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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
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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
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
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 FDA Indications
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.
NC O CH3 HN O O O CH2CH2CH2N(CH3)2·HBr Paroxetine CH2 Citalopram S-citalopram F N Cl Cl F3C C CH2 CH2 CH2 CH2 O CH3 H O C Sertraline N CH3 CH2 CH2 N O CH2 CH2 NH2 Fluvoxamine Fluoxetine H SSRI Structures Celexa Package Insert, Forest Laboratories, Inc. Physicians’ Desk Reference. 1998.
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% Switch Rates of SSRIsn = 573 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%).
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. Pharmacodynamics
Dose-response Curves Response Celexa Other SSRI’s Dose
80% 70% 60% fluoxetine 20mg sertraline 50mg paroxetine 20mg fluvoxamine 150mg citalopram 40mg % Blockade of 5-HT Preskorn 1998
Guidelines for Interpreting Ki (nmol/L) values • <10 • very potent • 10-1000 • moderately potent • >1000 • likely to have little clinical effect
5-HT Selectivity Uptake InhibitionKi (nmol/L) Drug 5-HT NE DA NE/5-HT Ratio Escitalopram 2.5 6,514 >100,000 2,606 Citalopram 9.6 5,029 >100,000 524 Paroxetine 0.34 156 963 459 Sertraline 2.8 925 315 330 Fluoxetine 105 5.7 599 5,960 Potency and Selectivity of the SSRIs Human Monoamine Uptake Inhibition lessselective A lower Ki reflects greater potencyA 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 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 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996
Selectivity for 5-HT vs. NE Transporter Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996
Escitalopram Citalopram Sertraline Fluoxetine Paroxetine 10000 1000 100 Ki (NE) / Ki (5-HT) more selective less selective Selectivity Owens et al., 2001
Possible Clinical Consequences of DA Reuptake Blockade • Psychomotor activation • Psychosis • Antiparkinsonian effects • Enhanced cognition
Dopamine Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996
Possible Clinical Consequences of Muscarinic Blockade • Blurred vision • Dry mouth • Sinus tachycardia • Constipation • Urinary retention • Memory dysfunction
Acetylcholine 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) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
Histamine (H1)-Receptor Binding lower affinity Ki (nM) Owens et al., 2001
fluoxetine (Prozac) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
sertraline (Zoloft) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
paroxetine (Paxil) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
fluvoxamine (Luvox) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
venlafaxine (Effexor) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
nefazodone (Serzone) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
citalopram (Celexa) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
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
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. Pharmacokinetics of the SSRIs
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) 27-32 35 96-386 21 26 Protein bound (%) 56% 80% 94% 95% 98% Absorption altered No No No No Yesby 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 Van Harten, 1993; Preskorn, 1997; Preskorn, 1993; Physician’s Desk Reference, 2002; Forest Laboratories, data on file, 2002
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 P-450 Enzymes and the SSRIs (at least moderate activity >50%) Preskorn, 1998
Substrates Analgesics Antidepressants Antipsychotics Cardiovascular preps Amphetamine Diphenhydramine Inhibitors Quinidine Paroxetine* Fluoxetine* CYP2D6
CYP2D6 Inhibition in Vitro Preskorn, 1998
Substrates Antidepressants Antihistamines Cardiovascular preps Sedative-hypnotics Corticosteroids Carbamazepine Terfenadine Inhibitors Ketoconazole Itraconazole Erythromycin Grapefruit juice nefazodone* fluvoxamine* norfluoxetine* CYP3A4
CYP3A4 Inhibition in Vitro Preskorn, 1998
Substrates Caffeine Clozapine Antidepressants Theophylline R-warfarin Inhibitors Fluvoxamine* CYP1A2
CYP1A2 Inhibition in Vitro Preskorn, 1998
Active Metabolites fluoxetine (1-4 days) norfluoxetine (7-15 days) No Active Metabolites sertraline, paroxetine, fluvoxamine, citalopram s-citalopram Active Metabolites and the SSRIs
Auto-inhibition fluoxetine paroxetine fluvoxamine No Auto-inhibition sertraline citalopram s-citalopram Auto-inhibition of Metabolism and the SSRIs