Psychiatric Drugs and Pharmacology

8/9/2019 Psychiatric Drugs and Pharmacology

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Antipsychotics side effects: are associated with an assortment of side effects, many of which can seriously affect a patient's physical

health and quality of life. Side effects occur because :

neurotransmitters are affected by drugs,

• drug half-life,

P450 liver enzyme system metabolism,

• and percentage of the drug bound to a given receptor.

By understanding these concepts, clinicians can better understand why and how side effects occur, and also predict to some degree in

which patients side effects will occur. The more factors involved in a given patient, the more lielihood side effects !ill occur .

"#$%&T%A"'()TT#% )"*&+*#(#"T )" ')# ##.T'

The tranquilizing effects of antipsychotic agents were originally discovered in the late !"#s when potent antihistamines were developed

to alleviate postoperative shoc$. The initial antipsychotic effect was thought to be attributed to antihistaminic qualities. %owever, the high

doses of chlorpromazine initially used to prevent postoperative shoc$ caused numerous severe and sometimes permanently disabling

multisystem side effects when used repeatedly.& (atients given doses in the range of )### mg daily started e*periencing severe

endocrine and neuromuscular side effects similar to those of (ar$inson's disease as well as acute and tardive dystonic reactions and

emotional flattening. The discovery in the !+#s of -dopa, used to treat the dopamine deficits of (ar$inson's disease, led to the

serendipitous understanding of the relationships between dopamine bloc$ade and the creation of antipsychotic effects, and provided the

first window into understanding side effects. s a deductive conclusion, the role of dopamine e*cess as etiologic in psychosis symptoms

led to an e*plosion of available phenothiazine-related antipsychotic drugs over the ne*t /# years. These original phenothiazine-type

drugs are referred to as typical or first-generation antipsychotics. 0rugs in this category typically have side effects related to e*cessive

bloc$ing of or more of the " ma1or dopamine tracts in the brain, resulting in primarily neuromuscular and neuroendocrine side effects

2Table 3. 4ventually ) ma1or dopamine subsystems were identified: 0 and 0). The 0) system is the primary system involved in

treating psychosis.

Table / opamine %eceptor amilies

0 family

0: substantia nigra, striatum, basal ganglia, nucleus accumbens, olfactory, amygdala

05: hippocampus, hypothalamus

0) family

0) subtype: striatum, nucleus accumbens, substantia nigra, olfactory bulb

0/: tuberoinfundibular-hypothalamus, nucleus accumbens, olfactory bulb

0": frontal corte*, midbrain, medulla

6a1or dopamine tracts in the brain

. 6esolimbic: originates in the ventral tegmental area of the brainstem and e*tends to the nucleus accumbens and limbic system,

thalamus, brainstem, and reticular-activating system


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a. 7nfluences control of autonomic and endocrine functions

b. 7nfluences perception, thin$ing, emotion

c. 8eurotransmitters involved

i. gonistic: dopamine, norepinephrine, acetylcholine

ii. ntagonistic: serotonin, 9B

d. ntagonism has antipsychotic effects

). 6esocortical: also pro1ects from the ventral tegmental area and sends a*ons to prefrontal corte* and involves the corpus and

ventral striatums

a. eceives stimuli from the e*ternal environment 2what can be evo$ed as memory and what can be discarded3

b. ;odes incoming information for distribution and intensity

c. Sends and receives information from memory storage areas in temporal and frontal lobes

d. 7nfluences interpretation of incoming information by coding it for storage

e. ntagonism has antipsychotic effects.

/. 8igrostriatal: originates in the substantia nigra area of brainstem and involves both upper and lower motor neurons and corpus

striatum including the e*trapyramidal nervous system

a. 6odulates and coordinates motor outflow to s$eletal muscles

b. ;ontrols


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industry research into brain function and pharmacologic therapies e*ploded. 3y 000, the list of approved atypical or second-

generation antipsychotics, also referred to as serotonindopamine antagonists 6blocers7,

gre! to include risperidone, olanzapine, 8uetiapine, and ziprasidone Their effects on multiple neurotransmitters, however,

produced a distinct set of side effects, including !eight gain, diabetes mellitus, dyslipidemias, and se9ual dysfunction.

)n 00, the first antipsychotic to not fully bloc dopamine, aripiprazole, was approved by the AS Cood and 0rug dministration.

7n addition to selective antagonism of various neurotransmitters, it has a partial agonist effect on dopamine ) receptors )n (ay 001,

iloperidone, with a pharmacologic profile similar to that of risperidone, was approved.

Because each atypical antipsychotic e*erts various antagonist or reupta$e bloc$ing actions on multiple neurotransmitters, an

understanding of the functions of the ma1or neurotransmitters is helpful in teaching patients about both the desired therapeutic and side

effect potentials of a given drug 2Table )3.

Table 'elected "eurotransmitters

"eurotransmitter Physiologic Action #ffect of #9cess #ffect of eficit

opamine 6catecholamine7

-(recursor is the amino acid tyrosine

-Cour ma1or tracts in the brain:

mesocortical, mesolimbic,

nigrostriatal, tuberoinfundibular

-Two ma1or receptor groups: 0-05

and 0), /, "

D Thin$ingD 0ecision-ma$ing

D espond with reward-see$ing

behaviors@ ie, the


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inverse relationship in adrenergic

nervous system

-(recursor is the amino acid

tryptophan

-6easured in urine as 5-%7

-)" ma1or receptor groups include ,

), /, ", 5, + with subgroups under

each ma1or group

D Temperature regulation

D Sleep cycle

D (ain perception

D egulates mood states

D (recursor to melatonin, which plays a

role in circadian rhythms, some

depressions, light-dar$ cycles, 1et lag,

female reproductive cycle, seasonal

s$in pigment changes

Acetylcholine

-(recursor is the amino acid choline

D (romotes preparation for action

D ;onserves energy

D ttention

D 6emory

D 0efense andIor aggression

D Thirst

D Se*ual behavior

D 6ood regulation

D bility to


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.$%%#"T+; A*A)+A3+# A"T)P';.


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Anfortunately, antipsychotic medications are not site-specific l i$e an antibiotic developed to combat a specific bacterium. Because of the

miniscule size and nature of the structure of the neuron and the fact that neural networ$s are multifunctional, each neurotransmission

can affect many different neurons in a process referred to as a


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;. Tardive dys$inesia: ate onset 2after a minimum of / months in adults and month in the elderly3 of dys$inesias. Tardive

dys$inesia can become permanent and must be treated at the first symptom

0. $athisia: (sychomotor restlessness, less intense than dystonias or dys$inesias

. 7ntolerance of inactivity

). ;ontinuous agitation and restlessness

/. (acing

". ;onstant leg and finger movements

5. oc$ing and shifting of weight while standing

+. Shifting of legs and tapping of feet while sitting

4. (seudopar$insonism: 6uscle movements that mimic (ar$inson's disease

. Stiffness and slowness of voluntary movement

). 6as$li$e immobility of facial muscles

/. Stooped posture

". Slow, monotonous speech

5. Shuffling gate that speeds up on its own

+. 7mmobility

)) .entral nervous system -- effects on alertness

. Sedation

B. (sychomotor retardation

;. owered seizure threshold

0. 0rug-induced depression

))) Autonomic nervous system

. nticholinergic 2parasympathetic nervous system3

. 0ry mouth

). Blurred vision

/. ;onstipation

". Arinary retention

5. Tachycardia 2heart beats more than # beats per minute3

+. 6ydriasis 2pupils dilate3

L. (aralytic ileus 2bloating due to absence of movement in the small bowel3

. Arinary hesitancy 2difficulty starting the stream of urine3

!. 0ental cavities

B. lpha-adrenergic bloc$ing


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. (ostural hypotension

). 7nhibition of e1aculation

/. 0iarrhea

". 6iosis

5. hinitis

+. Bradycardia

L. 0rooling

)* .ardiovascular

. engthening of the N- interval that could lead to Torsades de (oint

*


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Because ma1or neurotransmitter systems parallel each other in the same circuits, histamine, acetylcholine, alpha- and beta-adrenergic,

and muscarinic receptors are also often recipients of unwanted bloc$ade and side effects are created 2Table +3. Side effects occur

based on the specific receptors affected by the various drugs. %owever, the degree of bloc$ade 2receptor occupancy3 and length of time

a drug is on the receptor are what actually determine the degree of the side effect. There is also a close correlation to the half-life of

a drug and the length of drug occupancy on a given receptor .&"

The level of receptor occupancy is called i binding. The closer the =i is to , the higher the affinity of the drug for a given receptor

2Table L3. Cor e*ample, a patient on haloperidol with a 0opamine ) receptor =i value of #.L would be much more li$ely to e*perience

e*trapyramidal side effects than a patient on quetiapine that has a +# =i value.

)n looing at !eight gain, it is predictable that olanzapine will have the highest li$elihood because of a muscarinic =i value of ) when

compared to R ### for both aripiprazole and ziprasidone and R #,### for risperidone. 7t is important to realize that tremendous

variations can occur in individual patients.

Table 2 #ffects of %eceptor 3locade

'pecific %eceptor'ource +ocation #ffects of 3locade

lpha adrenergic : sympatheticImotor 0izziness, postural hypotension, tachycardia

lpha adrenergic ): sympatheticImotor n*iety, tachycardia, dilated pupils, tremor, sweating

Beta adrenergic : sympathetic neurons Erthostatic hypotension, sedation, se*ual dysfunction

6uscarinic: hippocampus and corte*@ activates = channels, postsynaptic

parasympathetic sites

;onstipation, blurred vision, dry mouth, memory

dysfunction, urinary retention, tachycardia

%istaminic: hypothalamus converts histadine Peight gain, drowsiness, hypotension, sedation

8icotinic: spinal autonomic ganglia@ preganglion 6uscle irritability, restlessness, insomnia

0opaminergic : substantia nigra, striatum, basal ganglia, nucleusaccumbens, olfactory, amygdale

4*trapyramidal side effects: dystonias, dys$inesia,a$athisias

0opaminergic ): striatum, olfactory, nucleus accumbens, substantia nigra4*trapyramidal side effects: dystonias, dys$inesia,

a$athisias

0opaminergic /: pituitary, nucleus accumbens, olfactory, hypothalamus 4ndocrine problems, weight gain, se*ual dysfunction

0opaminergic ": frontal corte*, midbrain, medulla (sychosis

Serotonergic : hippocampusraphe, corte*a -- an*iety 2buspirone is agonist3d -- cerebral arteries

constrict 2sumatriptan is antagonist3

Serotonergic ): ;orte*, olfactory system, claustrum (sychotic symptoms, an*iety, and appetite

Serotonergic /: rea postrema, corte*,


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isperidone "/# " # ! "!# ## .5 )5 .L . )# R #,###

Elanzapine / "! )L R ### ## " )/ ! 5## L .!

Nuetiapine )+ +# /"# +## LL -- )!5 # L 5## R #,###

Miprasidone 5)5 5 L /) / ) ." R ### 5# R ###

ripiprazole )+5 ./" .# "" .L -- /." 5 5L )## + R #,###

7loperidone )+ )." L. -- !). -- 5.+ "). ." +) -- "!

%aloperidol )# .L ) / ,## -- "5 R #,### + )# ""# R 5##

Sources: (res$orn S. ;lassification of neuropsychiatric medications by principal mechanism of action: a meaningful way to anticipate

pharmacodynamically mediated drug interactions. Psychiatr Pract . )##/@!: /L+-/" 2chart adapted and used with permission3@ Carah

. typicality of antipsychotics. (rimary ;are ;ompanion. #lin Psychiatry& )##5@L:)+-)L"@ 9oldstein >6. The new generation of

antipsychotic drugs: how atypical are they (nt Neuropsychopharmacol . )##/@/://!-/"!@ =al$man %E, Subramanian 8, %oyer 0.

4*tended radioligand binding profile of iloperidone: a broad spectrum dopamineIserotoninInorepinephrine receptor antagonist for the

management of psychotic disorders. Neuropsychopharmacology . )##@)5:!#"-!"

T


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The identification of cruciferous vegetables, arial hydrocarbons, caffeine, and St. >ohn's Port as enzyme inducers and grapefruit 1uice

as an enzyme inhibitor adds to the comple*ity of both patient assessment and education related to watching for side effects created by

foods, smo$e, caffeine, and herbal supplements.

Table D (etabolic Path!ays for Atypical Antipsychotics

.;P /A

.lozapine

&lanzapine

.;P 2

Aripiprazole

.lozapine

)loperidone

%isperidone

&lanzapine

Euetiapine

.;P =A4

Aripiprazole

.lozapine

)loperidone

Euetiapine

%isperidone

Fiprasidone

)nducer )nhibitor )nducer )nhibitor )nducer )nhibitor

Broccoli 2cruciferous

vegetables3Brussels sprouts

;arbamazepine

;harbroiled meats 2arial

hydrocarbons3

St. >ohn's Port

7nsulin

6odafinil

Emeprazole

Tobacco smo$e 2arial

hydrocarbons3

bupropion 2low3

cimetidineciproflo*acin

Cluvo*amine

2high3

Cluo*etine

2mod3

9rapefruit 1uice

mirtazapine

2low3

nefazodone

2low3

norfluo*etine

paro*etine

2mod3

sertraline 2low3

tertiary T;s

2mod3

venlafa*ine

2low3

de*amethason

eifampin

antipsychotics

bupropion 2low3cimetidine

fluo*etine

2high3

fluvo*amine

2low3

mirtazapine

2low3

nefazodone

2low3

paro*etine

2high3

quinidine

secondary

T;s

sertraline 2low3

venlafa*ine

2low3

carbamazepine

charbroiled meats 2arialhydrocarbons3

phenobarbital

phenytoin

rifampin

St. >ohn's Port

Tobacco smo$e 2arial

hydrocarbons

astemizole 2high3

erythromycin 2mod.3clarithromycin

fluvo*amine

fluo*etine

grapefruit 1uice

itraconazole

$etoconazole

mirtazapine 2low3

nefazodone 2high3

paro*etine 2low3

protease inhibitors

sertraline 2mod.3

Starfruit,

T;s 2mod.3

venlafa*ine 2low3

)#As = tricyclic antidepressants

Sources: ;ozza =, rmstrong S;, Esterheld >. #oncise Guide to *rug (nteraction Principles for edical Practice . )nd ed.

Pashington 0;: merican (sychiatric (ublishing, 7nc@ )##/@ %ansten (0, %orn >. )he )op +,, *rug (nteractions: A Guide to Patient

anagement . Creeland, Pashington: %Q% (ublications@ )##@

7ndiana Aniversity School of 6edicine 0ivision of ;linical (harmacy. 0rug-drug interactions. vailable at:

http:IIwww.medicine.iupui.eduIclinpharmI007sItable.asp ccessed 6ay L, )##!

*ariations in (etabolism

;?();! and ;?()0+ are bimodally distributed in the population allowing classification of individuals as either e*tensive or poor

metabolizers. This is referred to as genetic polymorphism. Tremendous research is going on to develop quic$ office-based tests to

determine who may be at ris$ for these significant metabolic variations.&5,+ dverse effects andIor to*icity from high levels of

unmetabolized drugs are more li$ely to develop in poor metabolizers. ppro*imately LF of whites and upward of //F of sians and

frican mericans are poor metabolizers. &L 4*tensive metabolizers are more li$ely to be nonresponders at the usual therapeutic dose

range. 7t is now possible through genotyping to predict up to !#F of individuals who will be poor metabolizers for ;?();! and

;?()0+.

'ummary


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The purpose of this article was to acquaint and alert the clinician to the comple*ities and often-subtle nuances behind drug side effects.

The prevention and early detection of antipsychotic side effects requires both art and science. The art of predicting, detecting, and

managing side effects includes a thorough assessment of lifestyle including the use of alcohol and smo$ing, dietary and beverage

choices, use of herbal supplements, and e*ercise and sleep patterns. The science of predicting, detecting, and managing side

effects re8uires no!ledge of the pharmacoinetic and pharmacologic action of prescribed drugs in combination !ith a

thorough understanding of comorbid medical conditions and the medications used to treat them ;linicians are encouraged to

consult with a pharmacist whenever a question of a potential drug-drug, drug-disease, andIor drug-diet interaction is suspected. By

using the charts and tables in this article, clinicians will be better informed to educate the patient in a variety of interventions that will

diminish the potential for medication side effects, promote better pharmacologic efficacy from prescribed medications, and improve the

overall quality of life.

P RIMUM NON NOCERE : AN EVOLUTIONARY ANALYSIS OF WHETHER ANTIDEPRESSANTS DO MORE HARM THAN GOODPaul W. Andrews1,2*, J. Anderson Thomson Jr.3,4, Ananda Amstadter2 and Michael C. Neale2

•1 e!artment o" Ps#cholo$#, Neuroscience and %eha&iour, McMaster 'ni&ersit#, (amilton, )N, Canada

• 2 ir$inia +nstitute "or Ps#chiatric and %eha&ioral enetics, ir$inia Commonwealth 'ni&ersit#, -ichmond, A, 'A•

3 Counselin$ and Ps#cholo$ical er&ices, tudent (ealth, 'ni&ersit# o" ir$inia, Charlottes&ille, A, 'A

•4 +nstitute o" /aw, Ps#chiatr# and Pu0lic Polic#, 'ni&ersit# o" ir$inia, Charlottes&ille, A, 'A

Antidepressant medications are the first-line treatment for people meeting current diagnostic criteria for major

depressive disorder. Most antidepressants are designed to perturb the mechanisms that regulate the neurotransmitter

serotonin – an evolutionarily ancient biochemical found in plants, animals, and fungi. Many adaptive processes evolved

to be regulated by serotonin, including emotion, development, neuronal growth and death, platelet activation and the

clotting process, attention, electrolyte balance, and reproduction. It is a principle of evolutionary medicine that the

disruption of evolved adaptations will degrade biological functioning. Because serotonin regulates many adaptive

processes, antidepressants could have many adverse health effects. or instance, while antidepressants are modestly

effective in reducing depressive symptoms, they increase the brain!s susceptibility to future episodes after they have been

discontinued. "ontrary to a widely held belief in psychiatry, studies that purport to show that antidepressants promoteneurogenesis are flawed because they all use a method that cannot, by itself, distinguish between neurogenesis and

neuronal death. In fact, antidepressants cause neuronal damage and mature neurons to revert to an immature state, both

of which may e#plain why antidepressants also cause neurons to undergo apoptosis $programmed death%.

Antidepressants can also cause developmental problems, they have adverse effects on se#ual and romantic life, and they

increase the ris& of hyponatremia $low sodium in the blood plasma%, bleeding, stro&e, and death in the elderly. 'ur

review supports the conclusion that antidepressants generally do more harm than good by disrupting a number of

adaptive processes regulated by serotonin. (owever, there may be specific conditions for which their use is warranted

$e.g., cancer, recovery from stro&e%. )e conclude that altered informed consent practices and greater caution in the

prescription of antidepressants are warranted.

INTRODUCTION

*erotonin $+-hydro#ytryptamine or +-(% is an ancient chemical, evolving at least one billion years ago, and it is present

in fungi, plants, and animals $ Amitia, //0%. It belongs to a class of biochemicals called monoamines, which also

includes norepinephrine $12%, and dopamine $3A%. Many adaptive processes evolved to be regulated by serotonin,

including cell differentiation, temperature, blood clotting, digestion and gut movement, insulin, electrolyte balance,

astrocytic activity, neuronal apoptosis, cerebral blood flow, attention, aggression, mood, reproductive function, and

mating behavior $4ohnson and hunhorst, 56607 Amitia, //5, //0, /5/74imene-rejo et al., //07 onseca et al.,

//67 8aulmann et al., //6%.

3rugs affecting the serotonergic system are among the most widely prescribed psychiatric medications. 3epression is the

most common psychiatric condition for which people see& help $8incus et al., 5666%, and the symptoms are regulated, at

least partly, by serotonin and norepinephrine $(eisler et al., 56697 Mayorga et al., //57 *antarelli et al., //:7 "ryan etal., //;7 Amat et al., //+, //


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and most of these drugs target serotonin and norepinephrine, although dopamine is affected to some degree as well

$*tahl, //9%. "ommonly prescribed classes of antidepressants are listed in able 5. Antidepressants may also be

prescribed to people with subclinical depression and many other conditions, including dysthymia, bipolar depression,

schioaffective disorder, post psychotic depression, generalied an#iety disorder, panic disorder $with or without

agoraphobia%, social phobia, substance abuse disorders, anore#ia, bulimia, obsessive compulsive disorder, post-traumatic

stress disorder, and chronic pain syndromes. hus, millions of people are prescribed antidepressants and affected by

them each year.

AB@2 5

Table 1. Classes of an!"e#$essan "$%&s alon& '!( (e!$ )(e*!)al an" $a"e na*es +!n #a$en(eses,.

he principle of primum non nocere reuires physicians to do no harm. (owever, there is increasing concern that

current diagnostic criteria and treatment practices may do more harm than good $(agen, //:7 (orwit and )a&efield,

//07 ?irsch et al., //97 Andrews and homson 4r., //67ournier et al., /5/7 )a&efield et al., /5/7 Andrews et al.,

/557 ava and 'ffidani, /55%, and these concerns are increasingly e#pressed in prominent public outlets $@ehrer,

/5/7 Angell, /55%. Moreover, many of the concerns have been driven by evolutionary conceptions about the nature of

disorder $ )a&efield, 566, 56667 )atson and Andrews, //7(agen, //:7 (orwit and )a&efield, //07 Andrews and

homson 4r.,//67 Andrews et al., /55%.

It is a principle of evolutionary medicine that the disruption of adaptive processes will degrade biological functioning

$1esse and )illiams, 566;%. or instance, a growing body of evidence indicates that fever is an evolutionarily ancient

adaptation for coordinating immune responses to infection $?luger et al., 56607 (asday et al., ///7 Blatteis,//:7 Appenheimer et al., //+%. *tudies in humans have shown that the disruption of fever with antipyretic $fever-

reducing% medication has a number of adverse effects on the immune response. In controlled e#periments, antipyretic

medication lengthens the time it ta&es the body to clear non-fatal infections such as rhinovirus $common cold%

and Varicella zoster $chic&enpo#7 *tanley et al., 560+7 3oran et al., 56967 raham et al., 566/%. Acetaminophen also

increased the duration of illness in Plasmodium falciparum $malaria% infections in an e#perimental paradigm $Brandts et

al., 5660%. In patients with more serious infections, such as bacterial sepsis, correlational studies commonly find fever is

associated with increased survival $Bryant et al., 56057 )einstein et al., 5609, 569:7 Mac&owia& et al., 569/7 *wenson et

al., //07 Cantala et al., //6%. here has been little e#perimental research on the mortality effects of antipyretic therapy

in humans with serious infections. In one e#periment, ibuprofen did not affect mortality among patients with bacterial

sepsis, but medication was not initiated until the infections had caused organ dysfunction $Bernard et al., 5660%. In a

preliminary analysis of another e#periment where acetaminophen was administered to trauma patients close to the onset

of fever, seven out of ;; $5


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their use is warranted. 1otably, our argument does not depend on the efficacy of antidepressants relative to other

possible treatments for depression. Cather, it depends on whether it is better for practitioners to refrain from prescribing

rather than to start a patient on antidepressants. or this reason, we do not discuss non-pharmacological alternatives,

although this is an active area of research. 'f course, we do not advocate that practitioners not provide treatment7

however, if results of a cost–benefit analysis suggest that providing no medication is a superior choice compared to that

of prescribing antidepressants in most situations, then practitioners might be more inclined to employ other treatments

with a lower side effect profile.

AB@2

Table -. S%**a$. of )osl. +C, an" benef!)!al +/, effe)s of an!"e#$essan *e"!)a!ons0 '!( so*e es!*ae of (e!$ effe)

s!e o$ f$e2%en). .

SEROTONIN AND HOMEOSTASIS

In animals, only about += of the body!s serotonin resides in the brain. Most of the body!s serotonin is housed in the gut,

with 6/= of that stored in enterochromaffin cells $where most of it is synthesied% and the remaining 5/= is synthesied

by and stored in myenteric interneurons $ershon, //;%. 2nterochromaffin cells also release serotonin into the blood

stream, where most of it is ta&en up by platelets. *erotonin does not pass the adult blood–brain barrier, so central and

peripheral sources do not communicate with each other $(ranilovic et al., /55%.

*erotonin is normally under homeostatic control in the brain, the gut, and blood plasma $(yman and 1estler,

566


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terminal regions that control the synthesis of serotonin $Best et al., /5/%. hus, when synaptic levels of serotonin are

perturbed upwards from their euilibrium level, autoreceptor activity causes a decrease in the firing of serotonergic

neurons and a reduction in synthesis, both of which tend to &eep synaptic levels relatively stable $Best et al., /5/%.

"onversely, when synaptic levels are perturbed downwards from euilibrium, firing and synthesis increase to maintain

euilibrium levels $Best et al., /5/%.

SEROTONIN IN THE GUT

Most of the serotonin in the body is produced by enterochromaffin cells that line the digestive tract from the stomach to

the colon. 2nterochromaffin cells turn over uic&ly because they form part of the epithelial layer, so neurons cannot form

tight junctions with them. "onseuently, enterochromaffin cells produce large amounts of serotonin to compensate for

the large intervening distance from neurons $ershon, //;%. (owever, too much e#tracellular serotonin in the intestinal

lining is harmful and can cause irritable bowel syndrome, characteried by symptoms of pain, diarrhea, constipation,

indigestion, bloating, and headache $ershon, //;%. here are no e#tracellular enymes for cataboliing serotonin, and

mucosal epithelial cells play an important role in maintaining homeostasis by clearing e#tracellular serotonin via the

same transporter that is e#pressed in the brain $ershon and ac&, //0%. hese cells then catabolie serotonin by

monoamine o#idase or other pathways $ershon, //;%.

SEROTONIN IN /LOOD PLASMA

he overflow of serotonin produced by enterochromaffin cells is also released into the bloodstream $ershon and ac&,

//0%. Blood plasma levels of serotonin are regulated by platelet cells via the action of the serotonin transporter, which is

e#pressed on the platelet cell membrane $@inder et al., //07 Mercado and ?ilic, /5/%.

ransporter molecules are stored in vesicles in the platelet cytoplasm and traffic&ing between the surface and

cytoplasmic stores ta&es place as a function of plasma levels of serotonin $Mercado and ?ilic, /5/%. )hen plasma levels

of serotonin are low, a relatively small increase in serotonin triggers a process by which the surface e#pression of the

transporter is increased, promoting the accumulation in platelets and maintaining low plasma levels. 8latelets store

serotonin in large granules that are crucial to the clotting process $(eger and "ollins, //;%, so this homeostatic

mechanism for regulating plasma serotonin levels is important for ensuring that clotting mechanisms are primed for the

onset of any injuries.

Farious cells in the s&in $melanocytes, mast cells, Mer&el cells% can synthesie and store serotonin $1ordlind et al.,

//9%. )hen an injury that punctures the s&in ta&es place, free serotonin levels rapidly increase in the area around the

wound $(ernande-"ueto et al., ///%. A large localied increase in plasma serotonin levels can reverse the surface

e#pression of transporter in platelets $Mercado and ?ilic, /5/%. *pecifically, traffic&ing reverses direction, reducing

transporter e#pression on the surface, increasing transporter accumulation in cytoplasmic vesicles, and reducing the

further upta&e of serotonin into the platelet. Moreover, high plasma levels of serotonin initiate a comple# process by

which the cytoplasmic stores of serotonin trigger the release of procoagulants from the platelet $Mercado and ?ilic,

/5/%, which promotes the clotting process at the site of injury.

THE EFFECTS OF A NTIDEPRESSANT MEDICATIONS ON /ODY S YSTEMS

According to the most prominent view in medicine and psychiatry, disorders stem from a brea&down or a decline in

biological functioning GAmerican 8sychiatric Association $A8A%, ///bH. *ince natural selection is the only natural force

capable of generating biological functions, and traits with biological functions are called adaptations, disorders can be

understood as involving a brea&down or a decline in the functioning of evolved adaptations $ )a&efield, 566, 5666%. In

principle, then, interventions that degrade or disrupt the functioning of homeostatic mechanisms can cause disorder.

Antidepressants are most commonly ta&en in pill form, though there are some that can be ta&en through a transdermal

patch. In either case, they enter the bloodstream, pass through the blood–brain barrier, and affect neuronal functioning.

Antidepressants perturb monoamine levels through a variety of mechanisms, the most common of which is by binding to

monoamine transporters. In the normally functioning rodent brain, transporter bloc&ade prevents the reupta&e of

monoamines into the presynaptic neuron, which causes e#tracellular monoamines to increase from euilibrium levels in

forebrain regions within minutes to hours of administration $see igure 57 Cutter and Auerbach, 566:7 Bymaster et al.,//7 elton et al., //:%. )ith prolonged antidepressant use, however, the brain!s homeostatic mechanisms buffer this

effect by ma&ing a number of compensatory changes $Best et al., /5/%, including an inhibition of synthesis that causes

the entire pool of serotonin in the forebrain $intracellular plus e#tracellular% to decline $(onig et al., //6%.

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"onseuently, e#tracellular levels in the forebrain return to euilibrium levels with prolonged treatment $8opa et al.,

/5/%. here are other changes that ta&e place with chronic antidepressant use to maintain homeostasis, including

alterations in the density and functioning of serotonin receptors, transporters, and enymes $(olt and Ba&er,

566


17/43

//;7 Amat et al., //+, //* ood and 3rug

Administration $3A% under the reedom of Information Act $'IA% to get access to the published and unpublished

studies submitted by pharmaceutical companies to get governmental approval for their drugs. hey found that 6;= of the

published studies showed an advantage of antidepressants over placebo. )hen the published and unpublished studies

were considered together, only +5= showed an advantage over placebo.

?irsch et al. $//9% also applied to the 3A under the 'IA to understand how much more effective antidepressants

were at reducing depressive symptoms compared to placebo. "hanges in depressive symptoms were measured with the

50-item (amilton 3epression Cating *cale $(3C*7(amilton, 56


18/43

Cecently, in an interview on the news program * 3A stated that the symptom

reducing effect of antidepressants relative to placebo is Jrather smallK $Bonin, /5%.

*ome have ta&en the evidence of the limited efficacy of antidepressants as evidence that serotonin is not involved in

regulating depressive symptoms. (owever, limited efficacy is also e#pected under the hypothesis that the homeostatic

mechanisms regulating serotonin are still intact, because the brain is e#pected to push bac& against the effects of

antidepressants $ Andrews et al., /55%.

EFFECTS OF PROLONGED A NTIDEPRESSANT TREATMENT

2ven among those who respond to antidepressant treatment, longer-term use is associated with a loss of symptom

reducing efficacy – sometimes causing a full-blown relapse. his is also consistent with the brain pushing bac& against

the symptom reducing effect of antidepressants. In an early review, studies showed that 6–+0= of long-term

antidepressant users met formal criteria for a relapse or a recurrence $Byrne and Cothschild, 5669%. More recent studies

have found similarly high rates of relapse among those who initially remitted on the drug. In one study of fluo#etine,

:+.= met relapse criteria after < months of continuous treatment, increasing to ;+.6= after 5 months $Mcrath et al.,

//


19/43

reuires invasive techniues, so we e#amined how much they increase monoamines in a region of the rodent prefrontal

corte# implicated in controlling depressive symptoms $ Amat et al., //+%. 8lacebo has no effect on monoamine levels in

the rodent brain, but the strongest antidepressants can increase prefrontal monoamine levels by ;//= or more

$Bymaster et al., //%. After controlling for covariates, we found strong positive relationships between the ris& of

relapse after discontinuation and the degree to which the antidepressant used in the study increases serotonin $igure %

and norepinephrine $igure :%. In other words, the more antidepressants perturb monoamine levels in the brain, the

more the brain appears to push bac&, which increases the ris& of relapse when the drug is discontinued. his positive

relationship also strongly suggests that patients who get better without the use of antidepressants $i.e., when serotonin

and norepinephrine levels are not perturbed% will have a lower ris& of relapse.

I>C2

F!&%$e -3 T(e $!s9 of $ela#se afe$ an!"e#$essan "!s)on!n%a!on +ya4!s, 5e$s%s (e #e$%$ba!onal effe) of an!"e#$essans

on se$oon!n !n (e $o"en *e"!al #$ef$onal )o$e4 + x a4!s,0 afe$ )on$oll!n& fo$ )o5a$!aes. A score of 5// on the x -a#is means the

antidepressant has no effect on serotonin levels.

I>C2 :

F!&%$e 63 T(e $!s9 of $ela#se afe$ an!"e#$essan "!s)on!n%a!on +ya4!s, 5e$s%s (e #e$%$ba!onal effe) of an!"e#$essans

on no$e#!ne#($!ne !n (e $o"en *e"!al #$ef$onal )o$e4 + x a4!s,0 afe$ )on$oll!n& fo$ )o5a$!aes. A score of 5// on the x -a#is

means the antidepressant has no effect on norepinephrine levels.

Altogether, the results of our meta-analysis further support the hypothesis that the homeostatic mechanisms regulating

serotonin and norepinephrine are pushing bac& against the effects of antidepressants. he fact that this pushbac& occurs

in patients meeting current diagnostic criteria for M33 casts some doubt on the hypothesis that serotonin levels are

dysregulated in such patients. his is because the sensor and negative feedbac& components of the homeostatic

mechanisms must be functioning to produce pushbac& against the effects of antidepressants. (owever, our results do not

rule out some dysfunction in the component that sets the euilibrium.

he results also are inconsistent with hypotheses that antidepressants interrupt stress responses and give the brain a

chance to heal so that it can become more resilient to depression $*apols&y, //57 ?ramer, //+%. Instead,

antidepressant use appears to increase susceptibility to depression.

o show how different antidepressants affect the ris& of relapse, for this paper we conducted a regression analysis on this

dataset including the major antidepressant classes and controlling for the covariates we identified as being important in

our prior wor&. luo#etine is uniue among the **CIs in that it increases prefrontal norepinephrine levels through a

mechanism other than reupta&e bloc&ade $Bymaster et al., //%, so we separated it from the other **CIs. he estimated

:-month ris& of relapse for patients who had remitted while on placebo was only 5.;=, while the ris& after

antidepressant discontinuation generally increased with the monoaminergic perturbational effect of the classE ;:.:=

$**CI%, ;0.0= $*1CI%, ++.= $"A%,


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*erotonin is involved in shaping the brain through a number of developmental processes, including cell differentiation,

neuronal apoptosis $programmed neuronal death%, neurogenesis $the birth and growth of new neurons%, and

neuroplasticity $ Amitia, //5%. Because of the comple# role that serotonin plays in shaping the brain, antidepressants

could have comple# effects on neuronal functioning.

Many studies have been conducted purporting to show that antidepressants promote neurogenesis $(anson et al., /55%,

and some have argued that this could be a fundamental and beneficial part of the antidepressant response $*antarelli et

al., //:7 3uman, //;7 )arner-*chmidt and 3uman, //


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retract, all of which indicate a return to an immature, undifferentiated state $"hen et al., 566;7 )ilson et al.,

56697 Amitia, //5%.

1euronal dematuration, particularly the retraction of neuronal processes, appears to play a role in triggering apoptosis

$ Amitia, //5%, which could e#plain why antidepressants induce neuronal death. But the functional reason for why

JdematurationK triggers apoptosis is not precisely clear. Apoptosis plays a role in removing damaged cells and

maintaining homeostasis of differentiated tissues by regulating the euilibrium between the cell death and cell birth

$(engartner, ///%. o maintain tissue homeostasis, inappropriately proliferating cells must be detected and &illed.

hus, the body must be able to differentiate between controlled and uncontrolled proliferation to appropriately direct

apoptotic processes. 3ematuration might be viewed as a signal that the neuron is changing into a malignant proliferative

state, ma&ing it a target for apoptosis. *imilarly, pharmacologically forcing mature neurons to go through a cell cycle

causes them to die through apoptotic processes $(errup et al., //;%, perhaps because the sudden change in proliferative

status mar&s them as possible neoplasms.

Another way antidepressants could target neurons for apoptosis is by directly inflicting structural damage on them, since

damaged neurons are often the targets of apoptosis $"otran et al., 56697 *tergiou and (engartner, //;%. )e are only

aware of one study that has tested whether antidepressants cause structural damage to neurons $ ?alia et al., ///%. he

study authors found that e#posure to clinically relevant doses of fluo#etine $55.; mg&g, oral% or sertraline $9.< mg&g,oral% for only ; days caused shortened a#ons, &in&s, and swollen nerve terminals in the brains of otherwise healthy

rodents. *uch morphological changes are often ta&en as de facto evidence of neuronal damage $?alia et al., ///%, and

similar morphological features are thought to play a role in 8ar&inson!s disease $"heng et al., /5/%.

2ven if they do not directly promote neurogenesis, antidepressants could do so indirectly. )hen pharmacological

interventions trigger neuronal apoptosis, the brain attempts to homeostatically compensate by upregulating

neurogenesis. or instance, the induction of neuronal apoptosis in the hippocampus by &ainic acid was subseuently

followed by an upregulation in neurogenesis in the dentate gyrus and "A: $3ong et al., //:%. he evidence of

neurogenesis was not significant 59 days after the administration of &ainic acid, but it was significant after :: days. 'ne

study has shown that fluo#etine increased neuronal progenitor cells, but this was only :/ days after fluo#etine treatment

had stopped $2ncinas et al., //la& et al., //


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writing about one!s strongest thoughts and feelings related to the episode% have been found to increase insight and

shorten the duration of episodes $(ayes et al., //+, //07 ortner et al., //nited ?ingdom $ibson et al., //6%. >sing the year prior

to drug e#posure as a baseline Gincident rate ratio $ICC% D 5H, people who too& **CIs were at a greater ris& of a driving

accident in the ;-wee& period before first being prescribed the drug $ICC D 5.0, 6+= "I D 5.;0–5.66%. his suggests that

depression, an#iety, or other conditions that lead to antidepressant use are ris& factors for accidents. In the first ;-wee&

period of **CI use, however, the ris& of driving accidents returned to baseline $ICC D /.6, 6+= "I D /.0+–5.5%. a&en

in isolation, this would seem to suggest antidepressants protect against driving accidents. But **CIs only reducesymptoms after several wee&s of continuous use, and this was not a placebo-controlled study, so it is possible that the

reduced ris& was attributable to other effects of see&ing help rather than the **CI. Indeed, there was a similar reduction

in driving accident ris& in the ;-wee& period of first use of other drugs that interfere with attention $benodiaepines,

non-benodiaepine hypnotics, beta-bloc&ers, opioids, and antihistamines%. After ; wee&s of use, however, the ris& of

driving accidents increased and remained increased for the duration of **CI treatment $ICC D 5.5


23/43


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recurrent ischemic stro&es, but this benefit is offset by the increased ris& of intracranial hemorrhages. *imilarly, the

beneficial effects of anticoagulants in reducing the freuency of pulmonary emboli are counter-balanced by the increased

ris& of e#tracranial hemorrhages $*andercoc& et al., //9%. iven the strength of this literature, it would be surprising if

future research demonstrated an unambiguous positive net effect of antidepressants on mortality in stro&e patients.

It has also been argued that antidepressants could promote recovery from stro&e $?ramer, /55%. A recent randomied

clinical trial in rance involved 559 patients with recent ischemic stro&e and given early treatment with fluo#etine or

placebo. he fluo#etine group showed greater motor recovery at a 6/ day follow up $"hollet et al., /55%. iven our

discussion above, it is unli&ely that fluo#etine promoted recovery due to a direct promotion of neurogenesis. (owever,

the clearance of damaged neurons through apoptosis, the dematuration of adult neurons $which might increase

plasticity%, and compensatory neurogenesis could have all contributed to greater recovery. Another way in which

antidepressants could contribute to motor recovery after stro&e is by enhancing e#tracellular serotonin levels, since

serotonin plays a role in repetitive and gross motor activity $4acobs and ornal, 566+, 5666%. In any event, while

promising, the effects of antidepressants on motor recovery after stro&e must be confirmed.

R EPRODUCTIVE FUNCTION

*erotonin is an important regulator of various aspects of reproduction $ Amitia, //5%. )hile depression is itself

associated with impaired se#ual behavior, most antidepressants increase the degree of impaired se#ual functioning inmen and women, including various aspects of desire, arousal, and orgasm $*erretti and "hiesa, //6%. "As and at least

some **CIs have adverse effects on sperm motility, volume, and morphology $(endric& et al., ///7 anri&ut et al.,

/5/%. here are also case reports that antidepressants may impair the affective dimensions of romantic love and

attachment $isher and homson, //


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3epression is a ris& factor for suicidal ideation and behavior, which suggests that antidepressants might reduce these

ris&s. (owever, there is well-&nown controversy over whether antidepressant use reduces or increases suicidal behavior

$Baldessarini et al., //07 Ceeves and @adner, /5/%. he largest, most recent meta-analyses of randomied, placebo-

controlled trials generally find a positive association between antidepressant use and suicidal behavior. In one meta-

analysis involving 0/ trials and over 90,/// patients, **CI use was associated with an increased ris& of suicide attempts

$ergusson et al., //+%. In another meta-analysis of :; randomied, double-blind, placebo-controlled trials submitted

to the 3A involving over 66,/// patients, antidepressant use was associated with an increased ris& of suicidal behavior

in children, adolescents, and young adults $*tone et al., //6%. But it had no overall effect in adults aged +–


26/43

do not yet have information on effect sie or freuency $e.g., antidepressant triggered apoptosis%. 2ach of these issues

could ma&e it more difficult to conclude what the overall effect of antidepressants is.

hese problems can largely be circumvented by e#amining the effects of antidepressants on mortality. Mortality data

naturally synthesies the multiple effects of a drug on biological functioning, including those not considered or identified.

If the beneficial effects of antidepressants in reducing any harmful symptoms outweigh the detrimental effects in

disrupting homeostatic mechanisms, then they should increase survival. "onversely, if the harmful effects of

antidepressants outweigh the beneficial effects, then they should decrease survival.

3epression itself is associated with an increased ris& of death, primarily through its effects on cardiovascular disease

$ Fan der ?ooy et al., //078ouelo et al., //6%. But does antidepressant use increase or decrease the ris& of deathQ

hree recent, large, prospective epidemiological studies have found that, even after controlling for depressive symptoms,

antidepressant use is associated with an increased ris& of death in the elderly $*moller et al., //67 Almeida et al.,

/5/7 "oupland et al., /55%.

he most recent study involved patients in the >nited ?ingdom over signal in the conte#t of antidepressant use. 3oes it reflect apoptosis, neurogenesis, or bothQ

8articularly helpful would be studies that e#amine the temporal relationship between the Brd> signal and independent

measures of apoptosis and neurogenesis. hird, more studies should e#amine the morphological changes in neurons that

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ta&e place with repeated administration of serotonergic antidepressants $?alia et al., ///%. ourth, greater research

should be devoted to e#ploring the possibility that the effects of prolonged antidepressant use on neuronal integrity may

cause cognitive decline and dementia $4ac&son, //97 oveas et al., /55%. inally, greater research should be devoted to

the effects of antidepressants on longevity. he uic&est e#periments could be done on rodents. hat such studies were

not done decades ago, before antidepressants were approved for widespread use, is troublesome.

*uch research will give us a better picture of the effects of antidepressants on overall functioning. 1evertheless, from a

legal, ethical, and public health perspective, it now seems prudent, on the basis of e#isting evidence, for individual

practitioners and professional medical organiations to revise informed consent guidelines and reconsider the status of

antidepressants in standards of care for many diagnoses and as the immediate front line treatment for depression. *ome

patients may be more li&ely to benefit from antidepressants and less li&ely to suffer adverse effects, but identifying them

will reuire further research and greater understanding of the etiology of depression.

8atients should be informed that current research suggests that unless they have very severe depression, the symptom

reducing effects of antidepressants are modest and are not considered clinically significant. >nless there are rapid-onset

adverse side effects, antidepressant therapy usually lasts for months. 8atients should be advised that prolonged use might

cause mild cognitive impairment and interfere with tas&s that reuire highly focused concentration, such as driving,

which may increase the ris& of accidents. 8atients should also be advised that antidepressants might trigger even moresevere depressive episodes when they are discontinued. All patients should be advised of the possible bleeding ris&s, and

physicians should e#ercise particular caution in prescribing these drugs in conjunction with other diuretic or anti-

thrombotic medications. he evidence of harm is strongest in the elderly, who should be advised of the ris&s of falling,

hyponatremia, bleeding, stro&e, and death.

CONFLICT OF INTEREST STATEMENT

he authors declare that the research was conducted in the absence of any commercial or financial relationships that

could be construed as a potential conflict of interest.

ANTI CONVULSANT’S SIDE EFFECT

CRITICAL ISSUES IN THE USE OF A NTIEPILEPTIC DRUGS=Caculty and 0isclosures

.(#.# )nformation

S(4;7 7SSA4S 78 ;%7048

The field of pediatric epilepsy encompasses a number of issues that are unique to childhood.&) 7n particular, the classification of

childhood seizures and the choice of treatments present challenges that are not encountered in the care of adults with epilepsy.

Curthermore, the social and educational needs of children are of paramount importance. Therefore, the cognitive and behavioral

adverse effects of treatments assume more importance in children than in adults or the elderly.&/ This section will discuss severalspecial issues related to the evaluation and treatment of childhood seizure disorders.

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igure /. 4pilepsy syndromes by usual age at onset, in years 2courtesy of >ohn 6. (elloc$, 60, 6edical ;ollege of Uirginia3.

S47MA4 ;SS7C7;T7E8

Cigure lists the epilepsy syndromes prevalent in children according to age of onset. The current classification scheme further

subdivides seizures into generalized and partial seizures based on seizure behavior and electroencephalogram 24493 findings.This scheme is a practical tool for classifying seizures in children older than " years but is inadequate for accurately classifying

seizures in younger children. Seizure semiology and the results of diagnostic tests in very young children do not follow the same

clinical rules as in older patients, ma$ing seizures more difficult to classify. Cor e*ample, a )-year-old child may have seizures

that appear behaviorally to be generalized and yet have an 449 that indicates focal ictal abnormalities. ;onversely, the ictal

449 may show a generalized epileptiform pattern in a -year-old patient whose seizures consist of unilateral clonic movements.

0rug study outcomes depend on the ages of sub1ects and the epilepsy syndromes eventually diagnosed in these sub1ects@ thus,

the difficulty in specifying seizure type in the very young patient with epilepsy confounds the interpretation of drug study results

and their application to clinical practice. lternatively, classification of patients by epilepsy syndrome is more useful, because the

seizures associated with specific epilepsy syndromes have been thoroughly studied with regard to choice and duration of 40

therapy, prognosis for seizure control, li$elihood of genetic transmission of epilepsy, and cognitive ability.&" Several epilepsy

syndromes are benign, but others are associated with intractable seizures 2Table 3.

S(4;7 7SSA4S 78 ;%7048

S47MA4 ;SS7C7;T7E8

Cigure lists the epilepsy syndromes prevalent in children according to age of onset. The current classification scheme further

subdivides seizures into generalized and partial seizures based on seizure behavior and electroencephalogram 24493 findings.

This scheme is a practical tool for classifying seizures in children older than " years but is inadequate for accurately classifying

seizures in younger children. Seizure semiology and the results of diagnostic tests in very young children do not follow the same

clinical rules as in older patients, ma$ing seizures more difficult to classify. Cor e*ample, a )-year-old child may have seizures

that appear behaviorally to be generalized and yet have an 449 that indicates focal ictal abnormalities. ;onversely, the ictal

449 may show a generalized epileptiform pattern in a -year-old patient whose seizures consist of unilateral clonic movements.

0rug study outcomes depend on the ages of sub1ects and the epilepsy syndromes eventually diagnosed in these sub1ects@ thus,the difficulty in specifying seizure type in the very young patient with epilepsy confounds the interpretation of drug study results

and their application to clinical practice. lternatively, classification of patients by epilepsy syndrome is more useful, because the

seizures associated with specific epilepsy syndromes have been thoroughly studied with regard to choice and duration of 40


29/43

therapy, prognosis for seizure control, li$elihood of genetic transmission of epilepsy, and cognitive ability.&" Several epilepsy

syndromes are benign, but others are associated with intractable seizures 2Table 3.

TB4 . 4(74(S? S?80E64S SSE;7T40 P7T% 6407;? 4C;TE? S47MA4S

78 ;%7048

4arly myoclonic encephalopathy

4arly infantile epileptic encephalopathy

7nfantile spasms

Severe myoclonic epilepsy in infancy

6yoclonic astatic epilepsy

6yoclonic absences

enno*-9astaut syndrome

;ontinuous spi$e waves during slow sleep

asmussen syndrome

T480S 78 T4T648T E(T7E8S

Acute vs chronic treatment Cigure ) describes the current treatment options for children with various epilepsy syndromes.

recent development in the therapy of pediatric seizures is the intermittent use of drugs in the acute setting for a time-limited

cluster of seizures or increase in seizure severity 2new seizure type, increased seizure duration, or status epilepticus3. This

acute or short-term therapy is superimposed on chronic, or continuing, long-term treatment. 7n the past, such therapy consisted

of a bolus dose of the e*isting 40 regularly ta$en by a patient@ in the newly treated patient, the choice of the short-term

treatment may have determined the choice of the long-term therapy. 8ow, rectal diazepam, &5 intravenous fosphenytoin,&+ and

intravenous valproate&L, can be used effectively when needed acutely to supplement long-term treatment in the event of a

temporary e*acerbation in seizure frequency or severity or to protect against seizure worsening during a crossover in chronic

treatment from one 40 to another. Cosphenytoin is a phosphate ester prodrug of phenytoin that has greater aqueous solubility,

compared with intravenous phenytoin, and a neutral p%, which results in less venous irritation and phlebitis than with

intravenous phenytoin. 7ntravenous valproate is indicated as an alternative in patients for whom oral administration of valproate

products is temporarily not feasible, but additional use for acute therapy is possible. &L,


30/43

igure Treatment options for various epilepsy syndromes 2courtesy of >ohn 6. (elloc$, 60, 6edical ;ollege of Uirginia3.

;BMVcarbamazepine@ 4SWVethosu*imide@ CB6Vfelbamate@ 9B(Vgabapentin@ T9Vlamotrigine@ (%TVphenytoin@

(BVphenobarbitol@ T9BVtiagabine@ TE(Vtopiramate@ U9BVvigabatrin@ U(Vvalproic acid@ M8SVzonisamide.

"onpharmacologic treatments lthough 40s continue to be the mainstay of seizure therapy for children, nonpharmacologic

treatments, including the $etogenic diet and high-dose vitamin therapies,&!- clearly have a role in pediatric epilepsy. The

$etogenic diet has demonstrated efficacy in virtually all types of seizures. 7n other countries, children with refractory epilepsy are

often prescribed pyrido*ine as a therapeutic trial.&) (yrido*ine is a cofactor of glutamic acid decarbo*ylase, the enzyme in

neurons that converts glutamate 2e*citatory neurotransmitter3 to gamma amino butyric acid 2inhibitory neurotransmitter3.

etogenic diet& The $etogenic diet was introduced in the early !)#s and was based on the observation that seizure frequency

decreased in people with seizure disorders who were starving. The diet was once thought to wor$ because of the $etosis that is

achieved. %owever, the mechanism of action remains unclear. 7t appears to be effective primarily in children, and is generally

reserved for patients with very frequent medically intractable seizures, including myoclonic and atonic seizures, absence

seizures, and infantile spasms. ;linical improvement usually occurs in the first ) wee$s. 7n one report,&/ nearly "#F of patients

had at least a 5#F reduction in seizure frequency, and )!F had nearly complete elimination of seizures. ong term

effectiveness has been reported, but loss of efficacy may be seen around the time of puberty, for unclear reasons.

Typically, the patient is first admitted to the hospital for a supervised fast. Ence this period of starvation and dehydration induces

$etones in the urine, the diet is begun. There are several versions of the $etogenic diet&" @ each version is high in fats and low in

proteins and carbohydrates. The original diet specifies that #F of the calories be long-chain fats such as butter and cream.

nother version, called the 6;T diet, utilizes medium-chain triglycerides 26;T3 in an oil form. third version combines /#Flong-chain fat with /#F 6;T. The diet is usually supplemented with multivitamins and minerals, and fluid restriction is

continued.

Phichever version of the diet is used, compliance is the main problem. Successful implementation requires the dedication of the

patient and family, and consultation with a $nowledgeable dietician. Side effects include diarrhea, elevations in serum lipids and

uric acid, hypercalciuria, hypoglycemia, and protein deficiency

'urgery s in adults, children older than / months with localization-related epilepsy, medically refractory seizures, and an

identified seizure focus that does not involve eloquent corte* are candidates for resective surgery.&5

;orpus callosotomy for the treatment of atonic seizures&+ is performed less often now because of adverse effects, limited

efficacy, and the availability of new therapies. Uagus nerve stimulator 2U8S3 therapy has shown efficacy for this seizure type,

which is only one of several types of seizures that U8S appears to benefit. &L-!


31/43

.agus ner"e stimulation& En >uly +, !!L, the Cood and 0rug dministration approved vagal nerve stimulation with the

8eurocybernetic (rosthesis 28;(3 as ad1unctive therapy for adults and adolescents over ) years of age whose partial-onset

seizures are refractory to antiepileptic medications. The implantation of this device may be considered reasonable and

necessary in specific clinical situations in which epilepsy adversely affects quality of life and continues despite multiple trials of

different, appropriate anticonvulsant medications alone or in combination.

The system&)#,)

consists of 23 a pulse generator@ 2)3 a bipolar U8S lead@ 2/3 a programming wand with accompanying softwarefor an 7B6-compatible computer@ 2"3 a tunneling tool@ and 253 hand-held magnets.

The implantation procedure usually lasts appro*imately hour and is typically carried out under general anesthesia to minimize

the possibility that a seizure will interfere with the operation. 6ost centers hospitalize patients the night after the implantation

procedure, though other sites perform the operation as day surgery.

Ence programmed, the generator delivers intermittent stimulation at the desired settings until any additional programming

instructions are received or the battery life is e*pended. 7n addition, the patient or a companion may activate the generator by

placing the supplied magnet over the generator for several seconds@ in some patients this may interrupt a seizure or reduce its

severity if administered at the onset of the seizure. &))

The mechanism of action of U8S is un$nown, though it clearly differs from 40s, which have direct effects on neuronal

membrane ionic conductance or on neurotransmitter and receptor binding-site functions. dditional studies are needed to

demonstrate 23 how to best optimize therapy with intermittent stimulation as well as acutely with the magnet@ 2)3 whether U8S

wor$s synergistically with 40s with particular mechanisms of action@ 2/3 how to prospectively identify patients who are most

li$ely to benefit from U8S@ and 2"3 the relative efficacy and tolerability profiles of add-on U8S compared with add-on 40

therapy.

(%6;E=784T7; 80 S C4T? ;E8S704T7E8S

7n general, children require 40 doses about /#F higher than adults on a milligram per $ilogram basis because of faster renal

and hepatic clearance. They also appear to be at greater ris$ than adults for developing serious rashes in response to many

classes of medications, including 40s. The ris$ of Stevens->ohnson rash from lamotrigine is appro*imately in ## to )## forchildren, appro*imately # times higher than in adults. The ris$ is greatest for children who are comedicated with valproate and

for those who have a rapid escalation of dose or a history of a drug-induced hypersensitivity reaction. &)/

There is a significant potential for to*ic effects in the liver in children who ta$e felbamate. 7n adults, bone marrow failure is

another feared complication. 7t appears that the ris$ factors for liver andIor bone marrow to*ic effects from felbamate include

prior idiosyncratic drug reaction, history of cytopenia, and history of autoimmune disease.

E*carbazepine is a recently approved drug for the treatment of partial seizures. E*carbazepine is chemically and structurally

similar to carbamazepine but has a completely different biotransformation. Phereas carbamazepine is o*idized to the #,

epo*ide and then hydrolyzed, o*carbazepine undergoes reduction of the carbonyl group to form monohydro*y derivative 26%03

by a cytosolic, nonmicrosomal, noninducible $etose reductase. &)" 6%0 is the active metabolite of o*carbazepine and accounts

for the antiseizure activity of o*carbazepine. Because the #, epo*ide of carbamazepine is responsible for many of the side

effects of carbamazepine, it is anticipated that o*carbazepine will be well tolerated in children, as confirmed by a double-blindstudy.&)5

Topiramate is associated with adverse cognitive effects in children that may manifest as language dysfunction or behavioral

changes.&)+ Cor most patients, however, the ris$-benefit ratio of topiramate favors a therapeutic trial of the drug. Similarly, some

cognitively impaired or developmentally delayed children have unacceptable behavioral effects -- especially hyperactivity &)L,) --

from gabapentin as well as other new and established 40s.

S(4;7 (407T7; S?80E64S

"eonatal seizures and infantile spasms 0espite the urgency to establish a diagnosis in a neonate with seizures, severalunique features of seizures in neonates may delay prompt recognition and treatment. Curthermore, the efficacy of 40s and the

prediction of behavioral outcomes of neonates with seizures are controversial.&)! recently published study showed equivalent


32/43

efficacy of phenobarbital and phenytoin when given in loading doses to neonates with frequent seizures secondary to hypo*ic

ischemic encephalopathy.&/# 0isappointingly, the ma*imum efficacy, even when the patients were dosed aggressively, was /F.

The treatment of infantile spasms is undergoing rapid change. 0espite studies of vigabatrin that show remar$ably high spasm-

free rates,&/,/) the ris$ of long-term retinal dysfunction with this drug has postponed, if not terminated, its consideration for

approval in the Anited States and has prompted a search for other effective therapies against spasms. &//

Monisamide appears promising for infantile spasms. 7n a study by Suzu$i and colleagues, infants with newly diagnosed

infantile spasms who did not respond to high-dose vitamin B+ were treated with zonisamide.&/" 7nitial doses were " to 5 mgI$g

per day, and steady-state zonisamide serum concentrations ranged from 5.) to +./ mgIm. Cour 2/+F3 of the infants had

cessation of seizures and disappearance of hypsarrhythmia in the 449 pattern characteristic of infantile spasms. Two other

children improved substantially. nother study found similar results.&/5Tiagabine has been studied as open-label treatment for

infantile spasms with mi*ed results. &/+

+enno9-astaut syndrome Celbamate is an effective drug for enno*-9astaut syndrome&/L@ however, because of the ris$ of

aplastic anemia and liver to*icity, its clinical use has been limited to therapy-resistant cases. amotrigine, topiramate, and U8S

have been used in this syndrome with good results. &/-"# 7n a placebo-controlled study&/! of lamotrigine in children, //F of

lamotrigine-treated patients had at least a 5#F reduction of all ma1or seizures compared with +F for placebo 2P V.#3. The

corresponding frequencies for drop attac$s were /LF and ))F, respectively 2P V.#"3. esults with topiramate in another

placebo-controlled study were equally significant.&)+

3enign epilepsies The strategy for treating benign epilepsy syndromes is to use a drug with a benign side effect profile, such

as gabapentin. study of gabapentin in children with benign childhood epilepsy with centrotemporal spi$es showed superiority

of gabapentin to placebo. &"

SA66?: 76(7;T7E8S CE ;787; (;T7;4

4pilepsy in children is different from epilepsy in adults.

7n the future, even more options will be available for treating seizures in children, including short-term and long-termtherapies. %owever, no matter how many treatments become available for specific seizure types and epilepsy syndromes,clinicians must ma$e the best choice as early as possible during a patientXs epilepsy.

;urrently, choosing treatment is an empiric matter, but with additional controlled studies, treatment selection will

become increasingly evidence-based. These studies must include the appropriate pharmaco$inetic evaluations andsub1ects in each C0-defined pediatric age group--neonates, young children, older prepubertal children, and adolescents.Curther, a variety of formulations must be developed that can be ta$en by children of all ages.

The goal of seizure freedom without adverse effects is attainable for more children now than ever before@ with further

research, even more children will be given a chance for a bright future.

S(4;7 7SSA4S 78 404? (T748TS P7T% 4(74(S?

The optimal care of older persons with epilepsy requires $nowledge of age-related changes in physiology, differences in the etiologies

and clinical presentations of seizures, and side effect profiles of 40s.

4(70467EE9?

The elderly segment of the population is growing at a much faster rate than other age groups. t the turn of the )#th century, the

number of people in the Anited States older than L5 years was !##,###. By !!#, the corresponding number reached # million@ by

)###, it is pro1ected to e*ceed / million.&")


33/43

The relationship between age and epilepsy is bimodal.&"/-"5 The incidence of epilepsy is nearly ## per ##,### in the first year of life

and then declines rapidly during the ne*t few years before leveling off and remaining stable for " to 5 decades. fter the age of +#

years, the incidence begins to rise mar$edly, to as high as /" of ##,### in persons older than +5 years.&"5

s a consequence of the growth in numbers of elderly persons and the high incidence of seizures in this age group, it has been

estimated that by the year )#)5, 5#F or more of new-onset seizures will occur in elderly patients. This represents a significant shif t in

the demographics of epilepsy compared with the past, when this disorder was primarily considered a pediatric condition.

; AS4 EC S47MA4S 78 T%4 404? 80 ;787; (4S48TT7E8

The most common cause of seizures in the elderly is cerebrovascular disease. ppro*imately "F to "F of cerebral infarcts are

associated with seizures within the first to ) wee$s, and up to #F are associated with seizures ) wee$s or more after the acute insult.

&"+-5# Ether common causes of seizures are degenerative dementias and neoplasms. (atients with lzheimer disease have a #F to

)#F ris$ of developing seizures by the fi fth year of their illness.&56ost neurologists are unaware of this association, because they may

not see patients with lzheimer disease in the later stages.

lthough a substantial proportion of elderly patients have no identifiable cause of their seizures, as in younger patients with epilepsy,

most nonetheless have one or more comorbid conditions, including hypertension, heart disease, diabetes, vascular disease,

depression, and degenerative dementias. ppro*imately )5F to /5F are idiopathic. These disorders and their treatments must be $ept

in mind for ) reasons. Cirst, drugs such as theophylline, tricyclic antidepressants, and the atypical antipsychotic clozapine, can cause

seizures,&5) as can the abrupt discontinuation of the use of sedatives. Second, the initiation of 40s in a patient ta$ing other medications

can result in drug-drug interactions.

Seizures among the elderly are nearly e*clusively partial onset@ comple* partial seizures are the most commonly occurring seizures in

this age group. ;ompared with younger patients, a higher proportion of partial seizures in the elderly li$ely arise from structures otherthan the limbic corte*, because nonlimbic areas of the brain are vulnerable to stro$es and tumors.

The clinical manifestations of comple* partial seizures in this age group are not well defined. Behaviors such as confusion,

disorientation, and unresponsive staring may be both subtle and prolonged. Some ictal behaviors, such as orofacial automatisms,

rubbing, tapping, stro$ing, disrobing, and wandering, may not be obviously seizure related -- e*cept to epileptologists -- because these

behaviors can have other causes in this age group. (ostictal confusion can last from hours to days.

6any patients with some degree of dementia who live in assisted settings, in nursing homes, or with relatives manifest similar behaviors

from time to time. 7t is not uncommon, therefore, for comple* partial seizures in these patients to be mista$en as part of the dementing

illnesses. s a result, many patients might have seizures that go unrecognized and untreated because the diagnosis is not considered

and pursued with the appropriate diagnostic studies.

(rimary generalized seizures in older patients do occur but only rarely. 6ost patients with these $inds of seizures have a history of

absence or tonic-clonic seizures that is e*acerbated, for un$nown reasons, in old age. 0istinguishing seizure type on clinical grounds

and by 449 is as important for selecting 40s in the elderly as it is in younger patients.

The medical complications of seizures in elderly patients are more e*treme than in other age groups. Calls from seizures or drug-

induced ata*ia are more li$ely to result in fractures and intracranial hemorrhages 2particularly subdural hematomas3 because of age-

related osteopenia and brain atrophy, respectively. Status epilepticus carries a mortality rate of more than 5#F in patients older than #

years.&5/,5"

T%4(4AT7; ;E8S704T7E8S


34/43

ging changes the pharmaco$inetics of drugs in several ways, because altered physiologic processes affect the absorption, distribution,

metabolism, and e*cretion of 40s. The net result is reduced drug clearance &55,5+@ consequently, the recommended approach to 40

therapy in this age group is to initiate therapy at lower doses and titrate the drugs more slowly than in younger patients.

Pith aging, the gastric p% increases. Phether this affects the absorption of 40s in the elderly, particularly gabapentin, is not yet

$nown. The ratio of body fat to lean body mass increases@ therefore, fat-soluble drugs, such as the benzodiazepines, have longer half-

lives. s the creatinine clearance is reduced, so is the clearance for renally e*creted 40s, such as gabapentin, o*carbazepine, and

levetiracetam. lbumin concentrations decline@ as a result, free concentrations of highly protein bound 40s such as phenytoin are

increased.

4lderly persons often ta$e / or more prescription medications for comorbid conditions.&55 7n these cases, drug interactions with 40s are

li$ely, particularly for 40s that induce or inhibit hepatic metabolism or are tightly protein bound. Cor e*ample, the metabolism of

warfarin is increased by enzyme-inducing 40s@ therefore, prothrombin times must be carefully monitored. Ever-the-counter

medications may interfere with 40 pharmaco$inetics as well. Cor e*ample, calcium-containing antacids may slow and reduce 40

absorption.

4CC7;;? 80 TE4B77T?

;urrent first-line drugs for the treatment of partial seizures in the elderly are phenytoin and carbamazepine. Ualproate may be effective

as well and is preferred for primary generalized seizures. %owever, considering the effects of age-related changes in physiology, as well

as the relative ease with which seizures in the elderly are controlled, &5L many clinicians prescribe gabapentin for elderly patients because

it has minimal potential for drug-drug interactions. amotrigine has been shown to be better tolerated than carbamazepine in this age

group.&5 double-blind trial comparing gabapentin, carbamazepine, and lamotrigine in elderly patients with new-onset seizures is under

way in the Ueterans dministration medical system.

s a general rule, adverse effects of 40s are e*aggerated in the elderly because of pre-e*isting comorbid conditions. These adverse

effects include sedation, behavioral effects, ata*ia, tremor, cognitive slowing, and hyponatremia. These effects may not be appreciated

as 40 adverse effects and therefore may be evaluated and treated unnecessarily. Cor e*ample, the tremor of valproate may be

misdiagnosed as a par$insonian tremor and treated with dopaminergic agents.

;linical e*perience in elderly patients with the newest 40s -- topiramate, tiagabine, levetiracetam, zonisamide, and o*carbazepine -- is

limited, although it appears that the propensity for hyponatremia is greater with o*carbazepine than with carbamazepine, especially in

patients ta$ing sodium-wasting diuretics. Curther research is needed to define the adverse effect profiles of these agents, particularly

cognitive effects.

4lderly patients may be unable to swallow pills during acute medical illnesses, and therefore 40s may need to be administered via a

nasogastric tube or intravenously or intramuscularly. The only 40s administered in the long term that are currently available with

intravenous formulations are phenytoin, valproate, and phenobarbital.

SA66?: 76(7;T7E8S CE ;787; (;T7;4

To achieve seizure freedom without adverse effects in elderly patients with epilepsy, physicians need to ma$e the right

diagnosis and tailor the 40 regimen to the patientXs seizure frequency, using 40s with minimal side effects and interactions with

other drugs that the elderly person is ta$ing.

Treatment should begin with a low dose and be increased slowly

Psychiatric Drugs and Pharmacology

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