hanipsych ssri

Selective Serotonin Reuptake Selective Serotonin Reuptake InhibitorsInhibitors

Prof. Hani Hamed Dessoki, M.D.PsychiatryProf. Hani Hamed Dessoki, M.D.Psychiatry

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

ManagementManagement

Management: Adjust dosage for Management: Adjust dosage for optimum benefit, safety and optimum benefit, safety and compliance. Use adjunctive and compliance. Use adjunctive and combination therapies if needed combination therapies if needed however always strive for the however always strive for the simplest regimen. Keep your simplest regimen. Keep your therapeutic endpoint in mind.therapeutic endpoint in mind.

44

In the good old days…In the good old days…

SSRIs were hailed as the cure SSRIs were hailed as the cure for everyonefor everyone

Few SSRIs on the market, all Few SSRIs on the market, all considered equally efficaciousconsidered equally efficacious

Nelson. Am J Psychiatry 2006; 163: 11: 1864–1866Nelson. Am J Psychiatry 2006; 163: 11: 1864–1866

Why do we still need to talk about treating Why do we still need to talk about treating depression? depression?

Where we are today Where we are today

The burden of depression is The burden of depression is increasingincreasing

Depression is still under-Depression is still under-recognised and undertreatedrecognised and undertreated

Many treated patients do not Many treated patients do not achieve remission and risk achieve remission and risk relapse relapse

How should the patient be How should the patient be treated and monitored to obtain treated and monitored to obtain remission?remission?

55

Improving treatment outcomesImproving treatment outcomes – a multi-faceted challenge – a multi-faceted challenge

• Correct diagnosis/correct treatment goalCorrect diagnosis/correct treatment goal

• Selecting the optimal treatment:Selecting the optimal treatment:

• Effectiveness, onset, tolerability, interactive potential Effectiveness, onset, tolerability, interactive potential • Matching treatment to patient:Matching treatment to patient:

• Psychopharmacological considerationsPsychopharmacological considerations• Identifying treatment moderatorsIdentifying treatment moderators

• ComplianceCompliance

• Timely, evidence-based dose optimization, switching, Timely, evidence-based dose optimization, switching, augmentationaugmentation

• Constant monitoring and follow-upConstant monitoring and follow-up

66

What is required for full remission? What is required for full remission? The patient perspectiveThe patient perspective

Patients definition of remission: Patients definition of remission: • Positive mental health (e.g. optimism Positive mental health (e.g. optimism and self-confidence)and self-confidence)

• Return to one’s usual, normal selfReturn to one’s usual, normal self

• Return to usual level of functioningReturn to usual level of functioning

• Absence of depressive symptomsAbsence of depressive symptoms

Zimmerman et al., Am J Psychiatry 2006; 163:148–150)Zimmerman et al., Am J Psychiatry 2006; 163:148–150)

Symptomatic improvement vs functional improvement – a Symptomatic improvement vs functional improvement – a question of timing ?question of timing ?

Are rating scales linked to functionality ?Are rating scales linked to functionality ?

77Adapted from: Nierenberg & DeCecco. J Clin Psychiatry 2001; 62 (Suppl 16): Adapted from: Nierenberg & DeCecco. J Clin Psychiatry 2001; 62 (Suppl 16): 5–95–9

Defining treatment goalsDefining treatment goals

RemissionRemissionNot officially defined; varies Not officially defined; varies between studies (e.g., HAM-between studies (e.g., HAM-

D <7–10)D <7–10)

Functional Functional recoveryrecovery

Outcomes were Outcomes were herehere

Outcomes are Outcomes are now herenow here

Ideal outcome Ideal outcome should be hereshould be here

ResponseResponse

50% improvement in a validated 50% improvement in a validated depression rating scale from depression rating scale from

baseline (e.g., HAM-D)baseline (e.g., HAM-D)

88

Is remission the optimal outcome?Is remission the optimal outcome?

• Remission (as measured by symptom scales) is an Remission (as measured by symptom scales) is an important target for treatmentimportant target for treatment

• Residual symptoms are predictors of relapse, Residual symptoms are predictors of relapse, chronicity and suicidalitychronicity and suicidality

• There are various remission criteriaThere are various remission criteria• But, does remission = ‘health’ or functional But, does remission = ‘health’ or functional recovery?recovery?

‘ ‘Health’ is a state of complete physical, mental, and Health’ is a state of complete physical, mental, and social well-being and not merely the absence of disease social well-being and not merely the absence of disease

or infirmity. or infirmity.

World Health World Health OrganizationOrganization

Preamble to the Constitution of the World Health Organization, 7 April 1948Preamble to the Constitution of the World Health Organization, 7 April 1948

Currently Available in U.S.A.Currently Available in U.S.A.

fluoxetine (Prozac) 1988fluoxetine (Prozac) 1988

sertraline (Zoloft) 1992sertraline (Zoloft) 1992

paroxetine (Paxil) 1993paroxetine (Paxil) 1993

fluvoxamine (Luvox) 1994fluvoxamine (Luvox) 1994

citalopram (Celexa) 1998citalopram (Celexa) 1998

s-citalopram (Lexapro) 2002s-citalopram (Lexapro) 2002

venlafaxine (Effexor) 1995venlafaxine (Effexor) 1995

nefazodone (Serzone) 1996nefazodone (Serzone) 1996

mirtazepine (Remeron) 1997mirtazepine (Remeron) 1997

2004- Duloxetine (Cymbalta)2004- Duloxetine (Cymbalta)

SSRIsSSRIs

Are all antidepressants the Are all antidepressants the sasame?me?

EfficacyEfficacy

All more effective than placebo (60-79%).All more effective than placebo (60-79%).

All have similar efficacy as TCAs (62-68%), when using 50% All have similar efficacy as TCAs (62-68%), when using 50% reduction in HAM-D scores (response).reduction in HAM-D scores (response).

Dual-mechanism antidepressants may show better efficacy Dual-mechanism antidepressants may show better efficacy when remission scores are used (HAM-D < 8).when remission scores are used (HAM-D < 8).

All prevent relapse in depressed patients vs. placebo (20% vs. All prevent relapse in depressed patients vs. placebo (20% vs. 50%).50%).

Pharmacokinetic Parameters of the SSRIsPharmacokinetic Parameters of the SSRIs

Half-life (hours)Half-life (hours) 27-3227-32 3535 96-38696-386 2121 2626

Protein bound (%)Protein bound (%) 56%56% 80%80% 94%94% 95%95% 98%98%

Absorption alteredAbsorption altered NoNo No No NoNo NoNo YesYes by fast or fed statusby fast or fed status

Linear kineticsLinear kinetics YesYes YesYes NoNo NoNo YesYes

Dose range (mg/day) Dose range (mg/day) 10-2010-20 20-6020-60 20-8020-80 10-5010-50 50-20050-200for MDDfor MDD

Escitalopram Citalopram Fluoxetine Paroxetine SertralineEscitalopram Citalopram Fluoxetine Paroxetine Sertraline

Van Harten, 1993; Preskorn, 1997; Preskorn, 1993; Van Harten, 1993; Preskorn, 1997; Preskorn, 1993; Physician’s Physician’s

Desk ReferenceDesk Reference, 2002; Forest Laboratories, data on file, , 2002; Forest Laboratories, data on file, 20022002

Active Metabolites and the SSRIsActive Metabolites and the SSRIs

Active MetabolitesActive Metabolites

fluoxetine (1-4 fluoxetine (1-4 days) days) norfluoxetine (7-norfluoxetine (7-15 days)15 days)

No Active MetabolitesNo Active Metabolites

sertraline,sertraline,

paroxetine,paroxetine,

fluvoxamine,fluvoxamine,

citalopramcitalopram

s-citaloprams-citalopram

Dose-response CurvesDose-response Curves

DoseDose

Res

pons

eR

espo

nse

CelexaCelexa

Oth

er S

SR

I’s

Oth

er S

SR

I’s

Potency and Selectivity of the Potency and Selectivity of the SSRIsSSRIs

Owens et al., 2001Owens et al., 2001

Uptake InhibitionUptake InhibitionKKii (nmol/L) (nmol/L)

5-HT 5-HT SelectivitySelectivity

5-HT5-HT NENE DADA NE/5-HT RatioNE/5-HT Ratio

DrugDrug

2.52.5 6,5146,514 >100,000>100,000 2,6062,606EscitalopramEscitalopram

9.69.6 5,0295,029 >100,000>100,000 524524CitalopramCitalopram

2.82.8 925925 315315 330330SertralineSertraline

5.75.7 599599 5,9605,960 105105FluoxetineFluoxetine

0.340.34 156156 963963 459459ParoxetineParoxetine

Human Monoamine Uptake InhibitionHuman Monoamine Uptake Inhibition

A lower KA lower Kii reflects greater potency reflects greater potency

A higher selectivity ratio [KA higher selectivity ratio [Kii (nmol/L) NE/ K (nmol/L) NE/ Kii (nmol/L) (nmol/L) 5-HT] reflects greater 5-HT] reflects greater

specificityspecificity

lesslessselectivselectiv

ee

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

5HT5HT22

There are three subtypes, 5HTThere are three subtypes, 5HT2A2A, 5HT, 5HT2B2B, and , and

5HT5HT2C2C . .

The 5HTThe 5HT2A2A receptors mediate platelet receptors mediate platelet

aggregation and smooth muscle aggregation and smooth muscle contraction. contraction.

Serotonin receptors:Serotonin receptors:

Serotonergic ReceptorsSerotonergic Receptors

Receptor Action

5 HT1a stimulation (agonist) Improvement of affective symptoms

(Antidepressant and anxiolytic effect) +

effects on cognitive symptoms, accelerator of dopamine

5HT1d, 5HT1f Anti migraine

5HT2a Cognition, target of atypical antipsychotics

- Brake of dopamine

5HT2b

Regulation of stomach contraction

5HT2c (previously 5HT1c)

Regulation of appetite, anxiety, seizures

- target of atypical antipsychotics

- Inverse agonist imrovement of negative symptoms


Receptor Action

5 HT3- Antagonists antiemetic, anxiolytic,

cognitive enhancement

5 HT4 Modulation of cognition and anxiety

5HT5a,b Unknown

5 HT6 -negative and cognitive symptoms

-Target of antipsychotics

5 HT7 -negative and cognitive symptoms

- Circadian rhythms


5‐HT2 receptor stimulation 5‐HT3 receptor stimulation

• Agitation

• Insomnia

• Sexual dysfunction

• Satiation-5‐HT2A receptor normally works to inhibit (brake) the

release of the neurotransmitter dopamine.

So, 5-HT2A antagonism – suppression of EPS

• Nausea

• Diarrhea

• Headache

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

Normal functionNormal function

Sunstantia nigra Sunstantia nigra pars pars

compactacompacta

5-HT5-HT2A2A

--

5-HT5-HT

RapheRaphe

5-HTT

5-HTT

Role of 5-HT in Nigrostriatal Dopaminergic SynapseRole of 5-HT in Nigrostriatal Dopaminergic Synapse

Nigrostriatal tractNigrostriatal tract

MMechanism of therapeutic action: echanism of therapeutic action: pharmacologic properties pharmacologic properties

shared by all five shared by all five SSRISSRIss

IImmediate blockade of serotonin transporter on mmediate blockade of serotonin transporter on axon terminals and in somatoaxon terminals and in somato--dendritic areas of dendritic areas of serotonergic neuronserotonergic neuronee

DDelayed down regulation/desensitielayed down regulation/desensitissation of ation of somatosomato--dendritic serotonin 1A receptorsdendritic serotonin 1A receptors

DDelayed disinhibition (elayed disinhibition (ii.e., .e., ‘‘turning onturning on’’) of ) of serotonin release from axon terminalsserotonin release from axon terminals

SSRI antidepressantsSSRI antidepressantsHalf-lifeHalf-life

Short: paroxetine & fluvoxamine (missed doses Short: paroxetine & fluvoxamine (missed doses can result in uncomfortable symptoms)can result in uncomfortable symptoms)

Moderate: sertraline, citalopram, escitalopramModerate: sertraline, citalopram, escitalopram

Long: fluoxetine (good for people who may miss Long: fluoxetine (good for people who may miss doses)doses)

Mechanism of side effectsMechanism of side effects: : pharmacologic properties pharmacologic properties

shared by all five SSRIsshared by all five SSRIs

UUnwanted stimulation of undesired serotonin nwanted stimulation of undesired serotonin receptor subtypesreceptor subtypes

‘‘CCost of doing businessost of doing business’’

EEspecially clinically relevant are unwanted specially clinically relevant are unwanted stimulation of stimulation of 5HT2A/2C and/or 5HT3/4 receptors5HT2A/2C and/or 5HT3/4 receptors in various specific pathways and tissuesin various specific pathways and tissues

AAll five ll five SSRISSRIs lead to indirect s lead to indirect stimulation of serotonin 2stimulation of serotonin 2AA

receptorsreceptors Linked to short term mediation of:Linked to short term mediation of:

–– anxiety/panic attacksanxiety/panic attacks

–– insomniainsomnia

–– agitation/jitterinessagitation/jitteriness

–– sexual dysfunction (especially anorgasmia sexual dysfunction (especially anorgasmia and ejaculatory delay)and ejaculatory delay)

–– apathy/anhedonia/decreased libido apathy/anhedonia/decreased libido

–– stimulation of 5HT2A receptors inhibits stimulation of 5HT2A receptors inhibits dopamine releasedopamine release

AAll five ll five SSRISSRIs lead to indirect s lead to indirect stimulation of serotonin 2stimulation of serotonin 2C C

receptors:receptors: (only fluoxetine also stimulates 5HT2C (only fluoxetine also stimulates 5HT2C

receptors directly) receptors directly)

Mice without 5HT2C receptors are obese Mice without 5HT2C receptors are obese

BBlockade of 5HT2C receptors, especially lockade of 5HT2C receptors, especially simultaneous with blockade of histamine 1 simultaneous with blockade of histamine 1 receptorsreceptors,, is associated with weight gain is associated with weight gain

AAcute stimulation can cause weight loss and cute stimulation can cause weight loss and anxietyanxiety

CChronic stimulation can cause weight gainhronic stimulation can cause weight gain

AAll five ll five SSRISSRIs indirectly stimulate s indirectly stimulate serotonin 3 and 4 receptorsserotonin 3 and 4 receptors

Decreased feeding (5HT3)Decreased feeding (5HT3)

Loss of appetite/nausea (5HT3)Loss of appetite/nausea (5HT3)

Vomiting (chemoreceptor trigger zone/5HT3)Vomiting (chemoreceptor trigger zone/5HT3)

Increased bowel motility (5HT3 and 5HT4)Increased bowel motility (5HT3 and 5HT4)

SSRI antidepressantsSSRI antidepressantsSide effectsSide effects

Decreased sex drive and impaired sexual function Decreased sex drive and impaired sexual function tend not to resolve with timetend not to resolve with time

Nausea, diarrhea, anorexia, vomiting Nausea, diarrhea, anorexia, vomiting

- all increase- all increase with with dose and can resolve with timedose and can resolve with time

Weight gain (esp. paroxetine) after initial GI effectsWeight gain (esp. paroxetine) after initial GI effects

Headache, dizziness, anxiety (esp. fluoxetine), rash, Headache, dizziness, anxiety (esp. fluoxetine), rash, insomnia, sedation, sweating, vivid dreams, tremor, insomnia, sedation, sweating, vivid dreams, tremor, dry mouth (esp. paroxetine), bruising, dry mouth (esp. paroxetine), bruising, ↑ ↑ prolactin prolactin

MedicationMedication

02

46

810

1214

161820

5-HT NE DA ACH H1

potency

fluoxetine (Prozac)fluoxetine (Prozac)

0

1

2

3

4

5

6

7

8

9

5-HT NE DA ACH H1

potency

Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Vol. 16, No3, Suppl. 2, June, 1996Vol. 16, No3, Suppl. 2, June, 1996

sertraline (Zoloft)sertraline (Zoloft)

0

5

10

15

20

25

30

5-HT NE DA ACH H1

potency


paroxetine (Paxil)paroxetine (Paxil)

0

20

40

60

80

100

120

140

5-HT NE DA ACH H1

potency


fluvoxamine (Luvox)fluvoxamine (Luvox)

0

2

4

6

8

10

12

14

5-HT NE DA ACH H1

potency


venlafaxine (Effexor)venlafaxine (Effexor)

0

0.5

1

1.5

2

2.5

3

5-HT NE DA ACH H1

potency


nefazodone (Serzone)nefazodone (Serzone)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

5-HT NE DA ACH H1

potency


citalopram (Celexa)citalopram (Celexa)

00.2

0.40.6

0.81

1.21.4

1.61.82

5-HT NE DA ACH H1

potency


s-citalopram (Lexapro)s-citalopram (Lexapro)

0

5

10

15

20

25

30

5-HT NE DA ACH H1

East

Secondary pharmacologic Secondary pharmacologic properties of various SSRIsproperties of various SSRIs

NRINRI

CY

P 2D

6C

YP

2D6

m-AChm-ACh SRISRI

5HT2C

5HT2C

NOSNOS

CYP 1A2

CYP 1A2CYP 3A3,4

CYP 3A3,4

DRIDRI

SSRISSRI

Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000

Potentially important secondary Potentially important secondary binding properties for each SSRIbinding properties for each SSRIPotentially important secondary Potentially important secondary binding properties for each SSRIbinding properties for each SSRI

Fluoxetine and serotonin 2C stimulationFluoxetine and serotonin 2C stimulation

Sertraline and dopaminergic stimulationSertraline and dopaminergic stimulation

Paroxetine and anticholinergic propertiesParoxetine and anticholinergic properties

Fluvoxamine and sigma properties Fluvoxamine and sigma properties

Citalopram and selectivityCitalopram and selectivity

5HT2C

5HT2C

5HT2C5HT2C agonistagonist

FluoxetineFluoxetine


m-AChm-ACh

Muscarinic cholinergic (m-ACh) Muscarinic cholinergic (m-ACh) blockadeblockade

ParoxetineParoxetine


Potential clinical relevance of Potential clinical relevance of blocking muscarinic cholinergic blocking muscarinic cholinergic

receptorsreceptors

Possibly well tolerated in anxious patients, even Possibly well tolerated in anxious patients, even reducing anxiety before delayed SSRI actions beginreducing anxiety before delayed SSRI actions begin

PPossibly able to improve sleep early in treatmentossibly able to improve sleep early in treatment

MMight be poorly tolerated in elderly with early cognitive ight be poorly tolerated in elderly with early cognitive problems or Alzheimer’s problems or Alzheimer’s ddiseaseisease

MMight cause mild ight cause mild ‘‘anticholinergicanticholinergic’’ side effects such as side effects such as constipation, dry mouth, blurred vision, sedationconstipation, dry mouth, blurred vision, sedation

MMight cause more sexual dysfunction, (especially ight cause more sexual dysfunction, (especially erectile dysfunction), more weight gain and more erectile dysfunction), more weight gain and more withdrawal problemswithdrawal problems

Sigma (Sigma () blockade) blockade

FluvoxamineFluvoxamine


(Sertraline)(Sertraline)

Potential clinical relevance of Potential clinical relevance of interacting at sigma receptorsinteracting at sigma receptors

Possible anxiolytic actionsPossible anxiolytic actions

Possible antipsychotic actionsPossible antipsychotic actions

Possible increased GI side effectsPossible increased GI side effects

DRIDRI

Dopamine reuptake inhibition (DRI)Dopamine reuptake inhibition (DRI)

SertralineSertraline


Potential clinical relevance of Potential clinical relevance of enhancing dopaminergic activityenhancing dopaminergic activity

Possible cognitive enhancementPossible cognitive enhancement

Less prolactin elevationLess prolactin elevation

Possibly less weight gain Possibly less weight gain

Possibly too activating in some patients, thus Possibly too activating in some patients, thus necessitating dose titration especially in those necessitating dose titration especially in those with anxiety disorderswith anxiety disorders

SRISRICitalopramCitalopram


Potential clinical relevance of Potential clinical relevance of selectivity without secondary selectivity without secondary

pharmacologic propertiespharmacologic properties

Side effects and therapeutic effects predictable Side effects and therapeutic effects predictable based upon serotonergic mechanisms alonebased upon serotonergic mechanisms alone

Possibly less activation and less sedation than Possibly less activation and less sedation than SSRIs with secondary actionsSSRIs with secondary actions

Possibly faster onset due to lack of side effects Possibly faster onset due to lack of side effects allowing rapid dose titrationallowing rapid dose titration

Possibly good compliance at initiation of dosing if Possibly good compliance at initiation of dosing if serotonergic side effects minimalserotonergic side effects minimal

SSRIs and the cytochrome SSRIs and the cytochrome PP450 450 drug metabolidrug metabolissing enzymesing enzymes

Fluoxetine inhibits CYP450 2D6 and 3A4Fluoxetine inhibits CYP450 2D6 and 3A4

Sertraline is a weak inhibitor of CYP450 2D6 Sertraline is a weak inhibitor of CYP450 2D6

Paroxetine inhibits CYP450 2D6Paroxetine inhibits CYP450 2D6

Fluvoxamine inhibits CYP450 1A2, 2C19 and 3A4Fluvoxamine inhibits CYP450 1A2, 2C19 and 3A4

Citalopram is a weak inhibitor of CYP450 2D6Citalopram is a weak inhibitor of CYP450 2D6

CYP 2C19

CYP 2C19

CYP 2C19CYP 2C19



CYP 1A2

CYP 1A2

CYP 1A2CYP 1A2



CY

P 2D

6C

YP

2D6

CYP 2D6CYP 2D6



FluoxetineFluoxetine (Sertraline)(Sertraline) (Citalopram)(Citalopram)

CYP 3A4

CYP 3A4

CYP 3A4CYP 3A4




1. Von Moltke et al. Drug Metab Dispos 2001;29:1102-9 2. Greenblatt et al. J Clin Psychiatry 1998;59:19-273. Albers et al. Psychiatry Res 2000;96:235-243

Low potential for drug-drug Low potential for drug-drug interactionsinteractions

3A4 2D6 1A2 2C19 2C9

Escitalopram 0 + 0 0 0

Citalopram 0 + + 0 0

Fluoxetine ++ +++ + ++ ++

Paroxetine + +++ + + +

Venlafaxine + + 0 0 0

Fluvoxamine ++ + +++ +++ ++

Sertraline + + + ++ +

0 = Negligible+ = Very weak interaction

Cytochrome P450 Isozyme Inhibition In Vitro/In Vivo

++ = Moderate interaction+++ = Strong interaction

•Ca+ antagonists•Erythromycin•Ketoconazole•Lidocaine•Cancer therapies

•Anti-Arrhythmic•B-blockers•Haloperidol•Neuroleptics

•Caffeine•Ciprofloxacin•Theophylline•Verapamil

•Diazepam•Propranolol•Moclobemide•Imipramine

•Miconazole•Phenytoin•S-warfarin•NSAIDs

SSRIs/SNRIs bind onlyonly to the primary site

The net result is

an intermittent

blockade of the

serotonin transporter

protein

Cipralex binds both to the primary and the allosteric siteThe net result is

Stronger and longer

binding to the serotonin

transporter protein

Cipralex binds to Cipralex binds to both Primary binding site and allosteric site .both Primary binding site and allosteric site .

Cipralex has a high affinity for the allosteric siteCipralex has a high affinity for the allosteric site

Cipralex is a more efficient blockade of the serotonin transporter protein .Cipralex is a more efficient blockade of the serotonin transporter protein .

This effect is the best explanation for the superior efficacy of Cipralex .This effect is the best explanation for the superior efficacy of Cipralex .

Cipralex is an extremely selective serotonin reuptake inhibitor Cipralex is an extremely selective serotonin reuptake inhibitor

Explaining the superior efficacy Explaining the superior efficacy of Cipralex vs. SSRIs \ SNRIsof Cipralex vs. SSRIs \ SNRIs

5959

Cipralex Cipralex reduces Functional Impairmentreduces Functional Impairment

6060

How does that fit with your clinical experience?How does that fit with your clinical experience?A

ccep

tabili

ty (

OR

)A

ccep

tabili

ty (

OR

)

Efficacy (OR)Efficacy (OR)

●●

0.80.800

0.80.855

0.90.900

0.90.955

1.01.000

1.01.055

1.11.100

1.11.155

1.21.200

1.21.255

0.0.88

0.0.99

1.1.00

1.1.11

1.1.22

1.1.33

1.1.44


CitalopramCitalopram

BupropionBupropion

VenlafaxineVenlafaxine

MirtazapineMirtazapine

SertralineSertraline

EscitalopramEscitalopram



DuloxetineDuloxetine

Cipriani et al. Lancet 2009; 373: 746–758Cipriani et al. Lancet 2009; 373: 746–758

Summary:Summary: mechanism of action and mechanism of action and pharmacokinetics of SSRIspharmacokinetics of SSRIs

All SSRIs share a common therapeutic mechanism All SSRIs share a common therapeutic mechanism of action in depression, OCD, paniof action in depression, OCD, panicc disorder, disorder, social phobia and PTSDsocial phobia and PTSD

All SSRIs can create unwanted side effects from All SSRIs can create unwanted side effects from stimulating 5HT2A and 5HT3 receptorsstimulating 5HT2A and 5HT3 receptors

Various SSRIs have potentially clinically significant Various SSRIs have potentially clinically significant drug interactions, but these differ from one SSRI to drug interactions, but these differ from one SSRI to anotheranother

No two SSRIs have the same secondary binding No two SSRIs have the same secondary binding features, and this may account for why some features, and this may account for why some patients respond to one SSRIpatients respond to one SSRI,, or tolerate one SSRI or tolerate one SSRI,, better than anotherbetter than another

Duloxitine Atomoxetine

Reboxetine Dapoxetine

SNRI selective norepinephrine reuptake inhibitor

Selective norepinephrine uptake inhibitor

Not FDA approved yet

30,60, = Joypox tab

ultrshort acting SSRI for treatment of premature ejaculation.

6363

ConclusionConclusion

• Functional improvements should be part of the patient Functional improvements should be part of the patient specific treatment goalspecific treatment goal

• There are differences among antidepressantsThere are differences among antidepressants

– Efficacy – tolerability – acceptability – safety - cost-Efficacy – tolerability – acceptability – safety - cost-effectivenesseffectiveness

Antidepressants Antidepressants areare different - choose different - choose carefully!carefully!

Future DirectionsFuture Directions

VortioxetineVortioxetine

Vortioxetine (formerly Lu AA21004) is described Vortioxetine (formerly Lu AA21004) is described as as a multimodal a multimodal antidepressant, working as a antidepressant, working as a

- serotonin 5-HT3 and 5-HT7 receptor antagonist, - serotonin 5-HT3 and 5-HT7 receptor antagonist, - 5-HT1b receptor partial agonist, - 5-HT1b receptor partial agonist,

- 5-HT1a receptor agonist - 5-HT1a receptor agonist

- an inhibitor of the serotonin transporter SERT - an inhibitor of the serotonin transporter SERT ((BrintellixBrintellix, H. Lundbeck A/S). , H. Lundbeck A/S).

hanipsych ssri

Health & Medicine

serotonin receptors

cognitive symptoms target

htt t ht ht

dendritic serotonin

serotonin release

j psychiatry

optimal treatment

dopamine brake