Review Article

Maintenance therapies in bipolar disorders

Introduction

As befits an early onset and inherently recurrentdisorder, maintenance treatment is the longestphase of treatment of bipolar disorder. For virtuallyall bipolar disorder patients, the question of main-tenance treatment is when, not if, although manypatients are resistant to this notion for many yearsand many episodes. For decades, only one treat-ment, lithium, had demonstrated any efficacy inpreventing episodes of mania ⁄hypomania and ⁄ordepression. Over the last decade, there has been adramatic increase in the number of maintenancetreatments evaluated and found to be effective.Despite this increase, however, and even with stateof the art treatment—whether monotherapy or

combination treatment—the natural course oftreated bipolar disorder is still characterized byrecurrent episodes. This article will review therationale for maintenance treatment, the data oncontrolled studies of single agents (monotherapy),and combination therapies, and conclude with abrief overview of adjunctive psychotherapies formaintenance treatment of bipolar disorder.

Maintenance treatment: conceptual considerations

Natural history of bipolar disorder

The inevitable consideration of maintenance treat-ment of bipolar disorder is predicated on theconsistent observation that bipolar disorder is an

Gitlin M, Frye MA. Maintenance therapies in bipolar disorders.Bipolar Disord 2012: 14 (Suppl. 2): 51–65. ª 2012 The Authors.Journal compilation ª 2012 John Wiley & Sons A ⁄S.

Objective: Bipolar disorder is an inherently recurrent disorder,requiring maintenance preventive treatments in the vast majority ofpatients. The authors review the data on maintenance treatments inbipolar disorder, highlighting the controlled trial literature.

Methods: Literature review using PubMed, Medline, and a hand searchof relevant literature.

Results: Over the last decade, a number of effective maintenancetreatments for bipolar disorder have been developed with an evidencebase for second-generation antipsychotics and some anticonvulsants.Increasing numbers of patients, therefore, are appropriately treated withmultiple medications as a maintenance regimen. For some medications,maintenance treatment has been demonstrated in randomized controlledtrials for both monotherapy and in combination with other moodstabilizers. Lithium continues as our oldest well-established maintenancetreatment in bipolar disorder with somewhat better efficacy in preventingmania than depression. Lamotrigine, olanzapine, and quetiapine havebimodal efficacy in preventing both mania and depression, althoughlamotrigine�s efficacy is more robust in preventing depression andolanzapine�s efficacy is greater in preventing mania. Aripiprazole,ziprasidone, and risperidone long-acting injection all prevent mania, butnot depression. Less controlled investigations have suggested someevidence of maintenance mood stabilization with carbamazepine,oxcarbazepine, and adjunctive psychotherapy.

Conclusions: Despite the number of agents with demonstrated efficacyas maintenance treatments in bipolar disorder, optimal treatmentregimens are still a combination of evidence-based therapy incombination with individualized creative treatment algorithms.

Michael Gitlina and Mark A Fryeb

aDepartment of Psychiatry, Geffen School of

Medicine, University of California, Los Angeles,

Los Angeles, CA, bDepartment of Psychiatry, Mayo

Clinic and Research Program, Mayo College of

Medicine, Rochester, MN, USA

doi: 10.1111/j.1399-5618.2012.00992.x

Key words: anticonvulsants – antipsychotics –

bipolar disorder – lithium – maintenance –

treatment

Received 9 July 2011, revised and accepted for

publication 10 October 2011

Corresponding author:

Michael Gitlin, M.D.

Department of Psychiatry

Geffen School of Medicine

University of California, Los Angeles

300 UCLA Medical Plaza, Suite 2200

Los Angeles, CA 90095, USA

Fax: 310-206-8387

E-mail: mgitlin@mednet.ucla.edu

Bipolar Disorders 2012: 14 (Suppl. 2): 51–65 ª 2012 John Wiley and Sons A/S

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inherently recurrent disorder with few individualsexperiencing one episode across a lifetime. Eventhough some early studies described many bipolardisorder patients as having one episode over alifetime (or, at least over decades), more recentstudies find that single-episode bipolar disorderpatients are rare at best (1). Assuredly, this discrep-ancy reflects at least, in part, different definitions ofwhat constitutes single episodes (e.g.,multiplepolarityshifts with continuous illness counted as one episodeas in older studies) as well as the inclusion of unipolarand bipolar disorder patients in earlier studies.Given the availability of mood stabilizers and

the morbidity of untreated bipolar disorder, fol-lowing patients for long time frames withouttreatment is unethical. Therefore, virtually allrecent studies on the natural course of bipolardisorder have examined naturalistically treatedpatients with varying degrees of response andtreatment adherence. In these studies, relapse rateshave generally been as high or higher than was seenin the pretreatment era with typical two-yearrelapse rates of 50% (2, 3) and five-year relapserates ranging from over 70% to almost 90% (2, 4).Even though manic ⁄hypomanic episodes are

the defining characteristic of bipolar disorder asmeasured by number of episodes and time spent inmood states, depression is the dominant, prevailingpole of naturalistically treated patients, as has beenincreasingly appreciated over the last decade.Virtually all studies have noted more depressivethan manic episodes, more time spent depressedthan manic ⁄hypomanic, and more time spentsubsyndromally depressed than subsyndromallymanic ⁄hypomanic, with the average patient spend-ing three times as much time depressed as manic (3,5, 6). This depressive dominance may be evengreater in bipolar II disorder patients (7). Addi-tionally, depressive symptoms may correlate morehighly with functional impairment than manicsymptoms (2, 8).

Definition and goals of maintenance treatment

The core goal of maintenance treatment in bipolardisorder is the prevention of future mood episodes,both manic ⁄hypomanic and depressive. Classically,the maintenance treatment phase follows the con-tinuation phase, in which the goal is preventing arelapse into the same episode (either manic ordepressive) for which acute treatment had begun.Unfortunately, there is no single consensus set ofdefinitions distinguishing when continuation treat-ment evolves intomaintenance treatment, although,recently a set of definitions has been proposed as afirst step towards establishing a nomenclature of

course and outcome (9). A reasonable estimatewould be that at least three months of moodstability should be required before a study can beconsidered truly a maintenance prevention study(10). For clinical purposes, three to six months ofclinical stability following an acute episode shouldbe required before the beginning of maintenancetreatment is assumed to have begun.Optimally, an effective maintenance treatment

would—assuming complete treatment adher-ence—completely prevent future episodes of illnessrecurrence. Realistically, however, given the natu-ralistic data reviewed above demonstrating thatbipolar disorder patients tend to exhibit recurrentepisodes even in ongoing treatment, other goalsbeyond complete episode prevention must also beconsidered as methods of tracking the efficacy ofmaintenance treatments. Table 1 shows the variedgoals of maintenance treatment of bipolar disorder.Demonstrating that a maintenance treatment hasdecreased the number of episodes for an individualrequires the treating clinician to literally count thenumber of episodes in a certain time period before atreatment was instituted and then compare it withthe number of episodes while the patient is beingtreated. This mirror design will enable the clinicianto possibly identify partially effective preventivetherapies. Similarly, decreasing the amplitude ofepisodes allows an effective maintenance treatmentto be seen as partially effective if recurrent episodeswith treatment are, for example, hypomania andmild depression, versus psychotic hospitalizedmania and suicidal or incapacitating depressionthat might be seen without treatment. Similarconsiderations apply for the length of mood epi-sodes. Finally, amelioration of subsyndromal symp-toms is a vital component of maintenance therapiesboth because subsyndromal symptoms are associ-ated with functional impairment and because theyare predictive of both earlier manic and depressiverelapses (3, 11, 12).

Maintenance treatment: general guidelines

Predicated on the natural history of bipolar disor-der, most practice guidelines (13–16) recommend

Table 1. Possible goals of maintenance treatment in bipolar disorder

• Abolition of episodes and mood swings• Decreased number of episodes• Decreased intensity of episodes• Decreased length of episodes• Greater mood stability (i.e., less subsyndromal symptoms)

between episodes• Decreased suicide rates

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that maintenance treatment be instituted after asingle manic episode. These guidelines are easy torecommend but are difficult to implement inpractice. With the typical emergence of bipolardisorder in late adolescence or early adulthood,those confronted with this issue after a first manicepisode are young, and most patients have greatdifficulty accepting the notion of an inevitablyrecurrent disorder that lasts a lifetime, after asingle episode. Although only some studies suggestlower adherence to maintenance treatment after afirst episode (compared to later in the course of thedisorder after multiple episodes), clinically, young,first-episode patients seem to have the most troubleaccepting the need for long-term treatment (17). Inthese circumstances, education about the nature ofbipolar disorder, potentially involving family mem-bers and, at times structured psychotherapy, maybe exceedingly helpful.In order to minimize patient burden, side effects,

and to promote greater treatment adherence, it isstandard to recommend monotherapy over com-bination therapy (or polypharmacy, as it is some-times called) and fewer medications over moremedications. Yet, multiple studies have docu-mented the rise of polypharmacy, specifically inthe maintenance treatment of bipolar disorder (18–21). Additionally, increasing numbers of controlledtrials in maintenance treatment of bipolar disorderhave utilized an adjunctive or combination design(discussed at greater length below) in which twomedications are compared to one active medicationplus placebo. Assuredly, this reflects the dissatis-faction of both patients and clinicians aliketowards monotherapy. Many monotherapies havedemonstrated greater efficacy than placebo inpreventing mania, depression, or both. However,recurrence rates for patients on these active med-ications are still unacceptably high. Since individ-ual agents have some efficacy, it is logical toassume that two agents may be better than one,three better than two, and so on. Although, inmany cases, this strategy turns out to provideoptimal treatment, it can also lead to patients beingtreated with four, five, or six mood stabilizers,none of which has shown any efficacy at all for thatparticular patient. Therefore, even though poly-pharmacy is the rule rather than the exception inthe maintenance treatment of bipolar disorder,clinicians should always be conscious of the burdenof multiple medications and review medicationregimens on a regular basis to ensure that patientsare being prescribed only medications that haveshown some benefit.Additionally, it is critical that clinicians utilize

the efficacy and side effect ⁄ safety data presented

below to create individualized treatment plans forpatients. It is clear that maintenance therapiesdiffer from each other regarding their relativeefficacy in preventing manic ⁄hypomanic versusdepressive states. Similarly, patients differ fromeach other as to the whether there is a dominantpole. Patients can be described as mania-dominant,depression-dominant, or pole-nondominant, andtreatment algorithms should differ across thesedifferent patient profiles. Therefore, relativelyaccurate lifetime histories of mood episodes arecritical in constructing a thoughtful treatmentalgorithm. If one adds side effect considerations,with some patients being more sensitive to and lesstolerant of some side effects than others, it becomesclear that treatments in bipolar disorders must beindividualized for optimal results.Finally, despite the marked increase in well-

designed controlled treatment studies in mainte-nance therapy of bipolar disorder published in thelast decade, the field still suffers from a relativepaucity of controlled studies, with many importantclinical questions unaddressed by currently avail-able data. Thus, at times, it is entirely appropriateto construct treatment plans not supported bystudies (especially if relevant studies have simplynot been done). Optimal treatment reflects not justan evidence-based approach that requires not onlysufficient amounts of evidence, but also reflectsconsensus clinical guidelines, thoughtful clinicalobservation, and, at times, novel approaches.

Efficacy

Controlled studies evaluating the efficacy of phar-macotherapy for bipolar disorder can be dividedinto two basic designs, with all studies lastingbetween six months and two years. One is theclassic monotherapy drug versus placebo study.The second design is the adjunctive or combinationdesign, in which all subjects are treated openly(typically with either lithium or valproate) and theexperimental medication or placebo is added in adouble-blind fashion. This second design can alsobe divided into two categories: (i) combinationtreatment, in which subjects are placed on thecombination therapy openly and the second med-ication is switched to placebo in a double-blindfashion; or (ii) an adjunctive design, in whichsubjects whose disorder was not adequately con-trolled initially by either lithium or valproatereceive the antipsychotic or placebo added to theoriginal medication.There is some controversy as to whether studies

that allow subjects into the experimental phaserelatively quickly after the resolution of an acute

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mania (e.g., two weeks) represent relapse preven-tion studies (in which relapsing patients representfailure of continuation treatment) versus thosestudies that require a longer stabilization phaseand, in which, relapses represent true failure ofmaintenance treatment (22, 23).Another critical design issue is that most, but not

all, maintenance treatment studies in bipolar dis-order include recently manic patients. The resultsfrom recently manic patients may not generalize tomore recently depressed or depression-predomi-nant patients.Table 2 lists the drug ⁄placebo randomized,

controlled trials (RCTs); and Table 3 presents theadjunctive and combination studies.

Lithium

Since the first evidence of its efficacy in preventingmood episodes (24), lithium has consistently been

touted as the gold standard of maintenance ther-apy in bipolar disorder due to its longevity and thesheer number of studies supporting its efficacy.Earlier studies—those published in the 1960s and1970s—have been criticized because of legitimatemethodological concerns: (i) very few studies wereclassic RCTs as has become the standard in today�sstudies [the study by Prien et al. 1973 (25) being anotable exception]; (ii) many were pre ⁄post mirrorstudies in which relapse rates pre-lithium werecompared to the rates post-lithium; (iii) the pop-ulation in these studies was frequently patientsenriched with acute lithium responders; and (iv)when lithium was discontinued after acute treat-ment, it was stopped suddenly with the likelihood(not known at that time) of lithium withdrawal-induced rebound mania (26–29). Despite thesejustified critiques, the data in support of lithium�sefficacy as a maintenance treatment was consistent(22, 30).

Table 2. Monotherapy for prevention of relapse in bipolar I disorder: overview of placebo-controlled studies

Maintenancetreatment

Primaryendpoint

Patient typeat enrollment Primary outcome

Lithium (24) 2 years Manic Fewer overall relapses and fewer manias but not depressionsDivalproex (32) 1 year Manic No significant difference in time to any mood episode between

divalproex, lithium, or placeboLamotrigine (33, 34) Up to 76 weeks Manic and depressed

and mixedDelayed time to any relapse, to mania, and to depression

Olanzapine (23) 48 weeks Manic and mixed Delayed time to any relapse, to mania, and to depressionAripiprazole (62) 26 weeks Manic and mixed Delayed time to any relapse and to mania, but not depressionQuetiapine (35) 2 years Manic, mixed,

and depressedDelayed time to any relapse, to mania, and to depression

Risperidone LAI (69) 2 years Manic or mixed Delayed time to any relapse and to mania, but not depression

LAI = long-acting injectable.

Table 3. Randomized, controlled trials of adjunctive ⁄ combination design in maintenance treatment of bipolar disorder

Antipsychotic ⁄ moodstabilizer combination

Adjunctive orcombinationtreatment

Follow-upperiod

Polarity of moodepisode at study entry Major results

OLAN + LITH ⁄ VAL (60) Adjunctive 18 months Manic and mixed Delayed time to relapse only for symptomatic,not syndromic, remission; not to mania ordepression

QUET + LITH ⁄ VAL (65) Combination 104 weeks Manic, mixed, depressive Delayed time to any relapse, to mania, and todepression

QUET + LITH ⁄ VAL (66) Combination 104 weeks Manic, mixed, or depressive Delayed time to any relapse, to mania, and todepression

ARIP + LITH ⁄ VAL (64) Adjunctive 52 weeks Manic and mixed Delayed time to any relapse and to mania, not todepression

ZIP + LITH ⁄ VAL (67) Adjunctive 6 months Manic and mixed Delayed time for any relapse and to mania,not to depression

RLAI + TAU (68) Adjunctive 52 weeks Most recent episode:manic ⁄ hypomanic,depressed, mixed

Delayed time to any relapse, but not specificallyto mania or depression

OLAN = olanzapine; LITH = lithium; VAL = valproate; QUET = quetiapine; ARIP = aripiprazole; ZIP = ziprasidone; RLAI = risperidonelong-acting injection; TAU = treatment-as-usual.

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Studies published since 1980—both RCTs andthose using other designs—have continued todemonstrate lithium�s efficacy, although less ro-bustly than in the earlier studies. The seeminglydecreased prophylactic efficacy assuredly reflects anumber of factors: (i) changes in study design, e.g.,tapering rather than suddenly discontinuing lith-ium (with consequently lower placebo relapse ratesdue to the elimination of lithium withdrawal-induced mania); (ii) the inclusion of a probablybroader range of bipolar disorder psychopathology(seen in studies of most psychiatric diagnoses overtime) with more treatment-resistant and less �clas-sic� cases entered into studies (31); and (iii) the useof enriched designs in which lithium was used asthe active comparator, with the study enriched forthe experimental drug.Nonetheless, more modern aggregate studies (32–

35) [with the Prien et al. study (25) sometimesincluded] published over the last few decades anddetailed in a number of reviews using meta-analytictechniques, hazard risks, and establishing numbers-to-treat (NNT) ratios have continued to demon-strate the efficacy of lithium in preventing moodepisodes (36–38). Lithium demonstrates statisticallysignificant efficacy in preventing any mood episodewith relative risk or hazard ratios (HR) estimated tobe in the 0.65–0.68 range (36, 37) and NNTstypically ranging from 3–7, indicating a robusteffect. A marked exception to these results is thefailed study of Bowden et al. (32) in which neitherlithium nor valproate separated from placebo.Lithium�s most robust effect is in preventing mania;by pooling studies, there were 47% fewer manicepisodes with NNTs of 2–4, depending on the study(37). Lithium�s efficacy in preventing depression isless well-established, with the estimation of 35%fewer depressive episodes, resulting only in a trendtowards statistical significance (36, 37).Lithium seems optimally effective for patients

who fit the profile of classic bipolar disorder—dis-crete episodes with typical symptom profiles (31,39). Thus, a family history of bipolar disorder, amania-depression-interval (MDI) pattern of epi-sodes [in contrast to biphasic episodes that beginwith a depression followed by mania (DMIpattern)], an intermediate age of onset, and fullremission between episodes, all predict betterpreventive efficacy. Consistent with these findings,in a more recent study the more atypical featurespresent, the poorer the response to prophylacticlithium (40). Rapid cycling does predict a poorerresponse to lithium but only when compared tonon-rapid cyclers. There is little systematic evi-dence that rapid cyclers respond less to lithiumthan to other mood stabilizers. In the one con-

trolled study, lithium and valproate were equallypoorly effective as maintenance treatments forrapid cyclers (41).

Valproate

Despite the frequent use of valproate as a mainte-nance treatment in bipolar disorder, it is notapproved by the United States Food and DrugAdministration (FDA) for this purpose and noRCT has demonstrated its efficacy. In the only largescale study, valproate in the form of divalproex(along with lithium as an active comparator) did notseparate from placebo on primary outcome vari-ables (32). A number of methodological features,such as the exclusion of more severely ill patients,which led to placebo-treated subjects having fewerrelapses than expected; a high number of dropoutspartly due to high lithium levels specified in theprotocol; the lack of an enriched design (in contrastto the design of all other RCTs evaluating othermaintenance treatments); and limited power mayexplain these results. Secondary analyses indicatesome efficacy in preventing mood episodes, espe-cially depression [relative risk (RR) = 0.6, 95%confidence interval (CI): 0.2–0.82] (42, 43).The only other large scale evaluation of val-

proate as a maintenance treatment for bipolardisorder is the BALANCE trial (44) in whichvalproate was less effective than lithium (or thecombination of lithium plus valproate). Because ofits unique design elements, BALANCE is discussedseparately below.Despite negative data from the only RCT,

valproate is often recommended for patients whopredominately experience mania (14, 16) due to itsdemonstrated efficacy and common use in treatingacute mania (45, 46), and its equivalent efficacy tolithium in rapid cyclers (41).

Lamotrigine

Lamotrigine was the second medication to receiveFDA approval as a maintenance treatment forbipolar disorder. The data supporting this werederived from two parallel double-blind studiescomparing lamotrigine to lithium or placebo over18 months (33, 34). Although some subtle differ-ences distinguished the design of the two studies,the primary difference was that in the one study allsubjects were recently manic ⁄hypomanic (33),while in the other study only recently depressedsubjects were included (34).A combined data set of both studies was also

analyzed (47). In general, lamotrigine was superiorto placebo and similar to lithium in delaying the

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need for intervention for any mood episode (theprimary outcome variable in the studies) with a32% reduction in mood episodes compared toplacebo. In the combined analysis (47), lamotriginesignificantly delayed both time to mania and timeto depression compared to placebo, although itsefficacy in delaying mania was significantly inferiorto lithium. Its efficacy in delaying time to depres-sion was numerically, but not statistically, superiorto lithium. A secondary analysis examining relapserates and NNT demonstrated less robust findingswith an NNT = 11 for overall episode prevention,an NNT = 20 for depression prevention (anonsignificant difference), and an NNT = 26 formania prevention (a nonsignificant difference) (38).Because the two foregoing registrational studies

used an enriched design in which patients wereexposed to lamotrigine in the open, preliminaryphase of the study and only those who did wellclinically and tolerated lamotrigine entered thecontrolled, double-blind phase, the generalizabilityof the results has been questioned (as would beappropriate for any enriched study). Recently,however, an open, randomized effectiveness studycomparing lamotrigine and lithium using a non-enriched design followed patients for up to fiveyears, and found similar results (48).Similar to the combined analysis of the two

registrational studies, in this study lithium andlamotrigine were equally effective in preventing anymood episode, with lamotrigine numerically supe-rior to lithium in preventing depression (HR =0.69, 95% CI: 0.41–1.22), and inferior in prevent-ing mania (HR = 1.91, 95% CI: 0.73–5.04). Nostatistically significant differences were found. In alonger term extension of another study, lamotri-gine added to lithium for acute bipolar depressionprolonged the time to depressive relapse (49).Combining these four studies, overall, lamotri-

gine appears to be equivalent to lithium as apreventive treatment in bipolar disorder withrelatively greater efficacy in preventing depressionand lower efficacy in preventing mania.In the only other controlled study with lamotri-

gine, rapid cycling bipolar I and II disorderpatients did somewhat better, but not statisticallysignificant, on lamotrigine compared to placeboover six months (50). Lamotrigine was significantlysuperior to placebo in bipolar II disorder subjectsin this study, whereas no differential efficacy wasseen in the bipolar I subset.

Carbamazepine and oxcarbazepine

Although carbamazepine was the first anticonvul-sant evaluated for efficacy in bipolar disorder and

has been prescribed for this purpose for 30 years,data supporting its efficacy in controlled mainte-nance treatment is still less than robust. Other thana small placebo-controlled study published overthree decades ago (51), the majority of studiesevaluating carbamazepine as a preventive treat-ment in bipolar disorder consist of comparisons tolithium or in combination with lithium (52, 53).These studies generally find that lithium is superiorto carbamazepine but, of course, one cannotexclude the possibility of carbamazepine�s efficacy.Results from a 2.5-year study (52, 54) suggestedthat bipolar disorder patients with nonclassicfeatures, such as mood-incongruent delusions ormixed features, did relatively better with carba-mazepine. A double-blind three-year study dem-onstrated that the combination of lithium pluscarbamazepine was somewhat more effective thaneither medication alone, especially for rapid cyclingbipolar disorder patients (55).Oxcarbazepine is an analogue of carbamazepine

associated with fewer pharmacokinetic interactionsand generally fewer side effects (see section onTolerability below for details) which has beenprescribed more recently for bipolar disorder. Theonly controlled study of oxcarbazepine as a main-tenance treatment in bipolar disorder utilized anadjunctive design in which 55 euthymic bipolardisorder patients on lithium were given eitheroxcarbazepine (up to 1200 mg ⁄day) or placebo forone year (56). Although no statistically significantdifferences in time to relapse or relapse rates werefound (not surprisingly, given the small number ofsubjects), those assigned to oxcarbazepine had fewerrelapses compared to placebo (38% versus 59%,respectively; p = 0.14; NNT = 5), especially fordepression (12%versus 31%; p < 0.09; NNT=9).Those treated with lithium plus oxcarbazepine hadsignificantly lower impulsivity scores.

Other anticonvulsants

No other anticonvulsant, including gabapentin,tiagabine, and topiramate, has shown benefit as amaintenance treatment in the prevention of maniaand ⁄or depression in placebo-controlled studies,other than a small cross-over adjunctive studydemonstrating the potential efficacy of phenytoin(57). Topiramate has shown some efficacy in longterm non-placebo controlled studies (58, 59).

Second-generation antipsychotics

The majority of the large scale RCTs in mainte-nance treatment for bipolar disorder published inthe last decade have examined the efficacy of

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second-generation antipsychotics. As a class, typ-ical and atypical antipsychotics are effective in thetreatment of acute mania, as evidenced by theFDA approval of chlorpromazine, ongoing use ofhaloperidol in emergency departments and inpa-tient psychiatric units, and every atypical antipsy-chotic except clozapine currently having a FDAindication. However, their efficacy in contempo-rary designed maintenance studies, assessing manicand depressive recurrence, is less clear.

Olanzapine

Olanzapine was the first second-generation anti-psychotic to demonstrate efficacy as a maintenancetreatment in bipolar disorder using both adrug ⁄placebo design (23), a combination design(60), and in a double-blind, non-placebo, con-trolled study in comparison to lithium (61). The2004 study by Tohen et al. (60) has been criticizedas a relapse prevention study rather than amaintenance (i.e., recurrence prevention) studysince subjects could be randomized to placeboafter as little as eight days of mania resolution andbecause those assigned to placebo showed anunusually rapid relapse rate. Nonetheless, in allthree studies, olanzapine demonstrated at leastsome efficacy. Overall, olanzapine�s efficacy wasgreater in preventing mania than depression.In the drug ⁄placebo study, the mean dose of

olanzapine was 12.5 mg ⁄day, NNT = 5 forprevention of mania, and NNT = 3 for preventionof any mood episode. In the adjunctive study,combination of olanzapine plus lithium or valpro-ate was only significantly more effective in pre-venting symptomatic relapse (using rating scalescores) but not syndromal relapse (using criteriafor a mood episode) (60). In the olanzapine versuslithium study (n = 431), acutely manic patientswere stabilized on the combination of lithium plusolanzapine and those meeting remission criteriawere then randomized to placebo substitution forone of the two medications and then followed forone year (61). No difference in relapse rates wasfound, but olanzapine (mean dose = 13.5 mg ⁄day)was significantly more effective in preventingmania (p = 0.001).

Aripiprazole

Aripiprazole has demonstrated efficacy as a main-tenance treatment of bipolar disorder in bothdrug ⁄placebo and adjunctive designs (62–64). Inthe six-month drug ⁄placebo study (62), aripipra-zole 15–30 mg ⁄day showed efficacy in preventingany mood episode and manic, but not depressive,

episodes. This trend continued to be evident in thetwo-year extension data (63). The NNT in the 100-week data set were 6 for any episode and 7 forprevention of mania.In the adjunctive study, manic patients not

responding to two weeks of either lithium orvalproate received adjunctive single-blind aripip-razole 10–30 mg ⁄day (64). Responders were ran-domized to lithium plus valproate plus eitheraripiprazole or placebo for one year. Consistentwith the drug ⁄placebo study, adjunctive aripip-razole was associated with overall efficacy com-pared to placebo (relapse rates = 17% versus29%, respectively; p = 0.014), significantly de-layed time to any relapse (HR = 0.54, 95% CI:0.33–0.89), and significantly fewer manic relapses(15% versus 5%, p = 0.013) but not depressiveepisodes.

Quetiapine

Quetiapine has demonstrated efficacy in two dou-ble-blind studies using a combination design (65,66) and in a recent study using a drug ⁄placebodesign (35). In the two combination studies,patients with any recent episode polarity that werestabilized with quetiapine plus lithium or valproatewere then randomized to either continued treat-ment or double-blind substitution of quetiapinewith placebo and then followed for up to twoyears. In both studies, the addition of quetiapine(with daily doses in the 400–800 mg range) wasassociated with fewer mood events and fewermanic and depressive episodes. The NNT for anyepisode = 4; NNT = 7 and 9 for mania in the twostudies, respectively; and NNT = 7 and 6 fordepression in the two studies, respectively.In the recent drug ⁄placebo study (35), quetia-

pine was equally as effective as lithium, with bothbeing superior to placebo in the prevention ofmood episodes over two years. NNT for anyepisode = 3, for mania = 3, and for depression =4. Overall, quetiapine showed clear efficacy inpreventing mood episodes and, in contrast toolanzapine and aripiprazole, relatively equivalentefficacy in preventing mania and depression inbipolar disorder patients.

Ziprasidone

Ziprasidone has shown efficacy as a maintenancetreatment in one double-blind adjunctive study(67). Bipolar disorder patients (n = 240) with amanic episode successfully treated with lithium orvalproate plus ziprasidone 80–160 mg ⁄day werethen randomized to continued treatment or

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placebo substitution for the antipsychotic. Over sixmonths, combination treatment with ziprasidonewas associated with fewer interventions comparedto placebo (20% versus 32%, respectively) andsignificantly longer time to intervention (p = 0.01)with an NNT = 8. This was due to the longer timeto intervention for manic (p = 0.004) but notdepressive episodes.

Risperidone long-acting injection (RLAI)

RLAI has demonstrated efficacy both as mono-therapy and as an adjunctive maintenance treat-ment for bipolar disorder on the basis of one RCTwith each design (68, 69). In the monotherapystudy, manic patients who were stabilized with oralrisperidone and then RLAI were subsequentlyrandomized to continued RLAI (modal dose =25 mg every two weeks) or placebo injections forup to two years (69). RLAI was associated withsignificantly longer time to any mood episodecompared to placebo (30% versus 56%, respec-tively; p < 0.001) and to manic (p < 0.001), butnot to depressive episodes. NNT = 4 for both anyepisode and for manic episodes.In the adjunctive RLAI study, bipolar I disorder

patients in any phase of the disorder had RLAIadded to their treatment as usual (which could bechanged during the stabilization phase). Remittedpatients were then assigned to either continuedtreatment (with modal RLAI dose = 25 mg everytwo weeks) or placebo substitution for the RLAI(68). Over one year, adjunctive RLAI treatmentwas associated with lower overall relapse ratescompared to placebo (23% versus 46%, respec-tively; p = 0.01) with NNT = 4 for any episodeand for mania. NNT was not significant fordepression.

BALANCE study

Although neither double-blind nor placebo-con-trolled, the BALANCE study (44) provides suffi-ciently important new data on maintenancetreatment in bipolar disorder to merit review.Bipolar I disorder patients (N = 330) were ran-domly and openly assigned to lithium (plasmaconcentration 0.4–1.0 mmol ⁄L), valproate (750–1250 mg ⁄day), or both agents in combination forup to two years after an eight-week run-in phasewith both study medications. Overall, the combi-nation was associated with longer time to a newepisode compared to valproate (HR = 0.59, 95%CI: 0.42–0.83; p < 0.01) but not compared tolithium alone. Lithium alone was associated withlonger time to a new episode compared to valpro-

ate (HR = 0.71, 95% CI: 0.51–1.00; p < 0.05).Subgroup analyses, including those restricted topatients taking adequate doses, were consistentwith the overall findings. In contrast to the trendseen in the earlier lithium ⁄valproate ⁄placebo study(32), lithium was significantly more effective thanvalproate in preventing depressive episodes (HR =0.63, 95% CI: 0.41–0.96; p < 0.04).With broad, nonrestrictive inclusion criteria

and few exclusion criteria, subjects in theBALANCE study more closely mimic those seenin clinical practice than do classical RCTs. Thus,its results may be more generalizable, and there-fore complement the results of more registrationalRCTs.

Clozapine

Clozapine plays a unique role in the maintenancetreatment of bipolar disorder: there is no RCTevaluating its efficacy, yet it is widely considered tobe an important option for treatment resistantbipolar disorder. A great number of case seriesdemonstrate clozapine�s seeming efficacy as amaintenance treatment for bipolar disorder (70).Only one study has systematically comparedclozapine as an add-on study to a treatment-as-usual group, using a random assignment but non-blinded design (71). In this study of 38 treatmentresistant bipolar I and schizoaffective patients,clozapine significantly decreased symptoms by30% or more in 82% of patients, compared to57% in the treatment-as-usual group after sixmonths of treatment. With the exception ofdepression rating scale scores, clozapine additionwas consistently significantly more effective asmeasured by multiple rating scales (with thedifference in depression scores differing at a signif-icance level of 0.06).Of course, clozapine�s great liability is in its

safety profile with marked sedation, weight gain,orthostatic hypotension, seizures, and agranulocy-tosis, necessitating regular monitoring of bloodcounts for as long as clozapine is prescribed. Thus,only highly motivated patients can be treated withclozapine.

Summary

Clearly, rigorous evidence for this importantphase of bipolar disorder is lacking and there isan urgent imperative for meaningful research,particularly with respect to long term prophylaxis.For clarity and ease of reference, the recom-mendations pertaining to efficacy have beensummarized in Box 1.

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Safety and tolerability

The data reviewed above on the efficacy of variouspharmacotherapies as maintenance treatments forbipolar disorder cannot be considered outside thecontext of tolerability. Although there are manyother reasons why bipolar disorder patients dis-continue their maintenance pharmacotherapies,side effects and concerns about long term safetyof these medications are important causes ofnonadherence. The medications reviewed haveremarkably different side effect profiles and poten-tial long term health consequences and need to beconsidered separately. Furthermore, there is acomplex interplay between side effects and therelationship between the patient and the prescriber.A sense of communication and trust—whichincludes believing that the prescribing physicianhas been straightforward about the medicationsand its side effects and that questions aboutthe prescribed medication have been effectivelyaddressed—is critical to the collaborative relation-ship that fosters medication adherence.

Lithium

As the oldest of our mood stabilizers, lithium�s sideeffect profile and long term health effects have beenwell characterized (22). Side effects most com-monly seen in maintenance studies are polyuria,polydipsia, tremor, weight gain, and cognitivedullness. At least one study has suggested thatthe weight gain and cognitive side effects, whichinclude cognitive dulling, complaints of impaired

memory and concentration, and diminishedcreativity, are the most problematic for patientsand may be more associated with nonadherence(72). Significant weight gain may be seen in 25% ormore of lithium-treated patients (73).Lithium may also have deleterious effects on

both renal function and thyroid function whentaken over long time periods. The classic sideeffects related to renal effects of lithium, polyuriaand polydipsia, are due to functional, and laterstructural, tubular changes in the kidneys and arenot typically associated with progressive glomeru-lar dysfunction (74). However, a smaller subset oflithium-treated patients exhibit �creeping creati-nine� in which the serum creatinine (reflectingdecreased glomerular filtration rate) increases overmonths and years (75). An even smaller subsetof patients will progress towards renal failure,dialysis, and ⁄or renal transplantation (76). Regularmeasurement of serum creatinine (but not ofcreatinine clearances) is an appropriate andmandatory component of maintenance lithiumtreatment.Long-term thyroid effects of lithium are due to

lithium�s capacity to interfere with iodine trappingin the thyroid gland and the release of thyroidhormones (77). This results, not infrequently, ineither subclinical or, at times, overt clinical hypo-thyroidism. There is increasing recognition ofsuboptimal maintenance response with relativelithium associated changes in thyroid economy.Controlled data would suggest that even subtlechanges in thyroid economy [i.e., relative increaseand decrease in thyroid-stimulating hormone

Box 1. Maintenance treatment

Key principles of pharmacotherapy

Goal

• Maintenance is the predominant treatment phase in which the core goal is to prevent future mood episodes.• Given the recurrent nature of bipolar disorder and the high rates of relapse, reductions in the number, intensity, and length of

mood episodes and elimination of subsyndromal symptoms between episodes, are perhaps more realistic markers of theeffectiveness of maintenance treatment in clinical practice.

Monotherapy ⁄ combination therapy

• Monotherapy is the ideal but is seldom achieved and may not be as effective as combination therapy. If adjunctive therapyis utilised, clinicians should be conscious of the side effect burden of multiple medications and continuously review medicalregimens to ensure only those which provide additional benefits continue to be administered.

Strength of evidence

• Lamotrigine, olanzapine, and quetiapine have established efficacy in preventing both mania and depression. Lamotrigine is moreefficacious in preventing depression whereas olanzapine is more effective in preventing mania.

Recommended pharmacotherapy

Mania predominance Equal Depression predominance

Monotherapy LithiumOlanzapine

Quetiapine Lamotrigine

Combination therapya Lithium or valproate + lamotrigineLithium or valproate + quetiapineLithium or valproate + aripiprazole

aRecommendations apply to all three clinical scenarios.

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(TSH) and free thyroxine, respectively] are associ-ated with depression recurrence and rapid cyclingin lithium maintenance (78, 79). Regular monitor-ing of thyroid function via serum TSH measure-ments is mandatory with lithium treatment.Supplemental thyroid treatment for a rising TSHand ⁄or overt hypothyroidism is not a contraindi-cation to ongoing lithium treatment.

Valproate

Common side effects seen with valproate includesedation, gastrointestinal side effects (includingnausea, vomiting, and ⁄or diarrhea), tremor, weightgain, and hair loss (80). In the one trial providingcomparative side-effect profiles of lithium andvalproate, valproate was associated with moreweight gain compared to lithium (21% versus13%, respectively) (32). Increases in hepatic trans-aminases or thrombocytopenia may occur withvalproate. More rarely, valproate is associated withtrue hepatitis and hepatic failure.Valproate has increasingly been reported to

cause polycystic ovarian disease at rates greaterthan those seen with other anticonvulsants (81, 82).Valproate is also the most teratogenic of allmaintenance treatments in bipolar disorder withhigh rates of neural tube defects in infants exposedduring the first trimester (83). These data areconcerning, particularly as it relates to long termmaintenance of women with bipolar disorder ofchild-bearing potential.

Lamotrigine

Lamotrigine is generally awell-toleratedmedicationwith a lower side effect burden than the other moodstabilizers. It is associated neither with sedation norweight gain. Benign rash (in approximately 5% ofpatients), nausea, and insomnia may be seen.The greatest concern about lamotrigine�s safety

as a maintenance treatment reflects the rareoccurrence of a hypersensitivity reaction, withspecific concerns about the development ofStevens–Johnson syndrome (SJS) and aseptic men-ingitis. (Ironically, carbamazepine is more likely tocause SJS, although most clinicians are unaware ofthis). The rate of serious rash with lamotriginerequiring hospitalization is approximately 1 ⁄1000,with the rate of SJS estimated as 1 ⁄6000 fromepilepsy studies (84, 85).

Carbamazepine ⁄ oxcarbazepine

Carbamazepine is associated with a significant sideeffect burden. Common dose-related side effects

include primarily neurological symptoms such asdiplopia, blurred vision, ataxia, and decreased finemotor coordination. Fatigue and nausea are alsocommonly seen. Mild asympomatic leukopeniamay occur and is relevant only insofar as itfrightens the treating physician. Hyponatremiamay also be seen and may be symptomatic,especially in the elderly.The important rare, serious side effect from

carbamazepine is the idiosyncratic occurrence ofagranulocytosis and ⁄or aplastic anemia, typicallyseen within the first six months of treatment. Theutility of frequent measurements of blood countsduring this time is unclear. Hypersensitivity reac-tions, including the development of SJS, rarelyoccur but are more frequent than with any othermood stabilizer (including lamotrigine) (85).Oxcarbazepine shares the same general side

effect profile as carbamazepine but in muchmilder form (86). However, agranulocytosis ⁄aplas-tic anemia seem not to occur with oxcarbazepine,and routine blood monitoring is never appropri-ate. The only side effect more commonly seenwith oxcarbazepine than with carbamazepine ishyponatremia.

Second-generation antipsychotics

The five second-generation antipsychotics reviewedabove share some common side effects and longterm health risks but differ sufficiently enough fromeach other to warrant separate discussions. Theonly important risks common to all of these agentsis the boxed warning for increased mortality inelderly patients with dementia-related psychosisand the liability for tardive dyskinesia. Eventhough second-generation antipsychotics in generalhave a substantially lower risk for tardive dyski-nesia compared to first-generation antipsychotics,the risk is not zero and has been estimated atapproximately 1 ⁄7 of that seen with the first-generation antipsychotics (87). Nonetheless, notruly long term studies of bipolar disorder patientstreated with second-generation antipsychotics areavailable and the likelihood of the development oftardive dyskinesia over years or decades of main-tenance treatment must always be considered as apotential risk.

Olanzapine

Long term side effect considerations with olanza-pine are dominated by appropriate concerns aboutweight gain, hyperlipidemia, the development ofmetabolic syndrome, and ⁄or new onset diabetesmellitus. Although most cases of new onset diabe-

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tes mellitus with olanzapine are associated withconcomitant weight gain, this link is not universaland insulin resistance in the absence of weight gainin both humans and animals has been demon-strated with both olanzapine and clozapine (88,89). With the possible exception of clozapine(which has unique risks and benefits), these risksare highest with olanzapine compared to all otherantipsychotics. Weight gain tends to be rapid butmay continue to progress for years (90). Sedation isthe other most common and distressing side effectof olanzapine.

Aripiprazole

Aripiprazole can, paradoxically, be associated witheither sedation or activation (whether classified asakathisia, insomnia, or generic stimulation effects).Extrapyramidal symptoms most commonly presentas akathasia, rather than stiffness. When akathisiaoccurs, it is typically early in treatment and tendsto diminish over time (91). In general, aripiprazoleis far less sedating than olanzapine but is associ-ated with much higher rates of stimulation sideeffects. Only a small subset of patients will showsignificant weight gain with aripiprazole. It has notbeen associated with increased risk of hyperglyce-mia and ⁄or metabolic syndrome parameters.

Quetiapine

Quetiapine�s side effect profile as a maintenancetreatment stands midway between olanzapine andaripiprazole in its weight gain and sedation liabil-ities (92). Although weight gain and sedation arethe most common side effects associated withquetiapine, these typically occur less frequentlycompared with olanzapine. Similarly, hyperglyce-mia and hyperlipidemia can be seen (93). It isprobably the least likely of the second-generationantipsychotics to be associated with classic extra-pyramidal symptoms (EPS).

Ziprasidone

Like ariprazole, ziprasidone can be either sedatingor stimulating, with insomnia and akathisia seenalong with sedation. (67). Ziprasidone is among themost weight neutral of the second-generationantipsychotics and may be associated with weightloss in some patients. Consistent with this,hyperlipidemia, hyperglycemia, and othermetabolic syndrome parameters seem not to occurwith ziprasidone. Earlier concerns about QTcprolongation have generally receded (94). In theadjunctive maintenance ziprasidone study, no

changes in mean QTc intervals with treatmentwere seen (89).

Risperidone long-acting injection (RLAI)

As expected, RLAI has a side effect profile similarto oral risperidone. In the two controlled studies,common side effects included weight gain, EPS(including akathisia, tremor, and muscle rigidity),hyperglycemia, and hyperprolactinemia (68, 69).Of the second-generation antipsychotics, RLAI hasthe highest liability for classic EPS and hyperpro-lactinemia and is moderate in its liability for weightgain and metabolic syndrome.

Adjunctive psychotherapies

As noted above, combination treatments often aremore effective than monotherapies as maintenancetreatments for bipolar disorder. Nowhere is thismore clear than in the consistent results of psycho-therapy studies which demonstrate that a variety ofevidence-based psychotherapies adjunctive to phar-macotherapy are associated with better outcome, asmeasured by longer survival time before relapse,fewer relapses, greater reductions in symptom ratingscales, enhanced adherence, fewer days in moodepisodes, improved social functioning, and fewerand shorter hospitalizations. A variety of differentstructured psychotherapies, listed in Table 4 havebeen evaluated and found to be effective. Detailsabout these psychotherapies would be beyond thescopeof this article but are reviewedat greater lengthin a number of recent articles (95, 96).Although each type of psychotherapy differs

somewhat from the others, some common themes,listed in Table 5, are evident across most of thetherapies and may explain the consistent efficacy,despite the diversity of approaches. Educationalprograms and systematic care programs may bemore effective for manic compared to depressivesymptoms, while family and cognitive behavioraltherapy (CBT) may be more effective for depressivesymptoms (96). However, at this point, it would beimpossible to suggest one specific psychotherapeu-tic approach over another. Group therapy wouldseem to be the most economical; family-focused

Table 4. Manual driven therapies

• Family-focused treatment• Cognitive therapy or cognitive behavioral therapy• Psychoeducation

• Group• Individual

• Interpersonal and social rhythm therapy• Systematic care model

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therapy may be optimal for patients with intrusive,hostile families. Additionally, although most clini-cians are not trained in these manual-driventherapies, given some of the common elementsacross the therapies, experienced clinicians canconsider adapting these elements and using them ina flexible manner as is universal in non-researchsettings. Thus, any patient with recurrent moodepisodes despite ongoing pharmacotherapy shouldat least be considered for adjunctive psychother-apy. Given the strength of the psychotherapyefficacy data in bipolar disorder, it would bereasonable to say that patients should not beconsidered treatment resistant until they have hada full trial of one of these psychotherapies.

Limitations

As noted above, even with the greater relativenumber of RCTs (and subsequent clinical indica-tions given by governmental bodies such as FDAin the USA) published over the last decadecompared to previous decades, it is still accurateto describe the area of maintenance treatment ofbipolar disorder as being in its infancy. Overall, thenumber of sufficiently powered studies systemati-cally examining the efficacy of the types of treat-ments prescribed by clinical practitionersthroughout the world is still rather small. Addi-tionally, the translation of the results of thesestudies is problematic given the typical inclu-sion ⁄ exclusion criteria used and the dropout rateswithin these studies. With their less restrictiveinclusion criteria, effectiveness studies such as theBALANCE study (44) help somewhat, but thereare far too few of these studies to answer the manyimportant treatment questions that require furtherresearch in the generation of better quality data.Thus, firmer conclusions and a more data-basedalgorithm for maintenance treatment of bipolardisorder await the generation and publication ofmore robust and clinically relevant data.

Conclusions

Given the inherently recurrent nature of bipolardisorder and the toll that both manic and depres-sive episodes take on individuals and their families,maintenance treatment, in which the goal is theprevention of mood episodes, is the most impor-

tant phase of overall treatment. It is ironic thatdespite the increased number of demonstratedeffective maintenance treatments, the naturalhistory of treated bipolar disorder continues to bedominated by breakthrough episodes continuing asthe rule, rather than the exception. This is likely tobe due to the effects of treatment nonadherenceand other factors that interfere with optimaltreatment outcome. Nonetheless, having a numberof potentially effective therapies gives clinicianstools that were scarcely imaginable 30 years agowhen lithium was the only effective maintenancetreatment available. Wise clinicians will utilizethese therapies, both pharmacotherapies and psy-chotherapies, and prescribe them in combinations(some of which have been evaluated and some not)for optimal treatment of bipolar disorder.

Disclosures

MG has served on the speakers bureau for Bristol-MyersSquibb, Eli Lilly & Co., and AstraZeneca. MAF has receivedgrant support from Pfizer, NARSAD, NIMH, the NationalInstitute of Alcohol Abuse and Alcoholism (NIAAA), and theMayo Foundation.

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