1/12/15

Antidepressant
Agents
REGIE A. LAYUG, MD
San Beda College of Medicine
San Beda College
Mendiola, Manila

January 2015

Depression
Depressed mood or loss of interest in
daily ac?vi?es > 2 weeks
Mood change from baseline
Impaired social, occupa?onal and
educa?onal func?oning
At least 5 specic symptoms:
Depressed mood or irritability
Decreased interest or pleasure in most
ac?vi?es
Signicant weight or appe?te change
Change in sleep
Change in ac?vity
Fa?gue or loss of energy
Guilt/worthlessness
Concentra?on
Suicidality

NEUROTROPHIC HYPOTHESIS
Depression is associated with
loss of neurotrophic support
Brain-derived neurotrophic
factor (BNDF)
Atrophic structural changes
in hippocampus (contextual
memory and HPA axis
regula?on) and medial
frontal cortex (memory,
learning and emo?on) and
anterior cingulate
(integra?on of emo?onal
s?muli and aSen?on
func?ons)

The neurotrophic hypothesis of major depression. Changes in trophic factors (especially brain -derived neurotrophic
factor, BDNF) and hormones appear to play a major role in the development of major depression (A). Successful
treatment results in changes in these factors (B). CREB, cAMP response element-binding (protein). BDNF, brain derived neurotrophic factor.
(Redrawn, with permission, from Nestler EJ: Neurobiology of depression. Neuron 2002;34[1]:13!25.)

Several lines of evidence support the neurotrophic hypothesis. Animal and human studies indicate that
stress and pain are associated with a drop in BDNF levels and that this loss of neurotrophic support
contributes to atrophic structural changes in the hippocampus and perhaps other areas such as the medial
frontal cortex and anterior cingulate. The hippocampus is known to be important both in contextual
memory and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Likewise, the anterior cingulate
plays a role in the integration of emotional stimuli and attention functions, whereas the medial orbital
frontal cortex is also thought to play a role in memory, learning, and emotion.
Over 30 structural imaging studies suggest that major depression is associated with a 5!10% loss of
volume in the hippocampus, although some studies have not replicated this finding. Depression and chronic

1/12/15

MONOAMINE HYPOTHESIS

stress

states

medial

have

orbital

increase

as

also

frontal

been

cortex.

function

of

the

associated
Loss

of

with

volume

duration

of

substantial

in

structures

illness

and

the

loss
such

of

volume

as

amount

the

of

in

the

anterior

hippocampus

time

that

the

cingulate

also

appears

depression

and

to

remains

untreated.
Another
direct
and

source

effects

lateral

classes
(but

of

not

of

and

with

of

evidence

BDNF

on

of

supporting

emotional

rodents
are

the

support

be
in

in

with

with

Direct

hypothesis

infusion

increase

BDNF

and

on

drop
B

may

of

of

in

BDNF

is

depression

BDNF

effect
in

levels

models.

into

animal
levels

the

also

comes

animal

from

with

thought

appear

to

studies

to

of

the

hippocampus,

Moreover,
models

associated

interventions

therapy,

midbrain,

models.

in

consistently

Other

all

with

known

chronic

increased

be

robustly

effective

in

stimulate

the

BDNF

models.

data

receptor

trials

an

in

animal

electroconvulsive
animal

animal

kinase

clinical

neurotrophic

antidepressant - like

these

the

associated

tyrosine

the

an

increase

in

including

neurogenesis

to

to

in

levels

regulation.

This

hippocampus
depression,

seem

BDNF

has

associated

administration.

in

appears

decrease

the

in

role

BDNF

activity.

be

of

neurotrophic

levels

in

the

Conversely,

associated

with

an

factors

in

cerebrospinal

administration
increase

in

stress

fluid
of

states.

and

serum

as

well

antidepressants

hippocampus

volume

in

patients.
evidence

concept.

anxious

have

in

proposed
are

supports

Animal

behaviors

found

decrease
A

there
been

major

hippocampus

studies

Depression
as

increases
some
Much
this
or

of

ventricles

antidepressants

acute)

neurogenesis
treatment
levels

Human

Depression is related to a
deciency in the amount or
func?on of cor?cal and limbic
serotonin (5-HT),
norephinephrine (NE), and
dopamine (DA)

an

the

to

be

neurotrophic

studies
that

increase

depressive

in

BDNF

would

in

BDNF

be

for

the

for

associated

hypothesis

knockout

expected

levels

behaviors

explanation

polymorphisms

found

with

after

with

that

mice
a

of

yield

anxiety

depression,

have

not

on

of

of

social

injections
the

very
and

role

but

always

deficiency

types

ventricle

findings

may

altered

with

some

lateral

discrepant

BDNF

not

all

evidence

suggested

BDNF.
stress

of

of

different

In

an

an

is

consistent

increase

addition,

and

some

increase

in

with

depressive

animal

rather

studies

than

BDNF.

neurotrophic
effects.

depressive

factors

Mutations

behavior

in

both

in

in

depression

the

animal

BDNF
and

is

gene

that

have

human

studies.
Thus,

the

potential

neurotrophic

targets

in

Monoamines
The

monoamine

deficiency

in

dopamine

(DA).

Figure

the

the

and

hypothesis
treatment

Other

hypothesis
amount

or

of

continues
of

to

be

intensely

investigated

and

has

yielded

new

insights

and

MDD.

Neurotransmitters

depression

function

of

(Figure

cortical

30!2)

and

limbic

suggests
serotonin

that

depression

(5 - HT),

is

related

norepinephrine

to

(NE),

and

30!2

The amine hypothesis of major depression. Depression appears to be associated with changes in serotonin or
norepinephrine signaling in the brain (or both) with significant downstream effects. Most antidepressants cause
changes in amine signaling. AC, adenylyl cyclase; 5-HT, serotonin; CREB, cAMP response element-binding
(protein); DAG, diacyl glycerol; IP 3 , inositol trisphosphate; MAO, monoamine oxidase; NET, norepinephrine
transporter; PKC, protein kinase C; PLC, phospholipase C; SERT, serotonin transporter.
(Redrawn, with permission, from Belmaker R, Agam G: Major depressive disorder. N Engl J Med 2008;358:59.)

Evidence to support the monoamine hypothesis comes from several sources. It has been known for many
years that reserpine treatment, which is known to deplete monoamines, is associated with depression in a

NEUROENDOCRINE FACTORS IN
DEPRESSION
Elevated cor?sol levels
Non-suppression of ACTH
release
Chronically elevated
cor?cotrophin-releasing
hormone
Thyroid dysregula?on
Estrogen deciency states/
severe testosterone deciency

CHEMISTRY AND SUBGROUPS

1/12/15

Selective Serotonin
Reuptake Inhibitors
Primary ac?on:
inhibi?on of SERT
Used in depression, GAD,
PTSD, OCD, panic
disorder, PMDD, bulimia
Highly lipophilic
Six members:
Fluoxe?ne, sertraline,
citalopram isomers
Paroxe?ne, uvoxamine
not op?cally ac?ve
Escitalopram S
enan?omer of citalopram

Serotonin-Norepinephrine
Reuptake Inhibitors
1.

Selec?ve Serotonin-Norephinephrine Reuptake Inhibitors

Bind SERT and NET transporters (similar to TCAs) but do not have
much anity for other receptors
Venlafaxine, desvenlafaxine bicyclic compounds
Duloxe?ne three-ring structure
Milnacipran cyclopropane ring

Serotonin-Norepinephrine
Reuptake Inhibitors
2. Tricyclic An?depressants

Iminodibenzyl (tricyclic) core

Used in depression unresponsive to SSRIs and SNRIs
Imipramine (prototype TCA) vs desipramine (metabolite) diers in
the methyl group

Imipramine highly an?cholinergic, rela?vely strong serotonin and NE

reuptake inhibitor
Desipramine less an?cholinergic, more potent, more selec?ve NE reuptake
inhibitor

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5-HT2 Antagonists
Trazodone triazolo moiety
M-CPP (m-chlorphenylpiperazine) metabolite and potent 5-HT2
antagonist
Unlabeled hypno?c, highly seda?ng, not associated with
tolerance or dependence

Nefazodone implicated in hepatotoxicity

depression, although both have also been used in the treatment of anxiety disorders.

TETRACYCLIC AND UNICYCLIC ANTIDEPRESSANTS

A number of antidepressants do not fit neatly into the other classes. Among these are
bupropion, mirtazapine, amoxapine, and maprotiline (Figure 30!5). Bupropion has a unicyclic
aminoketone structure. Its unique structure results in a different side -effect profile than most
antidepressants (described below). Bupropion somewhat resembles amphetamine in chemical structure and
like the stimulant, has central nervous system (CNS) activating properties.

Figure 30!5

Tetracyclic and Unicyclic

Antidepressants
Bupropion unicyclic aminoketone structure; resembles
amphetamine, has CNS ac?va?ng proper?es
Tetracyclic structured compounds
Mirtazapine no associated sexual side eects (unlike other
an?depressants)
Amoxapine N-methylated metabolite of loxapine
Mapro?line

mapro;line

Monoamine Oxidase Inhibitors

Treatment of depression unresponsive to other
an?depressants
Used to treat other illnesses
Selegiline Parkinsons disase

Types
Hydrazine deriva?ves: phenelzine, isocarboxazid
Non-hydrazine deriva?ves: tranylcypromine, selegiline,
moclobemide

1/12/15

PHARMACOKINETICS

Pharmacokinetics
The antidepressants share several pharmacokinetic features (Table 30!1). Most have fairly rapid oral
absorption, achieve peak plasma levels within 2!3 hours, are tightly bound to plasma proteins, undergo
hepatic metabolism, and are renally cleared. However, even within classes, the pharmacokinetics of
individual antidepressants vary considerably.

Table 30!1 Pharmacokinetic Profiles of Selected Antidepressants.

Class, Drug

Bioavailability Plasma t 1/2 Active Metabolite

(%)
t 1/2 (hours)
(hours)

Volume of
Distribution
(L/kg)

Protein
Binding
(%)

Citalopram

80

33!38

ND

15

80

Escitalopram

80

27!32

ND

12!15

80

Fluoxetine

70

48!72

180

12!97

95

Fluvoxamine

90

14!18

14!16

25

80

SSRIs

Paroxetine

50

20!23

ND

28!31

94

Sertraline

45

22!27

62!104

20

98

Duloxetine

50

12!15

ND

10!14

90

Venlafaxine 1

45

8!11

9!13

4!10

27

45

31!46

20!92

5!10

90

SNRIs

Tricyclics
Amitriptyline
Clomipramine

50

19!37

54!77

7!20

97

Imipramine

40

9!24

14!62

15!30

84

Nefazodone

20

2!4

ND

0.5!1

99

Trazodone

95

3!6

ND

1!3

96

5-HT 2
antagonists

Pharmacokinetics
The

antidepressants

absorption,
hepatic

achieve

share
peak

metabolism,

individual

Table

and

several

plasma
are

antidepressants

30!1

Class,

pharmacokinetic

levels

renally

vary

within

cleared.

features

2!3

hours,

However,

(Table
are

even

30!1).

tightly

within

Most

bound

classes,

to

the

have

fairly

plasma

rapid

proteins,

pharmacokinetics

oral

undergo
of

considerably.

Pharmacokinetic

Drug

Bioavailability
(%)

Profiles

Plasma

t 1/2

of

Selected

Antidepressants.

Active
Metabolite
t 1/2
(hours)

(hours)

Volume
of
Distribution
(L/kg)

Protein
Binding
(%)

SSRIs
Citalopram

80

Escitalopram

33!38

80

Fluoxetine

ND

27!32

70

15

ND

48!72

80

12!15

180

80

12!97

95

Fluvoxamine

90

14!18

14!16

25

80

Paroxetine

50

20!23

ND

28!31

94

Sertraline

45

22!27

62!104

20

98

SNRIs
Duloxetine

50

12!15

45

Venlafaxine 1

ND

8!11

10!14

9!13

90

4!10

27

Tricyclics
Amitriptyline

45

31!46

20!92

5!10

90

Clomipramine

50

19!37

54!77

7!20

97

Imipramine

40

9!24

14!62

15!30

84

5 - HT 2
antagonists
Nefazodone

20

2!4

ND

0.5!1

99

Trazodone

95

3!6

ND

1!3

96

Tetracyclics
unicyclic

and

Amoxapine

ND

Bupropion

7!12

70

Maprotiline

5!30

11!14

70

Mirtazapine

0.9!1.2

15!25

43!45

50

90

20!30

ND

20!40

84

23!27

20!40

88

3!7

85

MAOIs
Phenelzine

ND

Selegiline

11

1 Desvenlafaxine

has

ND

8!10
similar

properties

but

ND

9!11

is

less

SELECTIVE
The

SEROTONIN

prototype

Fluoxetine
greater

is

than

fluoxetine

SSRI,

metabolized
those

and

discontinued

REUPTAKE

fluoxetine,

of

weeks

or

to

an

to

active
The

the

longer

from

other

product,

in

half - life

half - life

an

SSRIs

some

norfluoxetine,

elimination

longest

before

99

metabolized.

SNRIs,

serotonin - norepinephrine

reuptake

INHIBITORS

differs

fluoxetine.

contributes

ND

8!10

completely

MAOIs, monoamine oxidase inhibitors; ND, no data found;

inhibitors; SSRIs, selective serotonin reuptake inhibitors.

MAOI

of

can

of

important

which

may

have

norfluoxetine

all

the

be

administered

SSRIs.

As

to

respects

is

plasma

about

result,

(Table

concentrations

three

times

fluoxetine

mitigate

the

30!1).

risk

has
of

longer

to

than

be

serotonin

syndrome.
Fluoxetine
drug

and

paroxetine

interactions

citalopram,

(see

are

drug

escitalopram,

potent

sertraline

the
is

drugs

is

extensively

lowest

protein

The

and

is

well

(97%)

unchanged

The

at
in

tend

to

in

be

night

of

not
the

all

of

more

of

isoenzyme,

CYP

is

an

and

this

inhibitor

contributes

of

CYP3A4,

to

potential

whereas

interactions.

Inhibitors

via

the

about

hours.

(27!30%).

about

of

12

Unlike

to

the

O - desmethylvenlafaxine

relatively

Venlafaxine
most
At

and

short

antidepressants,

least

45%

of

half - lives,

desvenlafaxine

have

desvenlafaxine

desvenlafaxine

is

venlafaxine.
hours

metabolism

unlike

isoenzyme

Despite

dosing.

metabolism.

4!8%

of

oxidative

levels

CYP2D6

11

once - daily

oxidative

with

half - life

extensive

duloxetine

CYP2D6

fluvoxamine

modest

INHIBITORS

liver
allow

extensive

compared
has

the

contrast,

the

that

antidepressants

and

alters

In

Reuptake

in

half - lives

undergo
urine

undergoes

the

to

kinetics.

well

urine.

be

absorbed

because

aromatic

genetic

secondary

linear

binding

similar

formulations

absorbed
and

significantly

tend

daily

agents

in

but
via

is

dosed

CYP2D6

once

and

daily.

It

CYP1A2.

is

tightly

bound

Hepatic

desvenlafaxine.

Antidepressants

TCAs

demethylation,

addition,

metabolized

have

does

unchanged

Duloxetine

impairment
Tricyclic
once

Both

available

protein

conjugated

excreted

to

are

have

REUPTAKE

Serotonin -Norepinephrine

Venlafaxine

(desvenlafaxine).
both

inhibitors

interactions).

and

SEROTONIN -NOREPINEPHRINE
Selective

of

and

their

The

TCAs

substantially

polymorphism

amine

TCAs,

These

TCAs

have

sedating

hydroxylation,
are

and

substrates

influenced
for

by

CYP2D6

including

have

long

TCAs

of

the

result
and

therapeutic

(Table

undergo

30!1).

CYP2D6

Only

system,

administration

in

low

or

and

lack

serum

result,

most

metabolism

about

and

of

extensive

nortriptyline,

window,

As

extensive

conjugation.

concurrent

may

desipramine

wide

half - lives

effects.

glucuronide

5%

the

drugs

of

serum

such

as

metabolism

active

levels

are

levels

dosed

of

excreted
these

fluoxetine.

of

the

metabolites

are

are

via

TCAs

reliable

In

TCAs.

and

in

have

fairly

predicting

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Selective Serotonin Reuptake

Inhibitors
Fluoxe?ne (prototype)
Metabolized to noruoxe?ne (greater plasma
concentra?on than parent drug)
Has to be discon?nued 4 weeks or more
before MAOI can administered to prevent
serotonin syndrome
Potent inhibitors of CYP2D6 isoenzyme
(together with paroxe?ne)
Fluvoxamine CYP3A4 inhibitor
Citalopram, escitalopram, sertraline modest CYP
interac?on

Serotonin-Norepinephrine
Reuptake Inhibitors
Selec?ve Serotonin-Norepinephrine Reuptake
Inhibitors
Venlafaxine
Metabolized in the liver via CYP2D6 to
desvenlafaxine
Half-life: 11 hours
Lowest protein binding of all an?depressants
(27-30%)
Desvenlafaxine does not undergo extensive
oxida?ve metabolism; 45% excreted unchanged in
the urine (4-8% of venlafaxine)

Serotonin-Norepinephrine
Reuptake Inhibitors
Selec?ve Serotonin-Norepinephrine Reuptake
Inhibitors
Duloxe?ne
Half life: 12 hours
Tightly bound to protein (97%)
Undergoes extensive oxida?ve metabolism
Hepa?c impairment signicantly alters duloxe?ne
levels (unlike desvenlafaxine)

1/12/15

Serotonin-Norepinephrine
Reuptake Inhibitors
Tricyclic An?depressants
Generally well absorbed and have long half-lives
Once daily dosing at night because of seda?ng eects
Mostly renally excreted into inac?ve metabolites
Substrates of CYP2D6 (maybe subject to inuence with
co-administra?on of other drugs or gene?c
polymorphism)

5-HT2 Antagonists
Trazodone, nefazodone
Extensive hepa?ve metabolism
Extensively protein bound and have limited
bioavailability
Short half-lives require split-dosing
Have ac?ve metabolites that exhibit 5-HT2 antagonism
Nefazodone potent inhibitor of CYP3A4

Tetracyclic and Unicyclic

Agents
Bupropion
Rapidly absorbed
85% mean protein binding
Extensive liver metabolism and substan?al rst-pass eect
Biphasic elimina?on: rst phase las?ng 1 hour and second
phase las?ng 14 hours

1/12/15

Tetracyclic and Unicyclic

Agents
Amoxapine
85% protein binding
Variable half-life administered in divided doses
Undergoes extensive hepa?c metabolism
7-hydroxyamoxapine (ac?ve metabolite): potent D2
blocker (an?psycho?c proper?es)

Tetracyclic and Unicyclic

Agents
Mapro?line
Orally well absorbed
88% protein bound
Extensive hepa?c metabolism
Mirtazapine
Demethyla?on hydroxyla?on glucoronida?on
Associated with several CYP isoenzymes
Half-life: 20-40 hours
Once nightly dosing because of seda?ng eects

Monoamine Oxidase Inhibitors

Metabolized via dierent pathways
Tranylcypromine: hydroxyla?on acetyla?on
Selegiline: demethyla?on hydroxyla?on
Extensive rst-pass eects
Well absorbed in GIT

1/12/15

PHARMACODYNAMICS

Selective Serotonin Reuptake

Inhibitors
Allosterically inhibit SERT
by binding the receptor at
a site other than ac?ve
binding site for serotonin
Binding to SERT is
associated with tonic
inhibi?on of the dopamine
system
LiSle or no eect on beta-
adrenoceptors or NET
Do not aggressively bind to
histamine, muscarinic or
other receptors

Serotonin-Norepinephrine
Reuptake Inhibitors

Bind both SERT and NET

Members dier in rela?ve anity to transporters
Venlafaxine: weak inhibitor of NET
Desvenlafaxine, duloxe?ne, milnacipran: balanced inhibi?on of both SERT
and NET
Lack potent an?histamine, alpha-adrenergic blocking and an?cholinergic eects
(compared to TCAs)

1/12/15

Tricyclic Antidepressants
An?depressant ac?vity primarily related to inhibi?on of
5-HT and NE reuptake

Tricyclic Antidepressants
Variability in anity among members
Clomipramine: SERT > NET
Desipramine, nortriptyline: NET > SERT
Imipramine: SERT (desipramine: NET)
An?muscarinic receptor anity dry mouth,
cons?pa?on
H1 receptor anity used as hypno?c and an?pruri?c
Alpha adrenoceptor blockade orthosta?c hypotension

5-HT2 Antagonists
Blockade of the 5-HT2A receptor an?anxiety,
an?psycho?c, an?depressant eects
Conversely, agonists of the same receptor:
hallucinogenic, anxiogenic (LSD, mescaline)
Nefazodone potent antagonist of 5-HT2A with weak
inhibi?on of SERT and NET
Trazodone weak but selec?ve inhibitor of SERT (liSle
eect on NET)

10

1/12/15

Tetracyclic and Unicyclic

Antidepressants
Buproprion
Modest to moderate inhibitors of NE and dopamine reuptake
Increases presynap?c availability of NE and dopamine
No eect on serotonin system

Mirtazapine

Antagonist of presynap?c alpha-2 autoreceptor

Enhances release of both NE and 5-HT
Antagonist of 5-HT2 and 5-HT3 receptors
Potent H1 antagonist (seda?ve eects)

Monoamine Oxidase Inhibitors

Mi?gates the ac?on of MAO in the neuron and increases
monoamine content
MAO-A
Present in both dopamine and NE neurons
Found in brain, gut, placenta, liver
Primary substrates: NE, epinephrine, serotonin
MAO-B
Found in serotonergic and histaminergic neurons
Brain, liver, platelets
Acts on tyramine, phenylethylamine, benzylamine

Monoamine Oxidase Inhibitors

Phenelzine, tranylcypromine irreversible, nonselec?ve
MAOIs
Moclobemide reversible selec?ve inhibitor of MAO-A
Selegiline irreversible MAO-B

11

1/12/15

ADVERSE EFFECTS

SSRIs
Enhanced serotonergic tone
GUT: nausea, GI upset, diarrhea, other GI symptoms
Spinal cord: diminished sexual func?on and interest
Headaches, changes in sleep paSern
Weight gain: paroxe?ne
Discon?nua?on syndrome dizziness, paresthesias
aper stopping the drug

SNRIs
Serotonergic eects as previously men?oned
Noradrenergic eects: increased BP (venlafaxine), HR
Cardiac toxicity: venlafaxine overdose (rare)
Hepa?c toxicity: duloxe?ne
CNS ac?va?on: insomnia, anxiety, agita?on

12

1/12/15

TCAs
An?cholinergic eects: dry mouth, cons?pa?on, urinary
reten?on, blurred vision, confusion
Alpha blockade: orthosta?c hypotension
H1 blockade: weight gain, seda?on
Interference with cardiac rhythm (class 1A)
Sexual eects (clomipramine)

5-HT2 Antagonists
Seda?on (trazodone)
GI distrubances
Priapism: trazodone
Alpha blockade: orthosta?c hypotension
Hepatotoxicity: nefazodone

Tetracyclics and Unicyclics

Amoxapine: parkisonian syndrome (D2 blockade)
Mirtazapine: seda?ve eect
Mapro?line: TCA-like eects (high anity for NET)
Buproprion: agita?on, insomnia, anorexia

13

1/12/15

Monoamine Oxidase Inhibitors

Orthosta?c hypotension
Weight gain
Sexual eects (anorgasmia) with irreversible non-
selec?ve MAOIs
Amphetamine like eects (ac?va?on, insomnia,
restlessness)
Seda?on phenelzine
Interac?on with certain foods and serotonergic drugs

Drug Interactions
interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs
that produce a serotonin syndrome (see below).

Table 30!4 Antidepressant!CYP450 Drug Interactions.

Enzyme

Substrates

Inhibitors

Inducers

1A2

Tertiary amine TCAs, duloxetine, theophylline,

phenacetin, TCAs (demethylation), clozapine,
diazepam, caffeine

Fluvoxamine, fluoxetine,
moclobemide, ramelteon

Tobacco,
omeprazole

2C19

TCAs, citalopram (partly), warfarin, tolbutamide,

phenytoin, diazepam

Fluoxetine, fluvoxamine,
sertraline, imipramine,
ketoconozole, omeprazole

Rifampin

2D6

Tricyclic antidepressants (TCAs), benztropine,

perphenazine, clozapine, haloperidol,
codeine/oxycodone, risperidone, class Ic
antiarrhythmics,
blockers, trazodone, paroxetine,
maprotiline, amoxapine, duloxetine, mirtazapine
(partly), venlafaxine, bupropion

Fluoxetine, paroxetine,
duloxetine,
hydroxybupropion,
methadone, cimetidine,
haloperidol, quinidine,
ritonavir

Phenobarbital,
rifampin

3A4

Citalopram, escitalopram, TCAs , glucocorticoids,

androgens/estrogens, carbamazepine,

Fluvoxamine, nefazodone,
sertraline, fluoxetine,
cimetidine, fluconazole,
erythromycin, protease
inhibitors, ketoconazole,
verapamil

Barbiturates,
glucocorticoids,
rifampin,
modafinil,
carbamazepine

erythromycin, Ca 2+ channel blockers, protease

inhibitors, sildenafil, alprazolam, triazolam,
vincristine/vinblastine, tamoxifen, zolpidem

SELECTIVE SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS AND TRICYCLIC

ANTIDEPRESSANTS
The SNRIs have relatively fewer CYP450 interactions than the SSRIs. Venlafaxine is a substrate but not an
inhibitor of CYP2D6 or other isoenzymes, whereas desvenlafaxine is a minor substrate for CYP3A4.
Duloxetine is a moderate inhibitor of CYP2D6 and so may elevate TCA and other CYP2D6 substrate levels.
Like all serotonergic antidepressants, SNRIs are contraindicated in combination with MAOIs.
Elevations of TCA levels may occur when combined with CYP2D6 inhibitors or from constitutional factors.
About 7% of the Caucasian population in the USA has a CYP2D6 polymorphism that is associated with slow
metabolism of TCAs and other 2D6 substrates. Combination of a known CYP2D6 inhibitor and a TCA in a
patient who is a slow metabolizer may result in additive effects. Such an interaction has been implicated,
though rarely, in cases of TCA toxicity. There may also be additive TCA effects such as anticholinergic or
antihistamine effects when combined with other agents that share these properties such as benztropine or
diphenhydramine. Similarly, antihypertensive drugs may exacerbate the orthostatic hypotension induced by
TCAs.
5-HT 2 ANTAGONISTS
Nefazodone is an inhibitor of the CYP3A4 isoenzyme, so it can raise the level and thus exacerbate adverse
effects of many 3A4 - dependent drugs. For example, triazolam levels are increased by concurrent
administration of nefazodone such that a reduction in triazolam dosage by 75% is recommended. Likewise,
administration of nefazodone with simvastatin has been associated with 20 - fold increase in plasma levels
of simvastatin.
Trazodone is a substrate but not a potent inhibitor of CYP3A4. As a result, combining trazodone with potent

Serotonin Syndrome
Serious drug interac?on associated with MAOIs +
serotonergic agents
Overs?mula?on of 5-HT receptors in the central gray
nuclei and medulla
Triad of cogni?ve, autonomic, and soma?c eects

14

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152

12. Antidepressants

DRUGS USED TO TREAT MANIA

and BIPOLAR DISORDER

Carbamazepine TEGRETOL, EQUETRO,

CARBATROL
Lithium ESKALITH
Valprioc acid DEPAKENE, DEPAKOTE
Figure 12.1 (continued)
Summary of antidepressants.
DRUG

UPTAKE INHIBITION
Norepinephrine

Selective serotonin
reuptake inhibitor
Fluoxetine

12

Antidepressants
I. OVERVIEW

II. MECHANISM OF ANTIDEPRESSANT DRUGS

Most clinically useful antidepressant drugs potentiate, either directly or
indirectly, the actions of norepinephrine and/or serotonin in the brain.
(See Figure 12.1 for a summary of the antidepressant agents.) This, along
with other evidence, led to the biogenic amine theory, which proposes
that depression is due to a deficiency of monoamines, such as norepinephrine and serotonin, at certain key sites in the brain. Conversely, the
theory proposes that mania is caused by an overproduction of these neurotransmitters. However, the amine theory of depression and mania is
overly simplistic. It fails to explain why the pharmacologic effects of any
of the antidepressant and anti-mania drugs on neurotransmission occur
immediately, whereas the time course for a therapeutic response occurs
over several weeks. Furthermore, the potency of the antidepressant drugs
in blocking neurotransmitter uptake often does not correlate with clinically observed antidepressant effects. This suggests that decreased uptake
of the neurotransmitter is only an initial effect of the drugs, which may
not be directly responsible for the antidepressant effects. It has been proposed that presynaptic inhibitory receptor densities in the brain decrease
over a 2 to 4 week period with antidepressant drug use. This down-regulation of inhibitory receptors permits greater synthesis and release of
neurotransmitters into the synaptic cleft and enhanced signaling in the
postsynaptic neurons, presumably leading to a therapeutic response.

III. SELECTIVE SEROTONIN REUPTAKE INHIBITORS

The selective serotonin reuptake inhibitors (SSRIs) are a group of chemically diverse antidepressant drugs that specifically inhibit serotonin
reuptake, having 300- to 3000-fold greater selectivity for the serotonin
transporter, as compared to the norepinephrine transporter. This contrasts
with the tricyclic antidepressants (TCAs, see p. 155) that nonselectively
inhibit the uptake of norepinephrine and serotonin (Figure 12.2). Both of
these antidepressant drug classes exhibit little ability to block the dop-

SELECTIVE SEROTONIN REUPTAKE

INHIBITORS (SSRIs)

A. Lithium
Lithium salts are used prophylactically for treating manic-depressive
patients and in the treatment of manic episodes and, thus, are considered mood stabilizers. Lithium is effective in treating 60 to 80 percent
of patients exhibiting mania and hypomania. Although many cellular
processes are altered by treatment with lithium salts, the mode of action
is unknown. [Note: Lithium is believed to attenuate signaling via receptors coupled to the phosphatidylinositol bisphosphate (PIP2) secondmessenger system. Lithium interferes with the resynthesis (recycling) of
PIP2, leading to its relative depletion in neuronal membranes of the CNS.
PIP2 levels in peripheral membranes are unaffected by lithium.] Lithium
is given orally, and the ion is excreted by the kidney. Lithium salts can be
toxic. Their safety factor and therapeutic index are extremely low and
comparable to those of digoxin. Common adverse effects may include
headache, dry mouth, polydipsia, polyuria, polyphagia, GI distress (give
lithium with food), fine hand tremor, dizziness, fatigue, dermatologic
reactions, and sedation. Adverse effects due to higher plasma levels
may include ataxia, slurred speech, coarse tremors, confusion, and convulsions. [Note: The diabetes insipidus that results from taking lithium
can be treated with amiloride.] Thyroid function may be decreased and
should be monitored. Lithium causes no noticeable effect on normal
individuals. It is not a sedative, euphoriant, or depressant.
B. Other drugs
Several antiepileptic drugs, including, most notably, carbamazepine,
valproic acid, and lamotrigine, have been identified and FDA approved
as mood stabilizers, being used successfully in the treatment of bipolar
disorder. Other agents that may improve manic symptoms include the
older (for example, chlorpromazine and haloperidol) and newer antipsychotics. The atypical antipsychotics (risperidone, olanzapine, ziprasidone,
aripiprazole, asenapine, and quetiapine) have also received FDA approval for the management of mania. Benzodiazepines are also frequently
used as adjunctive treatments for the acute stabilization of patients
with mania. (See the respective chapters on these psychotropics for a
more detailed description).

Pharm 5th 3-21-11.indb 159

++++
++++

++++

+++

Figure 12.2
Relative receptor specificity of some
antidepressant drugs. *Venlafaxine
inhibits norepinephrine reuptake
only at high doses. ++++ = very
strong affinity; +++ = strong affinity;
++ = moderate affinity; + = weak
affinity; 0 = little or no affinity.

Administration
of antidepressant

Depression

SEROTONIN/NOREPINEPHRINE
REUPTAKE INHIBITORS (SNRIs)

amine transporter. Moreover, the SSRIs have little blocking activity at muscarinic, A-adrenergic, and histaminic H1 receptors. Therefore, common side
effects associated with TCAs, such as orthostatic hypotension, sedation, dry
mouth, and blurred vision, are not commonly seen with the SSRIs. Because
they have fewer adverse effects and are relatively safe even in overdose,
the SSRIs have largely replaced TCAs and monoamine oxidase inhibitors
(MAOIs) as the drugs of choice in treating depression. SSRIs include fluoxetine [floo-OX-e-teen] (the prototypic drug), citalopram [sye-TAL-oh-pram],
escitalopram [es-sye-TAL-oh-pram], fluvoxamine [floo-VOX-e-meen], paroxetine [pa-ROX-e-teen], and sertraline [SER-tra-leen]. Both citalopram and fluoxetine are racemic mixtures, of which the respective S-enantiomers are the
more potent inhibitors of the serotonin reuptake pump. Escitalopram is the
pure S-enatiomer of citalopram.

2 to 12 weeks

transmission

Synaptic
vesicle

B. Therapeutic uses

POSTSYNAPTIC
NEURON

2:22:20 PM

Serotonin
Norepinephrine

TRICYCLIC ANTIDEPRESSANTS (TCAs)

Venlafaxine
Duloxetine

POSTSYNAPTIC
NEURON

SYNAPTIC
CLEFT

Postsynaptic response

Figure 12.5
Proposed mechanism of action of
selective serotonin/norepinephrine
reuptake inhibitor antidepressant
drugs.

MAOIs prevent inactivation

of monoamines within a
neuron, causing excess neurotransmitter to diffuse into the
synaptic space.

Most MAOIs, such as phenelzine, form stable complexes with the

enzyme, causing irreversible inactivation. This results in increased
stores of norepinephrine, serotonin, and dopamine within the neuron
and subsequent diffusion of excess neurotransmitter into the synaptic space (Figure 12.9). These drugs inhibit not only MAO in the brain,
but also MAO in the liver and gut that catalyze oxidative deamination
of drugs and potentially toxic substances, such as tyramine, which is
found in certain foods. The MAOIs, therefore, show a high incidence of
drug-drug and drug-food interactions. Selegiline administered as the
transdermal patch may produce less inhibition of gut and hepatic MAO
at low doses because it avoids first-pass metabolism.

Although MAO is fully inhibited after several days of treatment, the

antidepressant action of the MAOIs, like that of the SSRIs and TCAs, is
delayed several weeks. Selegiline and tranylcypromine have an amphetamine-like stimulant effect that may produce agitation or insomnia.
C. Therapeutic uses
The MAOIs are indicated for depressed patients who are unresponsive
or allergic to TCAs or who experience strong anxiety. Patients with low
psychomotor activity may benefit from the stimulant properties of the
MAOIs. These drugs are also useful in the treatment of phobic states.
A special subcategory of depression, called atypical depression, may
respond preferentially to MAOIs. Atypical depression is characterized
by labile mood, rejection sensitivity, and appetite disorders. Because of
their risk for drug-drug and drug-food interactions, the MAOIs are considered to be last-line agents in many treatment venues.
D. Pharmacokinetics
These drugs are well absorbed after oral administration, but antidepressant effects require at least 2 to 4 weeks of treatment. Enzyme regeneration, when irreversibly inactivated, varies, but it usually occurs several
weeks after termination of the drug. Thus, when switching antidepressant agents, a minimum of 2 weeks of delay must be allowed after termination of MAOI therapy and the initiation of another antidepressant from
any other class. MAOIs are metabolized and excreted rapidly in urine.
E. Adverse effects

Norepinephrine
Serotonin
Dopamine
SYNAPTIC
CLEFT

POSTSYNAPTIC
NEURON

IV. SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS

Venlafaxine [VEN-la-fax-een], desvenlafaxine [dez-VEN-la-fax-een], and
duloxetine (doo-LOX-e-teen) inhibit the reuptake of both serotonin and norepinephrine (Figure 12.5). These agents, termed selective serotonin/norepinephrine reuptake inhibitors (SNRIs), may be effective in treating depression in patients in whom SSRIs are ineffective. Furthermore, depression is
often accompanied by chronic painful symptoms, such as backache and
muscle aches, against which SSRIs are also relatively ineffective. This pain is,
in part, modulated by serotonin and norepinephrine pathways in the CNS.
Both SNRIs and TCAs, with their dual actions of inhibiting both serotonin
and norepinephrine reuptake, are sometimes effective in relieving physical symptoms of neuropathic pain such as diabetic peripheral neuropathy.
However, the SNRIs, unlike the TCAs, have little activity at adrenergic, muscarinic, or histamine receptors and, thus, have fewer of these receptor-mediated adverse effects than the TCAs (see Figure 12.2). Venlafaxine, desvenlafaxine, and duloxetine may precipitate a discontinuation syndrome if treatment is abruptly stopped.

Effect of MAOIs

Inactive
metabolites

5. Discontinuation syndrome: Whereas all of the SSRIs have the

potential for causing a discontinuation syndrome after their abrupt
withdrawal, the agents with the shorter half-lives and having inactive metabolites have a higher risk for such an adverse reaction.
Fluoxetine has the lowest risk of causing an SSRI discontinuation
syndrome. Possible signs and symptoms of such a serotonin-related
discontinuation syndrome include headache, malaise and flu-like
symptoms, agitation and irritability, nervousness, and changes in
sleep pattern.

PRESYNAPTIC
NEURON

SYNAPTIC
CLEFT

Postsynaptic response

MAO

12. Antidepressants

ATYPICAL ANTIDEPRESSANTS

Amitriptyline ELAVIL
Amoxapine ASENDIN
Clomipramine ANAFRANIL
Desipramine NORPRAMIN
Doxepin SINEQUAN
Imipramine TOFRANIL
Maprotiline LUDIOMIL
Nortriptyline PALMELOR
Protriptyline VIVACTIL
Trimipramine SURMONTIL

Synaptic
vesicle

A. Mechanism of action

B. Actions

Inactive
metabolites

Norepinephrine
Serotonin
Dopamine

All of the SSRIs are well absorbed after oral administration. Peak levels are seen in approximately 2 to 8 hours on average. Food has little
effect on absorption (except with sertraline, for which food increases
its absorption). Only sertraline undergoes significant first-pass metabolism. The majority of SSRIs have plasma half-lives that range between
16 and 36 hours. Metabolism by cytochrome P450 (CYP450)-dependent
enzymes and glucuronide or sulfate conjugation occur extensively.
[Note: These metabolites do not generally contribute to the pharmacologic activity.] Fluoxetine differs from the other members of the class
in two respects. First, it has a much longer half-life (50 hours) and is
available as a sustained-release preparation allowing once-weekly dosing. Second, the metabolite of the S-enantiomer, S-norfluoxetine, is as
potent as the parent compound. The half-life of the metabolite is quite
long, averaging 10 days. Fluoxetine and paroxetine are potent inhibitors
of a hepatic CYP450 isoenzyme (CYP2D6) responsible for the elimination
of TCAs, neuroleptic drugs, and some antiarrhythmic and -adrenergic
antagonist drugs. [Note: About 7 percent of the Caucasian population

3/21/11

MAO inactivates monoamines (norepinephrine,

serotonin, and dopamine)
that leak from a synaptic
vesicle.

MAO

The primary indication for SSRIs is depression, for which they are as
effective as the TCAs. A number of other psychiatric disorders also
respond favorably to SSRIs, including obsessive-compulsive disorder,
panic disorder, generalized anxiety disorder, posttraumatic stress disorder, social anxiety disorder, premenstrual dysphoric disorder, and bulimia nervosa (only fluoxetine is approved for this last indication).

152

Antidepressant
drug blocks
reuptake of the
neurotransmitter.

12. Antidepressants

A Normal monoamine

The SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and, ultimately,
to greater postsynaptic neuronal activity. Antidepressants, including
SSRIs, typically take at least 2 weeks to produce significant improvement in mood, and maximum benefit may require up to 12 weeks or
more (Figure 12.3). However, none of the antidepressants are uniformly
effective. Approximately 40 percent of depressed patients treated with
adequate doses for 4 to 8 weeks do not respond to the antidepressant agent. Patients who do not respond to one antidepressant may
respond to another, and approximately 80 percent or more will respond
to at least one antidepressant drug. [Note: These drugs do not usually
produce central nervous system (CNS) stimulation or mood elevation in
normal individuals.]

154

Bupropion WELLBUTRIN, ZYBAN

Mirtazapine REMERON
Nefazodone SERZONE
Trazodone DESYREL

158

A. Actions

C. Pharmacokinetics
Onset of action

Pharm 5th 3-21-11.indb

Desvenlafaxine PRISTIQ
Duloxetine CYMBALTA
Venlafaxine EFFEXOR

Postsynaptic response

Figure 12.9
Mechanism of action of monoamine oxidase inhibitors (MAOIs).

Severe and often unpredictable side effects, due to drug-food and

drug-drug interactions, limit the widespread use of MAOIs. For example, tyramine, which is contained in certain foods, such as aged cheeses and meats, chicken liver, pickled or smoked fish (such as anchovies
or herring), and red wines, is normally inactivated by MAO in the gut.
Individuals receiving a MAOI are unable to degrade tyramine obtained
from the diet. Tyramine causes the release of large amounts of stored
catecholamines from nerve terminals, resulting in what is termed a
hypertensive crisis, with signs and symptoms such as occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and, possibly, stroke. Patients must, therefore, be educated to avoid tyramine-containing foods. Phentolamine and prazosin
are helpful in the management of tyramine-induced hypertension.

Pharm 5th 3-21-11.indb 158

3/21/11 2:22:29 PM

A. Venlafaxine and desvenlafaxine

Venlafaxine is a potent inhibitor of serotonin reuptake and, at medium to higher doses, is an inhibitor of norepinephrine reuptake. It is
also a mild inhibitor of dopamine reuptake at high doses. Venlafaxine
has minimal inhibition of the CYP450 isoenzymes and is a substrate
of the CYP2D6 isoenzyme. The half-life of the parent compound plus
its active metabolite is approximately 11 hours. Desvenlafaxine is the
active, demethylated, metabolite of the parent compound venlafaxine.
The most common side effects of venlafaxine are nausea, headache,
sexual dysfunction, dizziness, insomnia, sedation, and constipation. At
high doses, there may be an increase in blood pressure and heart rate.
Desvenlafaxine is not considered to have a significantly different clinical
or adverse effect profile compared to venlafaxine.

MONOAMINE OXIDASE INHIBITORS

(MAOIs)

Isocarboxazid MARPLAN
Phenelzine NARDIL
Selegiline ELDEPRYL
Tranylcypromine PARNATE

B. Duloxetine

Figure 12.1
Summary of antidepressants.
(Continued on next page)

Duloxetine inhibits serotonin and norepinephrine reuptake at all doses. It is extensively metabolized in the liver to numerous metabolites.
Duloxetine should not be administered to patients with hepatic insufficiency. Metabolites are excreted in the urine, and the use of duloxetine is
not recommended in patients with end-stage renal disease. Food delays
the absorption of the drug. The half-life is approximately 12 hours. GI
side effects are common with duloxetine, including nausea, dry mouth,
and constipation. Diarrhea and vomiting are seen less often. Insomnia,
dizziness, somnolence, and sweating are also seen. Sexual dysfunction
also occurs along with the possible risk for an increase in either blood
pressure or heart rate. Duloxetine is a moderate inhibitor of CYP2D6 and
CYP3A4 isoenzymes.

3/21/11 2:22:19 PM

VIII. Treatment Of Mania And Bipolar Disorder

The treatment of bipolar disorder has increased in recent years, partly due
to the increased recognition of the disorder and also due to the increase in
the number of medications FDA-approved for the treatment of mania.

++*
++++

Figure 12.3
Onset of therapeutic effects of
the major antidepressant drugs
requires several weeks.

Citalopram CELEXA
Escitalopram LEXAPRO
Fluoxetine PROZAC
Fluvoxamine LUVOX CR
Paroxetine PAXIL
Sertraline ZOLOFT

Pharm 5th 3-21-11.indb 151

VIII. TREATMENT OF MANIA AND BIPOLAR DISORDER

Tricyclic
antidepressant
Imipramine

++++

Antidepressant
effects

The symptoms of depression are intense feelings of sadness, hopelessness, and despair as well as the inability to experience pleasure in usual
activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts. Mania is characterized by the opposite behavior: enthusiasm, rapid thought and speech patterns, extreme self-confidence, and
impaired judgment. [Note: Depression and mania are different from
schizophrenia (see p. 161), which produces disturbances in thought.]

[Note: Treatment with MAOIs may be dangerous in severely depressed

patients with suicidal tendencies. Purposeful consumption of
tyramine-containing foods is a possibility.] Other possible side effects
of treatment with MAOIs include drowsiness, orthostatic hypotension,
blurred vision, dry mouth, dysuria, and constipation. MAOIs and SSRIs
should not be coadministered due to the risk of the life-threatening
serotonin syndrome. Both types of drugs require washout periods
of at least 2 weeks before the other type is administered, with the
exception of fluoxetine, which should be discontinued at least 6 weeks
before a MAOI is initiated. Combination of MAOIs and bupropion can
produce seizures. Figure 12.10 summarizes the side effects of the antidepressant drugs.

Selective serotonin/
norepinephrine
reuptake inhibitors
Venlafaxine
Duloxetine

Serotonin

159

Gastrointestinal
distress
Sedating; may be
useful for agitation
SELECTIVE
SEROTONIN RE-UPTAKE
INHIBITORS
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
SEROTONIN/
NOREPINEPHRINE
REUPTAKE INHIBITORS
Duloxetine
Venlafaxine
Desvenlafaxine
ATYPICAL
ANTIDEPRESSANTS
Bupropion
Mirtazapine
Nefazodone
Trazodone
TRICYCLIC/POLYCYCLIC
ANTIDEPRESSANTS
Amitriptyline
Amoxapine
Clomipramine

Pharm 5th 3-21-11.indb 154

3/21/11 2:22:21 PM

REFERENCES:
Katzung, Basic and
Clinical Pharmacology
LippincoSs Illustrated
Pharmacology (for
graphics)

Desipramine
Doxepin
Imipramine
Maprotiline
Nortriptyline
Protriptyline
Trimipramine
MONOAMINE OXIDASE
INHIBITORS
Phenelzine
Tranylcypromine
High potential
for orthostatic
hypotension

Weight
gain

Figure 12.10
Side effects of some drugs used to
treat depression.

3/21/11 2:22:29 PM

15