anxiety and depression comparison of the serotonergic antidepressants douglas l. geenens, d.o....

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


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


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


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


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


sertraline (Zoloft)

0

5

10

15

20

25

30

5-HT NE DA ACH H1

potency


paroxetine (Paxil)

0

20

40

60

80

100

120

140

5-HT NE DA ACH H1

potency


fluvoxamine (Luvox)

0

2

4

6

8

10

12

14

5-HT NE DA ACH H1

potency


venlafaxine (Effexor)

0

0.5

1

1.5

2

2.5

3

5-HT NE DA ACH H1

potency


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


citalopram (Celexa)

00.2

0.40.6

0.81

1.21.4

1.61.8

2

5-HT NE DA ACH H1

potency


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

anxiety and depression comparison of the serotonergic antidepressants douglas l. geenens, d.o....

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