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. paroxetine • fluoxetine. sertraline • venlafaxine. paroxetine . paroxetine fluoxetine paroxetine sertraline. except Luvox fluoxetine sertraline. fluvoxamine • sertraline. except citalopram (s) All.

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

Inc. 1998. . Forest Laboratories.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. Physicians’ Desk Reference.

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

. • All prevent relapse in depressed patients vs. 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 have similar efficacy as TCAs (62-68%). placebo (20% vs.Efficacy • All more effective than placebo (60-79%). 50%).

Pharmacodynamics • Similarities • All inhibit neuronal reuptake of 5-HT. • Dose-response curves vary. . • Variable potency at blocking 5-HT at therapeutic doses. • 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 .

029 156 925 599 >100..8 5.7 5. 2001 .34 2.514 DA >100.5 NE 6.606 Citalopram Paroxetine Sertraline Fluoxetine 9.000 963 315 5.000 5-HT Selectivity NE/5-HT Ratio 2.6 0.Potency and Selectivity of the SSRIs Human Monoamine Uptake Inhibition Uptake Inhibition Ki (nmol/L) Drug Escitalopram 5-HT 2.960 524 459 330 105 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.

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

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

Possible Clinical Consequences of NE Reuptake Blockade • Antidepressant effect • Tremors • Tachycardia • Enhanced cognition .

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

Vol. 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 . Journal of Clinical Psychopharmacology. NE Transporter 900 800 700 600 500 400 300 200 100 0 selectivity Richelson E. Synaptic Effects of Antidepressants. No3. Suppl. 16.Selectivity for 5-HT vs. 2.

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 .

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 . Suppl.8 0. Journal of Clinical Psychopharmacology. 2.2 1 0. 16.4 0. Vol.6 0. No3. Synaptic Effects of Antidepressants.2 0 potency Richelson E.Dopamine 1.

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

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

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

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

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

2001 .Histamine (H1)-Receptor Binding escitalopram 0 citalopram R-citalopram 500 Ki (nM) 1000 1500 lower affinity 2000 Owens et al..

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

2. June. Vol. 1996 potency . Journal of Clinical Psychopharmacology. No3. Synaptic Effects of Antidepressants. Suppl.fluoxetine (Prozac) 9 8 7 6 5 4 3 2 1 0 5-HT NE DA ACH H1 Richelson E. 16.

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

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

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

No3. Vol. Synaptic Effects of Antidepressants. Journal of Clinical Psychopharmacology.5 1 0.5 2 1. Suppl.5 0 5-HT NE DA ACH H1 Richelson E. 1996 potency . 16. 2. June.venlafaxine (Effexor) 3 2.

Synaptic Effects of Antidepressants. 2. Vol.2 0. Suppl.3 0. 1996 potency .nefazodone (Serzone) 0. Journal of Clinical Psychopharmacology.8 0.6 0.4 0. June.1 0 5-HT NE DA ACH H1 Richelson E. 16.7 0.5 0. No3.

2 1 0.6 0. Suppl. June. 16. No3. Vol.8 1. 1996 potency . Synaptic Effects of Antidepressants.4 1. Journal of Clinical Psychopharmacology.2 0 5-HT NE DA ACH H1 Richelson E.6 1.4 0.citalopram (Celexa) 2 1. 2.8 0.

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. • All have variable affinity for blocking the p-450 isoenzymes. . • Different P-450 isoenzymes are inhibited by the SSRIs.

Issues to Consider in the Elderly • Burden on hepatic functioning. • Side-effects . • Potential for drug-drug interactions.

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

• Some SSRIs inhibit some P-450 enzymes.P-450 Enzymes and the SSRIs (at least moderate activity >50%) • Similarities • P-450 enzymes metabolize the SSRIs. 1998 . 2C19 • sertraline: none • paroxetine: 2D6 • fluvoxamine: 1A2. 2C9/10. mirtazepine: none Preskorn. 2C19. 3A3/4 • citalopram (s): none • venlafaxine. bupropion. • Differences • fluoxetine: 2D6.

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

15 0.45 0.4 0. 1998 .CYP2D6 Inhibition in Vitro 0.25 0.2 0.05 0 potency norfluoxetine fluvoxamine citalopram fluoxetine paroxetine sertraline Preskorn.3 0.5 0.35 0.1 0.

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

004 0.002 0 potency metabolites fluvoxamine citalopram fluoxetine paroxetine sertraline Preskorn. 1998 .012 0.CYP3A4 Inhibition in Vitro 0.008 0.006 0.01 0.

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

25 0.1 0.15 0.2 0. 1998 .CYP1A2 Inhibition in Vitro 0.5 0.45 0.05 0 potency fluvoxamine citalopram fluoxetine paroxetine sertraline Preskorn.35 0.4 0.3 0.

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

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

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

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

4) Effexor (159.7% 24.7) Serzone (324. 2001 • N = 1022 – – – – – – – – Celexa (28.Rates of Sexual Dysfunction Montejo et al.0% .7% 70.5) Zoloft (90.3% 57.6) – – – – – – – – 72.4) Luvox (115.5) Remeron (37.4% 8.7) Paxil (23.9% 62.7% 67.3% 62.7) Prozac (24.

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).

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

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

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

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

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

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

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