l.

OVERVIEW SELECTIVE SEROTONIN

REUPTAKE INHIBITORS (SSRls)

Citalopram CELEXA
The symptoms of depression are feelings of sadness and hopeless- EscitalopramLEXAPRO
ness. as well as the inability to experience pleasure in usual activities, Fluoxetine PROZAC
changes in sleep patterns and appetite, loss of energy. and suicidal Fluvoxamine LUVOX CR
thoughts, Mania is characterized by the opposite behavior: enthusiasm, ParoxetinePAXIL
SEROTONIN/NOREPINEPHRINE
anger, rapid thought and speech patterns, extreme self-confidence, and Sertraline INHIBITORS
REUPTAKE ZOLOFT (SNRls)
impaired judgment. This chapter provides an overview of drugs used for

VenlafaxineEFFEXOR
Most clinically useful antidepressant drugs (Figure 10.1) potentiate, ATYPICAL ANTIDEPRESSANTS
either directly or indirectly, the actions of norepinephrine and/or Bupropion WELLBUTRIN, ZYBAN

serotonin (5-HT) in the brain. This, along with other evidence, led to the Mirtazapine
REMERON
biogenic amine theory, which proposes that depression is due to a
Nefazodone
deficiency of monoamines. such as norepinephrine and serotonin, at rrazodoneDESYREL
certain key sites in the brain. Conversely, the theory proposes that Vilazodone
mania is caused by an overproduction of these neurotransmitters. VUBRYD
However, the biogenic amine theory Vortioxetine BRINTELLIX

Antidepressants
Jose A. Rey

the treatment of depression and mania.

Desvenlafaxine PRISTIQ
Duloxetine CYMBALTA
ll. MECHANISM OF ANTIDEPRESSANT DRUGS Levomi/nacipran
FETZIMA

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136 10. Antidepressants

TRICYCLIC ANTIDEPRESSANTS
cological effects of any of the antidepressant and antimania drugs on neu- Amitriptyline
(TCAs)
rotransmission, which often occur immediately; however, the time course Amoxapine of
for a therapeutic response occurs over several weeks. This suggests that Clomipramine ANAF
RANIL
decreased reuptake of neurotransmitters is only an initial effect of the Desipramine
NORPRAM'N
drugs, which may not be directly responsible for the antidepressant effects. Doxepin SINEQUA N
ImipramineTOFRANjL
Protriptyline VIVACTIL
MaprotilineLLJD10MlL
The selective serotonin reuptake inhibitors (SS Rls) are a group of antide- Trimipramine
Nortriptyline SU
Ill. SELECTIVE SEROTONIN REUPTAKE INHIBITORS RMONTIL
PAMELOR
depression and mania is overly simplistic. It fails to explain the pharma-
MONOAMINE OXIDASE INHIBITORS
3000-fold greater selectivity serotonin transporter, as compared to the (MAO's)
norepinephrine transporter This contrasts with the tricyclic Isocarboxazid MARYLAN
antidepressants (TCAs) and serotonin/norepinephrine reuptake Phenelzine NARDiL
inhibitors (SNRIS) that nonselectively inhibit the reuptake of Selegiline EMSAM
norepinephrine and serotonin (Figure 10.2). Moreover, the SSRls have TranylcyprominePARNATE
little blocking activity at muscarinic, cx-adrenergic, and histaminic H,
receptors, Therefore, common side effects associated with TCAs, such Figure 10.1
as orthostatic hypotension, sedation, dry mouth, and blurred vision, are Summary of
not commonly seen with antidepressants.
pressant drugs that specifically inhibit serotonin reuptake, having 300- to for the
DRUGS USED TO TREAT the SSRls. Because they have different adverse effects and are relatively
MANIA and BIPOLAR safe even in overdose, the SSRls have largely replaced TCAs and
Tricyclic anti d
DISORDER epressant:s
Carbamazepine TEGRETOL. EQUETRO. imipramine
CARBATROL

Lamotrigine LAMICJAL
Lithium
Valproie acid DEPAKENE, DEPAKOTE Figure 10.2
Relative receptor specificity Of some antidepressant drugs. •Verjlafaxine
inhibits norepinephrine reuptake only at high doses. +4+4 = very strong affinity;
Figure 10.1 (Continued) ++4 = strong affinity; ++ = moderate affinity; + = weak affinity;
DRUG UPTAKE
INHIBITION
Nor • Serotonin
brine

Selective seroton in
reupta ke inhibitor

Selective serotonin/
norepinephrine
reupta ke
inhibitors

Duloxetine

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 137
O improvement in mood, and maximum benefit may require up to 12
weeks or more (Figure 10.3). Patients who do not respond to one
antidepressant may respond to another, and approximately 80% or
more will respond to at least one antidepressant drug.

B. Therapeutic uses
The primary indication for SSRls 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 bulimia).

little or no affinity,
Figure 10.3
Onset of therapeutic effects of the
major antidepressant drugs
requires several weeks.
monoamine oxidase inhibitors
(MAOIS) as the drugs Of choice
in treating depression. The SSRls
include fluoxetine Ifloo-OX-e-
teen] (the prototypic drug),
citafopram (sye-TAL-oh-pram),
escitalopram [es-sye•TAL-
ohpram), fluvoxamine [floo-VOX-
e-meen], paroxetine [pa-ROX-e-
teen], and sertraline [SER-tra-
leenl. Escitalopram is the pure S-
enantiomer of citalopram
A. Actions
The SSRls block the reuptake
of serotonin, leading to
increased concentrations of
the neurotransmitter in the
synaptic cleft.
Antidepressants, including
SSRIs, typically take at least 2
weeks to produce significant
IV Serotonin/Norepinephrine Reuptake Inhibitors
C. Pharmacokinetics
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). The majority of SSRls have plasma half-
lives that range between 16 and 36 hours. Metabolism by
cytochrome P450 (CYP450)—dependent enzymes and glucuronide
or sulfate conjuga• tion occur extensively. Fluoxetine differs from
the other members of the class by having a much longer half-life
(50 hours), and the halflife of its active metabolite S-norfluoxetine
is quite long, averaging 10 days, It is available as a sustained-
release preparation allowing once-weekly dosing. Fluoxetine and
paroxetine are potent inhibitors of a CYP450 isoenzyme (CYP2D6)
responsible for the elimination of TCAs, antipsychotic drugs, and
some antiarrhythmic and l}-adrenergic antagonist drugs. Other
CYP450 isoenzymes (CYP2C9/19. CYP3A4. CYPI A2) are involved
with SSRI metabolism and may also be inhibited to various degrees
by the SSRls, Dosages of the SSRls should be reduced in patients
with hepatic impairment.
D. Adverse effects
Although the SSRIs are considered to have fewer and less severe
adverse effects than the TCAs and MAOIs, the SSRls are not
without adverse effects, such as headache, sweating, anxiety and
agitation, gastrointestinal (GI) effects (nausea, vomiting, diarrhea),
weakness and fatigue, sexual dysfunction. changes in weight, sleep
disturbances (insomnia and somnolence), and the above-
mentioned potential for drug—drug interactions (Figure 10.4).
Additionally, SSRIs have been

associated with hyponatremia, especially in the elderly and patients who

are volume depleted or taking diuretics.
1. Sleep disturbances: Paroxetine and fluvoxamine are generally more Nausea
sedating than activating, and they may be useful in patients who have

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Anxiety
138 10. Antidepressants
difficulty sleeping. Conversely, patients who are fatigued or complaining of excessive somnolence may
benefit from one of the more activating SSRls, such as fluoxetine or sertraline
2, Sexual dysfunction: Sexual dysfunction, which may include loss of libido, delayed ejaculation, and
anorgasmia, is common with the SSRls, One option for managing SSRl-induced sexual dysfunction is to
change the antidepressant to one with fewer sexual side effects. such as bupropion or mirtazapine.
Alternatively, the dose of the drug may be reduced.
3. Use in children and teenagers: Antidepressants should be used cautiously in children and teenagers,
because about 1 out of 50 children report suicidal ideation as a result of SSRI treatment. Pediatric
patients should be observed for worsening depression and suicidal thinking with initiation or dosage
change of any antidepressant. Fluoxetine, sertrafine, and fluvoxamine are approved for use in children to
treat obsessive—compulsive disorder, and fluoxetine and escitalopram are approved to treat childhood
depression.

4. Overdose: Overdose with SSRIs does not usually cause cardiac arrhythmias, with the exception of
citalopram, which may cause QT prolongation. [Note: The TCAs have a significant risk for arrhythmias in
overdose.] Seizures are a possibility because all antidepressants may lower the seizure threshold. All
SSRls have the potential to cause serotonin syndrome, especially when used in the presence of a MAOI
or other highly serotonergic drug. Serotonin syndrome may include the symptoms of hyperthermia,
muscle rigidity, sweating, myoclonus (clonic muscle twitching), and changes in mental status and vital
signs.

5. Discontinuation syndrome: All of the SSRIs have the potential to cause a discontinuation syndrome after
their abrupt withdrawal, particularly the agents with shorter half-lives and inactive metabolites.
Fluoxetine has the lowest risk of causing an SSRI discontinuation syndrome due to its longer half-life and
active metabolite.
Possible signs and symptoms of SSRI discontinuation syndrome Figure 10.4
include headache, malaise, and flu-like symptoms. agitation and Some commonly
observed adverse
effects
irritability, nervousness, and changes in sleep pattern. of selective serotonin
reuptake inhibitors.
IV. SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS

Ven/afaxine [VEN-Ia-fax-een], desven/afaxine [dez-VEN-Ia-fax-eenl,

fevomilnacipran [leevo-miI-NA-si-pranl, and duloxetine [doo-LOX-e-teenl
inhibit the reuptake of both serotonin and norepinephrine (Figure 10.5).
These agents, termed SNRls, may be effective in treating depression in
patients in whom SSRls 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

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 139
Antidepressant drug blocks in the central nervous system (CNS). Both SNRls and the TCAs. with
reuptake of the their dual inhibition of both serotonin and norepinephrine reuptake,
neurotransmitter.
PRESYNAPTIC are sometimes effective in relieving pain associated with diabetic
peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and low
back pain. The SNRls, unlike the TCAs, have little activity at a-
adrenergic, muscarinic, or histamine receptors and, thus, have fewer of
these receptor-mediated adverse effects than the TCAs, The SNRIs may
precipitate a discontinuation syndrome if treatment is abruptly
stopped.

A. Venlafåxine and desvenlafaxine

Ven/afaxine is a potent inhibitor of serotonin reuptake and, at
medium to higher doses, is an inhibitor of norepinephrine reuptake.
Venlafaxine has minimal inhibition of the CYP450 isoenzymes and is
a substrate of the CYP2D6 isoenzyme. Desvenlafaxine is the active,
demethylated metabolite of venlafaxine. The most common side
effects of venlafaxine are nausea, headache, sexual dysfunction,
NEURON dizziness, insomnia, sedation. and constipation. At high doses, there
SYNAPTIC may be an increase in blood pressure and heart rate. The clinical
Postsynaptic response activity and adverse effect profile of desvenlafaxine are similar to
NEURON that of ven/afaxine

Figure 10.5 B. Duloxetine

Proposed mechanism of action of
selective
serotonin/norepinephrine
reuptake inhibitor antidepressant
drugs.
Du/oxetine inhibits serotonin and norepinephrine reuptake at all
doses. It is extensively metabolized in the liver to inactive
metabolites and should be avoided in patients with liver
dysfunction. Gl side

effects are common with du/oxetine, including nausea, dry mouth, and
constipation. Insomnia, dizziness, somnolence, sweating, and sexual
dysfunction are also seem Duloxetine may increase blood pressure or
heart rate. Duloxetine is a moderate inhibitor of CYP2D€ isoenzymes
and may increase concentrations of drugs metabolized by this path.
way, such as antipsychotics.

C. Levomilnacipran
Levomilnacipran is an enantiomer of milnacipran (an older SNRI used for
the treatment of depression in Europe and fibromyalgia in the United
States). The adverse effect profile of levomilnacipran is similar to other
SNRIs- It is primarily metabolized by CYP3A4, and, thus, activity may be
altered by inducers or inhibitors of this enzyme system.

V. ATYPICAL ANTIDEPRESSANTS

The atypical antidepressants are a mixed group of agents that have actions
at several different sites. This group includes bupropion [byooPROE-pee-
on], mirtazapine [mir-TAZ-a-peenl, nefazodone (ne-FAZOh-done], trazodone

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140 10. Antidepressants
[TRAZ-oh-donel, vilazodone [vil-AZ-Oh-done], and vortioxetine [vor-TEE-ox-
e•teenJ4

A. Bupropion
Bupropion is a weak dopamine and norepinephrine reuptake inhibitor
that is used to alleviate the symptoms Of depression. Bupropion is also
useful for decreasing cravings and attenuating withdrawal
V. Atypical Antidepressants

symptoms of nicotine in patients trying to quit smoking. Side effects

may include dry mouth, sweating, nervousness, tremor, and a
dosedependent increased risk for seizures. It has a very low gain
incidence of sexual dysfunction. Bupropion is metabolized by the
CYP2B6 path• way and has a relatively low risk for drug—drug
interactions, given the few agents that inhibit/induce this enzyme.
However. bupropion may inhibit CYP2D6 and, thus, increase
exposure to substrates of this isoenzyme, Use of bupropion should
be avoided in patients at risk for seizures or those who have eating
disorders such as bulimia. Sedation

B. Mirtazapine
Mirtazapine enhances serotonin and norepinephrine Figure 10.6
neurotransmission by serving as an antagonist at presynaptic Some commonly observed
receptors. Additionally, some of the antidepressant activity may be adverse effects of
related to antagonism at 5-HT2 receptors, It is sedating because of its mirtazapine,
potent antihistaminic activity, but it does not cause the
antimuscarinic side effects of the TCAs, or interfere with sexual
function like the SSRls. Increased appetite and weight gain frequently
occur (Figure 10.6). Mirtazapine is markedly sedating, which may be
an advantage in
depressed patients having difficulty sleeping.

C. Nefazodone and trazodone

These drugs are weak inhibitors of serotonin reuptake. Their
therapeutic benefit appears to be related to their ability to block
postsynaptic 5-HT receptors. Both agents are sedating, probably
because Of their potent histamine Flt-blocking activity. Trazodone is
commonly used off-label for the management of insomnia, Trazodone
has been associated with priapism. and nefazodone has been asso•
ciated with a risk for hepatotoxicity. Both agents also have mild to
moderate receptor antagonism, contributing to orthostasis and
dizziness.

D. Vilazodone
Vilazodone is a serotonin reuptake inhibitor and a 5-HT,a partial
agonist. Although the extent to which the 5-HT,a receptor activity
contributes to its therapeutic effects is unknown, this possible
mechanism of action renders it unique from that Of the SSRls, The

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 141
adverse effect profile of vilazodone is similar to the SSRIs. including a
risk for discontinuation syndrome if abruptly stopped-

E. Vortioxetine
Vortioxetine utilizes a combination of serotonin reuptake inhibition, 5-
HT,a agonism, and 5-HT3 and 5-HT7 antagonism as its suggested
mechanisms of action to treat depression. It is unclear to what extent
the activities other than inhibition of serotonin reuptake influence the
overall effects of vortioxetine. The common adverse effects include
nausea, vomiting, and constipation, which may be expected due to its
serotonergic mechanisms.

VI. TRICYCLIC ANTIDEPRESSANTS

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142 10. Antidepressants
Weight The TCAs block norepinephrine and serotonin reuptake into the
presynaptic neuron and, thus, if discovered today, might have been
referred to as SNRls, except for their differences in adverse effects relative
to this newer class of antidepressants, The TCAs include the tertiary
amines imipramine lee-MIP-ra-meenl (the prototype drug), amitriptyline
Dry [a clomipramine (kloe-MIP-ra-meen], doxepin [DOXe-
pin], and trimpramine [trye-MlP-ra-meen], and the secondary amines
desipramine [dess-IP•ra-meen] and nortriptyline (the N-
demethylated metabolites of imipramine and amitripty/ine, respectively)
and protriptyline [proe-TRlP-ti-leen]. Maprotiline [ma-PROE-ti-leen] and
Con amoxapine are related "tetracyclic" antidepressant agents
and are commonly included in the general class of TCAs. Patients who do
not respond to one TCA may benefit from a different drug in this group.

A. Mechanism of action
Urin
retention I. Inhibition of neurotransmitter reuptake: TCAs and amoxapine are potent
inhibitors of the neuronal reuptake of norepinephrine and serotonin
into presynaptic nerve terminals. Maprotiline and desipramine are
relatively selective inhibitors of norepinephrine reuptake.
Blurred 2. Blocking of receptors: TCAs also block serotonergic, a-adrenergic, histaminic,
vision
and muscarinic receptors. It is not known if any of these actions produce the
therapeutic benefit of the TCAs. However, actions at these receptors are likely
responsible for many of their adverse effects. Amoxapine also blocks 5-HT2
and dopamine De receptors.
Tachycardia

B, Actions
The TCAs elevate mood, improve mental alertness, increase physical
activity, and reduce morbid preoccupation in 50% to 70% of individuals
with major depression. The onset of the mood elevation is slow, requiring
Arrhythmias
2 weeks or longer (Figure 10.3). Patient response can be used to adjust
dosage. After a therapeutic response, the dosage can be gradually
reduced to improve tolerability, unless relapse occurs. Physical and
psychological dependence have been rarely reported, This necessitates
slow withdrawal to minimize discontinuation syndromes and cholinergic
Nausea rebound effects.

C. Therapeutic uses
The TCAs are effective in treating moderate to severe depression. Some
Drowsin patients with panic disorder also respond to TCAs. Imipramine has been
used to control bed-wetting in children older than 6 years of age;
however, it has largely been replaced by desmopressin and
nonpharmacologic treatments (enuresis alarms). The TCAs, particularly
amitriptyline, have been used to help prevent migraine
Figure 10.7 headache and treat chronic pain syndromes (for example, neuro-
Some commonly pathic pain) in a number of conditions for which the cause of pain
observed adverse
effects of tricyclic is unclear. Low doses of TCAs, especially doxepin, can be used to
antidepressants. treat insomnia.

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 143
Vll. Monoamine Oxidase Inhibitors

D. Pharmacokinetics space. The four MAOis currently

TCAs are well absorbed upon oral administration. Because Of their available for treatment of
lipophilic nature, they are widely distributed and readily penetrate depression include phenetzine
into the CNS. As a result of their variable first-pass metabolism in the [FEN-el-zeenl, tranylcypromine
liver, TCAs have low and inconsistent bioavailability These drugs are [tran-iI-SIP-roe-meenl.
metabolized by the hepatic microsomal system (and, thus, may be isocarboxazid [eye-soe-car-BOX-
sensitive to agents that induce or inhibit the CYP450 isoenzymes) ih-zidJ, and selegiline (seh-
and conjugated with g) ucuronic acid, Ultimately, the TCAs are LEDGE-ah-leen]. [Note:
excreted as inactive metabolites via the kidney. Selegiline is also used for the
treatment of Parkinson's
disease. It is the only
E. Adverse effects antidepressant available in a
Blockade of muscarinic receptors leads to blurred vision, xerostomia transdermal delivery system,]
(dry mouth), urinary retention, sinus tachycardia, constipation, and Use of MAOIs is limited due to
aggravation of angle-closure glaucoma (Figure 10.7). These agents the complicated dietary
affect cardiac conduction similarly to quinidine and may precipitate restrictions required while
life-threatening arrhythmias in an overdose situation. The TCAs also taking these agents.
block a-adrenergic receptors, causing orthostatic hypotension,
dizziness, and reflex tachycardia. Impramine is the most likely, and Mutual enhancement:
nortriptyline the least likely, to cause orthostatic hypotension. hypertension, hyperpyrexia,
Sedation may be prominent, especially during the first several weeks convulsions, and coma
of treatment, and is related to the ability of these drugs to block
Potentiate effects
histamine H, receptors. Weight gain is a common adverse effect of of biogenic amine
the TCAs. Sexual dysfunction occurs in a minority Of patients, and drugs by
the incidence is lower than that associated with the SSRIs. preventing their
TCAs (like all antidepressants) should be used with caution in patients with removal from the
bipolar disorder, even during their depressed state, because MAO synaptic cleft
antidepressants may cause a switch to manic behavior, The TCAs have a
narrow therapeutic index (for example, five- to sixfold the maximal daily
dose Of imipraminecan be lethal). Depressed patients Who are
suicidal should be given only limited quantities of these drugs and be
monitored closely. Drug interactions with the TCAs are shown in
Figure 10.8, The TCAs may exacerbate certain medical conditions.
such as benign prostatic hyperplasia, epilepsy, and preexisting
arrhythmias.

Vil. MONOAMINE OXIDASE INHIBITORS

Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve

and other tissues, such as the gut and liver. In the neuron, MAO
functions as a "safety valve" to oxidatively deaminate and inactivate any
excess neurotransmitters (for example, norepinephrine, dopamine, and reaching
serotonin) that may leak out of synaptic vesicles when the neuron is at celluarsitesof action
Toxic sedation
rest. The MAO's may irreversibly or reversibly inactivate the enzyme,
permitting neurotransmitters to escape degradation and, therefore, to
accumulate within the presynaptic neuron and leak into the synaptic

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144 10. Antidepressants
Figure 10.8
Drugs interacting with tricyclic antidepressants. CNS = central nervous system; MAO
monoamine oxidase,

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 145
14
2

Syna

Synaptic
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SYNAPTIC
SYNAPTIC

Postsynaptic response
NEURON

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NEURON
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 10. Antidepressants
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 147
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 10. Antidepressants
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 149
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 10. Antidepressants
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 151
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 10. Antidepressants
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 153
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i
n T
e h
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l M
i A
k O
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a
s r
t e
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m di
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l a
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t d
f
e o
f r

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 10. Antidepressants
d t
e o
p T
r C
e A
s s
s a
e n
d d
S
p S
a R
t ls
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e r
n w
t h
s o
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w x
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ri
a e
r n
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e
u st
n r
r o
e n
s g
p a
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n xi
• e
ty
s ,
i A
v s
e p
e
o ci
r al
s
a u
l b
l c
e a
r t
g e
i g
c o

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 155
r o
y n
d
o p
f r
e
d f
e e
p r
r e
e n
s ti
s al
i ly
o t
n o
, M
A
c O
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l .
l B
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d c
a
a u
t s
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p o
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c t
a h
l ei
d r
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p s
r k
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s o
s r
i d
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n u
, g
—
m d
a r
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g
r a
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s d
p d

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 10. Antidepressants
r li
u n
g e
— a
f g
o e
o n
d ts
in
i m
n a
t n
e y
r tr
a e
c a
t t
i m
o e
n n
s t
, s
e
t t
h ti
e n
g
M s.
A
O T
I h
S e
s
a e
r d
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u
c g
o s
n a
s r
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d w
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r l
e a
d b
s
l o
a r
s b
t e
- d

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 157
a rr
f e
t v
e e
r rs
ib
o ly
r in
a a
l c
a ti
d v
m a
i t
n e
i d
s .
t v
r a
a ri
t e
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o b
n u
. t
it
E u
n s
z u
y al
m ly
e o
c
r c
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g rs
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n e
e v
r e
a r
t al
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o e
n e
. k
s
w a
h ft
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n r
t
i e

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 10. Antidepressants
r s
m s
i a
n n
a t
t a
i g
o e
n n
ts
o ,
f a
m
t in
h i
e m
u
d m
r o
u f
g 2
. w
e
T e
h k
u s
s o
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d
w el
h a
e y
n m
u
s st
w b
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t al
c lo
h w
i e
n d
g a
ft
a e
n r
t t
i e
d r
e m
p in
r a
e ti

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 159
o d
n e
p
o r
f e
s
M s
A a
O n
I t
fr
t o
h m
e a
r n
a y
p o
y t
h
a e
n r
d cl
a
t s
h s.
e M
A
i O
n Is
i a
t r
i e
a h
t e
i p
o a
n ti
c
o al
f ly
m
a e
n t
o a
t b
h ol
e iz
r e
d
a a
n n
t d
i e

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 10. Antidepressants
x e
c d
r a
e c
t
u
e
d t
el
r y
a a
p n
i d
d p
l r
y o
p
i
n h
yl
u a
r c
i ti
n c
e al
, ly
f
o
r
m
a
L n
i a
t gi
h n
i
VIII.
u Treatment of Mania and Bipolar Disorder
m
g
s bi
a p
l ol
t a
s r
p
a a
r ti
e e
n
u ts
s .

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 161
L a
i ti
t e
h n
i ts
u e
m x
hi
i bi
s ti
n
e g
f m
f a
e ni
c a
t a
i n
v d
e h
y
i p
n o
m
t a
r ni
e a.
a A
t lt
i h
n o
g u
g
6 h
0 m
% a
n
t y
o c
el
8 lu
0 la
% r
p
o r
f o
c
p e

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 10. Antidepressants
s ,
s t
e h
s e
m
a o
r d
e e
o
a f
l a
t c
e ti
r o
e n
d is
u
b n
y k
n
t o
r w
e n
a -
t T
m h
e e
n t
t h
e
w r
i a
t p
h e
u
l ti
i c
t in
h d
i e
u x
m o
f
s li
a t
l hi
t u
s m

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 163
.
i C
s o
m
e m
x o
t n
r a
e d
m v
e e
l rs
y e
e
l ff
o e
w ct
, s
a m
n a
d y
in
l cl
i u
t d
h e
i h
u e
m a
d
s a
a c
l h
t e,
s d
r
c y
a m
n o
u
b t
e h
,
t p
o ol
x y
i di
c p

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 10. Antidepressants
s
i w
a it
, h
p f
o o
l o
y d
u ),
r fi
i n
a e
, h
p a
o n
l d
y tr
p e
h m
a o
g r,
i di
a z
, zi
G n
I e
d s
i s,
s fa
t ti
r g
e u
s e,
s d
e
( r
g m
i a
v t
e ol
o
l gi
i c
t r
h e
i a
u c
m ti

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 165
o pl
n a
s s
, m
a a
n le
d v
el
s s
e m
d a
a y
t in
i di
o c
n a
- t
e
A t
d o
v xi
e ci
r t
s y
e a
n
e d
f in
f cl
e u
c d
t e
s a
t
d a
u xi
e a,
sl
t u
o rr
e
h d
i s
g p
h e
e e
r c
h

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 10. Antidepressants
, d
c f
o u
a n
r c
s ti
e o
n
t m
r a
e y
m b
o e
r d
s e
, cr
c e
o a
n s
f e
u d
s a
i n
o d
n s
, h
a o
n ul
d d
b
c e
o m
n o
v ni
u t
l o
s r
i e
o d
n .
s U
. nl
T ik
h e
y o
r t
o h
i e

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 167
r ,
a
m n
o d
o t
d h
o
s u
t g
a h
b c
i a
l u
i ti
z o
e n
r s
s h
, o
l ul
i d
t b
h e
i u
u s
m e
d
i w
s h
e
r n
e d
n o
a si
l n
l g
y t
hi
e s
l d
i r
m u
i g
n in
a r
t e
e n
d al

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 10. Antidepressants
l n
y p
a
i ti
m e
p n
a ts
i w
r it
e h
d h
e
p p
a a
t ti
i c
e i
n m
t p
s ai
, r
i m
t e
n
m t.
a
y S
e
b v
e e
r
t al
h a
e n
ti
b e
e pi
s le
t p
ti
c c
h d
o r
i u
c g
e s,
in
i cl

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 169
u e,
d h
i a
n v
g e
b
c e
a e
r n
b a
a p
m p
a r
z o
e v
p e
i d
n a
e s
, m
v o
a o
l d
p st
r a
o bi
i li
c z
e
a rs
c f
i o
d r
, bi
a p
n ol
d a
r
/ di
a s
m o
o r
t d
r er
i .
g O
i t
n h

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 10. Antidepressants
e e
r t
h
a e
g ol
e d
n e
t r
s (c
hl
t o
h r
a p
t r
o
m m
a a
y zi
n
i e
m a
p n
r d
o h
v al
e o
p
m e
a ri
n d
i o
c t)
a
s n
y d
m n
p e
t w
o e
m r
s a
n
i ti
n p
c s
l y
u c
d h

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 171
o n
t z
i a
c pi
s n
. e,
T zi
h p
e r
a
a si
t d
y o
p n
i e,
c a
a ri
l pi
a p
n r
t a
i z
p ol
s e,
y a
c s
h e
o n
t a
i pi
c n
s e,
a
r n
i d
s q
p u
e e
r ti
i a
d pi
o n
n e
e (s
, e
o e
l C
a h

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 10. Antidepressants
a ni
p a.
t Q
e u
r e
ti
I a
I pi
) n
e,
a [
r u
e r
a
a si
l d
s o
o n
e,
u a
s n
e d
d t
h
f e
o c
r o
m
t bi
h n
e a
ti
m o
a n
n o
a f
g ol
e a
m n
e z
n a
t pi
n
O e
f a
n
m d
a fl

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 173
u
o
x
e
t
i
n
e

h
a
v
e

b
e
e
n

a
p
p
r
o
v
e
d

f
o
r

b
i
p
o
l
a
r

d
e
io
p
n
r
.
e

s
s

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