Jefferson Journal of Psychiatry Jefferson Journal of Psychiatry

Volume 12 Issue 1 Article 4

January 1994

The Serotonin Theory of Depression The Serotonin Theory of Depression

Christopher W. Kerr Medical College of Ohio at Toledo

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Recommended Citation Recommended Citation Kerr, Christopher W. (1994) "The Serotonin Theory of Depression," Jefferson Journal of Psychiatry: Vol. 12 : Iss. 1 , Article 4. DOI: https://doi.org/10.29046/JJP.012.1.001 Available at: https://jdc.jefferson.edu/jeffjpsychiatry/vol12/iss1/4

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The Serotonin Theory of Depression

Christopher W. Kerr

Abs tract

In its simplestfo rm, the serotonin deficiency theoryofdepression postulates that there is a netreduction in serotonin transmission in depressive illness. The pathophy siological change may resultfr om two different mechanisms. Thejirst involves a decrease in serotonin (5-H T) availability whichhas the consequential tiffict ofcompensatory receptor up-regulation or supersensitiuity. The secondmechanism impliesa primary defect in receptor activity and/ orsignal transduction. Theobjectioeqfthis review is to analyze the serotonin system in depression as it relates to the above twopostulates.

Chemical imbalances in th e ce nt ral nervous syste m (CNS) have long beenth ou ght to underlie fluctuations in mood . The a mine hypothesis, th a t t he pat hop hysi­ology of depress ion involves impairment of ca techo la mines, has been expanded toinclude th e rol e of sero tonin, or 5-hyd roxyt ryp to phan (5-HT). Through its wide­spre ad distribution within th e neural axis, se ro tonin is th ou gh t to: "playa key ro le inth e modulation of excessive st im uli of a wid e va rie ty a nd in the orga nization ofappro pria te responses. It has been sugges te d th at th e overall fu nction of th ese ro to nine rg ic syste m is to enable th e organism to wa rd of feeli ngs of fear, helpless­ness and depression ( I )." Con sist ent with this hypoth esis is the evide nce th a talte ra t ions in se ro tonin acti vit y have a rol e in co re beh aviors which are also disturbedin a ffec tive illn ess ( 1,2) .

In it s sim ples t form, th e se ro to nin deficien cy theory of depression postu lat esth at th ere is a net reducti on in se ro to nin tran smi ssion in depressive illn ess. Thepathophysiological cha nge may result from two di fferen t mechanisms. The firstinvolv es a decrease in 5-HT ava ilability which has th e conseq ue nt ia l effect ofcom pe nsa tory receptor up-regul ation or supersen sitivit y. The second mechani smimplies a prima ry defect in receptor ac tivity and / or signa l tran sducti on . Alt ho ughth e se rotonin deficien cy th eory receives conside rable suppo r t in exp lanat ions ofdepression, recent stud ies have sug ge ste d that some forms of human depression ma ybe du e to an exce ss of serotonin at th e synapse (3) . The objective of th e followingreview is to a na lyze th e se ro to nin syste m in depression as it relat es to the above twopostulates.

The searc h for th e role of se ro to nin in depression has evolved from resea rch ondepression-related a lte rat ions in seroto nin levels, to cha nge s in 5-HT metabolism

Ch ristopher W. Ker 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 per is the win ning essay of the 1993 Kapl a n Essay Cont est for medi cal stude nts and waspr esented a t a sympos iu m for me d ica l students held in C incinnati in October, 1993.

3

4 J EFFERSON J O URNAL OF PSYCHIATRY

and more recently to 5-HT receptor stud ies. In t he following review, th e dat a will bedescribed in a similar sequen ce. It is important to not e th a t this disc ussion willinclude references to cont rad ict ions in experime ntal results. In part , this com plexityreflect s th e challe nge in isol ating the ac t ion(s) of se ro to nin given it s d ist ribu t ion infun ctionally di scr et e regions of th e C NS (4). Furthermore, se ro to nin medi at es adiverse a rray of ph ysiological respons es by interacting with seve ra l d ifferent 5-HTreceptor subtypes as well as int er acting with th e act ions of several non serot oniner gicsyst ems (5,6) . The challenge in research , th erefore, is to isolate th e act ion s of 5-HT,as well as th e effect ive ne ss of drugs on this syste m, given th e diversity in serotonindi stribution as well as the het erogen eity of 5-HT receptors. W ith regard to theclinical findings, in pa rt th e contradict ion in results reflect s th e d ifficulty in compar­ing individuals based on a subject ive assessme n t of sym ptomato logy despite thepossibility of different diagnosti c subg ro ups, associa ted et iologies and / or trea tmentexposure (s). This review will a tt empt to describe th e ro le of serotonin whil e acknowl­edging th e m ethodological difficulties and con t rad ict ions in find ings.

CSF AND BRAIN LEVELS O F 5-HT AND 5-HIAA

The ea rl iest studies whi ch focu sed on th e rol e of serotonin in depr essionmeasured th e ce re brospinal fluid (CSF) concen t ra t ion of se ro tonin or its majormet abolit e, 5-hyd roxyindoleace t ic acid (5-HIAA), as a n index of se ro to ninergicac t ivity . In humans , th e level of CS F 5-HlAA has been found to corre la te accura te lywith th e conce ntra tion of 5-H IAA in th e brain (7). Alt ho ug h some st udies have fou nddecr eased levels of th e serotonin met ab olite in depressed pa tien ts ot he rs have fa iledto report significant differen ces when compared to normal cont rols (8,9, 10). Interest ­ingly, a n t ide pressan t treatm ent with drugs whi ch in hib it 5-HT upt a ke (e.g. imipra­mi ne, a mitrip tyline) decr ease th e CS F 5-HIAA level altho ugh th e magnitude of theredu cti on does not co rrela te with the clinica l respon siveness to medicat ion ( I I). Thisaction is pr ed icted based on feedba ck effects involving incr eased post -syna pt icact ivity and up tak e with a subsequen t decr ease in serotonin .

In contrast to the above stu dies which focu sed on th e depressed patient , CSFstudies of suicide a ttempte rs repor t significa nt reducti ons in 5-H IAA (12). Mor eover,suicide vict ims wit h definit ive affective disord ers represent a subg ro up wit h signifi­ca n tly lowered CS F levels of 5-HlAA. Among this subgrouping the greates t reductionin CSF 5-H IAA is associa te d wit h uni pola r depression a nd abse n t in bip olar d isorder.Add it ion a l st udies report a di st inct ion be tween vio len t ve rsus nonviolent suicide withthe lowest levels associa te d wit h vio lent suicide. This observation is d ifficult toin terpre t; non et heless it has been su ggest ed by on e reviewer th at " since th e se lectio nof su icide met ho d is heavily dep end ent on ava ilability a nd mod el ing, it is probablethat th e associa t ion is actually with the ser iousness of in ten t or medi cal let hali ty ofthe meth od (13). " In addit ion to th e st ud ies focu sing on met abolit e levels, five ofseven st ud ies have report ed adecrease in 5-HT or 5-H IAA levels within th e brain ofsuicide vict ims or suicide at tempter s (12) . The reduced levels were found local ized tothe bra inst em with only one st ud y reporting red uct ions in higher co rt ica l ce n ters.

THE SEROTONIN THEORY OF DEPRE SSIO N 5

The reason for th e di scr epancies between region s a re unknown. One poss ibleexpla na t ion is that br ainst em levels may reflect changes at th e level of serotonin cellbodies, wh ereas co r t ical measures indicate som e as pec t of te rmi na l activity in whichbas al levels are lower by com pa rison.

It is difficult to address th e data discrepan cies between th ose stud ies based onth e purely depressed versu s th e sui cid e victim. There are seve ra l possible, butunproven expla na t ions. First , reducti on s in br ain se ro to nin may vary in magnitudebetween th e depressive a nd suicidal states such th at low CSF levels are not detectedin th e form er, perhaps du e to th e limit ed se ns itivity of th e assay. Second, indices ofserotonin may be transitory in nature and fluctuate acco rd ing to diet , time of day, e tc .Third, th e trauma of sui cid e may be associat ed with met ab olic alterations that a reunrelated to th e et iology of th e depressive illn ess. In fact , given th e di stinctionsbetween violent ve rs us non violent method s of su icide, th e suicide even t it self may bea n important a nd undefin ed va riable in th e findings. An ad d itio na l con cern lies inint erpreting th e anatomical finding of lowered se ro to n in con ten t in the brains ofsui cid e victims. There is some crit icism that th e serotonin being assayed ma y be inlon ger-t erm storage; th erefore the fun ctional importan ce may be uncl ear ( 13).Further, an a lte rat ion of th e level of se ro to nin does not necessarily imply a cha nge inth e conce n t rat ion of avail abl e or fun cti on all y effec tive sero tonin. For exam ple, alowering of neuronal serotonin may be com pe nsa ted by a n incr ease in the number ofpost-synaptic receptors or an alt eration in the release mech anism of 5-HT fro m th eneuronal pool. In reviewing th e lit erature, stud ies do not ap pear to have addressedth 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 depression . Desp ite th ese crit icisms, th e dat a do suggest th atth ere is an overall change towards a lower se ro to nine rg ic signal in those individualsattempting suicide.

PLASMA TRYPTOPHAN

Since th e availability of tryptophan is th e rate-limiting fact or in th e syn thesis ofneuronal serotonin, there have been numerous investigations conce rn ing th e conce n­trations of plasma tryptophan in un medi cated depressed patients. This wor k is bas edon th e pr emise that a reduction in ava ilable t ryptophan , possibly becau se of excessiveperipheral metabolism , may underlie th e reducti on in 5-HT measured in the brainsof some depress ed patients (1,13) . The data conce rn ing th e levels of plasm a trypto­phan are conflict ing, although some 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 normal cont rol subject sdemon strate a positive co rre la t ion between basal levels of plasm a t ryptopha n and th e5-HT metabolite 5-HIAA wh ereas depressed patients do not ( I) . In other words, inth e depress ed patient a n increase in th e substrate for se ro tonin (trypt ophan ) is notcorrela ted with an incr ease in serotonin end-produc t (5-HIAA) in plasma. The lack ofcorre la tion may sugges t th at some depressed patients abnormally met abolize trypto­ph an in peripheral organ syste ms, th ereby altering th e C IS cont ent of serotonin .

6 JEFFERSON JOURNAL OF PSYCHIATRY

However, firm conclus ions a re com plica te d by t he fact th at t rypt opha n may besequest ered (i.e . in liver a nd mu scle tissu e) a nd th e exact origin of plas ma 5-H IAA isunknown. Several studies have shown that large doses of t ryp toph an result in lowerplasma levels of tryptophan in some depress ed versu s con t ro l subj ect s (15,16) . Thissuggests that in some cases of depression th ere is a mor e ra pid clearan ce oftryptophan as opposed to an alteration in tryptophan br eakdown . Indeed , subsequentexpe rime n ts have demonstrated that so me depressed patients have increased red celltransport of tryptophan and, wh en com pa red to normal con trols, show a great er d ropin arterial versus venous levels of trypt ophan ( 17, 18). Thus, one interest ing possib ilit ysugges ts that incr eased peripheral uptak e and clearan ce of tryp toph an cont ribu tes toth e neuronal deficien cy of serotonin in depression .

The above findings support th e se ro to nin deficien cy hypothesis of depression a ndare corrobora te d by obs ervations th at alte ra t ions in th e ava ilability of t ryp tophan, or5-HT itself, influen ce th e mood of depressed individuals (20,2 1,22). In fact , onereviewer suggests that " the mo st pervasive evide nce for th e ro le of 5-HT in mooddisorders is the effec t oflowering brain 5-HT con centration in depressed pa tien ts a ndnormals (I). " Inhibition of se ro tonin synthesi s, throu gh the ad m inist ra tion ofp-chlorophenylalanine, has been shown to rapidly induce a recu rren ce of the dep res­sive episode in patients recovering from depression ( 19) . Further, 15 of2 1 a n tide pres­san t-t re a te d depressed patients who received a t ryptophan -free d iet showed asubs ta n t ia l incr ease in depressive sym pto ms (20) . However, t his sa me parad igmimproved the symptoms of 14 of 22 untreated depressed individ ua ls. T his la tt erfinding is a direct challe nge to th e th eory th at too little serot onin underl ies th econtinuation of depressive symptoms.

One crit ical factor that limits th e usefulness of tryptophan-depl etion studiesconcerns th e fact that uptake of tryptophan is not limited to se ro to ninerg ic neu ronsand th erefore plasma tryptophan may refle ct variations in peripheral metabolismonl y. As well , depl etion of tryptophan in normal individuals has been shown to have amood-elevating effec t (21) . The differential effec t of se ro to nin depl e tion in normalversu s depressed individuals sugges ts that additional factors alte r th e manifest at ion sof serotonin depl etion within th e eNS. In other words, th e deple tion of 5-HT innormal and depressed individuals results in oppos ite mo od outco mes that implydifferences in brain processing, perhaps because of variability of recept or-med ia tedeve n ts or serotoninergic neuronal release mechanism s.

Bas ed on th e premise that a reduction in tryptophan has a mood-l owering effectin some depressed patients, administration of tryptophan ha s been attempt ed asth erapeutic treatment in depression. Unfortunately , tryptophan has rarely beenfound to eleva te mood in depressive illn ess (11 ,19). This appears to challe ng e th e ro leof serotonin in depression exclusive ly in terms of a pr ecursor deficiency. Giv en th eth erapeutic ineffectiveness of tryptophan alone, it is al so difficult to resolve th ebeneficial ac tion of some antidepressants whi ch are com mo nly th ou ght to rais eavailable se rotonin. Perhaps exogenous tryptophan requires met ab olic processingand neuronal release mechanisms that are impaired in th e depressed and which maybe bypassed by the ac t ion of antidepressants. Sp ecifically, many a n t ide pres sa n ts block

THE SEROTONIN TH EORY OF DEPRESSION 7

eit her the re-uptak e or degrad ation of endoge no us serotonin ind ependent of neuro­nal pr ocessing.

While tryptophan alone has lit t le th era peu tic effec t, tryptophan administrationdoes enha nce th e effe ct iveness of some ant idepressants (2,22). For exa m ple, theeffect iveness of MAO inhibitors is pot en t ia ted by tryptophan administration in somepa ti ents. One in te r pre ta tion is th at req uire ments for t he tryptophan a re incr ea sed inth e drug-treated sta te a nd a re un related to th e e tiology of th e illness . That bothMAO inhibitors a nd tryptophan ac t to incr ease ava ila ble serotonin supports theth eory th at se ro to nin deficien cy is a ca usal factor in some forms of depression .

There a re also numerou s rep orts th at lith ium ca rbo nat e improves th e ac t ion ofa nt idepressants in a number of pat ien ts (50%) who fa il to respond to a nt ide pres sa n ttreat ment alone (2,22). Several authors suggest that lith ium may al so ac t to incr easeth e effec tiveness of serotonin t ransmission. BrieAy, levels of neuroendocrine hor­mo nes a re used to eva luate the ac t ivity of the seroto nin system as 5-HT is known topot entiat e th e release of hormon es throu gh it s den se innerva t ion to the hypothala­m us. Usi ng this mod el , lithium has been show n to incr ease pat ient a nd rod entrespon siveness to sero to nin a nd /or tryptophan as reflec ted by an incr ea se in endo ­cri ne hormon es such as prolac tin and cor t isol (24 ,25 ,26). Although th e use ofneuroendocrine parameters does provide a window to brain function , th e pr esen ce ofa d irect casual rela tionship is unclear. For example, th e hypothalamic-pituit ary axisis modula ted by numerou s neuroact ive che mica ls a nd ph ysiologica l sta te s. Therefor e,lithium may ac t ind ependent of se ro to nin to ac t iva te t he hypothal am ic ax is orpot entiat e exci tatory medi ators (i.e. re leasing factors) of this syst em.

In sum, t he a na lysis of basal plasm a t ryp tophan levels is inconclusive to dat e.However, whe n compared to normal con trols, increases in tryptophan do not corre­la te wit h increases in plasma 5-HT metab olit e levels in som e depressed patients. Thediscr epan cy between seroto nin subs trate (tryptopha n) and metabolit e (5-HlAA) maya rise from altera tions in met ab olism or incr eased clearance, perhaps by non­neuronal organ syste ms . A reduction of tryptophan levels lowers t he mood in somedepressed patients a nd eleva tes mo od in normal con t ro ls. Converse ly, eleva t ions int ryptophan levels have little, if a ny, mood a ltering action in the treatment ofdepression . This lat ter obse rvat ion cha lle nges the explana t ions of dep ression sole ly inter ms of se rotoni n deficien cy. However, in part , many ant idepressants do appear toenhance t he actions of sero to nin alt ho ug h th e specificity of this effec t is unclear.Collec t ively, th ese studies point to an overall decrease in seroto nin as a ca usal, ye t notexclusive, factor in so me forms of depressive illn ess.

~EROTONIN tJPTAKE SITES AND RECEPTORS

An other a pproach for assessin g the se rotonin system has involved the measu re­ment of se ro tonin receptor conte nt in post-mort em brain tissu e a nd blood platelet s.The following dis cu ss ion is subdivide d into two sec t ions to cla r ify the distinctionbetween th e data pertaining to th e uptak e of sero to nin versus th at re lated to 5-HT

8 JEFFERSON JO URNAL OF PSYCHIATRY

receptors whi ch mediate th e ac t ions of se ro to nin. The first section will reviewexpe rimen ts whi ch involve th e assay of ligand binding to 5-HT uptake sites on bloodplat elet s a nd se roto nine rg ic neuron s. It is important to clar ify that neuronal seroto­nin uptak e sit es a re distribut ed on sero to nine rg ic presynapt ic terminals. Therefore, areducti on in 5-HT uptake sites refers only to a loss of serotonin storage (presynapt i­ca lly) as opposed to a direct loss in post synaptic effect. The sec ond section descri besalte rat ions in serotonin receptors which a re di stribut ed pr imarily on post syn ap ticneuron s. These receptors a re found th roug ho u t th e nervou s syste m as well as onblood platelet s, wh ere th ey medi at e th e actions of se ro to nin. T he serotonin receptor sare ca tegorized into multiple subtypes based on differential affinity for va riou sligands (5,6). Bri efly, th e evolving dat a su ggest th at seroto nin receptor s ca n beca tegorized into three major famili es: 5-H T i , 5-HT 2 a nd 5-HT 3• T he 5-HT 1 class isrep ort ed to be het erogen eous a nd subd ivide d into th e 5-HT If\ ' 18, ic and II) receptor s.The ori ginal pharmacological distinctions have been confir med by studi es th at haveshown that eac h sub type is unique on th e bas is of a na to mica l distribut ion, signa ltransduction, ph ysio logical behavior and mo lecul ar com position.

S erotonin Uptake Sites

Early stud ies report cont rove rs ia l evide nce for a reduct ion in th e number ofserotonin uptak e sit es both in plat elet s and br ains of patients wit h major depression( 12,27,28,29,30). These results are com plica te d inpart by recen t indicat ion s th atseveral of th e ligands used (e .g. im pramine) recogni ze receptors of ot he r neurotra ns­mitters a nd th erefore lack 5-HT binding spe cificity.

Expe r ime nts with more select ive ligands (e.g . pa roxe t ine) have indicat ed asignifican t reducti on in th e den sit y of 5-HT uptak e si tes both in plat elet s a nd br aintissu e of depressed patients wh en com pare d to age-matched con t rols (28) . Co ns iste n twith th e se ro to n in deficiency hypothesis, a loss of plat elet 5-HT upta ke would beexpected to result in a loss of available seroto nin to th e nervous sys te m . In th e brain ,a reducti on in 5-HT uptak e would be expecte d to increase the a mo unt of ava ilablese ro tonin in th e synaptic cle ft. Indeed , th e a n tide pressan t fluoxc tine is th ou gh t toexer t its effec ts by blocking th e sa me serotonin uptak e mech anisms. It is cu rious tha tth ese same site s a re reduced in th e depressed patient. This a lso challen ges th eproposition that too litt le se roto nin is a ca usal fact or in depression. One reviewersugg es ts that th e decr ease in se rotonin uptak e site s may reflect a com pe nsa torymechanism wh ereby a primary reduction in 5-HT induces a decr ease in serot oninuptake at se rotonine rg ic te rm ina ls in order to incr ease available 5-HT in th e synap ticcleft (27) . This interest ing pr opo sition wou ld sugges t th at , when challe nge d by areducti on in 5-HT, th e brain 's own mech anism for maint ai ning ava ilable serotoninmimi cs th e act ion of some drugs by decr easin g th e a mo un t of 5-HT avai labl e to th epost synaptic neuron. It remains to be resolved wh ethe r the noted loss of 5-HTneuronal uptake signi fies a primary deficit or a secondary com pe nsa tory response tose ro to nin loss.

T HE SEROTONIN THEORY OF DEPR ESSION

S erotonin R eceptors

9

A review of the lit erature pertaining to th e 5-HT 2 rec eptor found t hree of fourstud ies which report ed a n increase in 5-HT 2 sites in t he cor te x of sui cid e victims(3 1,32,33,34) . Similarly, one study has repor ted an increase in pr efrontal 5-HT 2

rece pto rs in th e brains of depressed patients (35) . T hese findings suppo rt thesero to nin deficien cy mod el of depression whereby a re d uct ion in serotonin results in asu bse q ue n t up-regul at ion of postsynaptic 5-HT 2 receptors. Conversely, 5-HT2 recep­tor s a re down-regul ated by a va rie ty of a n tide pressants, including MAO inhibitorsa nd 5-HT uptak e inhibitors (e.g. impramine). Furt her, 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 tose lec tive ly decr ease 5-HT 2 receptors (36,3 7) . This docs not im ply that drug treatmentdirectl y induces receptor down-regul a tion. Theoreti cally, antidepressants may in­du ce 5-HT 2 receptor down -r egul ation as a n indi rect conseq uence of incr easingavai lable se roton in.

It is unclear, how ever, wh ether intact se rotonine rg ic neu rons are necessary forth e down-regul ation of associa ted receptors (38,39). In fact , selec t ive lesions ofse 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 mine -co nta ining neuron s (e.g. basal fore brain) do , however,result in receptor up -r egul ation of 5-HT 2 receptors (39) . It is possible, th erefore, th atalte ra t ions in 5-HT 2 receptors depend on interact ion s wit h other t ran smitt er path­ways th rou gh unknown mech anism s. In fac t, a rece n t pub lication reports a reducti onin t ryos ine hydroxylase, th e rat e-limi t ing enzyme of ca te chola mine syn the sis, indepression (40) .

In cont ras t to it s an t ide pressant ac t ion, it is in terest ing to note th at elec t rocon­vulsive shoc k treatment ca uses an up-regula t ion of 5-HT2 receptors (41). Further,th is effect is se lec t ively dependent on intact sero toninergic neurons (38) . It mu st benoted , however, th at electroconvulsive shoc k th erapy has widespread effects whichmay have value indep endent of it s ac tion on th e sero toni n syst em.

Com pa re d to t he 5-HT 2 recep tor class, studies of the 5-HT, receptors are morepr eliminary. In part , th e difficulty in definin g th e ro le of 5-HT, receptors indepression reflect s th e lack of se lec t ive ligands for this receptor class. And, unl ike th e5-HT 2 receptors whi ch occupy a post synaptic position , th e 5-HT, recep tors are foundpost synapticall y and pr esynaptically on se ro to nine rg ic neu ron s (a utorece ptors) andnonserotoninergic neurons (h ereroreceptors) (5,6). Earl y stud ies whic h did notdiscriminate between 5-HT 1 receptors fail ed to find a reducti on in total receptorconte nt (31,45,46). However, se lec t ive investigation of th e 5-HT'A recep tor haveshown a sig nifica n t incr ease (30%) in receptors in th e brains of suicide victims whenco m pa re d to con t ro ls (47 ,48).

The receptor binding ex pe rime n ts demon st rate that dep ression is associatedwith a reducti on of se ro to nin uptak e sites a nd a n up-regul a t ion in some classes of5-HT receptors. The challenge is to integrat e t he independent findings int o auni fyin g hypothesis . One in te rpre tat ion would sugges t that a pr imary loss in serot o­nin itself induces com pe nsa tory alterat ions in receptor cont en t wh ereby postsynaptic

10 J EFFERSO N J O URNAL OF PSYCHIATRY

sit es up-regul ate and pr esynaptic 5-HT uptak e sites down-regul at e. The net effec t ofsuc h a dynamic would be to increase available sero to nin (via uptak e down-regul ation)wh ile a m plifying post synaptic effect ive ness (via post synapt ic up -regu lation). Aga in ,th ese even ts would signify a n adapt ive receptor resp on se to a deficiency in se ro tonin.

An a lte rn a t ive hypothesis postulates that a lte ra tions of 5-HT rece ptors repre­se n t a primary or initiating fact or , as opposed to th e com pe nsatory response. Thiswould imply that an incr ease in net seroton in transm ission med iat es depressivesym pto ms du e to excessive se ro to nin at th e synapse as well as an a mplificat ion of th esigna l a t th e post synaptic site . As a conse q ue nce, levels of sero to nin and its metabo­lit e may be expec te d to drop.

The crit ical di stincti on between th ese hypotheses is whe t he r th e pr imary defectoccurs pr e or post synaptically. The latter mod el would im ply that incr eases inseroto nin ac t ivity me d ia te depression throu gh an a ltera t ion in serotonin receptors.Severa l lin es of evide nce pr esent ed pr eviou sly con t ra d ict th e serotonin deficien cyhypothesis pr esent ed first a nd support ed th e latt er conce pt th at depression ma y beassocia te d with excess ive se roto nin tran smission and /or a ltered post synap 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 synaptic 5-HT receptors. In add it ion, th e fact that serotonin dcn erva­tion fail s to a lte r th e conce n trat ion of so me receptors suggests that up-regulationoccurs exclus ive to reductions in ava ilable se ro to nin.

One study has attempted to di stingui sh bet ween th e ro les of pr e versuspost synaptic eve n ts in a nimal mod els of de pression (5 1). Dep ression was induced byth e ad minist ra t ion of5-HT or tet rab en azin e a nd defined in terms of degree of animalacti vity. In th e "de pressive" sta te, specific uptake blockers of serotonin (e.g. Auox­et ine) were found to potentiate th e depressive sym pto ms substant ia lly (200 %). Theincr eases in depressive behavior were corre la ted with incr eas es in brai n 5-HIAA, th eprincipl e se ro to nin metabolite. In cont ras t, post synaptic blockad e of serotonin recep ­tors (e .g. methylsergid e) almost com ple te ly abo lishe d the depressive action of 5-HT.Simila rly, se ro to n in-ind uce d depression was abo lishe d by some a nt idepressants (e .g.mianserin, imipramine) which exe r t th eir effec ts by block ing se ro to nin pos tsynapti­cally. Taken together, th e data imply th at depression may be mediat ed post synap t i­ca lly a nd induced by excess transmission of se ro to nin a t th e syna pse .

T o furthe r defin e th e func t iona l roles of 5-HT 1A receptors in depress ion ,expe rime n ts have a na lyzed ph ysiological respon ses associa ted with 5-HT 1A recep toracti vation. As mentioned , neuroendocrine paramet ers a re freq ue n t ly mon itored as afun ctional indicator of serotonin. ac t ivity. Compared to human controls, dep res sedpatients show a ttenuate d hypothalamic and neuroendocrine (e .g . ACT H, cort isol)responses to select ive 5-HT 1A agonists (49,50) . This findi ng was somewhat sp ecific fordepression wh en com pa re d to individual s with bipola r d isord er or obs essive­com pulsive illn ess. Thus, alteration s of 5-HT 1A receptor a nd /or it s signa l transduc­tion pathway appear to playa specific rol e in depression. The importan ce of thisobservation is that the depression -associated changes with in th e se ro ton in systemmay ex te nd beyond alterations in 5-HT conten t a nd involve di minish ed fun ctionaleffec t iveness.

T HE SEROTONIN T HEO RY OF DEPRESSION 11

In su m m ary, there is subs tan tial evidenc e to suggest that depress ion is associ­a te d wit h a reduction in serot onin upt ak e sites as we ll as a n increase in some cla ssesof sero to n in receptors. It is not kn own whe ther the receptor alterations represent apri mary d efect or a secondary consequence of lowered se ro to nin conte nt. T heserotonin theory has yet to uneq uivocall y assign a cause versu s effec t rol e to th e man yva riables kn own to be a lte red in depression. Although th e underlyin g dynamics a reunresolved, t he lit e ra ture typi call y defi nes the serotonin syst em as being " de ficie nt"in affec t ive illn ess. This d escript ion can be int erpre ted as either a reduction inse ro tonin a nd / or a loss in receptor-mediated signal.

CONCLUSIONS AND FUTU RE DIRECTIONS

T he ro le of se ro to ni n in affect ive illn ess is based in part on th e followingpathophysio logical changes found in depression : I) decr eased brainst em 5-HT a nd / or5-H IAA, 2) increased plasma tryptophan clearance, 3) tha t re d uc tion in tryptophanind uces depressive episodes in th e depressed , 4) t hat sero tonin uptake sites down­regula te while so me classes of serotonin recepto rs up-regu la te, 5) that neuroendo­crine ac tivi ty is su brespo nsive to serotonin stim ulation and 6) that many effect ivean t ide pressan t th erapies increase sero toninergic act ivity . To dat e , no un ifyin g th eorycan accou n t for th e obse rved changes in the seroto nin system as e ithe r a cause orconseq ue nce of depression .

The involvem en t of o the r transmitt e r sys te ms in depression has not beenaddressed due to the limited sco pe of this review. It is probably inaccu ra te to assumethat depressive illness involves a se lec tive im pairment within th e serotoninergicsystem. In fac t, th e bro ader descr ip ti on of depress ion as an amine d eficien cy has beenexpa nded based on curre n t concep ts wh ich em phasize t he dependent interrelation­ship between neurotransmitter sys te ms (52,53,54,57). T his int eraction is based onwell-documented reports that mult ipl e transmitt e rs a re co- localize d wit hin the sameneuron. Moreover, the ac t ions of distinct neurotransm itt e rs a re co up led at th e levelof transducti on . For exam ple , se roto nin utili zes G pro teins, second m ess en gers andion channe ls whi ch are a lso ac tivate d by other ne uro transmitt ers and peptides. Ino the r word s, se ro to nin a lte rs neu ronal res po ns ive ness th rough its shared interactionwith o the r neurotransmitt ers/peptides. Thus, th ere is an ever increasing challe ngeto th e d escript ion of " de ficits" in terms of sing le t rans mi tter sys tems. Further,depression may represent an alte ra tio n in sig na l transduct ion suc h that serotonin issusce pt ible to dysfunction th rough it s associa t ion with th ese second messengers.

It is a lso importan t to not e t ha t changes withi n th e serotonin axis do not accountfor the widespread pa tho logical changes foun d in d ep ressive illness . For exa mple,d epression is associa te d with the following abnormaliti es: lowered Na " -K+ ATPaseac t ivity, lowered Ca t t -Mg" " AT Pase ac tivity, lowered adrene rg ic beta2 recep torac t ivity a nd increased ad re ne rgic-a lpha2 receptor number/ activity (55) . Based ont he se obse rva tions, th ere is st ro ng impl ication for th e ro le of som e abno rmality withwides pread pathogenic conseq ue nces in d ep ressive illn ess. Sim ila rily, there are few

12 J EFFERSON J OURNAL OF PSYCHIATRY

referen ces in th e lit erature to mech anism s whi ch may induce or initiat e se ro to nindysfunction in depression.

The description of depression as a se ro to nin "deficiency" has follow ed th edi recti on of basic research from a focu s on transmitter deficiencies, to impairedsignaling mechanism s. The em phas is on ce llula r fun cti on com plica tes the interpret a­tion of data as it relates to depression. For exam ple, th e level of receptor content docsnot necessa rily correla te with degree of func tion as a single receptor has been shownto a m plify signa ls through th e ac t iva tion of m ultiple G prot ein mo lecules (56 ,57).Ther efor e, a future challe ng e will be th e translation of basic resea rch to behavioralsignifica nce . Sp ecificall y, in order to underst and th e ro le of serotonin in depression ,fu tu re s tud ies a re need ed to det ermine th e in terrelation sh ip between se rotonin a ndother physiological mediators th at a re a lso known alte re d in dep ression .

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