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Receptor Pharmacology in Depression Treatment

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

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  1. Receptor Pharmacologyin 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. www.nimh.nih.gov/statistics/2LIDD.shtml. Accessed April 17, 2012.

  3. “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.

  4. 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.

  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. 2012 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):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.

  8. 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

  9. 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.

  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):345-354.

  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 Kivalue? • Ki is the binding affinity of the inhibitor. It’s also called the Equilibrium Constant • Calculation is done as follows:

  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. 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

  15. Drugs Acting on SerotonergicNeurotransmisson TCAs SSRIs SNRIs Amphetamine Methylphenidate Modafinil MAOIs Reuptake inhibitors Storage inhibitors Degradation inhibitors Presynaptic agents Serotonin (5-HT) pharmacology

  16. 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

  17. Serotonin Antagonists Methysergide Ketanserin Atypical antipsychotics 5-HT2A/2C antagonist 5-HT receptor antagonists 5-HT3 antagonist

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  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 GABA Glutamate

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

  29. Receptor Modulation: Examining Opportunities vs Risks

  30. 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

  31. 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.

  32. Effects of Interacting With Different Neurotransmitter Receptors by Antipsychotics Sagud M et al. Psychiatr Danub. 2011;23(3):302-307.

  33. 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.

  34. 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.

  35. Nausea and Vomiting 5-HT3R: Hypothalamus Brainstem (CTZ) Nausea and Vomiting Singhal AK et al. J Postgrad Med. 2012;58(1):23-31.

  36. 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.

  37. 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.

  38. 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.

  39. 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.

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

  41. 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.

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

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

  44. 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

  45. 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

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

  47. 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.

  48. FDA Labels Are Evolving – And Have More Receptor Binding Profile Information Forest Pharmaceuticals, Inc. VIIBRYD® (vilazodoneHCl) prescribing information. 2011.

  49. 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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