1. 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

2. Variables to Compare
• Research and Development
• Indications
• Efficacy
• Structure
• Pharmacodynamics*
• Pharmacokinetics*
• Side-effects*
• Dosing Preparations
• Cost Considerations

3. 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

4. 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 • sertraline,
6-18) fluvoxamine
• PTSD • sertraline, paroxetine
• PMDD • fluoxetine, sertraline
• GAD • venlafaxine, paroxetine

5. 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.

6. 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.

7. 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

8. 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%).

9. 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.

10. Dose-response Curves
s I’
Response
SR
exa
er S
Cel
Oth
Dose

11. % Blockade of 5-HT
• 80% • fluoxetine 20mg
• sertraline 50mg
• paroxetine 20mg
• 70% • fluvoxamine 150mg
• 60% • citalopram 40mg
Preskorn 1998

12. Guidelines for Interpreting Ki
(nmol/L) values
• <10
– very potent
• 10-1000
– moderately potent
• >1000
– likely to have little clinical effect

13. 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

14. Possible Clinical Consequences
of 5-HT Reuptake Blockade
• Antidepressant effect
• Gastrointestinal disturbances
• Anxiety (dose-dependent)
• Sexual dysfunction
• Impaired cognition

15. Serotonin
140
120
100
80
60
potency
40
20
0
e
e
e
m
am
e
in
li n
n
ti n
ra
eti
m
pr
tra
xe
op
ox
xa
lo
ro
r
al
ita
vo
se
fl u
cit
pa
s-c
fl u
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996

16. Possible Clinical Consequences
of NE Reuptake Blockade
• Antidepressant effect
• Tremors
• Tachycardia
• Enhanced cognition

17. Norepinephrine
120
100
80
60
40 potency
20
0
e
i
ro e
e
s-c pram
am
e
dm
in
n
in
flu etin
ali
m
pr
et
rt r
xa
ox
x
lo
lo
ta
ita
vo
se
flu
pa
ci
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996

18. Selectivity for 5-HT vs. NE
Transporter
900
800
700
600
500
400
300 selectivity
200
100
0
e
e
e
m
am
e
in
l in
in
t in
ra
m
pr
et
tra
xe
op
ox
xa
lo
ro
r
al
ita
vo
se
fl u
cit
pa
s-c
fl u
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996

19. Selectivity
Escitalopram
Citalopram
Sertraline
Fluoxetine
Paroxetine
10000 1000 100
Ki (NE) / Ki (5-HT)
more less
selective selective
Owens et al., 2001

20. Possible Clinical Consequences
of DA Reuptake Blockade
• Psychomotor activation
• Psychosis
• Antiparkinsonian effects
• Enhanced cognition

21. Dopamine
1.2
1
0.8
0.6
0.4
potency
0.2
0
e
pa line
e
e
ph am
am
e
in
in
in
flu etin
m
am opr
et
pr
am
tra
xa
ox
x
lo
et
ro
r
tal
ta
vo
se
fl u
ci
ci
s-
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June 1996

22. Possible Clinical Consequences
of Muscarinic Blockade
• Blurred vision
• Dry mouth
• Sinus tachycardia
• Constipation
• Urinary retention
• Memory dysfunction

23. Acetylcholine
6
5
4
3
2
potency
1
0
e
i
se tine
vo ine
i
ta am
am
ro e
dm
am
c i mi n
pa lin
fl u xe t
pr
s- opr
e
ra
xa
ox
lo
rt
l
fl u
ta
ci
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996

24. 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

25. Possible Clinical Consequences
of Histamine (H1) Blockade
• Sedation and drowsiness
• Weight gain
• Hypotension

26. Histamine (H1)
100
90
80
70
60
50
40
30 potency
20
10
0
alo e
Be ine
m
pa line
e
yl
vo ne
it i m
in
n
s-c pra
am pra
dr
eti
flu xeti
yl
m
tra
na
xa
ox
pt
lo
ro
r
ita
se
fl u
cit
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996

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

28. Medication
20
18
16
14
12
10
potency
8
6
4
2
0
5-HT NE DA ACH H1

29. fluoxetine (Prozac)
9
8
7
6
5
4 potency
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

30. 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

31. paroxetine (Paxil)
140
120
100
80
60 potency
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

32. fluvoxamine (Luvox)
14
12
10
8
6 potency
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

33. 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

34. 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

35. 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
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,
Vol. 16, No3, Suppl. 2, June, 1996

36. s-citalopram (Lexapro)
30
25
20
15
East
10
5
0
5-HT NE DA ACH H1

37. 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

38. Pharmacokinetics of the SSRIs
• Similarities • Differences
• All require hepatic • Half-lives vary.
oxidative enzymes for
metabolism. • Different P-450
isoenzymes are
• All have variable inhibited by the
affinity for blocking SSRIs.
the p-450 isoenzymes.

39. Issues to Consider in the Elderly
• Burden on hepatic functioning.
• Potential for drug-drug interactions.
• Side-effects

40. 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

41. fl u
ox
0
10
20
30
40
50
60
70
80
et 90
in
se e
r tr
al
in
pa e
r ox
etin
fl u
vo e
xa
m
in
ci
ta e
lo
pr
s-c am
ita
lo
pr
am
Half-lives of the SSRIs
hours

42. P-450 Enzymes and the SSRIs
(at least moderate activity >50%)
• Similarities • Differences
• fluoxetine: 2D6, 2C9/10,
• P-450 enzymes 2C19
metabolize the SSRIs. • sertraline: none
• paroxetine: 2D6
• Some SSRIs inhibit some • fluvoxamine: 1A2, 2C19,
P-450 enzymes. 3A3/4
• citalopram (s): none
• venlafaxine, bupropion,
mirtazepine: none
Preskorn, 1998

43. CYP2D6
• Substrates • Inhibitors
• Analgesics • Quinidine
• Antidepressants • Paroxetine*
• Antipsychotics • Fluoxetine*
• Cardiovascular preps
• Amphetamine
• Diphenhydramine

44. 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

45. CYP3A4
• Substrates • Inhibitors
• Antidepressants • Ketoconazole
• Antihistamines • Itraconazole
• Cardiovascular preps • Erythromycin
• Sedative-hypnotics • Grapefruit juice
• Corticosteroids • nefazodone*
• Carbamazepine • fluvoxamine*
• Terfenadine • norfluoxetine*

46. CYP3A4 Inhibition in Vitro
0.012
0.01
0.008
0.006
0.004 potency
0.002 metabolites
0
fluvoxamine
citalopram
fluoxetine
sertraline
paroxetine
Preskorn, 1998

47. CYP1A2
• Substrates • Inhibitors
• Caffeine • Fluvoxamine*
• Clozapine
• Antidepressants
• Theophylline
• R-warfarin

48. 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
sertraline
paroxetine
Preskorn, 1998

49. Active Metabolites and the SSRIs
• Active Metabolites • No Active Metabolites
• fluoxetine (1-4 days) • sertraline,
norfluoxetine (7-15 • paroxetine,
days) • fluvoxamine,
• citalopram
• s-citalopram

50. Auto-inhibition of Metabolism
and the SSRIs
• Auto-inhibition • No Auto-inhibition
• fluoxetine • sertraline
• paroxetine • citalopram
• fluvoxamine • s-citalopram

51. Sertraline vs. Paroxetine
n=176 n=177
• diarrhea • constipation
• fatigue
• decreased libido
• urinary retention
• weight gain
• tachycardia
• increased sleep
p<.05, APA 1998

52. 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)

53. 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%

54. Dosing Preparations
• Similarities • Differences
• All available in tablets • Liquid preparations:
– fluoxetine (mint)
(fluoxetine 10 mg only).
– paroxetine (orange)
– sertraline (mint)
– citalopram (mint)
• Capsule preparation: fluoxetine
• Sustained release: paroxetine

55. 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.

56. 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).

57. 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).

58. 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.

59. 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.

60. 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).

61. S-citalopram (Lexapro)
• Most selective of the SSRIs
• Flat-dose response curve
• Potency of blocking 5-HT is comparable to
sertraline

62. 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.

63. 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