Anxiety and Depression: Douglas L. Geenens, D.O

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 • All, except citalopram (s)
• Major Depression • All, except Luvox
• Geriatric Depression • fluoxetine
• Panic Disorder • sertraline, paroxetine
• Bulimia • fluoxetine
• Social Phobia • paroxetine
• OCD in children (ages 6- • sertraline,
18)
fluvoxamine
• PTSD
• sertraline, paroxetine
• PMDD
• fluoxetine, sertraline
• GAD
• 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
Paroxetine
CH2
Citalopram
S-citalopram F N
Cl
F3C C CH2 CH2 CH2 CH2 O CH3 Cl H
O C
N Sertraline CH3
O CH2 CH2 NH2 CH2 CH2 N
Fluvoxamine Fluoxetine H
Celexa Package Insert, Forest Laboratories, Inc.

Physicians’ Desk Reference. 1998.
Switch Rates of SSRIs
n = 573
• Time course • Percentage of patients
– one month staying on initial drug
• 13% – fluoxetine
– three months • 50%
• 23% – 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 • Variable affinity for other

reuptake of 5-HT. neuro-receptors.
• Variable potency at
blocking 5-HT at
therapeutic doses.
• Dose-response curves vary.

Dose-response Curves
s I’
Response
SR
x a
er S
el e
C
Oth
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
Uptake Inhibition 5-HT
Ki (nmol/L) Selectivity
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 less
Fluoxetine 105 selective
5.7 599 5,960
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
20
0
e
e
e
am
am
e
in
in
n
ti n
eti
pr
al
pr
xe
rtr
xa
ox
lo
lo
ro
ita
ta
vo
se
flu
pa
ci
s-c
flu
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,

Vol. 16, No3, Suppl. 2, June 1996
of NE Reuptake Blockade
• Antidepressant effect
• Tremors
• Tachycardia
• Enhanced cognition
Norepinephrine
120
100
80
60
40 potency
20
0
e
i
ro e
ne
s-c pram
am
e
dm
in
in
flu etin
eti
pr
al
rt r
ox
xa
x
lo
o
al
ita
vo
se
flu
cit
pa

Selectivity for 5-HT vs. NE
Transporter
900
800
700
600
500
400
300 selectivity
200
100
0
e
ne
ne
am
am
e
in
tin
ali
eti
pr
pr
xe
rtr
ox
xa
lo
lo
ro
ita
ta
vo
se
flu
pa
ci
s-c
flu

Selectivity
Escitalopram
Citalopram
Sertraline
Fluoxetine
Paroxetine
10000 1000 100

Ki (NE) / Ki (5-HT)
more less
selective selective
Owens et al., 2001

of DA Reuptake Blockade
• Psychomotor activation
• Psychosis
• Antiparkinsonian effects
• Enhanced cognition
Dopamine
1.2
1
0.8
0.6
0.4
potency
0.2
0
alo e
pa line
se ne
ita m
ph am
e
e
in
in
flu etin
s-c pra
i
am opr
et
am
a
rtr
ox
xa
x
et
ro
l
vo
flu
cit

of Muscarinic Blockade
• Blurred vision
• Dry mouth
• Sinus tachycardia
• Constipation
• Urinary retention
• Memory dysfunction
Acetylcholine
6
5
4
3
2
potency
1
0
e
i
se tine
vo ine
i
ita am
am
ro e
dm
am
cit min
pa lin
flu xet
pr
s-c opr
e
ra
xa
ox
lo
rt
al
flu

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
of Histamine (H1) Blockade
• Sedation and drowsiness

• Weight gain
• Hypotension
Histamine (H1)
100
90
80
70
60
50
40
30 potency
20
10
0
alo e
Be ine
m
pa line
se ne
vo ne
i ti m
yl
in
s-c pra
am pra
dr
eti
flu xeti
yl
m
a
na
xa
rt r
ox
pt
lo
ro
ita
flu
cit

Histamine (H1)-Receptor Binding
escitalopram citalopram R-citalopram
0
500
Ki 1000
(nM)
1500
lower
2000
affinity
Owens et al., 2001

Medication
20
18
16
14
12
10
potency
8
6
4
2
0
5-HT NE DA ACH H1
fluoxetine (Prozac)
9
8
7
6
5
4 potency
3
2
1
0
5-HT NE DA ACH H1
sertraline (Zoloft)
30
25
20
15
potency
10
0
5-HT NE DA ACH H1
paroxetine (Paxil)
140
120
100
80
60 potency
40
20
0
5-HT NE DA ACH H1
fluvoxamine (Luvox)
14
12
10
8
6 potency
0
5-HT NE DA ACH H1
venlafaxine (Effexor)
3
2.5
1.5
potency
1
0.5
0
5-HT NE DA ACH H1
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
citalopram (Celexa)
2
1.8
1.6
1.4
1.2
1
potency
0.8
0.6
0.4
0.2
0
5-HT NE DA ACH H1
s-citalopram (Lexapro)
30
25
20
15
East
10
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
• All require hepatic • Half-lives vary.

oxidative enzymes for
metabolism.
• Different P-450
isoenzymes are
• All have variable inhibited by the
affinity for blocking the SSRIs.
p-450 isoenzymes.
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 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 50-200
for MDD
Van Harten, 1993; Preskorn, 1997; Preskorn, 1993; Physician’s

Desk Reference, 2002; Forest Laboratories, data on file, 2002
flu
ox
10
20
30
40
50
60
70
80
90
0
et
in
se e
r tr
al
in
pa e
r ox
et
in
flu
vo e
xa
m
in
cit e
al
op
ra
s-c m
i ta
lo
pr
am
Half-lives of the SSRIs
hours
P-450 Enzymes and the SSRIs
(at least moderate activity >50%)
• fluoxetine: 2D6, 2C9/10,
2C19
• P-450 enzymes
• sertraline: none
metabolize the SSRIs.
• paroxetine: 2D6
• fluvoxamine: 1A2, 2C19,
• Some SSRIs inhibit some
3A3/4
P-450 enzymes.
• citalopram (s): none
• venlafaxine, bupropion,
mirtazepine: none
Preskorn, 1998
CYP2D6
• Substrates • Inhibitors
• Analgesics • Quinidine
• Antidepressants • Paroxetine*
• Antipsychotics • Fluoxetine*
• Cardiovascular preps
• Amphetamine
• Diphenhydramine
CYP2D6 Inhibition in Vitro
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15 potency
0.1 norfluoxetine
0.05
0 fluvoxamine
citalopram
fluoxetine
sertraline
paroxetine
Preskorn, 1998
CYP3A4
• Antidepressants • Ketoconazole
• Antihistamines • Itraconazole
• Cardiovascular preps • Erythromycin
• Sedative-hypnotics • Grapefruit juice
• Corticosteroids • nefazodone*
• Carbamazepine • fluvoxamine*
• Terfenadine • norfluoxetine*
CYP3A4 Inhibition in Vitro
0.012
0.01
0.008
0.006
0.004 potency
0.002 metabolites
0
fluvoxamine
citalopram
fluoxetine
paroxetine
sertraline
Preskorn, 1998
CYP1A2
• Caffeine • Fluvoxamine*
• Clozapine
• Antidepressants
• Theophylline
• R-warfarin
CYP1A2 Inhibition in Vitro
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15 potency
0.1
0.05
0
fluvoxamine
citalopram
fluoxetine
paroxetine
sertraline
Preskorn, 1998
Active Metabolites and the SSRIs
• Active Metabolites • No Active Metabolites
• fluoxetine (1-4 days) • sertraline,

norfluoxetine (7-15 • paroxetine,
days) • fluvoxamine,
• citalopram
• s-citalopram
Auto-inhibition of Metabolism
and the SSRIs
• Auto-inhibition • No Auto-inhibition
• fluoxetine • sertraline
• paroxetine • citalopram
• fluvoxamine • 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) – 72.7%
– Paxil (23.4) – 70.7%
– Effexor (159.5) – 67.3%
– Zoloft (90.4) – 62.9%
– Luvox (115.7) – 62.3%
– Prozac (24.5) – 57.7%
– Remeron (37.7) – 24.4%
– Serzone (324.6) – 8.0%
Dosing Preparations
• Liquid preparations:
• All available in tablets
– fluoxetine (mint)
(fluoxetine 10 mg only). – 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.
• 5-HT2 block; weaker 5-

• Serzone HT and NE reuptake
block.
• 5-HT and NE increase (via

• Remeron alpha 2 antagonism); 5-
HT2 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

Anxiety and Depression: Douglas L. Geenens, D.O

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Anxiety and Depression

Comparison of the Serotonergic Antidepressants

Douglas L. Geenens, D.O.

• venlafaxine (Effexor) 1995

• This may account for the differential response we

• Rationale for differential response may be related

Celexa Package Insert, Forest Laboratories, Inc.

Kroenke et al., “Similar Effectiveness of Paroxetine, Fluoxetine, and Sertraline in Primary

• All have similar efficacy as TCAs (62-68%), when using

• Dual-mechanism antidepressants may show better efficacy

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

• All inhibit neuronal • Variable affinity for other

• Dose-response curves vary.

• 70% • fluvoxamine 150mg

• 60% • citalopram 40mg

Escitalopram 2.5 6,514 >100,000 2,606

Owens et al., 2001

Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,

Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,

Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,

10000 1000 100

Owens et al., 2001

Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,

Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,

• N = 24, nondepressed volunteers

• Sedation and drowsiness

Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,

Owens et al., 2001

• All require hepatic • Half-lives vary.

• Potential for drug-drug interactions.

Half-life (hours) 27-32 35 96-386 21 26

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

Linear kinetics Yes Yes No No Yes

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

• fluoxetine (1-4 days) • sertraline,

p<.05, APA 1998

• Paroxetine appears to cause higher rates of sexual

• Paroxetine may be the d.o.c. for premature

• Capsule preparation: fluoxetine

• Sustained release: paroxetine

• S-citalopram: 10 and 20 mg tabs. Both doses are scored.

• 5-HT2 block; weaker 5-

• 5-HT and NE increase (via

Douglas L. Geenens, D.O.

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