psychiatric drugs and pharmacology
TRANSCRIPT
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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%.
http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B23http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B23http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B23http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B67http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B67http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B68http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B67http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B68http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B68http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B124http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B82http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B141http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B141http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B86http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B6http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B6http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B189http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B190http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#F1http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#F1http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#F1http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B160http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B160http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B160http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B32http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B32http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B32http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B59http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B23http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B93http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B23http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B23http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B23http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B67http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B67http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B68http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B67http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B68http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B68http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B124http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B82http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B141http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B141http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B86http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B132http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B6http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B189http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B190http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#F1http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B160http://www.frontiersin.org/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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
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//;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
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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.,
//
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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
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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 +–
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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.
http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B107http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B98http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B72http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B72http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B107http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B98http://www.frontiersin.org/Evolutionary_Psychology/10.3389/fpsyg.2012.00117/full#B72
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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$ing seizures more difficult to classify. Cor e*ample, a )-year-old child may have seizures
that appear behaviorally to be generalized and yet have an 449 that indicates focal ictal abnormalities. ;onversely, the ictal
449 may show a generalized epileptiform pattern in a -year-old patient whose seizures consist of unilateral clonic movements.
0rug study outcomes depend on the ages of sub1ects and the epilepsy syndromes eventually diagnosed in these sub1ects@ thus,the difficulty in specifying seizure type in the very young patient with epilepsy confounds the interpretation of drug study results
and their application to clinical practice. lternatively, classification of patients by epilepsy syndrome is more useful, because the
seizures associated with specific epilepsy syndromes have been thoroughly studied with regard to choice and duration of 40
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therapy, prognosis for seizure control, li$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,
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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-!
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.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
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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 $nowledge of age-related changes in physiology, differences in the etiologies
and clinical presentations of seizures, and side effect profiles of 40s.
4(70467EE9?
The elderly segment of the population is growing at a much faster rate than other age groups. t the turn of the )#th century, the
number of people in the Anited States older than L5 years was !##,###. By !!#, the corresponding number reached # million@ by
)###, it is pro1ected to e*ceed / million.&")
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The relationship between age and epilepsy is bimodal.&"/-"5 The incidence of epilepsy is nearly ## per ##,### in the first year of life
and then declines rapidly during the ne*t few years before leveling off and remaining stable for " to 5 decades. fter the age of +#
years, the incidence begins to rise mar$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$ely to result in fractures and intracranial hemorrhages 2particularly subdural hematomas3 because of age-
related osteopenia and brain atrophy, respectively. Status epilepticus carries a mortality rate of more than 5#F in patients older than #
years.&5/,5"
T%4(4AT7; ;E8S704T7E8S
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ging changes the pharmaco$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