Comparison of the SSRIs

Report
Anxiety and Depression
Comparison 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
Variables to Compare
• Research and Development
• Indications
• Efficacy
• Structure
• Pharmacodynamics*
• Pharmacokinetics*
• Side-effects*
• Dosing Preparations
• Cost Considerations
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
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
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 related
to different morphology of the serotonin transport
protein.
SSRI Structures
NC
O
CH3
O
HN
O
O
CH2CH2CH2N(CH3)2·HBr
CH2
Citalopram
S-citalopram
F
Paroxetine
N
Cl
F3C
C CH2 CH2 CH2 CH2 O CH3
Cl
O
Sertraline
N
Fluvoxamine
H
C
O CH2 CH2 NH2
Celexa Package Insert, Forest Laboratories, Inc.
Physicians’ Desk Reference. 1998.
CH3
Fluoxetine
CH2 CH2 N
H
Switch Rates of SSRIs
n = 573
• Time course
– one month
• 13%
– three months
• 23%
• Percentage of patients
staying on initial drug
– fluoxetine
• 50%
– sertraline
– six months
• 43%
• 32%
– paroxetine
– nine months
• 41%
• 40%
Kroenke et al., “Similar Effectiveness of Paroxetine, Fluoxetine, and Sertraline in Primary
Care, JAMA, Dec 19, 2001, Vol. 286, No. 23
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%).
Pharmacodynamics
• Similarities
• Differences
• All inhibit neuronal
reuptake of 5-HT.
• Variable affinity for other
neuro-receptors.
• Variable potency at
blocking 5-HT at
therapeutic doses.
• Dose-response curves
vary.
Response
Dose-response Curves
Dose
% Blockade of 5-HT
• 80%
• fluoxetine 20mg
• sertraline 50mg
• paroxetine 20mg
• 70%
• fluvoxamine 150mg
• 60%
• citalopram 40mg
Preskorn 1998
Guidelines for Interpreting Ki
(nmol/L) values
• <10
– very potent
• 10-1000
– moderately potent
• >1000
– likely to have little clinical effect
Potency and Selectivity of the SSRIs
Human Monoamine Uptake Inhibition
5-HT
Selectivity
Uptake Inhibition
Ki (nmol/L)
Drug
5-HT
NE
DA
NE/5-HT Ratio
Escitalopram
2.5
6,514
>100,000
2,606
Citalopram
9.6
5,029
>100,000
524
Paroxetine
0.34
156
963
459
Sertraline
2.8
925
315
330
Fluoxetine
5.7
599
5,960
105
less
selective
A lower Ki reflects greater potency
A higher selectivity ratio [Ki (nmol/L) NE/ Ki (nmol/L) 5-HT] reflects greater specificity
Owens et al., 2001
Possible Clinical Consequences
of 5-HT Reuptake Blockade
• Antidepressant effect
• Gastrointestinal disturbances
• Anxiety (dose-dependent)
• Sexual dysfunction
• Impaired cognition
Serotonin
140
120
100
80
60
potency
40
flu
ox
eti
n
e
se
rtr
ali
ne
pa
ro
xe
tin
flu
e
vo
xa
m
in
cit
e
alo
pr
am
sci
tal
op
ra
m
20
0
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996
Possible Clinical Consequences
of NE Reuptake Blockade
• Antidepressant effect
• Tremors
• Tachycardia
• Enhanced cognition
Norepinephrine
120
100
80
60
40
potency
20
i
dm
tra
lin
pa
ro e
xe
tin
flu
e
vo
xa
m
in
cit
alo e
pr
sam
ci
tal
op
ra
m
se
r
flu
ox
eti
n
e
0
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996
Selectivity for 5-HT vs. NE
Transporter
900
800
700
600
500
400
300
200
100
0
flu
ox
eti
n
e
se
rtr
ali
ne
pa
ro
xe
tin
flu
e
vo
xa
m
in
e
cit
alo
pr
am
sci
tal
op
ra
m
selectivity
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996
Selectivity
Escitalopram
Citalopram
Sertraline
Fluoxetine
Paroxetine
10000
1000
100
Ki (NE) / Ki (5-HT)
more
selective
less
selective
Owens et al., 2001
Possible Clinical Consequences
of DA Reuptake Blockade
• Psychomotor activation
• Psychosis
• Antiparkinsonian effects
• Enhanced cognition
Dopamine
1.2
1
0.8
0.6
0.4
potency
0.2
flu
ox
eti
n
e
se
rtr
a
pa line
ro
x
flu etin
e
vo
xa
m
in
cit
alo e
pr
sam
ci
tal
am opr
ph am
et
am
in
e
0
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996
Possible Clinical Consequences
of Muscarinic Blockade
• Blurred vision
• Dry mouth
• Sinus tachycardia
• Constipation
• Urinary retention
• Memory dysfunction
Acetylcholine
6
5
4
3
2
potency
1
i
dm
i
am
flu
ox
e
se tine
rt
r
pa alin
ro e
flu xet
vo ine
xa
cit min
al
e
o
pr
sci
ta am
lo
pr
am
0
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
SSRI Effects on Vigilance and Cognition
A 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<.05). Why?
Schmitt et al, NCDEU Annual Meeting, 1999
Possible Clinical Consequences
of Histamine (H1) Blockade
• Sedation and drowsiness
• Weight gain
• Hypotension
Histamine (H1)
flu
ox
eti
se ne
rtr
a
pa line
ro
flu xeti
vo ne
xa
m
in
cit
alo e
s-c pra
m
ita
lo
am pra
iti m
pt
yl
Be ine
na
dr
yl
100
90
80
70
60
50
40
30
20
10
0
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
potency
Histamine (H1)-Receptor Binding
escitalopram
citalopram
R-citalopram
0
500
Ki
(nM)
1000
1500
lower
affinity
2000
Owens et al., 2001
Medication
20
18
16
14
12
10
8
6
4
2
0
potency
5-HT
NE
DA
ACH
H1
fluoxetine (Prozac)
9
8
7
6
5
potency
4
3
2
1
0
5-HT
NE
DA
ACH
H1
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
sertraline (Zoloft)
30
25
20
15
potency
10
5
0
5-HT
NE
DA
ACH
H1
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
paroxetine (Paxil)
140
120
100
80
potency
60
40
20
0
5-HT
NE
DA
ACH
H1
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
fluvoxamine (Luvox)
14
12
10
8
potency
6
4
2
0
5-HT
NE
DA
ACH
H1
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
venlafaxine (Effexor)
3
2.5
2
1.5
potency
1
0.5
0
5-HT
NE
DA
ACH
H1
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
nefazodone (Serzone)
0.8
0.7
0.6
0.5
0.4
potency
0.3
0.2
0.1
0
5-HT
NE
DA
ACH
H1
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
citalopram (Celexa)
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
potency
5-HT
NE
DA
ACH
H1
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996
s-citalopram (Lexapro)
30
25
20
15
East
10
5
0
5-HT
NE
DA
ACH
H1
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 blockade
– sertraline is the most potent
• Anticholinergic effect
– paroxetine is the most potent
Pharmacokinetics of the SSRIs
• Similarities
• Differences
• All require hepatic
oxidative enzymes for
metabolism.
• Half-lives vary.
• All have variable
affinity for blocking
the p-450 isoenzymes.
• Different P-450
isoenzymes are
inhibited by the
SSRIs.
Issues to Consider in the Elderly
• Burden on hepatic functioning.
• Potential for drug-drug interactions.
• Side-effects
Pharmacokinetic Parameters of the
SSRIs
Escitalopram Citalopram Fluoxetine Paroxetine Sertraline
Half-life (hours)
27-32
35
96-386
21
26
Protein bound (%)
56%
80%
94%
95%
98%
Absorption altered
by fast or fed status
No
No
No
No
Yes
Linear kinetics
Yes
Yes
No
No
Yes
20-60
20-80
10-50
50-200
Dose range (mg/day) 10-20
for MDD
Van Harten, 1993; Preskorn, 1997; Preskorn, 1993; Physician’s
Desk Reference, 2002; Forest Laboratories, data on file, 2002
ox
e
tr
al
in
e
tin
flu
e
vo
xa
m
in
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e
al
op
ra
sm
ci
ta
lo
pr
am
pa
r
se
r
et
in
e
flu
ox
Half-lives of the SSRIs
90
80
70
60
50
40
30
20
10
0
hours
P-450 Enzymes and the SSRIs
(at least moderate activity >50%)
• Similarities
• P-450 enzymes metabolize
the SSRIs.
• Some SSRIs inhibit some
P-450 enzymes.
Preskorn, 1998
• Differences
• fluoxetine: 2D6, 2C9/10,
2C19
• sertraline: none
• paroxetine: 2D6
• fluvoxamine: 1A2, 2C19,
3A3/4
• citalopram (s): none
• venlafaxine, bupropion,
mirtazepine: none
CYP2D6
• Substrates
• Inhibitors
•
•
•
•
•
•
• Quinidine
• Paroxetine*
• Fluoxetine*
Analgesics
Antidepressants
Antipsychotics
Cardiovascular preps
Amphetamine
Diphenhydramine
CYP2D6 Inhibition in Vitro
citalopram
fluvoxamine
paroxetine
sertraline
potency
norfluoxetine
fluoxetine
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
Preskorn, 1998
CYP3A4
• Substrates
• Inhibitors
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Antidepressants
Antihistamines
Cardiovascular preps
Sedative-hypnotics
Corticosteroids
Carbamazepine
Terfenadine
Ketoconazole
Itraconazole
Erythromycin
Grapefruit juice
nefazodone*
fluvoxamine*
norfluoxetine*
CYP3A4 Inhibition in Vitro
0.012
0.01
0.008
0.006
0.004
potency
metabolites
citalopram
fluvoxamine
paroxetine
sertraline
0
fluoxetine
0.002
Preskorn, 1998
CYP1A2
• Substrates
• Inhibitors
•
•
•
•
•
• Fluvoxamine*
Caffeine
Clozapine
Antidepressants
Theophylline
R-warfarin
CYP1A2 Inhibition in Vitro
citalopram
fluvoxamine
paroxetine
sertraline
potency
fluoxetine
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
Preskorn, 1998
Active Metabolites and the SSRIs
• Active Metabolites
• No Active Metabolites
• fluoxetine (1-4 days)
norfluoxetine (7-15
days)
•
•
•
•
•
sertraline,
paroxetine,
fluvoxamine,
citalopram
s-citalopram
Auto-inhibition of Metabolism
and the SSRIs
• Auto-inhibition
• No Auto-inhibition
• fluoxetine
• paroxetine
• fluvoxamine
• sertraline
• citalopram
• s-citalopram
Sertraline vs. Paroxetine
n=176
n=177
• diarrhea
•
•
•
•
•
•
•
constipation
fatigue
decreased libido
urinary retention
weight gain
tachycardia
increased sleep
p<.05, APA 1998
Sexual Dysfunction
• Clinical rates approximate 50% of patients.
• Paroxetine appears to cause higher rates of sexual
dysfunction 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)
Rates of Sexual Dysfunction
Montejo 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%
Dosing Preparations
• Similarities
• Differences
• All available in tablets
• Liquid preparations:
(fluoxetine 10 mg only).
–
–
–
–
fluoxetine (mint)
paroxetine (orange)
sertraline (mint)
citalopram (mint)
• Capsule preparation: fluoxetine
• Sustained release: paroxetine
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.
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).
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).
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.
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 expensive
at higher doses.
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).
S-citalopram (Lexapro)
• Most selective of the SSRIs
• Flat-dose response curve
• Potency of blocking 5-HT is comparable to
sertraline
Beyond the SSRIs
• Effexor
• 5-HT, NE, and DA
reuptake block.
• Serzone
• 5-HT2 block; weaker 5HT and NE reuptake
block.
• Remeron
• 5-HT and NE increase (via
alpha 2 antagonism); 5HT2 and 5-HT3 block.
Anxiety and Depression
Comparison of the Serotonergic Antidepressants
Douglas L. Geenens, D.O.
Faculty in Psychopharmacology, Menninger
Associate Clinical Professor, UHSCOM
Assistant Clinical Professor, UMKC
Adjunct Clinical Professor, KUMC

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