hanipsych ssri
TRANSCRIPT
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
Serotonergic ReceptorsSerotonergic Receptors
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
Serotonergic ReceptorsSerotonergic Receptors
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
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
paroxetine (Paxil)paroxetine (Paxil)
0
20
40
60
80
100
120
140
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
fluvoxamine (Luvox)fluvoxamine (Luvox)
0
2
4
6
8
10
12
14
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
venlafaxine (Effexor)venlafaxine (Effexor)
0
0.5
1
1.5
2
2.5
3
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
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
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
citalopram (Celexa)citalopram (Celexa)
00.2
0.40.6
0.81
1.21.4
1.61.82
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
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
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
m-AChm-ACh
Muscarinic cholinergic (m-ACh) Muscarinic cholinergic (m-ACh) blockadeblockade
ParoxetineParoxetine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
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
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
(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
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
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
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
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
FluvoxamineFluvoxamine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
CYP 1A2
CYP 1A2
CYP 1A2CYP 1A2
FluvoxamineFluvoxamine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
CY
P 2D
6C
YP
2D6
CYP 2D6CYP 2D6
ParoxetineParoxetine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
FluoxetineFluoxetine (Sertraline)(Sertraline) (Citalopram)(Citalopram)
CYP 3A4
CYP 3A4
CYP 3A4CYP 3A4
FluvoxamineFluvoxamine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
FluoxetineFluoxetine
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
FluvoxamineFluvoxamine
CitalopramCitalopram
BupropionBupropion
VenlafaxineVenlafaxine
MirtazapineMirtazapine
SertralineSertraline
EscitalopramEscitalopram
ParoxetineParoxetine
FluoxetineFluoxetine
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).