Depression (also called major depressive disorder or clinical depression) is a common but serious mood disorder. It causes severe symptoms that affect how we feel, think, and handle daily activities, such as sleeping, eating, or working. 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 world have depression

1. Depression and Antidepressant Drug
Presented By
Muhammad Kamal Hossain
PhD Student
Student ID- 202255221
School of Pharmacy
Jeonbuk National University (JBNU)

2. 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 world have
depression
It can cause the affected person to suffer greatly and
function poorly. At its worst, depression can lead to suicide.
Over 700 000 people die due to suicide every year. Suicide
is the fourth leading cause of death in 15-29 year-olds
Source:
1. Institute of Health Metrics and Evaluation. Global Health Data Exchange (GHDx).
2. https://ourworldindata.org/mental-health
Greenland
China
Depression (also called major depressive disorder or
clinical depression) is a common but serious mood
disorder. It causes severe symptoms that affect how we
feel, think, and handle daily activities, such as sleeping,
eating, or working.
Depression

3. There are different types of depression, some of which develop due
to specific circumstances.
•Major depression, which includes symptoms of depression most of
the time for at least 2 weeks that typically interfere with one’s ability
to work, sleep, study, and eat.
•Persistent depressive disorder (also called dysthymia), which
often includes less severe symptoms of depression that last much
longer, typically for at least 2 years.
•Perinatal depression, which occurs when a woman experiences
major depression during pregnancy or after delivery (postpartum
depression).
•Seasonal affective disorder, which comes and goes with the
seasons, typically starting in late fall and early winter and going
away during spring and summer.
•Depression with symptoms of psychosis, which is a severe
form of depression where a person experiences psychosis
symptoms, such as delusions (disturbing, false fixed beliefs) or
hallucinations (hearing or seeing things that others do not see or
hear). Source:
The National Institute of Mental Health (NIMH)
Types of depression

4. Causes of depression

5. Signs and Symptoms
•Persistent sad, anxious, or “empty” mood
•Feelings of hopelessness, or pessimism
•Feelings of irritability, frustration, or restlessness
•Feelings of guilt, worthlessness, or helplessness
•Loss of interest or pleasure in hobbies and activities
•Decreased energy, fatigue, or feeling "slowed down"
•Difficulty concentrating, remembering, or making decisions
•Difficulty sleeping, early morning awakening, or oversleeping
•Changes in appetite or unplanned weight changes
•Aches or pains, headaches, cramps, or digestive problems
without a clear physical cause that do not ease even with
treatment
•Suicide attempts or thoughts of death or suicide
Source: National Health and Nutrition Examination survey, USA (NHANES)

6. Research suggests that genetic, biological,
environmental, and psychological factors play a
role in depression.
Risk factors include:
1. Personal or family history of depression.
2. Age: Depression can happen at any age, but
often begins in adulthood. Depression is now
recognized as occurring in children and
adolescents.
3. Gender: Female are more prominent than male
4. Major life changes
5. Trauma, or stress
6. Certain physical illnesses and medications
Risk Factors

7. Depression, even the most severe cases, can be treated. The earlier treatment begins, the more effective it is.
Depression is usually treated with medications, psychotherapy, or a combination of the two. If these treatments do
not reduce symptoms, brain stimulation therapies like Electroconvulsive Therapy (ECT) may be options to
explore.
Medications
Antidepressants are medicines commonly used to
treat depression. They may help improve the way
brain uses certain chemicals that control mood or
stress.
Antidepressants take time usually 2 to 12 weeks to
work, and often, symptoms such as sleep, appetite,
and concentration problems improve before mood
lifts
Psychotherapies
Several types of psychotherapy (also called “talk therapy” or "counseling") can help people with depression
by teaching new ways of thinking and behaving and how to change habits that contribute to depression.
Examples of evidence-based approaches specific to the treatment of depression include-
1. Cognitive-behavioral therapy (CBT)
2. Interpersonal therapy (IPT)
Natural Products
FDA has not approved any natural
products for depression. While
research is ongoing, some people
find natural products, including
vitamin D and the herbal dietary
supplement
Treatment and Therapies

8. Brain Stimulation Therapies
Based on the latest research:
•Electroconvulsive therapy (ECT) can provide relief for people
with severe depression who have not been able to feel better
with other treatments. In some severe cases where a rapid
response is necessary or medications cannot be used safely,
ECT can even be a first-line intervention.
•The treatment consists of a series of sessions, typically 3 times
a week, for 2-4 weeks. ECT is not painful. Before ECT begins,
a patient is put under brief anesthesia and given a muscle
relaxant. Within one hour after the treatment session, which
takes only a few minutes, the patient is awake and alert.
•ECT may cause some side effects, including confusion,
disorientation, and memory loss. Usually these side effects are
short-term, but sometimes memory problems can linger,
especially for the months around the time of the treatment
course.

9. Antidepressant Drug
Antidepressants can help relieve the symptoms of
depression. They work by correcting chemical imbalances
of neurotransmitters in the brain.

10. Serotonin is involved with mood, happiness, anxiety, and sleep induction.
Raphe-Serotonin System normally modulates homeostasis, emotionality, and
tolerance to aversive experiences.
Norepinephrine in the brain helps regulate alertness, mood, functions in dream
sleep, and maintains arousal. It also can help in the response to stressful
situations.
Dopamine in the brain regulates reward and motivation. It motivates people to
take action toward goals, desires, and needs, and issues a surge of reinforcing
pleasure once they’ve been accomplished.
Sufficient levels are needed for the brain to function
properly and decreased levels have been found in
patients with depression
Ref: McCance & Huether, 2014
Brain Physiology: Normal Vs Depressive patient

11. Antidepressant therapies focus on increasing the
monoamine neurotransmitter levels within the
synapses.
The hypothalamic-pituitary-adrenal system (HPA)
plays an essential role in an individual’s ability to cope
with stress. Chronic activation of the HPA system and
chronic glucocorticoid secretion are found in 30-
70% of individuals with major depression
Neuroendocrine Dysregulation
20-30% cases of major depression have shown to
have an altered hypothalamic-pituitary-thyroid
(HPT) system. There is an increase in thyrotropin
releasing hormone, blunted thyroid stimulating
hormone in response to TRH challenge and decreased
nocturnal rise in TSH level that normally occur.
Neuroanatomic and Function Abnormalities
Alterations in frontal and limbic regions (such as the amygdala)
have shown a decreased number of glial cells in people with
unipolar disorders. As well as, a decreased prefrontal cortex
functioning and decreased frontal lobe volume.
Pathophysiology
Depression

12. Stress, Autophagy and Neuroinflammation Vs Major Depression Disorder

13. Classification and some list of Antidepressant Drug
The top 10 antidepressant drugs most commonly
prescribed in the U.S. include:
1.Duloxetine (Cymbalta) - SNRI
2.Desvenlafaxine (Pristiq) - SNRI
3.Vilazodone (Viibryd) - Atypical
4.Citalopram (Celexa) - SSRI
5.Sertraline (Zoloft) - SSRI
6.Fluoxetine (Prozac Weekly, Prozac) -SSRI
7.Trazodone (Desyrel) - Atypical
8.Escitalopram (Lexapro) - SSRI
9.Paroxetine (Paxil, Paxil CR) - SSRI
10.Venlafaxine (Effexor, Effexor XR) - SNRI
Source: www.emedicinehealth.com

14. Development of Antidepressant Drug

15. 1.Selective Serotonin Reuptake Inhibitors (SSRIs)
The selective serotonin reuptake inhibitors (SSRIs) are a
group of antidepressant drugs that specifically inhibit
serotonin reuptake, having 300- to 3000-fold greater
selectivity for the serotonin transporter, as compared to the
norepinephrine transporter.
This contrasts with the tricyclic antidepressants (TCAs) and
serotonin/norepinephrine reuptake inhibitors (SNRIs) that
nonselectively inhibit the reuptake of norepinephrine and
serotonin
Ref: Lippincott Illustrated Reviews: Pharmacology, 6th Edition

16. The SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft.
Antidepressants, including SSRIs, typically take at least 2 weeks to produce significant improvement in mood, and maximum
benefit may require up to 12 weeks or more. Patients who do not respond to one antidepressant may respond to another, and
approximately 80% or more will respond to at least one antidepressant drug.
Source: psychscenehub.com
Action of SSRIs
Source: ro Health Guide

17. Therapeutic Uses of SSRIs
The primary indication for SSRIs is depression, for which
they are as effective as the TCAs.
A number of other psychiatric disorders also respond
favorably to SSRIs, including-
 Obsessive compulsive disorder
 Panic disorder
 Generalized anxiety disorder
 Posttraumatic stress disorder
 Social anxiety disorder
 Premenstrual dysphoric disorder
 Bulimia nervosa (only fluoxetine is approved for bulimia)

18. Absorption: All of the SSRIs are well absorbed after oral
administration. Peak levels are seen in approximately 2 to 8
hours on average. Food has little effect on absorption (except
with sertraline, for which food increases its absorption).
Distribution: The majority of SSRIs have plasma half-lives that
range between 16 and 36 hours.
Elimination: Metabolism by cytochrome P450 (CYP450)–
dependent enzymes and glucuronide or sulfate conjugation
occur extensively.
Fluoxetine differs from the other members of the class by
having a much longer half-life (50 hours), and the half-life of its
active metabolite S-norfluoxetine is quite long, averaging 10
days. It is available as a sustained-release preparation
allowing once-weekly dosing.
Pharmacokinetics of SSRIs

19. Pharmacokinetics comparison of 1st Generation SSRIs

20. Possible Drug-Drug Interaction:
Fluoxetine and paroxetine are potent inhibitors of a CYP450 isoenzyme (CYP2D6) responsible for the
elimination of TCAs, antipsychotic drugs, and some antiarrhythmic and β-adrenergic antagonist drugs.
Dosages of the SSRIs should be reduced in patients with hepatic impairment
Bleeding risk
The combination of SSRIs with certain medications can
increase the risk of bleeding. To avoid this, it’s best to
avoid medications known to make blood thinner while
taking SSRIs. Some examples to avoid include:
•Aspirin
•Non-steroidal anti-inflammatory drugs (NSAIDs), such as
ibuprofen and naproxen
•Anticoagulant drugs, commonly called blood-thinners,
such as warfarin
•Antiplatelet drugs, such as clopidogrel

21. Although the SSRIs are considered to have fewer
and less severe adverse effects than the TCAs and
MAOIs, the SSRIs are not without adverse effects,
such as headache, sweating, anxiety and agitation,
gastrointestinal (GI) effects (nausea, vomiting,
diarrhea), weakness and fatigue, sexual dysfunction,
changes in weight, sleep disturbances (insomnia
and somnolence. Additionally, SSRIs have been
associated with hyponatremia, especially in the
elderly and patients who are volume depleted or
taking diuretics
Adverse Effects of SSRIs
Fig: Some commonly observed Adverse Effects of SSRIs
Source: Lippincott Illustrated Reviews: Pharmacology, 6th Edition

22. Comparison of Side Effects among 1st Generation SSRIs

23. All of the SSRIs have the potential to cause a discontinuation syndrome after their
abrupt withdrawal, particularly the agents with shorter half-lives and inactive
metabolites. Fluoxetine has the lowest risk of causing an SSRI discontinuation
syndrome due to its longer half-life and active metabolite. Possible signs and
symptoms of SSRI discontinuation syndrome include-
• Headache
• Malaise (Idiopathic Discomfortness)
• Flu-like symptoms
• Agitation and irritability
• Nervousness
• Changes in sleep pattern.
Overdose with SSRIs does not usually cause cardiac arrhythmias, with the exception of citalopram, which may cause QT
prolongation. Seizures are a possibility because all antidepressants may lower the seizure threshold. All SSRIs have the
potential to cause serotonin syndrome, especially when used in the presence of a MAOI or other highly serotonergic drug.
Serotonin syndrome may include the symptoms of hyperthermia, muscle rigidity, sweating, myoclonus (clonic muscle
twitching), and changes in mental status and vital signs.
Withdrawal syndrome
Overdose

24. 2. Serotonin / Norepinephrine Reuptake Inhibitors (SNRIs)
SNRIs is effective in treating depression in patients in whom SSRIs are ineffective. Furthermore,
depression is often accompanied by chronic painful symptoms, such as backache and muscle
aches, against which SSRIs are also relatively ineffective. This pain is, in part, modulated by
serotonin and norepinephrine pathways in the central nervous system (CNS). The dual inhibition of
both serotonin and norepinephrine reuptake, are sometimes effective in relieving pain as
fibromyalgia associated with diabetic peripheral neuropathy, post-herpetic neuralgia, and low back
pain.
Source: Lippincott Illustrated Reviews: Pharmacology, 6th Edition
SNRIs block the reabsorption (reuptake) of the
neurotransmitters serotonin and norepinephrine in the brain.
Changes in brain chemistry and communication in brain
nerve cell circuitry known to regulate mood.
Relieve Depression

25. Generic Use
Duloxetine
• Depression
• Generalized anxiety disorder (GAD)
• Chronic musculoskeletal pain
• Diabetic peripheral neuropathic pain
• Fibromyalgia
Venlafaxine
• Depression
• GAD
• Panic disorder
• Attention deficit hyperactive disorder (ADHD)
• Social anxiety disorder
Desvenlafaxine • Depression
Levomilnacipran • Depression
Milnacipran • Fibromyalgia
Therapeutic Uses of SNRIs

26. Pharmacokinetics of SNRIs
Duloxetine
It is extensively metabolized in the liver to inactive
metabolites and should be avoided in patients with
liver dysfunction. Duloxetine is a moderate inhibitor
of CYP2D6 isoenzymes and may increase
concentrations of drugs metabolized by this pathway,
such as antipsychotics
Venlafaxine and Desvenlafaxine
Venlafaxine has minimal inhibition of the CYP450
isoenzymes and is a substrate of the CYP2D6
isoenzyme. Desvenlafaxine is the active,
demethylated metabolite of venlafaxine.
Levomilnacipran
Levomilnacipran is an enantiomer of milnacipran (an
older SNRI used for the treatment of depression). It
is primarily metabolized by CYP3A4, and, thus,
activity may be altered by inducers or inhibitors of
this enzyme system.

27. • The most common side effects of venlafaxine are
nausea, headache, sexual dysfunction, dizziness,
insomnia, sedation, and constipation. At high doses,
there may be an increase in blood pressure and
heart rate.
• The clinical activity and adverse effect profile of
desvenlafaxine are similar to that of venlafaxine.
• GI side effects are common with duloxetine,
including nausea, dry mouth, and constipation.
Insomnia, dizziness, somnolence, sweating, and sexual
dysfunction are also seen. Duloxetine may increase
blood pressure or heart rate.
Adverse Effects of SNRIs
Insomnia
Dizziness
Somnolence
Sweating
Sexual dysfunction
Nausea

28. Mechanism of action
1. Inhibition of neurotransmitter reuptake: TCAs are
potent inhibitors of the neuronal reuptake of
norepinephrine and serotonin into presynaptic nerve
terminals. Maprotiline and desipramine are relatively
selective inhibitors of norepinephrine reuptake.
2. Blocking of receptors: TCAs also block serotonergic,
α-adrenergic, histaminic, and muscarinic receptors. It
is not known if any of these actions produce the
therapeutic benefit of the TCAs. Amoxapine also
blocks 5-HT2 and dopamine D2 receptors.
3. Tricyclic Antidepressants (TCAs)
Tricyclic antidepressants are so-named because their molecular structure is composed of three rings of
atoms

29. The TCAs are effective in treating moderate to severe depression. Some patients with panic disorder
also respond to TCAs. Imipramine has been used to control bed-wetting in children older than 6 years of age;
however, it has largely been replaced by desmopressin and non pharmacologic treatments (enuresis alarms).
The TCAs, particularly amitriptyline, have been used to help prevent migraine headache and treat chronic
pain syndromes (for example, neuropathic pain) in a number of conditions for which the cause of pain is
unclear. Low doses of TCAs, especially doxepin, can be used to treat insomnia.
Therapeutic uses

30. Absorption: TCAs are well absorbed upon oral administration.
Distribution: Because of their lipophilic nature, they are widely
distributed and readily penetrate into the CNS. As a result of their
variable first-pass metabolism in the liver, TCAs have low and
inconsistent bioavailability.
Metabolism: These drugs are metabolized by the hepatic
microsomal system (and, thus, may be sensitive to agents that
induce or inhibit the CYP450 isoenzymes) and conjugated with
glucuronic acid.
Excretion: TCAs are excreted as inactive metabolites via the kidney.
Pharmacokinetics of TCAs

31. Blockade of muscarinic receptors, leads to-
blurred vision, xerostomia (dry mouth), urinary retention, sinus tachycardia, constipation, and aggravation of angle-closure
glaucoma. These agents affect cardiac conduction similarly to quinidine and may precipitate life-threatening arrhythmias in an
overdose situation.
Blockade of α-adrenergic receptors, causing-
orthostatic hypotension, dizziness, and reflex tachycardia. Imipramine is the most likely, and nortriptyline the least likely, to
cause orthostatic hypotension.
Blockade of histamine H1 receptors, Causes-
Sedation, especially during the first several weeks of treatment.
Weight gain is a common adverse effect of the TCAs. Sexual dysfunction occurs in a minority of patients
Adverse Effects of TCAs

32. TCAs (like all antidepressants) should be used with caution in patients
with bipolar disorder, even during their depressed state, because
antidepressants may cause a switch to manic behavior. The TCAs
have a narrow therapeutic index (for example, five- to six fold the
maximal daily dose of imipramine can be lethal). Depressed patients
who are suicidal should be given only limited quantities of these
drugs and be monitored closely. The TCAs may exacerbate certain
medical conditions, such as benign prostatic hyperplasia,
epilepsy, and preexisting arrhythmias.
Precautions:

33. Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve and other tissues,
such as the gut and liver. In the neuron, MAO functions as a “safety valve” to oxidatively
deaminate and inactivate any excess neurotransmitters (for example, norepinephrine,
dopamine, and serotonin) that may leak out of synaptic vesicles when the neuron is at rest.
4. Monoamine oxidase (MAO) Inhibitors
The MAOIs may irreversibly or reversibly inactivate the MAO
enzyme and, therefore, and leak into the synaptic space
This results in increased stores of norepinephrine, serotonin,
and dopamine within the presynaptic neuron
Permitting neurotransmitters to escape degradation
Subsequent diffusion of excess neurotransmitter into the
synaptic space
Anti-Depressant Action
M/A of MAO Inhibitor:

34. • The MAOIs are indicated for depressed patients who are unresponsive or allergic to TCAs and SSRIs or who experience
strong anxiety.
• A special subcategory of depression, called atypical depression, may respond preferentially to MAOIs.
• Because of their risk for drug–drug and drug–food interactions, the MAOIs are considered last-line agents in many treatm
-ent settings.
Therapeutic uses
• These drugs are well absorbed after oral administration.
• Enzyme regeneration, when irreversibly inactivated, varies, but it
usually occurs several weeks after termination of the drug. Thus,
when switching antidepressant agents, a minimum of 2 weeks of
delay must be allowed after termination of MAOI therapy and
the initiation of another antidepressant from any other class.
• MAOIs are hepatically metabolized and excreted rapidly in urine.
Pharmacokinetics of MAOI

35. These drugs inhibit not only MAO in the brain but also MAO in the liver and gut that catalyzes oxidative deamination
of drugs and potentially toxic substances, such as tyramine, which is found in certain foods. The MAOI, therefore,
show a high incidence of drug–drug and drug–food interactions.
Precautions when taking MAOI

36. Patients experiences ---
• occipital headache
• stiff neck
• Tachycardia
• Nausea
• Hypertension
• cardiac arrhythmias
• Seizures
• Possibly, stroke.
Phentolamine and prazosin
are helpful in the management of
tyramine-induced hypertension
Receiving a MAOI
Unable to degrade tyramine obtained from the diet
Tyramine causes the release of large amounts of st
ored catecholamine's from nerve terminals
Resulting in a hypertensive crisis
Other side effects include-
• drowsiness,
• orthostatic hypotension
• blurred vision
• dry mouth, and
• constipation
Possible side effects of treatment with MAOIs

37. The atypical antidepressants are a mixed group of agents that have
actions at several different sites. This group includes-
• Bupropion
• Mirtazapine
• Nefazodone
• Trazodone
• Vilazodone and
• Vortioxetine
5. Atypical Antidepressant
Therapeutic Uses

38. A. Bupropion
• A weak dopamine and norepinephrine reuptake inhibitor
• useful for decreasing cravings and attenuating withdrawal symptoms of
nicotine in patients trying to quit smoking.
• Side effects may include dry mouth, sweating, nervousness, tremor, and
a dose dependent increased risk for seizures.
• Bupropion is metabolized by the CYP2B6 pathway and has a relatively l
ow risk for drug–drug interactions.
• Use of bupropion should be avoided in patients at risk for seizure
s or those who have eating disorders such as bulimia.
D. Vilazodone
• A serotonin reuptake inhibitor and a 5-HT1a partial agonist.
• The adverse effect profile of vilazodone is similar to the SSRIs, includin
g a risk for discontinuation syndrome if abruptly stopped
B. Mirtazapine
• It enhances serotonin and norepinephrine neurotransmission by serving
as an antagonist at presynaptic α2 receptors. Additionally, some of the a
ntidepressant activity may be related to antagonism at 5-HT2 receptors.
• Increased appetite and weight gain frequently occur
• Mirtazapine is markedly sedating, which may be an advantage in d
epressed patients having difficulty sleeping.
C. Nefazodone and Trazodone
• These drugs are weak inhibitors of serotonin reuptake. Their therapeutic
benefit appears to be related to their ability to block postsynaptic 5-HT2a
receptors.
• Both agents are sedating, probably because of their potent histamine H1
-blocking activity.
• Trazodone is commonly used off-label for the management of insomnia.
• Nefazodone has been associated with a risk for hepatotoxicity.
• Both agents also have mild to moderate α1 receptor antagonism, contrib
uting to orthostasis and dizziness.
E. Vortioxetine
• It utilizes a combination of serotonin reuptake inhibition, 5-HT1a agonism
, and 5-HT3 and 5-HT7 antagonism as its suggested mechanisms of acti
on to treat depression.
• The common adverse effects include nausea, vomiting, and constipation

39. Source: Managed Care
Development of Novel Antidepressant

40. Source: Nature Medicine 22, 2016
Potential Glutamatergic Targets for Novel Antidepressants
• NMDA antagonist
• mGluR2/3 antagonist
• AchM1 antagonist
• AMPA agonist
MAOI, TCA SSRI, SNRI 3rd Generation
Development of Novel Antidepressant
Esketamine (AMPA Rc ag)
Rapastinel (NMDA Rc partial ag)
Phase II Clinical Trial
Phase III Clinical Trial

41. Ref: Cartwright C, Gibson K, Read J, Cowan O, Dehar T. Long-term antidepressant use: Patient perspectives of benefits and adverse effects. Patient Prefer Adherence. 2016;10:1401–1407.
doi:10.2147/PPA.S110632
In 2016, the medical journal Patient Preference and Adherence published a paper
looking at what people taking antidepressants long-term had to say about the side
effects that they've seen. Overall, they did say they were less depressed and had
a better quality of life because of the drugs, but about 30% still said they had
moderate or severe depression.
The main side effects they complained about included:
• Sexual problems (72%), including the inability to reach orgasm (65%)
• Weight gain (65%)
• Feeling emotionally numb (65%)
• Not feeling like themselves (54%)
• Reduced positive feelings (46%)
• Feeling as if they're addicted (43%)
• Caring less about other people (36%)
• Feeling suicidal (36%)
About 74% of people also mentioned withdrawal symptoms
Long-Term Effects of Antidepressants

43. Thanks To All….