selective serotonin reuptake inhibitors 2016

Mohamed sedky

Selective Serotonin Reuptake Inhibitors

(SSRIs)

Psychiatric specialistBMHH2016

Introduction

• SSRIs are a class of antidepressants used mainly in the treatment of depression and anxiety disorders.

• They are the most commonly prescribed group of antidepressants.antidepressants.

• SSRIs increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell.

• The first drug in the SSRI class was Prozac (Fluoxetine), which hit the United States market in 1987. Prozac was FDA approved in December 29, 1987. It is manufactured by Eli Lilly and Company.

• Subsequently other SSRIs were introduced.

History

SSRI YEARSSRI YEAR

Fluoxetine 1987

Sertraline 1992

Paroxetine 1993

Fluvoxamine 1994

Citalopram 1998

Escitalopram 2002

Chemical Structure

• These compounds are structurally unrelated.

• This may account for the differential response we see in some patients with one antidepressant vs. another.some patients with one antidepressant vs. another.

• Rationale for differential response may be related to different morphology of the serotonin transport protein.

Paroxetine

O

OO

CH2

HN

CH3

SSRI Structures

O

NC

CH2CH2CH2N(CH3)2·HBr

Fluvoxamine

F3C C CH2 CH2 CH2 CH2 O CH3

N

O CH2 CH2 NH2

N

Fluoxetine

O CH

CH2 CH2 N

CH3

H

Sertraline

Cl

Cl

CitalopramEscitalopram F

• SSRIs Inhibit serotonin reuptake so increase synaptic serotonin levels.

• Clinical effect usually takes weeks so mechanism goes beyond simply increasing synaptic serotonin levels.

Mechanism of action

levels.

• Serotonin receptors are located throughout the body (especially GI tract).

Mechanism of action

- inhibition of 5-HT reuptake- ↑ of postsynapt. 5-HT1A sensitivity

Licensed indication of SSRIs

Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline

Major depressive disorder

√ √ √ √ √ √

Generalized anxiety disorder

√ √ √

Social anxiety disorders

√ √ √disorders

OCD √ √ √ √ √

PTSD √ √

Panic disorder ±Agoraphobia

√ √ √ √

Premenstrual dysphoric disorder

√ √ √ √

Bulimia nervosa √

Off-label indications of SSRIs

• Bipolar depression

• Psychosomatic conditions

• Irritable bowel syndrome (IBS)

• Menopausal symptoms

• Premature ejaculation• Premature ejaculation

• Migraine headache prophylaxis

• Chronic headache

• Musculo-skeletal pain

• Fibromyalgia

• Absorption – Well absorbed orally and have peak effects in the range of 3-8 hrs. Absorption of Sertraline may be slightly increased by food.

• Distribution – Differences in plasma protein binding percentages; with Sertraline, Fluoxetine & Paroxetine most highly bound; & Escitalopram least bound.

Pharmacokinetics

least bound.

• Metabolism – All SSRIs are metabolized in the liver by CYP 450 enzymes.

Wide Therapeutic Index-So their concentration not affected by other drugs. But, potential for slowing/blocking the metabolism of many drugs.

• Elimination

Pharmacokinetics

Drug Half-life

1. Fluoxetine 4-6 days

Norfluoxetine (Active Metabolite) 7-9 days

2. Citalopram 35 hours2. Citalopram 35 hours

3. Escitalopram 27-32 hours

4. Sertraline 26 hours

(Less active metabolite) 3-5 days

5. Paroxetine 21 hours

6. Fluvoxamine 15 hours

Half-lives of the SSRIs

5060708090

01020304050

fluox

etin

e

sert

ralin

e

parox

etin

e

fluvo

xam

ine

cital

opra

m

s-cita

lopra

m

hours

Maximum daily doseDrug Max daily dose

1. Fluoxetine 80 mg

2. Citalopram 60 mg

3. Escitalopram 20 mg

4. Sertraline 200 mg

5. Paroxetine 50 mg

6. Fluvoxamine 300 mg

SSRIs Selectivity

SSRIs specifically inhibit serotonin reuptake, having300- to 3000-fold greater selectivity for the serotonintransporter as compared to the norepinephrinetransporter.transporter.

As a class, SSRIs have little affinity for cholinergic,β-adrenergic or histamine receptors.

Selectivity for 5-HT vs. NE Transporter

500600700800900

0100200300400500

fluox

etin

e

sertr

alin

e

paro

xetin

e

fluvo

xam

ine

citalo

pram

s-cita

lopr

am

selectivity

Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Vol. 16, No3, Suppl. 2, June 1996

Medication

14

16

18

20

0

2

4

6

8

10

12

14

5-HT NE DA ACH H1

potency

Fluoxetine (Prozac)

6

7

8

9

0

1

2

3

4

5

6

5-HT NE DA ACH H1

potency

Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology,Vol. 16, No3, Suppl. 2, June, 1996

Sertraline (Lustral)

20

25

30

0

5

10

15

20

5-HT NE DA ACH H1

potency


paroxetine (Seroxat)

100

120

140

0

20

40

60

80

5-HT NE DA ACH H1

potency


Fluvoxamine (Faverin)

10

12

14

0

2

4

6

8

5-HT NE DA ACH H1

potency


Citalopram (Cipram)

1.4

1.6

1.8

2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

5-HT NE DA ACH H1

potency

Escitalopram (Cipralex)

20

25

30

0

5

10

15

20

5-HT NE DA ACH H1

East

Summaryof pharmacodynamic differences

• Dose-response curves

– Citalopram is linear

• Selectivity

– Citalopram and Escitalopram is the most selective

• Serotonergic reuptake blockade• Serotonergic reuptake blockade

– paroxetine is the most potent

• Dopamine reuptake blockade

– Sertraline is the most potent

• Anticholinergic effect

– paroxetine is the most potent

drug-drug interactions

The SSRIs are potent inhibitors of the CYP450.

The potential for drug-drug interactions differssignificantly across the SSRIs.significantly across the SSRIs.

Fluvoxamine, Paroxetine and Fluoxetine are potentCYP2D6 inhibitors responsible for the elimination ofTCA drugs, neuroleptic drugs, and someantiarrhythmic and β-adrenergic antagonist drugs.

SSRIs and Cytochrome p450Metabolized by or Substrate of

Induces Inhibits

Fluvoxamine 1A2, 2D6 None known 1A2, 2C19, 2B6, 2C9, 2D6, 3A4

Fluoxetine 2C9, 2D6, 1A2, 2B6, 2C19, 2E1, 3A4

None known 2D6, 2C19 (m), 1A2, 2B6, 2C9

3A4

Paroxetine 2D6 None known 2D6, 2B6 (m), 1A2, 2C9, 2C19, 3A4

Citalopram 3A4, 2C19, 2D6 None known 1A2, 2B6, 2C19, 2D6

Escitalopram 2C19, 3A4, 2D6 None known 1A2, 2C9, 2C19, 2D6, 2E1, 3A

Sertraline 2D6, 2B6, 2C9, 2C19, 3A4 None known 2B6 (m), 2C19 (m), 2D6 (m), 3A4 (m), 1A2, 2C8, 2C9

Fluoxetine (Prozac)

Pros Long ½ life so:

• Good for pts with medication noncompliance issues.• decreased incidence of discontinuation syndromes.• can be used to taper someone off SSRI when trying to prevent SSRI Discontinuation

Syndrome.• Once daily dosing (or even day after day).• Once daily dosing (or even day after day).

Initially activating so may provide increased energy.

Cons Long ½ life + active metabolite ↑ build-up of metabolites (e.g. not a

good choice in patients with hepatic illness). Significant P450 interactions so this may not be a good choice in pts

already on a number of meds (increased seizure risk with clozapine). Initial activation may increase anxiety and insomnia.

Sertraline (Lustral)

Pros Relatively fewer side-effects (watch for GI).

Lower potential for drug-drug interactions (very weak P450 interactions).

Intermediate ½ life + less active metabolite lower build-up of metabolites.metabolites.

Less sedating when compared to paroxetine.

Cons Max absorption requires a full stomach.

Increased number of GI adverse drug reactions (associated with a higher incidence of diarrhoea than other SSRI).

Paroxetine (Seroxat)

Pros Short ½ life + No active metabolite No build-up of metabolites.

Sedating properties (dose at night) offers good initial relief from anxiety and insomnia.

Available in sustained release form. Available in sustained release form.

Cons Likely to cause a discontinuation syndrome (short ½ life ).

Worst side effect profile (sedation, weight gain, sexual dysfunction and anticholinergic side effects).

Potential for drug-drug interactions (Significant CYP2D6 inhibition).

Fluvoxamine (Faverin)

Pros Short ½ life + No active metabolite No build-up of metabolites.

Found to possess some analgesic properties.

Cons Likely to cause a discontinuation syndrome (short ½ life ).

Side-effect profile is relatively worse (GI distress, headaches, sedation, weakness).

Strong inhibitor of CYP1A2 and CYP2C19 (Highest potential for drug-drug interactions with increased serum levels of Agomelatine and theophylline).

Citalopram (Cipram)

Pros Lower potential for drug-drug interactions (Low inhibition of P450

enzymes).

Fewer side effects at low doses.

Intermediate ½ life ( once daily dosing). Intermediate ½ life ( once daily dosing).

Cons Dose-dependent QT interval prolongation with doses of 10-40mg/day

(doses of >40mg/day needs monitoring of QT interval).

Can be sedating (has mild antagonism at H1 histamine receptor).

GI side effects (less than Sertraline).

Escitalopram (Cipralex)

Pros Low overall inhibition of P450s enzymes so fewer drug-drug

interactions.

Intermediate ½ life ( once daily dosing).

More effective than Citalopram in acute response and remission. More effective than Citalopram in acute response and remission.

Cons Dose-dependent QT interval prolongation with doses of 10-30mg daily

(doses of >30mg/day needs monitoring of QT interval).

Nausea, headache.

Adverse Effects Of SSRIs

Most common

Nausea (esp. Sertraline)

Sexual Dysfunction (esp. paroxetine & Sertraline)

Headache (esp. Fluoxetine)

Vomiting

Dry mouth (esp. paroxetine)

Abdominal pain


Weight changes: Weight gain (esp. paroxetine)

Or Weight loss (esp. Fluoxetine)

Increased risk of Bleeding

Discontinuation syndrome (esp. paroxetine & Fluvoxamine)

Increased potential for drug-drug interaction (esp. Fluvoxamine)

Risks during pregnancy: Teratogenicity

Persistent pulmonary hypertension

Neonatal withdrawal syndrome

Adverse Effects Of SSRIsMental and behavioral side effects

Apathy and Emotional blunting

Paradoxical anxiety (esp. Fluoxetine & Sertraline)

Nervousness

Irritability Irritability

Akathisia / restlessness

Suicidality (emergence of suicidal ideation)

Hypomania or mania (manic switching)

Abnormal dreaming

Adverse Effects Of SSRIsCentral & Peripheral Nervous System side effects

Sleep disturbance : Insomnia (esp. Fluoxetine)

Somnolence (esp. paroxetine & Fluvoxamine)

excessive dreaming

Headache (esp. Fluoxetine)

Dizziness

Yawning

Paraesthesia

Tremor

Extrapyramidal disorder

Adverse Effects Of SSRIsGastro-Intestinal System side effects ( esp. Sertraline and Fluvoxamine )

Nausea

Vomiting

Constipation

Diarrhoea Diarrhoea

Anorexia

Abdominal pain

Dyspepsia

Flatulence

Dry mouth


Cardiovascular side effects

QT- Prolongation and Torsade de Pointes ( esp. Citalopram & Escitalopram)

Palpitation

Autonomic side effects

Increased sweating

Flushing


Rare Adverse Effects

Serotonin syndrome

Hyponatraemia (probably more of an issue in the elderly)

hyperprolactinemia

Galactorrhea

Mammary hypertrophy and gynaecomastia

Extrapyramidal symptoms

Seizure (esp. Fluoxetine ≥ 100mg/ day)

Sexual Dysfunction

• Clinical rates approximate 50% of patients.

• Paroxetine and Sertraline appear to cause higher rates of sexual dysfunction in most head to head studies.of sexual dysfunction in most head to head studies.

SSRIs Affect all phases of the sexual response

Sexual Dysfunctions occurring in male includes:

Decreased libido

Erectile dysfunction

Delayed orgasm

Penile anaesthesia

Painful ejaculation

Priapism

Sexual Dysfunctions occurring in female includes

Decreased libido

Delayed orgasm

Decreased vaginal lubrication

Vaginal anaesthesia

Dyspareunia

Antidepressant induced sexual dysfunction

‘strategies for managing sexual dysfunction induced by antidepressant medication’

Reduce the dose

Delayed dosing

Drug ‘holidays’ Drug ‘holidays’

Switch to a different antidepressant that is less likely to cause the specific sexual problem experienced (e.g. Bupropion and Agomelatine).

Adding adjunctive or ‘antidote’ drugs: Bupropion, Mirtazapine, Trazodone, Sildenafil (Viagra) and Tadalafil (Snafi).

Serotonin Syndrome

• Administration of an SSRI in presence of another highly presence of another highly serotonergic drug life-threatening ‘serotonin syndrome’

Manifestations of serotonin syndrome

– NEURO: Myoclonus, Nystagmus, Headache, Tremors, Rigidity and Seizures.

–MENTAL STATE: Irritability, Confusions, –MENTAL STATE: Irritability, Confusions, Agitations, Hypomania and Coma.

– AUTONOMIC: Hyperpyrexia, sweating, diarrhea, cardiac arrythmia and death.

Management of serotonin syndrome

Discontinuation of all serotonergic agents

Supportive care aimed at normalization of vital signs (oxygen and intravenous fluids, continuous cardiac monitoring, and correction of vital signs).monitoring, and correction of vital signs).

Sedation with benzodiazepines

Administration of serotonin antagonists (Cyproheptadine)

SSRI discontinuation syndrome

Occurs on abrupt withdrawal of SSRIs.

Agents with short half-lives (Paroxetine/ Fluovoxamine), inactive metabolites abrupt washout higher risk.

So, Fluoxetine lowest risk for discontinuation syndrome.

No definitive pathophysiologic explanation.

SSRI discontinuation syndrome

experienced by at least a third of patients.

Doesn’t appear until at least 6 weeks of treatment & The onset of symptoms is usually within 3 days of stopping treatment and usually resolves spontaneously within 2 weeks.

‐ They are usually mild and self‐limiting (but can occasionally be severe

and prolonged).

the most commonly reported symptoms include: dizziness, nausea, lethargy, headache, electric shock-like sensations, sweating, , insomnia and tremor.

Management

If symptoms are mild reassurance.

If symptoms are severe:If symptoms are severe:Reintroduce the original antidepressant.

Or another with a longer half‐life (e.g. Fluoxetine).

SSRIs and bleeding

SSRIs will deplete platelet serotonin, leading to a reduced ability to form clots and a subsequent increase in the risk of bleeding.

SSRIs also increase gastric acid secretion and therefore may be irritant to the gastric mucosa. Use of SSRIs seems to increase the risk of peptic ulcer.

SSRIs increase the risk of GIT, cerebral and perioperative bleeding (those undergoing orthopaedic or breast surgery may be at greatest risk).

Risk is increased still further in those also receiving aspirin, NSAIDs or oral anticoagulants.

SSRIs and bleeding

SSRI + ASPIRIN, NSAIDs increases the risk of GIT bleeding.

SSRI + oral anticoagulants increases the risk of Non GIT bleeding.

Try to avoid SSRIs in patients receiving NSAIDs, aspirin or oral anticoagulants or with history of cerebral or GI bleeds.

If SSRI use cannot be avoided (in any anticoagulated or aspirin‐treated patient), monitor closely and prescribe gastroprotective proton pump inhibitors.

In patients taking Warfarin, suggest Citalopram or Escitalopram (probably lowest interaction potential).

Cardiac effects of SSRIs

SSRIs are generally safe in cardiac disease.

But, be aware of antiplatelet activity and ‐ ‐

But, be aware of antiplatelet activity and cytochrome‐mediated interactions with co‐administered cardiac drugs.

Cardiac effects of SSRIsDrug Heart rate Blood pressure QTc Arrhythmia Conduction

disturbancLicensed restrictions post M

Comments

Fluoxetine Small decrease in mean heart rat

Minimal effect on blood pressur

No effect on QTcinterval

None None caution. Clinical experience is limited

Evidence of safety post MI

Fluvoxamine Minimal effect on heart rate

Small drop in systolic blood pressure

No significant effect on QTc

None None Caution Limited changes in ECG have been observed

Paroxetine Small decrease in mean heart rate

Minimal effect on blood pressure


None None General caution in cardiac patients

Probably safe post MI

Sertraline Minimal effect on heart rate

Minimal effect on blood pressure


None None None – drug of choice

Safe post MI and inheart failure

Citalopram(assume same for escitalopram)

Small decrease inheart rate

Slight drop in systolic blood pressure

Dose‐related increase in QTc

Torsades de pointesreported, mainly in overdose

None Caution but some evidence of safety in cardiovascular disease

Minor metabolite which may ↑ QTcinterval. No clear evidence of increased risk of arrhythmia at any licensed dose

Use of SSRIs In Special Patient GroupsIn Special Patient Groups

Special patient groups

Pregnancy All SSRIs are rated pregnancy category C, with the exception of

paroxetine, which is a category D.

There is most experience with Sertraline and Fluoxetine

Paroxetine may be less safe than other SSRIs. Paroxetine may be less safe than other SSRIs.

Breast Feeding Sertraline is the drug of choice followed by Paroxetine.

Special patient groupsGeriatric• SSRIs are Safe & well tolerated in geriatric population.

• Minimal cardiotoxic, anticholinergic, antihistaminic or α adrenergic adverse effects except for Paroxetine which has some anticholinergicactivity.

PaediatricPaediatric


Renal Impairment No agent clearly preferred to another.

However Citalopram and Sertraline are suggested as reasonable choices.

Hepatic ImpairmentHepatic Impairment Fluoxetine (longer half life) to be avoided.

Citalopram & Escitalopram have minimal effects on hepatic enzymes so they are SSRIs of choice.


Diabetes Mellitus Fluoxetine has been associated with improvement in HbA 1c levels,

reduced insulin requirements, weight loss and enhanced insulin sensitivity.

Hypertention No agent clearly preferred to another (Minimal effect on blood pressure).


Cardiac Disorders Sertraline is recommended.

but other SSRIs are also likely to be safe.

Caution with Citalopram and Escitalopram (Dose‐related increase in QTc, especially with overdose).

‐especially with overdose).

Post Stroke Depression Fluoxetine, Citalopram are the most studied and seem to be effective and

safe and widely recommended for post-stroke depression.

Stroke can be embolic or haemorrhagic –SSRIs may protect against the former and provoke the latter.


Parkinson’s Disease SSRIs are considered to be first-line treatment.

Motor symptoms may be worsened (low risk).

SSRIs + Selegiline → Risk of Serotonin Syndrome

Epilepsy For SSRIs, the risk is generally considered to be low if no predisposing

factor is seen and it is not significantly different from the incidence of first seizure in the general population.

Reports of seizure with Fluoxetine and Citalopram overdose.


Cancer Pts Sertraline, Escitalopram are preferred due to least risk of drug

interaction.

Dementia the most common antidepressants used in dementia are sertraline followed

by citalopram.

citalopram up to 30 mg/day for agitation ??

selective serotonin reuptake inhibitors 2016

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