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Antidepressants
12I. OVERVIEWThe symptoms of depression are intense feelings of
sadness, hopeless-ness, and despair as well as the inability to
experience pleasure in usualactivities, changes in sleep patterns
and appetite, loss of energy, and sui-cidal thoughts. Mania is
characterized by the opposite behavior: enthu-siasm, rapid thought
and speech patterns, extreme self-condence, andimpaired judgment.
[Note: Depression and mania are diff erent fromschizophrenia (see
p. 161), which produces disturbances in thought.]
II. MECHANISM OF ANTIDEPRESSANT DRUGS
Most clinically useful antidepressant drugs potentiate, either
directly orindirectly, the actions of norepinephrine and/or
serotonin in the brain.(See Figure 12.1 for a summary of the
antidepressant agents.) This, alongwith other evidence, led to the
biogenic amine theory, which proposesthat depression is due to a
deciency of monoamines, such as norepi-nephrine and serotonin, at
certain key sites in the brain. Conversely, thetheory proposes that
mania is caused by an overproduction of these neu-rotransmitters.
However, the amine theory of depression and mania isoverly
simplistic. It fails to explain why the pharmacologic eff ects of
anyof the antidepressant and anti-mania drugs on neurotransmission
occurimmediately, whereas the time course for a therapeutic
response occursover several weeks. Furthermore, the potency of the
antidepressant drugsin blocking neurotransmitter uptake often does
not correlate with clinical-ly observed antidepressant eff ects.
This suggests that decreased uptakeof the neurotransmitter is only
an initial eff ect of the drugs, which maynot be directly
responsible for the antidepressant eff ects. It has been pro-posed
that presynaptic inhibitory receptor densities in the brain
decreaseover a 2 to 4 week period with antidepressant drug use.
This down-reg-ulation of inhibitory receptors permits greater
synthesis and release of neurotransmitters into the synaptic cleft
and enhanced signaling in thepostsynaptic neurons, presumably
leading to a therapeutic response.
III. SELECTIVE SEROTONIN REUPTAKE INHIBITORS
The selective serotonin reuptake inhibitors (SSRIs) are a group
of chemi-cally diverse antidepressant drugs that specically inhibit
serotoninreuptake, having 300- to 3000-fold greater selectivity for
the serotonintransporter, as compared to the norepinephrine
transporter. This contrastswith the tricyclic antidepressants
(TCAs, see p. 155) that nonselectivelyinhibit the uptake of
norepinephrine and serotonin (Figure 12.2). Both of these
antidepressant drug classes exhibit little ability to block the
dop-
SELECTIVE SEROTONINREUPTAKEINHIBITORS (SSRIs)Citalopram
CELEXAEscitalopram LEXAPROFluoxetine PROZACFluvoxamine LUVOX
CRParoxetine PAXILSertraline ZOLOFTSEROTONIN/NOREPINEPHRINEREUPTAKE
INHIBITORS (SNRIs)Desvenlafaxine PRISTIQDuloxetine
CYMBALTAVenlafaxineEFFEXOR
ATYPICALANTIDEPRESSANTS
Bupropion WELLBUTRIN, ZYBANMirtazapine REMERONNefazodone
SERZONETrazodone DESYREL
TRICYCLICANTIDEPRESSANTS (TCAs)
Amitriptyline ELAVIL
AmoxapineASENDINClomipramineANAFRANILDesipramine
NORPRAMINDoxepinSINEQUANImipramine
TOFRANILMaprotilineLUDIOMILNortriptyline
PALMELORProtriptylineVIVACTILTrimipramineSURMONTILMONOAMINE OXIDASE
INHIBITORS(MAOIs)IsocarboxazidMARPLAN Phenelzine NARDILSelegiline
ELDEPRYLTranylcypromine PARNATE
Figure 12.1Summary ofantidepressants.(Continued on next
page)
Pharm 5th 3-2 1-11.indb 151 3/21/ 11 2:22:19 PM
152 12. Antidepressant s
amine transporter. Moreover, the SSRIs have little blocking
activity at mus-carinic, -adrenergic, and histaminic H 1 receptors.
Therefore, common sidee ff ects associated with TCAs, such as
orthostatic hypotension, sedation, drymouth, and blurred vision,
are not commonly seen with the SSRIs. Becausethey have fewer
adverse e ff ects 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 uox-etine [ oo-OX-e-teen] (the proto typic drug),
citalopram [sye-TAL-oh-pram],escitalopram [es-sye-TAL-oh-pram],
uvoxamine [ oo-VOX-e-meen], parox-etine [pa-ROX-e-teen], and
sertraline [SER-tra-leen]. Both citalopram and u-oxetine are
racemic mixtures, of which the respective S-enantiomers are themore
potent inhibitors of the serotonin reuptake pump. Escitalopram is
thepure S-enatiomer of citalopram.
A. Actions
The SSRIs block the reuptake of serotonin, leading to increased
con-centrations of the neurotransmitter in the synaptic cleft and,
ultimately,to greater postsynaptic neuronal activity . A
ntidepressants, includingSSRIs, typically take at least 2 weeks to
produce signi cant improve-ment in mood, and maximum bene t may
require up to 12 weeks ormore (Figure 12.3). However, none of the
antidepressants are uniformlye ff ective. Approximately 40 percent
of depressed patients treated withadequate doses for 4 to 8 weeks
do not respond to the antidepres-sant agent. Patients who do not
respond to one antidepressant mayrespond to another, and
approximately 80 percent or more will respondto at least one
antidepressant drug. [Note: These drugs do not usuallyproduce
central nervous system (CNS) stimulation or mood elevation innormal
individuals.]
B. Therapeutic uses
The primary indication for SSRIs is depression, for which they
are ase ff ective as the TCAs. A number of other psychiatric
disorders alsorespond favorably to SSRIs, including
obsessive-compulsive disorder,panic disorder, generalized anxiety
disorder, posttraumatic stress disor-der, social anxiety disorder,
premenstrual dysphoric disorder, and buli-mia nervosa (only
uoxetine is approved for this last indication).
C. Pharmacokinetics
All of the SSRIs are well absorbed after oral administration.
Peak lev-els are seen in approximately 2 to 8 hours on average.
Food has littlee ff ect on absorption (except with sertraline , for
which food increasesits absorption). Only sertraline undergoes
signi cant rst-pass metabo-lism. The majority of SSRIs have plasma
half-lives that range between16 and 36 hours. Metabolism by
cytochrome P450 (CYP450)-dependentenzymes and glucuronide or
sulfate conjugation occur extensively.[Note: These metabolites do
not generally contribute to the pharma-cologic activity .]
Fluoxetine di ff ers from the other members of the classin two
respects. First, it has a much longer half-life (50 hours) and
isavailable as a sustained-release preparation allowing once-weekly
dos-ing. Second, the metabolite of the S-enantiomer, S-nor
uoxetine, is aspotent as the parent compound. The half-life of the
metabolite is quitelong, averaging 10 days. Fluoxetine and
paroxetine are potent inhibitorsof a hepatic CYP450 isoenzyme
(CYP2D6) responsible for the eliminationof TCAs, neuroleptic drugs,
and some antiarrhythmic and -adrenergicantagonist drugs. [Note:
About 7 percent of the Caucasian population
Figure 12.2Relativereceptor speci city ofsomeantidepressant
drugs.* Venlafaxineinhibits norepinephrinereuptakeonly at high
doses.++++ = verystronga ffi nity;+++ = stronga ffi nity;++ =
moderatea ffi nity;+ = weakaffi nity;0= littleor no a ffi nity.
D R U G U P T AK E I N H IB I T I ONNor-epinephrine
Serotonin
Tricyclicantidepressant Imipramine
++++ +++
Selectiveserotoninreuptakeinhibitor Fluoxetine 0 ++ ++
Selectiveserotonin/norepinephrinereuptakeinhibitors Venlafaxine
Duloxetine
+ +* + + +++ + ++ + + ++
Antidepressante ff ects
Adminis trationofantidepressant
Figure 12.3Onset oftherapeutic e ff ects of themajor
antidepressant drugsrequires several weeks.
2 to 12 weeks
On seto factio n
Depress ion
DRUGS USED TO TREATMANIAand BIPOLARDISOR DERCarbamazepine
TEGRETOL, EQUETRO,CARBATROLLithium ESKALITHValprioc acid DEPAKENE,
DEPAKOTE
Figure 12.1 (continued)Summary ofantidepressants.
Pharm 5th 3-21-11.i n db 1 52 3/ 21/11 2:22 :20 PM
154 12. Antidepressants
5. Discontinuation syndrome: Whereas all of the SSRIs have
thepotential for causing a discontinuation syndrome after their
abruptwithdrawal, the agents with the shorter half-lives and having
inac-tive metabolites have a higher risk for such an adverse
reaction.Fluoxetine has the lowest risk of causing an SSRI
discontinuationsyndrome. Possible signs and symptoms of such a
serotonin-relateddiscontinuation syndrome include headache, malaise
andu-likesymptoms, agitation and irritability, nervousness, and
changes insleep pattern.
IV. SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS
Venlafaxine [VEN-la-fax-een],desvenlafaxine
[dez-VEN-la-fax-een], andduloxetine (doo-LOX-e-teen) inhibit the
reuptake of both serotonin and nor-epinephrine (Figure 12.5). These
agents, termed selective serotonin/norepi-nephrine reuptake
inhibitors (SNRIs), may be eff ective in treating depres-sion in
patients in whom SSRIs are ineff ective. Furthermore, depression
isoften accompanied by chronic painful symptoms, such as backache
andmuscle aches, against which SSRIs are also relatively ineff
ective. 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 serotoninand norepinephrine
reuptake, are sometimes eff ective in relieving physi-cal symptoms
of neuropathic pain such as diabetic peripheral neuropathy.However,
the SNRIs, unlike the TCAs, have little activity a t adrenergic,
mus-carinic, or histamine receptors and, thus, have fewer of these
receptor-medi-ated adverse eff ects than the TCAs (see Figure
12.2).Venlafaxine, desvenla-faxine, and duloxetine may precipitate
a discontinuation syndrome if treat-ment is abruptly stopped.
A. Venlafaxine and desvenlafaxine
Venlafaxine is a potent inhibitor of serotonin reuptake and, at
medi-um to higher doses, is an inhibitor of norepinephrine
reuptake. It isalso a mild inhibitor of dopamine reuptake at high
doses.Venlafaxinehas minimal inhibition of the CYP450 isoenzymes
and is a substrateof the CYP2D6 isoenzyme. The half-life of the
parent compound plusits active metabolite is approximately 11
hours.Desvenlafaxine is theactive, demethylated, metabolite of the
parent compoundvenlafaxine.The most common side eff ects
ofvenlafaxine are nausea, headache,sexual dysfunction, dizziness,
insomnia, sedation, and constipation. Athigh doses, there may be an
increase in blood pressure and heart rate.Desvenlafaxine is not
considered to have a signi cantly diff erent clinicalor adverse eff
ect pro le compared tovenlafaxine.
B. Duloxetine
Duloxetine inhibits serotonin and norepinephrine reuptake at all
dos-es. It is extensively metabolized in the liver to numerous
metabolites.Duloxetine should not be administered to patients with
hepatic insuffi -ciency. Metabolites are excreted in the urine, and
the use ofduloxetineisnot recommended in patients with end-stage
renal disease. Food delaysthe absorption of the drug. The half-life
is approximately 12 hours. GIside eff ects are common
withduloxetine, including nausea, dry mouth,and constipation.
Diarrhea and vomiting are seen less often. Insomnia,dizziness,
somnolence, and sweating are also seen. Sexual dysfunctionalso
occurs along with the possible risk for an increase in either
bloodpressure or heart rate.Duloxetine is a moderate inhibitor of
CYP2D6 andCYP3A4 isoenzymes.
Postsynapticresponse
Antidepressantdrugblocksreuptake oftheneurotransmitter.
Figure 12.5Proposed mechanism ofaction of
selectiveserotonin/norepinephrinereuptakeinhibitor
antidepressantdrugs.
PRESYNAPTICNEURON
SYNAPTICCLEFT
NorepinephrineSerotonin
POST-SYNAPTICNEURON
VenlafaxineDuloxetine
Ph arm 5th 3- 21- 11.indb 154 3/21 /11 2 :22:2 1 PM
158 12.Ant id epressant s
A. Mechanism of action
Most MAOIs, such as phenelzine, form stable complexes with
theenzyme, causing irreversible inactivation. This results in
increasedstores of norepinephrine, serotonin, and dopamine within
the neuronand subsequent diff usion of excess neurotransmitter into
the synap-tic space (Figure 12.9). These drugs inhibit not only MAO
in the brain,but also MAO in the liver and gut that catalyze
oxidative deaminationof drugs and potentially toxic substances,
such as tyramine, which isfound in certain foods. The MAOIs,
therefore, show a high incidence of drug-drug and drug-food
interactions.Selegiline administered as thetransdermal patch may
produce less inhibition of gut and hepatic MAOat low doses because
it avoidsrst-pass metabolism.
B. Actions
Although MAO is fully inhibited after several days of treatment,
theantidepressant action of the MAOIs, like that of the SSRIs and
TCAs, isdelayed several weeks.Selegiline andtranylcypromine have an
amphet-amine-like stimulant eff ect that may produce agitation or
insomnia.
C. Therapeutic uses
The MAOIs are indicated for depressed patients who are
unresponsiveor allergic to TCAs or who experience strong anxiety.
Patients with lowpsychomotor activity may benet from the stimulant
properties of theMAOIs. These drugs are also useful in the tr
eatment of phobic states.A special subcategory of depression,
called atypical depression, mayrespond preferentially to MAOIs.
Atypical depression is characterizedby labile mood, rejection
sensitivity, and appetite disorders. Because of their risk for
drug-drug and drug-food interactions, the MAOIs are con-sidered to
be last-line agents in many treatment venues.
D. Pharmacokinetics
Thesedrugs arewell absorbed after oral administration,but
antidepres-sant eff ects requireat least 2to 4weeks
oftreatment.Enzymeregenera-tion,when irreversibly
inactivated,varies,but it usually occurs severalweeks after
termination ofthedrug.Thus,when switchingantidepres-sant agents,a
minimum of2weeks ofdelay must beallowed after termi-nation ofMAOI
therapy and theinitiation ofanother antidepressant fr omany other
class.MAOIs aremetabolized and excreted r apidly in urine.
E. Adverse eff ects
Severe and often unpredictable side eff ects, due to drug-food
anddrug-drug interactions, limit the widespread use of MAOIs. For
exam-ple, tyramine, which is contained in certain foods, such as
aged chees-es and meats, chicken liver, pickled or smokedsh (such
as anchoviesor herring), and red wines, is normally inactivated by
MAO in the gut.Individuals receiving a MAOI are unable to degrade
tyramine obtainedfrom the diet. Tyramine causes the release of
large amounts of storedcatecholamines from nerve terminals,
resulting in what is termed ahypertensive crisis,with signs and
symptoms such as occipital head-ache, stiff neck, tachycardia,
nausea, hypertension, cardiac arrhyth-mias, seizures, and,
possibly, stroke. Patients must, therefore, be edu-cated to avoid
tyramine-containing foods.Phentolamine and prazosinare helpful in
the management of tyramine-induced hypertension.
Figure 12.9Mechanism ofaction ofmono-amineoxidaseinhibitors
(MAOIs).
Synapticvesicle
MAO
Inactivemetabolites
NorepinephrineSerotoninDopamine
Synapticvesicle
MAO
Inactivemetabolites
NorepinephrineSerotonin
Dopamine
n pticvsicle
MAOIspreventinactivationofmonoamineswithin aneuron,
causingexcessneuro-transmitterto diff use into
thesynapticspace.
n ptic
MAO inactivatesmono-amines(norepinephrine,serotonin, and
dopamine)thatleakfroma synapticvesicle.
Normal monoamine transmission
Eff ectofMAOIs
A
B
Postsynapticresponse
SYNAPTICCLEFT
POST-SYNAPTICNEURON
Postsynapticresponse
SYNAPTICCLEFT
POST-SYNAPTICNEURON
Pharm 5th 3-21-11.indb 158 3/21/11 2:22:29 PM
VIII.Treatment OfMania And Bipolar Disorder 159
[Note: Treatment with MAOIs may be dangerous in severely
depressedpatients with suicidal tendencies. Purposeful consumption
of tyramine-containing foods is a possibility.] Other possible side
eff ectsof treatment with MAOIs include drowsiness, orthostatic
hypotension,blurred vision, dry mouth, dysuria, and constipation.
MAOIs and SSRIsshould not be coadministered due to the risk of the
life-threateningserotonin syndrome.Both types of drugs require
washout periodsof at least 2 weeks before the other type is
administered, with theexception of uoxetine, which should be
discontinued at least 6 weeksbefore a MAOI is initiated.
Combination of MAOIs andbupropion canproduce seizures. Figure 12.10
summarizes the side eff ects of the anti-depressant drugs.
VIII. TREATMENT OF MANIA AND BIPOLAR DISORDER
The treatment of bipolar disorder has increased in recent years,
partly dueto the increased recognition of the disorder and also due
to the increase inthe number of medications FDA-approved for the
treatment of mania.
A. Lithium
Lithium salts are used prophylactically for treating
manic-depressivepatients and in the treatment of manic episodes
and, thus, are consid-ered mood stabilizers.Lithium is eff ective
in treating 60 to 80 percentof patients exhibiting mania and
hypomania. Although many cellularprocesses are altered by treatment
withlithium salts, the mode of actionis unknown. [Note:Lithium is
believed to attenuate signaling via recep-tors coupled to the
phosphatidylinositol bisphosphate (PIP2) second-messenger 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 unaff ected
bylithium.]Lithium is given orally, and the ion is excreted by the
kidney.Lithium sal t s can betoxic. Their safety factor and
therapeutic index are extremely low andcomparable to those
ofdigoxin. Common adverse eff ects may includeheadache, dry mouth,
polydipsia, polyuria, polyphagia, GI distress (givelithium with
food),ne hand tremor, dizziness, fatigue, dermatologicreactions,
and sedation. Adverse eff ects due to higher plasma levelsmay
include ataxia, slurred speech, coarse tremors, confusion, and
con-vulsions. [Note: The diabetes insipidus that results from
takinglithium can be treated withamiloride.] Thyroid function may
be decreased andshould be monitored.Lithium causes no noticeable
eff ect on normalindividuals. It is not a sedative, euphoriant, or
depressant.
B. Other drugs
Several antiepileptic drugs, including, most
notably,carbamazepine, valproic acid,and lamotrigine, have been
identied and FDA approvedas mood stabilizers, being used
successfully in the treatment of bipolardisorder. Other agents that
may improve manic symptoms include theolder (for
example,chlorpromazine andhaloperidol ) and newer
antipsy-chotics.The atypical antipsychotics
(risperidone,olanzapine, ziprasidone,aripiprazole,asenapine,
andquetiapine) have also received FDA approv-al for the management
of mania. Benzodiazepines are also frequentlyused as adjunctive
treatments for the acute stabilization of patientswith mania. (See
the respective chapters on these psychotropics for amore detailed
description).
Figure 12.10Sideeff ects ofsomedrugs used totreat
depression.
Sedating; may beuseful foragitation
PhenelzineTranylcypromine
Amitriptyline
AmoxapineClomipramineDesipramineDoxepinImipramineMaprotilineNortriptylineProtriptylineTrimipramine
TRICYCLIC/POLYCYCLICANTIDEPRESSANTS
MONOAMINE OXIDASEINHIBITORS
Weightgain
BupropionMirtazapineNefazodoneTrazodone
ATYPICALANTIDEPRESSANTS
Gastro-intestinaldistress
CitalopramEscitalopramFluoxetineFluvoxamineParoxetineSertraline
SELECTIVESEROTONINRE-UPTAKE
INHIBITORS
SEROTONIN/NOREPINEPHRINE
REUPTAKE INHIBITORSDuloxetineVenlafaxine
Desvenlafaxine
High potentialfororthostatichypotension
Pharm 5th 3-21 -11.indb 15 9 3/21/1 1 2:22:29 PM
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