Describe The Mechanism/s of Action, Types, Doses, Side Effects, Indications and Contraindications of Antidepressant Drugs

Describe the mechanism/s of action, types, doses,
side effects, indications and contraindications of

antidepressant drugs
K;KH;Y;Lecture;written/viva
Dr. Sunil Kumar Pandey

Professor
Pharmacology, GVPIHC&MT
Objectives
• By the end of this chapter you should know:
• Depression
• Classes of antidepressants
• Pathophysiological reasons
• MoA, indication, CIs, interactions of drugs
Antidepressants. Dr. Sunil Kumar

07/30/2021 Pandey.Professor, Pharmacology 2
GVPIHC&MT
Depression, Symptoms and types
• Affective disorder- disorder of mood not
thought
• classified as major depression (i.e., unipolar
depression), persistent depressive disorder
(dysthymia), or bipolar I and II disorders (i.e.,
manic-depressive illness)
• Females are affected with major depression
twice as frequently as males
GVPIHC&MT
• sad mood, pessimistic worry, diminished interest in
normal activities, mental slowing and poor
concentration,
• Insomnia or increased sleep, significant weight loss
or gain due to altered eating and activity patterns,
psychomotor agitation or retardation, feelings of
guilt and worthlessness, decreased energy and
libido, and suicidal ideation.
• these symptoms occur most days for a period of at
least 2 weeks.
GVPIHC&MT
Theories- for primary or endogenous
depression
• Mono amine theory- Functional deficit of NE and /or
5-HT or of DA at certain sites in brain.
• Blocking of reuptake process in instant then why lag
phase?
• Upcoming theories- down regulation of adrenergic
receptors and 5-HT2
• In depression- significant drop in Brain derived
neurotrophic factor (BDNF- nerve growth factor)-
Antidepressants improves this and affect take 2-3
weeks.
GVPIHC&MT
Cause and complications
• Secondary to other illnesses, such as
hypothyroidism, Parkinson disease, and
inflammatory conditions. Further, depression
often complicates the management of other
medical conditions (e.g., severe trauma,
cancer, diabetes, and cardiovascular disease,
especially myocardial infarction)
• 10%–15% of those with severe depression
attempt suicide at some time
GVPIHC&MT
Classification
NE and 5-HT reuptake blockers- TCAs – Imipramine,Amitriptyline, doxepin
Selective SNRIs- Duloxetine, Venlafaxine, Milnacipran (No antihistaminic,

alpha blocking or anticholinergic activity)
NE Reuptake blocker – Desipramine, Nortriptyline, Protrptyline, Amoxapine
SSRIs- Sertraline fluoxetine, fluvoxamine, Citalopram, Escitalopram
Atypical Antidepressants – Trazodone, Mianserin, Bupropion, Mirtazapine
MAO Inhibitors- Non selective- Tranylcypromine

Selective MAO- A- Moclobemide
GVPIHC&MT
GVPIHC&MT
Clinical Considerations
• Treatment - “therapeutic lag” (3–4 weeks) effect
• sleep disturbances improving sooner and mood
and cognitive deficits later.
• 6- to 12-month maintenance treatment phase is
typical  gradually withdrawn.
• chronically depressed (i.e., has been depressed
for more than 2 years)- lifelong treatment

GVPIHC&MT
Selective Serotonin Reuptake Inhibitors
• SSRIs block reuptake. Relatively selective for

inhibition of SERT over NET.
• Repeated treatment with SSRIs reduces the
expression of SERT, resulting in reduced
clearance of released 5HT and increased
serotonergic neurotransmission
• Escitalopram is 100 time more potent than
citalopram
GVPIHC&MT
• the initial inhibition of SERT induces activation
of 5HT1A and 5HT1D autoreceptors, resulting
in a decrease in serotonergic
neurotransmission by a negative-feedback
mechanism until these serotonergic
autoreceptors are desensitized. Then, the
enhanced 5HT concentration in the synapse
can interact with postsynaptic 5HT receptors

GVPIHC&MT
Serotonin-Norepinephrine Reuptake
Inhibitors
• The SNRIs inhibit both SERT and NET
• the initial inhibition of SERT induces activation
of 5HT1A and 5HT1D autoreceptors, resulting
in a decrease in serotonergic
neurotransmission by a negative-feedback
mechanism until these serotonergic
autoreceptors are desensitized. Then, the
enhanced 5HT concentration in the synapse
can interact with postsynaptic 5HT receptors.
GVPIHC&MT
• Repeated treatment with SNRIs reduces the
expression of SERT or NET, resulting in reduced
neurotransmitter clearance and increased
serotonergic or noradrenergic neurotransmission
• Off-label uses include stress urinary incontinence
(duloxetine), autism, binge-eating disorders, hot
flashes, pain syndromes, premenstrual dysphoric
disorders, and Posttraumatic stress disorder
PTSD (venlafaxine).
GVPIHC&MT
Serotonin Receptor Antagonists/ Atypical
Antidepressants
• Trazodone, Mianserin
• Both mianserin and mirtazapine are quite
sedating and are treatments of choice for some
depressed patients with insomnia.
• Trazodone blocks 5HT2 and α1 adrenergic
receptors. also inhibits SERT
• mirtazapine and mianserin potently block
histamine H1 receptors, 5HT2A, 5HT2C, 5HT3, α2

GVPIHC&MT
Bupropion
• enhances both noradrenergic and dopaminergic
neurotransmission via inhibition of reuptake by
NET and DAT
• Bupropion’s mechanism of action also may involve
the presynaptic release of NE and DA and effects
on VMAT2
• The hydroxybupropion metabolite may contribute
to the therapeutic effects of the parent compound
• widely used in combination with SSRIs
GVPIHC&MT
Tricyclic Antidepressants
• antagonism of SERT and NET
• block other receptors (H1 histamine, 5HT2 , α1
adrenergic, and muscarinic cholinergic receptors)
• TCAs, poses some risk for the development of
extrapyramidal side effects such as tardive
dyskinesia.
• because of the roles of NE and 5HT in
nociception, these drugs are commonly used to
treat a variety of pain conditions
GVPIHC&MT
Monoamine Oxidase Inhibitors
• MAO are mitochondrial enzyme
• MAO activities in the GI tract and liver, mainly MAOA,
protect the body from biogenic amines in the diet.
• In pre-synaptic nerve terminals, MAO metabolizes
monoamine neurotransmitters via oxidative
deamination
• MAOA preferentially metabolizes 5HT and NE and can
metabolize DA; MAOB is effective against 5HT and DA

GVPIHC&MT
• MAOIs not preferred because of their toxicity and
interactions with some drugs (e.g., sympathomimetics and
some opioids) and foods.
• This potential to exacerbate the effects of indirectly acting
sympathomimetic amines seems to relate mainly to
inhibition of MAOA.
• Selegiline is an irreversible MAO inhibitor but with
specificity for MAOB at low doses, thereby sparing MAOA
activity in the GI tract and elsewhere, and is less likely to
cause this interaction (although at higher doses, selegiline
will also inhibit MAOA).
GVPIHC&MT
GVPIHC&MT
Pharmacokinetics- antidepressants
• mediated by hepatic CYPs
• SSRIs - orally active, fluoxetine, the combined
action of the parent and the demethylated
metabolite norfluoxetine allows for a once-
weekly formulation, CYP2D6 – for metabolism
• SNRIs- Duloxetine has a t 1/2 of 12 h,
Desmethylvenlafaxine is eliminated by hepatic
metabolism and by renal excretion,
GVPIHC&MT
Continued….
• Serotonin Receptor Antagonists - Mirtazapine
has an elimination t 1/2 of 16–30 h,
• Bupropion- elimination has a t 1/2 of 21 h and
involves both hepatic and renal routes.
• Tricyclic Antidepressants - TCAs, or their active
metabolites, have plasma half-lives of 8–80 h,
eliminated by hepatic CYPs.

GVPIHC&MT
Continued….
• Monoamine Oxidase Inhibitors- metabolized by
acetylation. A significant population are “slow
acetylators-exhibit elevated plasma levels.
• The nonselective MAOIs used in the treatment
of depression are irreversible inhibitors; thus, it
takes up to 2 weeks for MAO activity to recover.
• Recovery of normal enzyme function is
dependent on synthesis and transport of new
MAO to monoaminergic nerve terminals.
GVPIHC&MT
Adverse Effects
Selective Serotonin Reuptake Inhibitors and SNRIs- no
major cardiovascular side effects. do not block α
adrenergic receptors; do not block histamine receptors.
• excessive stimulation of brain 5HT2 receptors-
insomnia, increased anxiety, irritability, and decreased
libido,
• Excess activity at spinal 5HT2 - erectile dysfunction,
anorgasmia, and ejaculatory delay
• 5HT3 receptors- nausea but may include diarrhea and
emesis
GVPIHC&MT
• withdrawal may include dizziness, headache,
nervousness, nausea, and insomnia
• paroxetine is associated with an increased risk
of congenital cardiac malformations first
trimester of pregnancy .
• Venlafaxine also is associated with an
increased risk of perinatal complications

GVPIHC&MT
A/Es- Serotonin Receptor Antagonists
• Mirtazapine- somnolence, increased appetite,
and weight gain.
• Agranulocytosis- rare
• Bupropion- anxiety, mild tachycardia and
hypertension, irritability, and tremor. Other side
effects include headache, nausea, dry mouth,
constipation, appetite suppression, insomnia,
and, rarely, aggression, impulsivity, and
agitation.
GVPIHC&MT
A/Es- Tricyclic Antidepressants
• Muscarinc antagonist- (blurred vision, dry
mouth, tachycardia, constipation, difficulty
urinating)
• α1 adrenergic receptors contributes to
orthostatic hypotension and sedation
• lower the seizure threshold
• Slowed cardiac conduction

GVPIHC&MT
Monoamine Oxidase Inhibitors
• Hypertensive crisis – food interaction
• life-threatening issue with chronic
administration of MAOIs is hepatotoxicity.

GVPIHC&MT
Drug Interactions
Group A Group B Remark
MAOIs Other antidepressants Serotonin syndrome
SSRIs Drugs metabolized by increases in plasma
CYP2D6 concentrations of group B
Serotonin Receptor CYP3A4 inhibitors increases in plasma
antagonist concentrations of group A
TCA Inhibitors of CYP2D6 – increases in plasma
bupropion, SSRIs concentrations of group A

GVPIHC&MT
Clinical Considerations With Anxiolytic Drugs
• Among the commonly used anxiolytics, only

the benzodiazepines and β adrenergic
antagonists are effective acutely.
• the use of β adrenergic antagonists is generally
limited to treatment of situational anxiety.
• Chronic treatment with SSRIs, SNRIs, and
buspirone is required to produce and sustain
anxiolytic effects.

GVPIHC&MT
Thank You

GVPIHC&MT
Clinical cases and MCQs
• A 36-year-old woman presents with symptoms of major depression
that are unrelated to a general medical condition, bereavement, or
substance abuse. She is not currently taking any prescription or
over-the-counter medications. Drug treatment is to be initiated
with sertraline. In your information to the patient, you would tell
her that
• (A) Sertraline may take 2 wk or more to become effective
• (B) It is preferable that she take the drug in the morning
• (C) Muscle cramps and twitches can occur
• (D) She should notify you if she anticipates using other prescription
drugs
• (E) All of the above
GVPIHC&MT
Answer 1
• All the statements are appropriate regarding
the initiation of treatment with sertraline or
other SSRI in a depressed patient. The SSRIs
have CNS-stimulating effects and may cause
agitation, anxiety, “the jitters,” and insomnia,
especially early in treatment. Consequently,
the evening is not the best time to take SSRI
drugs. The answer is E.

GVPIHC&MT
2
• A 34-year-old male patient who was prescribed citalopram for
depression has decided he wants to stop taking the drug. When
questioned, he said that it was affecting his sexual performance.
You ascertain that he is also trying to overcome his dependency
on tobacco products. If you decide to reinstitute drug therapy in
this patient, the best choice would be
• (A) Amitriptyline
• (B) Bupropion
• (C) Fluoxetine
• (D) Imipramine
• (E) Venlafaxine

GVPIHC&MT
Answer2
• The SSRIs (eg, fluoxetine) and venlafaxine (an
SNRI) can cause sexual dysfunction with
decreased libido, erectile dysfunction, and
anorgasmia. TCAs may also decrease libido or
prevent ejaculation. Bupropion is the least likely
antidepressant to affect sexual performance.
The drug is also purportedly useful in
withdrawal from nicotine dependence, which
could be helpful in this patient. The answer is B.
GVPIHC&MT
3
Regarding the clinical use of antidepressant drugs, which statement is
accurate?
• (A) Chronic use of serotonin-norepinephrine reuptake inhibitors
(SNRIs) increases the activity of hepatic drug-metabolizing enzymes
• (B) In the treatment of major depressive disorders, citalopram is
usually more effective than paroxetine
• (C) Tricyclics are highly effective in depressions with attendant
anxiety, phobic features, and hypochondriasis
• (D) Weight gain often occurs during the first few months in patients
taking SSRIs
• (E) When selecting an appropriate drug for treatment of depression,
the history of patient response to specific drugs is a valuable guide
GVPIHC&MT
Answer 3
• No antidepressant has been shown to increase
hepatic drug metabolism. MAO inhibitors (not TCAs),
though now used infrequently, are the drugs most
likely to be effective in depression with attendant
anxiety, phobic features, and hypochondriasis. SSRIs
are usually associated with weight loss, at least during
the first 6 months of treatment. There is no evidence
that any SSRI is more effective than another, or more
effective overall than a tricyclic drug, in treatment of
major depressive disorder. The answer is E.
GVPIHC&MT
4
• A patient under treatment for a major depressive disorder
is brought to the emergency department after ingesting
30 times the normal daily therapeutic dose of imipramine.
Which of the following would be least useful?
• (A) Administer bicarbonate and potassium chloride (to
correct acidosis and hypokalemia)
• (B) Administer lidocaine (to control cardiac arrhythmias)
• (C) Initiate hemodialysis (to hasten drug elimination)
• (D) Maintain heart rhythm by electrical pacing
• (E) Use intravenous diazepam to control seizures
GVPIHC&MT
Answer 4
• Overdose with imipramine or any other tricyclic
antidepressant drug is a medical emergency. The “3
Cs”—coma, convulsions, and cardiac problems—are
the most common causes of death. Widening of the
QRS complex on the ECG is a major diagnostic feature
of cardiac toxicity. Arrhythmias resulting from cardiac
toxicity require the use of drugs with the least effect
on cardiac conductivity (eg, lidocaine). Hemodialysis
does not increase the rate of elimination of tricyclic
antidepressants in overdose. The answer is C
GVPIHC&MT
5
• Which drug is an antagonist at 5-HT2
receptors and widely used for the
management of insomnia?
• (A) Estazolam
• (B) Flurazepam
• (C) Trazodone
• (D) Triazolam
• (E) Zolpidem
GVPIHC&MT
Answer 5
• All of the drugs listed are effective hypnotic
drugs, but only trazodone is an antagonist at
5-HT2 receptors. Trazodone has wide use as a
sleeping aid, especially in patients with
symptoms of affective disorder. The answer is
C

GVPIHC&MT
7
A recently widowed 76-year-old female patient was treated with a
benzodiazepine for several weeks after the death of her husband, but
she did not like the daytime sedation it caused even at low dosage. Living
independently, she has no major medical problems but appears rather
infirm for her age and has poor eyesight. Because her depressive
symptoms are not abating, you decide on a trial of an antidepressant
medication. Which of the following drugs would be the most appropriate
choice for this patient?
• (B) Citalopram
• (C) Mirtazapine
• (D) Phenelzine
• (E) Trazodone
GVPIHC&MT
• Older patients are more likely to be sensitive
to antidepressant drugs that cause sedation,
atropine-like adverse effects, or postural
hypotension. Tricyclics and MAO inhibitors
cause many autonomic side effects;
mirtazapine and trazodone are highly
sedating. Citalopram (or another SSRI) is often
the best choice in such patients. The answer is
B.
GVPIHC&MT
8
SSRIs are much less effective than tricyclic
antidepressants in the management of
• (A) Bulimia
• (B) Chronic pain of neuropathic origin
• (C) Generalized anxiety disorder
• (D) Obsessive-compulsive disorder
• (E) Premenstrual dysphoric disorder

GVPIHC&MT
Answer 8
• The SSRIs are not effective in chronic pain of
neuropathic origin. All the other uses of SSRIs
are approved indications with clinical
effectiveness equivalent or superior to that of
tricyclic drugs. In addition to treatment of
chronic pain states and depression the
tricyclics are also used to treat enuresis and
attention deficit hyperkinetic disorder. The
answer is B.
GVPIHC&MT
9
Which of the following drugs is most likely to be
of value in obsessive-compulsive disorders?
(A) Amitriptyline
• (B) Bupropion
• (C) Clomipramine
• (D) Trazodone
• (E) Venlafaxine

GVPIHC&MT
Answer 9
• Clomipramine, a tricyclic agent, is a more
selective inhibitor of 5-HT reuptake than other
drugs in its class. This activity appears to be
important in the treatment of obsessive-
compulsive disorder. However, the SSRIs have
now become the drugs of choice for this
disorder because they are safer in overdose
than tricyclics. The answer is C

GVPIHC&MT
10
• To be effective in breast cancer, tamoxifen must be
converted to an active form by CYP2D6. Cases of
inadequate treatment of breast cancer have occurred
when tamoxifen was administered to patients who were
being treated with
• (B) Bupropion
• (C) Fluoxetine
• (D) Mirtazapine
• (E) Phenelzine
GVPIHC&MT
Answer 10
• Fluoxetine is an inhibitor of hepatic
cytochrome P450s especially CYP2D6, and to a
lesser extent CYP3A4. Dosages of several
drugs may need to be reduced if given
concomitantly with fluoxetine. In the case of
tamoxifen, however, its antineoplastic action
is dependent on its conversion to an active
metabolite by CYP2D6. The answer is C.

GVPIHC&MT
Case based question
• A 30-year-old woman presents to your office for the evaluation of fatigue.
For the past 2 months she has felt run down. She says that she doesn’t feel
like participating in activities that she previously enjoyed, such as her weekly
softball games. She has not been sleeping well and has not had much of an
appetite. On questioning, she admits to feeling “down in the dumps” most
of the time and has found herself crying frequently. She has never gone
through anything like this before. She denies any thoughts of wanting to
hurt herself or anyone else. Other than becoming tearful during her
interview, her physical examination is normal. Her blood tests, including a
complete blood count and thyroid function, are normal. A serum pregnancy
test is negative. You diagnose her as having a major depression and, along
with referring her for counseling, start her on fluoxetine.
• ◆ What is the mechanism of action of fluoxetine?
• ◆ What are the common side effects of fluoxetine?
GVPIHC&MT
Answer
• Summary: A 30-year-old woman with major
depression is prescribed fluoxetine.
• ◆ Mechanism of action of fluoxetine: Inhibition
of the reuptake of serotonin (5-
hydroxytryptamine, or 5-HT) at the
prejunctional nerve terminal.
• ◆ Common side effects: Headache, nausea,
agitation, insomnia, and sexual disturbances
(loss of libido and erectile dysfunction).
GVPIHC&MT
Question 1
• Which of the following agents is
contraindicated in a patient with epilepsy?
• A. Bupropion
• B. Fluoxetine
• C. Mirtazapine
• D. Venlafaxine

GVPIHC&MT
Answer
• A. Bupropion causes seizures in a small but
significant number of patients. This number is
reduced with use of the slow-release form.

GVPIHC&MT
The antidepressant action of imipramine is
thought to be caused by which of the following?
• A. Blockade of prejunctional α2 -adrenoceptors
• B. Blockade of prejunctional neuronal
norepinephrine and serotonin uptake
transporters in the CNS
• C. Increased numbers of β-adrenoceptors
• D. Inhibition of monoamine oxidase

GVPIHC&MT
Answer
• B. Imipramine and other TCAs block
prejunctional neuronal norepinephrine and or
serotonin uptake transporters in the CNS.
Phenelzine and tranylcypromine inhibit
monoamine oxidase. The heterocyclic agent
mirtazapine blocks prejunctional α2
-adrenoceptors to enhance serotonin and
norepinephrine neurotransmission

GVPIHC&MT
Question
• Which of the following antidepressant agents
inhibits hepatic microsomal enzymes to cause
clinically significant drug-drug interactions?
• A. Fluoxetine
• B. Imipramine
• C. Phenelzine
• D. Trazodone

GVPIHC&MT
Answer
• A. The SSRI fluoxetine inhibits cytochrome
P450 and therefore can significantly elevate
the level of other drugs metabolized by these
hepatic enzymes.

GVPIHC&MT
Thank You

GVPIHC&MT

Describe The Mechanism/s of Action, Types, Doses, Side Effects, Indications and Contraindications of Antidepressant Drugs

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Describe The Mechanism/s of Action, Types, Doses, Side Effects, Indications and Contraindications of Antidepressant Drugs

Uploaded by

Copyright:

Available Formats

Describe the mechanism/s of action, types, doses,

side effects, indications and contraindications of

Dr. Sunil Kumar Pandey

Antidepressants. Dr. Sunil Kumar

Selective SNRIs- Duloxetine, Venlafaxine, Milnacipran (No antihistaminic,

NE Reuptake blocker – Desipramine, Nortriptyline, Protrptyline, Amoxapine

SSRIs- Sertraline fluoxetine, fluvoxamine, Citalopram, Escitalopram

Atypical Antidepressants – Trazodone, Mianserin, Bupropion, Mirtazapine

MAO Inhibitors- Non selective- Tranylcypromine

Antidepressants. Dr. Sunil Kumar

• SSRIs block reuptake. Relatively selective for

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

• Among the commonly used anxiolytics, only

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

Antidepressants. Dr. Sunil Kumar

You might also like