1. 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

2. Research and Development
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
paroxetine
sertraline, fluvoxamine
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 Paroxetine Citalopram S-citalopram SertralineF O NC
CH2CH2CH2N(CH3)2·HBr
Paroxetine N O
CH2
Sertraline HN
CH3 Cl
Fluoxetine O C H
CH2 CH2 N
CH3
Fluvoxamine
F3C C
CH2 O
CH3 N
NH2
Celexa Package Insert, Forest Laboratories, Inc.
Physicians’ Desk Reference

7. Switch Rates of SSRIs n = 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%
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. Pharmacodynamics Differences Similarities
Variable affinity for other neuro-receptors.
Variable potency at blocking 5-HT at therapeutic doses.
Dose-response curves vary.
Similarities
All inhibit neuronal reuptake of 5-HT.

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

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

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

13. Potency and Selectivity of the SSRIs
Human Monoamine Uptake Inhibition
Uptake Inhibition Ki (nmol/L)
5-HT Selectivity
5-HT NE DA
NE/5-HT Ratio
Drug
2.5
6,514
>100,000
2,606
Escitalopram
9.6
5,029
524
Citalopram
2.8
925
315
330
Sertraline
5.7
599
5,960
105
Fluoxetine
0.34
156
963
459
Paroxetine
less selective
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 ;50(5):
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., 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. Selectivity Ki (NE) / Ki (5-HT) Escitalopram Citalopram Sertraline
Fluoxetine
Paroxetine
Ki (NE) / Ki (5-HT)
100
1000
10000
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 ;50(5):
less selective
more selective
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 Cognition A 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)
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 ;50(5):
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. 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

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
Escitalopram Citalopram Fluoxetine Paroxetine Sertraline
Half-life (hours)
Protein bound (%) 56% 80% 94% 95% 98%
Absorption altered No No No No Yes by fast or fed status
Linear kinetics Yes Yes No No Yes
Dose range (mg/day) for MDD
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 ;24:
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 ;32(suppl 1):1-21.
3. Preskorn SH. Pharmacokinetics of antidepressants: why and how they are relevant to treatment. J Clin Psychiatry ;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
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. 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
Preskorn, 1998

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

44. CYP2D6 Inhibition in Vitro
Preskorn, 1998

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

46. CYP3A4 Inhibition in Vitro
Preskorn, 1998

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

48. CYP1A2 Inhibition in Vitro
Preskorn, 1998

49. Active Metabolites and the SSRIs
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
fluoxetine
paroxetine
fluvoxamine
No Auto-inhibition
sertraline
citalopram
s-citalopram

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

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 Dysfunction Montejo et al, 2001
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 , 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 Depression Comparison 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