This document discusses antidepressant agents. It begins by describing the symptoms of depression and noting that major depression is one of the most common psychiatric disorders. Antidepressants are a class of drugs used to treat major depression by restoring mood and behavior. The document then provides a detailed history of antidepressants, describing early drugs like iproniazid and imipramine and how they led to the development of newer classes of antidepressants. It discusses the mechanisms of different classes of antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors, and atypical antidepressants.

1. ANTIDEPRESSANT AGENTS
MRS.REKHA AMIT BHALERAO
ASSISTANT PROFESSOR
PHARMACEUTICAL CHEMISTRY
PES MODERN COLLEGE OF PHARMACY, FOR LADIES

2. INTRODUCTION
Sadness, helplessness, inferiority, despair, worthlessness,
crying, guilt, suicidal tendencies, and episodic frequency
characterize depression. Major depression is one of the most
common psychiatric disorders affecting humankind. It has
been estimated that 7 to 12% of men and 20 to 25% of
women will experience a major depressive episode in their
lifetime.
Major depression is believed to arise from disturbances
in brain neurotransmitter systems.
Antidepressants are a class of psychotherapeutic drugs
that are used to treat major depression. The therapeutic
effect of antidepressants aims at the restoration of mood and
behavior.

3. They are also effective for dysthymia (lower grade chronic
depression). Antidepressant drugs are not generally effective
in milder forms of acute depression but a trial may be
considered in cases refractory to psychological treatments.
Decreased levels of the neurotransmitters norepinephrine,
serotonin, and dopamine contribute to depression, what
causes these reduced levels in the first place? In other words,
what causes the low levels of serotonin, norepinephrine, or
dopamine, which in turn may sometimes cause the
symptoms of depression?
Several things might potentially go wrong with this process
and lead to a neurotransmitter deficit.

4. Some of the possibilities include
Not enough of the neurotransmitter (for example,
serotonin) is produced
Not enough receptor sites to receive the neurotransmitter
The neurotransmitter is being taken back up too quickly
(into the presynaptic) before it can reach receptor sites
Chemical precursors (molecules from which
neurotransmitters are built) may be in short supply
Molecules that facilitate the production of
neurotransmitters, such as specific enzymes, may be in short
supply
As you can see, if there is a breakdown anywhere along the
path, neurotransmitter supplies may not be adequate for
your needs.
Inadequate supplies may then lead to the symptoms that
we know as depression.

5. HISTORY OF ANTIDEPRESSANTS
Iproniazid, the first modern antidepressant, was originally
developed as an antitubercular drug in the early 1950’s. In
addition to its ability to treat tuberculosis, Iproniazid was
observed to elevate mood and stimulate activity in many
patients.
These effects led researchers to investigate the ability of
iproniazid to treat the symptoms of depression. After
promising preliminary findings reported in 1957, iproniazid
was prescribed widely to patients with major depression.
Within the first year it was available as an antidepressant,
four hundred thousand depressed people were treated with
iproniazid.

6. Subsequent studies demonstrated the ability of this drug
to block the activity of monoamine oxidase, the enzyme that
destroys the monoamine neurotransmitters
(norepinephrine, serotonin and dopamine).
Although Iproniazid is no longer used as an
antidepressant because of toxic side-effects, the effectiveness
of this drug led to further interest in the idea that depression
might be alleviated by appropriate drugs.
The first tricyclic antidepressant, Imipramine, was
originally developed in a search for drugs useful in the
treatment of schizophrenia. Although clinical trials
demonstrated lack of effect in treating schizophrenia.

7. Early studies in 1957 and 1958 reported that imipramine
significantly alleviated symptoms in patients with major
depression.
Interestingly, although imipramine elevated mood and
increased energy in depressed patients, the drug proved to
be sedating in individuals without major depression.
These effects led to the idea that imipramine was
selectively reversing the depression, rather than simply
producing a general activating effect. Subsequent
biochemical studies on imipramine demonstrated that this
drug increased the activity of the monoamine
neurotransmitters, norepinephrine and serotonin, by
inhibiting their reuptake into neurons.

8. The monoaminooxidase inhibitors (MAOIs) and tricyclic
antidepressants (TCAs), although having different modes
of action, their primary effect is to increase the activity of
monoamines in the brain.
This observation, together with other findings, led to
monoamine theory of depression—the idea that depression
arises from a deficit in norepinephrine and/or serotonin
activity, and that antidepressants work by normalizing this
deficit.
This theory led to the development of the next major
class of antidepressants, the selective serotonin reuptake
inhibitors (SSRIs).

9. In order to develop an antidepressant that worked
effectively on the symptoms of depression, but that did
not have the side effects of the MAOIs or the tricyclics, a
systematic search was begun for drugs that selectively
enhance activity of one monoamine, but not others.
The first SSRI, fluoxetine was released in 1987. This
drug and other SSRIs, as the name implies, selectively
inhibit the reuptake of serotonin, and there by increase
serotonin activity in the brain.

10. Generic Name Usual Dosage
in mg.
Half
Life
(hours)
TCAs
Amitryptaline 50—300 31—46
Protryptiline
Imipramine
Trimipramine
Desipramine 50 —300 12—24
MAOIs
Phenelzine 30—90 1.5—4
CLASSIFICATION OF ANTIDEPRESSANTS

11. Isocarboxazid 30—50 —
Tranyl cypromine 20—60 1.5—3.2
SSRIs
Fluoxetine 1—100 2—5 days
Fluvoxamine 25—300 4—6 days
Paroxetine 10—50 5—21
Sertraline 12.5—200 24
Citalopram 10—60 23—45
Miscellaneous
Trazodone 50—400 4—9
Venlafaxine 25—375 3—7
Bupropion 200—300 8 days
Nefazodone 100—600 2—5

12. TRICYCLIC ANTIDEPRESSANTS
Tricyclic antidepressants inhibit the reuptake of the
neurotransmitters, serotonin and norepinephrine into
their respective nerve terminals. Reuptake is the first step
in the process of deactivating these neurotransmitters in
the brain.
After serotonin and norepinephrine are released from
neurons, they are removed from the extracellular space by
transporters, These compounds block the reuptake of
monoamines, thereby elevating levels of noradrenaline and
5-HT. By inhibiting reuptake, the drugs allow serotonin
and norepinephrine to remain active in the synapse longer,
thereby correcting a presumed deficit in the activity of
these neurotransmitters.

13. Chemistry of Tricyclic Antidepressants
The name tricyclic is a little misleading, referring to
the three ring chemical structure but many of the
drugs included in this class may actually contain
anywhere from one to four rings.
Because they are similar in structure to the
neuroleptics (with three rings), there are instances of
overlapping activities. Note the differences in
structure of the central ring. In general, the tricyclic
antidepressants are mood-elevating drugs.
Imipramine and amitriptyline are examples of
tricyclic antidepressants.

14. Amitriptyline
Amitriptyline is 5-(3-dimethylaminopropylidene)-5H-
[a,d]- dibenzo-10,11-dihydro- cycloheptene. However,
it is more potent in blocking the reuptake of
norepinephrine (NE) than 5-HT and much less potent
in blocking the reuptake of dopamine. It causes high
sedation and high weight gain.
Imipramine
Imipramine is the parent tricyclic antidepressant.
Imipramine is 5-(3-dimethylamino- propyl)-10, 11-
dihydro-5H- dibenz-[b, f]-azepine. It has weak D2
postsynaptic blocking, anticholinergic and sedative
activities.

15. Desipramine
Desipramine is 5-(3-methylaminopropyl)-10, 11-
dihydro-5H-dibenz-[b, f]-azepine. Imipramine
metabolism to desipramine is fast and desipramine
levels are higher than imipramine. It causes low
sedation, low weight gain.
Clozapine
This tricyclic dibenzodiazepine derivative has a
chemical formula of 8-chloro-11-(4-me- thyl-1-
piperazinyl)-5H-dibenzo [b, e] [1, 4] diazepine.
Clozapine is administered orally. It in- terferes with
the binding of dopamine molecules at the D1, D2,
D3, D4, and D5 dopamine receptors.

16. Uses of tricyclic antidepressants
1.Tricyclic antidepressants elevate mood, increase
physical activity, normalize appetite and sleep
patterns, and reduce morbid preoccupation in
60%–70% of patients with major depression.
2.Like the other classes of antidepressants,
therapeutic effects of the tricyclics may take from
two to six weeks to appear. Often, the first
symptom to subside is insomnia, followed a few
days later by an increase in activity and an
improvement in concentration and memory.

17. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Selective serotonin reuptake inhibitors (SSRIs) represent a
relatively new class of antidepressant drugs. These drugs
are referred to as “clean” drugs because they primarily
affect only serotonin (in contrast to MAOIs and tricyclics
which affect other monoamines).
Because SSRIs are more targeted, they have a lower
incidence of some of the side effects associated with
tricyclic antidepressants and MAOIs (e.g., blurred vision,
dizziness, constipation, dry mouth).

18. The SSRIs, inhibit reuptake of serotonin. Reuptake is
the first step in the process of deactivating this
neurotransmitter in the brain. After serotonin is released
from neurons, it is removed from the extracellular space
by transporters, or reuptake sites, located on the cell
membrane.
SSRIs block serotonin reuptake sites, allowing
serotonin to remain active in the synapse longer, thereby
correcting a presumed deficit in the activity of this
neurotransmitter.

19. Fluoxetine
Fluoxetine is the most widely used drug in this class. It
is N-methyl-3-phenyl-3-(p- trifluoromethyl)-phenoxy-
propylamine. It is a potent selective inhibitor of 5-HT
reuptake
Paroxetine
Paroxetine is (-)-trans-4-(p-fluorophenyl)-3-((3,4-
(methylenedioxy)phenoxy)methyl) piperidine.
Zimelidine
Zimeldine is (Z)-3-[1(p-bromophenyl)-3-
(dimethylamino) propenyl]pyridine.
Venlafaxine
Venlafaxine is N,N-dimethyl-2-cyclohexanol-3-(p-
methoxyphenylpropylamine.

20. ATYPICAL ANTIDEPRESSANTS
Atypical antidepressants are the newer classification of
neuroleptics. The conventional and atypical
antidepressants work equally well at treating the positive
symptoms of schizophrenia. But the conventional
neuroleptics have minimal effects on the negative
symptoms, the atypical drugs work well to treat this cluster
of symptoms.
The neurological effects are a result of antagonism at D2
receptors. There are side effects (tardive dyskinesia) which
appears mostly with chronic administration of the
conventional antipsychotics. Ex: Venlafaxine, Trazodone,
Nefazodone.