Clinical Distinctions

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Each antidepressant has its unique blend of characteristics, and in fact, even individual

drugs within the same class have important differences. General Pharmacology

Table 38-2 demonstrates the differing pharmacologic properties of the antidepressant

medications, whereas Table 38-3 delineates the results of those pharmacologic ac-7 8

tions. ' Monoamine oxidase inhibitors (MAOIs) inhibit the enzyme responsible for the intraneuronal breakdown of 5-HT, NE, and DA. Tricyclic antidepressants (TCAs)

possess both 5-HT (serotonin) reuptake inhibition (SRI) and NE reuptake inhibition (NRI) properties but unfortunately also block the so-called "dirty receptors," including ai-adrenergic, histamine-1, and muscarinic cholinergic receptors, which contribute to side effects but not efficacy. The selective serotonin reuptake inhibitors (SSRIs) are classified as such because SRI is the predominant effect. Bupropion is an NE and DA reuptake inhibitor (NDRI). Venlafaxine, desvenlafaxine, and duloxetine are 5-HT and NE reuptake inhibitors (SNRIs) but are also weak inhibitors of DA reuptake. Compared with venlafaxine and desvenlafaxine, which have primarily SRI activity, duloxetine has more balanced SRI and NRI activities and has a higher affinity for the reuptake sites. Nefazodone and trazodone are 5-HT antagonists/reuptake inhibitors. Their SRI activity is not as pronounced as that of SSRIs, but they potently block 5-HT2A receptors, which allows more 5-HT to interact at postsynaptic 5-HTia sites. In addition, trazodone blocks histaminergic and a-adrenergic receptors, whereas nefazodone possesses weak NRI and a-adrenergic blocking properties. Finally, mir-tazapine is a noradrenergic and specific serotonergic antidepressant. It blocks presyn-aptic a2 receptors, both autoreceptors on noradrenergic neurons and heteroreceptors on serotonergic neurons, with resulting increases in NE and 5-HT synaptic concentrations, respectively. Mirtazapine also blocks various postsynaptic serotonergic recept-

7_o ors and histamine-1 receptors.

Table 38-2 Primary Pharmacologic Actions of Antidepressants

I 2

*

H

Ti 1 — >

E 1

"3

1 r-,

4

Action

X

u

l/>

a

II

a

H

sc

3

.WanoamTie osidase inhibition

Ji

5eii>liiiiin rttiuUtjr inhibition

X

X

XX

X

X

X

Norepinephrine ioupi.ikf ■ inhibition

X

X

XX

X

Dopamo? reuptake inhibition

X

i: -ArJieneiQi; n?refiroi Wrxtifli'

X

iei(J1onin-2^ luccplor Wocki*do

X

X

X

S?K>i0iiiiv?i' rwepror h)M"liirii>

X

Seiolanin-3 ret<>plioi bkxkade

X

(?, rrctfjlpi blotfcdt&7

X

X

X

Histamine-1 netepjor bkxkade

X

X

X

MuKjiinit ihclnu.'rgic «.tcfflor blockadc

X

MA£X monoamine oxidase jnhibitoi: iSF^ selective serotonin reuptake inhibitor: TC^ Irtyclic antidepressant SWitefl far Jiicuiiion oi moiv-swondjrjfptiiiipnjQokKjk'actions From flefi ?-i

MA£X monoamine oxidase jnhibitoi: iSF^ selective serotonin reuptake inhibitor: TC^ Irtyclic antidepressant SWitefl far Jiicuiiion oi moiv-swondjrjfptiiiipnjQokKjk'actions From flefi ?-i

Table 38-3 Efficacy and Adverse-Effect Profiles Based on Pharmacology

Plibi rnu LDlagic ALlicn

ftttull

5H

AmKlep<ie™inT and andaiwisiy efficacy (via mieraciiofi of b lffar Siif-I ft receptors)

AiiKM'-l'y, ■■■.Mirnrii^. ^rKTJAl (Jyjfui*, tkjrl (vij inh'r.K (kjn c^f S-HI .:" |iHr-JA

Airily, anOrMil (i/i.i ifhlr.Hjc(soil of S I II <H jHTvCrL^uljOi^

Nausea, G problems iva Inter action of i HT ai Ell 1 i recepiorsj

NRl

AiVliclcfJii^WriT tfiiiiiy

Toner. tachycardia, siwsrting, jiticriness. increased blood prpsMjn?

Dc^amine rsupnal«" inhiNrion.

AmiiK'fTief.-iani -pfilcacy

[upfimw. piychfirn^or juration. ii(^M™titjno! psyilxHis

u.Adrenergic receptor bbikade

Increase in serotonergic and noradi^nerglc aclktty—see actors of iftl fhkJ Nftl shove

Serotonin 3A reoaplor blockade

ATM rtKHty ef fcacy

Increased HEM Joep-deerfmod seiujl dysfu*K(ion

Wütonin-Jt i«fVi(Oi

Amiarawy efltacy

inetiSMd ipprtnAMSsht yjin

Serotomn-3 leceptor btoi tide

Jimmausedni, decreased Gl problems

o, Adianeiyk reccüJtoi Htxfcatie

Ollioslalt hypottiroion. diiiirK1«. rvlle/ 1j;hycaidia

HMinnirx' i r^opiwblDcl^dc

S« "i l.i: k>■>. mrirjtifl lin

Wuicaimc choline<g«: leceptor blockade

Dry rrauth. blurred vision. constin»1>oi\ tmnary hesitancy sinus tachycardia memory problems

NRLNcxepreptYTi? reuptake Ti'iTjitUTi; SRI, leratonln ieuptake Inhibition. From Reis, l and a.

NRLNcxepreptYTi? reuptake Ti'iTjitUTi; SRI, leratonln ieuptake Inhibition. From Reis, l and a.

St. John's wort (Hypericum perforatum) is a herbal medication that has shown some efficacy in mild-to-moderate depression but minimal efficacy for moderate-to-severe depression. Many patients believe that herbal medications, being "natural" products, are devoid of adverse effects and drug interactions; however, St. John's wort

can cause GI irritation, headache, fatigue, and nervousness, and it triggers drug interactions through induction of CYP3A4 enzymes, as well as other potential mech-22

anisms. The safety and efficacy of St. John's wort combined with standard antidepressant medications remain unknown.16

Adverse Effects

The important adverse effects of the various antidepressants are often a function of their underlying pharmacologic profiles7,8 (Table 38-3). TCAs cause problematic sedative, anticholinergic, and cardiovascular adverse effects owing to their interaction with "dirty receptors." While these adverse effects generally are considered to be common and bothersome, they can be quite serious in some cases. For example, constipation in its extreme form can lead to paralytic ileus. The tertiary amines (e.g., amitriptyline, imipramine) are more sedative and anticholinergic than secondary amines (e.g., desipramine, nortriptyline). TCAs have a quinidine-like effect on the heart, which makes them quite toxic on overdose. The average lethal dose in a young

adult is only 30 mg/kg, which is typically less than a 1 month's supply. ' ' '

The adverse-effect profile of the SSRIs includes sexual dysfunction (e.g., delayed or absent orgasms), CNS stimulation (e.g., nervousness and insomnia), and GI dis-

turbances (e.g., nausea and diarrhea). ■ ■ ■ Sexual dysfunction is common and

challenging to manage and often leads to noncompliance. Various strategies to deal with antidepressant-induced sexual dysfunction include waiting for symptoms to subside, reducing the dosage, permitting periodic "drug holidays," prescribing ad-

junctive therapy, and switching antidepressants. However, waiting for symptoms to subside usually does not work because sexual dysfunction may very well persist throughout the duration of therapy. Reducing the dose and using drug holidays may weaken the antidepressant effects. Thus, clinicians often prescribe adjunctive therapy such as dopaminergic drugs (e.g., bupropion or amantadine), 5-HT2 antagonists (e.g., cyproheptadine or nefazodone), and phosphodiesterase inhibitors (e.g., sildenafil), or simply switch to a nt ide pressants with less like lihood of causing these effects, such as bupropion, mirtazapine, or nefazodone.24,25

Bupropion causes insomnia, nightmares, decreased appetite, anxiety, and tremors, but the most concerning adverse effect is seizures. Because of the risk for seizures, patients with a CNS lesion, history of seizures, head trauma, or bulimia should not receive the drug. The daily dose of bupropion should not exceed 450 mg/day, and any single dose of the immediate-release formulation should not exceed 150 mg. Occurrences of insomnia and/or nightmares often respond to moving the last daily dose

/9 2123

from bedtime to late afternoon.

Table 38-4 Relative Incidence of Adverse Effects of Various Newer Antidepressants

The adverse effects of SNRIs are similar to those of SSRIs. Nausea can be particularly troublesome with venlafaxine and desvenlafaxine, which sometimes necessitates using lower starting dosages than usual and giving the medication with food. A

dose-related elevation in blood pressure can occur at higher doses, probably owing to the NRI effects. Blood pressure monitoring should be conducted for patients receiving venlafaxine and desvenlafaxine therapy. As a rule, duloxetine should not be prescribed to patients with extensive alcohol use or evidence of chronic liver disease

Q 01 07

owing to the potential for hepatic injury. , , ,

Trazodone routinely causes sedation, which is why it is used far more often as an adjunct with other antidepressants for sleep than as an antidepressant. Priapism is a rare but serious adverse effect in males who take trazodone. In addition, or-thostatic hypotension and dizziness are more common with trazodone than with ne-fazodone because the latter agent has a weaker effect at a-adrenergic receptors and also has a balancing of adrenergic effects owing to weak NRI activity. Unfortunately, nefazodone has been associated with development of hepatotoxicity, which has led to a black-box warning and a great reduction in its use. It has been discontinued in some

7 9 21 23 countries.7,9,21,23

Mirtazapine can cause sedation and weight gain by virtue of blocking histamine-1 receptors. Despite being partially a serotonergic drug, it rarely causes serotonergic-re-lated adverse effects because it blocks the various postsynaptic 5-HT receptors. Although it carries a bolded warning for neutropenia owing to a handful of cases reported during clinical trials, it is questionable whether neutropenia is any more problematic with this agent than other antidepressants.9,21,23

The relative incidence of adverse effects among some of the newer antidepressant

9 13 28

agents are shown in Table 38-4. ' ' Pharmacokinetic Parameters

Pharmacokinetic parameters of the newer antidepressants are shown in Table 38-5.9,29 Several antidepressants are not highly protein-bound, and the most notable of these are venlafaxine and desvenlafaxine. The elimination half-lives of nefazodone and venlafaxine are relatively short compared with the other agents. Conversely, fluoxetine has a very long half-life (i.e., 5-9 days) with chronic dosing, and its active metabolite (norfluoxetine) has an even longer half-life. Owing to the extremely long half-life of fluoxetine and its active metabolite, a 5-week washout of fluoxetine is required before starting an MAOI. Sertraline and citalopram are the other SSRIs with active metabolites, but these metabolites (desmethylsertraline and desmethyl-citalopram, respectively) are only about one-eighth as potent as the parent compounds in terms of SRI activity.

Table 38-5 Pharmacokinetic Parameters of Newer Antidepressants

Protein

Elimination

Binding

Half-Life

Active

Drug

m

(hours)

Met aboli te (51

Bupropion

84

10-21

Yes.

Citatopram

80

33

Yes

Duloxetine

90

9-19

Mo

Escttalopiam

56

27-32

No

Huoyetine

94

4-6 days with

Yes

chronic

dosing:

4-16 days

(active

metabolite)

Flu voxa mine

11

15-26

No

Mirtazapine

85

20-40

No

Nefajodone

99

2-4

Yes

Paroxetine

95

21

No

Sertraline

98

27

Yes

Venlafaxine

27

5

Yes

Pesvènlafaxine

30

7.5

Drug Interactions

The major drug interactions of antidepressants are shown in

9,22,30 The usual pharmacodynamic drug interactions involve the "dirty receptors" blocked by some antidepressants. Hence, especially TCAs can cause significant additive effects with drugs that cause sedation, hypotension, or anticholinergic effects. Similarly, ne-fazodone and mirtazapine can interact with other drugs that cause hypotensive and sedative effects, respectively. By far, the most concerning pharmacodynamic interactions are hypertensive crisis and 5-HT syndrome, which are both potentially life-

threatening when they occur. Hypertensive crisis is characterized by sharply elevated blood pressure, occipital headache, stiff or sore neck, nausea, vomiting, and sweating. It may result during MAOI therapy if the patient takes a sympathomimetic drug, such as ephedrine, pseudoephedrine, phenylephrine, or phenylpropanolamine, or if the patient consumes foods rich in tyramine, such as tap beers, aged cheeses, fava beans,

yeast extracts, liver, dry sausage, sauerkraut, or tofu. There are extensive lists of foods and drinks that are permitted and not permitted during therapy with MAOIs, and these always should be provided to patients. Since many over-the-counter products contain sympathomimetics, patients always should be told to consult with their clinician and/or pharmacist prior to using these drugs. 5-HT syndrome is characterized by confusion, restlessness, fever, abnormal muscle movements, hyper-reflexia, sweating,

diarrhea, and shivering. It may result when a serotonergic agent is added to any sero-

tonergic antidepressant, but the MAOIs are strongly associated with severe cases of 31

5-HT syndrome. 5-HT syndrome is complicated by (a) an unawareness by clinicians 31

of the diagnosis and (b) the fact that many implicated drugs are not obviously serotonergic in nature, such as dextromethorphan, meperidine, and tramadol.

Several antidepressants, including most of the SSRIs, nefazodone, and duloxetine, are known to inhibit various cytochrome P450 isoenzymes, thereby elevating plasma levels of substrates for those isoenzymes and thus potentially leading to increased adverse effects or toxicity. The propensity to cause these drug interactions will vary with the particular antidepressant and the precise isoenzyme9,2 ,30 (Table 38_6).

Dosing

Dosing is summarized in Table 38-7.13,16,17,20,29,32 The extended-release formulations of venlafaxine and bupropion allow for once-daily dosing. The delayed-release capsule of fluoxetine can be given once weekly, which can be started 7 days after the last regular-release capsule or tablet. Selegiline is available as a transdermal patch and a dose of 6 mg/24 hours can be used without the usual dietary restrictions associated with MAOI use, although patients on the higher doses (9 and 12 mg/24 hours) should follow the usual dietary restrictions. Liquid dosage forms and disintegrating tablets of various antidepressants are ideal for patients who have difficulty swallowing tablets or capsules or those who otherwise may attempt to "cheek" their medication.

The starting dose is the usual therapeutic dose for most of the SSRIs, desvenlafax-ine, duloxetine, and mirtazapine, whereas there is usually need for at least some upward titration of venlafaxine, bupropion, and nefazodone. A particular disadvantage of TCAs is that the customary way of dosing them involves meticulous upward titra-

tion from a small starting dose to a wide usual therapeutic dosage range. On the contrary, one advantage of some TCAs is that plasma levels may be used to help guide dosing, especially for those that have well-defined therapeutic plasma level ranges, including nortriptyline (50-150 ng/mL or mcg/L, or 190-570 nmol/L), desipramine (100-160 ng/mL or mcg/L, or 375-600 nmol/L), amitriptyline (75-175 ng/mL or mcg/L, 255-595 nmol/L), and imipramine (200-300 ng/mL or mcg/L, or 714-1,071

nmol/L).28

Table 38-6 Drug Interactions of Antidepressantsa

Anlldcpreiunts

Type of Interaction

Examples of Interacting Drugs

TCAs. Jrauodone. niMaiapine

Pharmacodynamic—additive sedation

BermcdkiiepineSi alcohol, afitflintarnines

TC Aii trazodone

mainruccidynMnic—.idditlve hypotensive efiecls

antl|Hyiho1rcs

TC**

HyimaiOdyn^nk -iJdirive Wlfclioliniigk; iff« ti

PhtJXjtliiaiirU'S, bci\i[Jiiuirw

rcAi

Pharmacodynamic—additive cardiac toxicity

Thioridazine, qulmd me

TCAs

PfiaiimiOM^flWiTiC^-deaBosecliWihypertFnShc effect

Guanethitlnrxf. ctmidinp, mt'thyidbiJa

Bupropion

PftammacciOynamic—inc-ieased unure risk

TCAs, p4venoth<a^ines

IWMJ05

Ftuiimscixfynainic—hrt^reniiin? Crfeil

r^nrine-ikh fooils, s ymiMchoniiiiWk i

IMOKTCAs, SSRls, Sn RK SARIs

Ftiarmacodynairrc—i-HT syndrome

Serotona^c am depressant s, mepei idine, duxtiOi"«thO<plV)i> IrMMdol

Fruitoiamlne

PMarnnacc;kin«t—CtPlAJ Inhfcxnon

TCAs, clou aprne, theophylline

FruoMetineJkjvoaamne. sertraline

Pharmacokinetic—CVP2C inhibition

TCAs. piierytoin. woriarin, tolbutamide

N'.jcuwiinp, iiinc/ieilne. (Juloïeimp,

rtiainnacnkinflcc— CvPJDft inhaiirlon

f( As, hjloperkW, risfWrKVine, codeine,

witrâliiTi

riiit»j[WfcJ, piOfjjfvnurH."

NefaKKtofti1, fluoxerine,

Hhainrifli:ot(ifteiic—C.VPTA1 mhihUinn

I( Ai, alprazolam, v^pfimiL i arbamaief line.

iluuo*iirnin(i

touastattn

MAtH. monoammeoKida« inhibitor; 'îArtI, serotonin antagonist anrl reui^afcj? '^hihitor; iNflL serntonin anrl nonepnephiine ivupiifc' inhibitor; selective Jerotontrt 1(14^*6 ifihibiKir: TCA, Vkyïlk antkloprossarH.

'Not en al inclusive Int.

FiomFleis. 9, 72,301

Table 38-7 Dosing of Antidepressants in Adult Patients

Pherfiftine lianytcypramine

TC As and Tetracyclics

Airtnipiyline Amorapine Clompfannine

Pi nip« mm» Doropin Imipramine MSWlilini NQrlripdylirv?

HiilnfjlyllrK'

Ottfcpnm be :abp'aT Hluouftini?

Fluvoxamine PirtufiSne

Sertraline NDRI

Umal Dcugc

Initial Dose

liifHji

Usual Dosing

Brand Name

Generic

Desage Fnrmi

Íoij/díjí)

imj/day)

Schedule

Wjrdil

NO

Tablet

15—30

IÍHM

TivusdS!!)'

Patriate

Mo

Tjt.lL'l

10-2(1

3t>-60

Twee daily

imsam

MO

ff.illh

&

6-1?

[>v# daily

EW

IK«

Tahtei

25-30

1CO-SÍM

Once daily

^MirxJin*

yfe

Tabfcl

25-S0

tOO 400

Oicc U; twice diiOy

AndfranJ

Yes

t'jpsLile

25

100-250

Once daily

TJWOI

1W-JOO

OnfT d.iily

^¡n^Uiin

Hta

Capsule, wkilkjn

25* SO

W» 300

Once daily

Tofranil

Yes

Tablet, capsule

25-50

100-300

Once daily

Ludiomil*

VK

Tit*«

50-75

1W-225

OrK.iL U; twite djily

Pamelor

WB

Capsule, solution

25

M-isa

free daily

Vivac til

MO

Tjbk-I

5-tt

IS-Ó0

Once dally

SuiriXirnil

MO

ta piule

25-S0

1W-3W

Ox* daily

Ceieaj

T.ltlll-l. '.1 IILIIÍL>J-I

20

20-60

Otve daily

Lexapno

No

"úbiii, solution

10

10-20

free daily

If-OHC

ite

Tablet capsule; »liiton

10-70

20-30

On« daily

fUlEJC ivcetty

H(J

[Wo^l- ICleiW Cjpilllp

W

free weekly

iu™*

Hfcs

Tablet

SO

50-300

Twciidaify

Paadl

His

TahleT, ÍU^wiííoíi

10-29

29-SO

Once daily

PjjiilCR

lta

OCnBOfcthcteas* labfct

125 25

25-62,5

Once daily

Zofoit

Yes

Tablet, concentrate

25-50

50-200

Once daily

Sertraline NDRI

Pu|X>0[0«>n

Wi-III n in in

fes

ÍJWt.1

150-200

HHSO

iwijo ro ilvkfdaj^

Wellbutrin SR

Yes

Sioialned release tablet

ISO

300-100

Twice daily

'iVeftujtrlri XI

tsuenfleo-reiwise i^tiieT

IS?

JW-JW

Once diily

SNRIs

[Xjlcwoetine

Cymbaka

Yes

ijpsule

4Ü-W

■Í0-M

Once to twice daily

^nlílsíine

Ifferof

Yes

Tüblel

IF.Í-75

ÍÍ-375

TAice1 daily

Elleaof X»

Yes

Ejlerdpd-relüase capsule

J7.5-75

75-225

free daily

Desverilaíanine

Jtisljq

No

Emended rrkMsc (jblct

5D

50-100

Onoii daily

5ARJS

NcíjHüdDnc

ScrZOnu*

Tfa

Tublcl

100-200

300 600

Tivri-daily

Trazodone

Desyrel

Ties

Tablet

S0-I50

200-600

Twice daity

NiSSA

Mfrtaiapine

Pemeon

»B

Tablel, disintcguting

15

1545

frioe daily

MAOL monoamine c«idaf.L -nhitííícH: NuSSA* rraudronctyc and ipccilic scrdoner-gic antidepressant; NCfli, noíepineplririe and dflpamite negpiafc? inhiliiinr; &AKL «roh>mn ífliífjünisi and ríupMlii1 ¡nhibticf; ^NftU^iííiWin aiftd nnri?p¡i>e|ihílr>i? reuptake Inlvíjilor^fll, ■v?tei;rivf? íenotonm nnjptjkjp inhibrtoi; TCA, tricyclic jntdLTMeisanr.

Ufand no longer mailable in the Unned Statei. fcom ftefi. 13, It 17.20. 29,32.

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