Anidepressant Drugs

Pratik Khanal
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Classification:-

1.Selective Norepinephrine Reuptake Inhibitors (SNRIs)

Amoxapine, Desipramine, Nortriptyline, Protriptyline
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Amoxapine
2. Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram, Escitalopram (S-citalopram), Fluoxetine, Sertaline
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3. Norepinephrine and Serotonin Reuptake Inhibitors(NSRIs)
Amitriptyline, Doxepin, Duloxetine, Imipramine, Trimipamine
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4. Dopamine and Norepinephrine reuptake Inhibitors
(DNRIs)
Bupropion

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5. Serotonin antagonists/ Reuptake inhibitors (SARIs)
Aripiprazole, Trazodone

6. Mood Stabilizers
Lithium Carbonate

7. Monoamine Oxidase Inhibitors (MAOIs)

Phenelzine, Tranylcypromine

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Phenelzine
 In a depressed state, one feels hopeless and experiences an
overwhelming sense of despair. Depression immobilizes a person,
afflicting men and women, rich and poor, and young and old alike.
Depression makes one feel exhausted, worthless, helpless, and
hopeless. It is an illness that involves the body, mood, and thoughts
and affects the way one feels about oneself, and the way one thinks
about things.

Types of Depressive Disorders:-

Major Depression Disorder

also called unipolar depression is the most serious type of
depression; it is manifested through a combination of symptoms
that interfere with the ability to work, study, sleep, eat, and enjoy
once-pleasurable activities.
Dysthymia
This is a mild chronic depression that lasts for 2 years (1
year for children and adolescents) or longer and is characterised
by chronic symptoms that do not disable but that keep one from
functioning well or from feeling good about himself or herself.

Bipolar Disorder (Manic-Depressive Illness)

it can be divided into bipolar I (episodes of severe mood
swings from mania to depression), bipolar II (milder episodes of
hypomania that alternate with depression, cyclothymia (milder
episodes of bipolar II; low grade bipolar II), or rapid cycling
bipolar disorder.
Mechanism of Action:-
1.Selective Norepinephrine Reuptake Inhibitors (SNRIs)
Amoxapine, Desipramine, Nortriptyline, Protriptyline

After the neurotransmitter norepinephrine has been

released by a presynaptic neuron, the Norepinephrine transporter
(NET) is the primary mechanism for the for removing
Norepinephrine from the synapse. The transporter terminates the
synaptic activity of NE and recycles it for later reuse. Selective
Norepinephrine reuptake Inhibitors work by blocking reuptake of
NE into the presynaptic nerve terminal, thus increasing the
availability of NE in the synapse.
Their invitro affinity for inhibiting the NET essentially mirrors
more or less their clinical efficacy : desipramine > protriptyline>
amitriptyline = nortriptyline> amoxapine

They seem to be at least as effective as SSRIs in the

treatment of depressive illness by acting specifically at
noradrenergic sites. Despite the current popularity of SSRIs for
the treatment of depression, the noradrenergic neurons should not
be overlooked, because they also influence the depressed mood.
Despiramine:- is a dihydrodibenzazepine secondary amine TCA
that also is the active metabolite of imipramine. Desipramine
exhibits a greater potency and selectivity for the NET than do
other secondary TCAs. Its antidepressant effect results from
increases in the level of NE in CNS synapses, and long term
administration causes downregulation α1 – adrenoceptors and
desensitization of presynaptic α2-receptors, equilibrating the
noradrenergic system and thus, correcting the dysregulated output
of depressed patients.
2. Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram, Escitalopram (S-citalopram), Fluoxetine, Sertaline

After the neurotransmitter serotonin has been released by

a presynaptic neuron, the serotonin transporter (SERT) is the
primary mechanism for removing 5-HT from the synapse. The
transporter terminates the synaptic activity of 5-HT and recycles
it for later reuse. SSRIs work by blocking reuptake of 5-HT into
the presynaptic nerve terminal, thus increasing the availability of
5-HT in the synapse. Their invitro potency for selectivity
inhibiting the SERT more or less mirrors their clinical efficacy as
SSRIs paroxetine> sertaline> clomipramine> fluoxetine>
citalopram
3. Norepinephrine and Serotonin Reuptake Inhibitors
Amitriptyline, Doxepin, Duloxetine, Imipramine, Trimipamine

Norepinephrine and serotonin reuptake inhibitors block

both the NET and SERT , exhibiting dual affinity for both the
Selective Serotonin Reuptake inhibitors and Selective
Norepinephrine reuptake inhibitors. These dual inhibitors, as a
group, donot show a significant separation in the selectivity for
the NET and SERT reuptake transporter. Clinical studies suggest
that dual acting inhibitors of 5-HT and NE reuptake may be more
beneficial than selective inhibitors in managing depression.
4. Dopamine and Norepinephrine reuptake Inhibitors
(DNRIs)
Bupropion
The mechanism of antidepressant action for bupropion is
selective inhibition of DA reuptake at the DA presynaptic
neuronal membrane and NE reuptake and also induces the release
of DA and norepinephrine. An additional mechanism of action for
bupropion is a non competetive antagonist of several nAChRs (
Nicotinic Acetyl choline receptor). Thus the dual antidepressant
and antinicotinic activity of bupropion is mediated by its
stimulatory action on the DA and NE systems and inhibition of
the neuronal Nicotinic Acetyl Choline Receptor.
5. Serotonin antagonists/ Reuptake inhibitors (SARIs)
Aripiprazole, Trazodone

Serotonin receptor modulators are a class of

antidepressants, the functions of which is to modulate the
concentrations of 5-HT in the brain. A neuromodulator functions as
a “volume control in the brain and nervous system”. Regulating the
other neurotransmitters through its receptors in the brain in
response to external stimuli. Aripiprazole shows mechanism as a
partial agonist at the 5-HT1A receptor and antagonist at the 5-HT2A
receptor. It is an antagonist at the 5-HT7 receptor and acts as a
partial agonist at the 5-HT2C receptor.
5-HT1A:- In preclinical studies, 5-HT1A receptor agonists have
demonstrated antianxiety, antidepressant, antiaggressive, and
perhaps , anticraving, antiemetic, and neuroprotective properties.

5-HT2A:- having a role in thermoregulation and sleep, and they

could be involved in appetite control, learning, and along with
various other serotonergic receptor populations.

5-HT7:- could be involved in mood and learning

5-HT2C:- 5-HT2C receptor modulators could be could be useful

in the treatment of obesity, schizophrenia, depression, anxiety,
drug abuse, urinary incontinence, sexual dysfunction and
Parkinson’s disease.
6. Mood Stabilizers
Lithium Carbonate

Mood stabilizers have acute and long-term effects and, at a

minimum, are prophylactic for manic or depressive disorders.
Lithium is the classic mood stabilizer. Lithium ion directly
inhibits two signal transduction pathways. It supresses inositol
triphosphate signaling through depletion of intracellular inositol
and inhibits glycogen synthase kinase -3 (GSK-3), a
multifunctional protein kinase.
Inositol a naturally occuring isomer of glucose, is a key
intermediate of the phosphatidylinositol signaling pathway, a
second messenger system used by noradrenergic, serotonergic,
and cholinergic receptors. The suggestion that lithium might treat
maina via its reduction of inositol levels led to experiments
showing that oral doses of inositol reverse the behavioural effects
of lithium in animals and the side effects of lithium in humans.
CSF levels of inositol are low in depressed individuals. The
effectiveness of inositol in treating manic depresion was shown in
a double blind trial, which showed that large doses of inositol
(12g)increased inositol concentration in human CSF, by 70 % and
led to improvement in depressed patients compared to placebo.
7. Monoamine Oxidase Inhibitors (MAOIs)
Phenelzine, Tranylcypromine

Monoamine oxidase is an enzyme found mainly in nerve tissue

and in the liver and lungs, MAO catalyzes the oxidative
deamination of various amines, including epinephrine, NE, DA,
and 5-HT.
At least two isoforms of MAO exist, MAO-A and MAO-B, with
differences in substrate preference, inhibitor specificity, and tissue
distribution.
The MAO-A substrates include 5-HT, and MAO-B substrates
include phenylethylamine. Tyramine, epinephrine, NE, and DA are
substrates for both MAO-A and MAO-B.
A line of transgenic mice has been generated in which the gene
that encodes MAO-A is disrupted. MAO-A KO mice have
elevated brain levels of 5-HT, NE and DA and manifest
aggressive behavior similar to men with a deletion of MAO-A.
We have also generated mice deficient in MAO-B by
homologous recombination. Interestingly, MAO-B KO mice do
not exhibit aggression and only levels of PEA are increased.
Phenelzine:- is a hydrazine MAOI. Its mechanism of action is
the prolonged irreversible inhibition of the MAO-A and MAO-B.
Phenelzine has been used with some success in the management
of bulimia nervosa.If adverse neurologic reactions occur during
phenelzine therapy, phenelzine-induced pyridoxine deficiency
should be considered.

Tranylcypromine:- is a non-hydrazine, irreversible MAO

inhibitor antidepressant agent that was designed as the
cyclopropyl analogue of amphetamine. Instead of exhibiting
amphetamine like stimulation, its mechanism of action is non-
selective, irreversible inhibition of MAO. Its onset of
antidepressant action is more rapid than for phenelzine. Maximal
MAO inhibition, however, occurs within 5-10 days.
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Bulimia Nervosa:- is characterised by the cycle of bingeing and
purging. Bingeing is when a person eats a large amount of food in
a short period of time. Purging means to rid the body of all the
food in order to prevent weight gain. This is done by vomiting or
using drugs, such as diuretics or laxatives. Sometimes excessive
exercise is also used in an attempt to get rid of the extra calories.
Tricyclic Antidepressants:-

Tricyclic structure is not associated with affinity for any

particular receptor but, rather, contributes to a range of multiple
CNS pharmacodynamic (adverse) effects because of increased
lipophilicity.

1. Secondary amine tricyclic antidepressants:-

2. Tertiary amine tricyclic antidepressants:-
1. Secondary amine tricyclic antidepressants:-
Desipramine, Nortriptyline, Amoxapine, Protriptyline,
Maprotiline

2. Tertiary amine tricyclic antidepressants:-

Imipramine, Amitriptyline, Chlorimipramine, Trimipramine
SAR of tricyclic antidepressants:-

1. The tricyclic ring structure is formed by joining the two phenyl

rings into 6-6-6 or 6-7-6 ring systems, in which the central ring is
either a six-membered or seven membered carbocyclic or
heterocyclic ring and saturated or unsaturated.

2. Substituting a halogen (i.e., chlorine, cloimipramine) or cyano

group into the 3-position of the dihydrodibenzazepine ring
enhances preferential affinity for SERT.

3. 3-cyano imipramine was investigated as a potent SSRI but is

only used as a research probe for studying SERTs.
4. Branching the propyl side chain with a 2-methyl group (as in
trimipramine) significantly reduces the affinity (~100 times) of
imipramine for both SERT and NET.

5. The conformational mobility for the TCAs, including ring

inversion of the tricyclic ring system, flexing of the CH2X bridge
(X= CH2, O, N or S) in the central seven-membered ring seems to
be correlated with differences in potency.

6. The TCAs differ structurally from the antipsychotics

phenothiazines in that the two phenyl (aromatic) rings are
connected by a two-carbon link to form a central seven
membered ring instead of a sulphur bridge.
7. The Z (cis) geometry for the propylidine group in chiral TCAs
appears to be important for transporter selectivity and affinity
(e.g., doxepin).
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