NAME: Anoosha Farooqui

CLASS: 3rd year (5th Semester)

DEPARTMENT: Pharmacy
ROLL NO.: 501-S19-001
SUBJECT: Pharmacology and Therapeutics II-A
COURSE CODE: PHARM 512
Cr. Hr.: 3+1
SUBMITTED TO: Miss Halima
DATE OF SUBMISSION: 28th May 2021
TOPIC: Antidepressants
Contents:
 Introduction
 Definition of Depression
 Pathophysiology
 Symptoms
 Antidepressants
 Definition
 Working
 Uses
 Classification of Antidepressants
 Selective Serotonin Reuptake Inhibitors (SSRIs)
o Mechanism of action
o Indication
o Pharmacology
o Pharmacokinetics
o Contraindication
o Side effect
o Doses
 Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)
o Mechanism of action
o Indication
o Pharmacology
o Pharmacokinetics
o Contraindication
o Side effect
o Doses
 Tricyclic Antidepressants (TCAs)
o Mechanism of action
o Indication
o Pharmacology
o Pharmacokinetics
o Contraindication
o Side effect
o Doses
 Monoamine Oxidase Inhibitors (MAOIs)
o Mechanism of action
o Indication
o Pharmacology
o Pharmacokinetics
o Contraindication
o Side effect
o Doses
 Atypical Antidepressants
o Mechanism of action
o Indication
o Pharmacology
o Pharmacokinetics
o Contraindication
o Side effect
o Dose
ABSTRACT:
Depression being a state of sadness may be defined as a
psychoneurotic disorder characterized by mental and functional
activity, sadness, reduction in activity, difficulty in thinking, loss of
concentration, perturbations in appetite, sleeping, and feelings of
dejection, hopelessness and generation of suicidal tendencies. It is a
common and recurrent disorder causing significant morbidity and
mortality worldwide. The antidepressant compounds used against
depression are reported to be used also for treating pain, anxiety
syndromes etc. They have been grouped in five different categories
such as i. Tricyclic antidepressants (TCAs) ii. Selective serotonin-
reuptake inhibitors (SSRIs) iii. Monoamine oxidase inhibitors (MAOIs) iv.
Serotonin-norepinephrine reuptake inhibitor (SNRI) and v. Atypical
antidepressants based on their mode of action. The symptoms of
depression are intense feelings of sadness, hopelessness, and despair
as well as the inability to experience pleasure in usual activities,
changes in sleep patterns and appetite, loss of energy, and suicidal
thoughts. Mania is characterized by the opposite behavior: enthusiasm,
rapid thought and speech patterns, extreme self-confidence, and
impaired judgment. The main objective is to study about MOA,
indications, pharmacology, pharmacokinetics, contraindications, side
effects and dose of different classes of antidepressants.
INTRODUCTION:
DEFINITION OF DEPRESSION:
Depression (major depressive disorder or clinical depression) is a common but serious mood affective
disorder. It causes severe symptoms that affect how you feel, think, and handle daily activities, such as
sleeping, eating, or working. To be diagnosed with depression, the symptoms must be present for at
least two weeks.

Pathophysiology:
Neurotransmitter Imbalances & Dysregulation → creates a state of deficiency in monoamines → creates
a state of deficiency in NTs (serotonin (5 -HT), Dopamine, NE) Changes in mood are associated with
depression and/or mania. Disorders of mood rather than disturbance in thought or cognition.

Symptoms of depression
With major depressive episodes, the person experiences five or more of the following symptoms for at
least two weeks, with at least one of them being either low or a loss of pleasure or interest:

1.Depressed mood
2.Markedly diminished pleasure or interest in nearly all activities
3.Significant weight loss or gain or significant loss or increase in appetite
4.Slowdown in movements
5.Agitation
6.Loss of energy or fatigue
7.Decreased ability to concentrate or marked indecisiveness
8.The symptoms cause significant impairment and distress
9.Preoccupation with death or suicide; person plans or attempts suicide.

ANTIDEPRESSANTS
Definition:
Antidepressants were first developed in the 1950s and have been used regularly since then.
Antidepressants are those drugs which help in the reduction in symptoms of depressive disorders by
altering chemical imbalances of neurotransmitters in the brain. The change in mood and behavior is due
to chemical imbalance. Neurotransmitters are the communication link between neurons in the brain.
Neurotransmitters are located in vesicles found in nerve cells. The neurotransmitters such as serotonin,
dopamine and noradrenaline or norepinephrine are released by the exonic end of one nerve and
received by the other; the phenomenon called as reuptake. The antidepressants inhibit reuptake of
neurotransmitters through selective receptors thereby increasing the concentration of specific
neurotransmitter around the nerves in the brain

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Working:
Work by increasing the activity of certain chemicals work in our brains called neurotransmitters. They
pass signals from one brain cell to another. The chemicals most involved in depression are thought to be
serotonin and (noradrenaline).

Uses:
 Moderate to severe depressive illness (Not mild depression)
 Severe anxiety and panic attacks
 Obsessive compulsive disorders
 Chronic pain
 Eating disorders
 Post-traumatic stress disorder.

CLASSIFICATION:
There are a number of different types of antidepressants. Some of the most widely used types are
discussed below.
1. Selective Serotonin Reuptake Inhibitors (SSRIs)
2. Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)
3. Tricyclic Antidepressants (TCAs)
4. Monoamine Oxidase Inhibitors (MAOIs)
5. Atypical Antidepressants

A. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs):

The most widely utilized class of antidepressants in clinical practice. This group acts by increasing the
level of serotonin (5 -HT) in the synaptic gap by inhibiting its re-uptake within the brain. → Block 5 HT
transport → ↑ 5 -HT levels in synapse. They are called as selective because they affect only the reuptake
pumps responsible for Serotonin only.

Examples: Fluoxetine, Paroxetine, Fluvoxamine, Sertraline, Citalopram, Escitalopram

Mechanism of Action:
The SSRIs block the reuptake of serotonin, leading to increased
concentrations of the neurotransmitter in the synaptic cleft and,
ultimately, to greater postsynaptic neuronal activity.
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. However, none of the
antidepressants are uniformly effective. Approximately 40 percent of
depressed patients treated with adequate doses for 4 to 8 weeks do
not respond to the antidepressant agent. Patients who do not
respond to one antidepressant may respond to another, and
approximately 80 percent or more will respond to at least one

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antidepressant drug. [Note: These drugs do not usually produce central nervous system (CNS)
stimulation or mood elevation in normal individuals.]

INDICATION:
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, and bulimia nervosa (only fluoxetine is approved for this last
indication).

PHARMACOLOGY:
SSRIs treat depression by increasing levels of serotonin in the brain. Serotonin is one of the chemical
messengers (neurotransmitters) that carry signals between brain nerve cells (neurons). SSRIs block the
reabsorption (reuptake) of serotonin into neurons.

PHARMACOKINETICS:
All SSRI are well absorbed after oral administration. • Food has little effect on absorption (except
sertraline, for which food will increase its absorption). • Majority of SSRIs have plasma half –lives that
range of 16-36 h. • Metabolism by cytochrome P450 (CYP450)-dependent enzymes and glucuronide or
sulfate conjugation occur extensively. • SSRIs may affect the metabolism of multiple medications and its
excretion of the SSRIs is primarily through the kidneys, except for paroxetine and sertraline, which also
undergo fecal excretion (35 and 50 percent, respectively). • Dosages of all of these drugs should be
adjusted downward in patients with hepatic impairment.

• Fluoxetine differs from the other members of the class in two respects. First, it has a longer half-life
(50 hours) and is available as a sustained-release preparation allowing once-weekly dosing. • Second,
the metabolite of the S-enantiomer, S-norfluoxetine, is as potent as the parent compound. The half-life
of the metabolite is quite long, averaging 10 days. • Fluoxetine and paroxetine are potent inhibitors of a
hepatic CYP450 isoenzyme (CYP2D6) responsible for the elimination of TCAs, neuroleptic drugs, and
some antiarrhythmic and β- adrenergic antagonist drugs. Other cytochrome enzymes (CYP2C9/19,
CYP3A4, CYP1A2) are involved with SSRI metabolism and may also be inhibited to various degrees by the
SSRIs.

CONTAINDICATIONS:
SSRIs are contraindicated in patients having:
 Bipolar disorder and you're in a manic phase (a period of extremely excitable mood), although
they can be useful for depressive phases
 A bleeding disorder, such as hemophilia
 Type 1 diabetes or type 2 diabetes
 Epilepsy – SSRIs should only be taken if your epilepsy is well controlled, and they should be
stopped if your epilepsy gets worse
 Narrow angle glaucoma
 Serious kidney, liver or heart problems

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SSRIs may need to be used with caution or not at all if you have one of these conditions, because the
medication could increase your chance of experiencing serious side effects.

SIDE EFFECTS:
Although the SSRIs are considered to have fewer and less severe adverse effects than the TCAs and
MAOIs, the SSRIs are not without troublesome 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), and the above-
mentioned potential for drug-drug interactions.

1. Sleep disturbances: Paroxetine and fluvoxamine are generally more sedating than activating,
and they may be useful in patients who have difficulty sleeping. Conversely, patients who are
fatigued or complaining of excessive somnolence may benefit from one of the more activating
antidepressants, such as fluoxetine or sertraline.

2. Sexual dysfunction: Loss of libido, delayed ejaculation, and anorgasmia are underreported side
effects often noted by clinicians, but these are not prominently featured in the list of standard
side effects. One option for managing SSRI-induced sexual dysfunction is to replace the
offending antidepressant with an antidepressant having fewer sexual side effects, such as
bupropion or mirtazapine. Alternatively, the dose of the drug may be reduced. In men with
erectile dysfunction and depression, treatment with sildenafil, vardenafil, or tadalafil (see p.
363) may improve sexual function.

3. Use in children and teenagers: Antidepressants should be used cautiously in children and
teenagers, because about 1 out of 50 children report suicidal ideation as a result of SSRI
treatment. Pediatric patients should be observed for worsening depression and suicidal thinking
whenever any antidepressant is started or its dose is increased or decreased. Fluoxetine,
sertraline, and fluvoxamine are U.S. Food and Drug Administration (FDA)-approved for use in
children to treat obsessive-compulsive disorder, and fluoxetine is approved to treat childhood
depression.

4. Overdoses: Large intakes of SSRIs do not usually cause cardiac arrhythmias (compared to the
arrhythmia risk for the TCAs), but seizures are a possibility because all antidepressants may
lower the seizure threshold. All SSRIs have the potential to cause a serotonin syndrome that
may include the symptoms of hyperthermia, muscle rigidity, sweating, myoclonus (clonic muscle
twitching), and changes in mental status and vital signs when used in the presence of a MAOI or
other highly serotonergic drug. Therefore, extended periods of washout for each drug class
should occur prior to the administration of the other class of drugs.

5. Discontinuation syndrome: Whereas all of the SSRIs have the potential for causing a
discontinuation syndrome after their abrupt withdrawal, the agents with the shorter half-lives
and having inactive metabolites have a higher risk for such an adverse reaction. Fluoxetine has
the lowest risk of causing an SSRI discontinuation syndrome. Possible signs and symptoms of
such a serotonin-related discontinuation syndrome include headache, malaise and flu-like
symptoms, agitation and irritability, nervousness, and changes in sleep pattern.

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DOSE:
Drug:
Citalopram tablets come in different strengths ranging from 10mg to 40mg.
The usual dose of citalopram is 20mg/day in adults. But it may be started at a lower dose and increased
to a maximum dose of 40mg/day.
If you're over 65, or have liver problems, the maximum recommended dose is 20mg/day.
The usual dose of citalopram in children is 10mg/day, but this may be increased to 40mg/day.
With liquid drops of citalopram, 4 drops are equivalent to a 10mg tablet.

B. SEROTONIN AND NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

Venlafaxine, desvenlafaxine, and duloxetine inhibit the reuptake of both serotonin and norepinephrine.
These agents, termed selective serotonin/norepinephrine reuptake inhibitors (SNRIs), may be 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 CNS. SNRIs with their dual actions of inhibiting both serotonin and norepinephrine reuptake, are
sometimes effective in relieving physical symptoms of neuropathic pain such as diabetic peripheral
neuropathy. However, the SNRIs, unlike the TCAs, have little activity at adrenergic, muscarinic, or
histamine receptors and, thus, have fewer of these receptor-mediated adverse effects than the TCAs.
They may precipitate a discontinuation syndrome if treatment is abruptly stopped.

Examples: Venlafaxine, desvenlafaxine, and duloxetine

MECHANISM OF ACTION:
SNRIs work by increasing the levels of serotonin and
norepinephrine that are active in the brain. Serotonin and
norepinephrine are produced by nerves and released into the
surrounding tissues where they can attach to nearby receptors
on other nerves, thereby stimulating the other nerves. The
released serotonin and norepinephrine then are taken up and
released again by the nerves that produce them. SNRIs block the
uptake ("reuptake") of the serotonin and norepinephrine so that
more of the serotonin and norepinephrine are free in the tissues
surrounding the nerves.

INDICATION:
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 and
premenstrual dysphoric disorder. • Fluoxetine is approved for Bulimia nervosa. • Fluoxetine, sertraline,
and fluvoxamine are approved for use in children to treat obsessive-compulsive disorder, and fluoxetine
is approved to treat childhood depression by US-FDA.

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PHARMACOLOGY:
These are monoamine reuptake inhibitors. The class of serotonin and norepinephrine reuptake
inhibitors (SNRIs) now comprises three medications: venlafaxine, milnacipran, and duloxetine. These
drugs block the reuptake of both serotonin (5-HT) and norepinephrine with differing selectivity.
Tolerability of an SNRI at therapeutic doses varies within the class.

PHARMACOKINETICS:
Venlafaxine is extensively metabolized in the liver via the CYP2D6 isoenzyme to O-desmethylvenlafaxine.
Both have similar half-lives of about 8–11 hours. Despite the relatively short half-lives, both drugs are
available in formulations that allow once-daily dosing. Venlafaxine and desvenlafaxine have the lowest
protein binding of all antidepressants (27–30%). Unlike most antidepressants, desvenlafaxine is
conjugated and does not undergo extensive oxidative metabolism. At least 45% of desvenlafaxine is
excreted unchanged in the urine compared with 4–8% of venlafaxine. Duloxetine is well absorbed and
has a half-life of 12–15 hours but is dosed once daily. It is tightly bound to protein (97%) and undergoes
extensive oxidative metabolism via CYP2D6 and CYP1A2. Hepatic impairment significantly alters
duloxetine levels unlike desvenlafaxine. Both milnacipran and levomilnacipran are well absorbed after
oral dosing. Both have shorter half-lives and lower protein binding than venlafaxine (Table 30–1).
Milnacipran and levomilnacipran are largely excreted unchanged in the urine. Levomilnacipran also
undergoes demethylation via 3A3/4.

CONTAINDICATIONS:
Do not prescribe serotonin noradrenaline reuptake inhibitors (SNRIs) to people with:
 Conditions associated with high risk of cardiac arrhythmia. Uncontrolled hypertension.
 Prescribe SNRIs with caution to people with: A history of bleeding disorders. A history of
epilepsy.

SIDEEFFECTS
SNRIs have many of the serotonergic adverse effects associated with SSRIs. In addition, SNRIs may also
have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such
as insomnia, anxiety, and agitation. The hemodynamic effects of SNRIs tend not to be problematic in
most patients. A dose-related increase in blood pressure has been seen more commonly with the
immediate-release form of venlafaxine than with other SNRIs. Likewise, there are more reports of
cardiac toxicity with venlafaxine overdose than with either the other SNRIs or SSRIs. Duloxetine is rarely
associated with hepatic toxicity in patients with a history of liver damage. All the SNRIs have been
associated with a discontinuation syndrome resembling that seen with SSRI discontinuation.

DOSE:
Drug:
Duloxetine = 20-60mg/day

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C. TRICYCLIC ANTIDEPRESSANTS (TCAs):
The TCAs block norepinephrine and serotonin reuptake into the neuron and, thus, if discovered today,
might have been referred to as SNRIs except for their differences in adverse effects relative to this
newer class of antidepressants. The TCAs include the tertiary amines imipramine (the prototype drug),
amitriptyline, clomipramine, doxepin and trimipramine. The TCAs also include the secondary amines
desipramine and nortriptyline (the respective N-demethylated metabolites of imipramine and
amitriptyline) and protriptyline. Maprotiline and amoxapine are related “tetracyclic” antidepressant
agents and are commonly included in the general class of TCAs. All have similar therapeutic efficacy, and
the specific choice of drug may depend on such issues as patient tolerance to side effects, prior
response, preexisting medical conditions, and duration of action. Patients who do not respond to one
TCA may benefit from a different drug in this group. These drugs are a valuable alternative for patients
who do not respond to SSRIs.

Examples: Amitriptyline (Elavil), clomipramine (Anafranil), doxepin (Sinequan), imipramine (Tofranil)

MECHANISM OF ACTION:
1. Inhibition of neurotransmitter reuptake: TCAs and
amoxapine are potent inhibitors of the neuronal reuptake of
norepinephrine and serotonin into presynaptic nerve
terminals. At therapeutic concentrations, they do not block
dopamine transporters. By blocking the major route of
neurotransmitter removal, the TCAs cause increased
concentrations of monoamines in the synaptic cleft,
ultimately resulting in antidepressant effects. 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 TCAs’ therapeutic
benefit. However, actions at these receptors are likely
responsible for many of the adverse effects of the TCAs.
Amoxapine also blocks 5-HT2 and D2 receptors.

INDICATION
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 age 6
years) by causing contraction of the internal sphincter of the bladder. At present, it is used cautiously
because of the inducement of cardiac arrhythmias and other serious cardiovascular problems. The TCAs,
particularly amitriptyline, have been used to treat migraine headache and chronic pain syndromes (for
example, neuropathic pain) in a number of conditions for which the cause of the pain is unclear. Low
doses of TCAs, especially doxepin, can be used to treat insomnia.

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PHARMACOLOGY:
 Antidepressant activity relates to inhibition of serotonin (SERT) and noradrenaline (NET)
reuptake
 Also potent antagonists of ACh M (acetylcholine muscarinic), histamine (H1) receptors and
alpha-1 receptors (peripheral post-synaptic)
 Increases the amount of serotonin and noradrenaline in certain parts of the brain (cortex and
limbus)
 Also blocks Na and K channels
 Some blockade of 5-HT2 receptor.

PHARMACOKINETICS:
TCAs are well absorbed upon oral administration. Because of their lipophilic nature, they are widely
distributed and readily penetrate into the CNS. This lipid solubility also causes these drugs to have
variable halflives (for example, 4 to 17 hours for imipramine). As a result of their variable first-pass
metabolism in the liver, TCAs have low and inconsistent bioavailability. Therefore, the patient’s
response and plasma levels can be used to adjust dosage. The initial treatment period is typically 4 to 8
weeks. The dosage can be gradually reduced to improve tolerability, unless relapse occurs. These drugs
are metabolized by the hepatic microsomal system (and, thus, may be sensitive to agents that induce or
inhibit the CYP450 isoenzyme) and conjugated with glucuronic acid. Ultimately, the TCAs are excreted as
inactive metabolites via the kidney.

CONTRAINDICATIONS:
These are contraindicated in patients:
 Under age 25 or over age 65
 Having diabetes, heart problems, or a thyroid disorder
 Having any conditions affecting your urinary tract or an enlarged prostate
 Having glaucoma
 Having a liver disease
 Having a history of seizures.

SIDE EFFECTS:
 Anticholinergic effects
 Postural hypotension due to alpha-blocking effect
 Weight gain and sedation due to H1 antagonism
 Arrhythmogenic at higher doses
 Sexual effects
 Discontinuation syndrome characterized by cholinergic rebound and flu-like symptoms.

DOSE:
Drug:
Imipramine = 50-200mg/day

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D. Monoamine Oxidase Inhibitors (MAOIs)
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 neuro transmitter molecules (norepinephrine, dopamine, and serotonin) that may leak out of
synaptic vesicles when the neuron is at rest. The MAO inhibitors (MAOIs) may irreversibly or reversibly
inactivate the enzyme, permit ting neurotransmitter molecules to escape degradation and, therefore,
to both accumulate within the presynaptic neuron and leak into the synaptic space. This is believed to
cause activation of norepinephrine and serotonin receptors, and it may be responsible for the indirect
antidepressant action of these drugs.

Examples: Phenelzine, tranylcypromine, isocarboxazid and the agent that was prior-approved for
Parkinson disease, but is now also approved for depression, selegiline, which is the first antidepressant
available in a transdermal delivery system. Use of MAOIs is now limited due to the complicated dietary
restrictions required of patients taking them.

MECHANISM OF ACTION:
Most MAOIs, such as phenelzine, form stable complexes with
the enzyme, causing irreversible inactivation. This results in
increased stores of norepinephrine, serotonin, and dopamine
within the neuron and subsequent diffusion of excess
neurotransmitter into the synaptic space. These drugs inhibit
not only MAO in the brain, but also MAO in the liver and gut
that catalyze oxidative deamination of drugs and potentially
toxic substances, such as tyramine, which is found in certain
foods. The MAOIs, therefore, show a high incidence of drug-
drug and drug-food interactions. Selegiline administered as
the transdermal patch may produce less inhibition of gut and
hepatic MAO at low doses because it avoids first-pass
metabolism.

INDICATIONS:
The MAOIs are indicated for depressed patients who are unresponsive or allergic to TCAs or who
experience strong anxiety. Patients with low psychomotor activity may benefit from the stimulant
properties of the MAOIs. These drugs are also useful in the treatment of phobic states. A special
subcategory of depression, called atypical depression, may respond preferentially to MAOIs. Atypical
depression is characterized by labile mood, rejection sensitivity, and appetite disorders. Because of their
risk for drug-drug and drug-food interactions, the MAOIs are considered to be last-line agents in many
treatment venues.

PHARMACOLOGY
Arguably the first modern class of antidepressants, monoamine oxidase inhibitors (MAOIs) were
introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially
lethal food and drug interactions. Their primary use now is in the treatment of depression unresponsive
to other antidepressants. However, MAOIs have also been used historically to treat anxiety states,
including social anxiety and panic disorder. In addition, selegiline is used in the treatment of Parkinson’s

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disease. Current MAOIs include the hydrazine derivatives phenelzine and isocarboxazid and the
nonhydrazines tranylcypromine, selegiline, and moclobemide (the latter is not available in the USA). The
hydrazines and tranylcypromine bind irreversibly and nonselectively with MAO-A and -B, whereas other
MAOIs may have more selective or reversible properties. Some of the MAOIs such as tranylcypromine
resemble amphetamine in chemical structure, whereas other MAOIs such as selegiline have
amphetamine-like metabolites. As a result, these MAOIs tend to have substantial CNS-stimulating
effects.

PHARMACOKINETICS:
The different MAOIs are metabolized via different pathways but tend to have extensive first-pass effects
that may substantially decrease bioavailability. Tranylcypromine is ring hydroxylated and N-acetylated,
whereas acetylation appears to be a minor pathway for phenelzine. Selegiline is N-demethylated and
then hydroxylated. The MAOIs are well absorbed from the gastrointestinal tract. Because of the
prominent first-pass effects and their tendency to inhibit MAO in the gut (resulting in tyramine pressor
effects), alternative routes of administration are being developed. For example, selegiline is available in
both transdermal and sublingual forms that bypass both gut and liver. These routes decrease the risk of
food interactions and provide substantially increased bioavailability.

CONTRAINDICATIONS:

 Phenelzine
– Should not be used in patients who are hypersensitive to the drug or its ingredients, with
pheochromocytoma, congestive heart failure, severe renal impairment or renal disease, a
history of liver disease, or abnormal liver function tests.
– Phenelzine sulfate should not be used in combination with dextromethorphan or with CNS
depressants such as alcohol and certain narcotics.
– Phenelzine sulfate should not be administered together with or in rapid succession to other
MAO inhibitors because HYPERTENSIVE CRISES and convulsive seizures, fever, marked
sweating, excitation, delirium, tremor, coma, and circulatory collapse may occur.
 Tranylcypromine
– In patients with cerebrovascular defects or cardiovascular disorders
– In the presence of pheochromocytoma
– In combination with MAO inhibitors or with dibenzoazepine-related entities
 Isocarboxazid
– Hypersensitivity to isocarboxazid or any component of the formulation; cardiovascular disease
(including hypertension); cerebrovascular defect (suspected or confirmed); history of
headache; history of hepatic disease or abnormal liver function tests; pheochromocytoma;
severe renal impairment

SIDE EFFECTS:
The most common adverse effects of the MAOIs leading to discontinuation of these drugs are
orthostatic hypotension and weight gain. In addition, the irreversible nonselective MAOIs are associated
with the highest rates of sexual effects of all the antidepressants. Anorgasmia is fairly common with
therapeutic doses of some MAOIs. The amphetamine-like properties of some MAOIs contributes to
activation, insomnia, and restlessness in some patients. Phenelzine tends to be more sedating than
either selegiline or tranylcypromine. Confusion is also sometimes associated with higher doses of
MAOIs. Because they block metabolism of tyramine and similar ingested amines, MAOIs may cause

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 dangerous interactions with certain foods and with serotonergic drugs. Finally, MAOIs have been
associated with a sudden discontinuation syndrome manifested in a delirium-like presentation with
psychosis, excitement, and confusion.

DOSE:
Drug:
Tranylcypromine – Usual Adult Dose for Depression: • Usual effective dose: 30 mg per day, orally, in
divided doses (max. 60mg)

E. ATYPICAL ANTIDEPRESSANTS:
The atypical antidepressants are a mixed group of agents that have actions at several different sites. This
group includes bupropion, mirtazapine, nefazodone, and trazodone. They are not any more efficacious
than the TCAs or SSRIs, but their side effect profiles are different.

Examples: Bupropion, mirtazapine, nefazodone, and trazodone.

I. Bupropion:
This drug acts as a weak dopamine and norepinephrine reuptake inhibitor to alleviate the symptoms of
depression. Its short half-life may require more than once-a-day dosing or the administration of an
extended-release formulation. Bupropion also assists in decreasing the craving and attenuating the
withdrawal symptoms for nicotine in tobacco users trying to quit smoking. Side effects may include dry
mouth, sweating, nervousness, tremor, a very low incidence of sexual dysfunction, and an increased risk
for seizures at high doses. Bupropion is metabolized by the CYP2B6 pathway and is considered to have a
relatively low risk for drug-drug interactions. The daily dose of bupropion should be within the
manufacturer’s recommendations to minimize the risk of seizures that may occur in above
recommended doses. Its use should also be avoided in patients at risk for seizures or who have eating
disorders (such as bulimia).
II. Mirtazapine:
This drug enhances serotonin and norepinephrine neurotransmission via mechanisms related to its
ability to block presynaptic α2 receptors. Additionally, it may owe at least some of its antidepressant
activity to its ability to block 5-HT2 receptors. It is a sedative because of its potent antihistaminic
activity, but it does not cause the antimuscarinic side effects of the TCAs, or interfere with sexual
functioning, as do the SSRIs. Increased appetite and weight gain frequently occur. Mirtazapine is
markedly sedating, which may be an advantage in depressed patients having difficulty sleeping.
III. 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. With chronic use, these agents may desensitize
5-HT1A presynaptic autoreceptors and, thereby, increase serotonin release. Both agents are sedating,
probably because of their potent H1-blocking activity. Trazodone has been associated with causing
priapism, and nefazodone has been associated with the risk for hepatotoxicity. Both agents also have
mild to moderate α1-receptor antagonism contributing to orthostasis and dizziness.

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MECHANISM OF ACTION:
Atypical antidepressants ease depression by affecting chemical messengers (neurotransmitters) used to
communicate between brain cells. Most antidepressants work by changing the levels of one or more of
these naturally occurring brain chemicals. Atypical antidepressants affect neurotransmitters including
dopamine, serotonin and norepinephrine. Changing the balance of these chemicals seems to help brain
cells send and receive messages, which in turn boosts mood.

INDICATIONS:

 Oleptro (trazodone) and Brintellix (vortioxetine): Serotonin antagonist and reuptake inhibitors
(SARIs) used for major depression that both inhibits serotonin reuptake and block adrenergic
receptors.
 Remeron (mirtazapine): A noradrenergic antagonist used for major depression, that blocks
receptors of the stress hormone epinephrine (adrenaline) on the brain.
 Symbax: Combines the SSRI fluoxetine with the antipsychotic drug fluoxetine to treat bipolar
depression or treatment-resistant depression.
 Wellbutrin (bupropion): Classified as a dopamine reuptake inhibitor, used to treat depression
and seasonal affective disorder as well as a smoking cessation aid.

PHARMACOLOGY
Atypical antidepressants change the levels of one or more neurotransmitters, such as dopamine,
serotonin or norepinephrine.

SIDE EFFECTS:
 dry mouth
 dizziness
 lightheadedness

DOSE:
Drug:
Bupropion = 150mg/day

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CONCLUSION:
Depression is a serious psychological condition but it can be effectively treated with available therapies.
The stock of antidepressants available may be selectively used for treating depression safely without any
side effects. The right medication to an individual depends on the clinico-physiological conditions of the
patient such as symptoms, possible side effects, and interaction with other medications, state of
pregnancy or breast feeding and the mental conditions. Different classes of antidepressants are in
practice depending on the type and requirement of depression. Antidepressants include selective
serotonin reuptake inhibitors (SSRIs), Serotonin and norepinephrine reuptake inhibitors (SNRIs),
Norepinephrine and dopamine reuptake inhibitors (NDRIs: Bupropion (Wellbutrin, Aplenzin, Forfivo XL),
Atypical antidepressants (trazodone (Oleptro), mirtazapine (Remeron) and vortioxetine (Brintellix)),
Tricyclic antidepressants (imipramine (Tofranil), nortriptyline (Pamelor), amitriptyline, doxepin,
trimipramine (Surmontil), desipramine (Norpramin) and protriptyline (Vivactil)), Monoamine oxidase
inhibitors (MAOIs: tranylcypromine (Parnate), phenelzine (Nardil) and isocarboxazid (Marplan)) and
other medications such as such as mood stabilizers or antipsychotics all as well as anti-anxiety and
stimulant medications. Many of these medications have their side effects. It could be however
worthwhile to investigate the plant based principles to be used as more effective and safe
chemotherapeutic compared to the currently used synthetic regimen.

REFERENCES:
Books:
 basic and clinical pharmacology 15th edition
 Lippincott illustrated reviews pharmacology

Websites:
 https://litfl.com/pharm-101-tricyclic-antidepressants/
 https://studylib.net/doc/8358058/what-are-antidepressants
 https://www.academia.edu/29409575/Antidepressants
 https://slidetodoc.com/drugs-used-in-depression-old-new-depression-definition/

ARTICLES:
 https://www.researchgate.net/figure/Classification-of-antidepressants-based-on-MOA-and-
ocular-side-effects-7-25_tbl1_334595447

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