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Receptor Pharmacology in Depression Treatment Rakesh Jain, MD, MPH.

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Presentation on theme: "Receptor Pharmacology in Depression Treatment Rakesh Jain, MD, MPH."— 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 Gene Transcription Cascades Neurotrophins Systems Circuitry Neuronal Circuitry Intracellular Pathways Monoamine Neurotransmitter- level View “The King is Dead – Long Live the King”: Beyond the Monoamine Hypothesis of Depression Marsden WN. Med Hypotheses. 2011;77(4):

4 Neurotransmitter – Receptor – Intracellular – Gene Transcription Interactions Racagni G et al. World J Biol Psychiatry. 2011;12(8): Glutamate5-HT/NEBDNF5-HT/NE alpha 1 5-HT 2 alpha 2, beta-R, 5-HT 1A/7 CaM-kinase IV CaM-kinase II beta-R, 5-HT 4,7 Gs AC cAMP PKA Akt GSK-3b GluR1 BDNF Fos CREM ARC SoS Raf MEK ERK1/2 RSK2 NMDA SHC Ras CREB TrkB PP P P Modulation of gene transcription

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 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 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 Channels Tyrosine Kinase-Linked Receptors G-Protein Coupled Receptors Ligand-Activated Transcription Factors Connolly 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 nucleus Ligand-gated ion channels Tyrosine kinase- linked receptors G-protein coupled receptors Ligand-activated transcription factors Nicotinic acetylcholine receptor (milliseconds) (milliseconds)Insulinreceptor(seconds-minutes) β-adrenergic receptor(seconds-minutes)Estrogenreceptor(hours)ions Cellular effect Change in membrane potential or ionic concentration Change in membrane potential or ionic concentration Cellular effect Protein phosphorylation Cellular effect Intracellular 2 o messenger (eg, cAMP) Cellular effect mRNAmRNA proteinprotein 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 Brunton L et al. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. McGraw-Hill Professional; HORMONE OR NEUROTRANSMITTER RECEPTOR AGONIST ANTAGONIST

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 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):

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 vitro What is Ki value? –Ki is the binding affinity of the inhibitor. It’s also called the Equilibrium Constant Calculation 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 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.

13 Examining the Classification of Receptors Focus on the Serotonin System

14 5-HT55-HT5 5-HT65-HT6 5-HT75-HT7 5-HT receptors 5-HT35-HT3 5-HT45-HT4 5-HT15-HT1 5-HT25-HT2 5-HT1A5-HT1A 5-HT2A5-HT2A 5-HT1B5-HT1B 5-HT1C5-HT1C 5-HT2B5-HT2B 5-HT2C5-HT2C 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. The Serotonin Receptor System

15 Drugs Acting on Serotonergic Neurotransmisson Reuptake inhibitors Storage inhibitors TCAsTCAsSSRIsSSRIsSNRIsSNRIs Amphetamine Methylphenidate Modafinil Degradation inhibitors MAOIsMAOIs Presynaptic agents Serotonin (5-HT) pharmacology

16 Serotonin Agonists Non-selectiveNon-selective 5-HT receptor agonists SelectiveSelective 5-HT1A agonist BuspironeBuspirone 5-HT1B and 5-HT1D agonist 5-HT2 antagonist TriptansTriptans TrazodoneTrazodone 5-HT4 agonist CisaprideCisapride ErgotamineErgotamine LSDLSD

17 Serotonin Antagonists 5-HT3 antagonist 5-HT receptor antagonists 5-HT2A/2C antagonist KetanserinKetanserin MethysergideMethysergide Atypical antipsychotics

18 Focus on 5-HT1A, 5-HT2A, & 5-HT3A Receptors Puig MV, Gulledge AT. Mol Neurobiol. 2011;44(3): 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 3A

19 5-HT1A: Its Importance in Antidepressant Action Polter AM et al. Cell Signal. 2012;24(1):  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. AC cAMP PKA 5HT G1αG1α G1βG1β PDK Akt GSK3 P13K Fluoxetine 5HT Immobility Context Fear 5-HT1A 5-HTX G1γG1γ GIRK K+ GFR

20 How Norepinephrine Interacts With Serotonin: Role of Receptors Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd Edition. 2000:254. Presynaptic Alpha 2 Autoreceptor Postsynaptic Alpha 2 Hetero Receptor Alpha 1 Receptor Alpha 2 Antagonist 5-HT NE 5-HT Neuron Release the 5-HT brake NE Neuron Step on 5-HT Accelerator

21 Functional Connectivity Across the “Big Three” Monoamine Systems: Serotonin, Norepinephrine, and Dopamine Kennedy SH et al. J Affect Disord. 2011;132(Suppl 1):S21-S23; Trivedi MH et al. J Clin Psychiatry. 2008;69(2): HT NE DA HT1A D2 α1α1 α2α2 5-HT1B - D2 - α2α2 α2α2 Postsynaptic Neuron Interneuron 5-HT2A for NE neurons 5-HT2C for DA neurons

22 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

24 5-HT2 Alterations in Depression

25 5-HT3 Receptor Distribution in Depression

26 5-HT6 and 5-HT7 Receptor Changes in Depression

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

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

29 Peering into the Future – Potential Receptor Targets Currently in Development Potential 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): Inflammation Glutamine synthesis Presynaptic Glutamatergic Neuron EAAT 1&2 Glutamine Glutamate Postsynaptic Neuron Astrocyte 7 5 mGlu receptor (group II) mGlu receptor (groups II & III) Microglia Cytokines Oxidative stress IDO and its metabolites (kynurenic acid, quinolic acid) mGlu receptor (group I) Kainate receptor NMDA receptor AMPA receptor Ca 2 + Glutamine Glutamate Sigma-1 receptor Endoplasmic reticulum Glutamate Neuronal Plasticity 6 Glutaminase BDNF

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 occultist

32 Serotonin Receptors Their Central Role in the Pharmacological Treatment of Depression Rajkumar R, Mahesh R. Curr Neuropharmacol. 2008;6(3): X 5-HT 5-HT in vesicles 5-HT Transporter Postsynaptic 5-HT receptor Somatodendritic 5-HT receptor Inhibition X X X X 5-HT 1A Presynaptic region Synapse Postsynaptic region 5-HT MAO X 5-HT 1B/1D 5-HT 2A/2C 5-HT 3 5-HT 6 5-HT 7 SSRI SNRI SARI SRE MAO Inhibitors NaSSA 5-HIAA & other metabolites

33 Effects of Interacting With Different Neurotransmitter Receptors by Antipsychotics Sagud 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 Cortex DPFC, 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 Ferguson JM. Prim Care Companion J Clin Psychiatry. 2001;3(1): GastrointestinalGastrointestinal CentralNervousSystemCentralNervousSystemSexualDysfunctionSexualDysfunction Weight Gain Antidepressant Side Effects Antidepressant

36 Side Effects at the Basal Ganglia Poyurovsky M et al. J Clin Psychopharmacol. 2003;23(3): ; Lane RM. J Psychopharmacol. 1998;12(2): HT2AR5-HT2AR ++ Akathisia Psychomotor retardation Parkinsonism Dystonic movements

37 Nausea and Vomiting Singhal AK et al. J Postgrad Med. 2012;58(1): HT3R:Hypothalamus Brainstem (CTZ) 5-HT3R:Hypothalamus Nausea and Vomiting Nausea and Vomiting

38 Gastrointestinal Side Effects Camilleri M, Von der Ohe MR. Baillieres Clin Gastroenterol. 1994;8(2): Stimulation of 5-HT3R & 5-HT4R Stimulation of 5-HT3R & 5-HT4R Increased GI motility, GI cramps Increased GI motility, GI cramps Diarrhea

39 Chronic stimulation (≥2-3 weeks) Chronic stimulation (≥2-3 weeks) Mental Side Effects Suzuki Y et al. Neuropsychopharamcology. 2006;31(4): HT2A and 2C receptors Mental agitation Anxiety Panic attacks Mental agitation Anxiety Panic attacks Acute stimulation (days) (days) Resolution with Chronic Exposure

40 SSRI-Induced Sexual Side Effects Schweitzer I et al. Auzt N Z J Psychiatry. 2009;43(9):

41 Some of the Receptors Involved in Weight Gain Atypical Antipsychotics as an Example Ach, 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): HT2C-receptor H1-receptor α2-receptor Atypical antipsychotic VMHN PVN Stimulation Inhibition Increase Decrease Receptor blockade by atypical antipsychotics Food intake Energy expenditure Adipositas IL-6 Leptin resistance H1-receptor mediated SOCS-3 LeptinTNFα Adiponectin Insulin resistance Glucose intolerance

42 H1 and Anticholinergic Blockade Side Effects Stahl SM. CNS Spectr. 2008;12(12): H1 Receptor Antagonism Sedation Fatigue Weight Gain Cholinergic Receptor Blockade Dry Mouth Blurred vision Urinary retention/ Constipation

43 What is the Relationship Between H1 and M1 Antagonism? Using Antipsychotics as a Proxy to Examine this Issue Matsui-Sakata A et al. Drug Metab Pharmacokinet. 2005;20(5): Estimated Weight Change, kg H 1 Receptor Occupancy, % r s =0.81 P<0.01 X * ChlorpromazineClozapineXFluphenazineHaloperidolOlanzapine Risperidone * Thioridazine ZiprasidoneSertindole Estimated Weight Change, kg mACh Receptor Occupancy, % r s =0.83 P<0.01 X * + Molindone + +

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

45 Biopsychosocial Interactions in Depression Occur at the Cellular and Subcellular Level Matthew SJ et al. Neuropsychopharmacology. 2008;33(9): ; Charney DS, Manji HK. Sci STKE. 2004;2004(225):re5. NE Locus coeruleus Antidepressant α 2 AR Stress NE reuptake transporter 5-HT reuptake transporter Stress 5-HT 5-HT 1A Glu reuptake transporter Dorsal raphe Glu e b d c f h Stress Glia Stress ↑CRH ↑GC NMDAR MAPK modulators GC GR GC GR Ca 2+ -dependent or MAPK cascades ↑PKA AC g GiGi a cAMP Stress ↑CREB ↑BDNF Enhancement of cellular plasticity & resilience i P AMPAR G i or Gq j ↑Bcl-2 ↑TrkB

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

47 Poster Presented by Jain, R. at College of Psychiatric and Neurologic Pharmacists Annual Meeting, Tampa, Florida. May 29-2 Biomarkers in Deplin Trials and How Receptors / Inflammation / Nutrients Interact

48 Papakostas, et al POSTER PRESENTED AT THE SOCIETY FOR BIOLOGICAL PSYCHIATRY ANNUAL MEETING, MAY 3, 2012, PHILADELPHIA, PA Inflammation – and How it Becomes ‘Helpful’ with Novel Treatment Approaches

49 Papakostas, et al POSTER PRESENTED AT THE SOCIETY FOR BIOLOGICAL PSYCHIATRY ANNUAL MEETING, MAY 3, 2012, PHILADELPHIA, PA Effect Size – And Multiple Risk Factors

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 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): 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

51 FDA Labels Are Evolving – And Have More Receptor Binding Profile Information Forest Pharmaceuticals, Inc. VIIBRYD ® (vilazodone HCl) prescribing information

52 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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