Vomiting

    5-HT3R:

    Hypothalamus

    Brainstem (CTZ)

    Nausea and

    Vomiting

    Singhal AK et al. J Postgrad Med. 2012;58(1):23-31.


    Gastrointestinal side effects

    Gastrointestinal Side Effects

    Stimulation of

    5-HT3R & 5-HT4R

    Increased GI

    motility, GI cramps

    Diarrhea

    Camilleri M, Von derOhe MR. BaillieresClinGastroenterol. 1994;8(2):301-319.


    Mental side effects

    Mental Side Effects

    5-HT2A and 2C receptors

    Acute stimulation

    (days)

    Chronic stimulation

    (≥2-3 weeks)

    Resolution with Chronic Exposure

    Mental agitation

    Anxiety

    Panic attacks

    Suzuki Y et al. Neuropsychopharamcology. 2006;31(4):825-831.


    Ssri induced sexual side effects

    SSRI-Induced Sexual Side Effects

    Anorgasmia

    Diminished Libido

    Sexual

    Dysfunction

    Impotence

    Delayed Ejaculation

    Schweitzer I et al. Auzt N Z J Psychiatry. 2009;43(9):795-808.


    Some of the receptors involved in weight gain atypical antipsychotics as an example

    Some of the Receptors Involved in Weight GainAtypical Antipsychotics as an Example

    VMHN

    5HT2C-receptor

    H1-receptor

    PVN

    α2-receptor

    Receptor blockade byatypical antipsychotics

    Atypicalantipsychotic

    H1-receptormediated

    Food intakeEnergy expenditure

    Leptinresistance

    StimulationInhibitionIncreaseDecrease

    Adipositas

    SOCS-3

    IL-6

    Adiponectin

    Leptin

    TNFα

    Insulin resistanceGlucose intolerance

    Ach, acetylcholine; H1, histamine 1; VMHN, ventromedialhypthalamic nucleus; PVN, paraventricular nucleus; IL-6, interleukin 6; TNFα, tumor necrosis factor-alpha; SOCS-3, supressor of cytokine signalling 3.

    Starrenburg FC, Bogers JP. Eur Psychiatry. 2009;24(3):164-170.


    Receptor pharmacology in depression treatment

    Stahl SM. CNS Spectr. 2008;12(12):1027-1038.


    Receptor pharmacology in depression treatment

    What is the Relationship Between H1 and M1 Antagonism? Using Antipsychotics as a Proxy to Examine this Issue

    5

    5

    rs=0.81P<0.01

    rs=0.83P<0.01

    4

    4

    *

    *

    3

    3

    2

    2

    Estimated Weight Change, kg

    Estimated Weight Change, kg

    1

    1

    X

    X

    0

    0

    +

    +

    -1

    -1

    0

    0

    20

    20

    40

    40

    60

    60

    80

    80

    100

    100

    mACh Receptor Occupancy, %

    H1 Receptor Occupancy, %

    Chlorpromazine

    Clozapine

    X

    Fluphenazine

    Haloperidol

    Olanzapine

    Risperidone

    +

    *

    Thioridazine

    Molindone

    Ziprasidone

    Sertindole

    Matsui-Sakata A et al. Drug MetabPharmacokinet. 2005;20(5):368-378.


    Clinical applications and bio psycho social opportunities to enhance outcomes

    Clinical Applications and Bio-psycho-social Opportunities to Enhance Outcomes


    Receptor pharmacology in depression treatment

    Could l-methy folate as an add on to serotonin produce be beneficial – and why?


    Receptor pharmacology in depression treatment

    Biomarkers in Deplin Trials and How Receptors / Inflammation / Nutrients Interact

    Poster Presented by Jain, R. at College of Psychiatric and Neurologic Pharmacists Annual Meeting, Tampa, Florida. May 29-2


    Receptor pharmacology in depression treatment

    Inflammation – and How it Becomes ‘Helpful’ with Novel Treatment Approaches

    Papakostas, et al POSTER PRESENTED AT THE SOCIETY FOR BIOLOGICAL PSYCHIATRY ANNUAL MEETING, MAY 3, 2012, PHILADELPHIA, PA


    Receptor pharmacology in depression treatment

    Effect Size – And Multiple Risk Factors

    Papakostas, et al POSTER PRESENTED AT THE SOCIETY FOR BIOLOGICAL PSYCHIATRY ANNUAL MEETING, MAY 3, 2012, PHILADELPHIA, PA


    Psychotherapy and receptor changes is this even possible

    Psychotherapy and Receptor Changes Is this even possible?

    short-term psychodynamic psycho- therapy (PSY, n=8) or fluoxetine (FLU, 20 mg/d, in- creased up to 40 mg/d if needed, n=15) for 16 weeks

    This is the first direct demonstration of a specific neurotransmitter mechanism involved in the neurobiology of psychotherapy

    Increased serotonin 5-HT1A receptor binding in multiple cortical regions following psychotherapy in patients with MDD

    Significant increase in 5-HT1A density in the PSY (psychodynamic psychotherapy) group compared to the FLU (fluoxetine) group in the frontal, temporal, and parietal cortex (angular gyrus, medial prefrontal cortex, orbitofrontal cortex)

    Karrlson H et al. Psychol Med. 2010;40(3):523-528.


    Fda labels are evolving and have more receptor binding profile information

    FDA Labels Are Evolving – And Have More Receptor Binding Profile Information

    Forest Pharmaceuticals, Inc. VIIBRYD® (vilazodoneHCl) prescribing information. 2011.


    In conclusion

    In Conclusion

    • Receptors are central to the patho-physiology and its treatment

    • Both medications and psychotherapy affect Receptors

    • Emerging Science is teaching us how Receptors may impact benefits and side effects

    • Clinicians, when more aware of the science of Receptors, will be able to optimize treatment outcomes


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