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Receptor Pharmacology in Depression Treatment
Rakesh Jain, MD, MPH
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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.
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“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):
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Modulation of gene transcription
Neurotransmitter – Receptor – Intracellular – Gene Transcription Interactions Glutamate 5-HT/NE BDNF 5-HT/NE TrkB NMDA alpha1 5-HT2 beta-R, 5-HT4,7 alpha2, beta-R, 5-HT1A/7 SoS SHC Ras Gs AC Raf CaM-kinase IV cAMP MEK Akt CaM-kinase II PKA ERK1/2 GSK-3b GluR1 RSK2 BDNF Fos P P CREM CREB CREB ARC Modulation of gene transcription P P CREB CREB Racagni G et al. World J Biol Psychiatry. 2011;12(8):
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Receptors – Examining the Role They Play in Mood Regulation
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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.
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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:
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G-protein coupled receptors Ligand-activated transcription factors
Ligand-gated ion channels Tyrosine kinase-linked receptors Ligand-activated transcription factors ions Cellular effect Change in membrane potential or ionic concentration Cellular effect Protein phosphorylation Cellular effect Intracellular 2o messenger (eg, cAMP) nucleus Cellular effect mRNA protein Nicotinic acetylcholine receptor (milliseconds) Insulin receptor (seconds-minutes) β-adrenergic receptor (seconds-minutes) Estrogen receptor (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):
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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 response Many drugs work by mimicking a naturally occurring hormone or neurotransmitter If the drug causes the receptor to respond in the same way as the naturally occurring substance, then the drug is referred to as an agonist These are drugs that can “pick the lock” Other drugs work in the opposite way – as antagonists These drugs bind to the receptor, but do not produce a response Because the drug prevents the receptor from binding to the normal hormone or neurotransmitter, it has an inhibitory effect on the naturally occurring substance Hormone or Neurotransmitter RECEPTOR AGONIST ANTAGONIST Brunton L et al. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. McGraw-Hill Professional; 2008.
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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):
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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)
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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.
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Examining the Classification of Receptors
Focus on the Serotonin System
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The Serotonin Receptor System
5-HT1A 5-HT1B 5-HT1C 5-HT1 5-HT2 5-HT2A 5-HT2B 5-HT3 5-HT receptors 5-HT2C 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
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Drugs Acting on Serotonergic Neurotransmisson
Serotonin (5-HT) pharmacology Presynaptic agents Degradation inhibitors Storage inhibitors Reuptake inhibitors MAOIs Amphetamine Methylphenidate Modafinil SNRIs SSRIs TCAs
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Serotonin Agonists 5-HT1A agonist 5-HT1B and 5-HT1D agonist Triptans
Buspirone 5-HT1B and 5-HT1D agonist Triptans Selective 5-HT2 antagonist Trazodone 5-HT receptor agonists 5-HT4 agonist Cisapride Ergotamine Non-selective LSD
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Serotonin Antagonists
Ketanserin 5-HT2A/2C antagonist Methysergide Atypical antipsychotics 5-HT receptor antagonists 5-HT3 antagonist
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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):
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5-HT1A: Its Importance in Antidepressant Action
K+ Fluoxetine 5HT 5HT GIRK 5-HT1A GFR 5-HTX G1α P13K G1β G1γ PDK AC Akt cAMP PKA GSK3 Context Fear Immobility 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):
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How Norepinephrine Interacts With Serotonin: Role of Receptors
5-HT Neuron Release the 5-HT brake NE Neuron Step on 5-HT Accelerator Presynaptic Alpha 2 Autoreceptor Postsynaptic Alpha 2 Hetero Receptor Alpha 1 Receptor Alpha 2 Antagonist 5-HT NE KEY POINTS There 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. REFERENCE Stahl 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
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Functional Connectivity Across the “Big Three” Monoamine Systems: Serotonin, Norepinephrine, and Dopamine 5-HT NE DA + - 5-HT1A D2 α1 α2 5-HT1B Postsynaptic Neuron Interneuron 5-HT2A for NE neurons 5-HT2C for DA neurons Kennedy SH et al. J Affect Disord. 2011;132(Suppl 1):S21-S23; Trivedi MH et al. J Clin Psychiatry. 2008;69(2):
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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
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5-HT1A Receptor Distribution Changes in Depression
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5-HT2 Alterations in Depression
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5-HT3 Receptor Distribution in Depression
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5-HT6 and 5-HT7 Receptor Changes in Depression
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Beyond Receptors: Projections (Serotonin, Norepinephrine, GABA, and Glutamate Projections)
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What Does the Future of Receptor Pharmacology & Receptor Modulation Hold for Us?
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Peering into the Future – Potential Receptor Targets Currently in Development
Presynaptic Glutamatergic Neuron Glutamine Glutaminase mGlu receptor (groups II & III) Glutamate 8 4 Cytokines Oxidative stress IDO and its metabolites (kynurenic acid, quinolic acid) Glutamine EAAT 1&2 Glutamine synthesis Glutamate Inflammation 7 Glutamate NMDA receptor Kainate receptor AMPA receptor 1 2 Ca2+ mGlu receptor (group II) Ca2+ 9 mGlu receptor (group I) 5 BDNF 3 Sigma-1 receptor Microglia 6 Astrocyte Endoplasmic reticulum Postsynaptic Neuron Neuronal Plasticity 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):
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Receptor Modulation: Examining Opportunities vs Risks
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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 Picture: 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)
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Serotonin Receptors Their Central Role in the Pharmacological Treatment of Depression
X 5-HT1A Presynaptic region Synapse Postsynaptic region 5-HT MAO 5-HT1B/1D 5-HT2A/2C 5-HT3 5-HT6 5-HT7 SSRI SNRI SARI SRE MAO Inhibitors NaSSA 5-HIAA & other metabolites X 5-HT 5-HT in vesicles 5-HT Transporter Postsynaptic 5-HT receptor Somatodendritic 5-HT receptor Inhibition Rajkumar R, Mahesh R. Curr Neuropharmacol. 2008;6(3):
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Effects of Interacting With Different Neurotransmitter Receptors by Antipsychotics
Mechanism Proposed Effect Serotonin 5-HT1A receptor agonism Increase in dopamine release in frontal cortex Serotonin 5-HT2A receptor antagonism Serotonin 5-HT2C receptor antagonism Increase in dopamine and noradrenalin release in frontal cortex Adrenergic α-2 receptor antagonism Increase of dopamine, serotonin, and noradrenalin release in frontal cortex Serotonin 5-HT7 receptor antagonism Increase of serotonin in prefrontal cortex (PFC) Serotonin 5-HT6 receptor antagonism Increase of dopamine, noradrenalin, glutamate, and acetylcholine in frontal cortex and hippocampus Sagud M et al. Psychiatr Danub. 2011;23(3):
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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):
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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.
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Side Effects at the Basal Ganglia
Akathisia Psychomotor retardation Parkinsonism Dystonic movements + 5-HT2AR 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! Poyurovsky M et al. J Clin Psychopharmacol. 2003;23(3): ; Lane RM. J Psychopharmacol. 1998;12(2):
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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 and Vomiting Singhal AK et al. J Postgrad Med. 2012;58(1):23-31.
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Gastrointestinal Side Effects
Stimulation of 5-HT3R & 5-HT4R Increased GI motility, GI cramps 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! Diarrhea Camilleri M, Von der Ohe MR. Baillieres Clin Gastroenterol. 1994;8(2):
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Resolution with Chronic Exposure
Mental Side Effects 5-HT2A and 2C receptors Acute stimulation (days) Chronic stimulation (≥2-3 weeks) Mental agitation Anxiety Panic attacks Resolution with Chronic Exposure Suzuki Y et al. Neuropsychopharamcology. 2006;31(4):
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SSRI-Induced Sexual Side Effects
Dysfunction Diminished Libido Anorgasmia Impotence Delayed Ejaculation Schweitzer I et al. Auzt N Z J Psychiatry. 2009;43(9):
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Receptor blockade by atypical antipsychotics
Some of the Receptors Involved in Weight Gain Atypical Antipsychotics as an Example 5HT2C-receptor H1-receptor α2-receptor Atypical antipsychotic VMHN PVN Receptor blockade by atypical antipsychotics Food intake Energy expenditure Adipositas IL-6 Leptin resistance H1-receptor mediated SOCS-3 Leptin TNFα Adiponectin Insulin resistance Glucose intolerance Stimulation Inhibition Increase Decrease 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):
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Cholinergic Receptor Blockade Urinary retention/ Constipation
H1 and Anticholinergic Blockade Side Effects H1 Receptor Antagonism Sedation Fatigue Weight Gain Cholinergic Receptor Blockade Dry Mouth Blurred vision Urinary retention/ Constipation Stahl SM. CNS Spectr. 2008;12(12):
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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 -1 1 2 3 4 5 Estimated Weight Change, kg H1 Receptor Occupancy, % 20 40 60 80 100 rs=0.81 P<0.01 X * -1 1 2 3 4 5 Estimated Weight Change, kg mACh Receptor Occupancy, % 20 40 60 80 100 rs=0.83 P<0.01 X * + + Chlorpromazine Clozapine X Fluphenazine Haloperidol Olanzapine * Thioridazine Ziprasidone Sertindole Risperidone + Molindone Matsui-Sakata A et al. Drug Metab Pharmacokinet. 2005;20(5):
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Clinical Applications and Bio-psycho-social Opportunities to Enhance Outcomes
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Enhancement of cellular plasticity & resilience
Biopsychosocial Interactions in Depression Occur at the Cellular and Subcellular Level 5-HT 5-HT1A Glu Dorsal raphe NE Stress Glia α2AR Locus coeruleus Antidepressant Stress c 5-HT reuptake transporter Glu reuptake transporter g Stress d e h Stress NE reuptake transporter f Gi or Gq ↑CRH AC AMPAR ↑GC Gi NMDAR Ca2+-dependent or MAPK cascades cAMP MAPK modulators b a GC ↑PKA i GC GR P ↑CREB GR ↑BDNF ↑Bcl-2 ↑TrkB j Enhancement of cellular plasticity & resilience Stress Matthew SJ et al. Neuropsychopharmacology. 2008;33(9): ; Charney DS, Manji HK. Sci STKE. 2004;2004(225):re5.
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Could l-methy folate as an add on to serotonin produce be beneficial – and why?
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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
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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
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Effect Size – And Multiple Risk Factors
Papakostas, et al POSTER PRESENTED AT THE SOCIETY FOR BIOLOGICAL PSYCHIATRY ANNUAL MEETING, MAY 3, 2012, PHILADELPHIA, PA
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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) 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 Karrlson H et al. Psychol Med. 2010;40(3):
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FDA Labels Are Evolving – And Have More Receptor Binding Profile Information
Forest Pharmaceuticals, Inc. VIIBRYD® (vilazodone HCl) prescribing information
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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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