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Anxiety and DepressionComparison of the Serotonergic Antidepressants
Douglas L. Geenens, D.O.Faculty in Psychopharmacology, Menninger
Associate Clinical Professor, University of Health Sciences, College of Osteopathic Medicine
Assistant Clinical Professor, University of Missouri at Kansas City School of Medicine
Adjunct Clinical Professor, University of Kansas School of Medicine
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Variables to Compare
Research and Development
Indications
Efficacy Structure
Pharmacodynamics*
Pharmacokinetics*
Side-effects*
Dosing Preparations
Cost Considerations
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Currently Available in U.S.A.
fluoxetine (Prozac) 1988
sertraline (Zoloft) 1992
paroxetine (Paxil) 1993
fluvoxamine (Luvox) 1994
citalopram (Celexa) 1998
s-citalopram (Lexapro) 2002
venlafaxine (Effexor) 1995
nefazodone (Serzone) 1996
mirtazepine (Remeron) 1997
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FDA Indications
OCD
Major Depression
Geriatric Depression
Panic Disorder Bulimia
Social Phobia
OCD in children (ages
6-18) PTSD
PMDD
GAD
All, except citalopram (s)
All, except Luvox
fluoxetine
sertraline, paroxetine fluoxetine
paroxetine
sertraline,
fluvoxamine sertraline, paroxetine
fluoxetine, sertraline
venlafaxine, paroxetine
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Chemical Structure
These compounds are structurally unrelated.
This may account for the differential response we
see in some patients with one antidepressant vs.another.
Rationale for differential response may be relatedto different morphology of the serotonin transport
protein.
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Fluvoxamine
F3C C CH2 CH2 CH2 CH2 O CH3
N
O CH2 CH2 NH2
Paroxetine
N
O
OO
CH2
Fluoxetine
O CH
CH2 CH2 N
CH3
H
Sertraline
HN
CH3
Cl
Cl
SSRI Structures
Celexa Package Insert, Forest Laboratories, Inc.Physicians Desk Reference. 1998.
Citalopram
S-citalopram F
O
NC
CH2CH2CH2N(CH3)2HBr
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Switch Rates of SSRIs
n = 573 Time course
one month
13% three months
23%
six months
32% nine months
40%
Percentage of patients
staying on initial drug
fluoxetine 50%
sertraline
43%
paroxetine 41%
Kroenke et al., Similar Effectiveness of Paroxetine, Fluoxetine, and Sertraline in Primary
Care, JAMA, Dec 19, 2001, Vol. 286, No. 23
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Efficacy
All more effective than placebo (60-79%).
All have similar efficacy as TCAs (62-68%), when using
50% reduction in HAM-D scores (response).
Dual-mechanism antidepressants may show better efficacy
when remission scores are used (HAM-D < 8).
All prevent relapse in depressed patients vs. placebo (20%
vs. 50%).
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Pharmacodynamics
Similarities
All inhibit neuronal
reuptake of 5-HT.
Differences
Variable affinity for other
neuro-receptors.
Variable potency at
blocking 5-HT at
therapeutic doses.
Dose-response curves
vary.
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Dose-response Curves
Dose
R
esponse
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% Blockade of 5-HT
80%
70%
60%
fluoxetine 20mg
sertraline 50mg
paroxetine 20mg
fluvoxamine 150mg
citalopram 40mg
Preskorn 1998
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Guidelines for Interpreting Ki
(nmol/L) values 1000
likely to have little clinical effect
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Potency and Selectivity of the SSRIs
Owens et al., 2001
Uptake Inhibition
Ki (nmol/L)
5-HT
Selectivity
5-HT NE DA NE/5-HT RatioDrug
2.5 6,514 >100,000 2,606Escitalopram
9.6 5,029 >100,000 524Citalopram
2.8 925 315 330Sertraline
5.7 599 5,960 105Fluoxetine
0.34 156 963 459Paroxetine
Human Monoamine Uptake Inhibition
A lower Ki reflects greater potency
A higher selectivity ratio [Ki (nmol/L) NE/ Ki (nmol/L)5-HT] reflects greater specificity
lessselective
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Possible Clinical Consequences
of 5-HT Reuptake Blockade
Antidepressant effect
Gastrointestinal disturbances
Anxiety (dose-dependent)
Sexual dysfunction
Impaired cognition
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Serotonin
0
20
40
60
80
100
120
140
fluox
etin
e
sertr
alin
e
paroxe
tine
fluvo
xamin
e
citalo
pram
s-citalo
pram
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996
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Possible Clinical Consequences
of NE Reuptake Blockade
Antidepressant effect
Tremors
Tachycardia
Enhanced cognition
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Norepinephrine
0
20
40
60
80
100
120
fluox
etin
e
sertr
alin
e
paroxe
tine
fluvo
xamin
e
citalo
pram
s-citalo
pram dm
i
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996
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Selectivity for 5-HT vs. NE
Transporter
0
100
200
300
400
500600
700
800
900
fluox
etin
e
sertr
alin
e
paroxe
tine
fluvo
xamin
e
citalo
pram
s-citalo
pram
selectivity
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996
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Selectivity EscitalopramCitalopram
Sertraline
Fluoxetine
Paroxetine
Ki (NE) / Ki (5-HT)
100100010000
less
selective
more
selective
Owens et al., 2001
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Possible Clinical Consequences
of DA Reuptake Blockade
Psychomotor activation Psychosis
Antiparkinsonian effects
Enhanced cognition
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Dopamine
0
0.2
0.4
0.60.8
1
1.2
fluox
etin
e
sertr
alin
e
paroxe
tine
fluvo
xamin
e
citalo
pram
s-citalo
pram
amph
etam
ine
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996
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Possible Clinical Consequences
of Muscarinic Blockade
Blurred vision
Dry mouth Sinus tachycardia
Constipation
Urinary retention
Memory dysfunction
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Acetylcholine
0
1
2
34
5
6
fluox
etin
e
sertralin
e
paro
xetin
e
fluvo
xamin
e
citalo
pram
s-citalo
pram am
idm
i
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
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SSRI Effects on Vigilance and CognitionA Placebo-controlled Comparison of Sertraline and Paroxetine
N = 24, nondepressed volunteers
double-blind, crossover, prospective
measures of vigilance, memory, attention
span
Zoloft outperformed Paxil in all measures
(p
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Possible Clinical Consequences
of Histamine (H1) Blockade
Sedation and drowsiness
Weight gain
Hypotension
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Histamine (H1)
0
102030405060
708090
100
fluox
etin
e
sertr
alin
e
paroxe
tine
fluvo
xamin
e
citalo
pram
s-citalo
pram
amiti
ptylin
e
Ben
adryl
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
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0
500
1000
1500
2000
escitalopram citalopram R-citalopram
Ki
(nM)
Histamine (H1)-Receptor Binding
lower
affinity
Owens et al., 2001
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Medication
0
2
4
6
8
10
12
14
16
18
20
5-HT NE DA ACH H1
potency
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fluoxetine (Prozac)
0
12
3
4
5
6
7
8
9
5-HT NE DA ACH H1
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
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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,
Vol. 16, No3, Suppl. 2, June, 1996
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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,
Vol. 16, No3, Suppl. 2, June, 1996
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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,
Vol. 16, No3, Suppl. 2, June, 1996
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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,
Vol. 16, No3, Suppl. 2, June, 1996
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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,
Vol. 16, No3, Suppl. 2, June, 1996
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citalopram (Celexa)
0
0.20.4
0.6
0.8
1
1.21.4
1.6
1.8
2
5-HT NE DA ACH H1
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
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s-citalopram (Lexapro)
0
5
10
15
20
25
30
5-HT NE DA ACH H1
East
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Summary
of pharmacodynamic differences Dose-response curves
citalopram is linear
Serotonergic reuptake blockade
paroxetine is the most potent
Selectivity
citalopram is the most selective
Dopamine reuptake blockadesertraline is the most potent
Anticholinergic effect
paroxetine is the most potent
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Pharmacokinetics of the SSRIs
Similarities
All require hepaticoxidative enzymes for
metabolism.
All have variable
affinity for blocking
the p-450 isoenzymes.
Differences
Half-lives vary.
Different P-450
isoenzymes areinhibited by the
SSRIs.
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Issues to Consider in the Elderly
Burden on hepatic functioning.
Potential for drug-drug interactions.
Side-effects
Ph ki eti P ete f the
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Pharmacokinetic Parameters of the
SSRIs
Half-life (hours) 27-32 35 96-386 21 26
Protein bound (%) 56% 80% 94% 95% 98%Absorption altered No No No No Yes
by fast or fed status
Linear kinetics Yes Yes No No Yes
Dose range (mg/day) 10-20 20-60 20-80 10-50 50-200for MDD
Escitalopram Citalopram Fluoxetine Paroxetine Sertraline
Van Harten, 1993; Preskorn, 1997; Preskorn, 1993; Physicians
Desk Reference, 2002; Forest Laboratories, data on file, 2002
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Half-lives of the SSRIs
0
10
20
30
40
50
60
70
80
90
fluox
etin
e
sertralin
e
paro
xetin
e
fluvo
xamine
citalo
pram
s-citalo
pram
hours
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P-450 Enzymes and the SSRIs
(at least moderate activity >50%) Similarities
P-450 enzymes metabolizethe SSRIs.
Some SSRIs inhibit some
P-450 enzymes.
Differences
fluoxetine: 2D6, 2C9/10,
2C19
sertraline: none
paroxetine: 2D6
fluvoxamine: 1A2, 2C19,
3A3/4 citalopram (s): none
venlafaxine, bupropion,
mirtazepine: none
Preskorn, 1998
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CYP2D6
Substrates
Analgesics Antidepressants
Antipsychotics
Cardiovascular preps Amphetamine
Diphenhydramine
Inhibitors
Quinidine Paroxetine*
Fluoxetine*
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CYP2D6 Inhibition in Vitro
00.05
0.10.15
0.20.25
0.3
0.350.4
0.450.5
fluoxetin
e
sertralin
e
paroxetin
e
fluvoxamin
e
citalopram
potency
norfluoxetine
Preskorn, 1998
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CYP3A4
Substrates
Antidepressants Antihistamines
Cardiovascular preps
Sedative-hypnotics
Corticosteroids
Carbamazepine
Terfenadine
Inhibitors
Ketoconazole Itraconazole
Erythromycin
Grapefrui t juice
nefazodone*
fluvoxamine*
norfluoxetine*
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CYP3A4 Inhibition in Vitro
0
0.002
0.004
0.006
0.008
0.01
0.012
fluoxetin
e
sertralin
e
paroxetin
e
fluvoxamin
e
citalopram
potency
metabolites
Preskorn, 1998
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CYP1A2
Substrates
Caffeine Clozapine
Antidepressants
Theophylline R-warfarin
Inhibitors
Fluvoxamine*
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CYP1A2 Inhibition in Vitro
00.05
0.10.15
0.20.25
0.3
0.350.4
0.450.5
fluoxetin
e
sertralin
e
paroxetin
e
fluvoxamin
e
citalopram
potency
Preskorn, 1998
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Active Metabolites and the SSRIs
Active Metabolites
fluoxetine (1-4 days)norfluoxetine (7-15
days)
No Active Metabolites
sertraline, paroxetine,
fluvoxamine,
citalopram s-citalopram
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Auto-inhibition of Metabolism
and the SSRIs Auto-inhibition
fluoxetine paroxetine
fluvoxamine
No Auto-inhibition
sertraline citalopram
s-citalopram
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Sertraline vs. Paroxetine
n=176 n=177 diarrhea constipation
fatigue
decreased libido urinary retention
weight gain
tachycardia increased sleep
p
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Sexual Dysfunction
Clinical rates approximate 50% of patients.
Paroxetine appears to cause higher rates of sexualdysfunction in most head to head studies. (potency
and anti-ACH effects)
Paroxetine may be the d.o.c. for premature
ejaculation. (prolongs orgasmic latency 8 fold)
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Rates of Sexual DysfunctionMontejo et al, 2001
N = 1022
Celexa (28.7)
Paxil (23.4) Effexor (159.5)
Zoloft (90.4)
Luvox (115.7)
Prozac (24.5) Remeron (37.7)
Serzone (324.6)
72.7%
70.7% 67.3%
62.9%
62.3%
57.7% 24.4%
8.0%
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Dosing Preparations
Similarities
All available in tablets(fluoxetine 10 mg only).
Differences
Liquid preparations: fluoxetine (mint)
paroxetine (orange)
sertraline (mint)
citalopram (mint)
Capsule preparation: fluoxetine
Sustained release: paroxetine
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Cost Considerations fluoxetine:
10 mg scored tab, 10 and 20 mg pulvules are the same cost
40 mg dose offers no cost savings.
90 mg weekly is competitive
Generic preparation available
sertraline: 25, 50, and 100 mg tablets are the same cost. All are scored.
paroxetine: 10, 20, 30, 40 mg tablets are the same cost. 10 and 20 mg tablet
are scored. 12.5, 25, 37.5 CR are the same cost.
fluvoxamine: 25, 50, and 100 mg tabs. 50 and 100 mg tablets are scored.
citalopram: 20 and 40 mg tablets are the same cost. Both doses are scored.
S-citalopram: 10 and 20 mg tabs. Both doses are scored.
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fluoxetine (Prozac) Most US research across the diagnostic spectrum.
Indicated for Bulimia, Geriatric Depression, and PMDD,
plus two others.
Longest half-life. Relatively fewer side effects.
Potential for drug-drug interactions, especially psychiatric
(2D6) is a concern.
At doses below 10 mg, inexpensive. At higher doses, cost is incrementally higher. Some cost
savings with weekly dose and generic prep.
Available in a liquid dosing form (mint).
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sertraline (Zoloft)
Six indications, including PTSD, PMDD, and OCD in
children.
Most dopamine transporter blocking potency.
Intermediate half-life with no active metabolites.
Linear pharmacokinetics.
Lower potential for drug-drug interactions.
Relatively fewer side-effects (watch for GI). At lower doses, may be the most cost effective.
Available in liquid dosing form (mint).
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paroxetine (Paxil)
Indicated for Social Phobia, plus five others.
Significantly more anti-ACH affinity, thus more anti-ACH
side effects.
Intermediate half-life, no active metabolites. Potential for drug-drug interactions, especially psychiatric
(2D6) is of concern.
Worst side effect profile and highest rates of sexual
dysfunction. May be d.o.c. for premature ejaculation. Liquid preparation available (orange).
At higher doses, may be the most cost effective.
Available in sustained release form.
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fluvoxamine (Luvox)
Two indications, includes OCD in children.
Intermediate half-life, no active metabolites.
Side-effect profile is relatively worse. Dosing often requires titration.
Highest potential for drug-drug interactions.
May be inexpensive at lower doses, and expensiveat higher doses.
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citalopram (Celexa)
One indication, depression.
Low potency at 5-HT reuptake blockade (60% at 40mg).
Linear dose-response curve.
Intermediate half-life. No active metabolites. Linear pharmacokinetics.
Fewer side effects at low doses.
Lower potential for drug-drug interactions.
Cost effective throughout dosage range (40mg).
Liquid preparation available (mint).
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S-citalopram (Lexapro)
Most selective of the SSRIs
Flat-dose response curve
Potency of blocking 5-HT is comparable tosertraline
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Beyond the SSRIs
Effexor
Serzone
Remeron
5-HT, NE, and DA
reuptake block.
5-HT2 block; weaker 5-
HT and NE reuptake
block.
5-HT and NE increase (via
alpha 2 antagonism); 5-
HT2 and 5-HT3 block.
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Anxiety and DepressionComparison of the Serotonergic Antidepressants
Douglas L. Geenens, D.O.Faculty in Psychopharmacology, Menninger
Associate Clinical Professor, UHSCOMAssistant Clinical Professor, UMKC
Adjunct Clinical Professor, KUMC
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