Profiling Antidepressants by Charles Vannoy

Profiling Antidepressants
by Charles Vannoy
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 don’t
seem to be working properly).
They increase the activity of these chemicals
in our brains
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
Antidepressants Available in the
Market (Worldwide)1
1) Tricyclics and Tetracyclics (TCA)
Imipramine Doxepin
Maprotiline Clomipramine Amitriptyline
2) Monoamine Oxidase Inhibitors (MAOIs)
3) Serotonin Selective Reuptake Inhibitors (SSRIs)
Fluoxetine Fluvoxamine
Sertraline Paroxetine Citalopram
4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)
5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)
6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)
7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)
8) Noradrenalin Specific Reuptake Inhibitor (NRI)
9) Serotonin Reuptake Enhancer
Tricyclic Antidepressants (TCAs)
Between 1960 and 1980 tricyclic antidepressants (TCAs)
represented the major pharmacological treatment for
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
(α1) 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
Imipramine hydrochloride is
a member of the
dibenzazepine group of
compounds. It is designated
Dimethylamino)propyl]10,11- ihydro-5H-dibenz
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,
Amitriptyline HCl is
3-(10,11-dihydro-5Hdibenzo [a,d]
hydrochloride. Its
empirical formula is
Amitriptyline cont’d
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
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 C17H18F3NO•HCl.
Fluoxetine (Prozac) cont’d
Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and Sfluoxetine 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
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
Fluoxetine Dosage and Side
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 C17H17NCl2·HCl.
Sertraline (Zoloft) cont’d
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
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 widelyused 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
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 (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 [α- (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) cont’d
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 Senantiomer 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
Venlafaxine (Effexor) cont’d
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
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
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
Bupropion is designated as
(±)-1-(3-chlorophenyl)-2[(1,1-dimethylethyl)amino]-1propanone hydrochloride.
The empirical formula is
Bupropion (Wellbutrin, [SR], [XL])
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
75 mg
100 mg
Wellbutrin SR
100 mg
Wellbutrin SR
150 mg
Wellbutrin SR
200 mg
Zyban SR
150 mg
Wellbutrin XL
150 mg
Wellbutrin XL
300 mg
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.
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
Each day looks brighter and brighter for the
advancement of newer and better
(1) Ayflegül, Y., Saffet, A.G., Tamam, L. Mechanism of actions of antidepressants: beyond the
receptors. Klinik Psikofarmakoloji Bulteni, (2002), 12(4), 194-200.
(2)Wellbutrin. GlaxoSmithKline. 15 Nov 2004
(3) Bupropion. Wikipedia Online Encyclopedia. 14 Oct 2004
(4) Bupropion. Clinical Pharmacology. 10 Nov 2004
(5) Wellbutrin. 2004. Encyclopedia of Medicine. HealthSquare. 14 Oct 2004
(6) Fluoxetine. Wikipedia Online Encyclopedia. 14 Oct 2004
(7) Fluoxetine. Clinical Pharmacology. 11 Nov 2004
(8) Prozac. 2004. Encyclopedia of Medicine. HealthSquare. 14 Oct 2004
(9) Venlafaxine. Wikipedia Online Encyclopedia. 9 Nov 2004
(10) Venlafaxine. Clinical Pharmacology. 12 Nov 2004
(11) Wellington K, Perry CM. Venlafaxine Extended Release: A Review of its Use in the Management
of Major Depression. CNS Drugs (2001), 15, 643-669