ssris and its effects

7/30/2019 Ssris and its effects

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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


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Variables to Compare

Research and Development

Indications

Efficacy Structure

Pharmacodynamics*

Pharmacokinetics*

Side-effects*

Dosing Preparations

Cost Considerations


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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


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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


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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 relatedto different morphology of the serotonin transport

protein.


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Fluvoxamine

F3C C CH2 CH2 CH2 CH2 O CH3

N

O CH2 CH2 NH2

Paroxetine

N

O

OO

CH2

Fluoxetine

O CH

CH2 CH2 N

CH3

H

Sertraline

HN

CH3

Cl

Cl

SSRI Structures

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

Citalopram

S-citalopram F

O

NC

CH2CH2CH2N(CH3)2HBr


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Switch Rates of SSRIs

n = 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


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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%).


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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.


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Dose-response Curves

Dose

R

esponse


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% Blockade of 5-HT

80%

70%

60%

fluoxetine 20mg

sertraline 50mg

paroxetine 20mg

fluvoxamine 150mg

citalopram 40mg

Preskorn 1998


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Guidelines for Interpreting Ki

(nmol/L) values 1000

likely to have little clinical effect


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Potency and Selectivity of the SSRIs

Owens et al., 2001

Uptake Inhibition

Ki (nmol/L)

5-HT

Selectivity

5-HT NE DA NE/5-HT RatioDrug

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 potency

A higher selectivity ratio [Ki (nmol/L) NE/ Ki (nmol/L)5-HT] reflects greater specificity

lessselective


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Possible Clinical Consequences

of 5-HT Reuptake Blockade

Antidepressant effect

Gastrointestinal disturbances

Anxiety (dose-dependent)

Sexual dysfunction

Impaired cognition


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Serotonin

0

20

40

60

80

100

120

140

fluox

etin

e

sertr

alin

e

paroxe

tine

fluvo

xamin

e

citalo

pram

s-citalo

pram

potency

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

Vol. 16, No3, Suppl. 2, June 1996


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of NE Reuptake Blockade

Antidepressant effect

Tremors

Tachycardia

Enhanced cognition


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Norepinephrine

0

20

40

60

80

100

120

fluox

etin

e

sertr

alin

e

paroxe

tine

fluvo

xamin

e

citalo

pram

s-citalo

pram dm

i

potency




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Selectivity for 5-HT vs. NE

Transporter

0

100

200

300

400

500600

700

800

900

fluox

etin

e

sertr

alin

e

paroxe

tine

fluvo

xamin

e

citalo

pram

s-citalo

pram

selectivity




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Selectivity EscitalopramCitalopram

Sertraline

Fluoxetine

Paroxetine

Ki (NE) / Ki (5-HT)

100100010000

less

selective

more

selective

Owens et al., 2001


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of DA Reuptake Blockade

Psychomotor activation Psychosis

Antiparkinsonian effects

Enhanced cognition


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Dopamine

0

0.2

0.4

0.60.8

1

1.2

fluox

etin

e

sertr

alin

e

paroxe

tine

fluvo

xamin

e

citalo

pram

s-citalo

pram

amph

etam

ine

potency




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of Muscarinic Blockade

Blurred vision

Dry mouth Sinus tachycardia

Constipation

Urinary retention

Memory dysfunction


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Acetylcholine

0

1

2

34

5

6

fluox

etin

e

sertralin

e

paro

xetin

e

fluvo

xamin

e

citalo

pram

s-citalo

pram am

idm

i

potency


Vol. 16, No3, Suppl. 2, June, 1996


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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


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of Histamine (H1) Blockade

Sedation and drowsiness

Weight gain

Hypotension


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Histamine (H1)

0

102030405060

708090

100

fluox

etin

e

sertr

alin

e

paroxe

tine

fluvo

xamin

e

citalo

pram

s-citalo

pram

amiti

ptylin

e

Ben

adryl

potency




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0

500

1000

1500

2000

escitalopram citalopram R-citalopram

Ki

(nM)

Histamine (H1)-Receptor Binding

lower

affinity

Owens et al., 2001


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Medication

0

2

4

6

8

10

12

14

16

18

20

5-HT NE DA ACH H1

potency


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fluoxetine (Prozac)

0

12

3

4

5

6

7

8

9

5-HT NE DA ACH H1

potency




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sertraline (Zoloft)

0

5

10

15

20

25

30

5-HT NE DA ACH H1

potency




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paroxetine (Paxil)

0

20

40

60

80

100

120

140

5-HT NE DA ACH H1

potency




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fluvoxamine (Luvox)

0

2

4

6

8

10

12

14

5-HT NE DA ACH H1

potency




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venlafaxine (Effexor)

0

0.5

1

1.5

2

2.5

3

5-HT NE DA ACH H1

potency




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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




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citalopram (Celexa)

0

0.20.4

0.6

0.8

1

1.21.4

1.6

1.8

2

5-HT NE DA ACH H1

potency




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s-citalopram (Lexapro)

0

5

10

15

20

25

30

5-HT NE DA ACH H1

East


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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 blockadesertraline is the most potent

Anticholinergic effect

paroxetine is the most potent


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Pharmacokinetics of the SSRIs

Similarities

All require hepaticoxidative enzymes for

metabolism.

All have variable

affinity for blocking

the p-450 isoenzymes.

Differences

Half-lives vary.

Different P-450

isoenzymes areinhibited by the

SSRIs.


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Issues to Consider in the Elderly

Burden on hepatic functioning.

Potential for drug-drug interactions.

Side-effects

Ph ki eti P ete f the


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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; Physicians

Desk Reference, 2002; Forest Laboratories, data on file, 2002


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Half-lives of the SSRIs

0

10

20

30

40

50

60

70

80

90

fluox

etin

e

sertralin

e

paro

xetin

e

fluvo

xamine

citalo

pram

s-citalo

pram

hours


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P-450 Enzymes and the SSRIs

(at least moderate activity >50%) Similarities

P-450 enzymes metabolizethe 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


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CYP2D6

Substrates

Analgesics Antidepressants

Antipsychotics

Cardiovascular preps Amphetamine

Diphenhydramine

Inhibitors

Quinidine Paroxetine*

Fluoxetine*


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CYP2D6 Inhibition in Vitro

00.05

0.10.15

0.20.25

0.3

0.350.4

0.450.5

fluoxetin

e

sertralin

e

paroxetin

e

fluvoxamin

e

citalopram

potency

norfluoxetine

Preskorn, 1998


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CYP3A4

Substrates

Antidepressants Antihistamines

Cardiovascular preps

Sedative-hypnotics

Corticosteroids

Carbamazepine

Terfenadine

Inhibitors

Ketoconazole Itraconazole

Erythromycin

Grapefrui t juice

nefazodone*

fluvoxamine*

norfluoxetine*


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CYP3A4 Inhibition in Vitro

0

0.002

0.004

0.006

0.008

0.01

0.012

fluoxetin

e

sertralin

e

paroxetin

e

fluvoxamin

e

citalopram

potency

metabolites

Preskorn, 1998


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CYP1A2

Substrates

Caffeine Clozapine

Antidepressants

Theophylline R-warfarin

Inhibitors

Fluvoxamine*


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CYP1A2 Inhibition in Vitro

00.05

0.10.15

0.20.25

0.3

0.350.4

0.450.5

fluoxetin

e

sertralin

e

paroxetin

e

fluvoxamin

e

citalopram

potency

Preskorn, 1998


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Active Metabolites and the SSRIs

Active Metabolites

fluoxetine (1-4 days)norfluoxetine (7-15

days)

No Active Metabolites

sertraline, paroxetine,

fluvoxamine,

citalopram s-citalopram


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Auto-inhibition of Metabolism

and the SSRIs Auto-inhibition

fluoxetine paroxetine

fluvoxamine

No Auto-inhibition

sertraline citalopram

s-citalopram


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Sertraline vs. Paroxetine

n=176 n=177 diarrhea constipation

fatigue

decreased libido urinary retention

weight gain

tachycardia increased sleep

p


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Sexual Dysfunction

Clinical rates approximate 50% of patients.

Paroxetine appears to cause higher rates of sexualdysfunction 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)


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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%


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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


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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.


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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).


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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).


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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.


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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 expensiveat higher doses.


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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).


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S-citalopram (Lexapro)

Most selective of the SSRIs

Flat-dose response curve

Potency of blocking 5-HT is comparable tosertraline


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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.


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Anxiety and DepressionComparison of the Serotonergic Antidepressants

Douglas L. Geenens, D.O.Faculty in Psychopharmacology, Menninger

Associate Clinical Professor, UHSCOMAssistant Clinical Professor, UMKC

Adjunct Clinical Professor, KUMC


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ssris and its effects

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