Serotonine and Depressio

Prof. Hani Hamed Dessoki, M.D.PsychiatryProf. Hani Hamed Dessoki, M.D.PsychiatryActing Dean, Faculty of Applied Health sciencesActing Dean, Faculty of Applied Health sciences

Beni Suef UniversityBeni Suef University

Prof. PsychiatryProf. Psychiatry

Chairman of Psychiatry DepartmentChairman of Psychiatry Department

Beni Suef University Beni Suef University

Supervisor of Psychiatry DepartmentSupervisor of Psychiatry Department

El-Fayoum University El-Fayoum University

APA memberAPA member

Depressive IllnessDepressive Illness

Usually treatableUsually treatable

CommonCommon

Marked disabilityMarked disability

Reduced survivalReduced survival

Increased costsIncreased costs

Depression may beDepression may be

Coincidental associationCoincidental association

Complication of physical illnessComplication of physical illness

Cause of / exacerbate somatic symptomsCause of / exacerbate somatic symptoms

Depressive IllnessDepressive Illness

2% of population suffer from2% of population suffer from pure depressionpure depression

(evenly distributed between mild, moderate,(evenly distributed between mild, moderate, and severe)and severe)

Further 8% suffer from a mixture of anxietyFurther 8% suffer from a mixture of anxiety and depressionand depression

Patients with symptoms not severe enoughPatients with symptoms not severe enough to qualify for diagnosis of either to qualify for diagnosis of either anxiety or depression.....anxiety or depression.....

Impaired working and social lives and many unexplainedImpaired working and social lives and many unexplained physical symptomsphysical symptoms

Greater use of medical servicesGreater use of medical services

““Walking Well”Walking Well”

Major Depressive Disorder (MDD)

• MDD can be a chronic, recurrent, and progressive condition1

• The US 12-month community prevalence rate for this disorder is 7%.

• MDD is associated with alterations in functional and structural changes in the brain2

• MDD, stress, and pain are all associated with similar suppression of neurotrophic factors and compromised neuroplasticity2

1. Kendler et al. Am J Psychiatry 2000;157(8):1243-51.2. Maletic et al. Int J Clin Pract 2007;61(12):2030-40.

Major Depressive Disorder (MDD)

• Affects all ages (3 folds higher in the 18-29 age group).

• More in females• High rates of comorbidity along the whole

spectrum of psychiatric disorders (Further complicates management).

Delayed Diagnosis is common

• As many as two thirds of patients with depression do not recognize that they have the disorder.

• Stigmatizing factors (personal weakness, poor faith) among the public and medical profession further delays seeking treatment.

• In the primary care setting the symptoms are often somatic and mostly go unrecognized.

Types of Depression

Violent Offender StudiesViolent Offender Studies

Low 5-HIAALow 5-HIAA

Impulsive AggressionImpulsive Aggression

History of Suicide AttemptsHistory of Suicide Attempts

Linoila Linoila et al.et al. 1983 1983

Psychopathology of Disruptive Behaviour DisordersPsychopathology of Disruptive Behaviour Disorders

Stanford University, Division of Child PsychiatryStanford University, Division of Child Psychiatry

Trauma Related Disorders Personality Disorders

Mood & Affective Disorders Substances

DISRUPTIVEBEHAVIOURDISORDERS

Suicide StudiesSuicide Studies

Low 5-HT TransportersLow 5-HT Transporters

Low 5-HTLow 5-HT2A2A Receptors Receptors

Stanley Stanley et al.et al. 1982 1982

Serotonin PathwaySerotonin Pathway

Serotonin NeurotransmissionSerotonin Neurotransmission

Serotonin

5-Hydroxytryptamine (5-HT)

SynthesisTryptophan Tryptophan

Hydroxylase 5-Hydroxytrophan (5-HTP)

Amino AcidDecarboxylase5-Hydroxytryptamine (5-HT)

Metabolism

5-HT 5-HIAAMonoamineOxidase

5-HIAA: 5-Hydroxy indole amine acid

receptor 5HT1 5HT2 5HT3 5HT4 5ht5 5ht6

5HT7

subtype 5HT1A, 5HT1B, 5HT1D, 5ht1E, 5HT1F

5HT2A, 5HT2B, 5HT2C

5HT3A, 5HT3B

5ht1A, 5ht1B

major signaling pathway

cAMP↓ IP3 ion channel

cAMP cAMP? cAMP cAMP

5HT Receptors

Serotonin Receptors

• At least 15 types and subtypes• Multiple transduction mechanisms• 5HT-1A: role in anxiety/depression• 5HT-1D: role in migraine• 5HT-2: role in CNS various behaviors, and

in cardiovascular system• 5-HT3: role in nausea and vomiting esp.

due to Chemotherapy.

several families identified, eg. several families identified, eg.

5HT5HT1 1 5HT5HT2 2 5HT5HT3 3 5HT5HT4 4 5HT5HT5 5 5HT5HT6 6 5HT5HT77

What are the receptor types?What are the receptor types?

several subtypes of each family, eg.several subtypes of each family, eg.

5HT5HT1A1A 5HT 5HT1B 1B 5HT5HT1c 1c 5HT5HT1D1D

5HT5HT

• 5-HT1C has been renamed 5-HT2C to indicate that it belongs within this subfamily.

5HT2

• There are three subtypes, 5HT2A, 5HT2B, and 5HT2C .

• The 5HT2A receptors mediate platelet aggregation and smooth muscle contraction.

Serotonin receptors:

Serotonergic ReceptorsReceptorReceptor ActionAction

5 HT1a stimulation (agonist)5 HT1a stimulation (agonist) Improvement of affective symptomsImprovement of affective symptoms(Antidepressant and anxiolytic effect) (Antidepressant and anxiolytic effect)

+ + effects on cognitive symptoms,effects on cognitive symptoms,

accelerator of dopamineaccelerator of dopamine5HT1d, 5HT1f5HT1d, 5HT1f Anti migraineAnti migraine

5HT2a5HT2a Cognition, target of atypical Cognition, target of atypical antipsychoticsantipsychotics

- Brake of dopamine- Brake of dopamine5HT2b5HT2b

Regulation of stomach contraction   Regulation of stomach contraction  

5HT2c (previously 5HT1c)5HT2c (previously 5HT1c)Regulation of appetite, anxiety, Regulation of appetite, anxiety,

seizuresseizures - target of atypical antipsychotics- target of atypical antipsychotics- Inverse agonist imrovement of - Inverse agonist imrovement of negative symptomsnegative symptoms

Serotonergic Receptors

ReceptorReceptor ActionAction5 HT35 HT3

- Antagonists antiemetic, - Antagonists antiemetic,

anxiolytic, cognitive anxiolytic, cognitive

enhancement enhancement

5 HT45 HT4 Modulation of cognition and Modulation of cognition and anxietyanxiety

5HT5a,b5HT5a,b UnknownUnknown5 HT65 HT6 -negative and cognitive negative and cognitive

symptomssymptoms-Target of antipsychoticsTarget of antipsychotics

5 HT75 HT7 -negative and cognitive negative and cognitive symptomssymptoms

- Circadian rhythms Circadian rhythms

Serotonergic Receptors5‐HT2 receptor stimulation5‐HT2 receptor stimulation 5‐HT3 receptor stimulation5‐HT3 receptor stimulation

• • AgitationAgitation• • InsomniaInsomnia

• • Sexual dysfunctionSexual dysfunction• • SatiationSatiation

-5‐HT2A receptor normally works to inhibit (brake) 5‐HT2A receptor normally works to inhibit (brake) the release of the neurotransmitter dopamine. the release of the neurotransmitter dopamine.

So, So, 5-HT2A antagonism – suppression of EPS 5-HT2A antagonism – suppression of EPS

• • NauseaNausea• • DiarrheaDiarrhea• • HeadacheHeadache

• 5HT1A is dopamine accelerator. However, 5HT2A is dopamine brake (opposite effect is 5HT1A is dopamine accelerator. However, 5HT2A is dopamine brake (opposite effect is on glutamate). on glutamate).

So, So, 5-HT5-HT1A1A agonism – effects on cognitive symptoms, suppression of EPS agonism – effects on cognitive symptoms, suppression of EPS 5-HT5-HT2A2A antagonism – suppression of EPS antagonism – suppression of EPS

DADA

DD11DD22

Caudate/putamenCaudate/putamenNormal functionNormal function

Sunstantia nigra Sunstantia nigra pars pars

compactacompacta

5-HT5-HT2A2A

--

5-HT5-HT

RapheRaphe

5-HTT5-HTT

Role of 5-HT in Nigrostriatal Dopaminergic Synapse

Nigrostriatal tractNigrostriatal tract

Receptors• 7 major types;3 of relevance to current set of medications:

• 5HT1 “slow inhibition”: through G proteins, reduce adenylyl cyclase activity; exists as postsynaptic and presynaptic receptors.

• 5HT2 “slow excitation": through G proteins, increase K+ & Ca++ influx.CNS has mostly 5HT1A (found in prefrontal cortex).

• 5HT3 “Fast excitation”: ion-coupled to Na+;some modulation also of Ca++ channels, trigger vomiting.

Serotenergic Drugs• 5HT1A Buspirone treat anxiety, depression

(partial agonist)

• 5HT1D Sumatriptan, treat migraine (partial agonist)

• 5HT2A/2C trazodone, risperidone, ketanserin treat migraine, depression, schizophrenia (antagonist)

Drugs continued…

• 5HT3 Ondansetron treat chemotherapy- induced emesis (antagonist)

• 5HT4 Cisapride treat GI disorders (agonist)• 5HT transporter SSRIs (Fluoxetine,

sertraline) treat depression, OCD, panic disorder, social phobia, post traumatic stress disorder (inhibitor)

Antidepressants

• Decreased amounts and impaired function of 5-HT associated with aggression, depression and other forms of antisocial behavior

• Antidepressants attempt to increase 5-HT levels

Receptor Overview

5HT2 subtypes

FenfluramineFenfluramine

Centrally active drugCentrally active drug

Benzeneethanamine, N-ethyl-alpha-methyl-3 Benzeneethanamine, N-ethyl-alpha-methyl-3 (trifluoromethyl)(trifluoromethyl)

ReReleases 5-HT & Blocks 5-HT uptakeleases 5-HT & Blocks 5-HT uptake

Provokes transport-mediated 5-HT releaseProvokes transport-mediated 5-HT release

Leads to Prolactin responseLeads to Prolactin response

Treatment of obesity & several psychiatric disorders involving serotonergic Treatment of obesity & several psychiatric disorders involving serotonergic systemssystems

Mood disorders are an illness - Treat them !Mood disorders are an illness - Treat them !

Drugs extremely effectiveDrugs extremely effective

Concentration, mood, and thought Concentration, mood, and thought control restoredcontrol restored

Mood stabilizing drugsMood stabilizing drugs

Role of CaffeineRole of Caffeine

Tranquillizers & AntipsychoticsTranquillizers & Antipsychoticsacute episodic use onlyacute episodic use only

E.C.T effectivenessE.C.T effectiveness

Too much Serotonin?Too much Serotonin?

Selective Serotnin Re-uptake InhibitorsSelective Serotnin Re-uptake Inhibitors

Greater selectivity at blocking 5-Ht re-uptake than Greater selectivity at blocking 5-Ht re-uptake than norepinephrine re-uptakenorepinephrine re-uptake

Lack Na channel blocking (tricyclic action)Lack Na channel blocking (tricyclic action)so safer in overdoseso safer in overdose

Greater tolerability than tricyclicsGreater tolerability than tricyclics

All SSRI’s are not the sameAll SSRI’s are not the same

Most SSRI’s bind to other receptors which are alsoMost SSRI’s bind to other receptors which are alsoresponsible for their clinical actionsresponsible for their clinical actions

Each SSRI has it’s own “Each SSRI has it’s own “portfolioportfolio” of effects” of effects

Not-So Selective?Not-So Selective?

(1) norepinephrine reuptake, (2) dopamine reuptake, (3) serotonin-2C receptors, (4) muscarinic cholinergic receptors,(5) sigma receptors, (6) nitric oxide synthase, (7) cytochrome P450 2D6, (8) cytochrome P450 3A4, (9) cytochrome P450 1A2, and (10) cytochrome P450 2Cl9.

Review of the effects of 5 SSRI’sReview of the effects of 5 SSRI’s

A meta-analysis of 20 short term comparative studies of 5 SSRIs; citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline

No difference in efficacy between compounds

Slower onset of action of fluoxetine

Fluoxetine may cause more agitation, weight loss and dermatological reactions

More patients discontinued fluvoxamine

Fewer patients stopped sertraline because of adverse effects than others

Edwards & Anderson 1999

SummarySummary

Role of Serotonin in behaviour can be clearly defined

Behaviours more complex than just Serotonin

SSRI’s produce good results in most patients

SSRI’s advanced over older treatments

SSRI’s more complicated than just Serotonin Re-uptake

SSRI’s get a bad press from media

Clinical use of SSRI’s requires careful balance of 5-HT in patient

Pathogenesis of Mdd

Major Depression

Oxidative stress(ROS production, LPO)

Nitric oxide(L-arginine-NO-cGMP)

Reduced monoamine activity5-HT, NE, DA Reduced

neurotransmitter receptors function( AC-cAMP)

Increased proinflammatory cytokines(IL-1, IL-6, TNF-α, NF-ĸß)

Dysregulation of HPA axis

Reduced neurotrophic factors(BDNF)

Chopra K, Kumar B, Kuhad A.Pathobiological targets of depression. Expert Opin Ther Targets 2011;15(4):379-4000