Outline of Today’s Presentation Primer on Serotonin ...€¦ · Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York:

A Practical, Clinically Driven Primer on Serotonin Receptors and Targeted Pharmacotherapy

Rakesh Jain, MD, MPH

Clinical ProfessorDepartment of PsychiatryTexas Tech Health Sciences CenterSchool of MedicineMidland, Texas

Outline of Today’s Presentation

History/ Discovery

of Serotonin

Role of Serotonin in Brain / Body

functioning

Interplay of Serotonin with other Neurotrans‐

mitters

Serotonin Receptor Pharma‐cology

Role of Various

Receptors in the

Serotonin Family

Clinical Implications

of our Learnings

Discovery of Serotonin: An “accidental” discovery in search of a hypertension agent

(“Sero” = serum; “Tonin” = vascular tone)

Booji L, et al. J Psychiatry Neurosci. 2015;40(1):5-18. Frodl T, et al. J Psychiatry Neurosci. 2015;40(5):296-305.

Dr. Maurice Rapport 1948

Early in the morning, he would go to the Clevelandslaughterhouse and collect eight 15 L buckets ofblood

Did this 60 times

Distilled this through a 5‐step process to finallyisolate Serotonin

900 L of serum obtained from 2 tons of bull’s blood,before Serotonin was discovered

Original vial of Serotonin

(still displayed at Cleveland Clinic medical museum)

A Timeline of Important Serotonin Events

SSRI = selective serotonin reuptake inhibitor.Booji L, et al. J Psychiatry Neurosci. 2015;40(1):5-18. Frodl T, et al. J Psychiatry Neurosci. 2015;40(5):296-305.

• 5-HT “low” in depression (1966)

• Antidepressants act via 5-HT (1963–1969)

• Discovery of many 5-HT receptors

• Development of 5-HT antagonists

• Identification/isolation of 5-HT (1948–1953)

• Discovery of 5-HT in brain (1954)

• Development of SSRIs

• 5-HT “low” in suicide (1976)

• Identification of 5-HT genetic polymorphisms

• “Low” 5-HT as vulnerability factor for stress-related disorders (stress-diathesis)

Reason Why Serotonin Matters: Serotonin is intimately involved in the

regulations of a vast number of human behaviors

Kumar JS, et al. Cent Nerv Syst Agents Med Chem. 2014;14(2):96-112.

Mood

Modulate Aggression

Memory / Cognition

Sleep / Wakefulness

Neuroinflammation

Neuroendocrine Functioning Pain Modulation

Appetite / Satiety

Anxiety

Pleasure / Euphoria

Serotonin – A Life Story

Charnay Y, et al. Dialogues Clin Neurosci. 2010;12(4):471-487.

Steps:

Tryptophan is the precursor to serotonin.

Tryptophan is taken up by serotonergicneurons in restricted brain areas such as theraphe nucleus.

Once it enters the neurons, an enzymecalled tryptophan hydroxylase adds thehydroxyl group and produces 5-HTP (shortfor 5-hydroxytryptophan).

5-HTP is further decarboxylated by aromaticL-amino acid decarboxylase to produceserotonin.

Serotonin is then stored in synaptic vesiclesand docked at the nerve terminals, where itawaits an action potential.

Release of serotonin into the synaptic cleftactivates serotonergic receptors in the post-synaptic neurons.

Serotonin

Dorsal Raphe Cell

Dietary Tryptophan

Serotonin – Not Just in Humans: 5-HT is a “highly conserved” neurotransmitter and

Found in Multiple Places in Nature

Berger M, et al. Annu Rev Med. 2009;60:355-366. Badria FA. J Med Food. 2004;5(3):153-157.

Fungus

Found in all animal species

Plants

Fish species

Nuts / Seeds

Brain–Body distribution in humans

Serotonin

Serotonin in the Human Body, Where Does It Come From?

GI = gastrointestinal. Berger M, et al. Annu Rev Med. 2009;60:355-366.

90% of Human Serotonin, in the GI tract, the

Enterochromaffin cells are distributed widely in the

epithelium of the stomach, small intestine, and colon

5% of Human Serotonin comes from Myenteric Neurons, which are distributed in the muscle lining of the GI track

5% of Human Serotonin from the Brain – specifically the Dorsal Raphe, which then projects upwards to the

cortex, and downwards, to the cerebellum and spinal cord

Serotonin

Serotonin:Its Role in Human Emotion and Behavior


Gut Motility Regulation

Mood Regulation

Regulating Insulin Secretion

Inflammation / Immune Regulation

Aggression / Dominance Modulation

Sleep–Wake Cycle

Regulation

Regulating Bone Metabolism

(through effects on Osteoblasts and Osteoclasts)

Serotonin

Cognition / Memory / Learning

Serotonin:Its Critical Role Even Prior to Birth

Volpicelli F, et al. Front Behav Neurosci. 2014;8:318.

Together with its function as neurotransmitter, 5-HT regulates neurite outgrowth, dendritic spine shape and density, growth

cone motility, and synapse formation during development

5-HT is synthesized early in embryonic development and its receptors are early expressed

The brain of the fetus receives Serotonin also from the placenta of the mother. The contribution of these maternal–placental–fetal interactions appears to be critical for brain circuit wiring and for long-term brain functions

Serotonin and Its Receptors are Involved in Neurogenesis in the Hippocampus

Klempin F, et al. Front Mol Neurosci. 2010;3:14.

BrdU = Bromodeoxyuridine is commonly used in the

detection of proliferating cells in living tissues

Serotonin Appears to be Involved at Nearly Every Stage of Neurodevelopment and Neuropathology

HPA = hypothalamic pituitary adrenal.Booji L, et al. J Psychiatry Neurosci. 2015;40(1):5-18. Frodl T, et al. J Psychiatry Neurosci. 2015;40(5):296-305.

Altered DNA Methylation Patterns

Altered brain development /

brain functioning

Altered Response to Stress, via1. HPA axis2. Autonomic

System3. Inflammatory

systemDevelopment of Psychopathology

Serotonin Receptor Numbers and Functioning

are Altered

Serotonin Pathways – Anatomic Connections with Multiple Regions in the Brain

Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York: Cambridge University Press; 2013.

• Major origin in raphe nuclei of brain stem

• Project to forebrain• Median raphe nucleus innervates:

• Cingulate cortex• Septal nuclei• Hippocampus

• Dorsal raphe nucleus innervates:• Substantia nigra• Striatum• Amygdala• Nucleus accumbens

• Ascending pathways are implicated in the regulation of mood, feeding, sleep, and sexual behavior

• Descending projections appear to modulate spinal sensory and motor neurons

Raphe nuclei

PFC

ACC

Hy

T

S

A

H

C

C

Cerebral Cortex

NA

Serotonin Also Powerfully Modulates Other Neurotransmitter Systems and Inflammation

The Neural Circuitry of Monoamines is Extensively Interconnected

DA = dopamine; DRN = dorsal raphe nucleus; Glu = glutamate; LC = locus coeruleus; NE = norepinephrine; VTA = ventral tegmental area.El Mansari M, et al. CNS Neurosci Ther. 2010;16(3):e1-e17.

Glu Glu

Cortical pyramidal neurons

+

Β (+) α2A (─)

NENE

+

+

─

NE

NE

─α2

LCNE

─

DA

DA

D2/3 (─)

DA

DA

D2

α2

α1

VTA DA ─

5HT

─

D2 DRN5‐HT

+ indicates agonism or

stimulatory effect

─ indicates antagonism

or inhibitory effect

Serotonin: The “Thread” That Binds GABA and Glutamate in Health and Illness

GABA = γ-aminobutyric acid.Hurley LM, et al. Front Neural Circuits. 2012;6:58.

Serotonin and Immune Interactions in the Body

Kim K. Biomol Ther. 2012;20(6):506-512.

Serotonin Modulates and Impacts Glia Functioning – Astrocytes, Microglia, and Oligodendrocytes

Miyazaki I, et al. Curr Med Chem. 2016;23(7):686-700. Kolodziejczak M, et al. ACS Chem Neurosci.2015;6(7):1219-1230. Sankowski R, et al. Front Cell Neurosci. 2015;9:28.

A Quick Conversation about Receptor Affinity and Receptor Potency

In other words, let’s discuss these 2 concepts:

1. Ki Values

2. IC50 Values

Exploring the Concept of IC50 and Ki values

Copeland RA, et al. Bioorganic & Medicinal Chemistry Letters. 1995;5(17):1947-1952.

What is IC50?

• This quantitative measure indicates how much of a drug isneeded to inhibit a given biological process by half.According to the FDA, IC50 represents the concentration ofa 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 theEquilibrium Constant

• Calculation is done as follows:

Ki =(Conc Ligand) X (Conc Receptor)

(Conc of Ligand Receptor Complex)

Why is an Understanding of Both Affinity and Potency Important?

IA = intrinsic activity; SERT = serotonin transporter; VOR = vortioxetine.Sanchez C, et al. Pharmacol Ther. 2015;145:43-57.

So, based on Ki values – the order of affinity is SERT > 3 > 1 > 7 > 1B > 1D

So, based on IC50 values – the order of potency is SERT > 3 > 1B > 1A > 1D > 7

Let’s illustrate how these 2 can be different in a single molecule – vortioxetine as an example

Now you see why knowing both Affinity and Potency for receptors is important!

Agonism, Partial Agonism, Antagonism and Inverse Agonism – All are Important Concepts for Us

Clinicians to Fully Understand

Hoyer D, et al. Trends Pharmacol Sci. 1993;14(7):270-275. Gershon MD, et al. Gastroenterology. 2007;132(1):397-414.

Dose response curves of a full agonist, partial agonist, neutral antagonist, and inverse agonist

Another Way to Look at Agonism, Antagonism, Inverse Agonism at a Receptor

Hoyer D, et al. Trends Pharmacol Sci. 1993;14(7):270-275. Gershon MD, et al. Gastroenterology. 2007;132(1):397-414.

Serotonin Receptors

A quick primer for the busy, modern clinician

Why We Clinicians Need to Know More about Serotonin and Its Receptor Pharmacology

This enhanced knowledge could

diminish side‐effect burden

This enhanced knowledge could

increase therapeutic benefit

Caution: This is exciting, emerging science where much work still needs to be done

Why We Must be Interested in Receptor Pharmacology of the Serotonin System – Many Tools, Our Medications,

Work Through Serotonin Receptors

LSD = lysergic acid diethylamide; MAOI = monoamine oxidase inhibitor.Meltzer HY, et al. Curr Opin Pharmacol. 2011;11(1):59-67. Naughton M, et al. Hum Psychopharmacol. 2000;15(6):397-415.

Serotonin Acts Through Its “Messengers”: The 7 Members of Serotonin Receptor Family (5-HT1, 2, 3, 4, 5, 6, 7)


Serotonin Receptors:A Total of 14 Total Family Members


Serotonin Receptors and Their Regional Distribution

Brichta L, et al. Trends Neurosci. 2013;36(9):543-554.

Cerebral cortex1A, 2A, 1B, 2C, 1E, 5, 7

S1B, 1D, 1E, 2A, 2C, 3, 4, 6

NA1B, 1D, 2A, 2C, 4, 6

VTA2C

SN2C

RN1A, 1B, 1D

H1A, 1B, 2A, 2C, 3, 6, 7


5‐HT receptors in the human brain: distribution, putative functions, and related pathologies. Pre‐RNA *splicing and °editing variants.

X = dorsal motor n of the vagus nerve;

CAN = accumbens n;

Amy = amygdala;

Cc = corpus callosum;

Ce = cerebellum;

Cpu= caudate‐putamen;

Cx = cortex;

DRN = dorsal raphe n;

Fcx = frontal cortex;

Hip = hippocampus;

Hyp = hypothalamus;

LS = lateral septum;

MRN = n, nucleus;

SN = subtantia nigra;

Tha = thalamus;

VTA = ventral tegmental area.

5-HT1A – Why It Matters and How 5-HT1A Agonists / Partial Agonists Can Augment Antidepressant Effect

SNRI = serotonin-norepinephrine reuptake inhibitor.Celada P, et al. CNS Drugs. 2013;27(9):703-716. Chilmonczyk Z, et al. Int J Mol Sci. 2015;16(8):18474-18506. Stahl SM, et al. Curr Drug Targets. 2013;14(5):578-585.

Normal Serotonergic Neurotransmission

SSRI/SNRI Effects onSerotonergic Neurotransmission

5‐HT1A upregulation may lead to tachyphylaxis of antidepressant activity

5‐HT1A agonists/partial agonists can therefore augment antidepressants

How Atypical Antipsychotics May Putatively Work:The Emerging Role of Serotonin 5-HT2A and 5-HT1AReceptors in Facilitating an Antidepressant Effect

PFC = prefrontal cortex.Chilmonczyk Z, et al. Int J Mol Sci. 2015;16(8):18474-18506. Celada P, et al. CNS Drugs. 2013;27(9):703-716.

Serotonin 5-HT1A and 5-HT2A and GlutaminergicPyramidal Cells – Critical Importance of Serotonin’s

Control and Regulatory Properties

Celada P, et al. Front Integr Neurosci. 2013;7:25.

Serotonin plays a regularly role in other neurotransmitter release besides Glutamate.The others include:AcetylcholineDopamineGABAHistamine

5‐HT1A and 5‐HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC)

5-HT1A and 5-HT1B – Important Self Regulators: The Need for Agonistic Activity at These Receptors

Artigas F. Pharmacol Ther. 2013;137(1):119-131. Lutz PE. J Neurophysiol. 2013;109(9):2245-2249. El Mansari M, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(3):362-373.

5‐HT1A and 1B are regulatory of serotonin functioning

Chronic SSRI treatment was shown to induce desensitization and reduced expression of 5‐HT1Bautoreceptors, likely contributing to increased serotonergic tone during SSRI exposure

The 5‐HT1B receptor is another Gi‐coupled receptor, expressed both as an auto‐ and hetero‐receptor. In contrast to the somato‐dendritic 5‐HT1AR autoreceptor, the 5‐HT1BR is localized in axon

terminals of 5‐HT neurons thereby controlling 5‐HT release in projection regions

Another Serotonin Receptor of Interest – 5-HT7

CNS = central nervous system. Volpicelli F, et al. Front Behav Neurosci. 2014;8:318.

Ishibashi T, et al. J Pharmacol Exp. 2010;334(1):171-181.

Serotonin 5-HT7 Functions:

- Cloned for 3 independent laboratories in 1993- Important in normal embryonic brain

development - Expressed centrally and peripherally- In the CNS, the receptor is expressed in the

diencephalon, forebrain, and in the Purkinje neurons of the cerebellum

- Involved with circadian rhythms, sleep-wake cycle, thermoregulation, nociception, cognition such as learning and memory processes

- Thought to be involved in disorders such as anxiety, depression, epilepsy, impulsivity, migraine, etc

Evidence: An atypical with significant 5‐HT7 antagonistic activity (lurasidone) ameliorateslearning and memory deficits in animal model of schizophrenia and induces anantidepressant‐like response in animal models for depression and anxiety. Interestingly,these pharmacologic actions of lurasidone are mediated, at least partially, by 5‐HT7R

Many Drugs of Abuse / Misuse (and Some Incredible, Potential Clinical Benefits Too!) Exert Their Effects

Through the Serotonergic System – Focus on 5-HT2A

Carhart-Harris RL, et al. Psychol Med. 2016;46(7):1379-1390.

Atypical Anti‐psychotics

Psychedelics/ Hallucinogens

An Example of How a Side Effect Could be Diminished by Knowing More about Serotonin Receptor Pharmacology

Serotonin 5-HT2C Receptor and Body Weight

Meltzer HY, et al. J Clin Invest. 2013;123(12):4986-4991. Matsui-Sakata A, et al. Drug MetabPharmacokinet. 2005;20(5):368-378.

Multiple antipsychotics, some antidepressants

Lorcaserin

Serotonin Receptors: Weight Gain and Diabetes Risk

Matsui-Sakata A, et al. Drug Metab Pharmacokinet. 2005;20(5):368-378.

The correlation between receptor occupancies and the risks of adverse reactions (weight gain and morbidity rate of type 2 diabetes mellitus)

Receptor

Spearman Rank Correlation

Weight gain(Index l)

Morbidity rate of type 2 diabetes mellitus

rs rs

α1 Adrenergic 0.50 0.60

α2 Adrenergic 0.41 0.70

Dopamine D2 0.14 -0.10

Histamine H1 0.81 0.90

Muscarinic ACh 0.83 0.90

Serotonin 5-HT1A 0.26 0.70

Serotonin 5-HT2A 0.49 0.70

Serotonin 5-HT2c 0.53 0.90

Therapeutic Potential of Serotonin Receptor Polymorphism Testing

Will It be the Wave of the Future?

Kato M, et al. Nihon Shinkei Seishin Yakurigaku Zasshi. 2009;29(1):23-31.

• Rs6295C/G SNP in the 5‐HT1A gene (HTR1A) hasbeen found to affect the expression and functionof HTR1A

• Study examined the possible association of apanel of markers in strong linkage disequilibriumof HTR1A with SSRI/SNRI response in 137Japanese major depression participants followedfor 6 weeks

• A significant association of better response toantidepressant in rs10042486C/C (P < .0001),rs6295G/G (P < .0001), and rs1364043T/T (P =.018) genotype carriers, independently fromclinical variables

Another Example of Emerging Pharmacogenetics with Serotonin Receptors

Focus on 5-HT2A Receptor Polymorphism

BDNF = brain-derived neurotrophic factor; SNP = single nucleotide polymorphism.

Kautzky A, et al. Eur Neuropsychopharmacol. 2015;26(4):441-453.

• Findings from a 225‐patient, decade‐long study from the European Group for the study of Resistant Depression

• When 12 SNPs from 5‐HT2A, COMT, PPP3CC, and BDNF are combined with 8 clinical variables, this correctly predicted 25% of responders

Summarizing Thoughts on Serotonin Receptor Polymorphism

Kautzky A, et al. Eur Neuropsychopharmacol. 2015;26(4):441-453.

• This is an emerging, not settled scientific area of investigation

• Individual SNPs have low effect

• But, when using multiple SNPs, and using interactive models, statistically significant predictive models are emerging

• Stay tuned! Cautious optimism is warranted

Serotonin Receptors – Location and Function: Both are Important Elements of Important Clinical Knowledge

Meltzer HY, et al. J Clin Invest. 2013;123(12):4986-4991.

Members of the 5‐HT2 familydisplays distinct brain and tissuedistributions. The 5‐HT2A receptoris enriched in pyramidal neuronsin layer V of the cerebral cortex,where it mediates the actions ofpimavanserin and other atypicalantipsychotic drugs. The 5‐HT2Breceptor is enriched in interstitialcells of the heart valves, where itmediates the valvulopathic actionsof certain drugs like fenfluramine.The 5‐HT2C receptor is enriched inthe hypothalamus, among other areas,particularly in nuclei engaged inregulating feeding behavior, henceit’s a target for lorcaserin.

“Targeted”, Selective Serotonin Receptor-Based Drug Development2 Recent, FDA Approved Examples

Meltzer HY, et al. J Clin Invest. 2013;123(12):4986-4991.

1. Lorcaserin

FDA indication: Weight Loss

Mechanism of action: 5-HT2C

Agonist

2. Pimavanserin

FDA indication: Psychosis in Parkinson’s disease

Mechanism of action: 5-HT2A

antagonist (no dopamine effects)

FDA Labels are Evolving, and Have More Receptor Binding Profile Information

US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/.

In Conclusion

So, what are we clinicians to take home from our enhanced knowledge base on Serotonin and its receptors?

Conclusion: Part 1 of 3

• Serotonin has evolved with us humans over amillennia and play a hugely diverse role in mind–body functioning

• We humans, as early as in utero as fetuses, needoptimized Serotonin functioning

• Mental health and mental illnesses are intricatelytied with serotonin and its receptors’ functioning(or dysfunction)


• Drug development is showing a trend towardsselective targeting of serotonin receptors, with thegoal to improve efficacy and decrease side effects

• FDA labels increasingly point our serotoninreceptor profiles in the package inserts (section12.2 – “Pharmacodynamics”)


• Pharmacogenetics are increasingly (though notyet conclusively) pointing to the importance ofserotonin receptor genetic polymorphism as partof a reason for medication response (or lack thereof)

• We clinicians can increasingly use our enhancedknowledge base to offer treatments that aregeared towards increasing our clinical output (abalance between safety/tolerability and efficacy)

Documents

Outline of Today’s Presentation Primer on Serotonin ...€¦ · Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Fourth Edition. New York: