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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

‘turning on’) of serotonin release from axon terminals .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.

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

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

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

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 .

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

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 .

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

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    .

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. but agitation and unexpected panic attacks can occur when SSRI treatment is initiated Onset of action 3–8 weeks   . although ultimate dose may be higher than usual antidepressant doses Target symptoms not usually worsened at first.SSRI anti-social phobia profile  Response is often robust.

including panic. nightmares and flashbacks Onset of action 3–8 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.

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

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 .

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

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

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

is associated with weight gain Acute stimulation can cause weight loss and anxiety Chronic stimulation can cause weight gain   . especially simultaneous with blockade of histamine 1 receptors.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.

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) .

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

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

. 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)   .e.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.

2000 . Essential Psychopharmacology.Secondary pharmacologic properties of various SSRIs DRI SSRI SRI Stahl S.

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 .

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

dry mouth. 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. blurred vision. (especially erectile dysfunction). sedation Might cause more sexual dysfunction.Potential clinical relevance of blocking muscarinic cholinergic receptors  Possibly well tolerated in anxious patients. more weight gain and more withdrawal problems   .

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

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 .

Essential Psychopharmacology. 2000 .Citalopram SRI Stahl S.

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. 2000 . Essential Psychopharmacology.

CYP 1A2  Fluvoxamine Stahl S. 2000 . Essential Psychopharmacology.

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 .

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   .Potential clinical relevance of inhibiting CYP450 2D6  If switching from (or adding to) tricyclic antidepressants (TCAs).

2000 .CYP 3A4  Fluvoxamine  Fluoxetine Stahl S. Essential Psychopharmacology.

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

OCD. better than another   . or tolerate one SSRI. 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.Summary: mechanism of action and pharmacokinetics of SSRIs  All SSRIs share a common therapeutic mechanism of action in depression. panic disorder.