Depression, Sign and Symptoms, Risk factor and bburden, Types of Depression, treatment classification, Pipeline, Launched Drug for Depression

1. Depression
NILENDRA SINGH

2. Depression
• Depression (also known as major depression or
major depressive disorder) is a psychiatric disorder
that affects mood, behaviour, and overall health
• The World Health Organization (WHO) has been
issuing warnings about this pathology for years,
given that it affects over 300 million people all over
the world and is characterized by a high risk of
suicide (the second most common cause of death
in those aged between 15 and 29)
• In the United States, the 12-month prevalence is
~7%, although it is three times higher among those
aged between 18 and 29 than among those aged
60 or over. Moreover, the prevalence rates for
women are ~1.5–3 times higher than for men
Signs and Symptoms
Following signs and symptoms most of the day, nearly every day,
for at least two weeks, one might be suffering from depression:
• Persistent sad, anxious, or “empty” mood
• Feelings of hopelessness, or pessimism
• Irritability
• Feelings of guilt, worthlessness, or helplessness
• Loss of interest or pleasure in hobbies and activities
• Decreased energy or fatigue
• Moving or talking more slowly
• Feeling restless or having trouble sitting still
• Difficulty concentrating, remembering, or making decisions
• Difficulty sleeping, early-morning awakening, or oversleeping
• Appetite and/or weight changes
• Thoughts of death or suicide, or suicide attempts
Front. Psychol., 2019

3. Risk Factors
Current research suggests that depression is caused by a
combination of
• Genetic (having a first-degree relative with depression,
makes you two-to-three times more likely to have
depression tendencies),
• Biological (Hormonal-childbirth and menopause or
Medical condition - underactive thyroid, chronic pain
or Gut bacteria gut-brain axis, Certain physical illnesses
and medications)
• Environmental (loved one’s death, a messy divorce, or
financial problems), and
• Psychological factors (Major life changes, trauma, or
stress, Traumatic life events from childhood
Disease Burden
Depression by the numbers
American Psychological Association, (NIMH), Clinical Psychology Review

4. • Persistent Depressive Disorder (Dysthymia)
• Premenstrual Dysphoric Disorder
• Postpartum depression
• Substance/Medication-Induced Depressive
Disorder
• Depressive Disorder Due to Another Medical
Condition
• Single Depressive Episode
• Bipolar disorder
• Recurrent Depressive Disorder
• Persistent Mood [Affective] Disorders
Types of Depression Treatments for Depression
Medication focuses on root causes of depression and most
effective treatment is a mix of psychotherapy, medication,
lifestyle changes:
• Psychotherapy: Psychodynamic therapy, Cognitive
Behavioral Therapy (CBT), and interpersonal therapy
• Medication: Antidepressants, mood stabilizers, and/or
antipsychotic pills in order to decrease the symptoms of
depression
• SSRIs (selective serotonin reuptake inhibitors) SNRIs
(serotonin and norepinephrine reuptake inhibitors)
• TCAs (tricyclic antidepressants) and
• MAOIs (monoamine oxidase inhibitors)
• Brain Stimulation
• Electroconvulsive therapy (ECT)
• Repetitive transcranial magnetic stimulation (rTMS)
• vagus nerve stimulation (VNS)

5. Discovery Pipeline
Drug Name Companies Target-based Actions
5-HT1A receptor biased agonist depression Neurolixis Inc 5-HT 1a receptor agonist
neurotransmitter synaptosomal reuptake inhibitors Hong Kong University of Science &
Technology
astrocytes-targeting therapeutics (sleep
disorders/depression)
GliaCure Inc
MC-110034 Praeventix, LLC, 5-HT 7 receptor antagonist
escitalopram (BEPO long acting injectable depot
formulation, depression)
MedinCell SA
mGluR7 NAM inhibitors (oral, depression/post traumatic
stress disorder/generalized anxiety disorder)
Addex Therapeutics Ltd Metabotropic glutamate receptor 7 antagonist
M-084 Kunming Institute of Botany The
Chinese Academy of Sciences
TRP cation channel C4 inhibitor; TRP cation
channel C5 inhibitor
deuterated etifoxine GABA Therapeutics GABA A receptor beta-2 subunit stimulator;
oxitriptan, Duke University Evecxia Inc
Y-4, Yantai Yenepharma Biomedical Yantai Yenepharma Biomedical Co Ltd
NNI-351 NeuroNascent Inc DYRK-1 alpha protein kinase inhibitor
kappa opioid receptor antagonists (addiction) Cerevel Therapeutics LLC Opioid receptor kappa antagonist
trace amine-associated receptor 1 (TAAR1) agonists Roche Holding AG Trace amine associated receptor 1 agonist
AMS-410 FA Amorsa Therapeutics Inc NMDA receptor antagonist
lanicemine AstraZeneca plc NMDA receptor antagonist
KB-9520 Karo Bio Estrogen receptor beta agonist
CTC-501 Chase Therapeutics Corporation 5-HT receptor antagonist; Dopamine receptor
agonist
ketamine (sublingual lozenge, major depressive
disorder/anxiety)
Synergistic Therapeutics Llc NMDA receptor antagonist
CX-1942 RespireRx Pharmaceuticals Inc AMPA receptor modulator
AGT-110 ArmaGen Technologies Inc Insulin receptor antagonist; Type II TNF
receptor modulator
Phase III PipelineDrug Name Companies Target-based Actions
dextromethorphan + bupropion Axsome Therapeutics Inc NMDA receptor antagonist; Nicotinic acetylcholine
receptor antagonist;
amitifadine hydrochloride Ethismos Research Inc
zuranolone SAGE Therapeutics Inc GABA A receptor modulator
ganaxolone Marinus Pharmaceuticals Inc GABA A receptor agonist
rapastinel Allergan plc Glycine partial agonist; NMDA receptor modulator;
INSCOP RePurposed Therapeutics Inc
deudextromethorphan hydrobromide + ultra-low dose
quinidine sulfate
Avanir Pharmaceuticals Inc Cytochrome P450 2D6 inhibitor; NMDA receptor
antagonist;
cycloserine + lurasidone NeuroRx Inc 5-HT 1a receptor partial agonist; 5-HT 2a receptor
antagonist;
riluzole prodrug Biohaven Pharmaceutical Holding Co Ltd
(2R,6R)-hydroxynorketamine Small Pharma Ltd
metabotropic glutamate receptor 2/3 antagonists Eli Lilly & Co Metabotropic glutamate receptor 2 and 3 antagonist
GluN2B-selective NMDA antagonists Janssen Pharmaceuticals Inc NMDA receptor antagonist
major depression program Shanghai SIMR Biotech Co Ltd
monoamine uptake inhibitors Prous Institute For Biomedical Research Sa
R-(-)-ketamine hydrochloride Jiangsu Hengrui Medicine Co Ltd
ARX-211 Alte Biosciences
AMS-410 Janssen Pharmaceuticals Inc NMDA receptor antagonist
SIPI-5358 CSPC Pharmaceuticals Group Limited
antidepressants, Tasly Pharmaceutical Group Co Ltd
live biotherapeutic preparation 4D pharma plc
arketamine Perception Neuroscience LLC NMDA receptor antagonist
TRPC 4/5 inhibitor (anxiety/depression) Ono Pharmaceutical Co Ltd TRP cation channel C4 stimulator; TRP cation channel
C5 inhibitor
JNK1 inhibitor (anxiety/depression) National Institute on Aging Jun N terminal kinase inhibitor
peptide melanocortin-5 receptor inhibitor Akhu Therapeutics Inc Melanocortin MC5 receptor antagonist
AFC-08 Affectis Pharmaceuticals AG Tomoregulin 2 inhibitor
MRS-5474 Primetime Life Sciences LLC Adenosine A1 receptor agonist
GluN1/2A/GluN1/2C agonist H Lundbeck A/S NMDA receptor epsilon 1 subunit inhibitor; NMDA
receptor epsilon 3 subunit inhibitor
cycloartenyl ferulate Beijing Century Biocom Pharmaceutical
Technology Co Ltd
CB-2009, Cortibon Pharma Cortibon Pharma GmbH CRF-1 receptor antagonist
BMS-764459 Bristol-Myers Squibb Co CRF-1 receptor antagonist
P2X7 antagonists (neurological disease) Janssen Research & Development LLC P2X7 purinoceptor antagonist
ion channel modulators (depression/cognition/epilepsy) Bionomics Ltd Unspecified ion channel modulator
MC-RG19 Temple University 5-HT 7 receptor antagonist

6. Phase III PipelineDrug Name Companies Target-based Actions
CN-2097, Aingeal Therapeutics Aingeal therapeutics Brain derived neurotrophic factor ligand modulator; TrkB
receptor modulator
LCGA-17 Lactocore GABA A receptor modulator
NC-2800 Nippon Chemiphar Co Ltd Opioid receptor delta agonist
I-105 Impel NeuroPharma Dopamine D1 receptor modulator; Dopamine D2
receptor modulator
mGluR2 NAM (oral, Alzheimer's/depression/stroke) Addex Therapeutics Ltd Metabotropic glutamate receptor 2 antagonist
GABA A receptor alpha-6 subunit ligand University of Wisconsin-Milwaukee GABA A receptor alpha-6 subunit modulator
SDN-118 Sun Pharmaceutical Advanced Research Co Ltd
YAD-2128 Yungjin Pharmaceutical Co Ltd
YH-200 Peking University Health Science Center AMPA receptor modulator; Dopamine D2 , D3and D5
receptor modulator
HEC-113995-PA·H2O Guangdong HEC Pharmaceutical Co Ltd
YDP-2225 Yungjin Pharmaceutical Co Ltd
SUVN-1507035 Suven Life Sciences Ltd 5-HT 1a receptor modulator; 5-HT 2a receptor
modulator; Alpha 1B adrenoceptor modulator;
Dopamine D2 receptor modulator
OREX-1019 Orexigen Therapeutics Inc Opioid receptor kappa antagonist; Opioid receptor mu
partial agonist
peptidic KOR ligand therapeutics (drug dependence) University of Kansas Opioid receptor kappa agonist; Opioid receptor kappa
antagonist
AT-127 Astraea Therapeutics LLC ORL1 receptor agonist
CGP-3466B Johns Hopkins University MAO inhibitor; Triosephosphate dehydrogenase
inhibitor
PT-00114 Protagenic Therapeutics Inc Neuropeptide agonist
YL-IPA08 Institute of Pharmacology and Toxicology
Academy of Military Medical Sciences PLA
Translocator protein modulator
ANAVEX-1-41 Anavex Life Sciences Corp Chloride channel modulator; Muscarinic M1 receptor
agonist; Muscarinic M2 receptor antagonist;
pramipexole analogs Universiteit Maastricht Dopamine D3 receptor agonist; Frizzled-1 receptor
antagonist; Frizzled-2 receptor antagonist; Wnt ligand
ITI-333 Intra-Cellular Therapies Inc 5-HT 2a receptor antagonist; Dopamine D1 receptor
modulator; Opioid receptor mu antagonist
BrAD-R13 Shanghai Braegen Pharmaceutical TrkB receptor agonist
DPI-289 Dina Pharmaceuticals Inc Opioid receptor delta agonist; Opioid receptor mu
antagonist
PDE4b inhibitor program deCODE genetics ehf PDE 4b inhibitor
DRGT-65 Druggability Technologies Holdings Ltd
YC-5 Guangzhou Cellprotek Pharmaceutical Co Ltd
TNX-1600 Tonix Pharmaceuticals Holding Corp Dopamine transporter inhibitor; Noradrenaline
transporter inhibitor; Serotonin transporter inhibitor
osanetant Acer Therapeutics Inc NK3 receptor antagonist
PLD-116 Parke-Davis & Co Ltd
JNJ-3215 Janssen Research & Development LLC Orexin 1 receptor antagonist
quetiapine prodrug KemPharm Inc
5-HT2C receptor agonists AbbVie Deutschland GmbH & Co KG 5-HT 2c receptor agonist
CX-717 RespireRx Pharmaceuticals Inc AMPA receptor modulator
SKL-PSY Shanghai Medicilon Inc 5-HT 1a receptor modulator
Unmet Medical Need
• Even though rates of treatment seeking have increased,
many persons with major depression continue to
experience unmet need for treatment
• Most existing antidepressants share relatively
redundant mechanistic targets, posing obstacles for
devising truly novel combination drug therapies
• NIMH’s 2014 decision no longer to fund intramural or
extramural clinical trials for the sake of symptom relief,
but only when a drug can serve mainly as a ‘probe to
generate information about the mechanisms underlying
a disorder
• “Adequate” Treatment Is Difficult to Achieve because of
Adequate Dosage and Adequate Duration - Poor
Tolerability Nonadherence Safety Issues Lack of Efficacy
Comorbidities
• Rate of recovery diminishes with duration of depressive
disorder

7. Launched Drug in Last Few Years

8. Drug Name Active Indications Target-based Actions
fluoxetine (oral tablet, depression), EdgemontDepression
brexanolone Postnatal depression GABA A receptor modulator
reboxetine mesylate (oral capsule, depression), YaoPharmaDepression
bupropion hydrochloride (oral extended-release, VersaTab), IntelGenx
Depression Dopamine receptor agonist; Nicotinic
acetylcholine receptor agonist
moclobemide (oral tablet, depression), Shanghai Sine Promod PharmaceuticalDepression MAO A inhibitor
selegiline transdermal system, Mylan Depression MAO B inhibitor
sertraline hydrochloride + alprazolam (oral, anxiety/depression), RIMSA/InterLab
Anxiety disorder; Depression Benzodiazepine receptor agonist; GABA
receptor modulator
paroxetine + alprazolam Anxiety disorder; Depression Benzodiazepine receptor agonist
vilazodone Depression; Major depressive disorder 5-HT 1a receptor partial agonist
bupropion (enhanced-absorption salt, depression), Bausch Health
Depression; Major depressive disorder;
Seasonal affective disorder
Dopamine receptor agonist
paroxetine mesylate (depression/ anxiety), Noven
Depression; Generalized anxiety disorder;
Obsessive compulsive disorder; Panic
disorder
paroxetine hydrochloride (enteric-coated extended release tablet, major depressive disorder), GL PharmTechDepression
agomelatine
Depression 5-HT 2c receptor antagonist; Melatonin
MT1 receptor agonist; Melatonin MT2
receptor agonist; Melatonin receptor
agonist
reboxetine Depression Alpha 2 adrenoceptor antagonist
tianeptine sodium Depression
fluoxetine + olanzapine (bipolar depression), Lilly
Bipolar II disorder; Depression 5-HT receptor antagonist; Dopamine D2
receptor antagonist
venlafaxine hydrochloride (extended-release, depression), Pfizer
Depression; Generalized anxiety disorder;
Panic disorder; Social phobia
milnacipran Depression; Fibromyalgia
esketamine (intranasal), Janssen Research & DevelopmentDepression; Major depressive disorder NMDA receptor antagonist
trazodone (oral once-daily, Contramid), LabopharmDepression; Major depressive disorder
ademetionine
Depression; Metabolic disorder;
Osteoarthritis
Transferase stimulator
fluvoxamine
Depression; Obsessive compulsive
disorder; Social phobia
paroxetine hydrochloride hemihydrate (controlled release, GEOMATRIX), GlaxoSmithKline
Depression; Panic disorder; Premenstrual
syndrome; Social phobia
desvenlafaxine
Depression; Hot flashes; Major depressive
disorder
Drug Name Active Indications Target-based Actions
bupropion (oral extended release), GlaxoSmithKline/Bausch HealthDepression; Major depressive disorder; Seasonal affective
disorder
Dopamine receptor agonist
citalopram hydrobromide Depression; Obsessive compulsive disorder; Panic disorder
bupropion (oral sustained release), GlaxoSmithKlineDepression; Major depressive disorder; Nicotine dependence Dopamine receptor agonist
GV-971 Alzheimers disease; Autoimmune disease; Depression;
Parkinsons disease; Sleep disorder
Beta amyloid antagonist
minaprine Alzheimers disease; Cerebral infarction; Cognitive disorder;
Depression; Stroke
escitalopram Depression; Generalized anxiety disorder; Major depressive
disorder; Obsessive compulsive disorder; Panic disorder;
Social phobia
moclobemide Alzheimers disease; Anxiety disorder; Dementia; Depression;
Psychotic disorder; Social phobia
MAO A inhibitor
fluoxetine hydrochloride Bulimia nervosa; Depression; Major depressive disorder;
Obsessive compulsive disorder; Panic disorder; Premenstrual
syndrome
quetiapine fumarate (once-daily sustained release tablet), AstraZenecaBipolar II disorder; Bipolar disorder; Depression; Major
depressive disorder; Mania; Schizophrenia
5-HT 2 receptor antagonist; Dopamine D2
receptor antagonist
imidazolyl ethanamide pentandioic acid Bone marrow depression; Influenza virus infection;
Neutropenia; Radiation sickness; Thrombocytopenia; Viral
respiratory tract infection
paroxetine hydrochloride hemihydrate Anxiety disorder; Depression; Generalized anxiety disorder;
Major depressive disorder; Obsessive compulsive disorder;
Panic disorder; Post traumatic stress disorder; Social phobia
brexpiprazole Agitation; Bipolar I disorder; Borderline personality disorder;
Central nervous system disease; Depression; Major depressive
disorder; Mania; Post traumatic stress disorder; Schizophrenia
5-HT 1a receptor partial agonist; 5-HT 2a
receptor antagonist; Alpha 1B
adrenoceptor antagonist; Alpha 2C
adrenoceptor antagonist; Dopamine D2
receptor partial agonist; Dopamine D3
receptor partial agonist
sertraline Depression; Major depressive disorder; Obsessive compulsive
disorder; Panic disorder; Post traumatic stress disorder;
Premenstrual syndrome; Social phobia
duloxetine Back pain; Depression; Diabetic neuropathy; Diabetic
peripheral neuropathy; Fibromyalgia; Generalized anxiety
disorder; Lower back pain; Major depressive disorder;
Musculoskeletal pain; Osteoarthritis; Stress urinary
incontinence
levomilnacipran Major depressive disorder
vortioxetine hydrobromide Binge eating disorder; Bipolar I disorder; Bipolar II disorder;
Major depressive disorder
5-HT 1a receptor agonist; 5-HT 1b receptor
partial agonist; 5-HT 1d receptor
antagonist; 5-HT 3 receptor antagonist; 5-
HT 7 receptor antagonist; Serotonin
transporter inhibitor
tasimelteon Circadian rhythm sleep disorder; Insomnia Melatonin MT1 receptor agonist; Melatonin
MT2 receptor agonist
tandospirone Anxiety disorder; Cognitive disorder 5-HT 1a receptor partial agonist
buprenorphine (sublingual, opioid dependence), IndiviorOpiate dependence ORL1 receptor agonist; Opioid receptor mu
partial agonist
lurasidone Autism; Bipolar I disorder; Bipolar disorder; Schizophrenia 5-HT 1a receptor partial agonist; 5-HT 2a
receptor antagonist; 5-HT 7 receptor
antagonist; Alpha 2C adrenoceptor
antagonist; Dopamine D2 receptor
antagonist
febarbamate Aggression; Dementia
aripiprazole Autism; Bipolar disorder; Major depressive disorder; Mania;
Schizophrenia; Tourette syndrome
5-HT 1a receptor partial agonist; 5-HT 2a
receptor antagonist; Dopamine D2 receptor
partial agonist
solriamfetol Hypersomnia; Narcolepsy; Obstructive sleep apnea
tolcapone Parkinsons disease Catechol O-methyltransferase
inhibitor+A1A1:C25