Recent advancement in Antidepressant agents
Uttarakhand Technical UniversitySuddhowala, Dehradun 248015 India
Prashant GahtoriFaculty of Pharmacy
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
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?.
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
Antidepressants increases the neurotransmitters in the synapse.
1950s TCA and MAO-Is
1960-1970s TCA and MAO-IsSub type of MAO-IsMAO-A & MAO-B
1980-1990s TCA and MAO-IsSub type of MAO-IsMAO-A & MAO-BSelective Serotonin Reuptake Inhibitors (SSRI)Selective Serotonin (5HT)
1990-2000 TCA and MAO-IsSub type of MAO-IsMAO-A & MAO-BSelective 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-IsSub type of MAO-IsMAO-A & MAO-BSelective Serotonin Reuptake Inhibitors (SSRI)Selective Serotonin (5HT) Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)Reversible and Selective MAO-A InhibitorsNMDA 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
R1
R3 R2
DRUG NAME R1 R2 R3 Amitriyptyline C H C=CH(CH2)2N(CH3)2 Clomipramine C Cl N-(CH2)3N(CH3)2
Doxepine O H C=CH(CH2)2N(CH3)2
Imipramine C H N-(CH2)3N(CH3)2
Fig. 1a: Tertiary Amine Tricyclic Antidepressants
NCH2CH2CH2NCH3
Amoxapine DesipramineFig. 1b: Secondary Amine Tricyclic
Antidepressants
N
O
N
NH
Cl
1950s TCA and MAO-Is
Amphetamine Etilamfetamine
DextroamphetamineFig. 1c: MAO-Inhibitors
NH2HN
NH2
HN
O
CF3
HN
ClCl
N H
H3CO
O
O
Fluoxetine Paroxetine Sertaline
Fig. 2a: Selective Serotonin Reuptake Inhibitors (SSRI)
OCH3N
N(CH2)2 N
N
COH
I
NH
OCH N
H
OHH2C
P-MPPI LY-297996
Fig. 2b: Selective 5-HT1A Receptor Antagoinst
F
O
O NNN
O
NN
Cl
YM 39992
Nefazod
Fig. 2c: 5-HT2C Receptor Antagonist
1980-1990s Selective Serotonin Reuptake Inhibitors (SSRI)Selective Serotonin (5HT) Receptor Antagonist
SB-269,970Fig. 2d: Other 5-HT7 Receptor Antagonist
SO
ON N
HO
N
OH
H3CO
O
N
H2NO
SNH
Venlafaxine Milnacipran
DuloxetineFig. 3a: Serotonin / Norepinephrine Reuptake
Inhibitors
O
O
N
OC2H5
H
O
ON
H
OC2H5
OCH-CH2NH
OCH3
Viloxazine Reboxetine NisoxatineFig. 3b: Selective Norepinephrine Reuptake Inhibitors
1990-2000 Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)Reversible and Selective MAO-A Inhibitors
Moclobemide BrofaromineFig. 3c: Reversible Monoamine Oxidase
Inhibitors
O N CH2 CH2 NCH2
Cl
O ON
H3CO
Br
H
DOV 21,947Fig. 3d: Triple Monoamine Reuptake
Inhibitor
NH
Cl
Cl
O
HHOOC
COOHH2N
O
H
H
HOOC
COOH
NH2
Cl
Cl
H
N
LY341495 MGS0039 MPEP
Group II mGluR antagonist Selective mGluR5 AntagonistsFig. 8: Glutamate (NMDA) Receptor Antagonist
P NH3+
O
+OCGP 36742Fig. 9: GABAB Receptor
antagonist
2000-2009 NMDA Antagonist, GABAB Antagonist, NK Receptor Antagonist
N
O
H
F FF
FF
F N N
NO
H
H
N
OO
F
FF
F
FF
FN
NH
N
N
N
O
HH
L-733,060 MK-869 LY303870
Fig. 10: Neurokinin Receptor Antagonist
N
N N
N
N
N N
NN
N NN
N
N
Br
O O
CP-154,526 Antalarmin
SC-241Fig. 11: CRF Receptor Antagonist
NH
N NH N
HN
O
F
OMe
MeO
F
O O
O
SNAP-7941 MCL0129
Fig. 12: MCH1 and : MC4 Receptor antagonist
NN
MeO
N
N
F
4 HCl
SSR 149415Fig. 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
N
N
N
O
O
H N
N
N
OH
O
H N
N
N
OH
O
H
SNC 80 BW 373U86 DPI 287Fig. 15: δ-opiod Receptor agonist
OH
HO
O
OH
∆9-Tetrahydrocannibol (THF) CannabigerolFig. 16: Natural Cannabinoid
Crystal structure of IL-1a
Fig. 17: Pro-inflammatory cytokines
OMe
NMeOC
H
AgomelatineFig. 18: Melatonin agonist
2000-2009 δ-Opiod Receptor agonist, Natural Cannabinoid, Pro-inflammatory cytokines, Melatonin agonist
New Drug Treatments 2016 SSRI inhibitors and 5-HT4 receptor partial agonist
Vilazodone
SNRI inhibitorsLevomilnacipran
SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist
Vortioxetine
O
O
NH2
NN
NHN
O
NNH2
N
NH
S
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 DataOnline, 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 IIPexacerfont,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 IIDOV 21, 947 Dopamine, serotonin
and norepinephrine reuptake inhibitorDOV / Merck Depression Phase II
SEP-225289 Dopamine, serotoninand 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
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.
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 2004http://en.wikipedia.org/wiki/Bupropion
(4) Bupropion. Clinical Pharmacology. 10 Nov 2004http://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 2004http://en.wikipedia.org/wiki/Fluoxetine
(7) Fluoxetine. Clinical Pharmacology. 11 Nov 2004http://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 2004http://en.wikipedia.org/wiki/Venlafaxine
(10) Venlafaxine. Clinical Pharmacology. 12 Nov 2004http://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
Acetylcholinesterase inhibitors
Prashant Gahtori, PhD. Faculty of Pharmacy Uttarakhand Technical University Suddhowala Dehradun – 248015 Uttarakhand