SSRI(1)

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

By Somnath MondalBy Somnath Mondal

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




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


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


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


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


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


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



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




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)



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


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


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


(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


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


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



CYP 1A2

CYP 1A2

CYP 1A2CYP 1A2



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


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



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

SSRI(1)

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