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Anxiety and Depression Comparison of the Serotonergic Antidepressants

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 Depression Comparison of the Serotonergic Antidepressants

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  1. 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

  2. Variables to Compare • Research and Development • Indications • Efficacy • Structure • Pharmacodynamics* • Pharmacokinetics* • Side-effects* • Dosing Preparations • Cost Considerations

  3. 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

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. 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%).

  9. 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

  10. Dose-response Curves Response Celexa Other SSRI’s Dose

  11. 80% 70% 60% fluoxetine 20mg sertraline 50mg paroxetine 20mg fluvoxamine 150mg citalopram 40mg % Blockade of 5-HT Preskorn 1998

  12. Guidelines for Interpreting Ki (nmol/L) values • <10 • very potent • 10-1000 • moderately potent • >1000 • likely to have little clinical effect

  13. 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

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

  15. Serotonin Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996

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

  17. Norepinephrine Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996

  18. Selectivity for 5-HT vs. NE Transporter Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996

  19. Escitalopram Citalopram Sertraline Fluoxetine Paroxetine 10000 1000 100 Ki (NE) / Ki (5-HT) more selective less selective Selectivity Owens et al., 2001

  20. Possible Clinical Consequences of DA Reuptake Blockade • Psychomotor activation • Psychosis • Antiparkinsonian effects • Enhanced cognition

  21. Dopamine Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996

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

  23. Acetylcholine Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996

  24. 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

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

  26. Histamine (H1) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996

  27. Histamine (H1)-Receptor Binding lower affinity Ki (nM) Owens et al., 2001

  28. Medication

  29. fluoxetine (Prozac) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996

  30. sertraline (Zoloft) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996

  31. paroxetine (Paxil) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996

  32. fluvoxamine (Luvox) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996

  33. venlafaxine (Effexor) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996

  34. nefazodone (Serzone) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996

  35. citalopram (Celexa) Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996

  36. s-citalopram (Lexapro)

  37. 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

  38. 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

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

  40. 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

  41. Half-lives of the SSRIs

  42. 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

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

  44. CYP2D6 Inhibition in Vitro Preskorn, 1998

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

  46. CYP3A4 Inhibition in Vitro Preskorn, 1998

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

  48. CYP1A2 Inhibition in Vitro Preskorn, 1998

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

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

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