Bipolar Disorders 1999: 1: 13–16Printed in Ireland. All rights reser6ed

Commentary

‘‘Perspectives on lithium treatment of bipolardisorder’’ – by Mogens Schou: acommentary

Johnson GJ. ‘‘Perspectives on lithium treatment of bipolar disorder’’– by Mogens Schou: a commentary.Bipolar Disord 1999 1: 13–16. © Munksgaard, 1999

Gordon JohnsonDepartment of Psychological Medicine,University of Sydney, Repatriation GeneralHospital, Concord, New South Wales,2139, Australia

Received 25 February 1999, revised andaccepted for publication 3 March 1999

This year marks the 50th Anniversary of Cade’sreport of the effectiveness of lithium in the treat-ment of mania. Historically, the acceptance oflithium’s role in psychiatry has been punctuated bycontroversies concerning its efficacy and its safetyand this pattern seems set to continue into the newmillenium. In this issue, Mogens Schou has set outhis responses to recent criticisms of the evidencebase for lithium’s efficacy and its current place,particularly in the prophylactic treatment of bipo-lar disorder.

Questions concerning the clinical utility ofmaintenance treatment in patients with bipolar dis-order have arisen from a series of observations.

1. Follow-up studies reporting the benefits to bemodest compared to the results of clinical trials(1). Such studies are uncontrolled and by andlarge patients are derived from tertiary referralcentres, where there is an over-representationof patients with treatment resistance, chronicityor rapid cycling disorder. The presence of co-morbidity, particularly substance abuse, is fre-quent. Additionally, changing diagnosticcriteria since the original benchmark studieswith lithium, has shifted the boundaries ofbipolar disorder from what had been seen asclassical mania to include atypical patients withmood incongruent delusions and hallucina-tions.

2. Surveys of drug use have found a high propor-tion of bipolar patients receiving multiple med-ications, including neuroleptics, antidepres-sants, benzodiazepines and anticonvulsants, aswell as lithium (2). One investigator concluded

that lithium monotherapy is not sufficient forthe majority of manic patients who are referredfor tertiary care (3). The National Centre forHealth Statistics in the US found outpatientswith mania were four times more likely to betreated with multiple concurrent psychotropicmedications than were outpatients with nonpsychiatric diagnoses. Lithium was part of apolypharmacy regime in over 70% of the ambu-latory visits in which it was prescribed, and outof all psychotropic drugs, lithium was mostlikely to be used in combination with otherpsychotropic drugs. They conclude the two bestpredictors of psychotropic polypharmacy werethe prescription of lithium and a diagnosis ofmania (4).

These studies suggest that for many patientswith bipolar disorder, lithium is either ineffectiveor partially effective leading to combination medi-cation strategies. In others, initial benefit may notbe maintained or escape from effective prophylaxisoccurs. It has been suggested that this either repre-sents a lessening of a pharmacological action overtime or that the driving force of the illness over-whelms the prophylactic effects of lithium (5, 6). Incontrast, Berghofer et al. (7) reported sustainedprophylactic efficacy of lithium over 10 years. Gus-cott and Taylor (8), in reviewing outcome studieswith lithium in medical practice and comparisonwith clinical trials, stated that effectiveness in natu-ralistic studies showed poorer results than efficacystudies in all areas of medicine. Consistent withthis is a recent report of a long-term effectivenessof antidepressants in a naturalistic clinic setting,

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finding more modest benefits than expected fromclinical trials of the efficacy of antidepressants (9).

Major factors determining effectiveness in prac-tice are patient compliance and monitoring. In arecent follow-up study of 140 patients initiallyhospitalised with bipolar disorder and followedfor 1 year, 51% were partially or totally non com-pliant (10). Additionally, surveys of lithium use inhealth maintenance organisations show the pat-tern of use to be short term in the majority ofusers (11, 12). Intermittent lithium use increasesthe risk of episode recurrence, intercurrent mor-bidity and cumulative psychosocial sequelae. Sub-sequent refractoriness to further lithium treatmenthas been reported in some studies but not others(13, 14).

Effective use requires clinical and plasma levelmonitoring. The surveys of lithium monitoring inhospital and general practice in the UK highlightconcerns over monitoring practice (15). A recentsurvey found wide variation in monitoring prac-tice, with less than 33% of patients having lithiumlevels estimated at intervals of less than 13 weeks,while 76% had lithium levels at intervals of lessthan 26 weeks. Twenty-five percent of subjectshad lithium levels greater than 1.0 mmol/l, and ofthese, only 55% were followed by a repeat levelwithin 3 weeks. Eight percent had consistently lowlevels less than 0.4. Only 15% met their ideal mon-itoring criteria, i.e. at least three monthly lithiumassessments – lithium levels within the range 0.4–1.0 and action taken outside these levels, and sixmonthly electrolyte and thyroid assessments (16).I suspect that deficiencies in lithium monitoringpractices are not confined to the UK.

Alternatively, it has been claimed that the pro-phylactic efficacy of lithium treatment was neversatisfactorily documented due to deficiencies inclinical trials and that is why it does not work(17). These criticisms have been firmly rejected bySchou in this issue. This is consistent with otherpublished rebuttals (18). In a subsequent paper,Moncrieff (19) has also exaggerated the risks oflithium treatment by selective references and byallowing speculation rather than fact to determineconclusions. This is evident in the discussion ofincreased death rates, despite evidence to the con-trary that treatment with lithium is associatedwith a reduced mortality in patients with recurrentmood disorder. Also, in discussing the findings ofHestbech (20) of chronic renal lesions consistingof interstitial nephritis in patients on long-termlithium treatment, the author fails to mention thatsimilar non specific lesions have been reported inpatients who have never received lithium (21).Long-term prospective studies have not found evi-

dence of a decline in renal function in the major-ity of patients maintained on lithium treatment(22, 23).

In clinical practice, lithium still remains thetreatment of choice for the long-term prophylaxisof bipolar disorder. While the use of anticonvul-sants is growing substantially, clinical trial evi-dence concerning efficacy is either equivocal orlacking (24, 25). A recent randomised study oflithium versus carbemazepine in maintenancetreatment of bipolar disorder found no significantdifference over 2.5 years in further hospitalisationor recurrence rates; but when recurrences werecombined with co-medication and/or adverse ef-fects, the results were distinctly in favour of lithium(26). Adverse effects requiring discontinuation,mainly allergic skin reaction, were more frequentwith carbemazepine. For valproate, results areawaited of long-term studies. Studies in maniasuggest important differences in the clinical spec-trum of action with valproate compared to lithium(27). Whether such differences extend into prophy-laxis remains unknown, although there are somethat favour treatment of rapid cycling with ananticonvulsant prior to lithium (28). In addition toanticonvulsant monotherapy, combined lithiumand anticonvulsant regimes are being increasinglyused. A recent report found a combination oflithium and valproate to be more effective thanlithium alone for the continuation and mainte-nance of patients with bipolar disorder (29). Suchcombinations may exert a lithium-sparing effect,allowing a reduced lithium dose and serum level.While combination regimes usually follow ineffec-tive or poorly tolerated lithium treatment, theymay emerge as a first line option for some patients.

A number of new anticonvulsants have becomeavailable and a potential role in mood disorders isbeing explored with lamotrigine and gabapentin.The results of clinical trials are awaited withinterest.

Neuroleptics have been widely used in the treat-ment of mania and for the prophylactic treatmentof bipolar disorder, often in combination withlithium. The effectiveness of this approach hasnever been satisfactorily documented and the risksof long-term side effects, such as tardive dyskine-sia, is a documented safety concern. The atypicalantipsychotic clozapine is being increasingly usedin treatment refractory bipolar disorder with somereported benefit. The lower neurological side ef-fects make this an attractive option, but the re-quirement for blood monitoring and the risk ofagranulocytosis will limit its general use. Otheratypical antipsychotics are currently under evalua-tion in the acute and long-term treatment of bipo-

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Commentary

lar disorder. Their place in therapy is yet to bedetermined, but their long-term safety, particularlyfor tardive dyskinesia, appears low compared withtypical antipsychotics.

A number of studies have reported a reducedrisk of mortality in manic depressive patientsmaintained on lithium. This is largely achievedthrough a reduction in suicide rates. In discussingthese findings, Schou has hypothesised a specificanti-suicidal action of lithium treatment. Thedifficulty of confirming an anti-suicidal action in-dependent of prophylactic effects is evident in thestudy of Bocchetta et al. (30), who followed a highrisk cohort of 100 patients who had attemptedsuicide before commencing lithium prophylaxisand who were followed up for a mean of 10 years.They reported significantly higher frequency of sui-cide and suicide attempts when patients were offlithium treatment compared to periods on lithium.However, all but one of the patients who commit-ted suicide had discontinued lithium due to incom-plete response. An analogous situation has arisenwith clozapine, where mortality rates in patientswith schizophrenia were lower during currentclozapine use than during periods of non use. Doclozapine and lithium share some specific anti-sui-cidal actions, independent of their wider therapeu-tic effects? No doubt a biological basis could beformulated based on effects on serotonin function.Or is the reduction in suicidal behaviour relatedmore to the effectiveness of the treatment or simi-lar beneficial, but non specific, factors associatedwith the treatment programs? Schou admits thatsuch an action cannot be proven, but recommendsthe use of prophylactic lithium treatment in pa-tients with recurrent affective disorder who are athigh risk of committing suicide. That may be themajority of patients with a recurrent mood disor-der, depending on how you categorise suicide risk.The clinical scenarios that might arise are, e.g. abipolar patient on lithium who is a poor respon-der. Should he be switched to alternative medica-tion or should lithium be continued incombination with an anticonvulsant? Combinationtreatment could be clinically justified. However,what of a patient with recurrent depression who isresponding to antidepressants. Should lithium beadded? That would be difficult to justify. For clini-cians, suicide risk is important, but not the onlyimportant aspect that may determine the choice ofmedication.

Amongst all the debate concerning the effective-ness of lithium and anticonvulsants in mood disor-ders, surveys show that despite the availability ofeffective drugs, bipolar disorder is under treated.Assuming a life time prevalence of bipolar disorder

of conservatively 6/1000 of the population, andthat at least 75% should be in treatment at any onetime, the expected population rate should be 4–5/1000. Estimates for use for all indications forlithium range from 0.77 to 1.8/1000 of the popula-tion. Clearly, many patients who could benefitfrom treatment are not receiving it. How toachieve that is the critical question.

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30. Bocchetta A, Raffaella A, Burrai C, Chillotti C, QuesadaG, Del Zompo M. Suicidal behaviour on and off lithiumprophylaxis in a group of patients with prior suicide at-tempts. J Clin Psychopharmacol 1998; 18 (5): 384–389.

Corresponding author:Gordon Johnson MDDepartment of Psychological MedicineUniversity of SydneyRoom 6, Clinical Science BuildingRepatriation General Hospital, ConcordNew South Wales, 2139, AustraliaFax: +61 2 97677078E-mail: gjohnson@med.usyd.edu.au

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