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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
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.
Fluvoxamine
F3C C CH2 CH2 CH2 CH2 O CH3
N
O CH2 CH2 NH2
Paroxetine
N
O
OO
CH2
Fluoxetine
O CH
CH2 CH2 NCH3
H
Sertraline
HNCH3
Cl
Cl
SSRI Structures
Celexa Package Insert, Forest Laboratories, Inc.Physicians’ Desk Reference. 1998.
CitalopramS-citalopram F
O
NC
CH2CH2CH2N(CH3)2·HBr
Switch Rates of SSRIsn = 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
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
• 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.
Dose-response Curves
Dose
Res
pons
e
Celexa
Oth
er S
SRI’
s
% Blockade of 5-HT
• 80%
• 70%
• 60%
• fluoxetine 20mg• sertraline 50mg• paroxetine 20mg
• fluvoxamine 150mg
• 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
Owens et al., 2001
Uptake InhibitionKi (nmol/L)
5-HT Selectivity
5-HT NE DA NE/5-HT Ratio
Drug
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 potencyA higher selectivity ratio [Ki (nmol/L) NE/ Ki (nmol/L) 5-HT] reflects greater specificity
lessselective
Possible Clinical Consequences of 5-HT Reuptake Blockade
• Antidepressant effect
• Gastrointestinal disturbances
• Anxiety (dose-dependent)
• Sexual dysfunction
• Impaired cognition
Serotonin
0
20
40
60
80
100
120
140
fluox
etine
sertr
aline
paro
xetin
e
fluvo
xam
ine
citalo
pram
s-cita
lopr
am
potency
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
0
20
40
60
80
100
120
fluox
etine
sertr
aline
paro
xetin
e
fluvo
xam
ine
citalo
pram
s-cita
lopr
am dmi
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Vol. 16, No3, Suppl. 2, June 1996
Selectivity for 5-HT vs. NE Transporter
0100200300400500600700800900
fluox
etine
sertr
aline
paro
xetin
e
fluvo
xam
ine
citalo
pram
s-cita
lopr
am
selectivity
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Vol. 16, No3, Suppl. 2, June 1996
SelectivityEscitalopramCitalopramSertralineFluoxetineParoxetine
Ki (NE) / Ki (5-HT)
100100010000
less selective
more selective
Owens et al., 2001
Possible Clinical Consequences of DA Reuptake Blockade
• Psychomotor activation
• Psychosis
• Antiparkinsonian effects
• Enhanced cognition
Dopamine
0
0.2
0.4
0.6
0.8
1
1.2
fluox
etine
sertr
aline
paro
xetin
e
fluvo
xam
ine
citalo
pram
s-cita
lopr
am
amph
etam
ine
potency
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
0
1
2
3
4
5
6
fluox
etin
e
sert
ralin
e
parox
etin
e
fluvo
xam
ine
cital
opra
m
s-cita
lopra
m ami
dmi
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Vol. 16, No3, Suppl. 2, June, 1996
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<.05). Why?
Schmitt et al, NCDEU Annual Meeting, 1999
Possible Clinical Consequences of Histamine (H1) Blockade
• Sedation and drowsiness
• Weight gain
• Hypotension
Histamine (H1)
0102030405060708090
100
fluox
etine
sertr
aline
paro
xetin
eflu
voxa
min
ecit
alopr
ams-c
italo
pram
amiti
ptyl
ineBen
adry
l
potency
Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Vol. 16, No3, Suppl. 2, June, 1996
0
500
1000
1500
2000
escitalopram citalopram R-citalopram
Ki (nM)
Histamine (H1)-Receptor Binding
lower
affinity
Owens et al., 2001
Medication
02
46
810
1214
161820
5-HT NE DA ACH H1
potency
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,Vol. 16, No3, Suppl. 2, June, 1996
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
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
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
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
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
citalopram (Celexa)
00.2
0.40.6
0.81
1.21.4
1.61.8
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
s-citalopram (Lexapro)
0
5
10
15
20
25
30
5-HT NE DA ACH H1
East
Summaryof 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
• All require hepatic oxidative enzymes for metabolism.
• All have variable affinity for blocking the p-450 isoenzymes.
• Differences
• Half-lives vary.
• 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
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; Physician’s Desk Reference, 2002; Forest Laboratories, data on file, 2002
Half-lives of the SSRIs
0102030405060708090
fluox
etin
e
sert
ralin
e
parox
etin
e
fluvo
xam
ine
cital
opra
m
s-cita
lopra
m
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.
• Differences• fluoxetine: 2D6, 2C9/10,
2C19
• sertraline: none
• paroxetine: 2D6
• fluvoxamine: 1A2, 2C19, 3A3/4
• citalopram (s): none
• venlafaxine, bupropion, mirtazepine: none
Preskorn, 1998
CYP2D6
• Substrates
• Analgesics• Antidepressants• Antipsychotics• Cardiovascular preps• Amphetamine• Diphenhydramine
• Inhibitors
• Quinidine• Paroxetine*• Fluoxetine*
CYP2D6 Inhibition in Vitro
00.05
0.10.15
0.20.25
0.30.35
0.40.45
0.5fl
uoxe
tine
sert
rali
ne
paro
xeti
ne
fluv
oxam
ine
cita
lopr
am
potencynorfluoxetine
Preskorn, 1998
CYP3A4
• Substrates
• Antidepressants
• Antihistamines
• Cardiovascular preps
• Sedative-hypnotics
• Corticosteroids
• Carbamazepine
• Terfenadine
• Inhibitors
• Ketoconazole
• Itraconazole
• Erythromycin
• Grapefruit juice
• nefazodone*
• fluvoxamine*
• norfluoxetine*
CYP3A4 Inhibition in Vitro
0
0.002
0.004
0.006
0.008
0.01
0.012fl
uoxe
tine
sert
rali
ne
paro
xeti
ne
fluv
oxam
ine
cita
lopr
am
potencymetabolites
Preskorn, 1998
CYP1A2
• Substrates
• Caffeine• Clozapine• Antidepressants• Theophylline• R-warfarin
• Inhibitors
• Fluvoxamine*
CYP1A2 Inhibition in Vitro
00.05
0.10.15
0.20.25
0.30.35
0.40.45
0.5fl
uoxe
tine
sert
rali
ne
paro
xeti
ne
fluv
oxam
ine
cita
lopr
am
potency
Preskorn, 1998
Active Metabolites and the SSRIs
• Active Metabolites
• fluoxetine (1-4 days) norfluoxetine (7-15 days)
• No Active Metabolites
• sertraline,• paroxetine,• fluvoxamine,• citalopram• s-citalopram
Auto-inhibition of Metabolism and the SSRIs
• Auto-inhibition
• fluoxetine• paroxetine• fluvoxamine
• No Auto-inhibition
• sertraline• citalopram• s-citalopram
Sertraline vs. Paroxetinen=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 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%
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
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
• 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.
Anxiety and DepressionComparison 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