Recent advancements have been made in antidepressant drugs. Vilazodone was approved in 2011 and targets the serotonin transporter and 5-HT1A receptors. Levomilnacipran was approved in 2013 and potently inhibits the reuptake of serotonin and norepinephrine. Desipramine, a tricyclic antidepressant, is under investigation and selectively blocks the reuptake of norepinephrine while also inhibiting serotonin reuptake. Escitalopram was approved in 2002 and causes an increase in serotonin levels by preventing its reuptake. These drugs demonstrate improved mechanisms of action for the treatment of depression.

1. RECENT ADVANCEMENT IN
ANTIDEPRESSANT DRUGS

2. CONTENT
What is Depression?
Signs and Symptoms of Depression
Pathophysiology of Depression
Treatment
Recent advancement in antidepressant treatment
2

3. WHAT IS DEPRESSION?(RANG AND DALE'S PHARMACOLOGY)
 Depression is a common illness worldwide, with an
estimated 3.8% of the population affected, including 5.0%
among adults and 5.7% among adults older than 60 years.
 Approximately 280 million people in the word have
depression (https://www.who.int/news-room/fact-
sheets/detail/depression).
 Depression is a heterogeneous disorder, with patients
presenting with one or more core symptoms.
 Depression is may range from a very mild condition,
bordering on normality, to severe (psychotic) depression
accompanied by hallucinations and delusions.
3
https://www.health.harvard.edu/mind-and-mood/six-
common-depression-types

4.  Depression is associated with other psychiatric conditions, including anxiety,
eating disorders, schizophrenia, Parkinson’s disease and drug addiction.
 There are two distinct types of depressive syndrome:
• Mood changes are always in the same direction.
• Commonly about 75% of cases.
• Associated with stressful life events, and usually
accompanied by symptoms of anxiety and agitation.
UNIPOLAR
DEPRESSION
• Depression alternates with mania.
• Usually appears in early adult life.
• Less common and results in oscillating depression and
mania over a period of a few weeks.
BIPOLAR
DEPRESSION
4

5. SYMPTOMS
5
Low mood
Excessive rumination of negative thought
Low self-esteem: feelings of guilt, inadequacy and
ugliness
Loss of motivation
Loss of reward
Loss of libido
Sleep disturbance
Loss of appetite
Weight loss
Overreacting

6. PATHOPHYSIOLOGY OF DEPRESSION
 Depression cannot be attributed to altered neuronal activity within a single
brain region.
 Brain imaging studies have indicated that the prefrontal cortex, amygdala and
hippocampus may all be involved in different components of these disorders.
 Pathophysiology of depression pathway involves the hypothalamic–pituitary–
adrenal axis-activated by stress Enhances the excitotoxic action of
glutamate, mediated by NMDA receptors and switches on the expression of
genes that promote neural apoptosis in the hippocampus and prefrontal cortex.
6

7. 7
https://www.eurekaselect.com/article/74033

8. TREATMENT(PRINCIPLES OF PHARMACOLOGY: THE PATHOPHYSIOLOGIC BASIS OF DRUG THERAPY, 2011)
 The targets involved in antidepressive pathways are monoamines-
noradrenaline (NA) and 5-hydroxytryptamine (5-HT), which act on G protein–
coupled receptors, and the brain-derived neurotrophic factor (BDNF), which
acts on a kinase-linked receptor (TrkB)
 Antidepressive drugs acts on the target and results in switching of genes that
protect neurons against apoptosis and also promote neurogenesis.
8

9. CLASSIFICATION
Inhibitors of
monoamine
uptake
Selective
serotonin
reuptake
inhibitors
(SSRIs)
Fluoxetine
Fluvoxamine
Sertraline
Citalopram
Noradrenaline
reuptake
inhibitors
Reboxetine
Atomoxetine
Bupropion
Tricyclic
antidepressants
(TCAs)
Imipramine
Amitriptyline
Clomipramine
Mixed 5-HT and
noradrenaline
reuptake
inhibitors
Venlafaxine
Desvenlafaxine
Duloxetine
9

10. CLASSIFICATION
Monoamine
oxidase
(MAOIs)
Irreversible,
competitive
inhibitors
Phenelzine
Tranylcypromine
Reversible,
A-selective
inhibitors
Moclobemide
10

11. CLASSIFICATION
Melatonin receptor
agonist
Agomelatine
Miscellaneous agents
Ketamine
Monoamine receptor
antagonists
Mirtazapine
Trazodone
Mianserin
11

12. 12
RECENT ADVANCES IN ANTIDEPRESSANT DRUGS
1. VILAZODONE (Wang et al, 2016)
 Year of approval-January 21,2011
 Traget-5-HT transporter and 5-HT1A receptors
Mechanism of Action: Vilazodone increases serotonin levels in the brain by inhibiting the reuptake of
serotonin while acting as a partial agonist on serotonin-1A receptors. Due to this activity vilazodone has
sometimes been referred to as a selective partial agonist and reuptake inhibitor (SPARI).
Absorption: 72% when taken with food
Protein binding-96-99%
Half-life- 25 hrs
Metabolism- Vilazodone is mainly metabolized by cytochrome P450(CYP)3A4 and also to a minor extent by
CYP2C19 and CYP 2D6.
Route of elimination: 1% of the dose is recovered unchanged in the urine and 2% of the dose is recovered
unchanged in the feces.
Adverse effects: Vomiting, Hallucination, Fainting, Tremors, Thirst, Weakness
 Contraindicated in pregnancy

13. 2. LEVOMILNACIPRAN (Bruno et al, 2016)
 Year of approval- July 25, 2013
 Traget-5-HT and Norepinephrine
Mechanism of Action: Levomilnacipran potently binds with human serotonin (5-HT) and
norepinephrine (NE) transporters and inhibit 5-HT and NE reuptake.
Absorption: 92% for extended-release capsule
Protein binding- 22%
Half-life- 12 hrs
Metabolism- Levomilnacipran undergoes desethylation in the liver to form desethyl levomilnacipran
and hydroxylation to form p-hydroxyl-levomilnacipran.
Route of elimination: 58% of the dose is excreted in urine as unchanged levomilnacipran.
Adverse effects: Decreased appetite, Heart palpitation, Nausea, Erectile dysfunction, It may increase
suicidal thoughts in some children, teenagers or young adults, particularly in the first few months
of treatment. 13

14. 3. DESIPRAMINE (Maan et al)
 Under investigation
 Tricyclic antidepressant
 Traget-5-HT and Norepinephrine
Mechanism of Action: It is the active metabolite of imipramine, a tertiary amine TCA. Selectively
blocks reuptake of NE from the neuronal synapse. It also inhibits serotonin reuptake but to a lesser
extent. Inhibition of neurotransmitter reuptake increases stimulation of the post-synaptic neuron.
Absorption: Rapidly absorbed from gastrointestinal tract.
Protein binding- 73-92%
Metabolism- Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2
(minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine.
Route of elimination: 70% is excreted in the urine.
Adverse effects: Blurred vision, Constipation, Fatigue, Ringing in the years, Increased heart rate
14

15. 4. ZIPRASIDONE (Nelson et al)
 Year of approval- 2001
 Target- 5-HT2A receptor
Mechanism of Action: Binds to multiple serotonin receptors in addition to 5-HT2A and blocks
monoamine transporters which prevents 5HT and NE reuptake.
Absorption: Rapidly absorbed from gastrointestinal tract.
Protein binding-60% and 100% if taken with meal
Metabolism- Ziprasidone is heavily metabolized in the liver with less than 5% of the drug excreted
unchanged in the urine.
Route of elimination: Extensively metabolized after oral administration with only a small amount
excreted in the urine (<1%) or feces (<4%) as unchanged drug.
Adverse effects: Muscle pain, Diarrhea, Skin rash, Cough/Runny nose, Fainting, Heart palpitations.
15

16. 5. ESCITALOPRAM (Zhong et al)
 Year of approval- August, 2002
 Traget-5-HT
Mechanism of Action: These agents cause an increase in serotonin levels in neuronal synapses by
preventing the re-uptake of serotonin (5-HT) into the presynaptic terminals of serotonergic
neurons.
Absorption: 80%
Protein binding- 55-56%
Half-life- 27-32 hrs
Metabolism- The metabolism of escitalopram is mainly hepatic, mediated primarily by CYP2C19 and
CYP3A4 and, to a lesser extent, CYP2D6.
Route of elimination: 8% of the total dose is eliminated in the urine as unchanged escitalopram and
10% is eliminated in the urine as S-desmethylcitalopram
Adverse effects: Heartburn, Dry mouth, Yawning, Ringing in the ears.
 Contraindicated in pregnancy and in the patients taking MAO inhibitor. 16

17. REFERENCE
 Ritter J, Flower RJ, Henderson G, Loke YK, MacEwan DJ, Rang HP. Rang and Dale's pharmacology.
 Golan DE, Tashjian AH, Armstrong EJ, editors. Principles of pharmacology: the pathophysiologic basis of drug
therapy. Lippincott Williams & Wilkins; 2011 Dec 15.
 https://www.who.int/news-room/fact-sheets/detail/depression
 Jainer AK, Kamatchi R, Marzanski M, Somashekar B. Current advances in the treatment of major depression: Shift
towards receptor specific drugs. InMental Disorders-Theoretical and Empirical Perspectives 2013 Jan 16.
IntechOpen.
 Bruno A, Morabito P, Spina E, Rosaria Muscatello M. The role of levomilnacipran in the management of major
depressive disorder: a comprehensive review. Current neuropharmacology. 2016 Feb 1;14(2):191-9.
 Wang SM, Han C, Lee SJ, Patkar AA, Masand PS, Pae CU. Vilazodone for the treatment of depression: an update.
Chonnam medical journal. 2016 May 1;52(2):91-100.
 Maan JS, Rosani A, Saadabadi A. Desipramine.
 Nelson JC. Adjunctive ziprasidone in major depression and the current status of adjunctive atypical antipsychotics.
 Zhong H, Haddjeri N, Sánchez C. Escitalopram, an antidepressant with an allosteric effect at the serotonin
transporter—a review of current understanding of its mechanism of action. Psychopharmacology. 2012
Jan;219(1):1-3.
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18. THANK YOU