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