10.1192/bjp.171.2.113Access the most recent version at doi: 1997 171: 113-119 The British Journal of Psychiatry

  J Moncrieff  

Lithium: evidence reconsidered  

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prophylaxis of bipolar disorder (BPD) andaugmentation of treatment for acute depres.sion in resistant cases. It is also suggested forthe control of aggressive or agitated behaviour. There is extensive research on its use asan antidepressantand as a prophylacticin

unipolar disorder (UPD), but it is generallyaccepted that there are more effective alternatives in these situations (Gelder eta!, 1989).

This review examines the evidence for the

main current recommendations for lithiumuse in psychiatry and briefly summarises theliterature on its adverse consequences, in anattempt to develop an overall evaluation ofits potential role based on available evidence.An introductionto the historyof lithium isgiven because it is suggested that in both the19th and 20th centuries the social context inwhich lithium emerged, rather than the

quality of the scientific evidence, was decisivein determining its adoption as a treatment.

HISTORYOF LITHIUMTREATMENT

The history of lithium treatment is thoroughly documented by Johnson (1984). Theelement was first described in 1818 ataround the same period that medical practitioners were engaged in the struggle forprofessional recognition (Desmond, 1989).As the developing profession became increasingly united and confident, it was ableto propagate new explanatory theories withgreater credibility than before. When uricacid was discovered to be the cause of gout,its role was elaborated to explain a multitude

of conditions, known as the the ‘¿�uricaciddiathesis'. This included ideas about theaetiology of mood disorders, and terms suchas ‘¿�goutymania' were employed. When itwas suggested that lithium could dissolveuric acid stones, it began to be used as atreatment for gout and other uric aciddiathesis conditions, including depression(Haig, 1888). The popular imagination wasalso impressed by this new medical theory,and proprietary medications and fashionablemineral spas were marketed as containinglithium and other recommended antidotes touric acid. The utility of lithium began to be

questioned when experiments failed to confirm that it dissolved uric acid stones, and its

tSeeCookson,j.‘¿�Lithium:balancingrisksandbenefits',pp. 120-124,thisissue.

use also declined along with the influence ofthe uric acid diathesis theory. Vestiges of thetheory remained, however, and lithiumcontinued to be available for gout and‘¿�stones'in non-prescription preparationsuntil the 1970s in the UK.

The first era of lithium use in medicineset a precedent which facilitated its introduction into psychiatric practice. In a concrete sense, it also meant that supplies oflithium were readily available in hospitalpharmacies for use and experimentation inmania when this was first suggested. JohnCade, who discovered that lithium inducedlethargy in guinea pigs and went on toinvestigate its use in psychiatric patients,also experimented with strontium and cerium in psychiatric disorder, but this line of

research never became popular.In 1949 Cade published a report of 10

manic patients who had improved dramatically with oral lithium treatment (Cade,1949). His clinical notes, however, recordedlittle distinction between therapeutic andtoxic effects, and the published report failedto mention that there were three cases ofsevere toxicity with one death and one patientwho refused to comply. Johnson (1984)concluded that if the full facts of the caseshad been presented, the article would havereceived little attention. It has also been notedthat the original observations on animalswere likely to have been the result of lithiumtoxicity, as high doses were involved (Johnson, 1984; Price & Heninger, 1994).

However, psychiatry was ripe for theintroduction of new pharmacotherapies.Other areas of medicine had been invigorated by the development of antibiotics, andwith the discovery of chlorpromazine in thel9SOs, psychiatry also entered a phase ofbiologically-oriented therapeutic optimism.

MODERN INDICATIONS FORLITHIUM TREATMENT

Atpresent,thethreemainrecommendedusesof lithium are the treatment of acute mania,

Treatment of acute mania

Cade's research was enthusiastically received in Denmark, where the first clinicaltrial was conducted (Schou et a!, 1954).Placebo-controlled trials are listed in Table1. A review of the first three found them tobe methodologically unreliable (Shull &Sapira, 1970). Schou et a! (1954) includedan unknown number of non-randomised,openly treated patients in the analysis andused vague and subjective outcome measures without the use of statistics. Maggs(1963) selected only ‘¿�cooperative'patientsand analysed and reported only 18 treatment successes. The small trial by Goodwinet a! (1969) did not userandomisation,didnot report selection procedures and relied onsubjective conclusions without presentingdata or statistics. The crossover trial byStokes et a! (1971), which used alternativepatient allocation, was marred by the use ofsupplementary medication without a recordof how this relatedto experimentaltreatment. Lithium was significantly more effective than placebo during the first twoweek period but during the last two weeksthe difference was not significant. Fivepatients had toxic reactions (one severe),and this may have accounted for the initialsuperiority of lithium by inducing lethargy.The authors concluded that the superioreffect of lithium did not outweigh itsdisadvantages.

Interpretation of the results of the 21 -dayrandomised controlled trial (RCT) by Bowden et a! (1994) is also complicated byomission of details of the supplementarymedication required. Despite calculationsthat estimatedthat the study had 95%power to detect differences between lithiumand placebo, the lithium group was significantly better than placebo on only one of thefour measurement days. The proportions ofpremature terminations were also similar inthe lithium and the placebo groups, at 61and 75%, respectively (or 56 and 61%,excluding terminations due to recovery).

Lithium: evidence reconsideredt

JOANNA MONCRIEFF

TrialnDesignTreatmentcomparisonsSchou

et a!, I95438Crossover (random allocation for

some patients)Li

v.placeboMaggs,

96328Random crossoverLi v.placeboGoodwin

eta!, l9698Non-random crossoverLi v.placeboStokes

eta!,I97I28Non-random crossoverLi v.placeboJohnson

et a!, 968, 197142RCTLi v.CPZSpringeta!,

l97030RCTLiv.CPZPlatman,l97030RCTLiv.CPZPrien

et a!, 972255RCTLi v.CPZTakahashi

et a!, I97580RCTLi v.CPZShopsin

et a!, I97530RCTLi v.CPZ v.HALGarfinkeleta!,

9802lRCTLi v.HAL v.HAL+LiBraden

eta!, 98278RCT (mixedsampleofpsychoticadmissions)Li

v.CPZBowden

eta!, 99476RCTLi v. placebo v.SV

,,u@C@I!FF

ance, reduce the feasibility of lithium treatment for mania, but it is still recommendedas the principal element in the managementof this condition by some authors (Cook &Winokur, 1990).

Much of the original appeal of lithiumwas its claimed specificity for affectivepsychosis. This helped to validate psychiatric classification at a time (in the 1960s)when the concept of mental illness andpsychiatric diagnosis was under attack fromsociological theories of labelling anddeviance and the ‘¿�anti-psychiatry'movement. However, as the efficacy of lithiumin mania is unproved, its relative specificityfor this condition cannot be surmised. It hasalso been claimed that lithium has a selectiveeffect on the affective symptoms of maniawhen compared with neuroleptics (Goodwin & Zis, 1979) but the largest trial foundno such effect (Prien et a!, 1972) andevidence from the other trials is confusingand inconclusive.

Table I Trialscomparinglithiumwith placeboor neurolepticsfor treatment of acute mania

RCT,ranclomisedcontrolled trial (parallelgroup design);Li,lithium;CPZ, chlorpromazine; HAL,haloperidol;SV,sodiumvalproate.

Prophylaxis of bipolar disorder

Over the past 25 years the most uncontroversial indication for lithium has been theprophylaxis of bipolar disorder. A recentreview re-examined nine placebo-controlledRCTs of lithium prophylaxis and uncoveredsome serious methodological problems(Moncrieff, 1995). Five of the nine studiesused a discontinuation design, which isproblematic in view of the mounting cvidence, discussed below, suggesting thatlithium withdrawal precipitates mama. Recurrence of illness after discontinuation doesnot necessarily provide evidence of efficacy,as it is possible that the process of drugwithdrawal may itself have a negativeimpact on the course of the disorder.Psychotic episodes have also been noted inpredisposed individuals after withdrawal ofbenzodiazepines (Tyrer et a!, 1983). Theonly large prospective trial, by Prien Ct a!(1973a), had two important methodological

weaknesses. First, it was only single-blind,

and treating physicians had instructions toalter the dose of lithium according tosymptomatology, which was done for upto 28% of patients in the lithium group,thereby diminishing the comparability of thegroups; trials that are not double-blind havebeen found to yield significantly highertreatment effects in other areas of medicine(Schultz et a!, 1995). Second, all patientswere stabilised on lithium during the indexhospital admission prior to randomisation,creating the possibility that withdrawal

Table 1 also shows RCTs that havecompared lithium and neuroleptics in thetreatment of acute mania. Although earliersmaller studies reported that lithium wasequal or superior to neuroleptics, all sufferedfrom methodological problems such as prolonged wash-out periods prior to randomisation, which are likely to have excluded themost disturbed patients, failure to do intention-to-treat analyses and selective reportingor highlighting of outcomes favourable tolithium (Johnson et a!, 1968; Spring et a!,1970; Platman, 1970; Shopsin et a!, 1975).The large study by Prien et a! (1972) foundthat chlorpromazine was markedly superiorto lithium for highly active manic patientsalthough it was equally effective in the mildlyactive. The authors emphasised that highlydisturbed patients in the lithium group wereextremely difficult to manage and manyrequired seclusion to keep them in the trial.The mean daily dose was 1.8 mg chiorpromazine. Another study, with a mixed group of

admissions for manic and schizophrenicpsychoses, found the same picture, with meandoses of 1.4 g lithium and 682 mg chlorpromazine (Braden et a!, 1982). Between 21 and68% ofthe sample were categorised as havingaffective psychoses according to variousdiagnostic systems, but diagnosis did notpredict drug response. The effect of lithiummay have been overestimated, as manyeligible patients were not included becauseof a need for emergency sedation, and duringthe study patients on lithium were prescribed

additional sedatives (Braden et a!, 1982). Asmall study using haloperidol found it to besignificantly superior to lithium in a three

week trial, with patients on lithium showingno overall improvement (Garfinkel et a!,1980). Opposite findings emerged from thetrial by Takahashi et a! (1975), with 32% ofpatients improving on lithium compared withonly 12% on chiorpromazine. However, aftera long wash-out period the majority of thesample had only moderate symptoms, and themean dose of chlorpromazine was only250mgperdaycomparedwith1.1glithium.

Several trials have compared lithiumwith the anticonvulsants carbamazepineand sodium valproate (Lerer et a!, 1987;Small et a!, 1991; Freeman et a!, 1992;Bowden et a!, 1994). All these studies usedsupplementary benzodiazepines or barbiturates for sedation and those studies thatprovided details revealed that substantialdoses were used (Small et a!, 1991; Freemanet a!, 1992). In the smalleststudy, lithiumwas superior to sodium valproate on somemeasures (Freeman et a!, 1992) but in theothers no differences were found.

Overall therefore, the evidence thatlithium is superior to placebo in the treatment of acute mania is not compelling.Results of comparisons with other drugs areconflicting, but most studies suggest thatlithium is at least inferior to neuroleptics inthe treatment of severe mania. Practicalreasons, such as the frequent need for rapidparenteral sedation and likely non-compli

114

TrialnLength of

follow-upComparisongroupsOutcome

in lithium-treatedpatientsAhlforseta!,

l98l33l6 months

(mean)Liv. flupenthixolMean episodesper patient-year:0.6Quitkin

eta!,759 monthsLi v.Li+IM27% relapsed, 21%completed trialandl98l(mean)remainedwellPrien

eta!, 984I 724 monthsLi V.Li+lM V.IM25% relapsed into depression and 27% into

mania; I8—22%completed trial and

remainedwellPlacidi

et a!, 19868336 monthsLi v.CA20% relapsed, 34% completedtrialLuznat

et a!, 198840l2 monthsLi v.CA50% relapsed, 25% had ‘¿�satisfactory'

outcome.Coxhead

et a!,312 monthsLi v.CA53%relapsedI992Li,

lithium; IM, imipramine:CA, carbamazepine.

LITHIUM: EVIDENCE RECONSIDERED

induced mania occurred in some placebogroup patients. This possible explanation

would be in accordance with the findingthat the relapse rate in the placebo groupduring the study was higher than during thecorresponding period before the trial,although the difference was not significant(67% of placebo subjects had a severerelapse during the trial versus 54% before).A further small prospective trial was subjectto the same methodological problems (Prienet a!, 1973b) and the otherswere alsosmalland had other weaknesses. Small studiesmust be interpreted with caution because ofpossible publication bias. This was thoughtto be the explanation of the misleadingresults produced by a meta-analysis of smalltrials of magnesium treatment in myocardialinfarction (Yusuf & Flather, 1995).

Subsequent trials, which are listed inTable 2, have compared lithium with otherdrugs or combinations of drugs. These trialsare instructive because lithium-treatedgroups performed less well than in placebocontrolled trials. Some of these trials alsoexcluded early treatment failures by selectingpatients who had been stable on lithium for aperiod of time before randomisation (Quitkin et a!, 1981; Prien et a!, 1984). A re

analysis of the data from the largest study byPrien et a! (1984), done with the authors'agreement, found that only 18% of thelithium group, 22% of the combined groupand 9% of the imipramine group completedthe trial and remained well (Shapiro et a!,1989). One comparison of lithium withcarbamazepine in patients with bipolar andschizoaffective disorder found lower relapserates as defined by re-admission, but 78%and 44% of the lithium group requiredadditional treatment with neuroleptic andantidepressant medication, respectively (Placidi et a!, 1986). Loss to follow-up was alsohigh, with no indication about how this wasmanaged in the analysis. Overall, therefore,evidence for the superiority of lithium overplacebo in the prophylaxis of bipolar disorder is inconclusive, and results in latercomparative studies have been disappointing.

Research on the natural history ofbipolar disorder raises further doubts aboutthe impact of lithium. Lack of efficacy wasone explanation suggested for the increasedfrequency of admissions for mania inrelation to schizophrenia that was found tooccur between 1970 and 1985 (Symonds &Williams, 1981; Dickson & Kendell, 1986).In the ensuing correspondence it was sug.gested that this observation was due tochanging patterns of diagnosis, which has

Table 2 Comparative randomised controlled trials oflithium prophylaxis in bipolar disorder

been recognised in the USA (Schou, 1986;Grof, 1987), but Kendell & Dickson (1987)found no evidence to support this theory inScotland.

Table 3 shows the studies that provideinformation on the frequency of relapses inbipolar disorder. Comparison of studies ishazardous because of varying diagnosticpractices and definitions of relapse. Forexample, Lundquist (1945) found that only21 % of first admissions for mania had asubsequent attack in a period of 23 years,suggesting a far broader definition of mania

than the modern one. However, in thesubset of patients who had a second episode,50% relapsed in three years. A similarrelapse rate was found in a retrospectivecase note study (Winokur, 1975). In amodern study of the history of the disorderprior to lithium treatment, there was a meanrate of 0.54 episodes per patient-year,meaning that on average, patients experienced one episode every two years (Dunneret a!, 1979). When started on long-term

lithium treatment, 46% of this sample hadrelapses in a two-year period. In a famousfollow-up study of admissions between1959 and 1963, in a clinic in which studiesof lithium were also conducted, bipolarpatients had an average of 10 episodes inapproximately 20 years and the mean cyclelength was 2.8 years (Angst, 1986). Therewas no marked difference in the course ofbipolar I and bipolar II disorder in thisstudy. Coryell et a! (1989) also found littledifference in overall outcome, but patientswith bipolar I disorder were more likely tohave a manic or hypomanic relapse, with70% of them having such a relapse within

the first two years. An earlier paper specifiedthat 78% of this sample had taken lithiumfor at least some of the initial follow-upperiod (Coryell et a!, 1987). Direct comparisons of patients prescribed and not prescribed lithium have found no difference inrelapse rate and no indication of otherconfounding factors which might concealthe superiority of lithium (Marker & Mander, 1989; Harrow et a!, 1990). A studywith patients from a lithium clinic who hadbeen on lithium for at least one year, with amean of eight years, found a high rate ofrelapses which were mostly manic in oneyear of observation (O'Connell et a!, 1991).

In summary, follow-up studies suggestthat the natural history of bipolar disorderhas not improved since the introduction oflithium, and patients who are taking lithiumappear to be little better than those who arenot. Some authors have suggested that noncompliance and underprescribing might cxplain these disappointing findings (Guscott& Taylor, 1994) but another explanationcould be the ineffectiveness of the drugitself.

Lithium augmentation

Although lithium is rarely used as atreatment for acute depression, it hasbecome common to add it to antidepressantregimes in resistant cases. A meta-analysisof five RCTs of lithium augmentationconcluded that there was a small butsignificant effect when compared withplacebo (Austin et a!, 1991). However,the trials reviewed were short-term and

TrialnDesignSubjectsPeriodofobservationOutcomeLundquist,

194536RetrospectiveSubjects with 2 episodes ofmania3 years50%relapsedWinokur,

1975100RetrospectiveManic probands admitted l934—l944Mean 3,2 years57% men relapsed

42%womenrelapsedDunneret a!, 197696ProspectivePatients on long-term lithium attending a

lithium clinic2

years46%relapsedDunner

et a!, I979I 40RetrospectivePatients from a lithium clinic prior to

starting lithium5

years after admission

mean I I .4 yearsmean

2,2 relapses

0.54 episodes/patient

yearAngst,

986215 (BP I

& II)ProspectiveAdmissions1959—63Mean 20 yearsMedian 10episodesCoryell

et a!, 1989I l7 (BP I

& II)ProspectiveAdmissionsfor depression (most subjects on

lithiumforsometime)2

years

Syears70—80%

relapsed

90—95%relapsedMarker

& Mander, I98983RetrospectiveRecurrent affective disorder

(41 on lithium 42 noton lithium)2

years60% relapse bothgroupsHarrow

et a!, I99073ProspectiveAdmissions for maniaMean I.7 years40% manicrelapseO'Connell

eta!,1991248ProspectiveAttenders at lithium clinic (all on lithium

> I year)I

year44% relapsed

MONCRIEFF

Table 3 Relapsefrequency in bipolar disorder

BPI disorderisclassicalbipolardisorderwith severeepisodesofmansaanddepressionandat leastone episodeofmania requiringadmission.BPIIdisorderisdefinedbymilderepisodesofmaniawhichhavenot requiredadmission.

small, admitting the possibility of publication bias. The largest and longest of them,which followed up 34 patients for threeweeks, was negative (Stein & Bernadt,1988). Of the two trials that producedstatistically significant results favouringlithium, one produced an effect of onlytwo points average decrease in a 1S-pointnurses' rating scale in a sample of 15(Heninger et a!, 1983). The other trial bySchopf et a! (1989), with 27 subjects, founda significant difference between lithium andplacebo groups in one week of treatment.Subsequently, the placebo group was prescribed lithium but continued to have asignificantly poorer outcome. A more recenttrial of lithium augmentation, with a total of61 subjects and a six-week follow-up, wasnegative with respect to the overall scores onthe Hamilton Rating Scale for Depression,and response rates as defined a priori(Katona et a!, 1995). In a post hoc analysiswith response re-defined, significant differences were obtained in favour of lithium,but there is potential for bias in this sort ofprocedure and it should not thereforeobscure the essentially negative findings.

Some of these trials reported low cornpliance rates (Stein & Bernadt, 1988;Katona et a!, 1995). Although compliantsubjects did relatively well, this cannot beattributed with certainty to the effect of thedrug, as compliant behaviour has been

associated with better outcome in a varietyof conditions (Fuller et a!, 1986; O'Sullivaneta!, 1991).

Genuinely double-blind studies oflithium are difficult to conduct becauseside-effects may reveal the identity of mcdication to patients and investigators, and thiswas noted in the trial by Katona et a! (1995)(Edwards et a!, 1994). This introduces thepossibility of an ‘¿�amplifiedplacebo effect' inpatients (Thomson, 1982) and measurementbias by investigators. This may partly explainthe persistingdifferentialin outcomeperformance between lithium and placebo groupsafter the end of one of the trials (Schopf et a!,1989). The negative findings of the larger

trials are even more remarkable in view ofthese potential biases in favour of lithium.

ADVERSE EFFECTS OFLITHIUM

Withdrawal-induced mania

Evidence that mania is precipitated bywithdrawal of lithium is now substantial.Suppes et a! (1991) reviewed the literatureand found that 50% of new illness episodesoccurred within 10 weeks of discontinuationof lithium and that mania was more likelythan depression. In 16 patients in whom aprevious cycle length was known, the cyclelength after lithium withdrawal was significantly shorter than before lithium was

started. Mander (1986) retrospectively cornpared 29 patients who had discontinuedlithium while asymptomatic with 50 patients who were not on lithium, and found asignificantly higher relapse rate in theformer. In the discontinuation study oflithium prophylaxis by Cundall et a!(1972)therewasa higherratioof manictodepressive episodes after lithium discontinuation (3.5:1) than before (0.67:1) and theauthors concluded that withdrawal-inducedmania was a possible explanation of theirfindings. Goodwin (1994) described howlithium discontinuation could be conceptualised as bringing forward the risk of mania,

and even assuming efficacy, treatment waslikely to confer a net disadvantage onpatients treated for less than three yearscontinuously because of this phenomenon.

Not all authors accept this hypothesis.In an earlier review Sashidharan & McGuire(1983)concludedthattherewasnoevidenceof an increased risk of relapse within sixweeks of discontinuation, but fewer datawere available to them than to later reviewers, and it now appears that theincreased risk associated with discontinuation persists for longer than a few weeks.Schou (1993) presented data which showedthat the number of relapses was not greaterone year after discontinuation than it hadbeen in the year before lithium treatmentwas commenced. However, since lithium is

II'

LITHIUM: EVIDENCE RECONSIDERED

likely to be started during or after a relapse,this inflates the apparent pre-lithium relapserate, making it invalid as a comparison.

Toxicity

Deaths due to lithium toxicity occur at arate of 14 per million prescriptions oflithium (Henry, 1996, personal communication). This fatal toxicity index compareswith figures of 46.5 for amitriptyline, 50.0for dothiepin, 1 1.1 for clomipramine and

3.7 for lofepramine (Cassidy & Henry,

1987). These figures may conceal a higher

death rate per person treated with lithium

relative to other drugs, as it is probable thatlong-term prescriptions for lithium are notissued to as many people as long-termprescriptions for antidepressants. Permanentneurological sequelae are also increasinglyrecognised as possible consequences oftoxicity (Schou, 1984; Sansone & Ziegler,1985),andrenaldamagemayoccur.Toxicity is more commonly due to long-term

therapeutic administration than intentionaloverdose (Dyson et a!, 1987) but lithiumblood-level monitoring is not always pre

ventive, as several cases of toxicity andneurological damage have been reported atnormal blood levels (Nagaraja et a!, 1987;Bell et a!, 1993). Lithium also appears to bemildly neurotoxic at normal therapeuticdoses, as placebo-controlled experimentswith normal volunteers find it producessubjective dysphoria and impairment ofsome aspects of cognitive function in conjunction with physiological measurementsshowing reduced nerve conduction velocityand increased EEG slow waves (Small et a!,1972; Girke et a!, 1975; Karniol et a!, 1978;Kropf & Muller-Oerlinghausen, 1979;Weingartner et a!, 1985; Calil et a!, 1990).

The significance of these effects is debated(Calil et a!, 1990) but the frequency of poorcompliance with lithium treatment may be afurther indication of their importance.

Other physical complications

Oliguric renal failure occurs in acute intoxication and may result in a persistent reduction in creatinine clearance (Hestbech et a!,1977). Chronic renal lesions consisting ofinterstitial nephritis have been shown to occurin association with reduced renal concentrating ability in patients on long-term lithium

treatment (Hestbech, 1977). The clinicalsignificance of these changes has been questioned and some reviewers have concludedthat they are unlikely to lead to severe renalfailure (Hwang & Tuason, 1980), although it

is probable that vulnerability to lithiumtoxicity and other renal insults is increased.

Lithium may cause cardiac conductiondefects, most commonly sinus node dysfunction (Mitchell & Mackenzie, 1982), and ithas been associated with sudden death inpeople with pre-existing cardiovascular abnormalities or risk factors such as a familyhistory of cardiovascular disease (Shopsin eta!, 1979; Lyman et a!, 1984). It is also a

well-known teratogen which causes cardiacabnormalities and an increased risk ofEbstein's anomaly (Cohen et a!, 1994).Interactions with other drugs producing

increased vulnerability to lithium toxicityare well recognised, as is lithium-induced

impairment of thyroid function. Side-effectssuch as tremor and weight gain, which arecommon, may be less severe in medicalterms but may substantially impair qualityof life and normal functioning.

CONCLUSIONS

Studies which showed an effect of lithiummay have had biased results due to certainmethodological problems. Overall thereappears to be little evidence that lithium iseffective for three of its commonly recommended uses: treatment of acute mania,prophylaxis of bipolar disorder and augmentation of treatment in resistant depression. In addition, naturalistic follow-upstudies fail to reveal any beneficial effect oflithium on the course of bipolar disorder.Negative consequences of using lithium arean independent cause for concern, especiallythe risk of toxicity and the possibility of

mania provoked by lithium withdrawal.There are also long-term physical complications and side effects, while for some, taking

lithium is a subjectively unpleasant experience.

It appears that social and historicalfactors may have enabled lithium treatmentto become established on the basis ofinsubstantial evidence, despite its knowndangers. At a time when other pharmaceutical products were improving the outlook

for some psychiatric conditions, lithium heldout hope for the long-term suffering associated with bipolar disorder. It also presented an opportunity to psychiatrists at atime when the anti-psychiatry movementwas at its height, and its claimed specificityin affective disorder was used as a weaponagainst critics of psychiatric nosology (Spitzer, 1976). The serendipity of its introduction into psychiatry and the enthusiasm with

which it was adopted closely paralleled the

19th century experience of lithium therapy.I have suggested that there is inadequate

evidence that lithium has a beneficial effect,that there are indications that it is ineffectivein the long-term outlook of bipolar disorder,and that it is known to be associated withvarious forms of harm. Its place in psychiatry needs discussion and re-evaluation and

there may come a time to abandon this “¿�oldbut flourishing blunder―(Chemist & Druggist, 1888; quoted in Johnson, 1984) for thesecond time in history.

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Austin, M. RV., Souza, F.G. M. & Goodwin, G. M. (1991)Lithiumaugmentationin antidepressant-resistantpatients.BritishJournolof Psychiatry,159,510—514.

Bell, A.J., Col., A., Ecd.ston, D. & FerrI.,@ I. N. (1993)

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lu

ACKNOWLEDGEMENTS

I thank Dr Simon Wessely for his helpful comments

on the manuscript, and Southlhames NHS Executive

who are funding my current employment.

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