Recent advancement in

Antidepressant agents
Prashant Gahtori
Faculty of Pharmacy

Uttarakhand Technical University

Suddhowala, Dehradun 248007 India

Background: Depression
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)

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 1980s- SSRIs were developed
Now working on other antidepressant treatments

Antidepressants increases the neurotransmitters in the

synapse.

Table 1: Evolution of Antidepressants

1950s

TCA and MAO-Is

1960-1970s

TCA and MAO-Is

Sub type of MAO-Is
MAO-A & MAO-B
TCA and MAO-Is
Sub type of MAO-Is
MAO-A & MAO-B
Selective Serotonin Reuptake Inhibitors (SSRI)
Selective Serotonin (5HT)

1980-1990s

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, -Opiod Receptor agonist, Natural Cannabinoid, Pro-inflammatory cytokines, Melatonin agonist

1950s

TCA and MAO-Is

R1
R2

R3
DRUG NAME
Amitriyptyline
Clomipramine
Doxepine
Imipramine

R1
C
C
O

R2
H
Cl
H

R3
C=CH(CH 2)2N(CH3)2
N-(CH 2)3N(CH3)2
C=CH(CH 2)2N(CH3)2
N-(CH2)3N(CH3)2

Fig. 1a: Tertiary Amine Tricyclic Antidepressants

O
Cl
N
N

N
CH2CH2CH2NCH3

N
H

Amoxapine

Desipramine

Fig. 1b: Secondary Amine Tricyclic

Antidepressants

HN

NH 2

NH 2
Amphetamine

Etilamfetamine
Dextroamphetamine

Fig. 1c: MAO-Inhibitors

1980-1990s

Selective Serotonin Reuptake Inhibitors (SSRI)

Selective Serotonin (5HT) Receptor Antagonist
HN

O
O

H
N

H3CO

N H
CF3

Cl
Fluoxetine

N
OCH3
N

(CH2)2

N C
H O

H2C
O

Cl

Paroxetine
Sertaline

Fig. 2a: Selective Serotonin Reuptake Inhibitors (SSRI)

OH
CH N
O
H
O

N
H

N
N

F
YM 39992

P-MPPI
LY-297996

Cl

Nefazod

Fig. 2b: Selective 5-HT1A Receptor Antagoinst

Fig. 2c: 5-HT2C Receptor

Antagonist
HO

O
S O
N

SB-269,970
Fig. 2d: Other 5-HT7 Receptor Antagonist

N
N

1990-2000

Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)

Reversible and Selective MAO-A Inhibitors

H3CO

H2N

OH

N
H
O

N
Venlafaxine
Duloxetine

Milnacipran

Fig. 3a: Serotonin / Norepinephrine Reuptake

Inhibitors

OCH3
CH-CH2NH
O

OC2H5
O

OC2H5
O
O

O
N

N
H

Viloxazine

Reboxetine

Nisoxatine

Fig. 3b: Selective Norepinephrine Reuptake Inhibitors

Cl

Cl

H3CO

Cl

N H
O

N CH2

O
CH2
CH2 N
Moclobemide

O
Br

Brofaromine

Fig. 3c: Reversible Monoamine Oxidase

Inhibitors

N
H

DOV 21,947

Fig. 3d: Triple Monoamine Reuptake

Inhibitor

2000-2009

NMDA Antagonist, GABAB Antagonist, NK Receptor Antagonist

HOOC

H2N COOH

H H

COOH

Cl
O

O
HOOC

Cl

LY341495

H
NH2

MGS0039

Group II mGluR antagonist

MPEP
Selective mGluR5 Antagonists

Fig. 8: Glutamate (NMDA) Receptor Antagonist

O
P
+O

NH3+

CGP 36742
Fig. 9: GABAB Receptor
antagonist
F

F
F

O
F
N
H

F
F

H
N

O
N

F
F F

N N
F

L-733,060

MK-869
LY303870

Fig. 10: Neurokinin Receptor Antagonist

H
N
N
N
H

2000-2009

CRF Antagonist, MCH1 and MCH4 Receptor Antagonists, Vasopressin Receptor

Antagonist
O

N
N
N

N
N

CP-154,526

Antalarmin
SC-241

Fig. 11: CRF Receptor Antagonist

F

F
O

MeO

OMe

N
H

4 HCl

N
N
H

H
N

SNAP-7941

MeO

MCL0129

Fig. 12: MCH1 and : MC4 Receptor antagonist

OH

O
Cl

N
N
O
S
O

O
O

SSR 149415

Fig. 14: V1b Receptor antagonist

Br

2000-2009

-Opiod Receptor agonist, Natural Cannabinoid, Pro-inflammatory cytokines,

Melatonin agonist
O

O
O

OH
N
N

SNC 80

BW 373U86

DPI 287

Fig. 15: -opiod Receptor agonist

OH

OH
HO

O
9-Tetrahydrocannibol (THF)

Cannabigerol

Fig. 16: Natural Cannabinoid

OMe

MeOC
Crystal structure of IL-1a

Fig. 17: Pro-inflammatory cytokines

H
N
Agomelatine

Fig. 18: Melatonin agonist

OH

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
Norepinephrine reuptake inhibitors
CRF1 antagonist

Lundbeck

Depression,
Anxiety

Phase III

Eli Lilly
Bristol-Myers Squibb

Depression
Depression,
Anxiety

Phase II
Phase II

GSK 372475

Dopamine, Serotonin and norepinephrine reuptake inhibitor

GSK, Neurosearch

Depression

Phase II

GSK 856553
DOV 21, 947

P38 Kinase inhibitor

Dopamine, serotonin
and norepinephrine reuptake inhibitor

GSK
DOV / Merck

Depression
Depression

Phase II
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

ScheringPlough

Depression

Phase II

AZ6765

NMDA antagonist

Astrazeneca

Depression,
Anxiety

Phase II

Vabicaserin
(SCA-136)
Lu AA24530

5-HT2c agonist

Wyeth

Phase II

Mixed serotonin modulator

Lundbeck

Depression,
Anxiety
Depression,
Anxiety

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

LY2216684
Pexacerfont,
BMS-562086

Phase II

New Drug Treatments 2016

SSRI inhibitors and 5-HT4 receptor partial agonist

O
N

NH

NH 2
O
N

SNRI inhibitors

O
NH 2

Vilazodone

Levomilnacipran

SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist

S

Vortioxetine

N
NH

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) Ayegl, 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

Acetylcholinesterase inhibitors

Prashant Gahtori, PhD. Faculty of Pharmacy Uttarakhand Technical University Suddhowala Dehradun 248015 Uttarakhand