The Serotonin Theory of Depression

The Serotonin Theory of Depressio n
Christopher W. Kerr
Abs tract
In its simplestfo rm, the serotonin deficiency theory ofdepression postulates that there is a net
reduction in serotonin transmission in depressive illness. The pathophy siological change may result
fr om two different mechanisms. Thejirst involves a decrease in serotonin (5-H T) availability which
has the consequential tiffict ofcompensatory receptor up-regulation or supersensitiuity. The second
mechanism implies a primary defect in receptor activity and/ orsignal transduction. Theobjectioe qf
this review is to analyze the serotonin system in depression as it relates to the above two postulates.
Chemical imbalances in th e ce nt ra l nervous sys te m (CNS) have long been
th ou ght to und erli e fluctuations in mood . The a m ine hypoth esis, th a t t he pat hop hysiology of depress ion involves impairm ent of ca techo la m ines, has bee n expanded to
includ e th e rol e of sero to nin, or 5- hyd ro xyt ryp to phan (5- HT). Th ro ugh its widespre ad distribution within th e neural axis, se ro tonin is th ou gh t to: "playa key ro le in
th e modulation of excessive st im uli of a wid e va rie ty a nd in t he orga nization of
a ppro pria te responses. It has been sugges te d th at th e overa ll fu nction of th e
se ro to nine rg ic syste m is to enable th e orga nism to wa rd of feeli ngs of fear, helpl essness a nd d epression ( I )." C on sist ent with this hypoth esis is t he evide nce th a t
alte ra t ions in se ro tonin acti vit y have a rol e in co re beh aviors which are a lso disturbed
in a ffec tive illn ess ( 1,2) .
In it s sim ples t form , th e se ro to nin deficien cy t heory of d epression postu lat es
th at th ere is a net reducti on in se ro to nin tran smi ssion in depressive illn ess. The
pathophysiological cha nge may result fro m two di fferen t mec hanisms. The first
involv es a decrease in 5-HT ava ila bility whi ch has th e conse q ue nt ia l effect of
co m pe nsa tory receptor up-regul ation or supersen sitivit y. Th e second mech ani sm
impli es a prima ry d efect in receptor ac tivity a nd / or signa l tran sducti on . Alt ho ugh
th e se ro tonin deficien cy th eory receives conside rable suppo r t in exp lanat ions of
depression, recent stud ies have sug ge ste d that so me form s of hum an d epression ma y
be du e to an exce ss of serotonin at th e synapse (3) . Th e objective of th e following
review is to a na lyze th e se ro to nin sys te m in depression as it rel at es to t he a bove two
postulat es.
Th e sea rc h for th e role of se ro to nin in depression has evolved from resea rch on
depression-rel at ed a lte rat ions in seroto nin level s, to cha nge s in 5-HT metabolism
Ch ristoph er W. Ke r r is a fourth year m ed ica l stude nt at th e Med ica l Co lleg e of Ohio a t T oledo.
T his pa pe r is t he win ning es say of t he 1993 Kapl a n Essay Cont est for medi cal stude nts a nd was
pr esent ed a t a sym pos iu m for me d ica l students held in C in cinnati in O ctober, 1993.
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and more recently to 5-HT receptor st ud ies. In t he following review, th e d at a will be
d escribed in a similar sequ en ce. It is import ant to not e th a t this disc ussion will
includ e references to co nt rad ict ions in experime n tal results. In part , this com plexity
reflect s th e challe nge in isol ating t he ac t ion(s) of se ro to nin given it s d ist ribu t io n in
fun ctionally di scr et e regions of th e C NS (4). Furthermore, se ro to nin medi at es a
div ers e a rray of ph ysiological resp ons es by int eracting wit h seve ra l d iffere nt 5-H T
receptor subtypes as well as int er acting with th e act ions of sev e ra l non serot oniner gic
syst ems (5,6) . The challe nge in res earch , th erefore, is to isolat e th e act ion s of 5-HT,
as well as th e effect ive ne ss of drugs on this sys te m, give n th e diversity in serotonin
di stribution as well as the het erogen eity of 5-H T recepto rs. W ith regard to t he
clinical findings, in pa rt th e con tradict ion in r esults reflect s th e d ifficulty in comparing individuals based on a subject ive as sess me n t of sym p tomato logy despit e t he
possibility of different diagnosti c subg ro ups, associa t ed e t iologies a nd / or trea tm e nt
ex posure (s). This review will a tt emp t to describe th e ro le of serotonin whil e acknow ledging th e m ethodological difficulti es and con t rad ict ions in find ings.
CSF AND BRAIN LEVELS O F 5-HT AND 5-H IAA
The ea rl iest studi es whi ch focu sed on th e rol e of seroto ni n in d epr ession
m easured th e ce re brospin al fluid (C SF ) conce n t ra t ion of se ro t onin or its major
m et abolit e, 5-hyd ro xyindoleace t ic acid (5-HIAA), as a n index of se ro to ninergic
ac t ivity . In hum ans , th e level of CS F 5-H lAA has been found to cor re la te accu ra te ly
with th e conce n tra tio n of 5-H IAA in th e brain (7). Alt ho ug h som e st udies have fou nd
decr eased levels of th e se rotonin m et ab olit e in d epressed pa ti en ts o t he rs have fa iled
to report significant diffe ren ces wh en co m pared to no r m al co nt rols (8,9, 10). Int e rest ingly, a n t ide p ressa n t treatm ent with drugs whi ch in hib it 5-H T upt a ke (e. g. im iprami ne, a m itrip tyline) decr ease th e CS F 5-H IAA level a lt ho ugh th e magnitude of the
redu cti on does not co r rela t e wit h t he clinica l resp on siveness to medicat ion ( I I). Th is
acti on is pr ed ict ed based on feed ba ck effects involving incr eased post -syna pt ic
act ivity a nd up t ak e with a subseq uen t d ecr ease in seroto nin .
In con trast to t he a bove stu dies which focu sed on th e depres sed pati e nt , CSF
st udies of suicide a tt em p te rs repor t significa nt reducti o ns in 5-H IAA (12). Mor eove r,
suicide vict ims wit h definit ive affective disord e rs represent a subg ro up wit h sign ifica n tly lowe red CS F levels of 5-H lAA. Among t his subgro uping t he great es t reduction
in CSF 5-H IAA is associa te d wit h uni pola r depression a nd a bse n t in bip ola r d isorde r.
Add it ion a l st udies report a di st inct ion be tw een vio len t ve rsus non violent suicide wit h
t he lowest levels associa te d wit h vio lent suicid e. This ob servati on is d ifficult to
in terpre t; non e t he less it has bee n su ggest ed by on e reviewer th at " sinc e th e se lectio n
of su icide m et ho d is heavily dep e nd e nt on ava ila bility a nd mod el ing, it is probabl e
that th e associa t ion is actually wit h t he se riousn ess of in te n t or m edi cal let hali ty of
t he m e th od (13). " In addit ion to th e st ud ies focu sing on m et abolit e levels, five of
se ve n st ud ies have report ed a d ecrease in 5-H T or 5-H IAA levels within th e brain of
suicid e vict im s or suicid e at t e mp t er s (12) . The redu ced levels we re found local ized to
t he bra inst em wit h only o ne st ud y reporting red uct ions in hig her co rt ica l ce n ters.
TH E SERO TONIN THEORY OF DEPRE SSIO N
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The reason for th e di scr epancies between region s a re unknown. On e poss ibl e
expla na t ion is that br ainst em level s m ay reflect changes at th e leve l of serotonin cell
bodi es, wh ereas co r t ica l m easures indicat e som e as pec t of te rmi na l activity in whi ch
bas al levels a re lower by com pa rison .
It is difficult to address th e dat a discrepan cies betwe en th ose st ud ies based on
th e purely depressed versu s th e sui cid e victim . There a re seve ra l possibl e, but
unproven ex pla na t ions. First , reducti on s in br ain se ro to nin may vary in magn itude
between th e depressive a nd suicid a l states suc h th at low CSF levels are not detected
in th e form er, perhaps du e to th e limit ed se ns itivity of th e assay. Second , indices of
serotonin m ay be transitory in nature and fluctuat e acco rd ing to diet , tim e of day, e tc .
Third , th e trauma of sui cid e m ay be associat ed with m et ab olic alterations that a re
unrel ated to th e e t iology of th e depressive illn ess. In fact, given th e di stinctions
be tw een violent ve rs us non viol ent m ethod s of su icide, th e suicide even t it self may be
a n import ant a nd undefin ed va ria ble in th e findin gs. An ad d itio na l con cern lies in
int erpreting th e anatomical finding of lowered se ro to n in con ten t in t he brains of
sui cid e victims. Th ere is some crit icism that th e serot onin bei ng assayed ma y be in
lon ger-t erm stora ge; th erefore t he fun ctional import an ce may be uncl ear ( 13).
Furthe r, a n a lte ra t ion of th e level of se ro to nin does not necessarily imply a cha nge in
th e co nce n t ra t ion of avail abl e o r fun cti on all y effec tive sero tonin . For exa m ple, a
lowering of neuron al serotonin m ay be co m pe ns a te d by a n incr ease in t he number of
post-synaptic receptors or an alt eration in the rel ease m ech anism of 5-H T fro m th e
neuronal pool. In reviewing th e lit erature, st ud ies do not ap pear to have addressed
th e crit ica l qu estion conce rn ing a lte ra t ions in se ro tonin re lease (i.e. functionaI 5-HT)
as a conse q ue nce of d epression . Desp it e th ese crit icisms, th e d at a do suggest th at
th ere is an overall change tow ards a lower se ro to nine rg ic signal in t hos e individuals
att empting suicide.
PLASMA TRYPTOPHAN
Since th e availability of tryptophan is th e rat e-limiting fact or in th e syn thesis of
neuronal serotonin , there have been num erous investigations conce rn ing th e conce ntrations of plasma tryptophan in un m edi cat ed depressed patients. This wor k is bas ed
on th e pr emise that a reduction in ava ila ble t rypt ophan , possibl y becau se of excessive
peripheral m etaboli sm , m ay und erli e th e reducti on in 5-HT measured in the brains
of som e depress ed patients (1,13) . The dat a conce rn ing th e levels of plasm a tryptophan are co nflict ing, although so me studies do report a decr ease in plasm a t ryptoph an (14).
A more definitive finding is th e obse rva t ion th at nor m al co nt rol subj ect s
demon strat e a positive co r re la t ion between ba sal levels of plasm a t ryptopha n and th e
5-HT m etabolit e 5-H IAA wh ereas depressed patients do not ( I) . In o t her words, in
th e depress ed pati ent a n in crease in th e substrat e for se ro tonin (trypt ophan ) is not
correla ted with an incr ease in serotonin e nd-prod uc t (5-HIAA) in plasma. The lack of
cor re la tio n may sugge s t th at som e depress ed patients a bnormally m et a boli ze tryptoph an in peripheral orga n syste ms, th ereb y alt ering th e C IS cont ent of seroton in .
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However, firm co nclus ions a re co m plica te d by t he fact th at t rypt opha n may be
sequ est ered (i.e . in liver a nd mu scl e tissu e) a nd th e exact origin of plas m a 5-H IAA is
unknown . Several studies have sho wn that large doses of t ryp toph an result in lowe r
plasma levels of tryptophan in some depress ed versu s con t ro l subj ect s (15,16) . This
suggests that in som e cases of depression th ere is a m or e ra pid clearan ce of
tryptophan as opposed to an alt eration in tryptophan br eakdown . Ind eed , subsequ ent
expe rime n ts have d emonstrat ed that so me depressed pati ents have increased red cell
transport of tryptophan and , wh en co m pa red to normal con trols, show a great er d rop
in art erial versus venous levels of trypt ophan ( 17, 18). Thus, one int e rest ing possib ilit y
sugges ts that incr eased peripheral upt ak e a nd clearan ce of tryp toph an co nt ribu tes to
th e neuronal deficien cy of serotonin in d epression .
The a bove findings support th e se ro to nin deficien cy hyp othesis of depression a nd
are co r robora te d by obs ervations th at alte ra t ions in th e ava ila bility of t ryp topha n, or
5-HT it self, influ en ce th e mood of depress ed individu al s (20,2 1,22). In fact , one
reviewer suggests that " t he mo st pervasive evide nce for th e ro le of 5-HT in mood
disorders is the effec t oflowering brain 5-H T con centration in depressed pa ti en ts a nd
normals (I). " Inhibition of se ro tonin synthesi s, throu gh t he ad m inist ra tion of
p-chlorophenylalanine, has been shown to rapidly induce a recu rren ce of t he dep ressive e pisode in patients recovering fr om depressi on ( 19) . Further, 15 of2 1 a n tide pressa n t-t re a te d d epressed patients wh o received a t ryptophan -fr ee d iet showed a
subs t a n t ia l incr ease in d epressive sym pto ms (20) . However, t his sa m e parad igm
improved the symptoms of 14 of 22 untreat ed depress ed individ ua ls. T his la tt er
findin g is a direct ch a lle nge to th e th eory th at too littl e serot onin unde rl ies th e
continuation of depressive symptom s.
On e crit ica l factor that limit s th e us efulness of trypt ophan-d epl etion stud ies
concerns th e fact that uptake of tryptophan is not limited to se ro to nine rg ic neu rons
and th erefore plasma tryptophan may refle ct variations in periph eral m e t a bolism
onl y. As well , d epl etion of tryptophan in norm al individuals has been shown to ha ve a
mood-el evating effec t (21) . The diffe rential effec t of se ro to nin d epl e ti on in normal
versu s depressed individuals sugges ts that additional fact ors alte r th e manifest at ion s
of serotonin d epl etion within th e eNS. In other words, th e deple ti on of 5-HT in
normal and d epressed individuals results in oppos ite mo od ou tco mes that imply
differences in brain processing, perhaps because of variability of recept or-m ed ia ted
eve n ts or serotoninergic neuronal rel ease m echanism s.
Bas ed on th e premise that a reduction in trypt ophan has a mood-l owering effect
in som e depressed patients, administration of tryptophan ha s been att empt ed as
th erapeutic treatm ent in depression. Unfortunat ely , tryptophan has rarely been
found to eleva te mood in depressive illn ess (11 ,19). This appears to challe ng e th e ro le
of serotonin in depression exclusive ly in t erm s of a pr ecursor deficiency. Giv en th e
th erapeutic ineffectiveness of tryptophan alone, it is al so difficult to resolve th e
beneficial ac tion of som e antidepressants whi ch a re com mo nly th ou g ht to rais e
availabl e se ro tonin. Perhaps exoge nous tryptophan requires m et ab olic pro cessing
and neuronal release mechanisms that are impaired in th e d epressed a nd whi ch may
be bypass ed by the ac t ion of antidepressants. Sp ecificall y, many a n t ide pres sa n ts block
T HE SEROTONIN TH EORY OF DEPRESSION
7
e it he r the re-upt ak e o r d egrad ation of endoge no us serotonin ind ependent of neuronal pr ocessing.
Whil e trypt ophan a lone has lit t le th e ra peu tic effec t, tryptophan administration
does e n ha nce th e effe ct ive ness of some ant idepressants (2,22). For exa m ple, t he
effect ive ness of MAO inhibit ors is pot e n t ia t ed by tryptophan administrati on in som e
pa ti ent s. One in te r pre ta tion is th at req u ire men ts for t he tryptophan a re incr ea sed in
th e dru g-treat ed sta te a nd a re un relat ed to th e e tiology of th e illn ess . That both
MAO inhibit ors a nd tryptophan ac t to incr ease ava ila ble serotonin support s t he
th eory th at se ro to nin d eficien cy is a ca usal factor in so me forms of depressi on .
There a re also num erou s rep ort s th at lith ium ca rbo nat e improves th e ac t ion of
a nt idepressants in a number of pat ien ts (50 %) who fa il to respond to a nt ide pres sa n t
treat men t a lo ne (2,22). Several aut hors suggest t hat lith iu m may al so ac t to incr ease
th e effec tive ness of seroto nin t ransm ission. Bri eAy, levels of neuroendocrine hormo nes a re used to eva luate t he ac t ivity of t he seroto nin system as 5-HT is kn own to
pot enti at e th e rel ease of horm on es throu gh it s d en se innerva t ion to t he hypothalam us. Usi ng this mod el , lithium has bee n show n to incr ease pat ient a nd rod ent
resp on sive ness to sero to nin a nd /o r trypto phan as reflec ted by an incr ea se in e ndo cri ne hor mon es such as prolac tin and cor t isol (24 ,25 ,26). Although th e use of
neuroe ndocrine param eters does provid e a wi ndow to brain function , th e pr esen ce of
a d irect casual rel a ti onship is unclear. Fo r example, th e hypothalamic-pituit ary axis
is modula t ed by nu m erou s neuroact ive che m ica ls a nd ph ysiologica l sta te s. Therefor e,
lithium may ac t ind epend ent of se ro to ni n to ac t iva te t he hypo t hal a m ic ax is or
pot enti at e exci tatory m edi ators (i.e. re leasing factors) of t his syst em.
In su m , t he a na lysis of basal plasm a t ryp tophan levels is inconclusive to dat e.
Howeve r, whe n co mpared to normal con trols, increases in tryptophan do not correla t e wit h in creases in plasma 5-HT m e tab olit e leve ls in som e depressed patient s. Th e
discr epan cy between seroto nin subs trat e (trypto pha n) and m etabolit e (5-HlAA) may
a rise from altera tions in met ab olism or incr eased clearance, perhaps by nonneuronal orga n syste ms . A reduction of tryptophan levels lowers t he mood in some
d epressed patient s a nd eleva tes mo od in norm al con t ro ls. Converse ly, eleva t ions in
t ryptophan level s have littl e, if a ny, mood a ltering action in t he treatm ent of
depression . This lat ter obse rvat ion cha lle nges t he expla na t ions of d ep ression sole ly in
t e r ms of se rotoni n deficien cy. H owever, in part , many ant idepressants do appear to
en hance t he actio ns of sero to nin a lt ho ug h th e specificity of t his effec t is unclear.
Collec t ively, th ese st udies point to a n ove rall decrease in seroto nin as a ca usal, ye t not
exclusive, factor in so me form s of d epressive illn ess.
~ E R OTO NI N
t JPTAKE SITES AND RECEPTORS
An other a pproac h for assessin g t he se roto nin system has involved the measu rem ent of se ro t onin receptor co nte nt in post-mort e m brain ti ssu e a nd blood plat el et s.
Th e following dis cu ss ion is subdivide d into two sec t ions to cla rify t he distinction
between th e data pert aining to th e upt ak e of sero to nin versus th at re lated to 5-HT
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J EFFERSO N J O U RNAL OF PSYCHIATRY
recept ors whi ch m ediat e th e ac t ions of se ro to nin . Th e first sectio n will review
expe rimen ts whi ch involve th e assay of ligand bindi ng to 5-H T uptake sites on blood
plat el et s a nd se ro to nine rg ic neuron s. It is import ant to clarify that neuronal serotonin upt ak e sit es a re distribut ed o n sero to nine rg ic presyn apt ic terminals. Therefore, a
redu cti on in 5-H T uptake sites refers only to a loss of serotonin storage (presynapt ica lly) as oppose d to a direct loss in post syn aptic effect. Th e sec ond section descri bes
alte ra t ions in serotonin receptors which a re di stribut ed pr imarily on post syn ap tic
neu ron s. Th ese receptors a re found t h roug ho u t th e ne rvou s syste m as well as on
blood plat el et s, wh e re th ey m edi at e th e actions of se ro to nin . T he serotonin recept or s
are ca tegorized into multiple subtypes based o n differential affinity for va riou s
ligand s (5,6). Bri efly, th e evo lving d at a su ggest th at seroto ni n recept or s ca n be
ca tegorized into three major famili es: 5-H T i , 5-H T 2 a nd 5-H T 3 • T he 5-HT 1 class is
rep ort ed to be het erogen eous a nd subd ivide d int o th e 5-H T I f\ ' 18, ic a nd II) recept or s.
The ori ginal pharmacologi cal distinctions have been confir med by st udi es th at have
shown that eac h sub type is uniqu e on th e bas is of a na to m ica l distribut ion, sig na l
transduction, ph ysio logical behavior and mo lecul ar co m positio n.
S erotonin Uptake Sites
Early st ud ies report co nt rove rs ia l evide nc e for a reduct ion in th e number of
se ro tonin upt ak e sit es both in plat el et s a nd br ains of pati ent s wit h major depression
( 12,27,28,29,30). Th ese result s a re com plica te d inpart by recen t indicat ion s th at
several of th e ligands used (e .g. im pram ine) recogni ze rece pto rs of o t he r neurotra nsmitt ers a nd th erefore lack 5-HT binding spe cificity.
Expe r ime nts with more select ive ligands (e.g . pa ro xe t ine ) have indicat ed a
sig nifica n t reducti on in th e d en sit y of 5-H T upt ak e si tes both in plat elet s a nd br ain
ti ssu e of d epressed pati ents wh en com pa re d to age-matched con t rols (28) . Co ns iste n t
with th e se ro to n in d eficiency hypothesis, a loss of plat el et 5-HT upt a ke would be
ex pect ed to result in a loss of ava ila ble se ro to nin to th e ne rvous sys te m . In th e brain ,
a reducti on in 5-H T upt ak e would be expecte d to increase t he a mo unt of ava ila ble
se ro to nin in th e syn aptic cle ft. Ind eed , th e a n tide pressa n t fluoxc ti ne is th ou gh t to
exe r t its effec ts by blocking th e sa me serotonin upt ak e mech anism s. It is cu rious t ha t
th ese sam e site s a re redu ced in th e d epressed patient. This a lso challen ges th e
proposition that too litt le se ro to nin is a ca us a l fa ct or in d epression. On e reviewer
sugg es ts that th e d ecr ease in se roto nin upt ak e site s m ay reflect a co m pe nsa tory
m echanism wh ereby a primary reduction in 5-H T indu ces a decr ease in serot onin
uptake at se rotonine rg ic te r m ina ls in ord er to incr ease availa ble 5-HT in th e synap tic
cleft (27) . This int erest ing pr opo sition wou ld sugges t th at , when challe nge d by a
redu cti on in 5-HT, th e brain 's own m ech anism for m aint ai ning ava ila ble serot onin
m imi cs th e act io n of some drugs by decr easin g th e a mo un t of 5-H T avai labl e to th e
post syn aptic neuron. It remains to be resolved wh ethe r t he no t ed loss of 5-HT
neuronal uptake sig ni fies a primary deficit or a seconda ry co m pe nsa tory response to
se ro to nin loss.
T HE SE RO T ONIN THEORY OF DEPR ESSIO N
9
S erotonin R eceptors
A review of the lit erature pert aining to th e 5-H T 2 rec eptor found t hree of four
st ud ies which report ed a n increase in 5-H T 2 sites in t he co r te x of sui cid e victims
(3 1,32,33,34) . Simil arly, o ne st udy has repo r t ed an increase in pr efrontal 5-HT 2
rece pto rs in th e brains of d epressed patients (35) . T hese findings suppo rt the
se ro to nin d eficien cy m od el of depression wh ereby a re d uct ion in serotonin result s in a
su bse q ue n t up-regul at ion of postsynaptic 5-H T 2 recept ors. Conversely, 5-HT2 recep tor s a re down-regul at ed by a va ri e ty of a n tide pressants, including MAO inhibit ors
a nd 5-H T upt ak e inhibit ors (e.g. impramine ). Furt he r, high affinity 5-HT2 a n tagonists (e .g, mianserin) whi ch have sig nifica nt clini cal va lue , have a lso been shown to
se lec tive ly decr ease 5-H T 2 recept ors (36,3 7) . This docs not im ply that drug treatm ent
directl y induces recept or down-regul a tion. Theoreti call y, antidepressant s may indu ce 5-HT 2 receptor down -r egul ation as a n indi rect conseq ue nce of incr easing
avai la ble se ro ton in .
It is uncl ear, how ever, wh ether int act se ro to nine rg ic neu rons are necess ary for
th e down-regul ation of associa te d recept ors (38,39). In fa ct , selec t ive lesions of
se ro to nine rgic neuron s does not cons iste n tly ca use 5-HT 2 recep tor up-r egula t ion.
Lesion s of ca techola m ine -co nta ining neuron s (e.g. basal fore brain) do , how ever,
result in recept or up -r egul ation of 5-H T 2 recept o rs (39) . It is possible, th erefore, th at
alte ra t ions in 5-H T 2 recepto rs depend on int eract ion s wit h o t her t ran s m itt e r pathways th rou gh unknown m ech anism s. In fac t, a rece n t pub lication reports a reducti on
in t ryos ine hydroxylase, th e rat e-limi t in g e nzyme of ca te chola m ine syn t he sis, in
depression (40) .
In cont ras t to it s an t ide pressa nt ac t ion, it is in terest ing to note th at elec t roco nvu lsive shoc k treatm ent ca uses an up-regula t ion of 5-HT2 receptors (41). Further,
t h is effect is se lec t ively depend ent o n intact sero toninergic neurons (38) . It mu st be
no t ed , however, th at electroconvulsive shoc k th erapy has widespread effec ts whi ch
may have va lue indep endent of it s ac tion on th e sero toni n syst em.
Com pa re d to t he 5-H T 2 recep tor class, st udies of the 5- HT, receptors are more
pr eliminary. In part, th e difficulty in d efinin g th e ro le of 5- HT, receptors in
depression reflect s th e lack of se lec t ive ligands for t his receptor class. And, unl ike th e
5- HT 2 receptors whi ch occ u py a post synaptic position , th e 5-HT, recep to rs are found
post syn apticall y and pr esynapticall y on se ro to nine rg ic neu ron s (a utorece ptors) and
nonserotoninergic neurons (h er eroreceptors) (5,6). Earl y st ud ies whic h did not
dis criminat e between 5-H T 1 receptors fail ed to find a redu cti on in tot al receptor
co nte nt (31,45,46). However, se lec t ive investigation of th e 5-H T'A recep tor have
shown a sig nifica n t incr ease (30%) in receptors in th e brains of suicide victims wh en
co m pa re d to con t ro ls (47 ,48).
The receptor binding ex pe rime n ts demon st rat e t hat d ep ression is associat ed
with a reducti on of se ro to nin upt ak e sites a nd a n up-regul a t ion in some classes of
5-HT receptors. Th e challenge is to int eg rat e t he independent findings int o a
uni fyin g hypothesis . One in te rpre tat ion would sugges t t hat a pr imary loss in serot onin itself induces co m pe nsa tory alterat ions in recept or cont en t wh ereby postsynaptic
10
J EFFERSO N J O URNAL OF PSYCHIATRY
sit es up-regul at e a nd pr esyn aptic 5-H T upt ak e sites down-re gul at e. Th e net effec t of
suc h a dyn amic would be to increase availa ble sero to nin (via upt ak e down- regul ation)
wh ile a m plifying post syn aptic effe ct ive ness (via post synapt ic up -r egu lation ). Aga in ,
th ese eve n ts would sig nify a n ada pt ive receptor resp on se to a deficiency in se ro tonin.
An a lte rn a t ive hypothesis postulat es that a lte ra tio ns of 5-HT rece ptors represe n t a prim ary or initiating fact or , as opposed to th e co m pe nsatory response. This
would imply that an incr ease in net seroton in tra nsm issio n m ed iat es d epressive
sym pto ms du e to excessive se ro to nin at th e synapse as well as an a mplificat ion of th e
sig na l a t th e post syn aptic site . As a conse q ue nce, level s of sero to nin and its m etabolit e m ay be expec te d to drop .
The crit ica l di stincti on between th ese hyp oth eses is whe t he r th e pr imary d efect
occ u rs pr e or post syn apticall y. The latt e r mod el would im ply t hat incr eases in
seroto nin ac t ivity me d ia te d epression throu gh a n a ltera t ion in serotonin recepto rs.
Se ve ra l lin es of evide nce pr esent ed pr eviou sly con t ra d ict th e serotoni n d eficien cy
hypothesis pr esent ed first a nd support ed th e latt er co nce pt th at dep ression ma y be
associa te d with excess ive se ro to nin tran smission a nd /or a ltered post syn ap tic ac t ivity.
For exam ple, some a n t ide pre ssan ts exe rt th eir effects by bloc king and /or downregul ating post syn aptic 5-HT recept ors. In add it ion, th e fact that serotonin dcn ervati on fail s to a lte r th e conce n t rat io n of so me recept ors suggests that up-regulation
occurs exclus ive to reductions in ava ila ble se ro to nin .
On e st udy has att empt ed to di stingui sh bet ween th e ro les of pr e versus
post synaptic eve n ts in a nimal mod els of de pression (5 1). Dep ression was indu ced by
th e ad m inist ra t ion of 5-HT or t et rab en a zin e a nd d efin ed in terms of degree of anim al
acti vity. In th e " de pressive" sta te, specific u pta ke block ers of serotonin (e. g. Auoxe t ine) were found to pot enti at e th e depressive sym pto ms substant ia lly (200 %). The
incr eases in d epressive behavior were co r re la te d with incr eas es in brai n 5-HIAA, th e
principl e se ro to nin m etabolit e. In co nt ras t, post syn aptic blockad e of serotonin recep tors (e .g. m ethylsergid e ) a lmost co m ple te ly abo lishe d t he depressive action of 5-HT.
Sim ila rly, se ro to n in-ind uce d d epression wa s a bo lishe d by some a nt idepressants (e .g.
mianserin , imipramine) whi ch exe r t th eir effec ts by block ing se ro to nin pos tsynaptica lly. Taken together, th e data imply th at d epression m ay be mediat ed post syna p t ica lly a nd induced by excess transmission of se ro to nin a t th e sy na pse .
T o furt he r defin e th e func t iona l rol es of 5-HT 1A recept ors in depress ion ,
expe rime n ts have a na lyzed ph ysiological resp on ses associa ted with 5- HT 1A recep tor
acti vation. As m entioned , neuroendocrin e param et ers a re fre q ue n t ly mon it o red as a
fun ctional indicator of serotonin. ac t ivity. Compared to hum an co ntrols, dep res sed
pati ent s show a tte nuate d hypothalamic a nd neuroendocrine (e .g . AC T H, cort isol)
res po nses to select ive 5-H T 1A ago nists (49,50) . This findi ng was somewhat sp ecific for
d epressio n wh en co m pa re d to individu al s with bipola r d isord e r o r obs es sivecom pulsive illn ess. Thus, alt eration s of 5-HT 1A recept or a nd /or it s sig na l transduction pathway appear to pla ya specific rol e in depression. The import an ce of t his
ob servation is that the d epression -associat ed changes with in th e se ro ton in system
may ex te nd beyond alt erations in 5-HT co nte n t a nd involve di m inish ed fun ctional
effec t ive ness.
T HE SEROTONIN T HEO RY OF DEPRESSION
11
In su m m ary, there is s ubs ta n tial evide nc e to suggest t hat d epress ion is associa te d wit h a r eduction in serot onin u pt ak e sites as we ll as a n increase in som e cla sses
of sero to n in r ecept ors. It is not kn own whe t her the receptor alt erations represent a
p ri mary d e fect or a secondary consequence of lowe r ed se ro to nin con te n t. T he
serotonin t heory ha s yet to u neq uivocall y assign a cause versu s e ffec t rol e to th e m an y
va riables kn own to be a lte red in d e p r ession. Although th e und erlyin g dynamics a re
unresolved, t he lit e ra ture typi call y defi nes t he serotonin syst em a s being " de ficie n t"
in a ffec t ive illn ess. This d escript ion can be int erpre t ed as eith er a reduction in
se ro tonin a nd / or a loss in r eceptor-m ediat ed sig nal.
CONC LUSIONS AND FUTU RE DIRECTI O NS
T he ro le of se ro to ni n in affect ive illn ess is based in part o n th e following
pathophysio logical changes found in d epression : I) d ecr eased brainst em 5-HT a nd / or
5-H IAA, 2) in crea sed plasm a tryptophan cleara nce, 3) tha t re d uc tion in trypt ophan
ind uces d epr essive e piso des in th e d e pressed , 4) t hat sero tonin uptake sites do wnregula te while so me classes o f serotonin recep to rs u p-reg u la t e, 5) that neuroendocrine ac tivi ty is su brespo nsive to seroton in stim ulation and 6) that many e ffect ive
an t ide p ressa n t th erapies in cr ea se sero toni nergic act ivity. To dat e , no un ifyin g th eory
can acco u n t for th e obse rved cha nges in the seroto nin system as e it he r a ca use or
co nseq ue nce of d epres sion .
Th e involvem en t of o t he r transmitt e r sys te ms in d epression has not been
ad dressed du e to the limit ed sco pe of this review. It is probably ina ccu ra t e to assum e
that d epr essive illness involves a se lec tive im pairment within th e serotoninergic
system. In fac t, th e b ro ade r d escr ip ti on of dep ress ion as an amin e d eficien cy has been
ex pa nded based o n cu rre n t conce p ts wh ich em p hasize t he d epend en t int errelationship betwe en neurotransmitt er sys te ms (52,53,54,57). T his int eraction is based on
well-docum ent ed r eport s that mult ipl e transmitt e rs a re co- localize d wit hin t he same
neuron. M oreover, the ac t ions of di stinct neurotransm itt e rs a re co up led at th e level
o f transducti on . For exam ple , se roto nin utili zes G p ro teins, second m ess en g ers a nd
ion cha nne ls whi ch are a lso ac tiva te d by o ther ne uro transm itt ers and peptid es. In
o the r wo rd s, se ro to nin a lte rs neu ronal res po ns ive ness t h ro ug h its shared int eraction
wit h o t he r neurotransmitt ers/peptides. Thus, th ere is an ever increasing challe nge
to th e d escript ion of " de ficits" in terms of sing le t ra ns mi tter sys tems. Further,
d epression may represent an a lte ra tio n in sig na l transduct ion suc h t hat serotonin is
s usce p t ible to dysfunction th rou gh it s associa t ion wit h th ese second m essengers.
It is a lso importan t t o not e t ha t cha nges wit hi n th e serotonin axis do not account
for the wides p read pa t ho logical cha nges fo un d in d ep ressive illness . For exa m ple,
d ep r ession is associa te d wit h the foll owi ng ab normaliti es: lowe r ed Na " -K + ATPase
ac t ivity, lowered Ca t t -Mg" " AT Pase ac tivity, lowered adre ne rg ic beta2 recep tor
ac t ivity a nd in cr ea sed ad re ne rgic-a lp ha2 r ecept or number/ acti vit y (55) . Based on
t he se obse rva tio ns, th ere is st ro ng impl ication for th e ro le o f so m e a b no rmality with
wides pread pathog enic co nseq ue nces in d ep r essive illn ess. Sim ila rily, t here are few
12
J EFFERSON J O UR NA L OF PSYCHIATRY
referen ces in th e lit erature to m ech anism s whi ch may induce or initiat e se ro to nin
dysfunction in d epression.
Th e d escription of d epression as a se ro to ni n " deficie ncy" has follow ed th e
di recti on of ba sic research fr om a focu s on transmitt er d eficie ncies, to impair ed
signaling m echanism s. The e m phas is on ce llula r fun cti on co m plica tes t he interpret ation of data as it rel at es to depression. For exam ple, th e level of re ceptor cont ent docs
not necessa rily correla te with d eg ree of func tion as a single receptor has been shown
to a m plify sig na ls through th e ac t iva tio n of m ultipl e G prot e in mo lecules (56 ,57).
Th er efor e, a future cha lle ng e will be th e translati on of basic resea rch to behavioral
sig nifica nce . Sp ecificall y, in order to und erst and th e ro le of seroton in in d epression ,
fu t u re s t ud ies a re need ed to det ermine th e in terrelation sh ip betwe en se ro to nin a nd
other physiological m ediators th at a re a lso known alte re d in d ep ression .
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