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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.
• Th...
• The first drug in the SSRI class was Prozac (Fluoxetine), which hit the
United States market in 1987. Prozac was FDA app...
Chemical Structure
• These compounds are structurally unrelated.
• This may account for the differential response we see i...
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 ...
• SSRIs Inhibit serotonin reuptake so increase synaptic
serotonin levels.
• Clinical effect usually takes weeks so mechani...
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
disorde...
Off-label indications of SSRIs
• Bipolar depression
• Psychosomatic conditions
• Irritable bowel syndrome (IBS)
• Menopaus...
• Absorption – Well absorbed orally and have peak effects in the range of 3-8
hrs. Absorption of Sertraline may be slightl...
• Elimination
Pharmacokinetics
Drug Half-life
1. Fluoxetine 4-6 days
Norfluoxetine (Active Metabolite) 7-9 days
2. Citalop...
Half-lives of the SSRIs
50
60
70
80
90
0
10
20
30
40
50
fluoxetinesertralineparoxetinefluvoxam
inecitaloprams-citalopram
h...
Maximum daily dose
Drug Max daily dose
1. Fluoxetine 80 mg
2. Citalopram 60 mg
3. Escitalopram 20 mg
4. Sertraline 200 mg
...
SSRIs Selectivity
SSRIs specifically inhibit serotonin reuptake, having
300- to 3000-fold greater selectivity for the ser...
Selectivity for 5-HT vs. NE Transporter
500
600
700
800
900
0
100
200
300
400
500
fluoxetine
sertralineparoxetinefluvoxam
...
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, Jour...
Sertraline (Lustral)
20
25
30
0
5
10
15
20
5-HT NE DA ACH H1
potency
Richelson E, Synaptic Effects of Antidepressants, Jou...
paroxetine (Seroxat)
100
120
140
0
20
40
60
80
5-HT NE DA ACH H1
potency
Richelson E, Synaptic Effects of Antidepressants,...
Fluvoxamine (Faverin)
10
12
14
0
2
4
6
8
5-HT NE DA ACH H1
potency
Richelson E, Synaptic Effects of Antidepressants, Journ...
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 Escita...
drug-drug interactions
 The SSRIs are potent inhibitors of the CYP450.
 The potential for drug-drug interactions differs...
SSRIs and Cytochrome p450
Metabolized by or
Substrate of
Induces Inhibits
Fluvoxamine 1A2, 2D6 None known 1A2, 2C19, 2B6, ...
Fluoxetine (Prozac)
Pros
 Long ½ life so:
• Good for pts with medication noncompliance issues.
• decreased incidence of ...
Sertraline (Lustral)
 Pros
 Relatively fewer side-effects (watch for GI).
 Lower potential for drug-drug interactions (...
Paroxetine (Seroxat)
Pros
 Short ½ life + No active metabolite No build-up of metabolites.
 Sedating properties (dose ...
Fluvoxamine (Faverin)
Pros
 Short ½ life + No active metabolite  No build-up of metabolites.
 Found to possess some an...
Citalopram (Cipram)
Pros
 Lower potential for drug-drug interactions (Low inhibition of P450
enzymes).
 Fewer side effe...
Escitalopram (Cipralex)
Pros
 Low overall inhibition of P450s enzymes so fewer drug-drug
interactions.
 Intermediate ½ ...
Adverse Effects Of SSRIs
Most common
 Nausea (esp. Sertraline)
 Sexual Dysfunction (esp. paroxetine & Sertraline)
 Head...
Adverse Effects Of SSRIs
 Weight changes:
 Weight gain (esp. paroxetine)
 Or Weight loss (esp. Fluoxetine)
 Increased ...
Adverse Effects Of SSRIs
Mental and behavioral side effects
 Apathy and Emotional blunting
 Paradoxical anxiety (esp. Fl...
Adverse Effects Of SSRIs
Central & Peripheral Nervous System side effects
 Sleep disturbance :
 Insomnia (esp. Fluoxetin...
Adverse Effects Of SSRIs
Gastro-Intestinal System side effects ( esp. Sertraline and Fluvoxamine )
 Nausea
 Vomiting
 C...
Adverse Effects Of SSRIs
Cardiovascular side effects
 QT- Prolongation and Torsade de Pointes ( esp. Citalopram & Escital...
Adverse Effects Of SSRIs
Rare Adverse Effects
 Serotonin syndrome
 Hyponatraemia (probably more of an issue in the elder...
Sexual Dysfunction
• Clinical rates approximate 50% of patients.
• Paroxetine and Sertraline appear to cause higher rates
...
SSRIs Affect all phases of the sexual
response
 Sexual Dysfunctions occurring in male includes:
 Decreased libido
 Erec...
Antidepressant induced sexual dysfunction
‘strategies for managing sexual dysfunction
induced by antidepressant medication’
 Reduce the dose
 Delayed dosing
 Dru...
Serotonin Syndrome
• Administration of an SSRI in
presence of another highlypresence of another highly
serotonergic drug ...
Manifestations of serotonin syndrome
– NEURO: Myoclonus, Nystagmus, Headache,
Tremors, Rigidity and Seizures.
– MENTAL STA...
Management of serotonin syndrome
Discontinuation of all serotonergic agents
Supportive care aimed at normalization of vi...
SSRI discontinuation syndrome
 Occurs on abrupt withdrawal of SSRIs.
 Agents with short half-lives (Paroxetine/ Fluovoxa...
SSRI discontinuation syndrome
 experienced by at least a third of patients.
 Doesn’t appear until at least 6 weeks of tr...
Management
If symptoms are mild  reassurance.
If symptoms are severe:If symptoms are severe:
Reintroduce the original...
SSRIs and bleeding
 SSRIs will deplete platelet serotonin, leading to a reduced ability to form
clots and a subsequent in...
SSRIs and bleeding
 SSRI + ASPIRIN, NSAIDs increases the risk of GIT bleeding.
 SSRI + oral anticoagulants increases the...
Cardiac effects of SSRIs
SSRIs are generally safe in cardiac disease.
But, be aware of antiplatelet activity and
‐ ‐
Bu...
Cardiac effects of SSRIs
Drug Heart rate Blood pressure QTc Arrhythmia Conduction
disturbanc
Licensed
restrictions
post M
...
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...
Special patient groups
Geriatric
• SSRIs are Safe & well tolerated in geriatric population.
• Minimal cardiotoxic, antich...
Special patient groups
Renal Impairment
 No agent clearly preferred to another.
 However Citalopram and Sertraline are ...
Special patient groups
Diabetes Mellitus
 Fluoxetine has been associated with improvement in HbA 1c levels,
reduced insu...
Special patient groups
Cardiac Disorders
 Sertraline is recommended.
 but other SSRIs are also likely to be safe.
 Cau...
Special patient groups
Parkinson’s Disease
 SSRIs are considered to be first-line treatment.
 Motor symptoms may be wor...
Special patient groups
Cancer Pts
 Sertraline, Escitalopram are preferred due to least risk of drug
interaction.
Dement...
Selective serotonin reuptake inhibitors 2016
Selective serotonin reuptake inhibitors 2016
Selective serotonin reuptake inhibitors 2016
Selective serotonin reuptake inhibitors 2016
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Selective serotonin reuptake inhibitors 2016

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Selective serotonin reuptake inhibitors 2016

  1. 1. Mohamed sedky Selective Serotonin Reuptake Inhibitors (SSRIs) Psychiatric specialist BMHH 2016
  2. 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. 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. 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.
  5. 5. 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
  6. 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. 7. Mechanism of action - inhibition of 5-HT reuptake - ↑ of postsynapt. 5-HT1A sensitivity
  8. 8. 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 √
  9. 9. 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
  10. 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. 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. 12. Half-lives of the SSRIs 50 60 70 80 90 0 10 20 30 40 50 fluoxetinesertralineparoxetinefluvoxam inecitaloprams-citalopram hours
  13. 13. 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
  14. 14. 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.
  15. 15. 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
  16. 16. Medication 14 16 18 20 0 2 4 6 8 10 12 14 5-HT NE DA ACH H1 potency
  17. 17. 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
  18. 18. Sertraline (Lustral) 20 25 30 0 5 10 15 20 5-HT NE DA ACH H1 potency Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
  19. 19. paroxetine (Seroxat) 100 120 140 0 20 40 60 80 5-HT NE DA ACH H1 potency Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
  20. 20. Fluvoxamine (Faverin) 10 12 14 0 2 4 6 8 5-HT NE DA ACH H1 potency Richelson E, Synaptic Effects of Antidepressants, Journal of Clinical Psychopharmacology, Vol. 16, No3, Suppl. 2, June, 1996
  21. 21. 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
  22. 22. Escitalopram (Cipralex) 20 25 30 0 5 10 15 20 5-HT NE DA ACH H1 East
  23. 23. 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
  24. 24. 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.
  25. 25. 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
  26. 26. 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.
  27. 27. 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).
  28. 28. 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).
  29. 29. 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).
  30. 30. 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).
  31. 31. 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.
  32. 32. Adverse Effects Of SSRIs Most common  Nausea (esp. Sertraline)  Sexual Dysfunction (esp. paroxetine & Sertraline)  Headache (esp. Fluoxetine)  Vomiting  Dry mouth (esp. paroxetine)  Abdominal pain
  33. 33. 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
  34. 34. 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
  35. 35. Adverse Effects Of SSRIs 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
  36. 36. 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
  37. 37. Adverse Effects Of SSRIs Cardiovascular side effects  QT- Prolongation and Torsade de Pointes ( esp. Citalopram & Escitalopram)  Palpitation Autonomic side effects  Increased sweating  Flushing
  38. 38. 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)
  39. 39. 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.
  40. 40. 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
  41. 41. Antidepressant induced sexual dysfunction
  42. 42. ‘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).
  43. 43. Serotonin Syndrome • Administration of an SSRI in presence of another highlypresence of another highly serotonergic drug  life-threatening ‘serotonin syndrome’
  44. 44. 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.
  45. 45. 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)
  46. 46. 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.
  47. 47. 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.
  48. 48. 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).
  49. 49. 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.
  50. 50. 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).
  51. 51. 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.
  52. 52. 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
  53. 53. Use of SSRIs In Special Patient GroupsIn Special Patient Groups
  54. 54. 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.
  55. 55. 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. PaediatricPaediatric
  56. 56. Special patient groups 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.
  57. 57. 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).
  58. 58. 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.
  59. 59. 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.
  60. 60. 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 ??

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