anxiety and depression comparison of the serotonergic antidepressants

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. 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

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. SSRI Structures

7. Switch Rates of SSRIsn = 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%

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. 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.

10. Dose-response Curves

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

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

13. Potency and Selectivity of the SSRIs Owens and colleagues have assayed the relative potency of escitalopram and other SSRIs in the inhibition of the neuronal uptake of the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE) and dopamine (DA). A lower inhibitory constant (Ki) indicates that the compound produces inhibition at a lower concentration (represented in nanomoles per liter), i.e., it is more potent. Escitalopram and the other SSRIs are potent and selective serotonin reuptake inhibitors, but the serotonin selectivity ratio (comparing the extent of serotonin reuptake inhibition to the extent of inhibition of norepinephrine reuptake) indicates that escitalopram is the most selective inhibitor of serotonin reuptake studied to date. Both serotonergic and noradrenergic systems are thought to play a role in depression and in its treatment, and the selectivity of a compound to inhibit one transporter over another has not been associated with greater clinical efficacy. However, some of the CNS-related adverse effects associated with antidepressant therapy such as agitation, anxiety, nervousness, insomnia, and even tremor may be due to an increase in noradrenergic tone. Thus, treatment with an agent that has minimal effect on the noradrenergic system may result in a lower incidence of these side effects. Reference 1. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345-350. Owens and colleagues have assayed the relative potency of escitalopram and other SSRIs in the inhibition of the neuronal uptake of the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE) and dopamine (DA). A lower inhibitory constant (Ki) indicates that the compound produces inhibition at a lower concentration (represented in nanomoles per liter), i.e., it is more potent. Escitalopram and the other SSRIs are potent and selective serotonin reuptake inhibitors, but the serotonin selectivity ratio (comparing the extent of serotonin reuptake inhibition to the extent of inhibition of norepinephrine reuptake) indicates that escitalopram is the most selective inhibitor of serotonin reuptake studied to date. Both serotonergic and noradrenergic systems are thought to play a role in depression and in its treatment, and the selectivity of a compound to inhibit one transporter over another has not been associated with greater clinical efficacy. However, some of the CNS-related adverse effects associated with antidepressant therapy such as agitation, anxiety, nervousness, insomnia, and even tremor may be due to an increase in noradrenergic tone. Thus, treatment with an agent that has minimal effect on the noradrenergic system may result in a lower incidence of these side effects. Reference 1. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345-350.

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

15. Serotonin

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

17. Norepinephrine

18. Selectivity for 5-HT vs. NE Transporter

19. The relative selectivity of an SSRI can be expressed as a ratio of the compound�s affinity for the serotonin transporter compared with its affinity for other monoamine transporters. These studies were carried out using cloned human monoamine transporters and compared the uptake inhibition by escitalopram to each of the commercially available SSRIs. In comparing affinities for the serotonin and norepinephrine transporter, Owens and colleagues found that escitalopram is the most selective serotonin reuptake inhibitor studied to date � even more selective than citalopram, which itself is more selective than other SSRIs. Reference 1. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345-350. The relative selectivity of an SSRI can be expressed as a ratio of the compound�s affinity for the serotonin transporter compared with its affinity for other monoamine transporters. These studies were carried out using cloned human monoamine transporters and compared the uptake inhibition by escitalopram to each of the commercially available SSRIs. In comparing affinities for the serotonin and norepinephrine transporter, Owens and colleagues found that escitalopram is the most selective serotonin reuptake inhibitor studied to date � even more selective than citalopram, which itself is more selective than other SSRIs. Reference 1. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345-350.

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

21. Dopamine

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

23. Acetylcholine

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?

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

26. Histamine (H1)

27. Histamine (H1)-Receptor Binding Escitalopram lacks affinity for the histamine-1 receptor, having much less (i.e., an order of magnitude) affinity compared with citalopram and R-citalopram. The weak affinity of citalopram for the histamine receptor (an inhibitory constant (Ki) below 1000 nanomoles (nM) may be physiologically relevant) is attributable to R-citalopram. This suggests that escitalopram may be less likely than citalopram to produce antihistaminic effects such as sedation. Reference 1. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345-350. Escitalopram lacks affinity for the histamine-1 receptor, having much less (i.e., an order of magnitude) affinity compared with citalopram and R-citalopram. The weak affinity of citalopram for the histamine receptor (an inhibitory constant (Ki) below 1000 nanomoles (nM) may be physiologically relevant) is attributable to R-citalopram. This suggests that escitalopram may be less likely than citalopram to produce antihistaminic effects such as sedation. Reference 1. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50(5):345-350.

28. Medication

29. fluoxetine (Prozac)

30. sertraline (Zoloft)

31. paroxetine (Paxil)

32. fluvoxamine (Luvox)

33. venlafaxine (Effexor)

34. nefazodone (Serzone)

35. citalopram (Celexa)

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. Pharmacokinetics of the SSRIs 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.

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

40. Pharmacokinetic Parameters of the SSRIs Despite sharing a similar mechanism of action, the SSRIs are a heterogeneous group of compounds, which can be distinguished from one another pharmacokinetically, as shown on this slide. Drugs with longer half-lives, such as fluoxetine, citalopram, and escitalopram are likely to have fewer discontinuation symptoms if doses are missed or therapy is abruptly discontinued. Fluoxetine and norfluoxetine, its active metabolite, both contribute to the very prolonged half-life observed for fluoxetine. Fluoxetine, paroxetine, and sertraline are highly protein bound (? 94%), whereas the protein binding of escitalopram (56%) is considerably less. The absolute bioavailability of escitalopram, citalopram, fluoxetine, and paroxetine is not affected by food in the stomach. However, food does alter the pharmacokinetics of sertraline. Paroxetine and fluoxetine have nonlinear pharmacokinetics over their usual dosing range, whereas those for escitalopram, citalopram and sertraline are linear. As a rule, nonlinear pharmacokinetics result when a drug induces or inhibits its own CYP450 metabolism and the patient can develop disproportionate increases in plasma levels with dose increases, which may result in increased risk of adverse effects. In drugs that demonstrate linear pharmacokinetics, a change in dose will produce a proportional change in plasma drug concentration. The usual dose ranges for treatment of major depressive disorder (expressed as mg per day) are shown for the SSRIs. References 1. van Harten JV. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet. 1993;24:203-220. 2. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32(suppl 1):1-21. 3. Preskorn SH. Pharmacokinetics of antidepressants: why and how they are relevant to treatment. J Clin Psychiatry. 1993;54(suppl 9):14-34. 4. Physicians� Desk Reference. 56th ed. Montvale, NJ: Medical Economics Company; 2002. 5. Data on file, Forest Laboratories, Inc., 2002Despite sharing a similar mechanism of action, the SSRIs are a heterogeneous group of compounds, which can be distinguished from one another pharmacokinetically, as shown on this slide. Drugs with longer half-lives, such as fluoxetine, citalopram, and escitalopram are likely to have fewer discontinuation symptoms if doses are missed or therapy is abruptly discontinued. Fluoxetine and norfluoxetine, its active metabolite, both contribute to the very prolonged half-life observed for fluoxetine. Fluoxetine, paroxetine, and sertraline are highly protein bound (? 94%), whereas the protein binding of escitalopram (56%) is considerably less. The absolute bioavailability of escitalopram, citalopram, fluoxetine, and paroxetine is not affected by food in the stomach. However, food does alter the pharmacokinetics of sertraline. Paroxetine and fluoxetine have nonlinear pharmacokinetics over their usual dosing range, whereas those for escitalopram, citalopram and sertraline are linear. As a rule, nonlinear pharmacokinetics result when a drug induces or inhibits its own CYP450 metabolism and the patient can develop disproportionate increases in plasma levels with dose increases, which may result in increased risk of adverse effects. In drugs that demonstrate linear pharmacokinetics, a change in dose will produce a proportional change in plasma drug concentration. The usual dose ranges for treatment of major depressive disorder (expressed as mg per day) are shown for the SSRIs. References 1. van Harten JV. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet. 1993;24:203-220. 2. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32(suppl 1):1-21. 3. Preskorn SH. Pharmacokinetics of antidepressants: why and how they are relevant to treatment. J Clin Psychiatry. 1993;54(suppl 9):14-34. 4. Physicians� Desk Reference. 56th ed. Montvale, NJ: Medical Economics Company; 2002. 5. Data on file, Forest Laboratories, Inc., 2002

41. Half-lives of the SSRIs

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

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

44. CYP2D6 Inhibition in Vitro

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

46. CYP3A4 Inhibition in Vitro

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

48. CYP1A2 Inhibition in Vitro

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

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

51. Sertraline vs. Paroxetinen=176 n=177 diarrhea constipation fatigue decreased libido urinary retention weight gain tachycardia increased sleep

52. Sexual Dysfunction Clinical rates approximate 50% of patients. Paroxetine appears to cause higher rates of sexual dysfunction 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)

53. 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%

54. 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

55. 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.

56. 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).

57. 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).

58. 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.

59. 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 expensive at higher doses.

60. 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).

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

62. 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.

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