Pharmacology of

Antidepressants
 DEPRESSION
Depression is the most common of
the affective disorders (define as
disorders of mood rather than
disturbance of thought or
cognition). It may range from a
very mild condition, to sever
(psychotic) depression
accompanied by hallucination and
delusions.
 SYMPTOMS
The symptoms of depression include emotional and biological components.

• Emotional symptoms:
o misery, apathy and pessimism
o low self-esteem: feelings of guilt, inadequacy and ugliness
o Indecisiveness, loss of motivation.
The symptoms of depression include emotional and biological components.
• Biological symptoms:
o retardation of thought and action
o loss of libido
o sleep disturbance and loss of appetite
There are two distinct types of depressive syndrome, namely unipolar depression, in
which the mood swings are always in the same direction, and bipolar affective
disorder, in which depression alternates with mania
 PATHOPHYSIOLOGY OF MAJOR
DEPRESSION
The main biochemical theory of depression is the
monoamine hypothesis, which states that
depression is caused by a functional deficit of
monoamine transmitters at certain sites in the brain,
while mania results from a functional excess.
Although the monoamine hypothesis
The Monoamine Theory in its simple
form is insufficient as an explanation of depression,
pharmacological manipulation of monoamine
transmission remains the most successful
therapeutic approach
 PATHOPHYSIOLOGY OF MAJOR
DEPRESSION

Neurotrophic Hypothesis There is substantial

evidence that nerve growth factors such as brain-
derived neurotrophic factor (BDNF) are critical in the
regulation of neural plasticity, resilience, and
neurogenesis. The evidence suggests that depression
is associated with Thethe loss of
Monoamine neurotrophic support
Theory
and that effective antidepressant therapies increase
neurogenesis and synaptic connectivity in cortical
areas such as the hippocampus. BDNF is thought to
exert its influence on neuronal survival and growth
effects by activating the tyrosine kinase receptor B in
both neurons and glia
Classes of Antidepressants
1. Selective Serotonin Reuptake Inhibitors ( Fluoxetine
,Fluvoxamine, citalopram, Escitalopram Paroxetine,
Sertraline.
2. Tricyclic Antidepressants (Amitriptyline - Desipramine -
Doxepin - Imipramine - Nortriptyline - Protriptyline –
Trimipramine.
3. Selective Serotonin norepinephrine Reuptake Inhibitors
(Duloxetine,Venlafaxine, desvenlafaxine, duloxetine, and
levomilnacipran.)
Classes of Antidepressants
4. 5-HT2 Receptor Modulators Two antidepressants are thought to
act primarily as antagonists at the 5-HT2 receptor: trazodone and
nefazodone.
5. Tetracyclic and Unicyclic Antidepressants A number of
antidepressants do not fit neatly into the other classes. Among these
are bupropion, mirtazapine, amoxapine, vilazodone, and maprotiline
6. Monoamine Oxidase Inhibitors (selegiline ,Phenelzine
,Tranylcypromine
7.Allosteric Modulators of GABAA: Brexanolone
(allopregnanolone) is a member of a new class of neurosteroid
antidepressants that are thought to act primarily on the GABA
system. Brexanolone has been studied as a rapidly acting IV
antidepressant in women with postpartum depression and is
administered as a 60-hour IV infusion.
 Selective Serotonin-Reuptake Inhibitors
The selective serotonin-reuptake inhibitors
(SSRI) are a group of drugs that specifically
inhibit serotonin reuptake. This contrasts with
the tricyclic antidepressants that
nonselectively inhibit the uptake of
norepinephrine, and serotonin, and block
muscarinic, Hl-histaminic and α-adrenergic
receptors. At present, SSRIs are the most
commonly prescribed first-line agents in the
treatment of both MDD and anxiety disorders.
Their popularity comes from their ease of use,
tolerability, and safety in overdose.
 Pharmacokinetics:
All SSRI are well absorbed after oral
administration. Only sertraline undergo
significant first pass metabolism. Fluoxetine
and norfluoxetine are slowly cleared from the
body, with a 1 to 10 day half-life for the
parent compound, and 3 to 30 days for the
active metabolite. Excretion of SSRI is
primarily through the kidney except sertraline
and paroxetine which also undergo fecal
excretion.
 Adverse effects:
Increased serotonergic activity in the gut is commonly
associated with nausea, gastrointestinal upset, diarrhea,
and other gastrointestinal symptoms.
Increasing serotonergic tone at the level of the spinal
cord and above is associated with diminished sexual
function and interest. Some patients gain weight while
taking SSRIs, particularly paroxetine. Sudden
discontinuation of short half-life SSRIs such as
paroxetine and sertraline is associated with a
discontinuation syndrome in some patients
characterized by dizziness, paresthesias, and other
symptoms beginning 1 or 2 days after stopping the drug
and persisting for 1 week or longer.
Tricyclic Antidepressants
The tricyclic and polycyclic antidepressants block
norepinephrine, and serotonin uptake into the neuron.
Prolonged therapy probably leads to alterations in selected
central nervous system (CNS) receptors.
All the tricyclic antidepressants (TCAs) have similar
therapeutic efficacy, and the choice of drug depends on
tolerance of side effects and duration of action. Patients
who do not respond to one TCA may benefit from a
different drug in this group.
 Mode of action

1. Inhibition of neurotransmitter uptake: TCAs inhibit the

neuronal reuptake of norepinephrine, and serotonin into
presynaptic nerve terminals, at therapeutic dose it does not
block dopamine transporters . By blocking the major route
of neurotransmitter removal, the TCAs lead to increased
concentrations of monoamines in the synaptic cleft,
resulting in antidepressant effects.
2. Blocking of receptors: The TCAs also block serotonergic,
α-adrenergic, histamine, and muscarinic receptors. It is not
known which, if any, of these accounts for the therapeutic
benefit
 Pharmacokinetics
The TCAs are well absorbed upon oral administration
and because of their lipophilic nature, are widely
distributed and readily penetrate into the CNS. As a
result of their variable first pass metabolism in the
liver, TCAs have low and inconsistent bioavailability.
Therefore the patient's response is used to adjust
dosage. The initial treatment period is typically 4 to 8
weeks. The dosage can be gradually reduced unless
relapse occurs.
 Adverse effect
1. Antimuscarinic effects: Blockade of acetylcholine
receptors leads to blurred vision, xerostomia (dry mouth),
urinary retention, constipation, and aggravation of
glaucoma.
2. These agent slow cardiac conduction similarly to quinidine
which may precipitate life threatening arrhythmias..
3. Orthostatic hypotension: TCAs block α-adrenergic
receptors, causing orthostatic hypotension, dizziness and
reflex tachycardia. In clinical practice this is the most
serious problem in the elderly.
4. Sedation: Sedation may be prominent, especially during
the first several weeks of treatment. And is releated to the
ability of these drugs to block histamine H receptor.
 Serotonin norepinephrine Reuptake
Inhibitors .
These agent termed selective Serotonin
norepinephrine Reuptake Inhibitors (SNRIs), may be
effective in treating depression in patient in whom
the SSRI are ineffective, Both TCA and SNRI
sometimes are effective in relieving physical
symptom of neuropathic pain. The SNRI unlike TCA
have little or no activity on muscarinic, histamine
and adrenergic receptors, and thus have fewer
adverse effects than TCA.
Adverse effect
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.. All the SNRIs have been
associated with a discontinuation syndrome
resembling that seen with SSRI
discontinuation.
 5-HT Receptor Modulators
The principal action of both nefazodone and trazodone
appears to be blockade of the 5-HT2A receptor. Inhibition
of this receptor in both animal and human studies is
associated with substantial antianxiety, antipsychotic, and
antidepressant effects.
 Pharmacokinetics

Trazodone and nefazodone are rapidly absorbed and

undergo hepatic metabolism. Both drugs are bound to
protein and have limited bioavailability because of
extensive metabolism. Because of their short half-lives
split dosing is generally required when these drugs are
used as antidepressants. However, trazodone is often
prescribed as a single dose at night as a hypnotic in lower
doses than are used in the treatment of depression. Both
trazodone and nefazodone have active metabolites that
also exhibit 5-HT2 antagonism. Nefazodone is a potent
inhibitor of the CYP3A4 system
Tetracyclic and Unicyclic Antidepressants
The actions of bupropion remain poorly understood. A
more significant effect of bupropion is presynaptic release
of catecholamines.
Mirtazapine has a complex pharmacology. It is an
antagonist of the presynaptic α2 autoreceptor and
enhances the release of both norepinephrine and 5-HT. In
addition, mirtazapine is an antagonist of 5-HT2 and 5-
HT3 receptors. Finally, mirtazapine is a potent H1
antagonist.The actions of amoxapine and maprotiline
resemble those of TCAs Unlike the TCAs or other
antidepressants, amoxapine is a moderate inhibitor of the
postsynaptic D2 receptor. Vilazodone is a potent serotonin
reuptake inhibitor and a partial agonist of the 5-HT1A
 Adverse effect
Amoxapine is sometimes associated with a
parkinsonian syndrome due to its D2-blocking action.
Mirtazapine has significant sedative effect.
Maprotiline has a moderately high affinity for NET
and may cause TCA-like adverse effects and, rarely,
seizures. Bupropion is occasionally associated with
agitation, insomnia, and anorexia. Vilazodone may
have somewhat higher rates of gastrointestinal upset,
including diarrhea and nausea, than the SSRIs.
 MONOAMINE OXIDASE
INHIBITORS
Monoamine oxidase (MAO) is a mitochondrial
enzyme found in neural and other tissues, such as the
gut and liver. In the neuron, MAO functions as a
"safety valve" inactivate any excess neurotransmitter
molecules (norepinephrine, dopamine, and
serotonin) that may leak out of synaptic vesicles
when the neuron is at rest
 MONOAMINE OXIDASE
INHIBITORS
The MAO inhibitors may irreversibly or reversibly
inactivate the enzyme, permitting neurotransmitter
molecules to escape degradation and therefore to
both accumulate within the presynaptic neuron and
to leak into the synaptic space. This causes activation
of norepinephrine and serotonin receptors, and may
be responsible for the antidepressant action of these
drugs. Use of MAO inhibitors is now limited
because of the complicated dietary restrictions
 Clinical Indications
A. Depression
The goal of acute treatment of MDD is remission of all
symptoms. Since antidepressants may not achieve their
maximum benefit for 1–2 months or longer, it is not
unusual for a trial of therapy to last 8–12 weeks at
therapeutic doses. If an inadequate response is obtained,
therapy is often switched to another agent or augmented
by addition of another drug. For example, bupropion, an
atypical antipsychotic, or mirtazapine might be added to an
SSRI or SNRI to augment antidepressant benefit if
monotherapy is unsuccessful. Once an adequate response
is achieved, continuation therapy is recommended for a
minimum of 6–12 months to reduce the substantial risk of
relapse.
 Clinical Indications
A. Depression
Many patients have multiple recurrences, and these recurrence
may progress to more serious, chronic, and treatment-resistant
episodes. Thus, it is not unusual for patients to require
maintenance treatment to prevent recurrences. It is not clear
whether antidepressants are useful for all subtypes of
depression. For example, patients with bipolar depression may
not benefit much from antidepressants even when added to
mood stabilizers.
 Clinical Indications
B. Anxiety Disorders: After major depression, anxiety
disorders represent the most common application of
antidepressants. A number of SSRIs and SNRIs have been
approved for all the major anxiety disorders, including
PTSD, OCD, social anxiety disorder, GAD, and panic
disorder.
C. Pain Disorders Antidepressants possess analgesic
properties independent of their mood effects. TCAs have
been used in the treatment of neuropathic and other pain
conditions. Medications that possess both norepinephrine
and 5-HT reuptake blocking properties are often useful in
treating pain disorders. duloxetine was approved for the
treatment of chronic joint and muscle pain. Milnacipran is
approved for the treatment of fibromyalgia in the USA and
for MDD in other countries.
 Clinical Indications
D. Premenstrual Dysphoric Disorder The SSRIs are
known to be beneficial to many women with PMDD, and
fluoxetine and sertraline are approved for this indication.
Treating for 2 weeks out of the month in the luteal phase
may be as effective as continuous treatment. The rapid
effects of SSRIs in PMDD may be associated with rapid
increases in pregnenolone levels.
E. Smoking Cessation: Bupropion was approved in 1997
as a treatment for smoking cessation. Bupropion appears
to be about as effective as nicotine patches in smoking
cessation.
 Clinical Indications
F. Eating Disorders
Bulimia nervosa and anorexia nervosa are potentially
devastating disorders. Antidepressants appear to be helpful in
the treatment of bulimia but not anorexia. Fluoxetine was
approved for the treatment of bulimia in 1996, Bupropion may
have some benefits in treating obesity. Nondepressed, obese
patients treated with bupropion were able to lose somewhat
more weight and maintain the loss relative to a similar
population treated with placebo. However, the weight loss was
not robust, and there appear to be more effective options for
weight loss.
 Clinical Indications
G. Other Uses for Antidepressants. Enuresis in children is an
older labeled use for some TCAs. The SNRI duloxetine is
approved in Europe for the treatment of urinary stress
incontinence. Many of the serotonergic antidepressants appear
to be helpful for treating vasomotor symptoms in
perimenopause. SSRIs are sometimes used to treat premature
ejaculation. In addition, bupropion has been used to treat sexual
adverse effects associated with SSRI use, although its efficacy
for this use has not been consistently demonstrated in
controlled trials.