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 CH2CH2CH2N(CH3)2HBr CH3 HN O O O

CH2

Paroxetine

Citalopram S-citalopram

Cl F3C C CH2 CH2 CH2 CH2 O CH3 Cl O H C CH3 CH2 CH2 N H

Sertraline
O CH2 CH2 NH2

Fluvoxamine

Fluoxetine

Celexa Package Insert, Forest Laboratories, Inc. Physicians Desk Reference. 1998.

Switch Rates of SSRIs

n = 573

Time course
one month
13%

Percentage of patients staying on initial drug

fluoxetine
50%

three months
23%

sertraline
43%

six months
32%

paroxetine
41%

nine months
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 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

Response

Dose

% Blockade of 5-HT
80% fluoxetine 20mg sertraline 50mg paroxetine 20mg
fluvoxamine 150mg

70%

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 Ki (nmol/L) Drug Escitalopram 5-HT 2.5 NE 6,514 DA >100,000 5-HT Selectivity NE/5-HT Ratio 2,606

Citalopram Paroxetine
Sertraline Fluoxetine

9.6 0.34
2.8 5.7

5,029 156
925 599

>100,000 963
315 5,960

524 459
330 105
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 40 20 0

potency

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

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

flu

ox

eti n

Possible Clinical Consequences of NE Reuptake Blockade

Antidepressant effect Tremors Tachycardia Enhanced cognition

Norepinephrine
120 100 80 60 40 20 0 potency

tra lin pa ro e xe tin flu e vo xa m in cit alo e pr sam ci tal op ra m

ox

flu

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

se r

eti n

dm

Selectivity for 5-HT vs. NE Transporter

900 800 700 600 500 400 300 200 100 0

selectivity

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

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

flu

ox

eti n

Selectivity
Escitalopram Citalopram Sertraline Fluoxetine Paroxetine

10000 more selective

1000

100 less selective

Owens et al., 2001

Ki (NE) / Ki (5-HT)

Possible Clinical Consequences of DA Reuptake Blockade

Psychomotor activation Psychosis Antiparkinsonian effects Enhanced cognition

Dopamine
1.2 1 0.8 0.6 0.4 0.2 0 potency

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

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

flu

ox

eti n

Possible Clinical Consequences of Muscarinic Blockade

Blurred vision Dry mouth Sinus tachycardia Constipation Urinary retention Memory dysfunction

Acetylcholine
6 5 4 3 2 1 0 potency

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

i am

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

dm

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)
100 90 80 70 60 50 40 30 20 10 0

potency

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

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

flu

Histamine (H1)-Receptor Binding

escitalopram
0

citalopram

R-citalopram

500

Ki (nM)

1000

1500

lower affinity
2000

Owens et al., 2001

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

potency

fluoxetine (Prozac)
9 8 7 6 5 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

potency

sertraline (Zoloft)
30 25 20 15 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

potency

paroxetine (Paxil)
140 120 100 80 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

potency

fluvoxamine (Luvox)
14 12 10 8 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

potency

venlafaxine (Effexor)
3 2.5 2 1.5 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

potency

nefazodone (Serzone)
0.8 0.7 0.6 0.5 0.4 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

potency

citalopram (Celexa)
2 1.8 1.6 1.4 1.2 1 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

potency

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

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
All require hepatic oxidative enzymes for metabolism.

Differences
Half-lives vary. Different P-450 isoenzymes are inhibited by the SSRIs.

All have variable affinity for blocking the 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) Protein bound (%) Absorption altered by fast or fed status Linear kinetics 27-32 56% No Yes 35 80% No Yes 20-60 96-386 94% No No 20-80 21 95% No No 10-50 26 98% Yes Yes 50-200

Dose range (mg/day) 10-20 for MDD

Van Harten, 1993; Preskorn, 1997; Preskorn, 1993; Physicians Desk Reference, 2002; Forest Laboratories, data on file, 2002

flu ox
90 80 70 60 50 40 30 20 10 0

se r pa r tin flu e vo xa m in cit e al op ra sm ci ta lo pr am ox e tr al in e

Half-lives of the SSRIs

et in e

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

0.5 0.45 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0

potency norfluoxetine

fluvoxamine

citalopram

fluoxetine

paroxetine

sertraline

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

0.012 0.01 0.008 0.006 0.004 0.002 0 potency metabolites

fluvoxamine

citalopram

fluoxetine

paroxetine

sertraline

Preskorn, 1998

CYP1A2
Substrates
Caffeine Clozapine Antidepressants Theophylline R-warfarin

Inhibitors
Fluvoxamine*

CYP1A2 Inhibition in Vitro

0.5 0.45 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0

potency

fluvoxamine

citalopram

fluoxetine

paroxetine

sertraline

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. 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
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
5-HT, NE, and DA reuptake block.
5-HT2 block; weaker 5HT and NE reuptake block.

Serzone

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