SSRIs and SNRIs are commonly used to treat depression. SSRIs work by blocking the reuptake of serotonin, increasing levels of the neurotransmitter in the brain. Common SSRIs include fluoxetine, paroxetine, sertraline, and citalopram. SNRIs like venlafaxine also block the reuptake of serotonin and norepinephrine. These drugs are generally well-tolerated but side effects may include nausea, insomnia, sexual dysfunction, and agitation. Guidelines recommend SSRIs as first-line treatment for moderate to severe depression.

1. SSRIs and SNRIs:In adults Dr. Syed Faheem Shams Student of MD (Part-II) Psychiatry, BSMMU

2. Depression 3 rd largest cause of burden of disease GLOBAL BURDEN OF DISEASE STUDY 1995 SHOWS UNIPOLAR DEPRESSION 2nd to Coronary disease by 2020 ; 1 st by 2030

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

4. Antidepressants Tricyclic antidepressants (TCA) Monoamine oxidase inhibitors (MAOI) Selective Serotonin Re-uptake Inhibitors (SSRI) Other and atypical antidepressant Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) Noradrenaline and Dopamine Reuptake Inhibitors (NDRI) Noradrenaline Reuptake Inhibitors (NaRI) Noradrenergic/Specific Serotonergic Antidepressants (NaSSA)

5. HOW DOES THE MOST ANTIDEPRESSANTS WORK??

6. Neurotransmitter Receptor Hypothesis of Antidepressant Action Decreased state due to up-regulation of receptors Stahl S M, Essential Psychopharmacology (2000)

7. Neurotransmitter Receptor Hypothesis of Antidepressant Action 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)

8. SSRI’s Citalopram Escitalopram Fluoxetine Sertraline Fluvoxamine Paroxetine Fluoxetine Sertraline

9. SNRI--- Venlafaxine Duloxetine NaSSA --- Mirtazapine SARI--- Trazodone NDRI--- Buproprion NaRI--- Reboxetine

10. Why selective?? Affect only the reuptake pumps responsible for 5HT Because of this, SSRIs lack some of the side effects of the more general drugs

11. History Of SSRI’s SSRI’s were introduced in 1987 The first was Fluoxetine (Prozac:Eli Lilly & Company) FDA approved 1987 Sertraline (Zoloft; Pfizer, Inc) FDA approved 1991 Paroxetine (Paxil; GlaxoSmithKline) FDA approved 1992 Citalopram (Celexa; Forest Pharmaceuticals) FDA approved 2000 Escitalopram (Lexapro; Forest Pharmaceuticals) FDA approved 2002

12. Serotonin Also known as 5-HT, derived from tryptophan (amino acid) It is widely distributed in the animal and vegetable kingdoms In mammals it is found in --- gastrointestinal enterochromaffin cells blood platelets Brain nerve tissue (McGraw-Hill Encyclopedia of Science and Technology, 2005)

13. Serotonin (contd.) Serotonin is concentrated in certain areas of the brain--- the hypothalamus midbrain the cortex Cerebellum

16. Other indications of SSRI Anxiety disorders : generalized anxiety panic disorder social phobia obsessive-compulsive disorder Bulimia nervosa Pathological gambling

17. SNRIs SNRIs were developed more recently than SSRIs Relatively few Their efficacy as well as their tolerability appears to be somewhat better than the TCA’s.

18. Venlafaxine venlafaxine is approximately 3- to 5-fold more potent at inhibiting serotonin than noradrenaline reuptake It has low affinity for cholinergic, histamine H1 and adrenergic receptors. Venlafaxine is the first and most commonly used SNRI. Venlafaxine

19. Recognized minimum effective doses in MDD SSRIs Citalopram 20 mg/day Escitalopram 10 mg/day Fluoxetine 20 mg/day Fluvoxamine 50 mg/day Paroxetine 20 mg/day Sertraline 50 mg/day

20. Recognized minimum effective doses – antidepressants (except TCAs) Others Duloxetine 60 mg/day Mirtazapine 30 mg/day Reboxetine 8 mg/day Trazodone 150 mg/day Venlafaxine 75 mg/day

21. Licensed Dosing Citalopram--- 20-60mg/day Escitalopram--- 10-20mg/day Fluoxetine--- 20-60mg/day Sertraline--- 50-200mg/day Fluvoxamine--- 100-300mg/day Paroxetine--- 20-60mg/day

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

23. Plasma half life Fluvoxamine Paroxetine Sertraline Fluoxetine Escitalopram Citalopram 17-22h 24h 26h 4-6 days 30h 33h

24. Adverse Effects (A/Es) of SSRIs Nausea, vomiting, dyspepsia Irritability/ agitation Insomnia Skin rash Sexual dysfunction Hyponatraemia Cutaneous/ GI bleeding Discontinuation syndrome

25. Adverse Effects (A/Es) of SSRIs Nausea+ Fluvoxamine Discontinuation sym++ Paroxetine A/E Sertraline Insomnia++ Agitation++ Rash+ Fluoxetine A/E Escitalopram Agitation, Insomnia Citalopram

26. Major interactions (CP 450 inhibitor) Fluoxetine Sertraline Fluvoxamine Paroxetine Citalopram Escitalopram Avoid - MAOi, St. John’s wort. Plasma level of some antipsychotics/some benzos/carbamazepine/TCAs plasma level of theophylline (Fluvo) Avoid - MAOi, St. John’s wort. Caution with alcohol, NSAID’s, Warferin

27. Serotonin syndrome

28. Features of Serotonin Syndrome Classic clinical triad: Mental status changes Autonomic hyperactivity Neuromuscular abnormalities Wide ranging symptoms

29. Serotonin syndrome (contd.)

30. Serotonin syndrome (contd.)

31. Discontinuation Symptoms Paroxetine commonest Venlafaxine

32. Antidepressant-induced hyponatraemia Risk factors Old age Female sex Low body weight Low baseline sodium concentration Some drug treatments (e.g. diuretics, NSAIDs, carbamazepine, cancer chemotherapy) Reduced renal function (especially acute and chronic renal failure) Medical co-morbidity (e.g. hypothyroidism, diabetes, COPD, hypertension, head injury, CAD, various cancers) Warm weather (summer)

33. Antidepressant-induced hyponatraemia- monitoring All patients taking antidepressants should be observed for signs of hyponatraemia ( dizziness, nausea, lethargy, confusion, cramps, seizures ). Serum sodium should be determined (at baseline and 2 and 4 weeks, and then 3- monthly ) for those at high risk of drug- induced hyponatraemia.

34. Special situations Post stroke depression— SSRIs Mirtazapine 30-40% stroke pts develop MDD.

35. Special situations SSRIs and bleeding---- Pts with haemostatic defects Pts taking warferin or antiplatelet drugs NSAID’s Steroids P/h/o GI bleeding

36. Special situations In Diabetes Mellitus --- SSRI’s SNRI’s Mirtazapine TCA

37. Special situations In elder people– SSRI’s In Post MI patients- SSRI’s Mirtazapine

38. Special situations In pregnancy- -- Fluoxetine TCAs In breast feeding mother- -- Sertraline Paroxetine

39. Special situations In renal impairment — Citalopram Sertraline In hepatic impairment — Citalopram Paroxetine

40. Key points that patients should know A single episode of depression should be treated for at least 6–9 months after remission The risk of recurrence of depressive illness is high and increases with each episode Those who have had multiple episodes may require treatment for many years .The chances of staying well are greatly increased by taking antidepressants

41. Key points that patients should know Antidepressants are: effective not addictive not known to lose their efficacy over time not known to cause new long-term side effects The medication needs to be reduced slowly under the supervision of a doctor

42. Key points that patients should know Medication needs to be continued at the treatment dose. If side effects are intolerable, it may be possible to find a more suitable alternative If patients decide to stop their medication, this must not be done suddenly, as this may lead to unpleasant discontinuation effects

43. NICE guidelines on the treatment of depression Antidepressants are not recommended as first-line treatment in recent-onset, mild depression Antidepressants are recommended for the treatment of moderate to severe depression and for dysthymia

44. NICE guidelines on the treatment of depression For severe depression , a combination of an antidepressant and CBT is recommended For treatment-resistant depression recommended strategies include augmentation with lithium, an antipsychotic or a second antidepressant Patients with two prior episodes and functional impairment should be treated for at least 2 years The use of ECT is supported in severe and treatment-resistant depression

45. NICE guidelines on the treatment of depression When an antidepressant is prescribed, a generic SSRI is recommended All patients should be informed about the withdrawal (discontinuation) effects of antidepressants

46. NICE guidelines on the treatment of anxiety disorders with SSRIs ½ of the dose used in MDD. Response – 6-8 wks Duration of treatment-- ?? 6-8 months

48. Thank you all….

49. List of people with depression Abraham Lincoln (US president) William James & John B. Watson (pioneer psychologists) Sir Winston Churchill (British Prime Minister ) Brooke Shields (American actress) John Denver ( singer)