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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