Antidepressants

OUTLINE
1. Brief introduction to depression and its physiology

2. Classification of Antidepressants

• Indications of use of Antidepressants

• Pharmacokinetics of Antidepressants

• Administration and dosing

• Adverse Effects
 DEPRESSION
Depression is a common mental disorder that presents with depressed mood, loss of
interest or pleasure, decreased energy, feelings of guilt or low self-worth, disturbed
sleep or appetite, and poor concentration.
PHYSIOLOGY OF DEPRESSION
 ANTI-
DEPRESSANT
S
 ANTIDEPRESSANTS
• These are a range of medications Tricyclic and Tetracyclic Antidepressants
used in the treatment of depression (TCAs)
and other mental health conditions. Monoamine Oxidase Inhibitors (MAOIs)

• They are designed to change Selective Serotonin Reuptake Inhibitors

neurotransmitters in the brain that (SSRIs)
affect mood and emotions. Serotonin–Norepinephrine Reuptake
Inhibitors (SNRIs)
• Classes of antidepressants include:
Atypical Antidepressants

5-HT2 Receptor Agonists

 TRICYCLIC AND
TETRACYCLIC
ANTIDEPRESSANTS
TRICYCLIC AND TETRACYLIC ANTIDEPRESSANTS

• Among the earliest antidepressants developed

• They became first-line treatment for depression

• Now replaced by antidepressants that cause fewer side

effects

• The names depend on the number of rings in their

structure.
 TRICYCLIC AND TETRACYLIC
ANTIDEPRESSANTS
Tricyclic antidepressant Tetracyclic antidepressant

3 ringed structure 4 ringed structure

 TRICYCLIC ANTIDEPRESSANT
DRUGSTricyclic - Secondary Amines
Tricyclic - Tertiary Amines
Generic Names Brand Names
Generic Names Brand Names Desipramine Norpramin
Imipramine Tofranil Nortriptyline Pamelor ,Aventyl
(prototype)
Protriptyline Vivactyl
Amitriptyline Elavil
Clomipramine Anafranil, Clomicalm
Tetracyclic
Doxepin Sinequan, Quitaxon, 
Aponal Generic Names Brand Names
Trimipramine Surmontil Maprotiline Ludiomil
Amoxapine Asendin
MECHANISM OF ACTION
 INDICATIONS FOR USE
Major Depressive Disorder
• Tricyclic and tetracyclic antidepressants

Panic Disorder with Agoraphobia

• Imipramine
• Clomipramine

Generalized Anxiety Disorder

• Doxepin
• Imipramine
 INDICATIONS FOR USE
Obsessive-Compulsive
• Clomipramine

Pain
• Amitriptyline

Childhood Enuresis
• Imipramine

Insomnia
• Amitriptyline
• Doxepin
 METABOLISM
Peak Plasma Levels
Drug Half Life (hr)
(hr)
Amitriptyline 4-8 9-25
Clomipramine 3-5 12-36
Doxepin 2-4 33-80 (1.5 – 3.3 days)

Imipramine 2-6 19
Protriptyline 8-12 54-92
Trimipramine 1.5-6 23
Amoxapine 1-2 8-10
Maprotiline 8-24 27-58
 DOSING AND ADMINISTRATION
Therapeutic
Therapeutic
Drug Formulations and Strengths Dose Range
Index
(mg/day)
Amitriptyline -Tablets 150–300 Narrow
-10, 25, 50, 75, 100, 150 mg
Clomipramine -Capsules 100–250 Narrow
-25, 50, 75 mg
Doxepin -Capsules: 10, 25, 50, 75, 100, 150–300 Narrow
150 mg
-Oral solution: 10 mg/mL
Imipramine -Tablets 150–300 Narrow
-10, 25, 50 mg
 DOSING AND ADMINISTRATION
Therapeutic
Therapeutic
Drug Formulations and Strengths Dose Range
Index
(mg/day)
Protriptyline -Tablets 15–60 Narrow
- 5, 10 mg
Trimipramine -Capsules 150–300 Narrow
- 25, 50, 100 mg
Amoxapine -Tablets 150–400 Narrow
- 25, 50, 100, 150 mg
Maprotiline -Tablets 150–225 Narrow
-25, 50, 75 mg
 ADVERSE EFFECTS OF TCAs

Tachycardia
Dry mouth Constipation

Ventricular
Blurred vision Urinary retention fibrillation

Prolonged QT
Delirium intervals

Anticholinergic Effects Cardiac Effects

ADVERSE EFFECTS OF TCAs

Orthostatic
Sedation
Hypotension

Weight Gain Neurological Effects

Hepatic Effects Suicidal Ideation

 SAFETY CONSIDERATIONS
• Drug interactions
• Antidepressants and
 Monoamine Oxidase pregnancy
Inhibitors
 Antihypertensives • Suicidal ideations
 Antiarrhythmic Drugs
 Dopamine Receptor
Antagonists
 Central Nervous System
Depressants
 Sympathomimetics
 Oral Contraceptives
 OVERDOSE
• They have a narrow therapeutic index and are prone to toxicity if
intentional overdose occurs.

• Symptoms of overdose include ECG abnormalities, hypotension,

seizures, tremors, coma, xerostomia, urinary retention, and respiratory
depression.

• Death from TCAs most commonly occurs due to hypotension or

arrhythmias. 
MONOAMINE
OXIDASE
INHIBITORS
 MONOAMINE OXIDASE INHIBITORS
• They were introduced in the 1950s as the first drugs for depression.

• Isoniazid (1st MAOI), was intended to treat tuberculosis, but its antidepressant
properties were discovered by chance.

• While effective, they've generally been replaced by safer antidepressants that

have fewer side effects and concerns about food, and drug interactions.
 INDICATIONS OF USE
The primary clinical indication for MAOIs is for the treatment of depression.

Despite their side effects, MAOIs are still a good option for some, and are indicated when
several trials with other drugs have failed.

Effective in treating: depression (including atypical), panic disorder, social phobia and
other anxiety disorders.

MAOIs are evidenced to be more effective than TCAs in treating bipolar depression.

MAOIs can be used to treat Parkinson's disease, specifically Selegiline.

 MECHANISM OF ACTION
● MAOIs work by causing changes in the brain that are involved in depression.
● Mitigate depression by targeting the neurotransmitters that allow brain cells to
communicate with each other.

● The enzyme MAO is involved in removing these neurotransmitters from the brain.

● MAOIs prevent this from happening, increasing their concentration.

● Helps to elevate overall mood through improved brain cell communication

 Generic Name Brand Name(s)
1. Phenelzine TYPES Nardil

• Irreversible Nonselective:
2. Selegiline e.g such as phenelzine, tranylcypromine and
Eldepryl
isocarboxazid Carbex
Zelapar
Emsam
• Irreversible Selective: e.g as selegiline (deprenyl)
3. Tranylcypromine Parnate
• Reversible4.Selective : e.g moclobemide, toloxatone
Isocarboxazid Marplanand brofaromine

5. Moclobemide Aurorix
Amira
 Clobemix
Depnil
 NONSELECTIVE AND IRREVERSIBLE
MONOAMINE OXIDASE INHIBITORS
●All currently available MAOIs are nonselective and irreversible inhibitors of
MAO.

●Irreversible, nonselective monoamine oxidase (MAO) inhibitors were among the

first antidepressants.

●When an MAOI covalently binds to the enzyme, it is irreversibly inhibited.

●Enzyme activity cannot be restored until the body replaces the enzyme through
new enzyme synthesis.
SELECTIVE MONOAMINE OXIDASE INHIBITORS
●Drugs that selectively block MAO-B, such as selegiline.
●May substantially decrease the risk of hypertensive crises.
●At lower dosages, MAOIs works as a selective but irreversible inhibitor
of MAO-B. At higher dosages, both MAO-A and MAO-B will be
inhibited, possibly resulting in hypertensive crises.

●However, the selegiline transdermal formulation bypasses the gut and

liver allowing for higher plasma levels with a low risk of food
interactions; thus rectifying the problem.
 REVERSIBLE MONOAMINE OXIDASE
INHIBITORS (RIMA)
● Newest class of antidepressant MAOIs. They are less effective than
other drugs.

●A reversible inhibitor of MAO-A has a low affinity for MAO and would
be readily displaced by pressor amines, reducing the risk of a
hypertensive crisis.

●Moclobemide is effective in a wide range of depressive illnesses, due it

its tolerability and safety.
 DRUGS
MAOIs approved to treat depression include:
▪ Isocarboxazid (Marplan)
▪ Phenelzine (Nardil)
▪ Tranylcypromine (Parnate)
▪ Selegiline (Emsam)
▪ Moclobemide (Aurorix)
 DOSAGE ADMINISTRATION
MAOI Drug Formulations and Strengths Effective Therapeutic Index
Dosage
(mg/day)

1. Phenelzine Tablet: 15mg 45-90 Wide

(Nardil)
2. Selegiline Patch: 6mg/24hr, 9mg/24hr, 20-50 Wide
(Emsam) 12mg/24hr
3. Tranylcypromine Tablet: 10mg 30-60 Wide
(Parnate)
4. Isocarboxazid Tablet: 10mg 30-60 Wide
(Marplan)
5. Moclobemide Tablet: 150 mg 300-600 Wide
(Aurorix)
 METABOLISM
MAOI Drug Peak Plasma Half Life Metabolite
(Hours) (Hours)

1. Phenelzine 1-2 1.5-4 Phenylacetic acid and

(Nardil) p-hydroxyphenylacetic acid

2. Selegiline 1 1.5 N-desmethylselegiline or R(-)-

(Emsam) methamphetamine
3. Tranylcypromine 1-2 1.5-4 Amphetamine
(Parnate)
4. Isocarboxazid 1-2 1.5-4 Hippuric Acid
(Marplan)
5. Moclobemide 0.3-2 1-3 Moclobemide 4/5
(Aurorix)
 SIDE EFFECTS
• It has more side effects than other antidepressants, the most common being:

Orthostatic Dizziness or Drowsiness Insomnia

hypotension lightheadedness

Skin reaction at Nausea, diarrhea

Headache Dry mouth
the patch site or constipation
 SIDE EFFECTS
• Other possible side effects include:
-Weight gain

-Edema

-Sexual dysfunction

-Muscle cramps

-Paresthesia (Prickling or tingling sensation in the skin)

-Difficulty urinating
 OVERDOSE
Overdoses of MAOIs are not lethal.

Occurrence of symptoms of toxicity is preceded by an asymptomatic period of 1 to 6

hours after overdose.

MAOI overdose is characterized by agitation that can progress to a coma with

hyperthermia, hypertension, tachypnea, tachycardia, dilated pupils, and hyperactive
deep tendon reflexes.
Acidification of the urine would hasten the excretion of MAOIs.

Overdoses commonly involve other medications, resulting in serotonin syndromes or

hypertensive reactions.
 SAFETY CONCERNS WITH MAOIs
There are issues that need be considered and discussed with your doctor before
taking any MAOI.

• Serotonin syndrome
• Antidepressants and pregnancy
• Suicide risk and antidepressants
• Stopping treatment with MAOIs
• Food and beverage interactions
• Drug interactions
 FOOD AND BEVERAGE INTERACTIONS
● The most serious side effect of MAOIs is the tyramine-induced hypertensive
crisis.

● MAO inhibition by MAOIs may cause tyramine over-absorption.

● Interaction between tyramine and MAOIs can cause hypertensive crisis.

● Tyramine-containing foods should be avoided for 2 weeks after the last dose of
an irreversible MAOI.

● An MAOI-induced hypertensive crisis should be treated with α-adrenergic

antagonists.
 DRUG INTERACTIONS
● Dangerous reactions can occur when MAOI are taken with
medications like:
-Other antidepressants
-Pain drugs
-Cold and allergy medications
-Herbal supplements
-Serotonergic drugs
-Seizure medication
-Local anesthetics (containing sympathomimetic agents)
-Decongestants
SELECTIVE
SEROTONIN
REUPTAKE
INHIBITORS
 OVERVIEW OF SSRIs
Generic name Brand name(s)
• Selective serotonin reuptake inhibitors
Citalopram Celexaare the most commonly
prescribed class of antidepressants.
Escitalopram Lexapro
• HaveFluoxetine
surpassed tricyclic antidepressants and MAOIs as the first line
Prozac, Sarafem,
treatment for depressive disorders
Symbyax
Fluvoxamine Luvox
• SSRIs cause fewer side effects, have better efficacy, are more tolerable
Paroxetine
and have Paxil, Pexeva
reduced risk of lethal overdose when compared to other
antidepressants.
Sertraline Zoloft
Vilazodone Viibryd
MECHANISM OF ACTION OF SSRIs
MECHANISM OF ACTION OF SSRIs
 INDICATIONS FOR USE
SSRIs are indicated in conditions such as:

Obsessive Generalized
Major Depressive Compulsive Anxiety Disorder
Disorder (MDD) Disorder (OCD) (GAD)
 INDICATIONS FOR USE
SSRIs are indicated in conditions such as:

Post Traumatic Anorexia Nervosa Bulimia Nervosa

Stress Disorder (AN) (BN)
(PTSD)
SSRI Drug Formulations and Strengths
Effective Therapeutic
DOSAGE ADMINISTRATIONDosages
OF SSRIsIndex
(mg/day)
Citalopram • Tablets: 10, 20, 40 mg 20 – 40 Wide
(Celexa) • Oral solution: 10 mg/5 mL
(240-mL bottle)
Escitalopram • Tablets: 5, 10, 20 mg 20 – 40 Wide
(Lexapro) • Oral solution: 5 mg/5 mL
(240-mL bottle)
Fluoxetine • Capsules: 10, 20, 40 mg 20 – 60 Wide
(Prozac) • Oral solution: 20 mg/5 mL
(120-mL bottle)
• Tablets: 10, 20 mg
SSRI Drug Formulations and
Effective Therapeutic Index
Strengths
Dosages
DOSAGE ADMINISTRATION
(mg/day) OF SSRIs
Fluvoxamine • Tablets: 25, 50, 100 mg 100 – 200 Wide
(Luvox)
Paroxetine • Tablets: 10, 20, 30, 40 20 – 50 Wide
(Paxil) mg
• Oral suspension: 10
mg/5 mL (250-mL
bottle)
Sertraline • Tablets: 25, 50, 100 mg 50 – 200 Wide
(Zoloft) • Oral concentrate: 20
mg/mL (60-mL bottle)
 METABOLISM OF SSRIs
SSRI Drug Peak Plasma Half Metabolite
Level (Hours) Life
(hours)
Citalopram 4–6 35 NA
(Celexa)

Escitalopram 5 32 S-demethylcitalopram (7-

(Lexapro) 10 days)

Fluoxetine 6–8 24 – 72 Norfluoxetine

(Prozac) (7–14 days)
 METABOLISM OF SSRIs
SSRI Drug Peak Plasma Half Life Metabolite
Level (Hours) (hours)

Fluvoxamine 2–8 15 NA
(Luvox)

Paroxetine 2–8 <20 NA

(Paxil)

Sertraline 6–8 25 N-desmethylsertraline

(Zoloft) (2 –3 days)
 ADVERSE EFFECTS OF SSRIs

Nausea Headaches

Dizziness Somnolence

Constipation Insomnia

Diarrhea Tremors

Dry Mouth Seizures

Diaphoresis Sexual Dysfunction

 OVERDOSE
• Due to their wide therapeutic index, SSRIs are generally safe for use
and are not prone to toxicity.

• Few fatalities have resulted from overdosing on an SSRI alone. Most are
complicated by ingestion of other substances.

• The most common symptoms of large overdoses include: vomiting,

nausea, tremor, and sedation. At very high dosages, serious adverse effects
include: cardiovascular events, seizures, and altered or decreased
consciousness.

• Death from SSRIs typically result from complications of status epilepticus

and cardiovascular events such as arrhythmias.
 DRUG INTERACTIONS
● Dangerous reactions can occur when SSRIs are taken with medications
like:
• TCAs
• Type 1C antiarrhythmic agents
• Beta-blockers, especially propranalol and atenolol
• Benztropine
• Antipsychotic medications e.g. risperidone, quetiapine, olanzapine
• Other antidepressants
SEROTONIN SYNDROME
 SEROTONIN
NOREPINEPHRINE
REUPTAKE
INHIBITORS
 SEROTONIN-NOREPINEPHRINE REUPTAKE
INHIBITORS
Selectively inhibit the reuptake of both serotonin and
norepinephrine

• Duloxetine
• Venlafaxine
• Desvenlafaxine
• Levomilnacipran
Available • Milnacipran
SNRIs: • Atomoxetine
MECHANISM OF ACTION
INDICATIONS FOR USE
 DOSAGE AND ADMINISTRATION
SNRI Drug Formulations and Effective Dosage Therapeutic Index
Strengths (mg/day)
Duloxetine Tablets: 20mg, 30mg, 60 Wide
60mg
Venlafaxine Tablets: 25mg, 37.5mg, 75; 37.5 with decreased Narrow
50mg, 75mg, 100mg hepatic or renal function
Extended release
capsules: 37.5mg, 75mg,
150mg

Desvenlafaxine Extended release 50 -

capsules: 50mg, 100mg

Levomilnacipran Extended release 40-120 -

capsules: 40mg, 80mg,
120mg
 METABOLISM
SNRI Drug Peak Plasma Half-life (Hours) Metabolites
Concentration (Hours)

Duloxetine 6 12 Multiple, but fleeting or

inactive

Venlafaxine 2 5 Desvenlafaxine (o-

desmethyl-venlafaxine)

Desvenlafaxine 7.5 11 Inactive: N,O-

didesmethylvenlafaxine
etc.
Levomilnacipran 6-8 12 Inactive: N-desethyl
levomilnacipran etc.
 REUPTAKE EFFECTS
• 30-fold higher affinity for the reuptake inhibition of
serotonin
Venlafaxine • Sequential reuptake inhibition
• Weak inhibitory effect on dopamine reuptake

• 10-fold higher selectivity for serotonin reuptake inhibition

Duloxetine • Sequential reuptake inhibition
• Weak inhibitory effect on dopamine reuptake

• 10-fold higher selectivity for serotonin reuptake inhibition

Desvenlafaxine • Weak inhibitory effect on dopamine reuptake

• 2-fold greater potency for norepinephrine reuptake

inhibition
Levomilnacipran • Simultaneous reuptake inhibition effect
• No effects on dopamine
 ADVERSE EFFECTS

Sustained hypertension
Nausea Dry mouth
Sexual dysfunction
Insomnia
Headache Diaphoresis
Somnolence
Constipation
Loss of appetite
Nervousness
 SIGNIFICANT WARNINGS
• Serotonin Syndrome

• Abnormal bleeding

• Suicidal thoughts or behavior

• Discontinuation Syndrome
 ATYPICAL
ANTIDEPRESSAN
TS
 OVERVIEW
The atypical antidepressants are a mixed group of agents that have
actions at several different sites.

Though unable to fit into the other drug classes, they alter the levels
of dopamine, serotonin and norepinephrine like the other classes.

They are each unique medications that work in different ways from
one another.

Have been used for major depression, reactive depression, and

anxiety.

Reserved for patients that don’t respond to other antidepressants

COMMON ATYPICAL
ANTIDEPRESSANTSMirtazapine

Vortioxetine Bupropion

Vilazodone Trazodone

Nefazodone
 MIRTAZAPINE- INDICATIONS FOR USE
Indicated for the treatment of major depressive disorder and its associated
symptoms:
• Sleep disorders and insomnia
• Low body weight/ anorexia
• Vomiting and nausea in cancer patients
 Mirtazapine
Mechanism Of Action

• α2 (auto-receptor
and hetero-
Antagonist receptor)
• 5HT2A & 5HT2C
at several • 5HT3
receptors • H1 receptor
including:
 BUPROPION
INDICATIONS FOR USE

Major depressive Seasonal affective Aid to smoking

disorder (MDD) disorder (SAD) cessation.
 BUPROPION
MECHANISM OF ACTION

Bupropion is a weak dopamine and norepinephrine reuptake inhibitor that is used to

alleviate the symptoms of depression.
 TRAZODONE & NEFAZODONE
INDICATIONS FOR USE

Nephazodone
Trazodone
● Major Depressive Disorder
(MDD) Depression(MDD)

● Adjunct therapy in alcohol

dependence

● Anxiety and insomnia

TRAZODONE & NEFAZODONE
MECHANISM OF ACTION
 VILAZODONE
MECHANISM OF ACTION

● Is indicated for the treatment of Major

depressive disorder

● Its mechanism of action is best

described as having selective serotonin
reuptake inhibition with partial agonist
activity at the 5-HT1A receptor.
 VORTIOXETINE
MECHANISM OF ACTION
 PHARMACOKINETICS OF ATYPICAL ANTIDEPRESSANTS
Atypical Metabolism Half Life Route of Elimination
Antidepressant

Mertazapine Metabolized by means of 20-40 hours mainly excreted by the

Demethylation, hydroxylation and kidney
subsequent glucuronide conjugation

Bupropion Metabolized by means of 24 hours mainly excreted by the

hydroxylation, reduction and kidney
oxidation.

Vortioxetine extensively metabolized primarily Mean terminal half-­life is mainly excreted by the
through oxidation via cytochrome approximately 66 hours kidney and found in feces
P450 isozymes. as well
 PHARMACOKINETICS OF ATYPICAL ANTIDEPRESSANTS
Atypical Metabolism Half Life Route of Elimination
Antidepressant
Nefazodone metabolized by n-dealkylation and 2-4 hours Excreted in urine
hydroxylation

Trazodone metabolized hepatically by elimination half-life of 10- kidneys are responsible for
hydroxylation and oxidation  12 hours. 70 to 75% of trazodone
excretion

Vilazodone extensively metabolized via the 1% of the dose is recovered

CYP3A4 isoenzyme 25 hours unchanged in the urine and
2% of the dose is recovered
unchanged in the feces
 DOSAGE ADMINISTRATION OF ATYPICAL
Atypical
ANTIDEPRESSANTS
Formulations and strengths Effective Dosages Therapeutic Index
Antidepressant

Mertazapine 7.5-mg, 15-mg, 30-mg, and 45- 15 to 45 mg/day Narrow

mg tablets. A quick-dissolving
wafer formulation has been
commonly used in geriatric
patients.
Bupropion 75-mg and 100-mg tablets 150 mg/day Narrow

Vortioxetine 5-mg, 10-mg, 15-mg, 20-mg 5 to 20 mg orally once a Wide

tablets. day
 DOSAGE ADMINISTRATION OF ATYPICAL ANTIDEPRESSANTS

Atypical Formulations and strengths Effective Dosages Therapeutic Index

Antidepressant

Nefadozone 50mg, 100mg, 150mg, 200mg Starting dose: Wide

and 250mg tablets 100-200mg/BD
Effective maintenance
dose:
300 to 500 mg/day
Trazodone 50 mg, 100 mg, 150 mg and 300 50-100 mg/day Wide
mg tablets

Vilazodone available as 10 mg, 20 mg and 40 mg/day Wide

40 mg film-coated tablets.
SIDE EFFECTS OF ATYPICAL ANTIDEPRESSANTS

Mirtazapine
Weight gain
Dry mouth

Bupropion
Vortioxetine
Skin rash Nausea & diarrhea
Weight loss
Sexual dysfunction
SIDE EFFECTS OF ATYPICAL ANTIDEPRESSANTS

Trazodone
Priapism

Nefazodone Vilazodone
Dizziness Risk for discontinuation
Risk for hepatotoxicity syndrome
Erectile dysfunction
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