1. fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram
Mechanism of action and pharmacokinetic properties of selective serotonin reuptake inhibitors:
fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram 1

2. An educational programme supported by H
An educational programme supported by H. Lundbeck A/S, Copenhagen Some figures reproduced with permission from: Stahl SM, Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, Produced by the Neuroscience Education Institute, San Diego, California 1

3. Simplified concept SSRI
Stahl S. Essential Psychopharmacology, 2000

4. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

5. 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

6. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

7. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

8. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

9. SSRI antidepressant profile
Response is frequently complete recovery
Usual dose is the initial dose
Onset of action 3–8 weeks
Target symptoms not worsened at first

10. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

11. SSRI anti-OCD profile Response is frequently incomplete recovery
Usual dose is often higher than the initial dose
Onset of action 12–26 weeks
Target symptoms not worsened at first
Individual patients can respond quite differently to one SSRI compared to another

12. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

13. SSRI anti-panic profile
Response is frequently complete recovery (especially with concomitant benzodiazepines)
Usual starting dose is often lower than the starting doses for other indications
Target symptoms often worsened at first
Onset of action 3–8 weeks

14. SSRI anti-social phobia profile
Response is often robust, with complete recovery after many months of SSRI treatment more likely with concomitant behavioural therapy encouraging socialisation
Usual starting dose is often lower than the starting doses for other indications, although ultimate dose may be higher than usual antidepressant doses
Target symptoms not usually worsened at first, but agitation and unexpected panic attacks can occur when SSRI treatment is initiated
Onset of action 3–8 weeks

15. SSRI anti-PTSD profile
Response is frequently robust but incomplete at 8 weeks of treatment
Usual starting dose is lower than the starting doses for other indications to avoid activating side effects
Target symptoms often worsened at first, including panic, nightmares and flashbacks
Onset of action 3–8 weeks

16. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

17. SSRI anti-bulimia profile
Usual starting dose is higher than the starting doses for other indications
Target symptoms often rapidly improved
Not well established for prevention of relapses long term

18. 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

19. 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

20. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

21. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

22. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

23. 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

24. 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)

25. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

26. © Stahl SM. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000

27. Summary: common pharmacological properties of all five SSRIs
Blockade of serotonin transporters leads to increases in serotonin throughout the CNS and throughout the body
Increases of serotonin in the right places leads to therapeutic actions: i.e., at somato-dendritic autoreceptors in the midbrain raphe
Increases of serotonin in the wrong places can lead to side effects, especially at 5HT2A and 5HT3 receptors (but also at 5HT2C and 5HT4 receptors)

28. Secondary pharmacologic properties of various SSRIs
DRI
5HT2C
NRI
SSRI
m-ACh
SRI 
CYP 1A2
NOS
CYP 3A3,4
CYP 2D6
Stahl S. Essential Psychopharmacology, 2000

29. 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

30. 5HT2C agonist Fluoxetine 5HT2C
Stahl S. Essential Psychopharmacology, 2000

31. Potential clinical relevance of stimulating 5HT2C receptors
Possible weight loss or less weight gain
Possible increased efficacy in bulimia and binge eating
Possibly overly stimulating in some patients
Possibly harder to titrate in panic disorder, social phobia and PTSD due to activating and anxiogenic properties in some patients

32. Muscarinic cholinergic (m-ACh) blockade
Paroxetine
Stahl S. Essential Psychopharmacology, 2000

33. 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

34. Sigma () blockade Fluvoxamine (Sertraline) 
Stahl S. Essential Psychopharmacology, 2000

35. Potential clinical relevance of interacting at sigma receptors
Possible anxiolytic actions
Possible antipsychotic actions
Possible increased GI side effects

36. Dopamine reuptake inhibition (DRI)
Sertraline
Stahl S. Essential Psychopharmacology, 2000

37. 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

38. Citalopram
SRI
Stahl S. Essential Psychopharmacology, 2000

39. 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

40. 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

41. CYP 2C19
CYP 2C19
Fluvoxamine
Stahl S. Essential Psychopharmacology, 2000

42. CYP 1A2
CYP 1A2
Fluvoxamine
Stahl S. Essential Psychopharmacology, 2000

43. Potential clinical relevance of inhibiting CYP450 1A2
May require dose reduction of concomitantly administered theophylline (or caffeine)
May require dose reduction of concomitantly administered atypical antipsychotics (especially clozapine and olanzapine)

44. CYP 2D6 Paroxetine Fluoxetine (Sertraline) (Citalopram) CYP 2D6
Stahl S. Essential Psychopharmacology, 2000

45. Potential clinical relevance of inhibiting CYP450 2D6
If switching from (or adding to) tricyclic antidepressants (TCAs), may require dose reduction or monitoring of therapeutic drug levels of the TCA
May decrease the efficacy of codeine in pain relief and require substitution of another opiate analgesic
May require decreased dosages of some concomitantly administered beta-blockers

46. CYP 3A4 Fluvoxamine Fluoxetine CYP 3A4
Stahl S. Essential Psychopharmacology, 2000

47. Potential clinical relevance of inhibiting CYP450 3A4
Cannot administer with certain drugs, or a lethal reaction is possible (e.g., with cisapride, pimozide, astemazole and terfenadine)
May require dosage reduction of concomitantly administered alprazolam and triazolam

48. 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