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Mechanism of action and Mechanism of action and pharmacokinetic properties of pharmacokinetic properties of selective serotonin reuptake selective serotonin reuptake
inhibitorsinhibitors::
fluoxetine, sertraline, paroxetine, fluoxetine, sertraline, paroxetine, fluvoxamine and citalopramfluvoxamine and citalopram
An An eeducational ducational pprogramrogrammeme ssupported by upported by H. LH. Lundbeck A/S,undbeck A/S, Copenhagen Copenhagen
Some figures reproduced with permission from:Some figures reproduced with permission from:Stahl SM, Stahl SM, Essential PsychopharmacologyEssential Psychopharmacology, 2nd edition, , 2nd edition, Cambridge University Press, New York, 2000Cambridge University Press, New York, 2000
Produced by the Produced by the NNeuroscience euroscience EEducation ducation IInstitute, nstitute, San Diego, CaliforniaSan Diego, California
SRISRISRISRI
Simplified conceptSimplified concept
SSRISSRISSRISSRI
Stahl S.Stahl S. Essential PsychopharmacologyEssential Psychopharmacology,, 2000 2000
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
MMechanism of therapeutic action: echanism of therapeutic action: pharmacologic properties pharmacologic properties
shared by all five shared by all five SSRISSRIss
IImmediate blockade of serotonin transporter on mmediate blockade of serotonin transporter on axon terminals and in somatoaxon terminals and in somato--dendritic areas of dendritic areas of serotonergic neuronserotonergic neuronee
DDelayed down regulation/desensitielayed down regulation/desensitissation of ation of somatosomato--dendritic serotonin 1A receptorsdendritic serotonin 1A receptors
DDelayed disinhibition (elayed disinhibition (ii.e., .e., ‘‘turning onturning on’’) of ) of serotonin release from axon terminalsserotonin release from axon terminals
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
SSRI antidepressant profileSSRI antidepressant profile
RResponse is frequently complete recoveryesponse is frequently complete recovery
UUsual dose is the initial dosesual dose is the initial dose
OOnset of action 3nset of action 3––8 weeks8 weeks
TTarget symptoms not worsened at firstarget symptoms not worsened at first
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
SSRI anti-SSRI anti-OCDOCD profile profile
RResponse is frequently incomplete recoveryesponse is frequently incomplete recovery
UUsual dose is often higher than the initial dosesual dose is often higher than the initial dose
OOnset of action 12nset of action 12––26 weeks26 weeks
TTarget symptoms not worsened at firstarget symptoms not worsened at first
IIndividual patients can respond quite differently ndividual patients can respond quite differently to one SSRI compared to anotherto one SSRI compared to another
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
SSRI anti-panic profileSSRI anti-panic profile
RResponse is frequently complete recovery esponse is frequently complete recovery (especially with concomitant benzodiazepines)(especially with concomitant benzodiazepines)
UUsual starting dose is often lower than the sual starting dose is often lower than the starting doses for other indicationsstarting doses for other indications
TTarget symptoms often worsened at firstarget symptoms often worsened at first
OOnset of action 3nset of action 3––8 weeks8 weeks
SSRI anti-social phobia profileSSRI anti-social phobia profile RResponse is often robust, with complete recovery after esponse is often robust, with complete recovery after
many months of SSRI treatment more likely with many months of SSRI treatment more likely with cconcomitant behaviooncomitant behaviouural therapy encouraging socialiral therapy encouraging socialissationation
UUsual starting dose is often lower than the starting doses sual starting dose is often lower than the starting doses for other indications, although ultimate dosfor other indications, although ultimate dosee may be higher may be higher than usual antidepressant dosesthan usual antidepressant doses
TTarget symptoms not usually worsened at first, but arget symptoms not usually worsened at first, but agitation and unexpected panic attacks can occur when agitation and unexpected panic attacks can occur when SSRI treatment is initiatedSSRI treatment is initiated
OOnset of action 3nset of action 3––8 weeks8 weeks
SSRI anti-SSRI anti-PTSDPTSD profile profile
RResponse is frequently robust but incomplete at esponse is frequently robust but incomplete at 8 weeks of treatment8 weeks of treatment
UUsual starting dose is lower than the starting sual starting dose is lower than the starting doses for other indications to avoid activating doses for other indications to avoid activating side effectsside effects
TTarget symptoms often worsened at first, arget symptoms often worsened at first, including panic, nightmares and flashbacksincluding panic, nightmares and flashbacks
OOnset of action 3nset of action 3––8 weeks8 weeks
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
SSRI anti-bulimia profileSSRI anti-bulimia profile
UUsual starting dose is higher than the starting sual starting dose is higher than the starting doses for other indicationsdoses for other indications
TTarget symptoms often rapidly improvedarget symptoms often rapidly improved
NNot well established ot well established for for prevention prevention of of relapses relapses long termlong term
Mechanism of side effectsMechanism of side effects: : pharmacologic properties pharmacologic properties
shared by all five SSRIsshared by all five SSRIs
UUnwanted stimulation of undesired serotonin nwanted stimulation of undesired serotonin receptor subtypesreceptor subtypes
‘‘CCost of doing businessost of doing business’’
EEspecially clinically relevant are unwanted specially clinically relevant are unwanted stimulation of 5HT2A/2C and/or 5HT3/4 receptors stimulation of 5HT2A/2C and/or 5HT3/4 receptors in various specific pathways and tissuesin various specific pathways and tissues
AAll five ll five SSRISSRIs lead to indirect s lead to indirect stimulation of serotonin 2stimulation of serotonin 2AA
receptorsreceptors Linked to short term mediation of:Linked to short term mediation of:
–– anxiety/panic attacksanxiety/panic attacks
–– insomniainsomnia
–– agitation/jitterinessagitation/jitteriness
–– sexual dysfunction (especially anorgasmia sexual dysfunction (especially anorgasmia and ejaculatory delay)and ejaculatory delay)
–– apathy/anhedonia/decreased libido apathy/anhedonia/decreased libido
–– stimulation of 5HT2A receptors inhibits stimulation of 5HT2A receptors inhibits dopamine releasedopamine release
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
AAll five ll five SSRISSRIs lead to indirect s lead to indirect stimulation of serotonin 2stimulation of serotonin 2C C
receptors:receptors: (only fluoxetine also stimulates 5HT2C (only fluoxetine also stimulates 5HT2C
receptors directly) receptors directly)
Mice without 5HT2C receptors are obese Mice without 5HT2C receptors are obese
BBlockade of 5HT2C receptors, especially lockade of 5HT2C receptors, especially simultaneous with blockade of histamine 1 simultaneous with blockade of histamine 1 receptorsreceptors,, is associated with weight gain is associated with weight gain
AAcute stimulation can cause weight loss and cute stimulation can cause weight loss and anxietyanxiety
CChronic stimulation can cause weight gainhronic stimulation can cause weight gain
AAll five ll five SSRISSRIs indirectly stimulate s indirectly stimulate serotonin 3 and 4 receptorsserotonin 3 and 4 receptors
Decreased feeding (5HT3)Decreased feeding (5HT3)
Loss of appetite/nausea (5HT3)Loss of appetite/nausea (5HT3)
Vomiting (chemoreceptor trigger zone/5HT3)Vomiting (chemoreceptor trigger zone/5HT3)
Increased bowel motility (5HT3 and 5HT4)Increased bowel motility (5HT3 and 5HT4)
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
©© Stahl SMStahl SM.. Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000 Essential Psychopharmacology, 2nd edition, Cambridge University Press, New York, 2000
Summary: Summary: common pharmacological common pharmacological properties of all five SSRIsproperties of all five SSRIs
Blockade of serotonin transporters leads to Blockade of serotonin transporters leads to increases in serotonin throughout the CNS and increases in serotonin throughout the CNS and throughout the bodythroughout the body
Increases of serotonin in the right places leads to Increases of serotonin in the right places leads to therapeutic actions: therapeutic actions: ii.e., at somato.e., at somato--dendritic dendritic autoreceptorautoreceptorss in the midbrain raphe in the midbrain raphe
Increases of serotonin in the wrong places can Increases of serotonin in the wrong places can lealeadd to side effects, especially at 5HT2A and 5HT3 to side effects, especially at 5HT2A and 5HT3 receptors (but also at 5HT2C and 5HT4 receptors)receptors (but also at 5HT2C and 5HT4 receptors)
Secondary pharmacologic Secondary pharmacologic properties of various SSRIsproperties of various SSRIs
NRINRI
CY
P 2D
6C
YP
2D6
m-AChm-ACh SRISRI
5HT2C
5HT2C
NOSNOS
CYP 1A2
CYP 1A2CYP 3A3,4
CYP 3A3,4
DRIDRI
SSRISSRI
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
Potentially important secondary Potentially important secondary binding properties for each SSRIbinding properties for each SSRIPotentially important secondary Potentially important secondary binding properties for each SSRIbinding properties for each SSRI
Fluoxetine and serotonin 2C stimulationFluoxetine and serotonin 2C stimulation
Sertraline and dopaminergic stimulationSertraline and dopaminergic stimulation
Paroxetine and anticholinergic propertiesParoxetine and anticholinergic properties
Fluvoxamine and sigma properties Fluvoxamine and sigma properties
Citalopram and selectivityCitalopram and selectivity
5HT2C
5HT2C
5HT2C5HT2C agonistagonist
FluoxetineFluoxetine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
PPotential clinical relevance of otential clinical relevance of stimulating 5stimulating 5HTHT22CC receptors receptors
Possible weight loss or less weight gainPossible weight loss or less weight gain
Possible increased efficacy in bulimia and binge Possible increased efficacy in bulimia and binge eatingeating
Possibly overly stimulating in some patientsPossibly overly stimulating in some patients
Possibly harder to titrate in panic disorder, social Possibly harder to titrate in panic disorder, social phobia and PTSD due to activating and anxiogenic phobia and PTSD due to activating and anxiogenic properties in some patientsproperties in some patients
m-AChm-ACh
Muscarinic cholinergic (m-ACh) Muscarinic cholinergic (m-ACh) blockadeblockade
ParoxetineParoxetine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
Potential clinical relevance of Potential clinical relevance of blocking muscarinic cholinergic blocking muscarinic cholinergic
receptorsreceptors
Possibly well tolerated in anxious patients, even Possibly well tolerated in anxious patients, even reducing anxiety before delayed SSRI actions beginreducing anxiety before delayed SSRI actions begin
PPossibly able to improve sleep early in treatmentossibly able to improve sleep early in treatment
MMight be poorly tolerated in elderly with early cognitive ight be poorly tolerated in elderly with early cognitive problems or Alzheimer’s problems or Alzheimer’s ddiseaseisease
MMight cause mild ight cause mild ‘‘anticholinergicanticholinergic’’ side effects such as side effects such as constipation, dry mouth, blurred vision, sedationconstipation, dry mouth, blurred vision, sedation
MMight cause more sexual dysfunction, (especially ight cause more sexual dysfunction, (especially erectile dysfunction), more weight gain and more erectile dysfunction), more weight gain and more withdrawal problemswithdrawal problems
Sigma (Sigma () blockade) blockade
FluvoxamineFluvoxamine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
(Sertraline)(Sertraline)
Potential clinical relevance of Potential clinical relevance of interacting at sigma receptorsinteracting at sigma receptors
Possible anxiolytic actionsPossible anxiolytic actions
Possible antipsychotic actionsPossible antipsychotic actions
Possible increased GI side effectsPossible increased GI side effects
DRIDRI
Dopamine reuptake inhibition (DRI)Dopamine reuptake inhibition (DRI)
SertralineSertraline
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
Potential clinical relevance of Potential clinical relevance of enhancing dopaminergic activityenhancing dopaminergic activity
Possible cognitive enhancementPossible cognitive enhancement
Less prolactin elevationLess prolactin elevation
Possibly less weight gain Possibly less weight gain
Possibly too activating in some patients, thus Possibly too activating in some patients, thus necessitating dose titration especially in those necessitating dose titration especially in those with anxiety disorderswith anxiety disorders
SRISRICitalopramCitalopram
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
Potential clinical relevance of Potential clinical relevance of selectivity without secondary selectivity without secondary
pharmacologic propertiespharmacologic properties
Side effects and therapeutic effects predictable Side effects and therapeutic effects predictable based upon serotonergic mechanisms alonebased upon serotonergic mechanisms alone
Possibly less activation and less sedation than Possibly less activation and less sedation than SSRIs with secondary actionsSSRIs with secondary actions
Possibly faster onset due to lack of side effects Possibly faster onset due to lack of side effects allowing rapid dose titrationallowing rapid dose titration
Possibly good compliance at initiation of dosing if Possibly good compliance at initiation of dosing if serotonergic side effects minimalserotonergic side effects minimal
SSRIs and the cytochrome SSRIs and the cytochrome PP450 450 drug metabolidrug metabolissing enzymesing enzymes
Fluoxetine inhibits CYP450 2D6 and 3A4Fluoxetine inhibits CYP450 2D6 and 3A4
Sertraline is a weak inhibitor of CYP450 2D6 Sertraline is a weak inhibitor of CYP450 2D6
Paroxetine inhibits CYP450 2D6Paroxetine inhibits CYP450 2D6
Fluvoxamine inhibits CYP450 1A2, 2C19 and 3A4Fluvoxamine inhibits CYP450 1A2, 2C19 and 3A4
Citalopram is a weak inhibitor of CYP450 2D6Citalopram is a weak inhibitor of CYP450 2D6
CYP 2C19
CYP 2C19
CYP 2C19CYP 2C19
FluvoxamineFluvoxamine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
CYP 1A2
CYP 1A2
CYP 1A2CYP 1A2
FluvoxamineFluvoxamine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
Potential clinical relevance of Potential clinical relevance of inhibiting CYP450 1A2inhibiting CYP450 1A2
May require dose reduction of concomitantly May require dose reduction of concomitantly administered theophyllinadministered theophyllinee (or caffeine) (or caffeine)
May require dose reduction of concomitantly May require dose reduction of concomitantly administered atypical antipsychotics (especially administered atypical antipsychotics (especially clozapine and olanzapine)clozapine and olanzapine)
CY
P 2D
6C
YP
2D6
CYP 2D6CYP 2D6
ParoxetineParoxetine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
FluoxetineFluoxetine (Sertraline)(Sertraline) (Citalopram)(Citalopram)
Potential clinical relevance of Potential clinical relevance of inhibiting CYP450 2D6inhibiting CYP450 2D6
If switching from (or adding to) tricyclic If switching from (or adding to) tricyclic antidepressants (TCAs), may require dose antidepressants (TCAs), may require dose reduction or monitoring of therapeutic drug levels reduction or monitoring of therapeutic drug levels of the TCAof the TCA
MMay decrease the efficacy of codeine in pain relief ay decrease the efficacy of codeine in pain relief and require substitution of another opiate and require substitution of another opiate analgesicanalgesic
MMay require decreased dosages of some ay require decreased dosages of some concomitantly administered betaconcomitantly administered beta--blockersblockers
CYP 3A4
CYP 3A4
CYP 3A4CYP 3A4
FluvoxamineFluvoxamine
Stahl S. Essential PsychopharmacologyStahl S. Essential Psychopharmacology, , 20002000
FluoxetineFluoxetine
Potential clinical relevance of Potential clinical relevance of inhibiting CYP450 3A4inhibiting CYP450 3A4
Cannot administer with certain drugs, or a lethal Cannot administer with certain drugs, or a lethal reaction is possible (e.g., with cisapride, pimozide, reaction is possible (e.g., with cisapride, pimozide, astemazole and terfenastemazole and terfenaadine)dine)
May require dosage reduction of concomitantly May require dosage reduction of concomitantly administered alprazolam and triazolam administered alprazolam and triazolam
Summary:Summary: mechanism of action and mechanism of action and pharmacokinetics of SSRIspharmacokinetics of SSRIs
All SSRIs share a common therapeutic mechanism All SSRIs share a common therapeutic mechanism of action in depression, OCD, paniof action in depression, OCD, panicc disorder, disorder, social phobia and PTSDsocial phobia and PTSD
All SSRIs can create unwanted side effects from All SSRIs can create unwanted side effects from stimulating 5HT2A and 5HT3 receptorsstimulating 5HT2A and 5HT3 receptors
Various SSRIs have potentially clinically significant Various SSRIs have potentially clinically significant drug interactions, but these differ from one SSRI to drug interactions, but these differ from one SSRI to anotheranother
No two SSRIs have the same secondary binding No two SSRIs have the same secondary binding features, and this may account for why some features, and this may account for why some patients respond to one SSRIpatients respond to one SSRI,, or tolerate one SSRI or tolerate one SSRI,, better than anotherbetter than another