ANTIDEPRESSANTS - PHARMACODYNAMICS

1. ANTIDEPRESSANTS - PHARMACODYNAMICS DR. KAILASH S SENIOR RESIDENT

2. ANTIDEPRESSANT PHARMACODYNAMICS • Various classes of antidepressants differ in their mechanism of action • A thorough understanding of this can help us choose a antidepressant in a particular clinical situation on the basis of its efficacy and side effect profile. • The best way to understand the mechanism of action of a drug is to know the effects of the receptors on which the drug acts.

3. OVERVIEW • Receptors and their actions • Antidepressant classification • MOA & Important points of individual drugs • Drugs in the pipeline • Review

4. All monoaminergic systems share common pattern of anatomical features and metabolism.

5. REUPTAKE TRANSPORTERS • Plasma membrane transport protein and involves cotransport • Transporter molecules for serotonin (SERT), dopamine (DAT), and norepinephrine (NET) have been well characterized • Function: 1. Limiting the extent and duration of activation of monoaminergic receptors. 2. Primary mechanism for replenishing terminal monoamine neurotransmitter stores. • Interaction between significant life stressors and specific variant alleles in predisposing individuals to affective disorders.

6. TERMINATION OF ACTION • Action of serotonin is • terminated by • SERT Reuptake • Degradation of serotonin is • mediated by monoamine • oxidase type A (MAO-A) • MAO-A is located in • mitochondrial membranes • and is nonspecific • Levels of 5-HIAA are often • measured as a correlate of • serotonergic system activity

7. Serotonin Receptors

8. Serotonin Receptors Presynaptic 1A/1B/1D Postsynaptic

9. Presynaptic Receptors on Serotonergic Neurons Autoreceptors Presynaptic Receptors Heteroreceptors - α2 5HT – 1A - Somatodendritic AR Slows Neuronal Impulse Presynpaptic AutoReceptors 5HT – 1B/1D Terminal AR Blockade of 5HT Release

10. Circadian rhythm 5HT7 Gut - 4 Emesis - 3 Psychosis - 2A Cognition – 1A/1C Other NT Reg – 2A/2C Mood SERT/1A 2A/2C/7 BDNF 5HT6 Actions of Serotonin Sex 2A/2C Pain 1B/1D Sleep 2A/7 Appetite 2C

11. Monoamine and Neurotrophic hypothesis of Depression Decreased Synaptic Monoamine concentration Altered Neuroplasticity and cellular resilience

12. Stress, HPA axis and BDNF

13. BDNF and 5-HT Signalling

14. ANTIDEPRESSANT CLASSIFICATION • SSRI – Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Escitalopram, Citalopram • SNRI – Duloxetine, Venlafaxine, Desvenlafaxine, Milnacipran, Sibutramine • NDRI – Bupropion • 5HT 1A Partial Agonist - Buspirone • NARI - Reboxetine • NaSSA – Mirtazapine • SARI – Trazadone, Nefazadone • MaSSA - Agomelatine

15. ANTIDEPRESSANT CLASSIFICATION • Cyclic Antidepressants A.Tricyclic Tertiary Amines – Imipramine, Amitriptyline, Clomipramine, Dotheipin B.Tricyclic Secondary Amines – Nortriytyline, Desipramine C.Tetracyclic Antidepressants – Mianserin, Maprotiline, Amoxapine D.Bicyclic Antidepressant – Viloxazine • MAOI Reversible Selective MAOI MAOI – A (RIMAs) – Moclobemide MAOI – B – Selegiline

16. Receptor Profile of SSRI • Serotonin • Reduces Negative affect • No effect on/induces • reduced positive affect • Apathetic Recovery • Same Therapeutic mechanism • Different Efficacy and • Tolerability • Due to Secondary • Pharmacological action

17. Why do antidepressants take time to act?

18. Role of 5- HT & Antidepressant in Depression • Acute increase in Synaptic • 5-HT • Side effects • Downregulation of receptors • well before clinical resolution • Tolerance to side effects • Onset of action • Normalisation of CREB,BDNF • And altered brain morphology • Correlates with clinical • resolution of depression

19. Fluoxetine • 5HT2C Antagonism (NDDI) • Activation symptoms • Anorexia • Antibulimia action • at high doses • Boosts antidepressant action • of Olanzapine in BPD.

20. SertralineParoxetine For patients with anxiety because of calming and sedating property (M1 Antagonism) NRI - Additive antidepressant Inhibit NOS – Sexual dysfunction Notorious withdrawal reaction – Cholinergic rebound DOP – Energy, motivation and Concentration Sigma – Anxiolytic and useful in psychotic depression

21. FluvoxamineEscitalopram S – Enantiomer Robust increase in 5 HT. Most Selective and best tolerated SSRI. LeastCYP interactions. Sigma Agonist – Anxiety and Psychotic depression (more than sertraline) For OCD and Anxiety

22. SNRI Two and a half actions – Dopamine in PFC. Wider Clinical spectrum +ve & -ve affect. S.E. – Activation, Agitation, HT, Tachycardia Pseudo anticholinergic syndrome. Venlafaxamine - 5HT: NE – 5 : 1 Nausea, HT,withdrawal Desvenlafaxamine – Greater &predictable NE action Duloxetine - 5HT:NE – 9 : 1 less S.E than Venlafaxamine Milnacipran – NE:5HT – 3 : 1 • Depression with reduced • positive affect • Chronic painful physical • Symptoms with depression • Vasomotor symptoms of • menopause • Neuropathic pain of diabetes • Cognitive symptoms • Fibromyalgia

23. NaSSA - Mirtazapine

24. Mirtazapine • Potent(multiple mech) • Anxiolytic • (5HT2A/2C antag, 5HT1A agonist) • Sedating(5HT2A and H1 • Antagonism) • No Sexual dysfunction • Weight gain • (5HT2c and H1 antag)

25. Serotonin antagonist(2A/2C)/ reuptake(SERT) inhibitor(SARI) Low dose - Antagonist at 5HT2A/H1/α1 As Hypnotic; Augment ; Increase remission High Dose – SERT/5HT2C inhibition

26. NDRI - BUPROPION • Devoid of prominent Serotonin Enhancing Action • No Sexual side effects • Monotherapy • Augmentation of another antidepressant – Improves positive affect – Energy & Drive • In Smoking Cessation • Less Switch Rate • Seizures to be looked out for

27. NARI - REBOXETINE • Preferred in: • Depression • Fatigue • Apathy • Psychomotor retardation • Attention deficit and impaired concentration • Disorders (not limited to depression) characterized by cognitive slowing, especially, deficiencies in working memory and in the speed of information processing • Side Effects: • Unwanted Adrenergic Excess • Pseudoanticholinergic Syndrome

28. BUSPIRONE • 5HT-1A Partial Agonist • More pronounced presynaptic agonistic action, Decreases serotonin release and thus anti- anxiety effect • Postsynaptic 5HT-1A agonism is responsible for antidepressant effect • Advantages : No sedation, sexual dysfunction, weight gain, sleep disturbances,cognitive or psychomotor impairment • Disadvantages: Delayed onset of Action

29. NOVEL MELATONIN LINKED MECHANISM • Combines this property of 5HT2C antagonism and thus NDDI actions with additional agonist actions at melatonin receptors (MT1 and MT2) with 5HT2B antagonist properties. • Not only antidepressant actions but also sleep-enhancing properties due to MT1 and MT2 agonist actions. • No sexual side effects

30. Receptor profile of TCA’s α1 Antagonism – Orthostatic hypotension and dizziness H1 Antagonism - Sedation and weight gain M1 antagonism – Anticholinergic side effects M3 antagonism – Decreases insulin action Voltage gated ion channels – Heart – Cardiac arrythmias and arrest CNS - Seizures and coma ???DIRTY DRUG

31. PROFILE OF CYCLIC ANTIDEPRESSANTS • Prominent NE reuptake inhibitor: Nortriptyline Desipramine • Prominent 5HT reuptake inhibitor: Clomipramine • Mixed NE & 5HT reuptake inhibitor: Amitriptyline Imipramine

32. MAOIs • Irreversible – Phenelzine, Isocarboxazid& Tranylcypromine • Reversible MAOI B – Oral and transdermalSelegiline • Reversible MAOI A - Moclobemide Life threatening Hypertensive crisis Caution when used in combination of other drugs Adequate wash out period

33. VORTIOXETINE • On September 30, 2013, it was approved by the U.S. FDA for the treatment of major depressive disorder (MDD) in adults.[2]Vortioxetine was also investigated as a treatment for generalized anxiety disorder (GAD • Vortioxetineis a so-called "serotonin modulator and stimulator” It has been shown to possess the following pharmacological actions • Serotonin transporter (SERT) blocker (i.e. serotonin reuptake inhibitor (SRI)) • Norepinephrine transporter (NET) blocker • 5-HT1A receptor high-efficacy partial agonist/near-full agonist • 5-HT1B receptor • 5-HT1D receptorantagonist • 5-HT3A receptorantagonist • 5-HT7 receptorantagonist • Vortioxetine also has affinity for the β1-adrenergic receptor though any actions at this site are unlikely to contribute to its therapeutic effects and likely only to contribute to side effects

34. Triple reuptake inhibitors (TRIs) or serotonin-norepinephrine-dopamine-reuptake inhibitors (SNDRIs): The question for TRIs is how much blockade of dopamine transporter is desired? About10% to 25% inhibition of DAT Also increases the 4th neurotransmitter acetylcholine

35. HPA AXIS RELATED TREATMENT ACTIVATION OF HPA AXIS INCREASED VASOPRESSIN INCREASED CRF CRF1 antagonists PEXACERFONT CRF1/2 RECEPTORS INCREASED ACTH V1B RECEPTORS GLUCOCORTICOID SYNTHESIS INHIBITOR METYPARONE INCREASED STEROID SYNTHESIS V1B antagonists GR antagonists MEFIPRESTONE INCREASED ACTION OF STEROIDS

36. NOVEL NEUROPEPTIDE LINKED MECHANISM NEUROKININS • Ligand for NK1 receptor is Substance P. Aprepitant (NK1 antagonist) in Phase III for depression NK 2 receptor antagonist is Saredutant and is being studied as antidepressant

37. REVIEW.. • NDRI…? • NaSSA…? • Buspirone… MOA? • Agomelatine… MOA? • SSRI with prominent sigma receptor action…? • TCA have cardiac side effects because of..? • SNRI with highest NE:5HT ratio? • RIMA….? • SARI…? • NARI…? • Antidepressant for patients with sexual dysfunction..? • Antidepressant with highest weight gain potential?

38. THANK YOU