Mechanism of action and pharmacokinetic properties of selective serotonin reuptake inhibitors:

fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram

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, 2000 Produced by the Neuroscience Education Institute, San Diego, California

Simplified concept

SSRI

SRI

Stahl S. Essential Psychopharmacology, 2000

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

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

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

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

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

SSRI antidepressant profile

Response is frequently complete recovery Usual dose is the initial dose Onset of action 38 weeks Target symptoms not worsened at first

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

SSRI anti-OCD profile

Response is frequently incomplete recovery Usual dose is often higher than the initial dose Onset of action 1226 weeks

Target symptoms not worsened at first

Individual patients can respond quite differently to one SSRI compared to another

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

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 38 weeks

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 38 weeks

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 38 weeks

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

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

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

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

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

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

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

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

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)

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

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

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)

Secondary pharmacologic properties of various SSRIs

DRI

SSRI

SRI

Stahl S. Essential Psychopharmacology, 2000

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

5HT2C agonist

Fluoxetine

Stahl S. Essential Psychopharmacology, 2000

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

Muscarinic cholinergic (m-ACh) blockade

Paroxetine

Stahl S. Essential Psychopharmacology, 2000

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 Alzheimers 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

Sigma () blockade

Fluvoxamine (Sertraline)

Stahl S. Essential Psychopharmacology, 2000

Potential clinical relevance of interacting at sigma receptors

Possible anxiolytic actions Possible antipsychotic actions Possible increased GI side effects

Dopamine reuptake inhibition (DRI)

DRI

Sertraline

Stahl S. Essential Psychopharmacology, 2000

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

Citalopram

SRI

Stahl S. Essential Psychopharmacology, 2000

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

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

CYP 2C19

Fluvoxamine

Stahl S. Essential Psychopharmacology, 2000

CYP 1A2

Fluvoxamine

Stahl S. Essential Psychopharmacology, 2000

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)

CYP 2D6

Paroxetine Fluoxetine (Sertraline) (Citalopram)

Stahl S. Essential Psychopharmacology, 2000

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

CYP 3A4

Fluvoxamine Fluoxetine

Stahl S. Essential Psychopharmacology, 2000

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

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