Lithium Revisited. Roger S McIn tyre, MD, FRCPC 1, Deborah A Manc ini, MA 2, Sa gar Parikh, MD, FRCPC 3, Sid ney H Ken nedy, MD, FRCPC 4

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1 Lithium Revisited Roger S McIn tyre, MD, FRCPC 1, Deborah A Manc ini, MA 2, Sa gar Parikh, MD, FRCPC 3, Sid ney H Ken nedy, MD, FRCPC 4 Ob jec tive: To re view lithi um s utility in the treat ment of mood disorders. Method: We re viewed the safety, tol er abil ity, tera to gen ic ity, op ti mal dos ing regi mens, and mortality- lowering ef fects of lith ium. Clini cal rele vance and sci en tific rig our de ter mined which ar ti cles we se lected for re view. Re sults: Lith ium is the para dig matic treat ment for bi po lar dis or der (BD). In treating BD, op ti mal main te nance plasma lev els may be ap proxi mately 0.75 to 0.85 meq/l. Al though neph ro genic dia be tes in sip idus is not un com mon, ir re versi ble renal fail ure due to lith ium ap pears to be a rare, idio syn cratic event. Lithium- induced car dio vas cu lar tera tol ogy ap pears to be less com mon than pre vi ously thought. Op ti mal lith ium dosing may be once daily, this agent ap pears to be stow a ro bust suicide- lowering ef fect, and emerg ing data hint at neu ro trophic and neu ro pro tec tive ef fects. Con clu sion: Lith ium re mains an ef fec tive and in te gral agent in the treat ment of BD. Its ability to lower sui cide rates in per sons with BD war rants clini cal attention. (Can J Psy chia try 2001;46: ) Key Words: lithium, efficacy, augmentation, renal toxicity, teratogenicity, withdrawal, suicide, bipolar disorder, depression The ex pand ing phar ma copeia for treating bi po lar dis or der kid ney and thy roid tox ic ity as so ci ated with lith ium use re - (BD) has pro moted re ap praisal of lithi um s role in the main sig nifi cant limi ta tions (17). Fur ther, there has been treat ment of this com plex dis or der (1,2). Lithi um s calming ac cu mu lat ing evi dence for clini cal tox ic ity ; that is, the pos - ef fect in pa tients with manic de pres sion was so ro bust that it si bil ity of lithium- induced mood epi sodes emerg ing upon led Cade to specu late that this ill ness was a lithium de fi - abrupt dis con tinua tion (18). ciency dis ease (3). In the 1960s and 1970s, the more rig or ous con trolled stud ies that fol lowed early open in ves ti ga tion con - Mon crieff has re cently re kin dled ear lier criti cisms of lith ium. firmed lithium s bidi rec tional ef fi cacy against de pres sive and Ac cord ing to her in ter pre ta tion, ear lier lith ium ef fi cacy stud - manic symp toms (4,5). Nu mer ous authori ties and treat ment ies were gen er ally meth od ol ogi cally flawed and dif fi cult to guide lines from vari ous coun tries iden tify lith ium as a firstline treat ment both for classic acute mania and for pro phy - en tific data, pro moted its ac cep tance (1,19,20). in ter pret, and so cial and his tori cal factors, rather than sci - laxis (6). Apart from being a pri mary treatment for BD, lith - ium is an often- employed aug men ta tion strat egy for re sis tant non bi po lar de pres sion and a myr iad other psy chi at ric disor - ders (7 12). The past sev eral years have wit nessed in creas ing re fine ment of pre dic tors for non re sponse to acute lith ium ther apy (13 16). A par al lel gradient be tween lith ium ef fi cacy and prox im ity to the clas sic bi po lar pro to type is im pli cated. The high preva lence of adverse events and risk of long- term How should lith ium be con sid ered, given the dis crep ancy be - tween the real world of treat ment and re cent un fa vour able re analy sis of lith ium? This pa per pro vides health care pro fes - sion als with a brief lithium up date in clud ing evi dence for acute and pro phy lac tic ef fi cacy in treat ing BD, op ti mal plasma lev els, aug men ta tion, neph ro tox ic ity, tera to gen ic ity, lith ium with drawal mania, op ti mal dos ing, and an ti sui cide and neu ro trophic effects. Acute Mania Manuscript received April 1999, revised, and accepted January Staff Psychiatrist, Bipolar Clinic, Centre for Addiction and Mental Health; Assistant Professor of Psychiatry, University of Toronto, Toronto, Ontario. 2 Research Assistant, Cen tre for Addiction and Mental Health, Toronto, On - tario. 3 Head, Bipolar Clinic, Centre for Addiction and Mental Health; Associate Professor of Psychiatry, University of Toronto, Toronto, Ontario. 4 Head, Mood and Anxiety Program, University of Toronto, Toronto, On - tario. Address for correspondence: Dr RS McIn tyre, Mood Disorders Program, Clarke Division, CAMH, 250 College Street, Toronto, ON M5T 1R8 Roger_McIntyre@camh.net Ca de s initial open study of lith ium treat ment for acute ma nia (3) led to fur ther open tri als in the 1960s. Good win and Ebert re viewed these early trials (10 in number, to tal ling 413 pa - tients) (21). Over all, 81% of pa tients showed less manic symp to matol ogy. In ad di tion, 4 placebo- controlled cross over stud ies pub lished be tween 1954 and 1971 dem on strated an over all re sponse rate of 78% (22). In 1994, Bow den and oth - ers con ducted the first, and most rig or ous, con trolled trial with lith ium. Forty- nine percent of lithium- treated pa tients im proved, com pared with 48% of divalproex- treated pa tients and 25% of the pla cebo group (23). Can J Psychiatry, Vol 46, May

2 May 2001 Lithium Revisited 323 Acute re sponse la tency to lith ium is typi cally 7 to 10 days. Ad junc tive an tipsy chot ics and ben zo di azepines are of ten em - ployed to has ten re sponse. Al though an tipsy chot ics pro vide com pa ra ble an ti manic ef fi cacy, lith ium is vari ously de - scribed as of fer ing greater ef fi cacy against mood and idea - tional symp toms (24 27). Prophylaxis In 1951, Noack and Traut ner were the first to de scribe lithi - um s pro phy lac tic ef fi cacy in treating manic de pres sion (28). Good win and Ja mi son re viewed 10 placebo- controlled pro - phy lac tic stud ies of BD that ranged from 5 to 40 months du - ra tion. Over all, the lith ium re lapse rate was 34%, com pared with 81% for the pla cebo group (22). Lithi um s pro phy lac tic ef fi cacy against ma nia and de pres - sion re quires fur ther elu ci da tion. Al though con cep tu al ized by cli ni cians as of fer ing greater an ti manic ef fi cacy, 2 stud ies found lith ium to be more ef fec tive at pre vent ing hy po ma nia re cur rence and 2 studies were in con clu sive, while 4 stud ies found lithium to be equally ef fec tive against ma nia and de - pres sion (22). How do the re sults of con trolled main te nance tri als com pare with the natu ral is tic out come of BD? In 1990, Harrow and col leagues re ported the out come of 73 pa tients with ma nia 1.7 years af ter hos pi tali za tion un der rou tine clini cal con di - tions. Forty per cent of these pa tients ex pe ri enced a manic re - cur rence. The overall re cur rence rate did not dif fer be tween those taking and those not tak ing lithium (29). In a 5- year pro spec tive follow-up BD study, Kel ler and oth ers dem on strated that the 1- and 5- year cu mu la tive prob abil ity of re lapse was 48% and 81%, re spec tively (30). Pe selow and oth ers ex tended and cor robo rated these re sults, noting a pro - spec tive 5- year re cur rence risk of over 60% (31). Sev eral groups have at tempted to explain the dis crep ancy be - tween the ear lier prom is ing con trolled ef fi cacy data and more re cent un fa vour able natu ral is tic data. Over the past few years, there has been in creas ing re fine ment of lithi um s non - re sponse pre dic tors (Ta ble 1). Fur ther, some authors have de scribed lith ium discontinuation- induced re frac to ri ness, in which pa tients who ex hibit ro bust acute re sponse have dis con tin ued lith ium and sub se quently failed to re- respond when lithium was re ini - ti ated (32). Oth ers have sug gested that the prin ci pal predictor of poor out comes with lith ium is re lated to non com pli ance, es ti mated at 18% to 53% (22,23). In ad di tion, reports from some tertiary cen tres sug gest that pa tients with BD are pre - sent ing with more se vere ill ness. Frye and oth ers pro vided data from their in pa tient tertiary- referral co hort at the Na - tional In sti tute of Men tal Health. They de scribed the number of medi ca tions pa tients re ceived at dis charge over the past 25 years. Be tween 1970 and 1974, al most 75% of pa tients were Table 1. Predictors of acute nonresponse to lithium (31) able to be dis charged on mono ther apy (av er age 1.5 medi ca - tions), but this de creased to 31% from 1990 to 1994 (av er age 3 medi ca tions) (13). Ac cu mu lat ing ba sic and clini cal re - search sug gests strongly that lith ium is ef fec tive at ac com - plish ing all thera peu tic ob jec tives in a few pa tients with BD (that is, ef fec tively treat ing acute ma nia and de pres sion along with bidi rec tional pro phy laxis). Most pa tients with BD seem to re quire po lyphar ma co thera peu tic regi mens (a prac tice pat - tern com monly ob served in other chronic medi cal disorders) that may in clude lith ium. Plasma Levels The main te nance level of ap proxi mately 0.8 meq/l may be the op ti mal bal ance be tween pro phy lac tic ef fi cacy and tol er - abil ity (34). Ge len berg stud ied 94 pa tients with BD in a ran - dom ized double- blind pro spec tive trial of 2 dif fer ent doses of lith ium for main te nance ther apy: the stan dard dose, ad - justed to achieve se rum lith ium con cen tra tion of 0.8 to 1.0 mmol/l; and a low dose group achieving se rum con cen tra - tion of 0.4 to 0.6 mmol/l. Six of 47 pa tients (13%) as signed to lith ium doses pro duc ing se rum lev els in the stan dard range re lapsed, com pared with 18 of 47 (38%) in the low- dose group. The low- dose group re ported higher lev els of subthresh old symp toms and fewer adverse events. Other stud ies have had simi lar find ings (22). Augmentation Dys pho ric ma nia Rapid cycling Comor bid medi cal dis or der Po lar ity se quence Sub stance abuse Nega tive fam ily history Fre quent prior epi sodes On av er age, 50% to 70% of pa tients are de scribed as re spond - ers in an ti de pres sant tri als. This in cludes com plete and par tial re spond ers. Be tween 10% and 25% of acute re spond ers who re main on an ti de pres sants have a re cur rence within 2 years (7). Aug men ta tion there fore be comes a thera peu tic ne ces sity for up to one- half of pa tients with de pres sion. De Mon tigny added lith ium to tri cyc lic an ti de pres sants (TCAs) for 8 non re - spond ers and noted a dra matic im prove ment in 48 hours (35). Al though this dra matic im prove ment and short la tency to re - sponse has been difficult to rep li cate, placebo- controlled tri - als have con firmed the util ity of this strat egy. Aug men ta tion is suc cess ful for up to one- half of pa tients (36). There is some sug ges tion that lithium aug men ta tion may be a pref er able op tion if the in dex an ti de pres sant is par tially ef fec - tive as op posed to in ef fec tive. Lith ium aug men ta tion has been proven to be a use ful strat egy in treat ing de pres sion of

3 324 The Canadian Journal of Psychiatry Vol 46, No 4 vari able se ver ity, with and without psy chotic fea tures, in sidi - ous or acute in on set, and for sin gle and re cur rent epi sodes (36). Rouil lon and Gor wood ana lyzed the re sults of 64 lith ium aug - men ta tion stud ies, one- half of which ad dressed the is sue of re sponse la tency. For about one- half of the pa tients stud ied, the re sponse was suf fi ciently docu mented to clas sify pa tients into 1 of 3 cate go ries: 37% of evalu able pa tients re sponded within 48 hours, 36.5% re sponded within 2 days to 2 weeks, and 27.5% re sponded af ter 2 weeks. The du ra tion of treat - ment with the pri mary an ti de pres sant was not con trolled (36). The ex ist ing data suggests that the more in ten sive and pro - longed the pri mary an ti de pres sant trial, the slower the overall aug men ta tion re sponse (37). The op ti mal lith ium plasma level for an ti de pres sant aug men - ta tion re quires further de linea tion. Some studies ob serve higher plasma lev els in re spond ers than in non re spond ers, oth ers show no re la tion. Ro sen baum and oth ers point out that there is no clear plasma- response re la tion. If lith ium aug men - ta tion is ini ti ated, it is rea son able to begin at 600 mg daily, with target plasma lev els of at least 0.5mEq/L, in creas ing the level as nec es sary. In most pa tients, 4 to 6 weeks con sti tutes an ade quate lithium aug men ta tion trial. Renal Toxicity Sev eral symp to matic re nal con di tions have been at trib uted to lith ium, in clud ing dia be tes in sip idus, neph rotic syn drome, and re nal fail ure. The long- term course of these con di tions is not ade quately docu mented (17). It is es ti mated that im paired uri nary con cen trat ing ca pac ity occurs in at least 50% of pa - tients, with up to 20% ex hib it ing polyuria (av er age 24-hour urine vol ume 3 li tres). Sev eral studies with cross- sectional and pro spec tive de sign have shown lith ium ther apy to have lit tle or no ef fect on glom eru lar fil tra tion rate (GFR) (38,39). The pu ta tive mecha nism of im paired re nal con cen trat ing ca - pac ity is un known but may be due to an tidiu retic hor mone (ADH) an tago nism. Walker and oth ers iden ti fied a can di date le sion site in the dis tal neph ron felt to be re spon si ble for lith - ium re nal tox ic ity ac tion (40). Most cross- sectional and pro spec tive stud ies dem on strate that urine os mo latity re mains sta ble pro spec tively for most lithium- treated pa tients. Urine os mo lal ity wors ens sub stan - tially in a very few pa tients. More of ten af fected are those pa - tients who have re ceived higher cu mu la tive dos ing of lith ium. Bucht and Wahlin dem on strated that con cur rent use of neuro - lep tics may further lower maxi mum urine os mo lal ity, com - pared with lith ium mono ther apy (to date, how ever, pre clini cal ani mal studies have not rep li cated this clini cal ob - ser va tion) (41). A his tory of 1 or more epi sodes of lith ium in toxi ca tion is re - ported in about 30% of lithium- treated pa tients and does pre - dict de creased GFR. In a re cent re view of lith ium tox ic ity and re nal func tion, Johnson and oth ers con cluded that pro gres - sive im pair ment of glom eru lar and tu bu lar func tion af fects a small pro por tion of lithium- treated pa tients. They con cluded that de te rio rat ing re nal func tion is as so ci ated with lith ium in - toxi ca tion, higher plasma lith ium lev els, con cur rent medi ca - tion, so matic ill ness, and age rather than time on lithium (38). Over all, there is mini mal evi dence that most pa tients are at risk for pro gres sive re nal fail ure and, for a small sub group of sus cep ti ble pa tients, the risk ap pears idio syn cratic. Nev er the - less, cau tion is war ranted, and at least an nual es ti ma tions of plasma cre ati nine con cen tra tions should be car ried out to de - tect in di vidu als who may ex hibit serious re nal toxicity. Teratogenicity In the 1970s, a sig nifi cant as so cia tion was sug gested be tween ma ter nal lith ium treat ment dur ing preg nancy and Eb ste in s anom aly. This was based on data col lected from a reg is try of vol un tar ily sub mit ted cases. The rela tive risk for Eb ste in s anom aly cal cu lated from this da ta base was 400. More re - cently, Co hen and oth ers re viewed 2 co hort stud ies and 6 case- controlled studies (of which 4 dealt spe cifi cally with Eb - ste in s anom aly). In the 2 co hort stud ies, a risk ra tio of less than 3 for all con geni tal anoma lies was ob served. The risk ra - tio for car diac mal for ma tion in these stud ies was less than 7.7. No woman who took lithium was found among the casecontrol studies (42). Al though these data re quire rep li ca tion, it ap pears that tera to - genic risk during first- trimester ex po sure falls short of origi - nal es ti mates. Neo nates ex posed peri con cep tu ally to val proic acid or car ba mazepine have an ap proxi mate 1% risk of neu ral tube de fects (2). Clini cal cir cum stances that warrant lith ium ex po sure dur ing the first tri mes ter should in cor po rate in - creased fe tal moni tor ing. Lithium Withdrawal Mania Sup pes and oth ers ana lyzed 14 stud ies in volv ing 257 pa tients with bi po lar I dis or der who dis con tin ued pre vi ously suc cess - ful lithium treat ment. Fifty per cent of the new epi sodes of ill - ness oc curred within 2.5 months of treat ment dis con tinua tion. Preg nant women ex posed to lithium in the first tri mes ter do re quire closer sur veil lance and care ful ul tra - sonogra phy. For ma nia, the me dian time to re lapse was 2.5 months and for de pres sion, 6 months. Pa tients re ceived on av - er age 43 months of lithium treat ment. The mean cy cle length of 11 months (in terepi sode du ra tion) be fore lithium treatment com pared with 1.7 months af ter stop ping treat ment, a 6.8- fold dif fer ence. The risk of re cur rence, par ticu larly ma nia, was in creased fol low ing dis con tinua tion of lithium use and may ex ceed that pre dicted by the dis or der (43).

4 May 2001 Lithium Revisited 325 Dun ner and oth ers found that an av er age of 47 months elapsed be tween the first and sec ond bi po lar epi sodes, and 27 months elapsed be tween the third and fourth epi sodes (44). In the Sup pes study, a 50% overall risk of ma nia re cur ring within 3 months ex ceeds the mean epi sode in ter val of un - treated BD by ap proxi mately 2 years. Bald es sarini and oth ers stud ied 161 con secu tive adults (96 pa tients with bi po lar I, and 65 pa tients with bi po lar II, disor - der). These pa tients stopped lith ium treat ment af ter sus tained un in ter rupted treatment of at least 1 year. Eighty-five pa tients dis con tin ued lith ium abruptly (1 to 14 days), 59 gradu ally (15 to 30 days), and 17 af ter an un cer tain du ra tion. The overall me dian time to re cur rence dif fered 5- fold: 4 months for abrupt dis con tinua tion versus 20 months for grad ual. In ad di - tion, they found that the bene fit of grad ual re moval of lith ium, al though clearly pres ent in both groups, may be relatively greater in bi po lar II, com pared with bi po lar I, dis or der. Over - all, the risk of de pres sion tended to be in sig nifi cantly lower than the risk of mania, in terms of first re cur rence af ter rapid dis con tinua tion of lith ium (45). The notion of ma nia in duced by lith ium dis con tinua tion that is sug gested by this data should be kept in mind in the con text of vari ous clini cal situa tions, such as dis con tinu ing lith ium dur ing preg nancy, switching to an al ter na tive mood sta bi - lizer, and psycho edu ca tion de signed to promote treat ment com pli ance. Dosing Regimen Clini cal in ves ti ga tors have de bated the ad van tages of vari ous lith ium prepa ra tions and sched ules of ad mini stra tion. It has been noted that polyuria, a com mon side ef fect of lith ium treat ment, may be less fre quent when lithium is given as a sin - gle dose (22). Plenge and oth ers treated 2 groups of rats: the first group was given lith ium in the daily feed and the second group had the same amount of lith ium in jected intrape ri to - neally daily. Struc tural and func tional changes in the kid ney were much more pro nounced in the lithium- fed than in the in - jected rats, sug gest ing the im por tance of regu larly reaching lith ium con cen tra tions low enough to al low re nal re gen era - tive pro cesses to oc cur (46). The tu bu lar re gen era tion hy - pothe sis is, how ever, a less- than- adequate ex pla na tion be cause it has been re ported that pa tients re ceiv ing sustained- release lith ium had higher urine con cen tra tions than did pa tients re ceiv ing regu lar lithium (47). In the same pub li ca tion, re sults from a clini cal study where lith ium was given once daily showed a cor re la tion be tween mini mum se - rum lith ium con cen tra tion and urine vol ume, whereas no cor - re la tion was found be tween 12- hour dos ing and maxi mum se rum lith ium con cen tra tion and urine vol ume. The authors em pha sized the im por tance of achiev ing pe ri odi cally low lith ium lev els to avoid re nal dys func tion. In 1982, Plenge and oth ers de scribed 36 pa tients who were pre scribed lith ium in ei ther sin gle- or multiple- dose regi - mens. Re nal func tional and structural changes were most pro - nounced in pa tients re ceiv ing lith ium in di vided doses (46). In the Plenge and oth ers study, pa tients re ceiv ing mul ti ple doses re ceived a higher daily dose of lith ium. Perry and oth ers switched 8 pa tients from twice- daily to once-daily schedules. Al though the total daily dosage of lith ium was un changed, a sig nifi cant drop in urine vol ume was ob served af ter 12 days (48,49). Abra ham and oth ers moni tored renal func tion in di ces and other bio chemi cal tests af ter switching from a once-daily to a multiple- dose schedule or vice versa. They con cluded that lithium- dosing strate gies do not con sis tently af fect re nal func tion in lithium- treated pa tients (50). Clini cally, once- daily dos ing may en hance com pli ance. Single- dosing may impart a 30%-higher maxi mum plasma con cen tra tion (Cmax), when com pared with mul ti ple dos ing. Lith ium pro phy lac tic ef fi cacy ap pears un re lated to the dosing sched ule. Some pa tients are sen si tive to cog ni tive side ef fects from lithium (22). For these pa tients, per haps a sustainedrelease prepa ra tion or mul ti ple dos ing would be pref er able, al though its su pe rior cog ni tive pro file awaits con fir ma tion. For most pa tients, cli ni cians could either start with once- daily dos ing at night or with mul ti ple dos ing, with the op tion of con soli dat ing the dosing to once daily after ade quate plasma lev els are at tained. Lith ium moni tor ing should be com pleted 12 hours af ter the last dose of lith ium. Antimortality and Antisuicide Potential The risk of sui cide in pa tients with BD has been es ti mated at 15% (22). Black and oth ers re ported the Stan dard ized Mor - tal ity Ra tio (SMR) in women to be more than dou ble that of men in a group of pa tients with bi po lar de pres sion (51). Ex - cess mor tal ity in BD is due both to un natu ral and to natu ral causes. Of ex cess deaths in pa tients with BD, 17% to 42% are due to car dio vas cu lar causes (22,52). The link be tween car - dio vas cu lar dis ease and mood dis or ders has been re viewed by Mus sel man and oth ers (53). To what ex tent can ex cess mor tal ity in BD be in flu enced by long- term lithium treat ment? The In ter na tional Group for the Study of Lith ium (IG SLI) fol lowed 879 pa tients for pe ri ods rang ing from 6 months to 22 years. Over all, mor tal ity and cause- specific mor tal ity among the pa tients were com pared with the gen eral popu la tion to de ter mine SMR. The overall SMR was 1.14 (54,55). This re sult was simi lar to that ob - served by Cop pen and oth ers, who fol lowed 103 pa tients at - tend ing a lithium clinic for an av er age of 11 years and com pared mor tal ity rates with over all mor tal ity rates in the Eng lish and Welsh gen eral popu la tion. They found that lith - ium re versed any excess mor tal ity as so ci ated with re cur rent BD (56).

5 326 The Canadian Journal of Psychiatry Vol 46, No 4 Fur ther, the IG SLI study did not find ex cess car dio vas cu lar mor tal ity among the lithium- treated pa tients, specifically those treated for more than 2 years. This pro voca tive finding may be re lated to long- term sym pa thetic mecha nisms provid - ing auto nomic in ner va tion of car dio vas cu lar tone (57). The mecha nism of the po ten tial suicide- lowering effect is un - known. One mecha nism may be re lated to its an ti ag gres sive po ten tial, per haps me di ated through a se ro to ner gic mecha - nism (58). The re duced sui ci dal ity seen with lithium may not seem to be due to gen eral symp tom re duc tion. Thies- Flechtner fol lowed 378 pa tients with major uni po lar, bi po lar, or schi zoaf fec tive dis or der for 2.5 years. Pa tients with a bi po lar course were ran - dom ized to lithium or car ba mazepine, those with a uni po lar course to amitrip tyline or lith ium. There were no sui cides or at tempts in pa tients treated with lith ium, while there were 4 sui cides and 5 at tempts in pa tients treated with car ba - mazepine. In pa tients treated with amitrip tyline, there were 5 sui cides. Pa tients who bene fited from car ba mazepine still ex - hib ited sui ci dal be hav iour, and pa tients with schi zoaf fec tive dis or der treated with lithium showed no sui ci dal be hav iour, de spite lithi um s being a pro phy lac tic medi ca tion that is in fe - rior to car ba mazepine when treat ing this group (55). Other mood sta bi liz ers have yet to dem on strate re duced mortality from sui cide, com pared with other medi cal causes. It has very re cently been noted that lith ium ther apy may ex ert long- term bene fi cial ef fects in per sons with mood dis or ders by mark edly in creas ing the lev els of sev eral pu ta tive neuro - portec tive and neu ro trophic fac tors. This area is un der ac tive in ves ti ga tion and holds prom ise for clari fy ing pa tho physio - logi cal mod els of this dis ease and de vel op ing novel ra tional thera peu tic ap proaches (59). Conclusion Lith ium re mains a cor ner stone of treat ment in BD, serv ing as both an acute and a main te nance treat ment for per sons with clas sic BD. Op ti mal main te nance lithium plasma lev els in those with BD seem to be ap proxi mately 0.8 meq/l. Al - though lith ium may pre sage re nal dys func tion, re nal fail ure ap pears to be rela tively rare when other vari ables are con - trolled. Lithi um s tera to genic po ten tial ap pears lower than was es ti mated earlier. The evi dence sup port ing lithium with - drawal ma nia is pre dicted in sev eral stud ies. Thus, any plan to re move lithium treat ment should be car ried out gradu ally. Al - though there is a sug ges tion that once- daily lith ium dosing may re duce ana tomi cal and functional tox ic ity, the data re - main equivo cal. The cur rent data sug gest that lith ium has mortality- lowering and an ti sui cide ef fects. Fur ther, re cent data sug gest neu ro pro tec tive and neu ro trophic ef fects with this medi ca tion. Al though Schou has re cently ex pressed dis - ap point ment that there is no su pe rior or better- understood Clinical Implications Lithium offers unequivocal acute and prophylactic efficacy against mania and depression in classical bipolar disorder (BD). Lithium-related renal failure seems to be a rare event influenced by a disparate assortment of nonlithium variables. Extant data strongly suggest lithium s antisuicide effect, as well as its neuroprotective and neurotrophic effects. Limi ta tions The quality and quantity of data for lithium topics reviewed were highly variable. 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J Af fect Dis ord 1995;33: Sheard MH, Marini JL, Bridges CI, Wag ner E. The ef fects of lith ium on im pul sive ag gres sive be hav iour in man. Am J Psy chia try 1976;33: Husseini KM, Greg ory JM, Guang C. Lith ium upregu lates the cy to pro tec tive pro - tein bcl-2 in the cns in vivo: a role for neu ro trophic and neu ro pro tec tive ef fects in manic de pres sive ill ness. J Clin Psy chia try 2000;61 (Suppl 9):82. Résumé Évaluation du lithium Ob jec tif : Ex am iner l u til ité du lith ium dans le traite ment des trou bles de l hu meur. Méth ode : Nous avons ex aminé la sûreté, la tolé rabil ité, la té ra togé nie et les ré gimes de dos age op ti mal du lith ium ainsi que ses ef fets sur la baisse de la mor tal ité. L u til ité clin ique et la rigueur sci en ti fique ont dé ter miné le choix des ar ti cles pour l étude. Résul tats : Le lith ium est le traite ment type du trou ble bi po laire (TB). Le traite ment du TB exige des con cen tra tions plas ma tiques d en tre tien op ti mal d en vi ron 0,75 à 0,85 mé/l. Bien que le di abète in sip ide néph rogé nique soit répandu, l in suffi sance rénale irréversi ble causée par le lith ium sem ble être un évé ne ment rare, idio syn cra tique. La téra tolo gie car dio vas cu laire in duite par le lith ium semble moins répan due qu on ne l a vait cru au para vant. Le dos age op ti mal du lithi um peut être une fois par jour. Cet agent sem ble in flu encer for te ment la baisse du sui cide, et les nou velles données in diquent des ef fets neu ro tro phiques et neu ro pro tecteurs. Con clu sion : Le lith ium de meure un agent ef fi cace et inté gré du traite ment du TB. Sa ca pacité de réduire les taux de sui cide des per son nes souf frant de TB mérite une at ten tion clin ique.