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 (K i ) 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.
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.
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.
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 . 56 th ed. Montvale, NJ: Medical Economics Company; 2002. 5. Data on file, Forest Laboratories, Inc., 2002
Anxiety and Depression Comparison of the Serotonergic Antidepressants Douglas L. Geenens, D.O. Faculty in Psychopharmacology, MenningerAssociate 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
FDA Indications• OCD • All, except citalopram (s)• Major Depression • All, except Luvox• Geriatric Depression • fluoxetine• Panic Disorder • sertraline, paroxetine• Bulimia • fluoxetine• Social Phobia • paroxetine• OCD in children (ages • sertraline, 6-18) fluvoxamine• PTSD • sertraline, paroxetine• PMDD • fluoxetine, sertraline• GAD • venlafaxine, paroxetine
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.
SSRI Structures NC O CH3 O HN O O CH2CH2CH2N(CH3)2·HBr Paroxetine CH2 Citalopram S-citalopram F N Cl F3C C CH2 CH2 CH2 CH2 O CH3 Cl H O C N Sertraline CH3 O CH2 CH2 NH2 CH2 CH2 N Fluvoxamine Fluoxetine HCelexa Package Insert, Forest Laboratories, Inc.Physicians’ Desk Reference. 1998.
Switch Rates of SSRIs n = 573• Time course • Percentage of patients – one month staying on initial drug • 13% – fluoxetine – three months • 50% • 23% – sertraline – six months • 43% • 32% – paroxetine – nine months • 41% • 40% 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%).
Pharmacodynamics• Similarities • Differences• All inhibit neuronal • Variable affinity for other reuptake of 5-HT. neuro-receptors. • Variable potency at blocking 5-HT at therapeutic doses. • Dose-response curves vary.
Dose-response Curves s I’Response SR exa er S Cel Oth Dose
Guidelines for Interpreting Ki (nmol/L) values• <10 – very potent• 10-1000 – moderately potent• >1000 – likely to have little clinical effect
Potency and Selectivity of the SSRIs Human Monoamine Uptake Inhibition Uptake Inhibition 5-HT Ki (nmol/L) SelectivityDrug 5-HT NE DA NE/5-HT RatioEscitalopram 2.5 6,514 >100,000 2,606Citalopram 9.6 5,029 >100,000 524Paroxetine 0.34 156 963 459Sertraline 2.8 925 315 330 lessFluoxetine 105 selective 5.7 599 5,960A 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 140 120 100 80 60 potency 40 20 0 e e e m am e in li n n ti n ra eti m pr tra xe op ox xa lo ro r al ita vo sefl u cit pa s-c fl u 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 120 100 80 60 40 potency 20 0 e i ro e e s-c pram am e dm in n in flu etin ali m pr et rt r xa ox x lo lo ta ita vo seflu pa ci Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996
Selectivity for 5-HT vs. NE Transporter 900 800 700 600 500 400 300 selectivity 200 100 0 e e e m am e in l in in t in ra m pr et tra xe op ox xa lo ro r al ita vo se fl u cit pa s-c fl u Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996
Selectivity Escitalopram Citalopram Sertraline Fluoxetine Paroxetine 10000 1000 100 Ki (NE) / Ki (5-HT)more lessselective selective Owens et al., 2001
Possible Clinical Consequences of DA Reuptake Blockade • Psychomotor activation • Psychosis • Antiparkinsonian effects • Enhanced cognition
Dopamine 1.2 1 0.8 0.6 0.4 potency 0.2 0 e pa line e e ph am am e in in in flu etin m am opr et pr am tra xa ox x lo et ro r tal ta vo sefl u ci ci s- Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June 1996
Acetylcholine 6 5 4 3 2 potency 1 0 e i se tine vo ine i ta am am ro e dm am c i mi n pa lin fl u xe t prs- opr e ra xa ox lo rt l fl u ta ciRichelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Vol. 16, No3, Suppl. 2, June, 1996
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
Possible Clinical Consequences of Histamine (H1) Blockade • Sedation and drowsiness • Weight gain • Hypotension
Histamine (H1) 100 90 80 70 60 50 40 30 potency 20 10 0 alo e Be ine m pa line e yl vo ne it i m in n s-c pra am pra dr eti flu xeti yl m tra na xa ox pt lo ro r ita sefl u citRichelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Vol. 16, No3, Suppl. 2, June, 1996
Histamine (H1)-Receptor Binding escitalopram citalopram R-citalopram 0 500 Ki 1000 (nM) 1500lower 2000affinity Owens et al., 2001
Medication201816141210 potency 8 6 4 2 0 5-HT NE DA ACH H1
fluoxetine (Prozac)987654 potency3210 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
sertraline (Zoloft)30252015 potency10 5 0 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
paroxetine (Paxil)140120100 80 60 potency 40 20 0 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
fluvoxamine (Luvox)141210 8 6 potency 4 2 0 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
venlafaxine (Effexor) 32.5 21.5 potency 10.5 0 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
nefazodone (Serzone)0.80.70.60.50.4 potency0.30.20.1 0 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
citalopram (Celexa) 184.108.40.206.2 1 potency0.80.60.40.2 0 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
s-citalopram (Lexapro)30252015 East10 5 0 5-HT NE DA ACH H1
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 • Differences• All require hepatic • Half-lives vary. oxidative enzymes for metabolism. • Different P-450 isoenzymes are• All have variable inhibited by the affinity for blocking SSRIs. the p-450 isoenzymes.
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 SertralineHalf-life (hours) 27-32 35 96-386 21 26Protein bound (%) 56% 80% 94% 95% 98%Absorption altered No No No No Yesby fast or fed statusLinear kinetics Yes Yes No No YesDose 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
fl u ox 0 10 20 30 40 50 60 70 80 et 90 in se e r tr al in pa e r ox etin fl u vo e xa m in ci ta e lo prs-c am ita lo pr am Half-lives of the SSRIs hours
P-450 Enzymes and the SSRIs(at least moderate activity >50%)• Similarities • Differences • fluoxetine: 2D6, 2C9/10,• P-450 enzymes 2C19 metabolize the SSRIs. • sertraline: none • paroxetine: 2D6• Some SSRIs inhibit some • fluvoxamine: 1A2, 2C19, P-450 enzymes. 3A3/4 • citalopram (s): none • venlafaxine, bupropion, mirtazepine: none Preskorn, 1998
Active Metabolites and the SSRIs• Active Metabolites • No Active Metabolites• fluoxetine (1-4 days) • sertraline, norfluoxetine (7-15 • paroxetine, days) • fluvoxamine, • citalopram • s-citalopram
Auto-inhibition of Metabolism and the SSRIs• Auto-inhibition • No Auto-inhibition• fluoxetine • sertraline• paroxetine • citalopram• fluvoxamine • s-citalopram
Sertraline vs. Paroxetine n=176 n=177• diarrhea • constipation • fatigue • decreased libido • urinary retention • weight gain • tachycardia • increased sleep p<.05, APA 1998
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)
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).
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).
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.
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.
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).
S-citalopram (Lexapro) • Most selective of the SSRIs • Flat-dose response curve• Potency of blocking 5-HT is comparable to sertraline
Beyond the SSRIs• Effexor • 5-HT, NE, and DA reuptake block. • 5-HT2 block; weaker 5-• Serzone HT and NE reuptake block. • 5-HT and NE increase (via• Remeron alpha 2 antagonism); 5- HT2 and 5-HT3 block.
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