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

paroxetine fluoxetine paroxetine sertraline. paroxetine . fluvoxamine • sertraline.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. sertraline • venlafaxine. paroxetine • fluoxetine.

• This may account for the differential response we see in some patients with one antidepressant vs. . • Rationale for differential response may be related to different morphology of the serotonin transport protein. another.Chemical Structure • These compounds are structurally unrelated.

Inc. 1998. Forest Laboratories. . Physicians’ Desk Reference.SSRI Structures NC O CH2CH2CH2N(CH3)2·HBr CH3 HN O O O CH2 Paroxetine Citalopram S-citalopram F N Cl F3C C CH2 CH2 CH2 CH2 O CH3 Cl O H C CH3 CH2 CH2 N H N Sertraline O CH2 CH2 NH2 Fluvoxamine Fluoxetine Celexa Package Insert.

23 . Vol. Fluoxetine.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. JAMA. 2001. 286. Dec 19.. No. and Sertraline in Primary Care. “Similar Effectiveness of Paroxetine.

50%).Efficacy • All more effective than placebo (60-79%). placebo (20% vs. • Dual-mechanism antidepressants may show better efficacy when remission scores are used (HAM-D < 8). when using 50% reduction in HAM-D scores (response). . • All prevent relapse in depressed patients vs. • All have similar efficacy as TCAs (62-68%).

. • Dose-response curves vary. • Variable potency at blocking 5-HT at therapeutic doses.Pharmacodynamics • Similarities • All inhibit neuronal reuptake of 5-HT. • Differences • Variable affinity for other neuro-receptors.

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 .

6 0.000 963 315 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.000 5-HT Selectivity NE/5-HT Ratio 2..7 5.Potency and Selectivity of the SSRIs Human Monoamine Uptake Inhibition Uptake Inhibition Ki (nmol/L) Drug Escitalopram 5-HT 2.029 156 925 599 >100.606 Citalopram Paroxetine Sertraline Fluoxetine 9. 2001 .34 2.5 NE 6.8 5.514 DA >100.

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

Journal of Clinical Psychopharmacology. No3. 16. 2. Synaptic Effects of Antidepressants. Vol. Suppl.Serotonin 140 120 100 80 60 40 20 0 potency Richelson E. 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 .

2. Suppl.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 e ox flu Richelson E. Journal of Clinical Psychopharmacology. 16. Vol. Synaptic Effects of Antidepressants. No3. June 1996 se r eti n dm i .

16. Synaptic Effects of Antidepressants. Journal of Clinical Psychopharmacology. 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 for 5-HT vs. No3. Vol. NE Transporter 900 800 700 600 500 400 300 200 100 0 selectivity Richelson E.

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 .

Suppl. No3. 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 . 2.6 0. 16.2 1 0. Synaptic Effects of Antidepressants. Journal of Clinical Psychopharmacology.8 0.Dopamine 1.4 0. Vol.2 0 potency Richelson E.

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

Journal of Clinical Psychopharmacology. Vol. Synaptic Effects of Antidepressants. 1996 dm i . No3. June. 16. Suppl.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. 2.

05). crossover. 1999 . attention span • Zoloft outperformed Paxil in all measures (p<. nondepressed volunteers • double-blind. Why? Schmitt et al.SSRI Effects on Vigilance and Cognition A Placebo-controlled Comparison of Sertraline and Paroxetine • N = 24. prospective • measures of vigilance. memory. NCDEU Annual Meeting.

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

16. Journal of Clinical Psychopharmacology.Histamine (H1) 100 90 80 70 60 50 40 30 20 10 0 potency Richelson E. 2. No3. Suppl. 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 . Synaptic Effects of Antidepressants. Vol.

.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. Vol. June. Synaptic Effects of Antidepressants. 16. 2. No3. Journal of Clinical Psychopharmacology. 1996 potency . Suppl.

Journal of Clinical Psychopharmacology.sertraline (Zoloft) 30 25 20 15 10 5 0 5-HT NE DA ACH H1 Richelson E. June. 2. 16. No3. Vol. Suppl. 1996 potency . Synaptic Effects of Antidepressants.

16. Vol. 1996 potency . June. Journal of Clinical Psychopharmacology. Suppl. 2. Synaptic Effects of Antidepressants.paroxetine (Paxil) 140 120 100 80 60 40 20 0 5-HT NE DA ACH H1 Richelson E. No3.

1996 potency . 16. Suppl.fluvoxamine (Luvox) 14 12 10 8 6 4 2 0 5-HT NE DA ACH H1 Richelson E. June. Vol. Synaptic Effects of Antidepressants. 2. Journal of Clinical Psychopharmacology. No3.

Journal of Clinical Psychopharmacology.venlafaxine (Effexor) 3 2.5 1 0. Suppl. Synaptic Effects of Antidepressants. 1996 potency . No3. 16.5 0 5-HT NE DA ACH H1 Richelson E. June. 2.5 2 1. Vol.

Suppl.nefazodone (Serzone) 0.8 0.7 0. Synaptic Effects of Antidepressants.5 0.4 0. 2. Vol. 16. Journal of Clinical Psychopharmacology.6 0.1 0 5-HT NE DA ACH H1 Richelson E. June.3 0.2 0. 1996 potency . No3.

4 0. 2.6 1.6 0. 16.citalopram (Celexa) 2 1.8 0. Suppl.2 1 0.8 1. June. Journal of Clinical Psychopharmacology. Vol. No3.4 1.2 0 5-HT NE DA ACH H1 Richelson E. Synaptic Effects of Antidepressants. 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. • Different P-450 isoenzymes are inhibited by the SSRIs. • Differences • Half-lives vary. . • 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 .

1997. Preskorn. Preskorn. data on file. 2002. 2002 . 1993. Forest Laboratories. 1993. Physician’s Desk Reference.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.

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 .

3A3/4 • citalopram (s): none • venlafaxine. 2C19 • sertraline: none • paroxetine: 2D6 • fluvoxamine: 1A2. • Differences • fluoxetine: 2D6.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. mirtazepine: none Preskorn. bupropion. 2C9/10. 1998 . 2C19.

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

1998 .25 0.35 0.4 0.45 0.CYP2D6 Inhibition in Vitro 0.05 0 potency norfluoxetine fluvoxamine citalopram fluoxetine paroxetine sertraline Preskorn.3 0.1 0.5 0.15 0.2 0.

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

1998 .004 0.CYP3A4 Inhibition in Vitro 0.012 0.008 0.006 0.002 0 potency metabolites fluvoxamine citalopram fluoxetine paroxetine sertraline Preskorn.01 0.

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

15 0.5 0.1 0.2 0.3 0.4 0.35 0.45 0.05 0 potency fluvoxamine citalopram fluoxetine paroxetine sertraline Preskorn. 1998 .25 0.CYP1A2 Inhibition in Vitro 0.

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

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

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

c. (prolongs orgasmic latency 8 fold) . (potency and anti-ACH effects) • Paroxetine may be the d. • Paroxetine appears to cause higher rates of sexual dysfunction in most head to head studies.o.Sexual Dysfunction • Clinical rates approximate 50% of patients. for premature ejaculation.

0% . 2001 • N = 1022 – – – – – – – – Celexa (28.7% 67.4) Luvox (115.7) Prozac (24.3% 62.5) Zoloft (90.4) Effexor (159.5) Remeron (37.Rates of Sexual Dysfunction Montejo et al.3% 57.4% 8.7) Paxil (23.7) Serzone (324.7% 24.9% 62.7% 70.6) – – – – – – – – 72.

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).

• Relatively fewer side-effects (watch for GI). PMDD. . may be the most cost effective. • Available in liquid dosing form (mint). and OCD in children. • Most dopamine transporter blocking potency. • Lower potential for drug-drug interactions. • Intermediate half-life with no active metabolites. • At lower doses. including PTSD.sertraline (Zoloft) • Six indications. • Linear pharmacokinetics.

• Potential for drug-drug interactions.paroxetine (Paxil) • Indicated for Social Phobia. May be d. may be the most cost effective. • Significantly more anti-ACH affinity. • At higher doses.o. no active metabolites.c. • Liquid preparation available (orange). . plus five others. thus more anti-ACH side effects. • Intermediate half-life. • Available in sustained release form. • Worst side effect profile and highest rates of sexual dysfunction. for premature ejaculation. especially psychiatric (2D6) is of concern.

• May be inexpensive at lower doses.fluvoxamine (Luvox) • Two indications. includes OCD in children. . • Dosing often requires titration. no active metabolites. • Side-effect profile is relatively worse. • Intermediate half-life. and expensive at higher doses. • Highest potential for drug-drug interactions.

. • Low potency at 5-HT reuptake blockade (60% at 40mg). • Intermediate half-life. depression. No active metabolites. • Linear pharmacokinetics. • Cost effective throughout dosage range (40mg). • Lower potential for drug-drug interactions.citalopram (Celexa) • One indication. • Liquid preparation available (mint). • Fewer side effects at low doses. • Linear dose-response curve.

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

NE. • Serzone • Remeron • 5-HT and NE increase (via alpha 2 antagonism).Beyond the SSRIs • Effexor • 5-HT. • 5-HT2 block. 5HT2 and 5-HT3 block. and DA reuptake block. . weaker 5HT and NE reuptake block.

D. Geenens. KUMC . UHSCOM Assistant Clinical Professor. UMKC Adjunct Clinical Professor.Anxiety and Depression Comparison of the Serotonergic Antidepressants Douglas L.O. Faculty in Psychopharmacology. Menninger Associate Clinical Professor.

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