04-Apr-11

Antidepressants

Dr. Hiwa K. Saaed, PhD

Department of Pharmacology & Toxicology
College of Pharmacy
University of Sulaimani

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Antidepressant Drugs

Depression: is a serious disorder that characterized

by:

1. intense feeling of sadness

2. hopelessness and despair
3. as well as the inability to experience pleasure in
usual activities,
4. changes in sleep patterns and appetite,
5. loss of energy and suicidal thoughts.

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Mania
Mania is characterized by the opposite behavior
that is
1. enthusiasm
2. rapid thought and speech patterns
3. extreme self confidence
4. and impaired judgment.

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Major types of depression

The three major types of depression are:

1.Reactive depression, a 2. Bipolar affective (manic-

response to external event depressive) disorder:

adverse life events,
expansive mood,

grief,
grandiosity,

physical illness,
inflated self-esteem,

and drugs (reserpine).
pressured speech,

flight of ideas,

and poverty of sleep.

3. Major depressive disorder

(unipolar, endogenous depression):

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Major types of depression

3. Major depressive disorder (unipolar, endogenous
depression):
a depression of mood without any obvious medical or
situational causes, manifested by

inability to cope with ordinary events or
experience pleasure,

anorexia, with significant weight loss,

insomnia,

fatigue

and inability to concentrate.

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Biologic Amine Hypothesis

Depression is due to deficiency in neuronal and synaptic

catecholamine concentration, such as NE and 5-HT at certain
key sites in the brain.

Mania: excess amines

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Biologic Amine Hypothesis

This theory was based on observations that:
1. Most clinically useful antidepressant drugs potentiate, either
directly or indirectly, the actions of norepinephrine (NE)
and/or serotonin (5-HT) in the brain.
2. Reserpine (which was used to Rx schizophrenia and HTN)
caused sever depression in ~15% of patients. This drug
depletes neuronal stotres of monoamines.
3. Iproniazide used to treat TB sometimes induced euphoria,.
This drug prevents metabolic degradation of monoamine by
inhibiting the enzyme monoamine oxidase

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Mechanism of action
Although antidepressant drugs may cause
changes in brain amine activity within hours,
weeks may be required for them to achieve
clinical effects!!!!

Q. What is happen in depression?

1. The monoamine in the limbic system are
depleted→upregulation of postsynaptic β
receptor & presynaptic α2, 5-HT2A, 5-HT2C.

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Q. What is antidepressant do?

1. Antidepressant drug decrease the
presynaptic inhibitory receptor
densities in the brain over a two-
to four-week period
(upregulation→downregulation).

2. This downregulation of receptors

permits greater synthesis and
release of neurotransmitters into
the synaptic cleft and enhanced
signalling in the postsynaptic
neurons, presumably leading to
therapeutic response.
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Drug categories
Class drugs
TCA Imipramine, Amitriptyline, Cloimpramine,
Doxepin, Trimpramine
Heterocyclic Desipramine, Nortriptyline, Amoxapine,
Maprotiline, Portriptyline
5-HT/NE RIs Venlafaxine, Duloxetine
Atypical Bupropion, Mirtazapine Nefazodone,
Trazodone
SSRIs Fluoxetine, Citalopram, Escitalopram,
Fluvoxamine, Paroxetine, Sertraline
MAOIs Phenelzine, Moclobemide, Isocarboxazid,
Tranylcypromine

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Classification:
*SSRI:
1. fluoxetine
2. citalopram
3. paroxetine
4. sertraline
5. Fluvoxamine

*5-HT/NE RI:
1. venlafaxine
2. duloxetine

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Classification:
*atypical antidepressants :
1. bupropion
2. mirtazapine
3. nefazodone
4. trazodon
*monoamine oxidase inhibitors (MAOIs):
1. phenelzine
2. Moclobemide
3. isocarboxazide
4. tranylcypromine

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Chemical Classification:
*cyclic antidepressants:
Tricyclic (TCA)
1. Imipramine
2. Amitryptiline
3. Clomipramine
4. Doxepin
5. trimipramine
Heterocyclic
1. Desipramine
2. Nortriptylinr
3. Amoxapine
4. Maproltiline
5. protriptylline

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Selective serotonin reuptake inhibitors

a group of chemically unique drugs

They specifically inhibit serotonin reuptake,

They have 300 to 3000 fold greater selectivity
for the serotonin transporter as compared to
the norepinephrine transporter .

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Actions

They typically take 2 to 12 weeks to
produce improvement in mood

SSRI have little ability to block the
dopamine transporter.

SSRI have little blocking activity at
muscarinic, α-adrenergic, and
histaminic H1 receptors (fewer side
effects).

They are well tolerated by
 patients with heart disease
 the elderly, who are especially sensitive
to the anticholinergic and orthostatic
effects of the TCA.
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Therapeutic uses of SSRIs:

1. Depression.
2. Obsessive compulsive disorder (the only indication
for fluvoxamine ).
3. Panic disorder .
4. Generalized anxiety .
5. Premenstrual dysphoric disorder .
6. Bulimia nervosa .

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Pharmacokinetics

All the SSRIs are well absorbed after oral

administration,

Only sertraline undergoes significant first-
pass metabolism.

Fluoxetine (Prozac) and Sertraline (Zoloft)
are given in the morning because of its
potential for being activating and causing
insomnia.

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The majority of SSRIs have plasma half-lives that

range between 16 and 36 hours

Metabolism by P450-dependent enzymes and
glucuronide or sulphate conjugation occur
extensively.

Excretion of SSRIs is primarily through the
kidneys, except for paroxetine and sertraline,
which also undergo fecal excretion.

Fluoxetine differs from the other members of the
class in two respects :
1. It has a much longer half-life (50hrs).
2. The metabolite is as potent as the parent
compound . the half-life of the metabolite is quite
long, ~10 days.

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Fluoxetine and paroxetine are potent

inhibitors of a hepatic CYP P450
isoenzyme (CYP2D6) responsible for the
elimination of TCA drugs, neuroleptic
drugs, and some antiarrhythmic and β-
adrenergic antagonist drugs.
Note; about 7% of the white population lack
(CYP2D6) and, therefore matabolize
fluoxetine very slowly.

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Adverse affects :

With initiation of therapy with an SSRI, some
patients describe anxiety or agitation.

Insomnia

Paroxetine and fluvoxamine are sedating,
and may be useful in patients who have
difficulty sleeping.

Conversely, patients who are fatigued may
benefit from one of the more activating
antidepressants, such as fluoxetine.

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Adverse effects

Sexual dysfunction: loss of libido, delayed
ejaculation, and anorgasmia.
replace the offending antidepressant with a drug
having fewer sexual side effects, such as Bupropion
or mirtazapine.

The SSRIs tend to be weight neutral with the
exception of paroxetine (Paxil), which is associated
with weight gain.

Use in children and teenagers: 1/50 children
become more suicidal as a result of SSRIs
treatment.

Serotonin syndrome

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Serotonin syndrome

All SSRIs have the potential to cause a

serotonin syndrome when used in the
presence of MAOIs
characterized by:

hyperthermia,

muscle rigidity,

myoclonus

and changes in mental status and vital signs.

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Serotonin/NE re-uptake inhibitor:

Venlafaxine and duloxetine,
selectively inhibit the reuptake of both
serotonin and NE.

May be effective in treating depression
and neuropathic pain (such as
backache and muscle aches) in
patients in which SSRIs are
ineffective.

SNRIs, unlike the TCAs, have no
activity at adrenergic, muscarinic, or
histamine receptors and thus have
fewer side effects than the TCAs.

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Venlafaxine
1. Venlafaxine: Is a potent inhibitor of serotonin
reuptake and, at higher doses, is an inhibitor of NE
reuptake. It is also a mild inhibitor of dopamine
reuptake.

It has minimal inhibition of the CYP P450
isoenzymes. The t1/2 of the parent compounds plus
its active metabolite is approximately 11 hours.

SE: nausea, dizziness, insomnia, sedation, and
constipation. At high doses, there may be an
increase in blood pressure..

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Duloxetine
2. duloxetine :inhibits serotonin and NE
reuptake at all doses.
3. It is extensively metabolized in the liver to
numerous metabolites, should not be
administered to patients with hepatic
insufficiency. Metabolites are excreted in
the urine.
4. Food delays the absorption of the drug. t1/2
is ~12 hours.

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Side effects of Duloxetine include:

nausea,

dry mouth,

and constipation are common.

Insomnia,

dizziness,

somnolence,

sweating.

Sexual dysfunction also occurs.
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Atypical antidepressants
They are a mixed group of agents that have actions at
several different sites.
1. Bupropion:

Acts at unidentified site. It has minimal effects on NE
or 5-HT systems, but blocks DA reuptake.

Its short half-life may require more than once-a-day
dosing or the administration of an extended release
formulation, it decreases the craving of nicotine in
tobacco abusers.

Side effects include: dry mouth ,sweating ,tremor and
seizures at high doses.

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2. Mirtazapine:

block 5-HT2 and α2 receptors.

It is a sedative because of its potent
antihistaminic activity, which may be used to
advantage in depressed patients having
difficulty sleeping,

but it does not cause the antimuscarinic SEs
of TCAs,

Does not interfere with sexual functioning, as
do the SSRIs.

Increased appetite and weight gain frequently
occur.
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Nefazodone and trazodone:

Nefazodone (P450 inhibitor) blocks both NE
and 5-HT reuptake, and is a 5-HT2 antagonist,

trazodone weak inhibitor of serotonin reuptake
by blocking 5-HT1 presynaptic autoreceptors
and thereby, increase serotonin release, and is
a 5-HT2 antagonist.

Both are sedating because of potent H1
blocking activity.

Trazodone has been associated with causing
priapism.
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Tricyclic antidepressants (TCAs)

Tertiary amines; imipramine (prototype),

amitriptyline, clomipramine, doxepin and
trimipramine

Secondary amines; desipramine, and
nortryptyline (N-demethylated metabolites of
imipramine and amitriptyline respectively),
amoxapine, maprotiline, and protriptyline.

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Tricyclic antidepressants (TCAs):

Mechanism of action:

Inhibition of neurotransmitter (serotonin and
NE) uptake: ↑adrenergic and serotonergic
neurotransmission.

Blocking of four receptors: serotonergic, α-
adrenergic, histaminic, and muscarinic
receptors.
actions at these receptors are probably
responsible for many of the untoward
effects of TCAs.
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Mechanism of action:

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Therapeutic uses

Sever major depression,

phobic and panic anxiety disorders,

Neuropathic pain,

obsessive compulsive disorder (OCD),

nocturnal enuresis; Imipramine has been
used to control bed-wetting in children (older
than six years) by causing contraction of the
internal sphincter of the bladder.

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Adverse effects:

Muscarinic blockade leads to blurred vision,

xerostomia (dry mouth), urinary retention,
constipation, and aggravation of glaucoma and
epilepsy.

Sympathomimetic: Increased catecholamine
activity results in tremor, and cardiac
overstimulation, arrhythmia.

α-adrenergic receptors blockade, causing
orthostatic hypotension and reflex tachycardia.
Imipramine is most likely and nortriptyline is least
likely to cause orthostatic hypotension.

H1 receptors blockade; Sedation
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Adverse effects

Metabolic: Weight gain is a common adverse

effect of the TCAs.

Endocrine: Sexual dysfunction, as evidenced
by erectile dysfunction in men and
anorgasmia in women.

Drug interactions:

Hyperthermia, seizures, coma, and death with
MAOIs, serotonin syndrome with SSRIs,

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Monoamine Oxidase inhibitors

Mechanism of action :

They increase stores of
norepinephrine ,serotonin and
dopamine within the neuron and
subsequent diffusion of excess
neurotransmitter into the synaptic
space.

These drugs inhibit not only
monoamine oxidase in the brain but
also peripheral oxidase, therefore
MAOIs show a high incidence of drug-
drug and drug-food interactions .

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Therapeutic uses

1. Indicated for depressed patients who are

unresponsive or allergic to TCAs.

1. Patient with low psychomotor activity.

1. Treatment of phobic states .

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Adverse effects

Individuals receiving MAOIs are unable to degrade

tyramine obtained from the diet ,tyramine causes the
release of large amounts of stored catecholamine
from nerve terminals ,resulting in headache
,tachycardia ,nausea ,hypertension ,cardiac
arrhythmias and stroke .

Other side effects include :drowsiness ,orthostatic
hypotension ,blurred vision ,dry mouth ,dysuria and
constipation .

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Treatment of mania and bipolar disorder

Lithium salts , Carbamazepine and Valporic acid

For more than 40 years, Lithium (Li+) has

been used to treat mania.

lithium carbonate is effective in 60 to 80% of
all acute manic episodes within 5 to 21 days of
beginning treatment.

Because of its delayed onset of action in the
manic patient, Li+ is often used in conjunction
with low doses of high-potency anxiolytics
(e.g.,lorazepam) and antipsychotics
(e.g.haloperidol) to stabilize the behaviour of
the patient..
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Mechanism of action:

Lithium interferes with the resynthesis

(recycling) of PIP2, by inhibition of the
dephosphorylation of both IP2 to IP1, and IP1
to IP, necessary steps in the recycling of
inositol→↓ PIP2 in neuronal membranes of
the CNS.

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Mechanism of LI+ action

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Lithium is given orally, and the ion is excreted

by the kidney like Na+;

low Na+ diet or chronic diuretic treatment
enhances toxicity, medical conditions
(diarrhoea), or physical activities (those that
induce sweating) that deplete the body of
Na+.

Lithium salts are very toxic. Their safety
factor and therapeutic index are extremely
low- comparable to those of digitalis.
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Adverse effects

ataxia, tremors, confusion, convulsions,

acne, edema,

visual dysfunction,

goiter,

hypothyroidism;

nephrogenic diabetes insipidus (treat with
amiloride, not thiazides),

teratogenicity (cardiac malformations,
neonatal cyanosis, and hepatomegaly);

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Other Mood-Stabilizing Agents

Several anticonvulsant; Valproic acid and
carbamazepine are the best studied to date.

In 1995, valproic acid was approved by the
FDA for treatment of acute mania and is
now considered a first-line agent.

In pregnancy clonazepam or gabapentin are
preferred.

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Other Mood-Stabilizing Agents

Other anticonvulsants under investigation

include lamotrigine and topiramate.

The atypical antipsychotic agent olanzapine
received FDA approval in 2000 for use in
acute mania and mixed episodes associated
with bipolar disorder.

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