Neurotransmitter Functioning In Major Depressive Disorder Otsuka Pharmaceutical Development & Commercialization, Inc. 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD January 2017 Lundbeck, LLC. MRC2.CORP.D.00181 1 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
This program was developed with the support of Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck, LLC. The speakers are either employees or paid contractors of Otsuka Pharmaceutical Development & Commercialization, Inc. 2 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
Monoamine Imbalance Theory of Major Depressive Disorder (MDD) Imbalance theory describes patients with depression having deficient 1 : Dopamine (DA), Serotonin (5-HT), Norepinephrine (NE) Monoaminergic deficiencies may be caused by depleted or dysregulated 2 : Monoamine synthesis Monoamine receptor signaling The efficacy of SSRIs, SNRIs, and dopamine agonists as antidepressants supports this theory 3 AC, adenylate cyclase; camp, cyclic adenosine monophosphate; MAO-A, monoamine oxidase A; PLC, phospholipase-c; PI, phosphoinositide; SNRIs, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors. 1. Delgado PL. J Clin Psychiatry. 2006;67 Suppl 4:22-6. 2. Perovic B, et al. Neuropsychiatr Dis Treat. 2010;6:343-364. 3. Tran P, et al. J of Psychiatric Research. 2012;46:64-71. Presynaptic neuron 5-HT transporter Tryptophan Tyrosine Tryptophan hydroxylase 5-HT 1B 5-HT 1A 5-HT PI-coupled monoamine receptors MAO-A metabolism Vesicles Tyrosine hydroxylase NE α 2 -adrenergic receptor NE transporter camp-coupledg proteins monoamine receptors camp IP 3 DAG Secondary messengers effect Cytoplasm downstream signaling and gene expression in postsynaptic neuron Nucleus Figure adapted from Perovic et al. 2010 2 3
Monoamine Pathways Overlap in Several Areas of the Brain 1 8 PFC Substantia nigra and VTA ACC Cerebral cortex S A T Hy H A1, A2, A5, A7 Locus coeruleus Raphe nuclei C A = amygdala ACC = anterior cingulate cortex C = cerebellum H = hippocampus Hy = hypothalamus NA = nucleus accumbens PFC = prefrontal cortex S = striatum T = thalamus VTA = ventral tegmental area. Norepinephrine Dopamine Serotonin 1. Fuchs E, Flugge G. Dialogues Clin Neurosci. 2004;6(2):171-183; 2. Stahl SM. Chapter 7. In: Stahl SM, ed. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Application. 4th ed; 2013:284-369; 3. Jacobs BL, Azmitia EC. Physiol Rev. 1992;72(1):165-229; 4. Abercrombie ED, et al. J Neurochem. 1989;52(5):1655-1658; 5. Stanford SC. Pharmacol Ther. 1995;68(2):297-242; 6. Meana JJ, et al. Biol Psychiatry. 1992;31:471-490; 7. Garcia-Sevilla JA, et al. J Neurochem. 1999;72(1):282-291; 8. Roiser JP, Sahakian BJ. CNS Spectr. 2013;18(3):139-149. 4
Neural Circuitry of Monoamines and GABAergic Neurons Overlap GABAergic interneurons provide a link between several classes of serotonergic receptors and monoaminergic neurons Long-loop feedback inhibition is likely mediated by descending glutamatergic neurons which act via stimulation of GABAergic interneurons 5-HT X, serotonin receptor X; α/β X, noradrenaline receptor X; GABA, gamma-aminobutyric acid; GABA X, gamma-aminobutyric acid receptor X; D X, dopamine receptor X; DA, dopamine; FCX, frontal cortex; NA, noradrenaline. Millan MJ. Pharmacol Ther. 2006;110:135-370. Image from Millan et al. 2006 5
Overlap Between Monoamine Neurotransmitter Systems Plays a Role in Emotional Behavior NE Energy, Interest Anxiety Irritable Behavior Impulsive Behavior 5-HT Motivation Mood, Emotion Cognitive Function Sex Appetite Aggressive Behavior Drive 5-HT, serotonin; DA, dopamine: NE, norepinephrine. Zajecka J, et al. J Clin Psychiatry. 2013;74:407-414. DA 6
Serotonin (5-HT) Findings from research with depressed patients 1 : 5-HT projections in the brain 2 Low levels of blood platelet 5-HT Low plasma levels of L-tryptophan Depletion of dietary tryptophan induces depression Tryptophan administration seems to provide beneficial effects 1. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786. 2. Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4 th Edition. New York, NY: Cambridge University Press; 2013. 7
5-HT 1A Presynaptic 5-HT 1A 1 Auto-receptor Regulates 5-HT release Rapidly desensitize after activation 5-HT 1A Postsynaptic 5-HT 1A 1 Hetero-receptor Regulate inhibition of non-5-ht neurons Do not desensitize 5-HT cell body 5-HT 1A 5-HT( 1A ), serotonin (receptor 1A). Image adapted from Panesar K, et al. 2 1. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786. 2. Panesar K, et al. 5-HT1A Receptors in Psychopharmacology. Psychopharmacology Institute. Available at: http://psychopharmacologyinstitute.com/cns-receptors/5-ht1a-receptors/ 8
5-HT 1B Similar to 5-HT 1A, 5-HT 1B is expressed 1 : Presynaptically (auto-receptor) Postsynaptically (hetero-receptor) GABA 5-HT 1A Densely expressed in basal ganglia, nucleus accumbens, and substantia nigra 1 Stress upregulates 5-HT 1B receptor expression in the dorsal raphe nucleus 1 Antidepressants dramatically effect 5-HT 1B, possibly underlying their antidepressant and anxiolytic effects 1 Glutamate 5-HT 1B 5-HT 1A 5-HT 1B 5-HT( 1A/1B ), serotonin (receptor 1A/1B); GABA, gamma-aminobutyric acid. Image from: Saitow et al. 2009 2 1. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786. 2. Saitow F, et al. J Neurophysiol. 2009;101(3):1361-1374. 9
5-HT 2A Highly expressed in the frontal cortex, basal ganglia, and parts of the limbic system 1 Depressed patients have greater 5-HT 2A receptor density 2 Promotor region of 5-HT 2A variant shows increased risk of depression 2 Some SSRIs downregulate 5-HT 2 2A Dopamine neuron 5-HT 2A receptor 5-HT 2A receptor Serotonin Dopamine Serotonin neuron 5-HT( 2A ), serotonin (receptor 2A); SSRI, selective serotonin reuptake inhibitor. 1. Siegel GJ et al. Basic Neurochemistry Molecular, Cellular and Medical Aspects. 7 th Edition. Boston, MA: Elsevier; 2006; 2. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786; 3. Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd Edition. New York, NY: Cambridge University Press; 2000. Image adapted from Stahl. 2000 3 10
Modulating DA Activity via 5-HT Receptors Solid line = active Dotted line = inactive 5-HT 2A 5-HT 1A Glu DA Proposed Actions: 5-HT projections connect with glutamatergic pyramidal neurons in the cortex Cortical 5-HT 1A receptor stimulation inhibits glutamatergic neurons, increasing DA release in the striatum Cortical 5-HT 2A receptor activation stimulates glutamatergic neuron, inhibiting DA release in the striatum Therefore, it is proposed that blockade of cortical 5-HT 2A receptors relieves inhibition of DA release (functionally analogous to 5-HT 1A stimulation) Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th Edition. New York, NY: Cambridge University Press; 2013. 11
5-HT Transporter (SERT) Removes excess 5-HT from extracellular space 1 Main target of antidepressants, SSRIs and SNRIs 1,2 Mainly expressed by 5-HT neurons 1 Genetic link to SERT: patients with a functional polymorphism tend to have higher probability of depression 1 SERT undergo adaptive changes with SSRI treatment 1 Image adapted from Fakhoury. 2016 1 SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin re-uptake inhibitors.; 1. Fakhoury M. Mol Neurobiol. 2016;53(5):2778-2786. 2. Zhao Z, et al. Neuropsychopharmacology. 2009;34(6):1467-1481. 12
Dopamine (DA) Observed dopaminergic dysregulation in patients with depression includes: Functional deficiencies in synaptic DA 1 Reduced homovanillic acid (HVA) 1 Lower DA binding to the DAT 1 Genetic alterations in D 4 receptors, DAT, and COMT 2 Neural activation during reward processing tasks differ in patients with depression versus healthy controls: A single major depressive episode, or recurrent MDD, is associated with reduced activation in the caudate and nucleus accumbens 3 3-MT HVA 3-MT HVA Dopaminergic Signaling AC DAT G VMAT L-tyrosine TH L-dopa Dopamine D 1 D 2 + - camp G Downstream signaling AC Presynaptic neuron AC G D 2 autoreceptor Dopamine 3-MT, 3-methoxytyramine; AC, adenyl cyclase: camp, cyclic AMP; COMT, catechol O-methyltransferase; DX, dopamine receptor subtype X; DAT, dopamine transporter; G, G protein; MAO-B, monoamine oxidase B; MDD, major depressive disorder; TH, tyrosine hydroxylase; VMAT, vesicular monoamine transporter. 1. Robinson DS. Primary Psychiatry. 2007;14(5):21-23; 2. Dunlop BW, et al. Arch Gen Psychiatry. 2007;64(3):327-337; 3. Whitton AE, et al. Curr Opin Psychiatry. 2015;28(1):7-12. Postsynaptic neuron Image from Dunlop et al. 2007 2 13
Norepinephrine (NE) Post-mortem tissue and functional imaging studies have elaborated on adrenergic modulations in depression 1 : Suicide victims with depression have shown an altered α 2 receptor density and sensitivity Patients with MDD demonstrated decreased norepinephrine transporter (NET) binding in the locus coeruleus Depleting NE levels during remission in patients with depression resulted in the rapid reappearance of depressive symptoms 1* * Patients were in remission and no longer taking any antidepressant medication. α 2, alpha-2 adrenergic receptor; PFC, prefrontal cortex. 1. Moret C, et al. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):9-13. 2. Tully K, et al. Mol Brain. 2010;3:15. Image from Tully K, et al. 2010. 2 14
α Receptors Appear to Modulate 5-HT Release in MDD 1,2 NE reciprocally regulates 5-HT neurons: α 1 receptors (located on 5-HT neurons) promote 5-HT release 5-HT neuron NE 5-HT Postsynaptic α 2 receptor α 2 receptors (located postsynaptically on 5-HT neurons) indirectly attenuate 5-HT release Antagonism of α 2 receptors indirectly decreases 5-HT inhibition NE neuron α 1 receptor Presynaptic α 2 receptor 5-HT, serotonin; α, alpha adrenergic receptor; NE, norepinephrine. 1. Stahl SM. Stahl s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd Edition. New York, NY: Cambridge University Press; 2011. (Image based on Stahl). 2. Cedraz-Mercez PL, et al. Exp Physiol. 2007;92.5:923-931. 15
Theorized Involvement of Non-monoamine Neurotransmitters in MDD Pathophysiology 1 5-HT, serotonin; GABA, GABA, gamma-aminobutyric acid MDD, major depressive disorder; NE, norepinephrine. Zhao et al. J Affect Disord. 2012;138(3):494-502. Image from: Zhao et al. 2012 16
Glutamate Hypothesis of Depression Glutamatergic dysregulation has been implicated in the pathophysiology of several psychiatric and neurological disorders Compared with healthy controls, observed alterations in the glutamate system in patients with MDD include: Neuroanatomically specific modulations in glutamate levels Reduced NMDA receptor-binding affinity Reduced glutamate transporter expression Antidepressants and mood stabilizers used in the treatment of mood disorders affect many facets of the glutamate system Several agents that affect the glutamate system have been explored as potential treatments in mood disorders. These include: Inhibitors of glutamate release NMDA antagonists NMDA partial antagonists NMDA, N-methyl-D-aspartate. Sanacora G et al. Nat Rev Drug Discov. 2008;7(5):426-437. 17
Neurotransmitter Functioning In Major Depressive Disorder Otsuka Pharmaceutical Development & Commercialization, Inc. 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD January 2017 Lundbeck, LLC. MRC2.CORP.D.00181 18 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.