enhancing medication adherence in patients with bipolar disorder

human psychopharmacology

Hum. Psychopharmacol Clin Exp 2010; 25: 1–16.

Published online in Wiley InterScience

(www.interscience.wiley.com) DOI: 10.1002/hup.1081

REVIEW ARTICLE

Enhancing medication adherence in patients with bipolar disorder

Lesley Berk1,2,3, Karen T. Hallam1,3,6, Francesc Colom5, Eduard Vieta5, Melissa Hasty3,Craig Macneil3 and Michael Berk1,2,3,4*

1University of Melbourne, Victoria, Australia2Barwon Health and The Geelong Clinic, Victoria, Australia3Orygen Research Centre, Parkville, Australia4Mental Health Research Institute, Parkville, Australia5Bipolar Disorders Program, Institute of Neuroscience, Hospital Clinic, IDIBAPS, CIBERSAM, University of Barcelona, Catalonia, Spain6Department of Psychology, Victoria University, Victoria, Australia

Objectives Medication adherence contributes to the efficacy-effectiveness gap of treatment in patients with bipolar disorder. This paperaims to examine the challenges involved in improving medication adherence in bipolar disorder, and to extract some suggestions for futuredirections from the core psychosocial studies that have targeted adherence as a primary or secondary outcome.Methods A search was conducted for articles that focused on medication adherence in bipolar disorder, with emphasis on publications from1996 to 2008 using Medline, Web of Science, CINAHL PLUS, and PsychINFO. The following key words were used: adherence, compliance,alliance, adherence assessment, adherence measurement, risk factors, psychosocial interventions, and psycho-education.Results There are a number of challenges to understanding non-adherence including the difficulty in defining and measuring it and thevarious risk factors that need to be considered when aiming to enhance adherence. Nevertheless, the importance of addressing adherence isevidenced by the connection between adherence problems and poor outcome. Despite these challenges, a number of small psychosocialstudies targeting adherence as a primary outcome point to the potential usefulness of psycho-education aimed at improving knowledge,attitudes, and adherence behavior, but more large scale randomized controlled trials are needed in this area. Evidence of improved outcomesfrom larger randomized controlled trials of psychosocial interventions that target medication adherence as a secondary outcome suggests thattackling other factors besides medication adherence may also be an advantage. While some of these larger studies demonstrate animprovement in medication adherence, the translation of these interventions into real life settings may not always be practical. A personcentered approach that considers risk factors for non-adherence and barriers to other health behaviors may assist with the development of moretargeted briefer interventions. Integral to improving medication adherence is the delivery of psycho-education, and attention needs to be paidto the implementation, and timing of psycho-education. Progress in the understanding of how medicines work may add to the credibility ofpsycho-education in the future.Conclusions Enhancement of treatment adherence in bipolar patients is a necessary and promising management component as an adjunct topharmacotherapy. The current literature on psychosocial interventions that target medication adherence in bipolar disorder points to thepossibility of refining the concept of non-adherence and adapting psycho-education to the needs of certain subgroups of people with bipolardisorder. Large scale randomized controlled trials of briefer or more condensed interventions are needed that can inform clinical practice.Copyright # 2009 John Wiley & Sons, Ltd.

key words—bipolar disorder; adherence; treatment; psychosocial intervention

INTRODUCTION

Bipolar disorder is a chronic disease with periods ofremission and relapse (Sachs and Rush, 2003). TheWorld Health Organization (WHO) has reported thatbipolar disorder is the world’s sixth leading cause of

*Correspondence to: M. Berk, Department of Clinical and BiomedicalSciences, University of Melbourne, Swanston Centre, PO Box 281, Gee-long, Victoria 3220, Australia. Tel:þ61 3 52267450. Fax:þ61 3 52267436.E-mail: [email protected]

Copyright # 2009 John Wiley & Sons, Ltd.

disability among people aged 15–44 years (Ayuso-Mateos, 2000; Murray and Lopez, 1996). Bipolardisorder is common, with 1% lifetime incidence ofbipolar I disorder, 1.1% incidence of bipolar II disorder,and 2.4% incidence of sub-threshold bipolar disorder(Akiskal et al., 2007). Bipolar disorder is particularlycrippling to many patients, and suicide attempts occurin 25–50% of patients (Berk et al., 2004). Comorbidityis also common with substance abuse, anxietydisorders, and personality disorders frequently com-plicating the bipolar disorder milieu, increasing

Received 20 May 2008

Accepted 22 October 2009

2 l. berk ET AL.

treatment complexity, and leading to poorer thera-peutic outcomes (Jones et al., 2005).Psychopharmacolgy plays an important role in both

the acute and maintenance phases of the illness(Geddes et al., 2004). Following the resolution of anacute illness episode, long-term prophylaxis is requiredto prevent recurrence. Despite an increasing pharma-copoeia of effective medications for the treatment ofbipolar disorder, patient outcomes continue to beimpacted by treatment adherence (Sajatovic et al.,2007c). Non-adherence to treatments is also a majorobstacle in translating efficacy in research settings intoeffectiveness in clinical practice (Lingam and Scott,2002). Evidence further indicates that while cliniciansmay not routinely address non-adherence as a riskfactor for poor outcomes (Havens and Ghaemi, 2005),the benefits of pharmacotherapy may be enhanced ifcombined with psychosocial interventions (Cochran,1984; Scott and Tacchi 2002) that have been showninter alia to improve adherence (Miklowitz, 2006).Enhancing adherence is a complex clinical chal-

lenge, owing to the complexity of the concept anddifficulty measuring adherence, the number of riskfactors to consider and the challenge of extractingstrategies that have proven to promote adherence fromthe encouraging studies of psychosocial interventionsin the area (Demyttenaere and Haddad, 2000; Sajatovicet al., 2007b). This paper examines the literature onmedication adherence in bipolar disorder, and thechallenges involved in addressing and reducingadherence problems and makes some suggestions forfuture research and clinical practice.

METHODS

A comprehensive literature search was undertakenthrough Medline, Web of Science, CINAHL PLUS,PsychINFo for papers published between 1996 and2008. These database were searched using thefollowing key words; bipolar disorder and adherence,compliance, alliance, adherence assessment, adher-ence measurement, risk factors, psychosocial inter-ventions, and psycho-education. This search high-lighted some important articles published earlier thanthese dates that were also included in this review. Theresults indicated a number of key areas to examine inorder to understand the difficulty, but importance ofaddressing medication adherence problems in bipolardisorder, and the efforts that have been made toimprove adherence in psychosocial interventionstudies. Common to all these studies is a psycho-education component. The literature to date points tofuture directions to enhance psycho-education in order


to improve adherence tomedication in real life settings.Hence we focused on the following areas:

(1) T
he definition and measurement of medicationadherence.
(2) T
he impact of poor adherence on clinical, func-tional, and illness outcomes.
(3) R
isk factors associated with adherence issues. (4) P sychosocial interventions to increase adherence. (5) I mproving psycho-education.
RESULTS

The definition and measurement of adherence

Defining adherence. Early conceptions of adherencestem from the traditional medical model, with itsauthoritarian connotations, which equated adherencewith compliance. A more recent concept of adherenceinvolves following treatment in the context of acollaborative model where the patient is included in acollaborative process as an active participant in theirown treatment (Berk et al., 2004). This concept ofadherence emphasizes the therapeutic relationship asthe vehicle for exchanging information and opening updiscussion aimed at reaching a ‘concordance’ abouttreatment. In addition, on a purely practical level,adherence involves a number of behaviors includingaccessing treatment, obtaining medications, under-standing and following instructions about taking andmonitoring medications and remembering to takemedications. Non-adherence may be ‘‘voluntary’’ orintentional when the person decides not to adhere totreatment or ‘‘involuntary’ where the lack of adherenceis unintentional, for example they forget to take theirmedication (Colom et al., 2005b).It has been noted that patients may modify, rather

than completely accept or abandon treatment regimens(Noble, 1998). This varying medication regimens leadsto partial (i.e., client takes only part of their full doses)or irregular (i.e., client ‘‘stops and starts’’ treatmentsporadically for varying intervals) adherence as opposedto ‘‘all or none’’ decisions about taking medications(Colom and Vieta, 2002). Another way of failing tofollow recommended treatment is through possible‘‘abuse’’ of prescription medication. A further issue isthat clients may be ‘‘selective’’, adhering fully to somemedications but not others at different times (Colomet al., 2005b). These factors indicate that adherence isdynamic, varying in a number of ways, thus requiringrepeated discussion throughout treatment.While some studies have viewed adherence as the

acceptance and taking of prescribed medication(Dharmendra and Eagles, 2003), a comprehensive

Hum. Psychopharmacol Clin Exp 2010; 25: 1–16.DOI: 10.1002/hup

medication adherence in bipolar disorder 3

definition of adherence focuses on broader adaptivehealth behaviors (Cochran, 1984; Wright, 1993). Thisdefinition encapsulates attendance at consultations andcommitment to a healthy lifestyle, as well as takingprescribed medication at the appropriate dose and time.Although this broader definition may encapsulateadherence behavior more thoroughly, this paperinvestigates medication adherence more specifically,as there is little available information on other types ofnon-adherence in bipolar disorder.

Measuring adherence. The realization that adherenceis not an all or nothing phenomenon and may forexample be partial, irregular and selective placesincreasing demands on developing measurement toolsthat accurately capture all these dimensions. Preciseevaluation and assessment of treatment adherence isdifficult in patients with bipolar disorder (Sajatovicet al., 2004). This difficulty is further exacerbated bythe lack of agreement about how best to measureadherence (Pomykacz et al., 2007).There is currently no ideal measure of adherence.

Techniques used include self-report, reports by familymembers or significant others, biological tests (e.g.,plasma lithium levels), and independent evaluation ofadherence patterns. All of these assessments ofadherence have limitations, for example, it has beensuggested that self-assessment by patients is potentiallyunreliable, as they may overestimate or over-report theirtreatment adherence when being asked by their clinician(Sajatovic et al., 2007b). However, Scott (2000) foundthat self-report assessment correlated highly with serumlithium levels. Moreover, if only plasma drug levels areconsidered, adherence with drugs with a long half-life,such as antipsychotics, may be overestimated, and theassessment of some drugs with a great inter-individualvariation of serum levels such as antidepressant drugswould be confusing (Colom and Vieta, 2002).Byerly et al. (2005) used electronic monitoring

packs for medication to monitor adherence toantipsychotics in outpatients. The results indicatedclinically significant non-adherence was evident inaround 50% of patients. In contrast, cliniciansindicated that none of these patients were non-adherent, thus indicating significant discrepancies inadherence estimates and electronic measures.Although electronic medication packs may providemore reliable information about medication adherence,associated costs tend to be prohibitive for use inclinical practice. Data from pill count assessment maybe unreliable as patients may not necessarily beingesting the pills after removing them from packagingor pill box (dosette) (Sajatovic et al., 2007b). Blood


measurement may also be unreliable as medicationadherence for only a few days before blood testing canraise blood levels to appropriate levels (Vieta, 2005).Based on these restraints, a more reliable and practicalmethodology for adherence assessment may be tocombine modalities such as; patients’ reports, care-givers’ reports (if congruent with family engagementand consent), and unscheduled blood monitoring. It ishowever unclear what weight to give each of thesemeasures in assessing an individual’s adherence status(Sajatovic et al., 2007b). It is possible that combiningsubjective and objective quantitative assessment with amore qualitative interview may shed more accuratelight on a person’s overall adherence status and provideinformation on different aspects of their adherence. Forexample, if it is selective and irregular. Despite thesechallenges, studies have been conducted using variousdefinitions of adherence and measurement techniquesto examine the impact of adherence status on outcome,to identify risk factors and to evaluate the effects ofadjunctive psychosocial interventions.

The impact of poor adherence on clinical,functional, and illness outcomes

Mood stabilizers are considered to be highly effectivein the treatment of clinical trial populations withbipolar disorder. However, rates of relapse in patientswith bipolar disorder (even when taking moodstabilizers) are as high as 40% in the first year, 60%in the second year, and 73% over 5 or more years(Gitlin et al., 1995). Johnson and McFarland (Johnsonand McFarland, 1996) followed 1500 patients treatedwith lithium and reported that the mean duration ofcontinuous lithium adherence was 76 days. Thus, thepotential benefits of pharmacological treatment onrecovery, preventing relapse and reducing mortality aresignificantly undermined by poor adherence.Studies that have examined the effects of stopping

medication highlight the serious consequences of non-adherence (Keck et al., 1998; Svarstad et al., 2001).The cause and effect relationship underlying thischange in adherence may be bi-directional. Morespecifically, it may be that adherence decreases whenclients are becoming unwell. Alternatively, failing toadhere to medication may lead to relapses in moodepisodes (Keck et al., 1996). Suppes et al. (1991)showed that the time to a 50% failure of remission afterlithium discontinuation was 5.0 months after stoppingtherapy. Cavanagh et al. (2004) demonstrated pooreroutcomes and increased risk of relapse after acutelithium withdrawal through a review of clinical patientfiles over 7 years.


4 l. berk ET AL.

Faedda et al. (1993) raise the possibility that how amedication is discontinued may be a factor thatinfluences relapse, and the understanding of the effectof non-adherence on outcome. They reported a greaterrisk of a new episode of mania after rapid rather thangradual lithium discontinuation, an effect that was evengreater for depression. Baldessarini et al. (1999) havealso demonstrated that rapid cessation of lithium leadsto an even greater risk of relapse than not having takenthe drug at all, and that within 5 months of cessation,50% of patients have relapsed (mainly into mania). Areview by Colom et al. (2005b) also reported that rapiddiscontinuation of lithium was associated with relapserates of 50% in the 3 months following cessation,compared with less than 10% in people who continuedtaking prophylactic medication. While complete non-adherence has known impacts on outcomes, it must benoted that partial adherence also impacts risk of relapseand re-hospitalization (Scott and Pope, 2002a). Kecket al., (1998) also reported that fully adherentindividuals are more likely to achieve syndromicrecovery than those who are non- or partially adherent.The importance of adherence in bipolar disorder is

further highlighted when considering suicide andmortality in bipolar disorder (Baldessarini et al.,2006). It is notable that untreated bipolar patients are5 times more likely to commit suicide (Angst et al.,2005), and other deaths are also more frequent in

Figure 1. Factors that influence adherence status


untreated patients (Angst et al., 2002). This impliesthat medication adherence has a protective effect.Adherence with mood stabilizers, particularly lithium,has been found to significantly reduce the likelihood ofattempted or completed suicide in people with bipolardisorder (Goodwin et al., 2003). For example, in aprospective 10-year follow up study of the relationshipbetween suicidal acts and adherence to lithium inbipolar patients, Gonzalez-Pinto et al. (2006) found a5.2 fold increased suicide rate in patients with pooradherence compared to highly adherent patients. Thesestudies confirm the usefulness of targeting adherence toimprove both clinical and safety outcomes in bipolardisorder. Identifying risk factors for adherenceproblems and researching possible ways to addressthese problems may make a difference to people withbipolar disorder and their families.

Risk factors associated with adherence issues

A number of factors, some of which are amenable tochange have been associated with medication non-adherence in bipolar disorder (Figure 1). These include

(1) D
emographic and illness related factors. (2) K nowledge, attitudes, and beliefs. (3) T reatment variables.


Demographic and illness related factors. Adherenceproblems may be linked to specific demographic fac-tors such as age, comorbidity, social support, andgender, and may inform interventions that target adher-ence in these specific groups of people with bipolardisorder. For example, a recent study by Sajatovic et al.(2007c) assessed medication adherence in 44 637patients receiving either lithium or anticonvulsantmedication, using the medication possession ratio(MPR: days of supply/ 365 days). Results indicatedthat non-adherent patients were more likely to beyounger, non-Caucasian, single, homeless, to havesubstance use disorders, and attend less outpatientvisits compared to patients who were fully or partiallyadherent. Interestingly, patients receiving two moodstabilizing agents were more adherent than patientsreceiving a single agent.In a study examining age comparisons and treatment

adherence to antipsychotic medications, Sajatovic et al.(2007a) found that age (over 60 years versus youngerpatients), was a significant predictor of adherence toantipsychotic medications. More specifically, it wasreported that 61% of the older individuals were fullyadherent, compared to 49.5% in younger individuals.The authors highlight that even with these figures, thepatients in the older age group still experience adherenceproblems. This may be connected to an increasednumber of medications being required to treat physicalcomorbidity, and a decrease in cognitive ability resultingin unintentionally forgetting to take medication (Deppet al., 2007). Providing tools to prompt adherencebehavior and help organize daily doses may beparticularly helpful in this group of people. Studieshave found conflicting evidence about the link betweenyounger age and non-adherence (Colom et al., 2005b).Colom et al. (2000) highlight that from a clinical pointof view it may be wise to look out for non-adherence inrefractory patients that fall in the two extremes of thelifespan, teenagers and the elderly.Comorbid substance abuse was found to be a

predictor of non-adherence in both younger and olderpatient groups (Sajatovic et al., 2007a). In a study byManwani et al. (2007), lifetime adherence to moodstabilizers was 65.5% for the group of people withbipolar disorder and co-occurring substance usedisorders compared to 85% in those people withbipolar disorder without substance use disorders(p< 0.05). People with bipolar disorder and comorbidsubstance use disorders provided different reasons fornon-adherence compared to reasons provided by thosewithout this comorbidity, highlighting the importanceof addressing this specific risk factor when aiming toimprove adherence. In a recent review of the treatment


adherence literature, Gaudiano et al. (2008) highlightthe need to address this risk factor for non-adherence inadherence programs. Most existing psychosocialinterventions exclude people with co-occurring sub-stance use although 60% of people with bipolardisorder have a lifetime history of substance usedisorders comorbidity and this is connected with worsecourse of bipolar illness, greater impairment, andhigher suicide rates (Gaudiano et al., 2008). Othercomorbid disorders that may affect adherence includepsychosis (Miklowitz, 1992) and personality disorders(Colom et al., 2000).Cognitive deficits in bipolar disorder do not only

occur in old age. They may be present in acute moodstates and euthymic bipolar patients, and there is agrowing awareness of the need to find treatments toaddress these deficits and their impact on functioning(Burdick et al., 2007, Vieta, 2005). Helpful behavioraltools to prompt adherence may help compensate forimpairment.In terms of social factors, marriage appears to be a

protective factor that increases adherence (Connelly etal., 1982; Sajatovic et al., 2007b). Perceived continuityof care was also associated with adherence withconsultation appointments.The role of gender on adherence is still unclear, with

studies reporting conflicting findings. For example,Kessing et al. (2007) reported that woman weresignificantly more likely to have poorer adherence tolithium in a naturalistic study in Denmark, whereasSajatovic et al. (2006) did not find gender significant intheir study of adherence to antipsychotics in veteranswith bipolar disorder. The latter study reported thatwoman may have been under-represented in theirsample. This highlights the difficulty of identifying riskfactors for poor adherence across studies to assessdifferent kinds of medications.Examining adherence problems in the different

phases and stages of illness may also increaseunderstanding of high-risk times. For example, ahigh-risk time for adherence problems has beenconnected to manic symptoms, with the risk increasingwith the severity of manic symptom (Keck et al.,1996). This may be linked to cognitive deficits or poorinsight common to this phase of illness (Colom et al.,2005b; Copeland et al., 2008). An area for futureresearch on adherence difficulties may be thedepressed phase. For example, little is known abouthow negative cognitions or other depressive symptomsaffect adherence behavior (Gaudiano et al., 2008).Adherence problems may be prevalent at specificstages in the course of illness such as prior to ‘‘Lateadherence’’ when patients adhere to medication after


6 l. berk ET AL.

experiencing repeated relapses and eventually accept-ing the need for medication. ‘‘Late non-adherence’’typically occurs when a person has been taking a moodstabilizer for a few years, and begins to question theneed for medication as they have been well, or to worryabout the dangers of long-term use (Colom and Vieta,2002).

Knowledge, attitudes, and beliefs. Having knowledgeabout their illness and treatment can assist people inmaking informed decisions about illness managementand reduce inaccurate and negative beliefs aboutmedications. Several studies have examined the impactof knowledge, beliefs, and attitudes on medicationadherence in bipolar disorder, and have foundadherence to be associated with patients increasedunderstanding of their illness and need for preventative(prophylactic) treatment. For example, Rosa et al.(2007) assessed medication adherence and its relatedfactors using the lithium attitudes questionnaire (LAQ),lithium knowledge test (LKT), andmedication adherencerating scale (MARS) in patients with bipolar disorder.They reported that patients’ knowledge about thedisorder and medication was positively correlated withtreatment adherence to lithium prophylaxis. The largeGamian-Europe/ Beam survey found an improvement inquality of life and medication adherence in people withbipolar disorder who were more informed about theirillness and its treatment (Morselli et al., 2004).In an effort to further understand the impact of

patient perception on adherence, Adams and Scott(2000) reported that highly adherent subjects showed ahigher perception of illness severity and strongerbeliefs about the benefits of treatment, contributing43% of the variance in adherence behavior. Kleindienstand Greil (2004) showed that adherence to medicationwas associated with inflated scores on the subscales ofthe Illness Concept Scale (ICS) relating to trust inmedication and clinicians, and absence of negativeexpectations toward treatment. A recent small qual-itative study also found that patients made decisionsabout taking medication or not based on theirperceptions of the illness and treatment (Clatworthyet al., 2007). In addition to examining intentional orvoluntary non-adherence they found a different riskfactor for involuntary non-adherence. This uninten-tional non-adherence was commonly linked to forget-ting especially when becoming manic. While addres-sing perceptions about illness and treatment is vital,exploring other aspects of non-adherence can informadditional strategies that may be needed to boostadherence. Interestingly, Clatworthy and colleague’sstudy is intended to inform the development of a


questionnaire to assess the common illness andtreatment perceptions that affect adherence status inbipolar disorder. Such a questionnaire may facilitateeasier detection of these risk factors.Difficulties in accepting bipolar disorder may

impede adherence. Scott and Pope (2002) found thatin a cohort of patients with affective disordersreceiving long-term medication, three factors, denialof illness, previous non-adherence, and being pre-scribed a mood stabilizer for a long time, were highlypredictive of partial adherence. For some people, thestigma and idea of having a chronic mental illness maydeter adherence (Cochran 1984). Conversely, abnormalillness behavior, attachment to the ‘‘sick role’’ orpursuit of elevated moods and sensation seeking mayalso result in adherence problems (Berk et al., 2004).For some individuals, illness may become an unwittingescape from life’s demands and complexities. Inter-estingly, patients with a more internal locus of controlmay show aversion to be controlled by medication.However, the link between internal locus of control andpoor adherence is controversial with studies displayingconflicting results (Adams and Scott, 2000; Darling,et al., 2008).The views of significant others such as family

members and clinicians may influence patient attitudesand beliefs about the illness and its treatment and affectadherence. Therefore, understanding the beliefs ofsignificant others and caregivers, and their impact onpatients’ adherence behavior, is important (Cochranand Gitlin, 1988). Family factors including highexpressed emotion and particularly over involvementhave also been associated with poorer adherence andpoorer overall outcomes in bipolar patients (Miklowitzet al., 1986; Perlick et al., 2004). Based on thesefindings, it would be predicted that interventions thatinclude family members as well as patients ascollaborative partners may improve adherence andimpact on outcomes.From a clinical point of view, understanding the

patients’ attitudes and beliefs about the illness andtreatment may indicate targets for clarifying infor-mation and discussion to improve adherence. Inter-estingly, Johnson and Fulford (2008) have developed aself-report scale, the ‘‘Treatment Attitudes Question-naire’’ that assesses awareness of illness and attitudesto treatment, to help identify patients at risk ofadherence problems and facilitate further research toinform treatment planning.

Treatment variables. Large-scale studies of typicalrisk factors connected to treatment variables couldultimately inform psychosocial interventions and



clinical practice, and have a positive effect onadherence. Notably, a treatment variable that mayhave a protective effect on adherence is a soundtherapeutic alliance. A recent study of veterans withbipolar disorder found that positive therapeutic alliancewas connected to medication adherence. Cliniciansencouraging regular contact with patients and patientshaving regular reviews of their progress wereparticularly important factors in self-reported adher-ence (Zeber et al., 2008). Strauss and Johnson (2006)reported that a strong therapeutic alliance had apositive influence on beliefs and attitudes resulting inless negative attitudes about medication and greateracceptance of illness and improved adherence. Lingamand Scott (2002) also highlighted the importance of thetherapeutic alliance, reporting that poor clinician–patient interaction was four times more common withnon-adherent patients compared to those who wereadherent. The importance of the therapeutic alliance inadherence may apply cross culturally, as evidenced bya survey of Chinese patients, that found that thetreatment alliance was more important than knowledgeabout treatment in sustained adherence to prophylacticlithium (Lee et al., 1992). The research by Bultman andSvarstad (2002) indicated that the benefit of therapeuticrelationships may extend to pharmacists, with resultsof their study indicating that pharmacist monitoringplayed a positive role in medication adherence,especially during the initiation of treatment.Pope and Scott (2003) reported a marked difference

between the reasons for non-adherence stated by theclinician versus the reasons for non-adherence statedby patients. This suggests a divide between clinicianand patients views on this issue, and a need forclinicians to listen to patients reasons for non-adherence and good communication to facilitate theexchange of information. Sajatovic et al. (2005)suggest that adherence is most likely when a strongcollaborative relationship exists between patient andclinician. There may be utility in developing colla-borative treatment plans that involve shared decisionmaking between clinician and patient, which in turnencourages a sense of ownership of the treatmentdecisions, contributing to adherence.It is particularly notable that although clinicians

commonly attribute their patients’ medication non-adherence to side effects, a large survey found that theyare not a major determinant of adherence. This largesurvey (Morselli et al., 2003, 2004) was conducted in anational patient organization in 30 European countries.The results indicated that only 18.3% of the patientsstated that side effects were the main reason fordiscontinuation of pharmacological treatments. The


major reasons for poor adherence that were citedincluded fear of being dependant on medication (30%)as well as poor medication information, and fear oflong-term side effects (20.2%). Of concern, the surveyfound that about 35% of the patients did not receive anyinformation on the possible side effects of themedications, and more than 50% had not receivedguidance on side effect management. Lack ofinformation may have contributed to the fear of sideeffects. Scott and Pope (2002b) showed that fear of sideeffects was a stronger predictor of non-adherencerather than the side effects experienced. In contrast,earlier studies, when medication adherence wasconsidered in the traditional medical model frame-work, showed a greater correlation between side effectsand non-adherence in bipolar patients (Gitlin et al.,1989). On the other hand, the fact that despite havingmore tolerable drugs than in the past, the non-adherence figures have remained basically the same,diminishes the importance of side effects on non-adherence. Interestingly a recent study involving a websurvey found that satisfaction with medication mightstill be worth considering. They reported thatmedications that improved depressive episodes andhad few cognitive side effects and little weight gainwere connected with improved satisfaction andadherence (Reed et al., 2007).A number of studies investigated the impact of

medication class on adherence, with the focus largelyon antipsychotics used in bipolar disorder. Gianfran-cesco et al. (2006) compared adherence to differentantipsychotics in patients with bipolar disorder.Adherence was evaluated by MPR and length oftreatment episodes. This study found that adherencewas higher with quetiapine than risperidone, olanza-pine, or typical antipsychotics. The adherence inten-sities of olanzapine and ziprasidone were additionallyhigher than with risperidone. In addition, the treatmentdurations of quetiapine and risperidone were signifi-cantly longer than with olanzapine, ziprasidone, andthe typical antipsychotics, although overall studydifferences were small. Dolder et al. (2002) reportedthat outpatient veterans who received atypical anti-psychotics had higher adherence rates than those whoreceived typical ones. However, Lingam and Scott(2002) have suggested that adherence has not beenimproved by the introduction of newer pharmacologi-cal agents and findings of Sajatovic et al. (2006)showed that adherence with atypical antipsychotics isstill low, with just over half (51.9%) of the bipolarpatients prescribed atypical antipsychotics being fullyadherent, while 48.1% of the patients were eitherpartially adherent or non-adherent. Baldessarini et al.


8 l. berk ET AL.

(2008) found that adherence did not vary acrosstherapeutic classes, but was rather influenced byfactors such as alcohol-dependence, youth, greateraffective morbidity, various side effects, comorbidobsessive-compulsive disorder, or recovery frommania–hypomania. Further studies are needed to betterunderstand treatment adherence to different pharma-cological agents used to treat bipolar disorder.Treatment adherence in bipolar disorder may be

influenced by a number of variables associated with thepatient, clinician, family, illness, and treatment andmany of these risk factors are amenable to interventionand could serve as clinical targets (Berk et al., 2008). Itis clear that there are many risk factors that may workindividually or compound with other factors to increaserisk of non-adherence. This implies that risk factorsmay differ from person to person and form predictableclusters in certain subgroups of people with bipolardisorder. These risk factors or clusters may not onlychange in relation to each other and the illness, but alsoacross time. Future research might consider exploringthe links between certain types of non-adherence andparticular risk factors in different subgroups of patientsat different stages of treatment to establish vulner-ability trends that could be addressed by adjunctivepsychosocial interventions. From a clinical point ofview, this plethora of risk factors highlights theimportance of not just providing information to thepatient but also of fostering a collaborative therapeuticrelationship whereby individual reasons for non-adherence can be discussed and addressed.

Psychosocial interventions for enhancingadherence

A combination of pharmacotherapy and psychotherapymay be optimal for achieving positive long-termoutcomes (Colom et al., 2003). Psychosocial inter-ventions targeting adherence as a primary outcomemeasure range from focusing exclusively on psycho-education about the illness and its treatment to thosethat utilize psycho-education plus behavioral andcognitive skills to enhance positive attitudes andadherence behaviors. Interventions that treat adherenceas a secondary outcome tend to be longer andinclude more complex interventions with a numberof illness management skills (Colom et al., 2003; Lamet al., 2005; Miklowitz et al., 2003). A common threadthat links all adjunctive psychosocial studies thattarget adherence is psycho-education. Most interven-tions require the establishment of collaborativerelationships with patients, clinicians, and sometimesfamilies to enhance adherence behavior. Psychother-


apeutic approaches to adherence include approachessuch as psycho- education, cognitive-behavioraltherapy, family interventions, and group therapy(Table 1). Overall the studies that do exist, despitethe differences in focus, types of intervention, durationand adherence measures used, point to the potentialusefulness of combining pharmacotherapy with psy-chotherapy to improve medication adherence.

Studies that target medication adherence as a primaryoutcome. Only a handful of studies have focusedprimarily on improving adherence. Peet and Harvey(1991) conducted a short psycho-education interven-tion aimed at improving adherence to lithium. Patientsin the treatment group were given a videotaped lectureand written handout with information about lithiumand follow up visits, while patients in the waiting listcontrol group did not receive any psycho-education.People who received the education had improvedknowledge about lithium at 6 weeks follow up.Interestingly, improved attitudes to lithium, ratherthan actual knowledge, in both the intervention andcontrol groups, was related to improved adherence.Patients in the intervention group reported missingfewer doses of lithium compared to the control group,but this did not quite reach statistical significance, andno differences were found between groups regardingplasma and serum RBC lithium levels. In a smallcontrolled study (n¼ 26), Dogan and Sabanciogullari(2003) found that giving bipolar patients a short three-session education program regarding the disorder andlithium treatment improved medication knowledge,quality of life and resulted in more regular medicationuse and a decrease in symptom levels at 3 months in thegroup that received the intervention.Some approaches have added cognitive and beha-

vioral strategies, aiming not only to increase knowl-edge, but to change attitudes to treatment and fosteradherence behavior. Cochran (1984) examinedwhether 6 weekly sessions of cognitive behavioraltherapy could improve adherence. This was measured,with patients’, informants and physicians’ reports,serum lithium levels and a composite measureincluding attendance at medical appointments, medi-cation consumption and lithium levels. Resultsindicated a significant improvement in patient adher-ence in the intervention, as opposed to the standardcare group at post treatment and 6 months later on thiscomposite measurement of adherence, as well as onphysicians ratings. Patients in the intervention groupwere less likely to stop lithium against their doctor’sadvice or to relapse and be hospitalized. Although thiswas a small study (n¼ 28), it highlights the potential


Table 1. Interventions targeting medication adherence as a primary outcome (T) and comprehensive interventions (C)

StudyNo. ofpatients Study design Outcome

Cochran (1984), T 28 Randomized controlled study of six sessions ofindividual cognitive behavioral therapy targetingadherence. Follow up occurred post trial, 3 monthsand 6 months

Increased adherence in intervention group on some ofthe measures, less people terminated lithium againstmedical advice, less hospitalization or relapses relatedto poor adherence (p� 0.05)

Peet and Harvey (1991), T 60 Wait list controlled study involving videotape andhandout plus follow-up visit. Study conducted over24 weeks

Knowledge of lithium improved in interventiongroup. No significant differences in adherence asassessed by self-report or plasma and RBC levels

Scott and Tacchi (2002), T. 10 Open pilot study of Concordance therapy (CCT):bipolar patients with self-reported problems receivedCCT. Psychiatric follow-up for 6 months

Improvement in attitude toward lithium associatedwith improvement in self-reported adherence. Serumlithium levels significantly increased after CCT (from0.4 to 0.6, effect size 1.7)

Dogan andSabanciogullari (2003), T

26 Bipolar patients on lithium therapy were given shorteducation program. Outcome was assessed at3 months in treatment and control groups

Educated group had increased medication knowledge,improved quality of life, reduced symptom level, andimprovedmedication adherence compared to baseline

Miklowitz et al. (2003), C 101 Randomized controlled trial of Family-focusedtherapy (FFT): FFT and pharmacotherapy versuscrisis management (CM) and pharmacotherapy.Outcomes were assessed every 3–6 months for 2 years

FFT-treated patients had fewer relapses (11/31, 35%)than CM patients (38/70, 54%, hazard ratio, 0.38,95% CI, 0.20-0.75, P¼ 0.003). FFT group had bettermedication adherence than CM group

Colom et al. (2003), C 120 Randomized controlled trial: Standard psychiatriccare plus group psycho-education versus unstructuredgroup meetings for 21 sessions. Outcomes assessedmonthly over 2-year follow up

Intervention group showed reduction in relapses,reduction in recurrences per person and hospitalization.Mean serum lithium levels were higher and more stablein intervention group

Lam et al. (2005), C 103 Randomized controlled trial of individual cognitivetherapy (CT): bipolar patients with frequent relapsewere randomized into control and CT group andfollowed up for 30 months

Compared to control, CT group had better survival tobipolar or depressive episodes, higher social functioning,less mood symptoms. Improvements in self and clinicianreported medication adherence

Ball et al. (2006) C 52 Randomized controlled trial of individual cognitivetherapy or treatment as usual over 12 months followup

Improvements in adherence did not differ betweengroups. There were significantly less severe depressionscores in the CT group

Frank et al. (2005) C 175 Randomized controlled trial of 4 combinations ofacute and maintenance phases of IPSRT and ICM.

No between group differences in adherence. Therewas greater time to new illness episode for thoseparticipants assigned to IPSRT in the acute phase

Depp et al. (2007), T 21 Quasi-experimental clinical trial, 12 group sessionswith middle aged tand elderley adults,divided into4 components (education, motivational training,medication management and symptom management)

Improvements in self-reported medication adherence,medication management ability, depressive symptoms,and selected indices of health-related quality of life


benefits of short cognitive behavioral interventionstargeting treatment adherence.Scott and Tacchi (2002) assessed the efficacy of six

sessions of concordance therapy in improving adher-ence with lithium prophylaxis over 6 months in a smallopen pilot study of ten outpatients with bipolardisorder. Concordance therapy is a form of cognitivetherapy (CT) that treats each person as an individual,and focuses on the choices that are concordant withtheir belief and value systems. A psycho-educationcomponent was supplemented with strategies aimed atachieving changes in attitudes to treatment in order tochange adherence behavior. The concordance approachaims to develop a shared understanding betweenclinician and patient about bipolar disorder and itstreatment and the formation of collaborative treatmentgoals, and has parallels with the notion of thecollaborative alliance (Berk et al., 2008). Thisconcordance encourages adherence to treatment regi-mens that are practical and meaningful to the patient.


Clarification of inaccurate beliefs and expectationsabout treatment and a problem solving approach toadherence difficulties assist in personalizing medi-cation adherence as an effective coping strategy. Thispilot study showed significant improvements inattitudes linked to improvements in self-reportedadherence and serum lithium levels.A recent small pilot study (n¼ 21) specifically

targeting medication adherence in middle aged andelderly adults with bipolar disorder demonstratedencouraging results for a 12 week group basedintervention involving medication adherence skillstraining using a quasi experimental design (Depp et al.,2007). Therewas a high retention rate, satisfaction withthe program and improvements in self-reportedmedication adherence, medication management abilityas well as depressive symptoms and aspects of healthrelated quality of life. The authors point out that alarger sample, follow up data and a control group isneeded to evaluate this intervention more thoroughly.


10 l. berk ET AL.

Interestingly, the reasons for non-adherence werelinked directly to the skills included in the interventionsuch as ways to remind oneself to take medications andcommunication with clinicians. These reasons for non-adherence were found to be more salient for this oldersubgroup of people with bipolar disorder than negativeattitudes, emphasizing the need for a patient centeredapproach to improving adherence.In summary, although these few studies have

limitations in that some are pilot studies, and thereis a need for larger longer term randomized controlledevaluation of interventions, they highlight the potentialof relatively brief focused efforts to improve medi-cation adherence. Such interventions may need toadopt a patient centered approach in targeting riskfactors that are patient specific.

Psychosocial interventions that target medicationadherence as a secondary outcome. There are anumber of randomized controlled studies of compre-hensive adjunctive psychosocial interventions thatimprove outcomes in bipolar disorder (Colom et al.,2003; Lam et al., 2005; Miklowitz et al., 2003). Theseinterventions have numerous targets besides medi-cation adherence, including psycho-education aboutthe illness and its treatment, identification andreduction of triggers and warning signs of illness,stress management, and regulating lifestyle and sleep.These comprehensive interventions expose the com-plexity of the Interacting mechanisms of actionresponsible for positive outcomes.Lam et al. (2005) conducted a complex randomised

controlled trial of a CT intervention with 103 out-patients with bipolar disorder who had experiencedfrequent relapses despite pharmacological treatment.The active intervention involved an average of14 sessions over 6 months with two booster sessionsin the following 6 months, in addition to the moodstabilizers and psychiatric follow up received by thecontrol group. Serum lithium levels were onlyavailable for about half the patients and differencesbetween the control and intervention groups were notsignificant. In the group receiving CT there weresignificant improvements in patient and clinicianreports of medication adherence. The positive effecton relapse reduction was significant in the first year ofthe study, but this was not sustained over the last18 months of the study. However, when controlling formedication adherence the intervention group still hadfewer days in episode, had better mood ratings, copedbetter with prodromes and had improved socialfunctioning and attitudes to goal attainment over the30 months. This study demonstrates that CT may


improve medication adherence, but there are a numberof mechanisms of action that may contribute to positiveoutcomes.Another randomized study using a different kind of

individual CT that included emotive techniques, alsoreported positive benefits of the intervention, particu-larly with regard to depressive relapse, modification ofdysfunctional attitudes, and some improvement infunctioning (Ball et al., 2006). These benefits, like theprevious study, diminished with time from activetreatment. Future research may usefully examine long-term adherence to psychosocial illness managementskills that may lag once the impetus of the activeintervention is over. Booster sessions or other factorssuch as family involvement may play a role insustaining such adherence. In this CT study, there wasno significant difference in self-reported medicationadherence between the groups. Scott et al. (2006) in alarge study of Cognitive Behavioral Therapy (CBT),also did not find that medication adherence wasimproved in the intervention group despite a specificpart of the intervention being devoted to targetingdysfunctional cognitions related to treatment adher-ence (Scott et al., 2006).A different type of comprehensive intervention

comparing Interpersonal and Social Rhythm Therapy(IPSRT) to Intensive Case Management (ICM) alsofound no differences in medication adherence betweengroups, although the group receiving (ISPRT) in theacute phase showed greater time to new illness episode(Frank et al., 2005). This confirms that othermechanisms of action, besides medication adherencemay contribute to positive outcomes. Interestingly inthis study, patients with medical or anxiety relatedcomorbidity benefited more from ICM than ISPRThighlighting the role of patient variables in predictingoutcomes. This is confirmed by Scott et al. (2006) whoreported that patients with fewer than 12 previousepisodes had less recurrences with CBT, but this wasnot true of those with more than 12 episodes whodeteriorated with the intervention. These studies high-light the need to consider patient variables and refinethe use of adjunctive psychosocial interventions forspecific subgroups of people with bipolar disorder.The intervention forokagated by Miklowitz et al.

(2003) includes family members together with thepatient and provides psycho-education on the illnessand its treatment as well as emphasizing communi-cation skills and problem solving in the family. Theycompared patients assigned to either pharmacotherapyand Family-Focused Treatment (FFT, 21 sessionsinvolving psycho-education, communication training,and problem solving skills), or pharmacotherapy with a



less intensive crisis management intervention (twosessions of family psycho-education, and ongoingintervention support). The results indicated that overthe 2-year follow up period, 45% of patients receivingFFT were fully adherent (consistent use of prescribedmood stabilizers) compared with 21% of patients whoreceived Crisis Management. No differences wereevident in partial adherence but non-adherence wasabout three times higher in the Crisis Managementgroup (Miklowitz, 2006). There was evidence ofsignificantly greater reductions in mood symptoms andincreased time to relapse in patients who received theFFT intervention compared to in the comparison group,particularly with regard to depression. Positive resultson medication adherence were also reported in anearlier study of an intervention involving maritaltherapy and psycho-education, with a positive impacton functioning rather than symptoms (Clarkin et al.,1998). No difference was evident in an early groupbased intervention for partners that did not include thepatients themselves (van Gent and Zwart, 1991). Thus,interventions that include family members have showna positive influence on medication adherence and otheroutcomes. They may also help to reduce suicide risk(Miklowitz and Taylor, 2006).FFT was also associated with sustained benefits in

terms of relapse rates and re-hospitalization in thesecond follow up year, once active treatment was overcompared to individual psycho-education (Rea et al.,2003). A possible explanation could be the addedadvantage of the positive long-term influence offamilies on medication adherence. However, impor-tantly, there was no difference in medication adherencebetween the patients in the FFT group compared tothose who received individual psycho-education in thisstudy. This means that other explanations linked to thepossible mechanisms of actions of family therapymight explain these improved outcomes, for example,involving family members in detecting and respondingto warning signs of illness or reducing interpersonalstress.It is notable that improvedmedication adherencewas

considered to be one of the factors that contributed tothe beneficial outcomes of group psycho-education(Colom et al., 2003). In a randomized controlled trial,120 patients with bipolar disorder were randomized toreceive 21 sessions of group psycho-education or 21sessions of non-structured group meetings in additionto standard psychiatric care. At 6-months and 2-yearsfollow-up patients who received the psycho-educationprogram had significantly fewer recurrences, and anincreased length of time to depressive, manic,hypomanic, and mixed episodes. Analysis of patients


that were on lithium during the study showed thatpatients who received group psycho-education hadmore optimal and stable lithium levels compared tocontrol patients (Colom et al., 2005a). Adherence wasnot the sole mediator of improved outcome asparticipants who were already highly adherent alsoshowed significant improvement as a result of thepsycho-education intervention. Group psycho-education was further associated with lower relapserates at a 5-year follow up, suggesting a sustainedbenefit that may in part be mediated by adherence(Colom et al., 2009).The Life Goals program combined group psycho-

education with regular individual follow up andmonitoring of prodromes and medication problemswithin a collaborative care model. Active involvementin treatment was encouraged through the collaborativerelationship between patient and clinician. Thisprogram demonstrated good adherence levels to bothmedication and clinical attendance and reportedpositive results on relapse and manic symptomatology(Simon et al., 2006). However, neither the number ofmedication visits nor atypical antipsychotic medi-cations was related to lower mania ratings.From this review of studies that target medication

adherence as a secondary outcome, it is evident thatsuch a holistic approach can provide a useful adjunct topharmacological treatment and significantly improvepatient outcomes (for example, Colom et al., 2003;Miklowitz et al., 2003). More detailed attention needsto be given to the influence of different mechanisms ofaction and sustaining benefits over time (Lam et al.,2005). In the context of future practice, this raisesquestions about whether to focus on developing brieferinterventions that target treatment adherence alone andto assess these in large randomized controlled trials, orto continue to promote adherence as a component ofmore complex interventions. People may be moreamenable to addressing treatment adherence issueswithin a more comprehensive holistic approach thatincludes other areas that are meaningful and importantto them, for example stress management. However,concerns about the translation of these interventionsinto clinical world outcomes and their cost-effective-ness need to be addressed (Scott, 2006). A possibilitymay be to isolate core parts of more comprehensiveinterventions and their applications to specific sub-groups of patients with bipolar disorder to enhancereal-world outcomes. On the other hand restraintson resources and costs may point to the usefulnessof even briefer targeted approaches that focusexclusively on a relevant health behavior likeadherence that affects clinical outcomes. Addressing


12 l. berk ET AL.

relevant risk factors for non-adherence for particularsubgroups of people with bipolar disorder within thecontext of briefer family, group, and individual modelsmay significantly improve medication adherence andother outcomes. However, notably, there is a lack oflarge scale randomized controlled psychosocial studiesof briefer interventions targeting medication adherenceto inform best practice.Studies that specifically address attitudes, beliefs,

and behaviors to improve medication adherence mayhave more chance of improving adherence than thosethat do not include such a specific focus. For example,Perry et al. (1999) targeted warning signs of illness(Gaudiano et al., 2008). However, to enhanceadherence, this specific focus needs to be tailored tothe complex needs of people with bipolar disorder, forexample, people with comorbidity, and to specificadherence problems, for example, involuntary versusvoluntary non-adherence (Depp et al., 2007; Franket al., 2005; Scott et al., 2006).Perhaps, ultimately a more needs based approach

relying on more sophisticated assessment of individualdifficulties in managing bipolar disorder may assist inmatching briefer interventions to core problem areas.For example, people who are already adherent tomedication might benefit more at that point in timefrom an intervention that targets different aspects ofillness management.

Improving psycho-education

Psycho-education is a primary component of thecollaborative model of treatment that advocates therights of the patient to make informed decisions abouttheir treatment (Sajatovic et al., 2007b). Psychosocialstudies recognize the usefulness of psycho-educationas a tool to foster adherence and other outcomes. Onestudy demonstrated the impact of poor psycho-education in bipolar disorder through a recentconsumer survey of 223 members of the US ManicDepression fellowship (Bowskill et al., 2007). Theyfound that people with more dissatisfaction withinformation about their medications reported loweradherence. High levels of dissatisfaction in this studywere reported about information on potential problemsrelated to their medications such as side effects, andhowmedications would affect their sex life. In additionthere was dissatisfaction about information on howmedicines work.While psycho-education is a potentially useful tool,

to havemaximum effect, a number of variables relatingto the patient, the stage of illness, and the treatment


relationship may need to be considered. Targetedpsycho-education about the illness, treatment, andhelpful behavioral skills may assist in reducing thedifferent aspects of non-adherence including voluntary,involuntary, partial, irregular, and selective non-adherence and abuse (Colom et al., 2005b). Cliniciansmay need to consider peoples current level ofknowledge and different requirements for informationabout their medicines and that these requirements maychange at different stages of treatment (Bowskill et al.,2007). Attention may also need to be given to thetiming and delivery of information. For example,providing lots of information when a person is too ill toprocess it may overwhelm the patient, leading toinformation overload and anxiety. Further, informationmay need to be adapted to take into account cognitivedeficits (Depp et al., 2007). McGorry and McConville,(1999) highlight the dangers of too much informationtoo soon, especially early in treatment for people withpsychotic disorders. Insight into the reality that one hasa mental illness may lead to a fall in self-concept,demoralization, and a protective denial of the illness, orthe need for treatment to deal with this cognitivedissonance.Information may need to be conveyed in a way that is

sensitive to these issues and employs the individual’sown language and draws on their personal conceptionsof illness and treatment rather than in a didactic way.Essential to this process is a good therapeutic alliance,which facilitates the optimal exchange of informationbetween clinician and patient (Berk et al., 2008).Similarly facilitating a supportive group process orcollaborative family interaction may make it easier forindividuals to consider, openly question and integrateinformation about their illness, and to develop positiveattitudes toward treatment.A group format has the advantage of peer support

and cost effectiveness. Although it may not be possibleto focus on each individual difference in terms ofrequirements of information, it may be feasible toidentify people with bipolar disorder that have certaincommon risk factors and apply psycho-education moreselectively and appropriately within these subgroups.Thus, more targeted psycho-education within asupportive collaborative therapeutic relationship and/or group or family context may help improve real worldoutcomes (Scott, 2006). Research is needed to test outthe advantages of this approach, perhaps by comparingit to interventions that simply provide general writteninformation.Information on how medicines work is progressing,

and may ultimately inform psycho-education andcontribute to informed choices about adhering to



medication. Advances in identifying biologicalchanges that help explain the positive impact ofadherence on outcome could assist people in under-standing the rationale behind adherence and possiblyhave a useful place in psycho-educational interven-tions. Further, increasingly evidence indicates that thetiming of medication in the illness course and targetingmedication to the stage of the illness is anotherextremely important factor when considering adher-ence (Berk et al., 2007), particularly as studiesdemonstrate that earlier pharmacological interventionis associated with better outcomes (Franchini et al.,1999). There is awareness that bipolar disorder isassociated with cellular atrophy and/or volumetricdecreases in the brain (Shaltiel et al., 2007). In contrast,recent evidence indicates that mood stabilizingmedications may protect the brain from this neuronalatrophy and degeneration (i.e., be neuroprotective).Specifically, lithium has demonstrated neuroprotectiveproperties in a number of studies (Bearden et al., 2007;Sassi et al., 2004). In adolescent bipolar disorder, moodstabilizers are associated with sparing the corticalvolume loss observed in patients not on moodstabilizers (Chang et al., 2005). Evidence indicatesthat adherence to lithium in bipolar disorder also mayprevent gray matter volume losses in bipolar disorder(Moore et al., 2000). These results, while tentative,have led to mood stabilizers now being consideredneuroprotective, leading to an even greater emphasison adherence to prevent progression of structuralchanges. Conveying this information may be key inenhancing adherence.

CONCLUSION

There is a need to explore ways of maximisingmedication adherence that translate into effective real-world practice. The concept of non-adherence mayneed to be refined to include different aspects, forexample, involuntary, voluntary, irregular, and selec-tive non-adherence. Identifying common risk factorsfor these specific forms of non-adherence and thosethat are more likely to be relevant to certain subgroupsof people with bipolar disorder may assist indeveloping briefer targeted interventions to improveclinical outcomes.This review indicates that adjunctive psychotherapy

may augment pharmacological interventions, in part byimproving treatment adherence resulting in improvedoutcomes. The long-term cost effectiveness of complexlengthy interventions needs more research. Brieferinterventions that significantly improve outcomes may


arise from more sensitive matching of interventions toparticular needs and risk factors, not only for thedifferent aspects of non-adherence but for other healthbehaviors that also impact on outcome. Existingcomprehensive psychosocial interventions may beable to be consolidated into a brief cost-effectiveformat or/and short stand alone interventions that targetmedication adherence or other health behaviors asprimary targets and could be provided on an as neededbasis. Large-scale effectiveness trials of more con-solidated versions of existing comprehensive interven-tions as well as brief psychosocial interventionsutilising medication adherence as a primary outcomemay provide evidence on the usefulness of theseapproaches.This review demonstrates that clinicians working

with bipolar populations should consider the vulner-ability of a particular patient to the different types ofnon-adherence, as well as the specific risk factors fornon-adherence over the course of treatment. It may behelpful to adopt a patient centered approach to thedelivery of psycho-education within the context of acollaborative patient–clinician alliance. This mayencourage patients to get the most benefits from theirmedications and maximize symptomatic and func-tional recovery. Further research into the delivery ofpsycho-education may facilitate these improvedclinical outcomes. As our understanding about howmedicines work increases, the rationale for taking themis becoming clearer, knowledge that should empowerboth patient and clinician in making informedtreatment decisions.

ACKNOWLEDGEMENTS

Francesc Colom and Eduard Vieta would like to thank thesupport and funding of the Spanish Ministry of Health,Instituto de Salud Carlos III, CIBER-SAM. Dr Colom isfunded by the Spanish Ministry of Science and Innovation,Instituto Carlos III, through a ‘‘Miguel Servet’’ postdoctoralcontract (CP08/00140) Lesley Berk was supported by theNHMRC.

DISCLOSURE OF INTEREST

Dr. Francesc Colom has served as advisory or speakerfor the following companies: Astra Zeneca, Bristol-Myers, Pfizer Inc, Glaxo-Smith-Kline, Eli-Lilly,Sanofi-Aventis, Otsuka,Tecnifar & Shire.Dr Eduard Vieta has served as consultant, advisor or

speaker for the following companies: AstraZeneca,Bial, Bristol-Myers, Eli Lilly, Glaxo-Smith-Kline,Jannssen-Cilag, Lundbeck, Merck-Sharp and Dohme,


14 l. berk ET AL.

Novartis, Organon, Otsuka, Pfizer Inc, Sanofi-Aventis,.Servier & UCB Pharmaceuticals.

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