Presentation on theme: "Receptor Pharmacology in Depression Treatment"— Presentation transcript:
1 Receptor Pharmacology in Depression Treatment Rakesh Jain, MD, MPH
2 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. Accessed April 17, 2012.
3 “The King is Dead – Long Live the King”: Beyond the Monoamine Hypothesis of Depression Gene Transcription CascadesNeurotrophinsSystems CircuitryNeuronal CircuitryIntracellular PathwaysMonoamine Neurotransmitter-level ViewMarsden WN. Med Hypotheses. 2011;77(4):
4 Modulation of gene transcription Neurotransmitter – Receptor – Intracellular – Gene Transcription InteractionsGlutamate5-HT/NEBDNF5-HT/NETrkBNMDAalpha15-HT2beta-R, 5-HT4,7alpha2, beta-R, 5-HT1A/7SoSSHCRasGsACRafCaM-kinase IVcAMPMEKAktCaM-kinase IIPKAERK1/2GSK-3bGluR1RSK2BDNFFosPPCREMCREB CREBARCModulation of gene transcriptionPPCREB CREBRacagni G et al. World J Biol Psychiatry. 2011;12(8):
5 Receptors – Examining the Role They Play in Mood Regulation
6 What is a Receptor?The term “receptor” specifically refers to proteins that participate in intracellular communication via chemical signalsUpon recognition of an appropriate chemical signaling molecule (ligand), receptor proteins transmit the signal into a biochemical change in the target cellLigands include drugs as well as endogenous signaling molecules such as hormones and neurotransmittersThe beneficial therapeutic effects and unwanted toxic effects of drugs are elicited through interactions with proteinsEnzymes (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 Apr 13;[Epub ahead of print]; Brunton L et al. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. McGraw-Hill Professional; 2008.
7 Major Classes of Receptors Ligand-Gated Ion ChannelsTyrosine Kinase-Linked ReceptorsG-Protein Coupled ReceptorsLigand-Activated Transcription FactorsConnolly CN, Wafford KA. Biochem Soc Trans. 2004;32(Pt 3): ; Samartzis N et al. Reprod Biol Endocrinol. 2012;10(1):30; Philippidou P et al. Proc Natl Acad Sci U S A. 2011;108(2): ; Maurice P et al. Adv Pharmacol. 2011;62:
8 G-protein coupled receptors Ligand-activated transcription factors Ligand-gated ion channelsTyrosine kinase-linked receptorsLigand-activated transcription factorsionsCellular effectChange inmembrane potentialorionic concentrationCellular effectProtein phosphorylationCellular effectIntracellular 2o messenger (eg, cAMP)nucleusCellular effectmRNAproteinNicotinic acetylcholinereceptor(milliseconds)Insulinreceptor(seconds-minutes)β-adrenergicreceptor(seconds-minutes)Estrogenreceptor(hours)Samartzis N et al. Reprod Biol Endocrinol. 2012;10(1):30; Philippidou P et al. Proc Natl Acad Sci U S A. 2011;108(2):
9 The Lock and Key Model of Ligand-Receptor Interaction A ligand such as a hormone or neurotransmitter (the “key”) bind to specific receptors (the “lock”)This binding “unlocks” the cell’s responseMany drugs work by mimicking a naturally occurring hormone or neurotransmitterIf the drug causes the receptor to respond in the same way as the naturally occurring substance, then the drug is referred to as an agonistThese are drugs that can “pick the lock”Other drugs work in the opposite way – as antagonistsThese drugs bind to the receptor, but do not produce a responseBecause the drug prevents the receptor from binding to the normal hormone or neurotransmitter, it has an inhibitory effect on the naturally occurring substanceHormone or NeurotransmitterRECEPTORAGONISTANTAGONISTBrunton L et al. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. McGraw-Hill Professional; 2008.
10 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 depressionBoth blockade and inactivation of the receptor have resulted in an antidepressant-like profile in models of depressionSupporting evidence has also been obtained in sleep studiesEspecially interesting are the augmented effects achieved by combining antidepressants and 5-HT7 receptor antagonistsHedlund PB. Psychopharmacology (Berl). 2009;206(3):
11 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 vitroWhat is Ki value?Ki is the binding affinity of the inhibitor. It’s also called the Equilibrium ConstantCalculation is done as follows:Ki =(Conc Ligand) X (Conc Receptor)(Conc of Ligand Receptor Complex)
12 Receptors Are So Important to Our Fundamental Understanding of Medications, the FDA Uses Receptor Pharmacology to Label Most, But Not All AntidepressantsExamplesSSRIs – selective serotonin reuptake inhibitorsSNRIs – serotonin-norepinephrine reuptake inhibitorsNDRIs – norepinephrine-dopamine reuptake inhibitorsSARIs – serotonin antagonist and reuptake inhibitorsNaSSA – noradrenergic and specific serotonergic antidepressantsExceptions – TCAs (structure-based classification), MAOIs (enzyme-based classification)TCAs, tricyclic antidepressants; MAOIs, monoamine oxidase inhibitors.
13 Examining the Classification of Receptors Focus on the Serotonin System
14 The Serotonin Receptor System 5-HT1A5-HT1B5-HT1C5-HT15-HT25-HT2A5-HT2B5-HT35-HT receptors5-HT2C5-HT45-HT5Based 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-HT65-HT7
18 Focus on 5-HT1A, 5-HT2A, & 5-HT3A Receptors 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.Puig MV, Gulledge AT. Mol Neurobiol. 2011;44(3):
19 5-HT1A: Its Importance in Antidepressant Action K+Fluoxetine5HT5HTGIRK5-HT1AGFR5-HTXG1αP13KG1βG1γPDKACAktcAMPPKAGSK3Context FearImmobility 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):
20 How Norepinephrine Interacts With Serotonin: Role of Receptors 5-HT NeuronRelease the 5-HT brakeNE NeuronStep on 5-HT AcceleratorPresynaptic Alpha 2 AutoreceptorPostsynaptic Alpha 2 Hetero ReceptorAlpha 1 ReceptorAlpha 2 Antagonist5-HTNEKEY POINTSThere is “cross-talk” between 5-HT and NE.Pharmacologic selectivity may not translate into physiologic selectivity.5-HT and NE modulate each other’s release at the point of origin and at the terminal end.REFERENCEStahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed.New York, NY: Cambridge University Press; 2000:254.Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd Edition. 2000:254.Confidential: For Training Purposes Only.20
21 Functional Connectivity Across the “Big Three” Monoamine Systems: Serotonin, Norepinephrine, and Dopamine5-HTNEDA+-5-HT1AD2α1α25-HT1BPostsynaptic NeuronInterneuron 5-HT2A for NE neurons 5-HT2C for DA neuronsKennedy SH et al. J Affect Disord. 2011;132(Suppl 1):S21-S23; Trivedi MH et al. J Clin Psychiatry. 2008;69(2):
22 Where Do Receptors “Live” in Our Brains Where Do Receptors “Live” in Our Brains? How Does Depression Change Their Distribution?Focus on Serotonin Receptor Subtypes
23 5-HT1A Receptor Distribution Changes in Depression
27 Beyond Receptors: Projections (Serotonin, Norepinephrine, GABA, and Glutamate Projections)
28 What Does the Future of Receptor Pharmacology & Receptor Modulation Hold for Us?
29 Peering into the Future – Potential Receptor Targets Currently in Development Presynaptic Glutamatergic NeuronGlutamineGlutaminasemGlu receptor (groups II & III)Glutamate84Cytokines Oxidative stress IDO and its metabolites (kynurenic acid, quinolic acid)GlutamineEAAT 1&2Glutamine synthesisGlutamateInflammation7GlutamateNMDA receptorKainate receptorAMPA receptor12Ca2+mGlu receptor (group II)Ca2+9mGlu receptor (group I)5BDNF3Sigma-1 receptorMicroglia6AstrocyteEndoplasmic reticulumPostsynaptic NeuronNeuronal PlasticityPotential therapeutic targets for MDD : NMDA receptor antagonists (eg, ketamine, NR2B subunit antagonist CP-101,606),: AMPA receptor potentiators, : Group I mGlu R antagonists, : Group II mGlu R antagonists, : Group III mGlu R agonists, : Sigma-1 receptor agonists (eg, fluvoxamine, SA4503), : Glutamate transporter EAAT1/2 enhancer (eg, ceftriaxone), : Anti-inflammatory drugs (eg, minocycline) and antioxidants (eg, N-acetyl-l-cysteine [NAC]), : BDNF.Hashimoto K. Brain Res Rev. 2009;61(2):
30 Receptor Modulation: Examining Opportunities vs Risks
31 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 occultistPicture: This image is in the public domain and is free for your use.(THERE ARE 14 PICTURES IN THIS GALLERY, SO FEEL FREE TO USE ANOTHER ONE)
32 Serotonin Receptors Their Central Role in the Pharmacological Treatment of Depression X5-HT1APresynaptic regionSynapsePostsynaptic region5-HTMAO5-HT1B/1D5-HT2A/2C5-HT35-HT65-HT7SSRI SNRISARISREMAO InhibitorsNaSSA5-HIAA & other metabolitesX5-HT5-HT in vesicles5-HT TransporterPostsynaptic 5-HT receptorSomatodendritic 5-HT receptorInhibitionRajkumar R, Mahesh R. Curr Neuropharmacol. 2008;6(3):
33 Effects of Interacting With Different Neurotransmitter Receptors by Antipsychotics MechanismProposed EffectSerotonin 5-HT1A receptor agonismIncrease in dopamine release in frontal cortexSerotonin 5-HT2A receptor antagonismSerotonin 5-HT2C receptor antagonismIncrease in dopamine and noradrenalin release in frontal cortexAdrenergic α-2 receptor antagonismIncrease of dopamine, serotonin, and noradrenalin release in frontal cortexSerotonin 5-HT7 receptor antagonismIncrease of serotonin in prefrontal cortex (PFC)Serotonin 5-HT6 receptor antagonismIncrease of dopamine, noradrenalin, glutamate, and acetylcholine in frontal cortex and hippocampusSagud M et al. Psychiatr Danub. 2011;23(3):
34 Treatment-Resistance in Unipolar Melancholic Depression Characterized by Decreased 5-HT2A Receptors in the Dorsal Prefrontal Anterior Cingulate CortexDPFC, dorsal prefrontal cortex; VPFC, ventral prefrontal cortex; OFC, orbitofrontal cortex; ACC, anterior cingulate cortex; ADN, antidepressant-naïve; TRD, treatment-resistant depression; BI, Binding Index.Left: Overview of the different volumes of interest (VOIs); Right: B) Results of the prefrontal cortical VOIs represented in bar graphs. *Significant different group effects at a two-tailed probability of P<0.05.Baeken C et al. Neuropharmacology. 2012;62(1):
35 Antidepressant Side Effects CentralNervousSystemSexualDysfunctionAntidepressantSide EffectsGastrointestinalWeight GainFerguson JM. Prim Care Companion J Clin Psychiatry. 2001;3(1):22-27.
36 Side Effects at the Basal Ganglia AkathisiaPsychomotor retardationParkinsonismDystonic movements+5-HT2ARGraphic: WPClipart is an ever-growing collection of artwork for schoolkids and others that is free of copyright concerns as well as safe from inappropriate images. Use in school research and reports is my main focus when creating, or finding and editing -- but there are photos and clips here that work great for commercial uses, book illustrations, office presentations, and some just for fun... All the images here are Public Domain. So enjoy, come back often and tell your friends!Poyurovsky M et al. J Clin Psychopharmacol. 2003;23(3): ; Lane RM. J Psychopharmacol. 1998;12(2):
37 Nausea and Vomiting Nausea and Vomiting 5-HT3R: Hypothalamus Brainstem (CTZ)Graphic: WPClipart is an ever-growing collection of artwork for schoolkids and others that is free of copyright concerns as well as safe from inappropriate images. Use in school research and reports is my main focus when creating, or finding and editing -- but there are photos and clips here that work great for commercial uses, book illustrations, office presentations, and some just for fun... All the images here are Public Domain. So enjoy, come back often and tell your friends!Nausea andVomitingSinghal AK et al. J Postgrad Med. 2012;58(1):23-31.
38 Gastrointestinal Side Effects Stimulation of5-HT3R & 5-HT4RIncreased GImotility, GI crampsGraphic: WPClipart is an ever-growing collection of artwork for schoolkids and others that is free of copyright concerns as well as safe from inappropriate images. Use in school research and reports is my main focus when creating, or finding and editing -- but there are photos and clips here that work great for commercial uses, book illustrations, office presentations, and some just for fun... All the images here are Public Domain. So enjoy, come back often and tell your friends!DiarrheaCamilleri M, Von der Ohe MR. Baillieres Clin Gastroenterol. 1994;8(2):
39 Resolution with Chronic Exposure Mental Side Effects5-HT2A and 2C receptorsAcute stimulation(days)Chronic stimulation(≥2-3 weeks)Mental agitationAnxietyPanic attacksResolution with Chronic ExposureSuzuki Y et al. Neuropsychopharamcology. 2006;31(4):
40 SSRI-Induced Sexual Side Effects DysfunctionDiminished LibidoAnorgasmiaImpotenceDelayed EjaculationSchweitzer I et al. Auzt N Z J Psychiatry. 2009;43(9):
41 Receptor blockade by atypical antipsychotics Some of the Receptors Involved in Weight Gain Atypical Antipsychotics as an Example5HT2C-receptorH1-receptorα2-receptorAtypical antipsychoticVMHNPVNReceptor blockade by atypical antipsychoticsFood intake Energy expenditureAdipositasIL-6Leptin resistanceH1-receptor mediatedSOCS-3LeptinTNFαAdiponectinInsulin resistance Glucose intoleranceStimulation Inhibition Increase DecreaseAch, acetylcholine; H1, histamine 1; VMHN, ventromedial hypthalamic 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):
42 Cholinergic Receptor Blockade Urinary retention/ Constipation H1 and Anticholinergic Blockade Side EffectsH1 Receptor AntagonismSedationFatigueWeight GainCholinergic Receptor BlockadeDry MouthBlurred visionUrinary retention/ ConstipationStahl SM. CNS Spectr. 2008;12(12):
43 What is the Relationship Between H1 and M1 Antagonism What is the Relationship Between H1 and M1 Antagonism? Using Antipsychotics as a Proxy to Examine this Issue-112345Estimated Weight Change, kgH1 Receptor Occupancy, %20406080100rs=0.81 P<0.01X*-112345Estimated Weight Change, kgmACh Receptor Occupancy, %20406080100rs=0.83 P<0.01X*++ChlorpromazineClozapineXFluphenazineHaloperidolOlanzapine*ThioridazineZiprasidoneSertindoleRisperidone+MolindoneMatsui-Sakata A et al. Drug Metab Pharmacokinet. 2005;20(5):
44 Clinical Applications and Bio-psycho-social Opportunities to Enhance Outcomes
45 Enhancement of cellular plasticity & resilience Biopsychosocial Interactions in Depression Occur at the Cellular and Subcellular Level5-HT5-HT1AGluDorsal rapheNEStressGliaα2ARLocus coeruleusAntidepressantStressc5-HT reuptake transporterGlu reuptake transportergStressdehStressNE reuptake transporterfGi or Gq↑CRHACAMPAR↑GCGiNMDARCa2+-dependent or MAPK cascadescAMPMAPK modulatorsbaGC↑PKAiGCGRP↑CREBGR↑BDNF↑Bcl-2↑TrkBjEnhancement of cellular plasticity & resilienceStressMatthew SJ et al. Neuropsychopharmacology. 2008;33(9): ; Charney DS, Manji HK. Sci STKE. 2004;2004(225):re5.
46 Could l-methy folate as an add on to serotonin produce be beneficial – and why?
47 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
48 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
49 Effect Size – And Multiple Risk Factors Papakostas, et al POSTER PRESENTED AT THE SOCIETY FOR BIOLOGICAL PSYCHIATRY ANNUAL MEETING, MAY 3, 2012, PHILADELPHIA, PA
50 Psychotherapy and Receptor Changes Is this even possible? This is the first direct demonstration of a specific neurotransmitter mechanism involved in the neurobiology of psychotherapyIncreased serotonin 5-HT1A receptor binding in multiple cortical regions following psychotherapy in patients with MDDSignificant 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)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 weeksKarrlson H et al. Psychol Med. 2010;40(3):
51 FDA Labels Are Evolving – And Have More Receptor Binding Profile Information Forest Pharmaceuticals, Inc. VIIBRYD® (vilazodone HCl) prescribing information
52 In ConclusionReceptors are central to the patho-physiology and its treatmentBoth medications and psychotherapy affect ReceptorsEmerging Science is teaching us how Receptors may impact benefits and side effectsClinicians, when more aware of the science of Receptors, will be able to optimize treatment outcomes
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