Selective serotonin reuptake inhibitors 2016

Mohamed sedky
Selective Serotonin Reuptake Inhibitors
(SSRIs)
Psychiatric specialist
BMHH
2016

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
O
O
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 C
H
CH2 CH2 N
CH3
H
Sertraline
Cl
Cl
Citalopram
Escitalopram 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
50
60
70
80
90
0
10
20
30
40
50
fluoxetinesertralineparoxetinefluvoxam
inecitaloprams-citalopram
hours

Maximum daily dose
Drug 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, having
300- to 3000-fold greater selectivity for the serotonin
transporter as compared to the norepinephrine
transporter.transporter.
As a class, SSRIs have little affinity for cholinergic,
β-adrenergic or histamine receptors.

Selectivity for 5-HT vs. NE Transporter
500
600
700
800
900
0
100
200
300
400
500
fluoxetine
sertralineparoxetinefluvoxam
inecitaloprams-citalopram
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
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

Summary
of 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 differs
significantly across the SSRIs.significantly across the SSRIs.
 Fluvoxamine, Paroxetine and Fluoxetine are potent
CYP2D6 inhibitors responsible for the elimination of
TCA drugs, neuroleptic drugs, and some
antiarrhythmic and β-adrenergic antagonist drugs.

SSRIs and Cytochrome p450
Metabolized 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

Mental 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

Central & 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

Gastro-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 highlypresence 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 SSRIs
Drug Heart rate Blood pressure QTc Arrhythmia Conduction
disturbanc
Licensed
restrictions
post M
Comments
Fluoxetine Small decrease in
mean heart rat
Minimal effect on
blood pressur
No effect on QTc
interval
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
No effect on QTc
interval
None None General caution in
cardiac patients
Probably safe post MI
Sertraline Minimal effect on
heart rate
Minimal effect on
blood pressure
No effect on QTc
interval
None None None – drug of
choice
Safe post MI and in
heart failure
Citalopram
(assume same
for
escitalopram)
Small decrease in
heart rate
Slight drop in
systolic blood
pressure
Dose‐related
increase in QTc
Torsades de
pointes
reported, mainly
in overdose
None Caution but some
evidence of safety
in cardiovascular
disease
Minor metabolite
which may ↑ QTc
interval. 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.

Geriatric
• SSRIs are Safe & well tolerated in geriatric population.
• Minimal cardiotoxic, anticholinergic, antihistaminic or α adrenergic
adverse effects except for Paroxetine which has some anticholinergic
activity.
PaediatricPaediatric

Renal Impairment
 No agent clearly preferred to another.
 However Citalopram and Sertraline are suggested as reasonable choices.
Hepatic ImpairmentHepatic 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

Selective serotonin reuptake inhibitors 2016

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