Recent advancement in Antidepressant agents

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  1. Recent advancement in Antidepressant agents Uttarakhand Technical University Suddhowala, Dehradun 248015 India Prashant Gahtori Faculty of Pharmacy 2.  Depressions…
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  • 1. Recent advancement in Antidepressant agents Uttarakhand Technical University Suddhowala, Dehradun 248015 India Prashant Gahtori Faculty of Pharmacy
  • 2.  Depressions is a complex mental illness that is associated with:  Disability  Reduced quality of life for the person with depression  Substantial societal burden  It is common among adults and adolescents.  It is characterized by chronic, recurrent episodes that significantly impact disability and mortality.  Depression is a common mental disorder which estimates lifetime prevalence around 21% of the general population. It is also recommended that 5-10% of the population at any given time is suffering from identifiable depression need psychiatric treatment or psychosocial intervention. (Burroughs et al. 2009; World Health Organization report 2012) Background: Depression
  • 3. Biogenic Theory of Depression  The precise cause of affective disorders remains elusive.  Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT). ↓ Activity of NE and 5 -HT systems?.
  • 4. Treatment of Depression  Antidepressant Pharmacology  First introduced 40 years ago  Also used for treatment of other disorders including: -Anxiety disorders, dysthymia, chronic pain and behavioral problems  Evolution of drug therapy  Antidepressants discovered accidentally while investigating antipsychotic efficacy of modifications of phenothiazines  Imipramine - first antidepressant discovered  Around the same time, monoamine oxidase inhibitors were identified  Second generation antidepressants identified to address problems with first generation antidepressants  Late 1980’s- SSRI’s were developed  Now working on other antidepressant treatments
  • 5. Antidepressants increases the neurotransmitters in the synapse.
  • 6. 1950s TCA and MAO-Is 1960-1970s TCA and MAO-Is Sub type of MAO-Is MAO-A & MAO-B 1980-1990s TCA and MAO-Is Sub type of MAO-Is MAO-A & MAO-B Selective Serotonin Reuptake Inhibitors (SSRI) Selective Serotonin (5HT) 1990-2000 TCA and MAO-Is Sub type of MAO-Is MAO-A & MAO-B Selective Serotonin Reuptake Inhibitors (SSRI) Selective Serotonin (5HT) Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) Reversible and Selective MAO-A Inhibitors 2000 and later TCA and MAO-Is Sub type of MAO-Is MAO-A & MAO-B Selective Serotonin Reuptake Inhibitors (SSRI) Selective Serotonin (5HT) Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) Reversible and Selective MAO-A Inhibitors NMDA Antagonist, GABAB Antagonist, NK Receptor Antagonist, CRF Antagonist, MCH1 and MCH4 Receptor Antagonists, Vasopressin Receptor Antagonist, δ-Opiod Receptor agonist, Natural Cannabinoid, Pro-inflammatory cytokines, Melatonin agonist Table 1: Evolution of Antidepressants
  • 7. R1 R3 R2 DRUG NAME R1 R2 R3 Amitriyptyline C H C=CH(CH2 )2 N(CH3 )2 Clomipramine C Cl N-(CH2 )3 N(CH3 )2 Doxepine O H C=CH(CH2 )2 N(CH3 )2 Imipramine C H N-(CH2 )3 N(CH3 )2 Fig. 1a: Tertiary Amine Tricyclic Antidepressants N CH2CH2CH2NCH3 Amoxapine Desipramine Fig. 1b: Secondary Amine Tricyclic Antidepressants N O N N H Cl 1950s TCA and MAO-Is Amphetamine Etilamfetamine Dextroamphetamine Fig. 1c: MAO-Inhibitors NH2 HN NH2
  • 8. H N O CF3 HN Cl Cl N H H3CO O O Fluoxetine Paroxetine Sertaline Fig. 2a: Selective Serotonin Reuptake Inhibitors (SSRI) OCH3 N N (CH2)2 N N C OH I N H O CH N H OH H2C P-MPPI LY-297996 Fig. 2b: Selective 5-HT1A Receptor Antagoinst F O O N N N O N N Cl YM 39992 Nefazod Fig. 2c: 5-HT2C Receptor Antagonist 1980-1990s Selective Serotonin Reuptake Inhibitors (SSRI) Selective Serotonin (5HT) Receptor Antagonist SB-269,970 Fig. 2d: Other 5-HT7 Receptor Antagonist S O O N N HO
  • 9. N OH H3CO O N H2N O S N H Venlafaxine Milnacipran Duloxetine Fig. 3a: Serotonin / Norepinephrine Reuptake Inhibitors O O N OC2H5 H O O N H OC2H5 O CH-CH2NH OCH3 Viloxazine Reboxetine Nisoxatine Fig. 3b: Selective Norepinephrine Reuptake Inhibitors 1990-2000 Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) Reversible and Selective MAO-A Inhibitors Moclobemide Brofaromine Fig. 3c: Reversible Monoamine Oxidase Inhibitors O N CH2 CH2 N CH2 Cl O O N H3CO Br H DOV 21,947 Fig. 3d: Triple Monoamine Reuptake Inhibitor N H Cl Cl
  • 10. O H HOOC COOHH2N O H H HOOC COOH NH2 Cl Cl H N LY341495 MGS0039 MPEP Group II mGluR antagonist Selective mGluR5 Antagonists Fig. 8: Glutamate (NMDA) Receptor Antagonist P NH3 + O + O CGP 36742 Fig. 9: GABAB Receptor antagonist 2000-2009 NMDA Antagonist, GABAB Antagonist, NK Receptor Antagonist N O H F F F F F F N N N O H H N O O F F F F F F F N N H N N N O H H L-733,060 MK-869 LY303870 Fig. 10: Neurokinin Receptor Antagonist
  • 11. N N N N N N N N N N N N N N Br O O CP-154,526 Antalarmin SC-241 Fig. 11: CRF Receptor Antagonist N H N N H N H N O F OMe MeO F O O O SNAP-7941 MCL0129 Fig. 12: MCH1 and : MC4 Receptor antagonist N N MeO N N F 4 HCl SSR 149415 Fig. 14: V1b Receptor antagonist O S O O N O Cl O O N N O OH 2000-2009 CRF Antagonist, MCH1 and MCH4 Receptor Antagonists, Vasopressin Receptor Antagonist
  • 12. N N N O O H N N N OH O H N N N OH O H SNC 80 BW 373U86 DPI 287 Fig. 15: δ-opiod Receptor agonist OH HO O OH ∆9 -Tetrahydrocannibol (THF) Cannabigerol Fig. 16: Natural Cannabinoid Crystal structure of IL-1a Fig. 17: Pro-inflammatory cytokines OMe N MeOC H Agomelatine Fig. 18: Melatonin agonist 2000-2009 δ-Opiod Receptor agonist, Natural Cannabinoid, Pro-inflammatory cytokines, Melatonin agonist
  • 13. New Drug Treatments 2016  SSRI inhibitors and 5-HT4 receptor partial agonist Vilazodone  SNRI inhibitors Levomilnacipran  SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist Vortioxetine O O NH2 N N NHN O N NH2 N NH S
  • 14. TABLE 2 : DRUGS UNDER CLINICAL TRIAL FOR DEPRESSION Drug Name Pharmacological Action Company Indications Developmental Phase Vilazodone 5-HT1A partial agonist, serotonin reuptake inhibitor Clinical Data Online, Inc Depression Phase III Lu AA21004 5-HT3 antagonist, 5-HT1A partial agonist Lundbeck Depression, Anxiety Phase III LY2216684 Norepinephrine reuptake inhibitors Eli Lilly Depression Phase II Pexacerfont, BMS-562086 CRF1 antagonist Bristol-Myers Squibb Depression, Anxiety Phase II GSK 372475 Dopamine, Serotonin and norepinephrine reuptake inhibitor GSK, Neurosearch Depression Phase II GSK 856553 P38 Kinase inhibitor GSK Depression Phase II DOV 21, 947 Dopamine, serotonin and norepinephrine reuptake inhibitor DOV / Merck Depression Phase II SEP-225289 Dopamine, serotonin and norepinephrine reuptake inhibitor Sepracor Depression, Anxiety Phase II JNJ-18038683 5-HT7 receptor antagonist Johnson & Johnson Depression Phase II ORG 3417/34850 Glucocorticoid Receptor Antagonist Schering- Plough Depression Phase II AZ6765 NMDA antagonist Astrazeneca Depression, Anxiety Phase II Vabicaserin (SCA-136) 5-HT2c agonist Wyeth Depression, Anxiety Phase II Lu AA24530 Mixed serotonin modulator Lundbeck Depression, Anxiety Phase II ONO-2333Ms CRF1 antagonist Ono Pharmaceuticals Depression, Anxiety Phase II TGBA01AD Serotonin reuptake inhibitors, 5-HT2 agonist, 5-HT1A agonist Fabre-Kramer Depression Phase II Orvepitant (GW823296) NK1 antagonist GSK Depression, Anxiety Phase I Tyrima Reversible monoamine oxidase A inhibitor CeNeRx Depression, Anxiety Phase I
  • 15. The Future  We are far from the discovery of an ideal regimen. Gastrointestinal, weight gain, sexual dysfunction etc. are major side effect.  The best available options for depression are: SSRIs (Fluoxetine, Citalopram, Sertraline, Paroxetine and Escitalopram) and SNRIs (venlafaxine and duloxetine)  Efficacy of medication can vary with physiological factors like age, diet, sex etc. therefore some instances older tricyclics, tetracyclics, or MAOIs may be efficacious.  With the rapidly increasing information about depression and associated research many potential drugs can be identified and validated in near future. This would lead to discontinuation of side effects, quick onset of action and most importantly, improved treatments for nonresponders.  Some timely examples of recent advances and opportunity in depression have been reviewed here.
  • 16. References (1) Uppal A, Singh A, Gahtori P, Ghosh SK, Ahmad MZ. Antidepressants: Current Strategies and Future Opportunities. Current Pharmaceutical Design (2010), 16, 4243-4253 (2) Ayflegül, Y., Saffet, A.G., Tamam, L. Mechanism of actions of antidepressants: beyond the receptors. Klinik Psikofarmakoloji Bulteni, (2002), 12(4), 194-200. (3) Bupropion. Wikipedia Online Encyclopedia. 14 Oct 2004 http://en.wikipedia.org/wiki/Bupropion (4) Bupropion. Clinical Pharmacology. 10 Nov 2004 http://www.rxlist.com/cgi/generic/buprop_cp.htm (5) Wellbutrin. 2004. Encyclopedia of Medicine. HealthSquare. 14 Oct 2004 http://www.healthsquare.com/newrx/WEL1488.HTM (6) Fluoxetine. Wikipedia Online Encyclopedia. 14 Oct 2004 http://en.wikipedia.org/wiki/Fluoxetine (7) Fluoxetine. Clinical Pharmacology. 11 Nov 2004 http://www.rxlist.com/cgi/generic/fluoxetine_cp.htm (8) Prozac. 2004. Encyclopedia of Medicine. HealthSquare. 14 Oct 2004 http://www.healthsquare.com/newrx/PRO1362.HTM (9) Venlafaxine. Wikipedia Online Encyclopedia. 9 Nov 2004 http://en.wikipedia.org/wiki/Venlafaxine (10) Venlafaxine. Clinical Pharmacology. 12 Nov 2004 http://www.rxlist.com/cgi/generic/venlafax_cp.htm (11) Wellington K, Perry CM. Venlafaxine Extended Release: A Review of its Use in the Management of Major Depression. CNS Drugs (2001), 15, 643-669
  • 17. Acetylcholinesterase inhibitors Prashant Gahtori, PhD. Faculty of Pharmacy Uttarakhand Technical University Suddhowala Dehradun – 248015 Uttarakhand
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