ssnri

SSRIs and SNRIs:In adultsSSRIs and SNRIs:In adults

PRESENTED BY PRESENTED BY NOMAN RAJPUTNOMAN RAJPUT

DepressionDepression

• 33rdrd largest cause of burden of diseaselargest cause of burden of disease

• GLOBAL BURDEN OF DISEASE STUDY GLOBAL BURDEN OF DISEASE STUDY 1995 SHOWS UNIPOLAR DEPRESSION 1995 SHOWS UNIPOLAR DEPRESSION 2nd2nd to Coronary disease by to Coronary disease by 20202020;;11stst by by 20302030

Prevalence in Prevalence in BangladeshBangladesh• WHO + NIMH---- ‘03-‘05WHO + NIMH---- ‘03-‘05 Psychiatric disorder ---- >18 yrs --- Psychiatric disorder ---- >18 yrs --- 16.05%.16.05%.• MDD--- 4.6%MDD--- 4.6%• GAD--- 2.9%GAD--- 2.9%• Somatoform D--- 1.4%Somatoform D--- 1.4%• Panic--- 1.3%Panic--- 1.3%• Agorophobia—0.9%Agorophobia—0.9%• OCD--- 0.5%OCD--- 0.5%• Simple Phobia--- 0.3%Simple Phobia--- 0.3%

AntidepressantsAntidepressants

– Tricyclic antidepressants (TCA)Tricyclic antidepressants (TCA) – Monoamine oxidase inhibitors (MAOI)Monoamine oxidase inhibitors (MAOI)– Selective Serotonin Re-uptake Inhibitors Selective Serotonin Re-uptake Inhibitors

(SSRI)(SSRI)– Other and atypical antidepressantOther and atypical antidepressant

• Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) • Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)• Noradrenaline and Dopamine Reuptake Inhibitors (NDRI)Noradrenaline and Dopamine Reuptake Inhibitors (NDRI)• Noradrenaline Reuptake Inhibitors (NaRI)Noradrenaline Reuptake Inhibitors (NaRI)• Noradrenergic/Specific Serotonergic Antidepressants Noradrenergic/Specific Serotonergic Antidepressants

(NaSSA)(NaSSA)

HOW DOES THE MOST HOW DOES THE MOST ANTIDEPRESSANTS WORK??ANTIDEPRESSANTS WORK??

Neurotransmitter Receptor Neurotransmitter Receptor Hypothesis of Antidepressant Hypothesis of Antidepressant ActionAction

Decreased state due to up-regulation of receptors

Stahl S M, Essential Psychopharmacology (2000)

Neurotransmitter Receptor Neurotransmitter Receptor Hypothesis of Antidepressant Hypothesis of Antidepressant ActionAction

Antidepressant blocks the reuptake pump, causing more NT to be in the synapse

Increase in NT causes receptors to down-regulate

Stahl S M, Essential Psychopharmacology (2000)

SSRI’sSSRI’s

• CitalopramCitalopram

• EscitalopramEscitalopram

• FluoxetineFluoxetine

• SertralineSertraline

• FluvoxamineFluvoxamine

• ParoxetineParoxetine

Fluoxetine

Sertraline

• SNRI---SNRI--- VenlafaxineVenlafaxine DuloxetineDuloxetine• NaSSA ---NaSSA --- MirtazapineMirtazapine• SARI---SARI--- TrazodoneTrazodone• NDRI---NDRI--- BuproprionBuproprion• NaRI---NaRI--- ReboxetineReboxetine

Why selective??Why selective??

• Affect only the reuptake pumps Affect only the reuptake pumps responsible for 5HTresponsible for 5HT

• Because of this, SSRIs lack some of the Because of this, SSRIs lack some of the side effects of the more general drugsside effects of the more general drugs

History Of SSRI’sHistory Of SSRI’s

• SSRI’s were introduced in 1987 SSRI’s were introduced in 1987 • The first was Fluoxetine (Prozac:Eli Lilly & The first was Fluoxetine (Prozac:Eli Lilly &

Company) FDA approved 1987Company) FDA approved 1987• Sertraline (Zoloft; Pfizer, Inc) FDA approved Sertraline (Zoloft; Pfizer, Inc) FDA approved

19911991• Paroxetine (Paxil; GlaxoSmithKline) FDA Paroxetine (Paxil; GlaxoSmithKline) FDA

approved 1992approved 1992• Citalopram (Celexa; Forest Citalopram (Celexa; Forest

Pharmaceuticals) FDA approved 2000Pharmaceuticals) FDA approved 2000• Escitalopram (Lexapro; Forest Escitalopram (Lexapro; Forest

Pharmaceuticals) FDA approved 2002Pharmaceuticals) FDA approved 2002

SerotoninSerotonin

• Also known as 5-HT, derived from Also known as 5-HT, derived from tryptophan (amino acid)tryptophan (amino acid)

• It is widely distributed in the animal and It is widely distributed in the animal and vegetable kingdomsvegetable kingdoms

• In mammals it is found in ---In mammals it is found in --- gastrointestinal enterochromaffin cellsgastrointestinal enterochromaffin cells blood plateletsblood platelets BrainBrain nerve tissuenerve tissue

(McGraw-Hill Encyclopedia of Science and Technology, 2005)

Serotonin (contd.)Serotonin (contd.)

Serotonin is concentrated in certain Serotonin is concentrated in certain areas of the brain---areas of the brain---

• the hypothalamus the hypothalamus

• midbrain midbrain

• the cortex the cortex

• CerebellumCerebellum

Other indications of Other indications of SSRISSRI Anxiety disordersAnxiety disorders::

• generalized anxietygeneralized anxiety

• panic disorder panic disorder

• social phobia social phobia

• obsessive-compulsive disorderobsessive-compulsive disorder

Bulimia nervosaBulimia nervosa

Pathological gamblingPathological gambling

SNRIsSNRIs

• SNRIs were developed more recently SNRIs were developed more recently than SSRIsthan SSRIs

• Relatively few Relatively few

• Their efficacy as well as their tolerability Their efficacy as well as their tolerability appears to be somewhat better than the appears to be somewhat better than the TCA’s.TCA’s.

VenlafaxineVenlafaxine

•venlafaxine is approximately 3- to venlafaxine is approximately 3- to 5-fold more potent at inhibiting 5-fold more potent at inhibiting serotonin than noradrenaline serotonin than noradrenaline reuptakereuptake

• It has low affinity for cholinergic, It has low affinity for cholinergic, histamine H1 and adrenergic histamine H1 and adrenergic receptors.receptors.Venlafaxine is the first and most commonly used SNRI.

Venlafaxine

Recognized minimum Recognized minimum effective doses in MDDeffective doses in MDD

SSRIsSSRIs Citalopram 20 mg/day Citalopram 20 mg/day Escitalopram 10 mg/day Escitalopram 10 mg/day Fluoxetine 20 mg/day Fluoxetine 20 mg/day Fluvoxamine 50 mg/day Fluvoxamine 50 mg/day Paroxetine 20 mg/day Paroxetine 20 mg/day Sertraline 50 mg/day Sertraline 50 mg/day

Recognized minimum effective Recognized minimum effective doses – antidepressantsdoses – antidepressants (except TCAs) (except TCAs)

•OthersOthers Duloxetine 60 mg/day Duloxetine 60 mg/day Mirtazapine 30 mg/day Mirtazapine 30 mg/day Reboxetine 8 mg/day Reboxetine 8 mg/day Trazodone 150 mg/day Trazodone 150 mg/day Venlafaxine 75 mg/day Venlafaxine 75 mg/day

Licensed DosingLicensed Dosing

• Citalopram--- 20-60mg/dayCitalopram--- 20-60mg/day

• Escitalopram--- 10-20mg/dayEscitalopram--- 10-20mg/day

• Fluoxetine--- 20-60mg/dayFluoxetine--- 20-60mg/day

• Sertraline--- 50-200mg/daySertraline--- 50-200mg/day

• Fluvoxamine--- 100-300mg/dayFluvoxamine--- 100-300mg/day

• Paroxetine--- 20-60mg/dayParoxetine--- 20-60mg/day

Licensed DosingLicensed Dosing

Duloxetine 60-120 mg/day Duloxetine 60-120 mg/day Mirtazapine 15-45 mg/day Mirtazapine 15-45 mg/day Reboxetine 8-12 mg/day Reboxetine 8-12 mg/day Trazodone 150-300 mg/day Trazodone 150-300 mg/day Venlafaxine 75-375 mg/day Venlafaxine 75-375 mg/day

Plasma half lifePlasma half life

CitalopramCitalopram 33h33h

EscitalopramEscitalopram 30h30h

FluoxetineFluoxetine 4-6 days4-6 days

SertralineSertraline 26h26h

ParoxetineParoxetine 24h24h

FluvoxamineFluvoxamine 17-22h17-22h

Adverse Effects (A/Es) of Adverse Effects (A/Es) of SSRIsSSRIs

• Nausea, vomiting, dyspepsiaNausea, vomiting, dyspepsia• Irritability/ agitationIrritability/ agitation• InsomniaInsomnia• Skin rashSkin rash• Sexual dysfunctionSexual dysfunction• HyponatraemiaHyponatraemia• Cutaneous/ GI bleedingCutaneous/ GI bleeding• Discontinuation syndromeDiscontinuation syndrome

Adverse Effects (A/Es) of Adverse Effects (A/Es) of SSRIsSSRIs

CitalopramCitalopram Agitation, InsomniaAgitation, Insomnia

EscitalopramEscitalopram A/EA/E

FluoxetineFluoxetine Insomnia++Insomnia++

Agitation++Agitation++

Rash+Rash+

SertralineSertraline A/EA/E

ParoxetineParoxetine Discontinuation sym++Discontinuation sym++

FluvoxamineFluvoxamine Nausea+Nausea+

Major interactions (CPMajor interactions (CP450450 inhibitor)inhibitor)CitalopramCitalopram

EscitalopramEscitalopramAvoidAvoid- MAOi, St. - MAOi, St. John’s wort. John’s wort.

CautionCaution with alcohol, with alcohol, NSAID’s, WarferinNSAID’s, Warferin

FluoxetineFluoxetine

SertralineSertraline

FluvoxamineFluvoxamine

ParoxetineParoxetine

AvoidAvoid- MAOi, St. - MAOi, St. John’s wort.John’s wort. Plasma level of Plasma level of some some antipsychotics/some antipsychotics/some benzos/carbamazepinbenzos/carbamazepine/TCAse/TCAs

plasma level of plasma level of theophylline (Fluvo)theophylline (Fluvo)

Serotonin syndromeSerotonin syndrome

Features of Serotonin Features of Serotonin SyndromeSyndrome

• Classic clinical Classic clinical triad:triad:– Mental status Mental status

changeschanges– Autonomic Autonomic

hyperactivityhyperactivity– Neuromuscular Neuromuscular

abnormalitiesabnormalities

• Wide ranging Wide ranging symptomssymptoms

Serotonin syndrome Serotonin syndrome (contd.)(contd.)

Serotonin syndrome Serotonin syndrome (contd.)(contd.)

Discontinuation Discontinuation SymptomsSymptoms

• ParoxetineParoxetine commonest commonest

• VenlafaxineVenlafaxine

Antidepressant-induced Antidepressant-induced hyponatraemiahyponatraemia

Risk factorsRisk factors Old ageOld age Female sexFemale sex Low body weightLow body weight Low baseline sodium concentrationLow baseline sodium concentration Some drug treatments (e.g. diuretics, NSAIDs, Some drug treatments (e.g. diuretics, NSAIDs,

carbamazepine, cancer chemotherapy)carbamazepine, cancer chemotherapy) Reduced renal function (especially acute and chronic Reduced renal function (especially acute and chronic

renal failure)renal failure) Medical co-morbidity (e.g. hypothyroidism, diabetes, Medical co-morbidity (e.g. hypothyroidism, diabetes,

COPD, hypertension, head injury, CAD, various COPD, hypertension, head injury, CAD, various cancers)cancers)

Warm weather (summer)Warm weather (summer)

Antidepressant-induced Antidepressant-induced hyponatraemia-hyponatraemia- monitoring monitoring

All patients taking antidepressants should beAll patients taking antidepressants should be observed for signs of hyponatraemiaobserved for signs of hyponatraemia ((dizziness, nausea, lethargy, confusion,dizziness, nausea, lethargy, confusion, cramps, seizurescramps, seizures).).

Serum sodium should be determined (atSerum sodium should be determined (at baselinebaseline and 2 and 4 weeks, and then and 2 and 4 weeks, and then 3-3- monthlymonthly) for those at high risk of drug-) for those at high risk of drug- induced hyponatraemia. induced hyponatraemia.

Special situationsSpecial situations

• Post stroke depression—Post stroke depression—

SSRIsSSRIs

Mirtazapine Mirtazapine

30-40% stroke pts develop MDD.30-40% stroke pts develop MDD.

Special situationsSpecial situations

• SSRIs and bleeding----SSRIs and bleeding---- Pts with haemostatic defectsPts with haemostatic defects Pts taking warferin or antiplatelet Pts taking warferin or antiplatelet

drugsdrugs NSAID’s NSAID’s SteroidsSteroids P/h/o GI bleedingP/h/o GI bleeding

Special situationsSpecial situations

• In Diabetes Mellitus ---In Diabetes Mellitus ---

SSRI’sSSRI’s

SNRI’sSNRI’s

MirtazapineMirtazapine

TCATCA

Special situationsSpecial situations

• In elder people– In elder people–

SSRI’sSSRI’s

• In Post MI patients-In Post MI patients-

SSRI’sSSRI’s

MirtazapineMirtazapine

Special situationsSpecial situations

• In pregnancy-In pregnancy-----

FluoxetineFluoxetine

TCAsTCAs

• In breast feeding mother-In breast feeding mother-----

SertralineSertraline

ParoxetineParoxetine

Special situationsSpecial situations

• In renal impairmentIn renal impairment——

CitalopramCitalopram

SertralineSertraline

• In hepatic impairmentIn hepatic impairment——

Citalopram Citalopram

ParoxetineParoxetine

Key points that patients Key points that patients should knowshould know A A single episodesingle episode of depression should be of depression should be

treated for at least treated for at least 6–9 months6–9 months after remission after remission

The risk of The risk of recurrencerecurrence of depressive illness is of depressive illness is highhigh and and increasesincreases with each episode with each episode

Those who have had Those who have had multiple episodesmultiple episodes may may require treatment for require treatment for many yearsmany years .The .The chances of staying well are greatly increased chances of staying well are greatly increased by taking antidepressantsby taking antidepressants

Key points that patients Key points that patients should knowshould know

Antidepressants are: Antidepressants are: effective effective not addictive not addictive not known to lose their efficacy over time not known to lose their efficacy over time not known to cause new long-term side effectsnot known to cause new long-term side effects

The medication needs to be The medication needs to be reduced reduced slowlyslowly under the supervision of a under the supervision of a doctordoctor

Key points that patients Key points that patients should knowshould know

Medication needs to be continued at Medication needs to be continued at the treatment dose. If the treatment dose. If side effectsside effects are intolerable, it may be possible to are intolerable, it may be possible to find a more suitable alternativefind a more suitable alternative

If patients If patients decide to stopdecide to stop their their medication, this must not be done medication, this must not be done suddenly, as this may lead to suddenly, as this may lead to unpleasant discontinuation effects unpleasant discontinuation effects

NICE guidelines on the NICE guidelines on the treatment of depressiontreatment of depression

Antidepressants are not Antidepressants are not recommended as first-line treatment recommended as first-line treatment in recent-onset, mild depressionin recent-onset, mild depression

Antidepressants are recommended Antidepressants are recommended for the treatment of for the treatment of moderate to moderate to severesevere depression and for dysthymia depression and for dysthymia

NICE guidelines on the NICE guidelines on the treatment of depressiontreatment of depression For For severe depressionsevere depression, a combination of an , a combination of an

antidepressant and CBT is recommendedantidepressant and CBT is recommended

For For treatment-resistant depressiontreatment-resistant depression recommended recommended strategies include augmentation with lithium, an strategies include augmentation with lithium, an antipsychotic or a second antidepressantantipsychotic or a second antidepressant

Patients with two prior episodes and functional Patients with two prior episodes and functional impairment should be treated for at least impairment should be treated for at least 2 years2 years

The use of The use of ECTECT is supported in severe and is supported in severe and treatment-resistant depressiontreatment-resistant depression

NICE guidelines on the NICE guidelines on the treatment of depressiontreatment of depression

When an antidepressant is When an antidepressant is prescribed, a generic prescribed, a generic SSRI SSRI is is recommendedrecommended

All patients should be informed about All patients should be informed about the the withdrawal (discontinuation) withdrawal (discontinuation) effectseffects of antidepressants of antidepressants

NICE guidelines on the NICE guidelines on the treatment of anxiety treatment of anxiety disorders with SSRIsdisorders with SSRIs• ½ ½ of the dose used in MDD.of the dose used in MDD.

• Response – 6-8 wksResponse – 6-8 wks

• Duration of treatment-- ?? 6-8 Duration of treatment-- ?? 6-8 monthsmonths

Thank you all….Thank you all….

List of people with List of people with depressiondepression

• Abraham Lincoln (US president)Abraham Lincoln (US president)

• William James & John B. Watson William James & John B. Watson (pioneer psychologists)(pioneer psychologists)

• Sir Winston Churchill (British Prime Sir Winston Churchill (British Prime Minister )Minister )

• Brooke Shields (American actress) Brooke Shields (American actress)

• John Denver ( singer)John Denver ( singer)