DRUG THERAPY OF DEPRESSION

Igor Iezhitsa
Lecture Outcomes
At the end of the plenary, students should be able to
1. Classify antidepressant agents and state commonly used drugs for each drug class.
a. Selective serotonin reuptake inhibitors (SSRI): Fluoxetine
b. Tricyclic antidepressants: amitryptyline
c. Monoamine oxidase (MAO) inhibitors: phenelzine
d. Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI): venlafaxine
e. Atypical antidepressants: mirtazapine
2. Describe the primary cellular targets of antidepressant agents and discuss the
mechanism of action of the different classes of antidepressants.
3. Describe therapeutic indications of antidepressant agents and explain their clinical
importance.
4. Describe the most common/major adverse effects of these agents.
5. Explain the important drug interactions of these agents.
6. Describe the signs and symptoms of overdose of the different classes of
antidepressants.
10 Notable People Who Struggled
With Depression
 Major Depressive Episode
Characteristics
• intense feelings of persistent sadness, helplessness
& hopelessness
• inability to experience pleasure in activities that are
normally pleasurable (anhedonia)
• tiredness & lack of energy
• abnormal sleep & eating patterns (increased or
decreased)
• cognitive impairments – difficulty concentrating,
deficits in memory & execution of tasks
Depression: Etiology
• Biological Influence
• genetic predisposition
• neurochemical imbalance
• stress hormones

• Psychological/Behavioral Influence
• learned helplessness/hopelessness
• depressive attributional style
• disturbed sleep habits

• Social Influence
• stressful events serve as triggers
 Hypothese for the pathogenesis
of major depression
The Biogenic Amine Hypothesis Cons.:
(early 1950s) • The Biogenic Amine Hypothesis alone
cannot explain the delay in time of
Pros.: onset of clinical relief of depression of
• The hypothesis states that depression up to 6-8 weeks.
is caused by a deficiency of
noradrenaline, serotonin and
dopamine.
• Drugs that decrease monoamines
precipitate depression, and drugs that
increase monoamines relieve
depression
 Classification of
antidepressants
• Tricyclic antidepressants (TCAs) • Selective Serotonin Reuptake
• Amitriptyline Inhibitors (SSRIs)
• Fluoxetine
• Monoamine oxidase inhibitors
(MAOIs) • Serotonin/Norepinephrine Reuptake
• Phenelzine Inhibitors (SNRIs)
• Venlafaxine

• Atypical antidepressants
• Bupropion
Tricyclic antidepressants
Mechanism of action
• They block norepinephrine and serotonin uptake, do not block
dopamine transporter
• Action is delayed several weeks

Tricyclic AD blocking
reuptake Synaptic clef

Presynaptic neuron Postsynaptic neuron

Synaptic vesicles
Receptor sites
Re-uptake
Neurotransmitter
Tricyclic antidepressants
Tricyclic antidepressants

Pharmacokinetics
• well absorbed orally
• highly lipophilic
•  readily penetrate into CNS
•  long half lives
•  variable first-past metabolism in liver
• Metabolized by hepatic microsomal system
Tricyclic antidepressants
Major adverse effects
• Anticholinergic AE include: dry mouth, constipation,
blurred vision and urinary retention
• Orthostatic hypotension (block -adrenergic
receptors)
• Sedation (block histamine H1 receptors)
• Weight gain
• Impaired sexual function

• Severe adverse effects

• Cardiotoxicity: due to Na+ channel inhibition in the
myocardium: changes in cardiac conductivity velocity,
arrhythmias, prolonged QT interval (predisposes to
Torsades de Pointes), wide QRS complex
Tricyclic antidepressants
• Drug-drug interactions (DDI)
• Potentiation of CNS depressant effect: Benzodiazepines
• Risk of serotonin syndrome (if used concomitantly with other
serotonergic drugs (e.g., MAOIs)

• Cautions
• Narrow therap. index: Overdose is frequently fatal
• NOT a first- or second-line antidepressant today because of extensive
side-effect profile and risk of lethal overdose

Indications
• Severe major depression
Monoamine Oxidase Inhibitors (MAOIs)
MAO-A MAO-B

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Monoamine Oxidase Inhibitors (MAOIs)

Available drugs
• Phenelzine (non-selective and irreversible monoamine oxidase
inhibitor)

Mechanism of action
• MAO oxidatively deaminate and inactivate norepinephrine,
dopamine, and serotonin
• MAO inhibitors (MAOIs) irreversibly or reversibly inactivate MAO
enzyme  inhibition of norepinephrine, dopamine, and serotonin
degradation  accumulation in synaptic space  activation
norepinephrine, dopamine, and serotonin receptors 
antidepressant action
• Action is delayed several weeks
Monoamine Oxidase Inhibitors

Features
• Last line of treatment, used only when other classes of antidepressant
drugs (for example tricyclic antidepressants) are ineffective.
• Very long duration requiring caution when mixing with restricted
substances or medications (Serotonin syndrome)

Tyramine containing foods (“Cheese Effect”)

• Certain ones may be consumed in moderation
• Many cheeses, chocolate, soybeans, … etc.
Mechanism of “Cheese Effect”
Serotonin syndrome and “serotonin
toxicity triangle”

Increased risk with:

• Concurrent use of two or more serotonergic
drugs
• Switching from one serotonergic drug to
another without tapering

Psychiatric drugs:
• MAOIs, SSRIs, SNRIs, TCAs

Other drugs:
• tramadol, ondansetron, dextromethorphan,
meperidine, St. John's wort,
 Serotonin syndrome and “serotonin
toxicity triangle”
Serotonin syndrome (MAOI + SSRI)
• diarrhea, tremor, sweating, restlessness,
hyperreflexia
• progression of symptoms if untreated 
disorientation, rigidity, fever, coma 
seizures, death (approximately 10%
mortality rate)

Treatment:
• Immediate discontinuation of serotonergic
drugs + supportive care
• Benzodiazepines for sedation
• Cyproheptadine: 5-HT1A and 5-HT2A receptor
antagonists
Monoamine Oxidase Inhibitor
Side Effects
Common side effects:
• CNS stimulation
• Sexual dysfunction
• Orthostatic hypotension
• Weight gain

After-Effects:
• Clinical effects of the drug may be observed for several weeks after
termination of therapy (MAO is irreversibly inhibited, and it takes time for
biosynthesis of new MAO)
• ~2 weeks after discontinuing MAOI drug therapy before new enzyme synthesis
can restore ~50% of normal activity
Monoamine Oxidase Inhibitor
Side Effects

Indications:
• Major depressive disorder (third- or fourth-line therapy)
• Atypical depression (e.g. a patient is depressed but sleeps & eats
excessively)

• MAO inhibitors are NOT considered to be first-line antidepressants

because of their:
• dietary restrictions (consumption of tyramine rich foods can cause a
hypertensive crisis)
• drug-drug interactions (P450 interactions & coadministration with
other antidepressants)
can cause either a hypertensive crisis or a serotonin syndrome.
SSRI antidepressants

Fluoxetine

Mechanism of action
• Inhibit serotonin reuptake so
increase synaptic serotonin
levels and more receptors are
activated
• Typically take weeks to produce
improvement in mood, and
maximum benefit may require
twelve weeks or more
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SSRI antidepressants
Advantages of their use include the following:
• low incidence of side effects compared to other agents, safer in
cases of overdose, no food restrictions

Indications
• Major depressive disorder (first-line therapy)

Pharmacokinetics
• Well absorbed after oral administration.

• Metabolism by P450-dependent enzymes

SSRI antidepressants

Adverse effects
• Impaired sexual function (erectile dysfunction, ↓ libido)
• GIT disorders: nausea, vomiting, diarrhea, anorexia,
• CNS: Headache, dizziness, anxiety, insomnia, sweating, tremor

Serotonin syndrome (if used concomitantly with other serotonergic drugs

(e.g., MAOIs).
• To avoid serotonin syndrome, SSRIs should be discontinued at least two
weeks before starting an MAOI.
Serotonin/Norepinephrine Reuptake
Inhibitors (SNRIs)
Venlafaxine

Indications
• treatment of depression in patients in which SSRIs are ineffective.
• relieving physical symptoms of neuropatic pain (backache, muscle
aches) in which SSRIs are ineffective.

• SNRIs has NO activity at adrenergic, muscarinic, or histaminic

receptors and, thus, have fewer adverse effects than tricyclic
antidepressants
Comparison between SNRIs and TCAs
Serotonin/Norepinephrine Reuptake
Inhibitors (SNRIs)
Venlafaxine
• potent inhibitor of serotonin re-uptake and a weaker inhibitor of norepinephrine
transport

Pharmacokinetics
• similar to those of the TCAs
• minimal inhibitory effect on cytochrome P450
• short plasma half-live

Drug-drug interaction
• minimal DDI

Adverse effects
• minimal AE
• causes nausea, dizziness, insomnia, sedation, constipation
 Atypical antidepressants
• newer antidepressants that are not/less serotonin specific or affect
serotonin differently than SSRIs
• not more efficacious than TCAs and SSRIs, but their side effect profiles are
different

Mechanism of action
• Bupropion has norepinephrine and dopamine activity
• strong norepinephrine and weak dopamine reuptake inhibitor (NDRI)

• Mirtazapine has serotonin subtype & norepinephrine activity

• Block 5HT2 and 2 receptors
Atypical antidepressants
Indications
• Many similar uses to SSRIs
• Treatment of depression
• Nicotine addiction (bupropion)
• Insomnia (Mirtazapine)

Side effect
• Bupropion and Mirtazapine do not usually have associated sexual
dysfunction
• Potential DDIs not often significant (except MAOIs)
• Bupropion: seizure risk in certain patients (↑ risk at ↑ dose)
• Mirtazapine: sedation (H1 blocking activity) & weight gain
Antidepressants are used to
treat:
They are not just for depression!
• Autism (SSRIs) • Obsessive-compusive Disorder
• Dysthymia (SSRIs) (SSRIs, TCAs)
• Eating Disorders (SSRIs, TCAs, MAOIs) • Panic Disorder (SSRIs, TCAs, MAOIs)
• Enuresis (TCAs) • Posttraumatic Stress Disorder (SSRIs,
• Migraine Headaches (TCAs, SSRIs, TCAs)
Buproprion) • Premenstrual Dysphoric Disorder
• Neuropathic pain analgesic (TCAs) (SSRIs)
• Smoking Cessation (Buproprion)
Antidepressants: Summary
Self Assessment Questions
Question 1

A 58 year old post-menopausal woman is suffering from

major depression. Her medical history indicates that she had
an inadequate clinical benefit from previous treatment of
fluoxetine and imipramine. After discussion, you decide that
she should start a treatment with an SNRI after tapering her
dose of fluoxetine. What drug is most likely prescribed to this
patient?

1.  Amitriptyline
2. Venlafaxine
3. Bupropion
4. Phenelzine
Self Assessment Questions

Question 2

52 year-old man is suffering from his first episode of major

depression. He has a history of angina, and survived an MI three
months ago. Which agent would be contraindicated for treating
his depression?

1.  Amitriptyline
2. Venlafaxine
3. Bupropion
4. Phenelzine
Self Assessment Questions
Question 3

56-year-old man with a history of hypertension who recently

underwent a coronary artery bypass graft procedure. Jimmy has
a past history of cigarette smoking (1/2 pack per day for the past
20 years). During the recovery phase of his open heart surgery,
he is diagnosed with major depression and seeks treatment.
Which antidepressant may be able to treat both his mental
disorder & help him decrease his craving for cigarettes?

1.  Amitriptyline
2. Venlafaxine
3. Bupropion
4. Phenelzine
Self Assessment Questions
Question 4

A patient with a long history of drug-resistant depression is

given a new drug prescription by his primary care physician.
Before handing the patient his prescription, he mentions a list of
known side effects that include: dry mouth, constipation,
urinary retention, sedation, increased QRS interval, orthostatic
hypotension, tachycardia, and erectile dysfunction. What drug
was most likely being prescribed?

1.  Amitriptyline
2. Venlafaxine
3. Bupropion
4. Phenelzine
Self Assessment Questions
Question 4

A 24-year-old man is recently diagnosed with major depressive

disorder. Michael's medical history indicates that he suffered
from several years of absence seizures when he was younger.
Which of the following would have the highest risk for
producing a potentially serious "side effect" if used to treat
Michael's depression?

1.  Amitriptyline
2. Venlafaxine
3. Bupropion
4. Phenelzine
Clinical Case
• Susan, a 27-year-old student in her 3rd year of graduate school presents to Dr John, her
primary care physician, with a 7 kg weight loss over the last 3 months. Susan tearfully explains
that she has been suffering from feelings of extreme sadness, and has not had a good night of
sleep in several weeks. She feels constantly “down in the dumps” and “doesn't care anymore”
about her favorite hobbies. She has also become worried about occasional thoughts of suicide.
She tells her physician that she had felt like this about a year ago, but that it had only lasted a
few weeks. Her physician asks her about her sleep patterns, appetite, energy level, ability to
concentrate, mood, her general state of health. Susan denies any significant level of substance
abuse (beyond an occasional glass of wine). He asks her specific questions about thoughts of
suicide, particularly whether she has ever attempted suicide. Her physician explains to Susan
that she has major depressive disorder, likely caused by a stress-induced chemical imbalance in
her brain, and he prescribes the 2nd generation antidepressant, fluoxetine
• Two weeks later, Susan calls Dr John to complain that her medication isn't working, and that
she is still feeling depressed. He explains that this is normal, and that the medication takes 3-8
weeks to achieve its therapeutic effect. After two additional weeks (6 weeks since beginning
therapy), Susan begins to notice that she is feeling more normal, and is sleeping and eating
more normally.
Clinical Case: questions

• What is the mechanism of action of fluoxetine?

• Why did the physician prescribe a 2nd generation antidepressant
instead of a 1st generation drug?
• What common side effects should Dr. John warn Susan about?
• Should Dr. John warn her about the Black Box warning for
antidepressants?
• Why did it take more than a month for Susan's medication to
produce a therapeutic effect?
References
Prescribed textbook
Brunton, L. Chabner, B. Knollman, B. Goodman & Gilman’s Pharmacological Basis of Therapeutics.
12th Edition. United States: The McGraw-Hill Companies, Inc.

Recommended textbook
Katzung BG. eds. Basic & Clinical Pharmacology, 14e New York, NY: McGraw-Hill; .
Rang, HP, Dale, MM, Ritter, JM, Flower, RJ, Henderson, G (2012). Rang and Dale's Pharmacology.
7th ed. London: Elsevier Churchill Livingstone

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YouTube
Pharmacology - ANTIDEPRESSANTS - SSRIs, SNRIs, TCAs, MAOIs, Lithium ( MADE EASY)
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