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- 2. Selective Serotonin Reuptake Inhibitors Prof. Hani Hamed Dessoki, M.D.Psychiatry Prof. Psychiatry Chairman of Psychiatry Department Beni Suef University Supervisor of Psychiatry Department El-Fayoum University APA member
- 3. Management Management: Adjust dosage for optimum benefit, safety and compliance. Use adjunctive and combination therapies if needed however always strive for the simplest regimen. Keep your therapeutic endpoint in mind.
- 4. Why do we still need to talk about treating depression? In the good old days… SSRIs were hailed as the cure for everyone Few SSRIs on the market, all considered equally efficacious Where we are today The burden of depression is increasing Depression is still under-recognised and undertreated Many treated patients do not achieve remission and risk relapse How should the patient be treated and monitored to obtain remission? Nelson. Am J Psychiatry 2006; 163: 11: 1864–1866 4
- 5. Improving treatment outcomes – a multi-faceted challenge • Correct diagnosis/correct treatment goal • Selecting the optimal treatment: • • Effectiveness, onset, tolerability, interactive potential Matching treatment to patient: • Psychopharmacological considerations • Identifying treatment moderators • Compliance • Timely, evidence-based dose optimization, switching, augmentation • Constant monitoring and follow-up 5
- 6. What is required for full remission? The patient perspective Patients definition of remission: • Positive mental health (e.g. optimism and self-confidence) • Return to one’s usual, normal self • Return to usual level of functioning • Absence of depressive symptoms Symptomatic improvement vs functional improvement – a question of timing ? Are rating scales linked to functionality ? Zimmerman et al., Am J Psychiatry 2006; 163:148–150) 6
- 7. Defining treatment goals Outcomes are now here Ideal outcome should be here Outcomes were here Functional recovery Remission Response 50% improvement in a validated depression rating scale from baseline (e.g., HAM-D) Not officially defined; varies between studies (e.g., HAMD <7–10) Adapted from: Nierenberg & DeCecco. J Clin Psychiatry 2001; 62 (Suppl 16): 5–9 7
- 8. Is remission the optimal outcome? • Remission (as measured by symptom scales) is an important target for treatment • Residual symptoms are predictors of relapse, chronicity and suicidality • There are various remission criteria • But, does remission = ‘health’ or functional recovery? ‘Health’ is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity. World Health Organization Preamble to the Constitution of the World Health Organization, 7 April 1948 8
- 9. 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 2004- Duloxetine (Cymbalta)
- 10. SSRIs
- 11. Are all antidepressants the sa me?
- 12. 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%).
- 13. Pharmacokinetic Parameters of the SSRI Escitalopram Citalopram Fluoxetine Paroxetine Sertra Half-life (hours) 27-32 35 96-386 21 26 Protein bound (%) 56% 80% 94% 95% 98% Absorption altered by fast or fed status No No No No Yes Linear kinetics Yes Yes No No Yes 20-60 20-80 10-50 50-200 Dose range (mg/day) 10-20 for MDD Van Harten, 1993; Preskorn, 1997; Preskorn, 1993; Physician’s Desk Reference, 2002; Forest Laboratories, data on file, 2002
- 14. Active Metabolites and the SSRIs Active Metabolites fluoxetine (1-4 days) norfluoxetine (715 days) No Active Metabolites sertraline, paroxetine, fluvoxamine, citalopram s-citalopram
- 15. es nops e R Ot h er SS R I’ s Dose-response Curves xa ele C Dose
- 16. Potency and Selectivity of the Human Monoamine Uptake Inhibition SSRIs 5-HT Selectivity Uptake Inhibition Ki (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 5.7 599 5,960 105 A lower Ki reflects greater potency A higher selectivity ratio [Ki (nmol/L) NE/ Ki (nmol/L) 5-HT] reflects greater specificity less selectiv e Owens et al., 2001
- 17. 5HT What are the receptor types? several families identified, eg. 5HT1 5HT2 5HT3 5HT4 5HT5 5HT6 5HT7 several subtypes of each family, eg. 5HT1A 5HT1B 5HT1c 5HT1D
- 18. Serotonin receptors: 5-HT1C has been renamed 5-HT2C to indicate that it belongs within this subfamily. 5HT 2 There are three subtypes, 5HT 2A , 5HT 2B , and 5HT 2C . The 5HT 2A receptors mediate platelet aggregation and smooth muscle contraction.
- 19. Serotonergic Receptors Receptor Action 5 HT1a stimulation (agonist) Improvement of affective symptoms (Antidepressant and anxiolytic effect) + effects on cognitive symptoms, 5HT1d, 5HT1f 5HT2a accelerator of dopamine Anti migraine Cognition, target of atypical antipsychotics - Brake of dopamine 5HT2b Regulation of stomach contraction 5HT2c (previously 5HT1c) Regulation of appetite, anxiety, seizures - target of atypical antipsychotics - Inverse agonist imrovement of negative symptoms
- 20. Serotonergic Receptors Receptor Action 5 HT3 - Antagonists antiemetic, anxiolytic, cognitive enhancement 5 HT4 Modulation of cognition and anxiety 5HT5a,b Unknown 5 HT6 -negative and cognitive symptoms -Target of antipsychotics 5 HT7 -negative and cognitive symptoms - Circadian rhythms
- 21. Serotonergic Receptors 5‐ HT2 receptor stimulation • Agitation • Insomnia • Sexual dysfunction • Satiation -5‐HT2A receptor normally works to inhibit (brake) the release of the neurotransmitter dopamine. 5‐ HT3 receptor stimulation • Nausea • Diarrhea • Headache So, 5-HT2A antagonism – suppression of EPS • 5HT1A is dopamine accelerator. However, 5HT2A is dopamine brake (opposite effect is on glutamate). So, 5-HT1A agonism – effects on cognitive symptoms, suppression of EPS 5-HT2A antagonism – suppression of EPS
- 22. Role of 5-HT in Nigrostriatal Dopaminergic Synapse Sunstantia nigra pars compacta Raphe Nigrostriatal tract 5-HT T T HT HT 55- - 5-HT2A DA D1 D2 Normal function Caudate/putamen
- 23. Mechanism of therapeutic action: pharmacologic properties shared by all five SSRIs Immediate blockade of serotonin transporter on axon terminals and in somato-dendritic areas of serotonergic neurone Delayed down regulation/desensitisation of somato-dendritic serotonin 1A receptors Delayed disinhibition (i.e., ‘turning on’) of serotonin release from axon terminals
- 24. SSRI Half-life antidepressants Short: paroxetine & fluvoxamine (missed doses can result in uncomfortable symptoms) Moderate: sertraline, citalopram, escitalopram Long: fluoxetine (good for people who may miss doses)
- 25. Mechanism of side effects: pharmacologic properties shared by all five SSRIs Unwanted stimulation of undesired serotonin receptor subtypes ‘Cost of doing business’ Especially clinically relevant are unwanted stimulation of 5HT2A/2C and/or 5HT3/4 receptors in various specific pathways and tissues
- 26. All five SSRIs lead to indirect stimulation of serotonin 2A receptors Linked to short term mediation of: – anxiety/panic attacks – insomnia – agitation/jitteriness – sexual dysfunction (especially anorgasmia and ejaculatory delay) – apathy/anhedonia/decreased libido – stimulation of 5HT2A receptors inhibits dopamine release
- 27. All five SSRIs lead to indirect stimulation of serotonin 2C receptors: (only fluoxetine also stimulates 5HT2C receptors directly) Mice without 5HT2C receptors are obese Blockade of 5HT2C receptors, especially simultaneous with blockade of histamine 1 receptors, is associated with weight gain Acute stimulation can cause weight loss and anxiety Chronic stimulation can cause weight gain
- 28. All five SSRIs indirectly stimulate serotonin 3 and 4 receptors Decreased feeding (5HT3) Loss of appetite/nausea (5HT3) Vomiting (chemoreceptor trigger zone/5HT3) Increased bowel motility (5HT3 and 5HT4)
- 29. SSRI antidepressants Side effects Decreased sex drive and impaired sexual function tend not to resolve with time Nausea, diarrhea, anorexia, vomiting - all increase with dose and can resolve with time Weight gain (esp. paroxetine) after initial GI effects Headache, dizziness, anxiety (esp. fluoxetine), rash, insomnia, sedation, sweating, vivid dreams, tremor, dry mouth (esp. paroxetine), bruising, ↑ prolactin
- 31. fluoxetine (Prozac) 9 8 7 6 5 potency 4 3 2 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
- 32. sertraline (Zoloft) 30 25 20 15 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
- 33. paroxetine (Paxil) 140 120 100 80 potency 60 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
- 34. fluvoxamine (Luvox) 14 12 10 8 potency 6 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
- 35. venlafaxine (Effexor) 3 2.5 2 1.5 potency 1 0.5 0 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
- 36. nefazodone (Serzone) 0.8 0.7 0.6 0.5 0.4 potency 0.3 0.2 0.1 0 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
- 37. citalopram (Celexa) 2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 potency 5-HT NE DA ACH H1 Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
- 39. Secondary pharmacologic properties of various SSRIs 5H T2 C DRI m-AC h SSRI σ Stahl S. Essential Psychopharmacology, 2000 CYP 2D6 CYP 2D6 NO S RI N SRI CY P1 CY A2 P 3A 3, 4
- 40. Potentially important secondary binding properties for each SSRI Fluoxetine and serotonin 2C stimulation Sertraline and dopaminergic stimulation Paroxetine and anticholinergic properties Fluvoxamine and sigma properties Citalopram and selectivity
- 41. 5HT2C agonist 5H T2 C Fluoxetine Stahl S. Essential Psychopharmacology, 2000
- 42. Muscarinic cholinergic (m-ACh) blockade m-AC h Paroxetine Stahl S. Essential Psychopharmacology, 2000
- 43. Potential clinical relevance of blocking muscarinic cholinergic receptors Possibly well tolerated in anxious patients, even reducing anxiety before delayed SSRI actions begin Possibly able to improve sleep early in treatment Might be poorly tolerated in elderly with early cognitive problems or Alzheimer’s disease Might cause mild ‘anticholinergic’ side effects such as constipation, dry mouth, blurred vision, sedation Might cause more sexual dysfunction, (especially erectile dysfunction), more weight gain and more withdrawal problems
- 44. Sigma (σ ) blockade Fluvoxamine (Sertraline) σ Stahl S. Essential Psychopharmacology, 2000
- 45. Potential clinical relevance of interacting at sigma receptors Possible anxiolytic actions Possible antipsychotic actions Possible increased GI side effects
- 46. Dopamine reuptake inhibition (DRI) DRI Sertraline Stahl S. Essential Psychopharmacology, 2000
- 47. Potential clinical relevance of enhancing dopaminergic activity Possible cognitive enhancement Less prolactin elevation Possibly less weight gain Possibly too activating in some patients, thus necessitating dose titration especially in those with anxiety disorders
- 48. Citalopram Stahl S. Essential Psychopharmacology, 2000 SRI
- 49. Potential clinical relevance of selectivity without secondary pharmacologic properties Side effects and therapeutic effects predictable based upon serotonergic mechanisms alone Possibly less activation and less sedation than SSRIs with secondary actions Possibly faster onset due to lack of side effects allowing rapid dose titration Possibly good compliance at initiation of dosing if serotonergic side effects minimal
- 50. SSRIs and the cytochrome P450 drug metabolising enzymes Fluoxetine inhibits CYP450 2D6 and 3A4 Sertraline is a weak inhibitor of CYP450 2D6 Paroxetine inhibits CYP450 2D6 Fluvoxamine inhibits CYP450 1A2, 2C19 and 3A4 Citalopram is a weak inhibitor of CYP450 2D6
- 51. CYP 2C19 Fluvoxamine CY P2 C1 9 Stahl S. Essential Psychopharmacology, 2000
- 52. CYP 1A2 Fluvoxamine CY P1 A2 Stahl S. Essential Psychopharmacology, 2000
- 53. CYP 2D6 Paroxetine Fluoxetine (Sertraline) (Citalopram) CYP 2D6 CYP 2D6 Stahl S. Essential Psychopharmacology, 2000
- 54. CYP 3A4 Fluvoxamine Fluoxetine CY P Stahl S. Essential Psychopharmacology, 2000 3A 4
- 55. Low potential for drug-drug interactions Cytochrome P450 Isozyme Inhibition In Vitro/In Vivo 3A4 2D6 1A2 2C19 2C9 Escitalopram 0 + 0 0 0 Citalopram 0 + + 0 0 Fluoxetine ++ +++ + ++ ++ Paroxetine + +++ + + + Venlafaxine + + 0 0 0 Fluvoxamine ++ + +++ +++ ++ Sertraline + + + ++ + Anti-Arrhythmic ++ = •Ca+ 0 •= Negligible •Caffeine •Diazepam Moderate interaction antagonists •Miconazole + •= Very weak interaction +++ = Strong interaction B-blockersCiprofloxacin •Erythromycin • •Propranolol •Phenytoin •Haloperidol •Ketoconazole •Theophylline •Moclobemide •S-warfarin •Neuroleptics •Lidocaine •Verapamil•Imipramine •NSAIDs 1. Von Moltke et al. Drug Metab Dispos 2001;29:1102-9 •Cancer therapies 2. Greenblatt et al. J Clin Psychiatry 1998;59:19-27 3. Albers et al. Psychiatry Res 2000;96:235-243
- 56. SSRIs/SNRIs bind only to the primary The net result is site an intermittent blockade of the serotonin transporter protein
- 57. Cipralex binds both to the primary and the The net result is allosteric site Stronger and longer binding to the serotonin transporter protein
- 58. Explaining the superior efficacy of to both Primary binding site and vs. Cipralex bindsCipralex allosteric site . SSRIs SNRIs Cipralex has a high affinity for the allosteric site Cipralex is a more efficient blockade of the serotonin transporter protein . This effect is the best explanation for the superior efficacy of Cipralex . Cipralex is an extremely selective serotonin reuptake inhibitor
- 59. Cipralex reduces Functional Impairment 59
- 60. How does that fit with your clinical experience? 1.25 Escitalopram 1.20 Acceptability (OR) 1.15 Sertraline Bupropion Citalopram 1.10 1.05 Fluoxetine Mirtazapine 1.00 Venlafaxine 0.95 0.90 0.85 ● Paroxetine Duloxetine Fluvoxamine 0.80 0.8 0.9 1.0 1.1 Efficacy (OR) 1.2 1.3 1.4 Cipriani et al. Lancet 2009; 373: 746–758 60
- 61. Summary: mechanism of action and pharmacokinetics of SSRIs All SSRIs share a common therapeutic mechanism of action in depression, OCD, panic disorder, social phobia and PTSD All SSRIs can create unwanted side effects from stimulating 5HT2A and 5HT3 receptors Various SSRIs have potentially clinically significant drug interactions, but these differ from one SSRI to another No two SSRIs have the same secondary binding features, and this may account for why some patients respond to one SSRI, or tolerate one SSRI, better than another
- 62. Duloxitine Atomoxeti Reboxetine Dapoxetine ne SNRI selective norepineph rine reuptake inhibitor Selective norepineph rine uptake inhibitor Not FDA approved yet 30,60, = Joypox tab ultrshort acting SSRI for treatment of premature ejaculation.
- 63. Conclusion • Functional improvements should be part of the patient specific treatment goal • There are differences among antidepressants – Efficacy – tolerability – acceptability – safety - costeffectiveness Antidepressants are different - choose carefully! 63
- 65. Vortioxetine Vortioxetine (formerly Lu AA21004) is described as a multimodal antidepressant, working as a - serotonin 5-HT3 and 5-HT7 receptor antagonist, - 5-HT1b receptor partial agonist, - 5-HT1a receptor agonist - an inhibitor of the serotonin transporter SERT (Brintellix, H. Lundbeck A/S).
Notas del editor
- Should we treat the patients until they response? Until they get to remission? How to measure remission? How do you identify remission? Do you take functionality into account?
- Psychopharmacological considerations: matching the pharmacological properties of the drug to the presenting symptoms Treatment moderator: need to discover treatment moderators which identify sub-populations of MDD patients who are more likely to experience the benefits of a given treatment (biologic markers, clinical markers) e.g. esc in severely depressed patients
- DISCUSSION NOTES: Evidence for treatment response has traditionally been the foundation for the approval of new antidepressants. Clinical rating scales such as the Hamilton Depression Rating Scale for Depression have been the gold standard for measuring patient response and remission, however, these measures can leave patients with residual symptoms of depression that can impair patient functioning. Guidelines currently recommend that patients should be treated to symptomatic remission. With the recognition that patients in remission may still exhibit residual symptoms (which are associated with depressive relapse or recurrence), the bar is being raised once again, with the ultimate goal for the treatment of depression now moving towards functional recovery.
- 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., 2002
- 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.
- Drug-drug interaction: Interactions may arise when SSRIs are administrated with other drugs that share a common metabolic pathway via the Cytochrome P450 isoenzyme system. Many psychotropics – including SSRIs - inhibit to varying degrees specific Cytochrom P450 isoenzymes involved in the elimination of drugs. Escitalopram has a very low potential for drug-drug interactions, mainly because of the absent or very low inhibition of the Cytochrom P450 isoenzymes. (Speaker note: Regarding CYP 2D6 – in vitro data did not reveal an inhibitory effect of escitalopram. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram 20 mg/day.)
- Citalopram is a racemic mixure of S-citalopram ( Escitalopram ) and R-citalopram . Only Escitalopram binds to the the primary binding site . Both S- and R – citalopram bind to the allosteric binding site , like other SSRIs, R-Citalopram has a low affinity for the allosteric binding site .
- On administration of Escitalopram , its interaction with the allosteric site results in a greater stabilization of escitalopram at the primary binding site compared to when R-citalopram is bound .
- INclude again the slide on Ciprini with accepta and effic.