2. 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.
3. • 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
4. 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.
6. • 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).
7. Mechanism of action
- inhibition of 5-HT reuptake
- ↑ of postsynapt. 5-HT1A sensitivity
10. • 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.
11. • 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
12. Half-lives of the SSRIs
50
60
70
80
90
0
10
20
30
40
50
fluoxetinesertralineparoxetinefluvoxam
inecitaloprams-citalopram
hours
15. 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.
16. 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
24. 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
25. 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.
26. 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
27. 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.
28. 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).
29. 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).
30. 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).
31. 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).
32. 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.
33. Adverse Effects Of SSRIs
Most common
Nausea (esp. Sertraline)
Sexual Dysfunction (esp. paroxetine & Sertraline)
Headache (esp. Fluoxetine)
Vomiting
Dry mouth (esp. paroxetine)
Abdominal pain
34. Adverse Effects Of SSRIs
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
35. Adverse Effects Of SSRIs
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
37. Adverse Effects Of SSRIs
Gastro-Intestinal System side effects ( esp. Sertraline and Fluvoxamine )
Nausea
Vomiting
Constipation
Diarrhoea Diarrhoea
Anorexia
Abdominal pain
Dyspepsia
Flatulence
Dry mouth
38. Adverse Effects Of SSRIs
Cardiovascular side effects
QT- Prolongation and Torsade de Pointes ( esp. Citalopram & Escitalopram)
Palpitation
Autonomic side effects
Increased sweating
Flushing
39. Adverse Effects Of SSRIs
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)
40. 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.
41. 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
43. ‘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).
44. Serotonin Syndrome
• Administration of an SSRI in
presence of another highlypresence of another highly
serotonergic drug life-threatening
‘serotonin syndrome’
45. 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.
46.
47. 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)
48. 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.
49. 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.
50.
51. 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).
52. 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.
53. 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).
54. 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.
55. 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
56. Use of SSRIs
In Special Patient GroupsIn Special Patient Groups
57. 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.
58. Special patient groups
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.
PaediatricPaediatric
59. Special patient groups
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.
60. Special patient groups
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).
61. Special patient groups
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.
62. Special patient groups
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.
63. Special patient groups
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 ??