Antidepressants

Prajogo Wibowo

What are antidepressants???

Drugs that are used to relieve or prevent
psychic depression.
Work by altering the way in which specific
chemicals, called neurotransmitters, work in
our brains (i.e. in the case of depression,
some of the neurotransmitter systems dont
seem to be working properly).
They increase the activity of these chemicals
in our brains

History

Antidepressants were first developed in the 1950s and

have been used on a regular basis since then.
There are many different types, for example, the older
tricyclics and the newer SSRIs (Selective Serotonin
Reuptake Inhibitors).

These two types account for about 95% if the

antidepressants prescribed.

Now there are newer, more popular types, such as SNRI

(Dual Serotonin and Norepinephrine Reuptake Inhibitor)
and NDRI (Norepinephrine and Dopamine Reuptake
Inhibitor)

Antidepressants
Classification

1) Tricyclics and Tetracyclics (TCA)

Imipramine
Doxepin
Desipramine
Amoxepine
Trimipramine
Maprotiline
Clomipramine Amitriptyline
Nortriptyline
Protriptyline
2) Monoamine Oxidase Inhibitors (MAOIs)
Tranylcypramine
Phenelzine Moclobemide
3) Serotonin Selective Reuptake Inhibitors (SSRIs)
Fluoxetine
Fluvoxamine
Sertraline
Paroxetine Citalopram
4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)
Venlafaxine
Duloxetine
5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)
Nefazodone
Trazodone
6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)
Bupropion
7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)
Mirtazapine
8) Noradrenalin Specific Reuptake Inhibitor (NRI)
Reboxetine
9) Serotonin Reuptake Enhancer
Tianeptine

Tricyclic Antidepressants (TCAs)

Between 1960 and 1980 tricyclic antidepressants (TCAs)

represented the major pharmacological treatment for
depression.
They have been considered a homogeneous group of
drugs differing mostly in their potency to inhibit
presynaptic norepinephrine or serotonin uptake and in
their propensity for causing variety of unwanted effects.
The TCAs induce anticholinergic, antihistaminergic, and
cardiotoxic side effects which are related to their action
on muscarinic (mainly M1), histamine (H1), adrenergic
(1) receptors and cardiac Na+ and Ca2+ channels.

TCA Drugs

The first tricyclic

antidepressant discovered
was imipramine, which was
discovered accidentally in a
search for a new
antipsychotic in the late
1950s.
Imipramine hydrochloride is
a member of the
dibenzazepine group of
compounds. It is designated
5-[3-( Dimethylamino)propyl]10,11- ihydro-5H-dibenz [b,1azepine] Monohydrochloride.

Imipramine (Tofranil)

Imipramine (Tofranil)

Imipramine is the prototypic tricyclic

antidepressant utilized in the treatment of
major depression and exerts its therapeutic
efficacy only after prolonged administration.
The mechanism of action of imipramine
hydrochloride is not definitely known. However,
it does not act primarily by stimulation of the
central nervous system. The clinical effect is
hypothesized as being due to potentiation of
adrenergic synapses by blocking uptake of
norepinephrine at nerve endings.

Amitriptyline (Elavil, Tryptanol,

Endep)

Amitriptyline HCl is
3-(10,11-dihydro-5Hdibenzo [a,d]
cycloheptene-5ylidene)-N,Ndimethyl-1propanamine
hydrochloride. Its
empirical formula is
C20H23NHCl.

Amitriptyline

Amitriptyline

Amitriptyline HCl is an antidepressant with sedative

effects. Its mechanism of action is not known. It is not a
monoamine oxidase inhibitor and it does not act primarily
by stimulation of the central nervous system.
Amitriptyline inhibits the membrane pump mechanism
responsible for uptake of norepinephrine and serotonin in
adrenergic and serotonergic neurons. Pharmacologically
this action may potentiate or prolong neuronal activity
since reuptake of these biogenic amines is important
physiologically in terminating transmitting activity. This
interference with the reuptake of norepinephrine and/or
serotonin is believed by some to underlie the
antidepressant activity of amitriptyline.

Side Effects of TCAs

The side effects of tricyclic antidepressant may

include drowsiness, anxiety, restlessness, dry
mouth, constipation, urinary retention or
difficulty with urination, cognitive and memory
difficulties, weight gain, sweating, dizziness,
decrease in sexual ability and desire, muscle
twitches, weakness, nausea, increased heart
rate and irregular heart rhythms (rare). Some
of these side effects relate to their
anticholinergic properties.

Selective Serotonin Reuptake

Inhibitors (SSRIs)

The SSRIs are currently the most widely utilized class of

antidepressants in clinical practice.
They act within the brain to increase the amount of the
neurotransmitter, serotonin (5-hydroxytryptamine or 5-HT), in
the synaptic gap by inhibiting its re-uptake.
Instead of being discovered by accident, SSRIs were
specifically designed while considering the biological causes
of depression.
SSRIs are described as 'selective' because they affect only
the reuptake pumps responsible for serotonin, as opposed
to earlier antidepressants, which affect other monoamine
neurotransmitters as well. Because of this, SSRIs lack some
of the side effects of the more general drugs.

SSRI Drugs

Fluoxetine

Sertraline

SSRI drugs include many of the popular drugs

on the market today
They include Fluoxetine (Prozac) and
Sertraline (Zoloft).

Fluoxetine (Prozac)

Fluoxetine, also known as Prozac, was initially approved

for treatment of depression in Belgium in 198617, and
then Eli Lilly's Prozac was approved by the FDA on
December 27th 1987 and introduced in the United States
at the beginning of 1988.
Prozac was the first of a new class of drugs, called
selective serotonin reuptake inhibitors (SSRIs), to be
approved for use in the United States.
Fluoxetine hydrochloride is an antidepressant for oral
administration. It is chemically unrelated to tricyclic,
tetracyclic, or other available antidepressant agents. It is
designated ()-N-methyl-3-phenyl-3-[(a,a,a-trifluoro-ptolyl)-oxy]propylamine hydrochloride and has the empirical
formula of C17H18F3NOHCl.

Fluoxetine (Prozac)

Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine

enantiomers, where both enantiomers are specific and potent serotonin
uptake inhibitors with essentially equivalent pharmacologic activity. But,
the S-fluoxetine enantiomer is eliminated more slowly and is the
predominant enantiomer present in plasma at steady state.
The body eliminates Fluoxetine very slowly. The half-life of fluoxetine
after a single dose is 2 days and after multiple dosing 4 days. The liver
then metabolizes fluoxetine into norfluoxetine, a desmethyl metabolite,
which is also a serotonin reuptake inhibitor; norfluoxetine has an even
longer half-life, i.e. 8.6 and 9.3 days for single and repeated dosage
respectively.
Because fluoxetine's metabolism involves the P450IID6 system,
concomitant therapy with drugs also metabolized by this enzyme system
(such as the tricyclic antidepressants) may lead to drug interactions.
Hence, the complexity of the metabolism of fluoxetine has several
consequences that may potentially affect fluoxetine's clinical use.

Fluoxetine Dosage and Side

Effects

It is marketed in capsules containing 10, 20, or

40 mg of active ingredient or in tablets
containing 10 mg. Dosages in the range of 2060 mg per day are standard, with 80 mg
considered a maximum.
Fluoxetine has a wide range of published
interactions, notably with monoamine oxidase
inhibitors. Common side-effects include
anxiety, restlessness, trembling, weakness,
skin rash, anorgasmia, itching, and a decrease
in sexual drive.

Sertraline (Zoloft)

Sertraline HCl is a selective serotonin reuptake

inhibitor (SSRI) for oral administration. It is
chemically unrelated to other SSRIs, tricyclic,
tetracyclic, or other available antidepressant
agents. Sertraline hydrochloride has the
following chemical name: (1S-cis)-4-(3,4dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1nanphthalenamine hydrochloride. The
empirical formula is C17H17NCl2HCl.

Sertraline (Zoloft)

The mechanism of action of sertraline is presumed to be linked

to its inhibition of CNS neuronal uptake of serotonin (5HT).
In vitro studies have shown that sertraline has no significant
affinity for adrenergic (alpha1, alpha2, beta), cholinergic,
GABA, dopaminergic, histaminergic, serotonergic (5HT1A,
5HT1B, 5HT2), or benzodiazepine receptors; antagonism of
such receptors has been hypothesized to be associated with
various anticholinergic, sedative, and cardiovascular effects for
other psychotropic drugs. Sertraline does not inhibit
monoamine oxidase.
Sertraline undergoes extensive first pass metabolism. The
principal initial pathway of metabolism for sertraline is Ndemethylation. N-desmethylsertraline has a plasma terminal
elimination half-life of 62 to 104 hours.

Sertraline Dosage and Side

Effects

Sertraline is manufactured by Pfizer as small green

25 mg tablets, blue 50 mg tablets, or off-yellow 100
mg tablets. It is used in dosages of between 25 mg
and a maximum of 200 mg per day.
It has a number of adverse effects including
insomnia, asthenia, gastrointestinal complaints,
tremours, confusion, and dizziness; it can induce
mania or hypomania in around 0.5% of patients. One
property of sertraline is that it appears to be also a
minor inhibitor of dopamine reuptake.

Serotonin and Noradrenaline

Reuptake Inhibitors (SNRIs)

Serotonin norepinephrine reuptake inhibitors (SNRIs) are a class of

antidepressant used in the treatment of clinical depression and
other affective disorders.
They act upon two neurotransmitters in the brain that are known to
play an important part in mood, namely, serotonin and
norepinephrine. This can be contrasted with the more widely-used
selective serotonin reuptake inhibitors (SSRIs), which act only on
serotonin.
SNRIs were developed more recently than SSRIs, and there are
relatively few of them. Their efficacy as well as their tolerability
appears to be somewhat better than the SSRIs, owing to their
compound effect.
These new drugs, because of their specificity for the serotonin and
norepinephrine reuptake proteins, lack most of the adverse side
effects of tricyclic antidepressants and monoamine oxidase
inhibitors.

SNRI Drugs

SNRIs are currently

some of the newest
antidepressant drugs
available on the
market, and due to
this there are only a
few selected drugs
that have been
approved by the FDA
for use.

Venlafaxine

Venlafaxine (Effexor)

Venlafaxine hydrochloride is a prescription antidepressant

first introduced by Wyeth in 1993, and marketed under
the tradename Effexor. It is used primarily for the
treatment of depression, generalized anxiety disorder,
and social anxiety disorder in adults. The chemical
structure of Venlafaxine is designated (R/S)-1-[2(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol
hydrochloride or ()-1-[a [- (dimethylamino)methyl] pmethoxybenzyl] cyclohexanol hydrochloride and it has the
empirical formula of C17H27NO2 HCl.
Venlafaxine is the first and most commonly used SNRI.

Venlafaxine (Effexor)

Venlafaxine has a single chiral centre and exists

as a racemic mixture of R-()- and S-(+)enantiomers. The R-enantiomer exhibits dual
presynaptic inhibition of serotonin and
noradrenaline reuptake, while the S-enantiomer
is predominantly a serotonin reuptake inhibitor.
In vitro, venlafaxine is approximately 3- to 5-fold
more potent at inhibiting serotonin than
noradrenaline reuptake. It has low affinity for
muscarinic cholinergic, histamine H1 and
adrenergic receptors.

Venlafaxine (Effexor)

The mechanism of the antidepressant action of

venlafaxine in humans is believed to be associated with
its potentiation of neurotransmitter activity in the CNS.
Venlafaxine and its active metabolite, Odesmethylvenlafaxine (ODV), are potent inhibitors of
neuronal serotonin and norepinephrine reuptake and
weak inhibitors of dopamine reuptake. Venlafaxine and
ODV have no significant affinity for muscarinic,
histaminergic, or a-1 adrenergic receptors
Venlafaxine is primarily metabolized by the cytochrome
P450 (CYP) 2D6 isoenzyme, with the CYP3A3/4 system
providing a secondary metabolic pathway. The drug only
modestly inhibits CYP2D6, and its metabolite has no
effect on this isozyme.

Venlafaxine Dosage and Side

Effects

Prescribed dosages are typically in the range of 75mg225mg per day, but higher dosages are sometimes used
for the treatment of severe or treatment-resistant
depression. Because of its relatively short half-life of 4
hours, Effexor should be administered in divided dosages
throughout the day.
Side effects may include nausea, dizziness, sleepiness,
abnormal ejaculation, sweating,dry mouth, gas or
stomach pain, abnormal vision, nervousness, insomnia,
loss of appetite, constipation, confusion/agitation,
tremors, and drowsiness.

Norepinephrine and Dopamine

Reuptake Inhibitor (NDRI)

These are a class of antidepressants that are

not really categorized as a special group of
antidepressants.
The only antidepressant in this group is
Bupropion, which is an antidepressant of the
aminoketone class, chemically unrelated to
tricyclics or SSRIs. It is similar in structure to
the stimulant cathinone, and to
phenethylamines in general.

Bupropion (Wellbutrin, [SR], [XL])

Bupropion was first

synthesized by Burroughs
Research in 1966, and
patented by BurroughsWellcome (later GlaxoWellcome) in 1974. It was
approved by the FDA in 1985
and marketed under the
name Wellbutrin as an
antidepressant.
Bupropion is designated as
()-1-(3-chlorophenyl)-2[(1,1-dimethylethyl)amino]-1propanone hydrochloride.
The empirical formula is
C13H18ClNOHCl.

Bupropion

Bupropion (Wellbutrin, [SR], [XL])

contd

Bupropion is a selective catecholamine (norepinephrine

and dopamine) reuptake inhibitor. It has only a small
effect on serotonin reuptake. It does not inhibit MAO. The
actual mechanism behind bupropion's action is not
known, but it is thought to be due to the effects on
dopaminergic and noradrenergic mechanisms.
Bupropion is metabolised in the liver. It has at least three
active metabolites; hydroxybupropion,
threohydrobupropion and erythrohydrobupropion. These
active metabolites are further metabolised to inactive
metabolites and eliminated through excretion into the
urine. The half-life of bupropion is 20 hours as is
hydroxybupropion's. Threohydrobupropion's half-life is 37
hours and erythrohydrobupropion's 33 hours.

Bupropion and its Metabolites

Bupropion Dosage

Wellbutrin pills are

available in three
forms: immediate
release, sustained
release (SR) and
extended release (XL).
Generic forms of
immediate and
sustained release are
available.

Name

Dosage

Color

Wellbutrin

75 mg

yellow-gold

Wellbutrin

100 mg

red

Wellbutrin SR

100 mg

blue

Wellbutrin SR

150 mg

purple

Wellbutrin SR

200 mg

pink

Zyban SR

150 mg

purple

Wellbutrin XL

150 mg

white

Wellbutrin XL

300 mg

white

Bupropion Side Effects

Common side effects include dry mouth,

tremors, anxiety, loss of appetite, agitation,
dizziness, headache, excessive sweating,
increased risk of seizure, and insomnia.
Bupropion causes less insomnia if it is taken
just before going to bed.
Sexual side effects normally accompanying
SSRI's do not accompany bupropion.
Interestingly, patients commonly report
increased libido, perhaps evidence of its
dopaminergic properties.

Conclusion

Over the past half century there have been

many new advances in antidepressants.
Continued progress in understanding the
neurobiology of antidepressant drugs will lead
to further identification of the phenomenon of
how the drugs act and work and development
of more effective and faster acting therapeutic
agents.
Each day looks brighter and brighter for the
advancement of newer and better
antidepressants.

References

(1) Ayegl, Y., Saffet, A.G., Tamam, L. Mechanism of actions of antidepressants: beyond the
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Psikofarmakoloji Bulteni, (2002), 12(4), 194-200.
(2)Wellbutrin. GlaxoSmithKline. 15 Nov 2004
<http://us.gsk.com/products/assets/us_wellbutrinXLpdf>
(3) Bupropion. Wikipedia Online Encyclopedia. 14 Oct 2004
http://en.wikipedia.org/wiki/Bupropion
(4) Bupropion. Clinical Pharmacology. 10 Nov 2004
http://www.rxlist.com/cgi/generic/buprop_cp.htm
(5) Wellbutrin. 2004. Encyclopedia of Medicine. HealthSquare. 14 Oct 2004
http://www.healthsquare.com/newrx/WEL1488.HTM
(6) Fluoxetine. Wikipedia Online Encyclopedia. 14 Oct 2004
<http://en.wikipedia.org/wiki/Fluoxetine>
(7) Fluoxetine. Clinical Pharmacology. 11 Nov 2004
http://www.rxlist.com/cgi/generic/fluoxetine_cp.htm
(8) Prozac. 2004. Encyclopedia of Medicine. HealthSquare. 14 Oct 2004
<http://www.healthsquare.com/newrx/PRO1362.HTM>
(9) Venlafaxine. Wikipedia Online Encyclopedia. 9 Nov 2004
http://en.wikipedia.org/wiki/Venlafaxine
(10) Venlafaxine. Clinical Pharmacology. 12 Nov 2004
<http://www.rxlist.com/cgi/generic/venlafax_cp.htm>
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