The Syndrome of Antidiuretic Hormone Secretion in Psychiatric Patients Kathleen Crapanzano, M.D .

Abs tract Th e syndrome qf inapprop riate secretion qf antidiuretic hormone (S IADH) is a common medical illness which has many etiologies-some ofwhich are particular to psychiatric pat ients. Th is review will discuss the diagnosis qfSIADH and then the various etiologiesfor its development wi th emphasis on those which are more relevant to psychiat ric p atients. Future research will be directed to afu rther understanding qf this disorder, as well as to treatment opt ions to decrease the significant morbidity associated with th is condition.

" Is it only the mouth and th e belly whic h are inju red by hunger and thirst ? Men 's m inds are also injured by th em ." Mencius , Works, Book VII 372-289 Be INTR O DUCTI ON

D isor de rs of wat er m et ab olism in psychi atric patie n ts have been not ed since th e ea rly pa rt of the ce n t u ry. The res ults of ph ysiological studies of schizophreni a in th e 1930's ( 1-4) have becom e the basis for all fu t ure research in this area . In th ese ea rly st udies, th e find ings of increased u rin e volu mes in schizophreni cs were un expect ed a nd of unknown sign ifica nce, a nd some sixty years lat er, t he qu estions rai sed in th ese st ud ies remain largely unanswered . Mu ch of what has bee n publish ed in thi s area, however, has implicat ed th e role of a n tid iure tic horm one (ADH) or argin ine vasopressin (AVP ). This pape r will review th e di agn osis of SIADH and d iscuss its etiolog ies wit h e m phasis on a psychi at ric popu la ti on . The to pic of psych ogeni c po lydipsia will be tou ched upon, but th e reade r is referred to a review by IlIowsky a nd Ki rch (5) for a thorou gh dis cu ssion of t he subject. The find ing of a di sturbed wa te r regul atory syst em in t he psyc hiatric popul at ion has been la belled by suc h te rm s as self-ind uce d wat e r in toxi cat ion, com pulsive polydipsia, psych ogeni c polydipsia , a nd prim a ry polydi psia . Far from bein g a sim ple prob le m of drinkin g too m uc h, the disorders of wate r m etabolism a re th e result of permut ations of th e d elicat e bal ance of re nal , e ndocrine, cardiac and thirst syste ms of th e bod y. Fu ture work in this a rea will hop efull y elicit t he answers to th e num e rou s qu esti on s that will be rai sed in thi s pape r. 17

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PHYSIOLOGY OF ADH

Th e pathological stat es of a n t idiure t ic horm on e include both a bse nce a nd excess . Diabet es insipidus is a ph ysiological absence or lowering of ADH . In ce nt ra l di ab etes insipidus, th ere are defect s in the synt hesis a nd /or secre tion of ADH. Dep ending on th e se verity of th e di sease, pol ydipsia /polyuria fr om 3-20 lit ers in 24 hours will result. Pati ents ge ne ra lly have a preference for cold wat er, and th ere is littl e diurnal vari ation in th eir sym p to ms . With a n intact thi rst m ech a nism , pat ien ts ca n rem ain as ymptomatic, but without a n int act thirst m ech anism , life- t hrea t en ing wat er depl etion a nd hypernatremia ca n result. In nephrogen ic d iab et es insipid us, no sig nifica n t urinary conce n t ra tio n occ u rs in spite of no rm al circ u lati ng levels of antidiuretic hormone. A clinical picture sim ila r to ce n t ral di ab e t es ins ipidu s occ urs . G enerall y, hyponatremi a is th e result of an impairm ent in ren al wat er exc re t ion du e to an exce ss of ADH secr etion or some intrarenal a bno r mality in u rin e dilution (6). Hyponatremia with a d ecr ease in os m ola rity sho uld be q uest ion ed for e rror or ps eudohyponatremia. Hyponatremia associa te d wit h a n in cr eased tot a l body sodium will occur in patients with a n in cr ea se in body sodium , but a la rge r increase in body wa te r. G en erall y, th ere is a decr eas e in effec t ive blood volu me, ca use d by co nd it ions su ch as conges t ive heart failure, hepatic cirr hosis, and neph ro tic synd ro me . Hypon atremia with a decr eas ed tot al body sodiu m is ge ne ra lly a lso hyp ovole m ic, a nd can be see n in advanced ch ronic ren al in suffi cien cy, m edull ary cyst ic d isease, polycysti c kidney dis eas e, th e us e of diuretics, o r adrenal insu fficien cy. H yponat re mi a wit h clinically undetect abl e a lt e ra tions in body sodiu m sho uld a lert th e clinician for th e possibility of SIADH, but , in add ition, e mo t iona l st ress, hyp o th yr oid ism , and m ed ication effec ts should be co nside re d . The syndrom e of inapprop ria t e secr etion of antidiuretic hormon e is d efin ed by the following crite ria proposed by Ba r t te r a nd Schwartz (7): I. H yponatremia or hypoosmolarity of plasma a nd ex t race llula r fluid 2. Ren al sodium loss 3. Abs ence of clinical evide nce of fluid volum e exce ss or d epl et ion 4. O smol arity of th e urine g re a te r th an a ppro pria te for th e co nco mitant tonicit y of th e plasm a (i.e., urin e is less t han maxim all y dilu te) 5. Nor mal ren al a nd ad re nal fun ction.

A sixth crite ria is the actual m easure of ADH level s, which is now ava ilable by assay.

EVIDENCE FO R ADH DYSFUNCTION IN PSYCHIATRI C PATIENTS

There is much evide nce in th e lit eratu re that th ere a re subg ro ups of psychi a tric patients in ge ne ral a nd schizophrenic patients in particul ar th at ha ndl e wat er m et abolism defectively (1-4, 8-1 3) . In a series of studi es exa m ining th e ph ysiology of sc hizo p hre nia a pp roximate ly sixty years a go, significantly before the adve n t of psych otropic m edi ca t ion s, H oskins, Sleeper, and J ellinik (1-4) sh owed urin e output of schizo phr eni c subjects to be

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consiste nt ly double th at of normal co ntrols. Alt hough H osk ins and Sleeper origina lly concl ude d an orga nic basis to th eir find ings, o nly t h re e yea rs lat er Sleeper a nd ] ellin ek sta te "the ex pla na t ion of th e polyuria seems to reside more in th e psychi cal than in th e ph ysiological or t he bioch emical dom ain ." The finding of polyuri a in schizo ph re nia has been largely ign ored in th e lit erature until rece ntly, a nd repeat s t ud ies in th e mod ern e ra hav e sho wn sim ila r findin gs ( 14). Nume ro us case rep orts have been publish ed wh ich establish th e pr op ensit y so me psychi atric patients have to handle wa ter load s inappropriat ely ( 15- 18) . The concl usions of t hese re po r ts have inva riably be e n t ha t a state of antidiuretic hormon e excess exists wit h or wit ho u t a co nco m itant sta te of po lydips ia . Studies ac t ua lly m easuring AD H und er va rious co ndi tions have been few. Raski nd e t a l. ( 19) is th e first to have measu re d a n tid iure t ic hormon e level s in ac ute ly psych ot ic patient s. All th e subjects were non sm ok ers a nd we re off psych ot ropic m edi cation s for four weeks. The results of th e m easurem ents sugges t e leva t ions of ADH, which are post ula ted to occ ur during psychotic illn ess and produce hyponatremia in polydipsic pat ients. Vi eweg et al. (20 ,21) report a t least six patients with polydipsia , hypon at re m ia , and SIADH wh o hav e eleva te d levels of ADH on random blood eva luat ions . All th e patient s were smo ke rs, however, whi ch co m plicat es th ese findi ngs as nicotin e is a known pot ent stim ula to r of ADH rel ease (22). Go ldman e t a l. (8) re port t hree find ings as a result of th eir eva lua t ion of polydipsic sc hizo phre nic patien ts wit h wa te r load t est ing and a hyp ertoni c sal ine load - an e nhance d ren al sens it ivity to AD H, a lowe red osmotic threshold for release of ADH , and a di sturban ce in thirst regul ation . Ems ley e t al. (9) gave a sta ndard wat er load test to 23 unm edicat ed psych o tic pati ent s who did not disp lay polydipsia and found smaller urine output a nd high er minimu m u rin e osmolaliti es in th e psychiatric patients ove r th e co nt ro ls in his st udy. H oweve r, th ere is a signifi cant co rre la t io n between a nx ie ty m easure m e n ts a nd vasopressin levels. Beca use of thi s, th e a u t ho rs postulat e e mo tio nal st ress may play a ro le in th e m easured ADH elevations. Kishimot o et a l. ( 10) a lso measured AD H levels in psychiatric patients. In th e st udy, AD H is m easured in schizoph re nic pa ti en ts with and without hyp on atre mia . The a u t hors observe t hat th e se nsit ivity of ADH respon se to osmolal ity is decr eased in schizo p hre nic patients, rega rd less of th e presence of hyponatrem ia . In sum mary, Kishimot o postulat es th at th e prim a ry low se nsi t ivity of t he osmo recept ors in addition to th e renal hypersen sitivity postulat ed by Go ldman may co m bine to ca use SIAD H a nd th ereb y impair exc re t ion of free wat er. T o review, th ere have been m an y case re po rts of psychia tric pati ents with lab o rat or y findings t hat imply a s tate of AD H excess. Th e studi es that have docum en t ed t his a re few a nd cont ra d ictory. Raski nd et a l. and Vieweg e t a l. have docume nted ca ses of elevate d ADH, whereas Go ldman e t al. did not , under more co n t ro lle d co ndi tions. Emsley e t a l. found a n elevat ed resting ADH in psych oti c pa ti e n ts who were anxious, but a no rmal AD H respo nse to wat er loading. Kishimot o e t a l. fo und a decreased se nsit ivity of ADH sec ret ion, similar to th e findin gs of G oldma n e t a l. The o ne co nsiste n t find ing, howeve r, is an impairm ent of fr ee wat er

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clearance and an impairm ent of urin e dilution with or wit ho ut eleva tion of ADH in psychotic su bgrou ps.

SIADH AND ITS MULTIPLE CAUSES IN PSYCHIATRIC PATIENTS M edical Conditions

Th ere a re a multitud e of m edi cal co nd itio ns th at can cause SIADH includ ing pulmonary di seas e, malign ant tum or s (com m onl y of the lu ng and rarely of t he duodenum a nd pancr eas) , po rphyri a , disord e rs of th e ce n t ral nervous syst em (m eningitis, head injuries, brain a bscess, intracr anial tumors, e ncepha litis , subarachnoid hemorrhage) , infecti ou s di seases inclu ding pn eumon ia , tube rcul osis, and aspergillo sis, conges tive heart failu re, Addison 's di sease , hypothyr oid ism , cirrhosis of th e liver , a nd post op erative states.

M edications

Many m edi cations have been found to produce SIADH includ ing ace ta m inophe n, ch lor pro pa m ide , tolbut amide, diuretics, vinc ris tine, cyclo phosphamide, a nd clofibrat e. More ge r mane to thi s di scu ssion a re t he rep orts of psychiatric m edi cations th at cause SIADH . Th ere are 41 ca se reports of het erocyclic a ntide pressan t-induced SIADH in th e lit erature (23) . The vast maj ority a re secondary to tricyclic antidepressants, but fluo xetine is represent ed as well as monamine ox idase inhibitors. Haloperidol (24 ), thioridazin e (25,26), thi othixen e (27) , and fluph enazin e (28 ) have been report ed on th e lit era tu re to ca use SIADH . If t he antipsychotic medications do con t ribu te to the d evelopm ent of SIADH, t he mechanism of this would be difficult to und erst and . Sklar and Schrie r (29) wr ite th at traditional antipsychotic dru gs, a ll dopamin e-r eceptor a n tagon ists, sho uld su ppress psyc hic and hormonal ex pressions of th e dis ease if th e reason for SIADH in psychi at ric pat ients is exc es sive ce n t ral dopaminergic neurotransmission . T h is makes it di fficult to explain why a n tipsyc hotics co uld ca use a sta te of ADH excess . Kishimoto et al. (10) show that chronic neuroleptic ad m inist ra tion ca uses a reversibl e increase in the sensitivity of ADH sec re tion in th eir study on rabbits. H owever, thi s is not confirmed in h is human st ud ies. They co nclude that low se nsitivities of os morece ptors in t he psychiatric population a re d et ermined by unk nown ge ne tic or biologic factors rather than neuroleptic m edi cations. Ra skind et al. (30 ) fou nd t hat inj ections of a ntipsych oti c drugs do not eleva te vasopressin, exce p t throu gh th e barorece ptor re flex me chanism of hypot en sion . In fact , they found a normaliz ation of elevated ADH in two psych otic patients afte r antipsyc ho tic m edi cation treatmen t. Carbamaz epine-induced hypon at remia is we ll es tablished in t he lite ra t ure. Lahr (31) shows a 21.7% pr eval en ce of hyponatre m ia in patients tak in g carbamazepine in a st udy of e pile p tic pati ent s who were also m ent ally ret a rd ed. It is thought th at

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ca rba m a ze pine st im u la tes th e release of ADH, a nd it has been used success fully in th e treatm ent of pati ents with diabet es insipidu s. Nicotine

The ro le of nicotin e in SIAD H in th e psychi atric popula tion is a n import a n t one. Recent evid e nce sugges ts th at psychi atric pati ent s smo ke mo re th an th e ge neral public (32) for largely unknown reasons . As Husain e t al. (22) repor t, nicot ine is a pot ent st im ulus fo r both vaso press in a nd neurophysin release in so me , but not all, normal individu al s. In a n e pide m iologica l st udy designed to be tt er de fine th e cha rac te rist ics of pa ti ent s a t risk for self-ind uced wat er int ox icat ion , J ose and Eve nson (60) found th a t 69% of th ese pat ient s we re sm okers. Blum (34) rep ort s a cas e ofS IAD H in a psychi atric pa t ie nt wit h a long histo ry of polydipsia , smo ki ng , schizo p hre nia, a nd treatm ent with neu rol e pt ics. With ad lib wat er intake a nd no ciga r ett es, this pati ent wa s a ble to mai ntain his normal sodi u m level s; limit ed smo king ca us ed a mod est d rop in hi s sod ium , an d ad lib smoking resul t ed in hyp on atremia. Sim ila rly, C h in (35) rep ort s a case of a co m pulsive water d rink e r with th e syndro m e of in approp ri a te secret ion of AD H wh o a lso had a normal wa ter loading t est wit h no ciga re ttes, bu t whose exc re t io n dropped to 26% du ring a repeat t est wit h th e ad m inist rat ion of 15 ciga re ttes. Us ing two schizophrenic pat ie nt s wit h a hi st ory of wat er intoxi cati on a nd six norm al con trols, Allo n e t a l. (36) postu la te th at ciga re t te use may con t ribu t e to hyponatremia , since wat er exc re t ion was impaired in both groups aft e r nicotine usc. [ico t ine has a very pot ent effec t o n t he rel ease of ADH fr om th e pos terior pit uitary in norma l, as well as psychi a tric pat ien ts. While it is no t necessa ry for a pat ie nt to be a cigare tte smoke r (or tobacco ingestor) to d evelop hypon a t re m ia , the use of ciga re ttes in a susce pt ible pa ti e nt , defi ned as a psychi a tric pa ti e nt wit h impaired wat er excre to ry m ech anisms, m ay be su fficie n t to induce hypona t re m ia a nd its conse q ue nce s. Psychosis and IVfective Disorders

The re has bee n a report ed associa t io n bet wee n affect ive di sord ers a nd SIADH

( 11- 13). H owever, in t he six re po rt ed ca se s, five of t he pat ients were psych o t ic, a nd at least th ree we re polyd ipsic. This ca lls into qu esti on wh e t her th e SIAD H is secondary to so me aspec t of t he psych oti c process o r th e affective d iso rd er it self. T he re have bee n qu it e a few case reports as socia t ing psych osis a nd SIAD H. T argow la (37) not es ac u te psychoti c pati ent s wit h wat e r re te ntion th a t improved with improvem ent in th eir psychosis. Multiple researc hers ( 17,18,22,38-43) report cases of SIAD H in psychot ic pat ients, sugges ting a link bet ween th e two entities. D ubovsky e t al. (44) present a n int erest in g case of a person whose SIADH appeared a nd remitt ed in conj u nc tion wit h his psychotic sym p to ms . She n e t a l. (45) an d J ones (46) pr opose t hat inst ead of a ca use a nd effec t relat ion ship bet ween psychosis and SIAD H , t hat SIADH is a dopa mi ne rgic supe rse ns it ivity phe no me non ind uced by

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neuroleptic exposure a nd / or neuroleptic withdrawal. Although t hi s is a n in teresting hypothesis worthy of evalua tion, th e ph ysiologi cal st ud ies of schizophreni c pati en ts ( 1-4) cond uc te d prior to th e adve n t of antipsychotic m edi cat ions weak e n th is a rg u me nt. In add ition, Barahal 's (47) publi sh ed case of wa te r int oxi ca ti on was pr ior to th e use of m edi cation s. In con t ras t to th e a bove, Fowle r et al. (4 1) prese n t t he idea th a t nonsp ecific st ress ca n increase ADH release in a n imals a nd m ay be ope rat ive in psychotic illn ess; thi s th eory was support ed by Emsley et a l. (9) . "Psychogenic Polydipsia "

The evide nce a t thi s poin t does not suppo r t psych oge nic polydipsia as a ca use of SIADH, but ra t her as a coexisting cond ition. This population of psych iatric pat ien ts wh o com prise som ew he re bet ween 6.6% a nd 17.5% of psych ia tric pat ie nt s (48,49) has shown a d efect in fr ee wat er clearance a nd urina ry conce n trat ing a bility th at meet s th e crite ria for SIADH, but whi ch alon e are insufficient to acco u n t for th e seve re episodes of hyponatremia and hypoo sm olarity th at th ese patients peri odi call y suffe r. In addition, psych ogeni c polydipsic pati ents a re a het e roge nous gro up with so me ex hibiting polydipsia without episod es of hypon atremia , some having lowe r threshold for ADH release (rese t os mos ta t) , a nd so me becoming int ermitt en tly hypon at re mic. It is uncl ear wh ethe r th es e diffe rent clinical pr esent ation s of polydipsic patient s a re part of th e natural history of th e wat er regul atory di sturbance, whe t her t hese are different clinical expre ssions of th e sam e illn ess, or wh eth er th ese a re different cond itions all to gether. Raskind e t al. (30) propose a unit a ry di st u rb ance of lim bic syste m fun cti on to produce th e clinical picture of psych osis, po lydipsia, a nd SIADH . H e not es th e close relation ship between th e limbic system com pone n ts involved in beh avior, ce n t ral regu la to ry si tes for wat er drinking beh aviors, a nd t he nuclei responsibl e for th e release of ADH .

ECT In th e va rIO US case rep ort s of SIADH a nd polydipsia , ECT is a common trea t m e n t m od ality (50-52). The role th at ECT may play in t he develop men t of SIADH is un clear, however. Finl ayson et a l. (52) repo r t a case of hypona t re m ia after EC T a nd postulat e th a t th e hypon a tremia is seco nda ry to polydipsia . Howeve r, a no t he r possibility is that th e seizu re activity d eregulat es th e thi rs t m echanism s a nd stim ula tes th e release of ADH (53) , ca us ing, in co m binat ion , t he clinical pictu re of SIADH wit h polydipsia a nd res ultan t hypon atremi a. DISC USSIO N

In eva lua ting a pati en t wit h possibl e SIADH , t he d iagnosis mu st firs t be es ta blishe d acco rd ing to th e crite ria of Bartte r a nd Schwart z (7) d iscussed earlier. Once th e di agn osis is esta blishe d, th e e tiology for th e disorde r mus t be so ug h t. The work up shou ld includ e a t horou gh history a nd physica l exam ina tion, blood work to

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includ e blood che m ist ry, co m ple te blood co un t, liver fun cti on t est s, t hyroid fun cti on test s, and an AM co r t isol. A ches t X-ray, as well as a CT scan of t he head to rul e out central nervous syst em pathology are nec essary. The next ste p would be to inv estigat e th e us e of nicotin e a nd a ny m edi cations th e pati ent is takin g. If a medication is implicat ed in th e ca usa t ion of SIADH, it sho uld be rech all e nged to t he pati ent to ass ure th at it is resp onsibl e for th e clinical pr esent ation of th e pati ent. A con sult ant could be ca lle d at this point for furth er suggestions in eva lua t ion a nd for ass istance with treatment. Only aft er th e above diagnostic workup ca n t he pati en t 's SIADH be attribut ed to his psychiatric cond itio n. SIADH is co m mo n in a psychi atric population for a number of reason s that have been discussed. Becaus e of th e seriou s com plica t io ns th at ca n develop from SIADH if it is unrecognized (su ch as hyponatremi a, se izu res, co m a, a nd d eath), t his condit ion sho uld be aggressive ly eva lua te d and treat ed . For a review of th e trea tm ent of wat er m et abolism disorders in psychi atric pati ents, th e read er is referred to a recen t review by Goldman on th e subj ect (54) . Th e area of wat er m et ab olic disorders in psychi atric pa ti en ts is on e with num erous avenu es for research availabl e. As seen in this rev iew, m uch of what is publish ed in this a rea is purely a necdo tal a nd based on cas e repor ts. Those studies whi ch have att empt ed to furth er eva lua te the probl em oft en re port result s on fewe r th an ten patients. One area in particul ar th at need s to be ex plored in d e tail is a thorou gh scru tiny of all param et ers involved in wat er m e tab olism , no t just ADH m easurem ents. The effec ts of lon g t erm pol ydipsia have on ly begun to be ex plored (54), and furth er studi es need to be initiat ed , particul arly explor ing th c cffects on the kidney. To that e nd, studies eva lua t ing th e natural hist ory of th e illn ess should be att empt ed. Finall y, t reat me n t opt ions to be explore d includ e a ng iote nsin-converting e nzy me inhibitors, whi ch d ecr ease a ng iote nsi n II st im ula t ed thirst, br om ocrip tine, a dopamine receptor a go nist, (because of its effec t on d ecr easin g thirst) , an d calcium channe l blo ckers to d ecr ease ca lciu m influx and subse q ue n t ADH rel ease (29) .

REFERENCE S I. Hoskins RG : Schizophr e nia from the physiological po int of view. Ann Int Med 7:445-456, 1933 2. Hoskin s RG , Slee pe r F: Organi c fun cti on s in schizoph re nia. Arch Ne ur Psyc 30: 123-140, 1933 3. Slee pe r FH : Investi gati on of polyuri a in schizophr enia. Am J Psyc 9 1: I0 19- 103 1, 1935 4. Slee pe r F, J ellin ek E: A comparat ive physiologic, psycho logic , and psychi atric study of polyuri c a nd nonpolyu ric sch izophrenic pati ent s.J Nerv Men t Dis 83:557-563, 1936 5. Illowsky B, Kir ch D: Polydip sia a nd hypon atremi a in psychi atric pa tients . Am J Psyc 145:675-683,1988 6. Ber! T , And erson R, McDon al d K, et a l: C lin ica l diso rders of wat er metabolism . Kid ney Int 10:11 7-1 32,1 976 7. Bartt er FC , Schwartz WB : The syndrome of inapp ropriat e secret ion of antidiureti c horm on e. AmJ Med 42:790-806,1 967

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