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DR. KAILASH S SENIOR RESIDENT ANTIDEPRESSANTS - PHARMACODYNAMICS

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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.

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

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

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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.

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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

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Serotonin Receptors

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Presynaptic 1A/1B/1D Postsynaptic

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Presynaptic Receptors on Serotonergic Neurons Autoreceptors Presynaptic Receptors Heteroreceptors - 2 5HT 1A - Somatodendritic AR Slows Neuronal Impulse Presynpaptic AutoReceptors 5HT 1B/1D Terminal AR Blockade of 5HT Release

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

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

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Stress, HPA axis and BDNF

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BDNF and 5-HT Signalling

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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

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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

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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

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Why do antidepressants take time to act?

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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

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

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Sertraline Paroxetine DOP Energy, motivation and Concentration Sigma Anxiolytic and useful in psychotic depression For patients with anxiety because of calming and sedating property (M 1 Antagonism) NRI - Additive antidepressant Inhibit NOS Sexual dysfunction Notorious withdrawal reaction Cholinergic rebound

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Fluvoxamine Escitalopram Sigma Agonist Anxiety and Psychotic depression (more than sertraline) For OCD and Anxiety S Enantiomer Robust increase in 5 HT. Most Selective and best tolerated SSRI. Least CYP interactions.

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SNRI Depression with reduced positive affect Chronic painful physical Symptoms with depression Vasomotor symptoms of menopause Neuropathic pain of diabetes Cognitive symptoms Fibromyalgia 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

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NaSSA - Mirtazapine

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Mirtazapine Potent(multiple mech) Anxiolytic ( 5HT2A/2C antag, 5HT1A agonist) Sedating(5HT2A and H 1 Antagonism) No Sexual dysfunction Weight gain ( 5HT2c and H1 antag)

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Serotonin antagonist( 2A/2C )/ reuptake( SERT ) inhibitor(SARI) Low dose - Antagonist at 5HT2A/H1/ 1 As Hypnotic; Augment ; Increase remission High Dose SERT/5HT2C inhibition

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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

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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

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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

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NOVEL MELATONIN LINKED MECHANISM

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Receptor profile of TCAs 1 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

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

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

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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 (GADFDAmajor depressive disorder [2]generalized anxiety disorder Vortioxetine is 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)) Serotonin transporterserotonin reuptake inhibitor Norepinephrine transporter (NET) blocker Norepinephrine transporter 5-HT 1A receptor high-efficacy partial agonist/near-full agonist 5-HT 1A receptorpartial agonist/near-full agonist 5-HT 1B receptor 5-HT 1B receptor 5-HT 1D receptor antagonist 5-HT 1D receptorantagonist 5-HT 3A receptor antagonist 5-HT 3A receptor 5-HT 7 receptor antagonist 5-HT 7 receptor Vortioxetine also has affinity for the 1 -adrenergic receptor though any actions at this site are unlikely to contribute to its therapeutic effects and likely only to contribute to side effectsaffinity 1 -adrenergic receptor

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Triple reuptake inhibitors (TRIs) or serotonin- norepinephrine-dopamine-reuptake inhibitors (SNDRIs):

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HPA AXIS RELATED TREATMENT

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NEUROKININS Ligand for NK1 receptor is Substance P. Aprepitant (NK1 antagonist) in Phase III for depression NOVEL NEUROPEPTIDE LINKED MECHANISM

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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?

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