Enhancing Medication Adherence in Patients With Bipolar Disorder

human psychopharmacology
Hum. Psychopharmacol Clin Exp 2010; 25: 116. 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*
1 2
University of Melbourne, Victoria, Australia Barwon Health and The Geelong Clinic, Victoria, Australia 3 Orygen Research Centre, Parkville, Australia 4 Mental Health Research Institute, Parkville, Australia 5 Bipolar Disorders Program, Institute of Neuroscience, Hospital Clinic, IDIBAPS, CIBERSAM, University of Barcelona, Catalonia, Spain 6 Department of Psychology, Victoria University, Victoria, Australia
Objectives Medication adherence contributes to the efcacy-effectiveness gap of treatment in patients with bipolar disorder. This paper aims to examine the challenges involved in improving medication adherence in bipolar disorder, and to extract some suggestions for future directions 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 from 1996 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 difculty in dening and measuring it and the various risk factors that need to be considered when aiming to enhance adherence. Nevertheless, the importance of addressing adherence is evidenced by the connection between adherence problems and poor outcome. Despite these challenges, a number of small psychosocial studies 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 outcomes from larger randomized controlled trials of psychosocial interventions that target medication adherence as a secondary outcome suggests that tackling other factors besides medication adherence may also be an advantage. While some of these larger studies demonstrate an improvement in medication adherence, the translation of these interventions into real life settings may not always be practical. A person centered approach that considers risk factors for non-adherence and barriers to other health behaviors may assist with the development of more targeted briefer interventions. Integral to improving medication adherence is the delivery of psycho-education, and attention needs to be paid to the implementation, and timing of psycho-education. Progress in the understanding of how medicines work may add to the credibility of psycho-education in the future. Conclusions Enhancement of treatment adherence in bipolar patients is a necessary and promising management component as an adjunct to pharmacotherapy. The current literature on psychosocial interventions that target medication adherence in bipolar disorder points to the possibility of rening the concept of non-adherence and adapting psycho-education to the needs of certain subgroups of people with bipolar disorder. 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 of remission and relapse (Sachs and Rush, 2003). The World Health Organization (WHO) has reported that bipolar disorder is the worlds sixth leading cause of
* Correspondence to: M. Berk, Department of Clinical and Biomedical Sciences, University of Melbourne, Swanston Centre, PO Box 281, Geelong, Victoria 3220, Australia. Tel: 61 3 52267450. Fax: 61 3 52267436. E-mail: mikebe@barwonhealth.org.au
disability among people aged 1544 years (AyusoMateos, 2000; Murray and Lopez, 1996). Bipolar disorder is common, with 1% lifetime incidence of bipolar 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 particularly crippling to many patients, and suicide attempts occur in 2550% of patients (Berk et al., 2004). Comorbidity is also common with substance abuse, anxiety disorders, and personality disorders frequently complicating the bipolar disorder milieu, increasing
Received 20 May 2008 Accepted 22 October 2009
Copyright # 2009 John Wiley & Sons, Ltd.
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treatment complexity, and leading to poorer therapeutic 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 an acute illness episode, long-term prophylaxis is required to prevent recurrence. Despite an increasing pharmacopoeia of effective medications for the treatment of bipolar disorder, patient outcomes continue to be impacted by treatment adherence (Sajatovic et al., 2007c). Non-adherence to treatments is also a major obstacle in translating efcacy in research settings into effectiveness in clinical practice (Lingam and Scott, 2002). Evidence further indicates that while clinicians may not routinely address non-adherence as a risk factor for poor outcomes (Havens and Ghaemi, 2005), the benets of pharmacotherapy may be enhanced if combined with psychosocial interventions (Cochran, 1984; Scott and Tacchi 2002) that have been shown inter alia to improve adherence (Miklowitz, 2006). Enhancing adherence is a complex clinical challenge, owing to the complexity of the concept and difculty measuring adherence, the number of risk factors to consider and the challenge of extracting strategies that have proven to promote adherence from the encouraging studies of psychosocial interventions in the area (Demyttenaere and Haddad, 2000; Sajatovic et al., 2007b). This paper examines the literature on medication adherence in bipolar disorder, and the challenges involved in addressing and reducing adherence problems and makes some suggestions for future research and clinical practice. METHODS A comprehensive literature search was undertaken through Medline, Web of Science, CINAHL PLUS, PsychINFo for papers published between 1996 and 2008. These database were searched using the following key words; bipolar disorder and adherence, compliance, alliance, adherence assessment, adherence measurement, risk factors, psychosocial interventions, and psycho-education. This search highlighted some important articles published earlier than these dates that were also included in this review. The results indicated a number of key areas to examine in order to understand the difculty, but importance of addressing medication adherence problems in bipolar disorder, and the efforts that have been made to improve adherence in psychosocial intervention studies. Common to all these studies is a psychoeducation component. The literature to date points to future directions to enhance psycho-education in order
to improve adherence to medication in real life settings. Hence we focused on the following areas: (1) The denition and measurement of medication adherence. (2) The impact of poor adherence on clinical, functional, and illness outcomes. (3) Risk factors associated with adherence issues. (4) Psychosocial interventions to increase adherence. (5) Improving psycho-education. RESULTS The denition and measurement of adherence Dening adherence. Early conceptions of adherence stem from the traditional medical model, with its authoritarian connotations, which equated adherence with compliance. A more recent concept of adherence involves following treatment in the context of a collaborative model where the patient is included in a collaborative process as an active participant in their own treatment (Berk et al., 2004). This concept of adherence emphasizes the therapeutic relationship as the vehicle for exchanging information and opening up discussion aimed at reaching a concordance about treatment. In addition, on a purely practical level, adherence involves a number of behaviors including accessing treatment, obtaining medications, understanding and following instructions about taking and monitoring medications and remembering to take medications. Non-adherence may be voluntary or intentional when the person decides not to adhere to treatment or involuntary where the lack of adherence is unintentional, for example they forget to take their medication (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 leads to partial (i.e., client takes only part of their full doses) or irregular (i.e., client stops and starts treatment sporadically for varying intervals) adherence as opposed to all or none decisions about taking medications (Colom and Vieta, 2002). Another way of failing to follow recommended treatment is through possible abuse of prescription medication. A further issue is that clients may be selective, adhering fully to some medications but not others at different times (Colom et al., 2005b). These factors indicate that adherence is dynamic, varying in a number of ways, thus requiring repeated 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: 116. DOI: 10.1002/hup
medication adherence in bipolar disorder
denition of adherence focuses on broader adaptive health behaviors (Cochran, 1984; Wright, 1993). This denition encapsulates attendance at consultations and commitment to a healthy lifestyle, as well as taking prescribed medication at the appropriate dose and time. Although this broader denition may encapsulate adherence behavior more thoroughly, this paper investigates medication adherence more specically, as there is little available information on other types of non-adherence in bipolar disorder. Measuring adherence. The realization that adherence is not an all or nothing phenomenon and may for example be partial, irregular and selective places increasing demands on developing measurement tools that accurately capture all these dimensions. Precise evaluation and assessment of treatment adherence is difcult in patients with bipolar disorder (Sajatovic et al., 2004). This difculty is further exacerbated by the lack of agreement about how best to measure adherence (Pomykacz et al., 2007). There is currently no ideal measure of adherence. Techniques used include self-report, reports by family members or signicant others, biological tests (e.g., plasma lithium levels), and independent evaluation of adherence patterns. All of these assessments of adherence have limitations, for example, it has been suggested that self-assessment by patients is potentially unreliable, as they may overestimate or over-report their treatment adherence when being asked by their clinician (Sajatovic et al., 2007b). However, Scott (2000) found that self-report assessment correlated highly with serum lithium levels. Moreover, if only plasma drug levels are considered, adherence with drugs with a long half-life, such as antipsychotics, may be overestimated, and the assessment of some drugs with a great inter-individual variation of serum levels such as antidepressant drugs would be confusing (Colom and Vieta, 2002). Byerly et al. (2005) used electronic monitoring packs for medication to monitor adherence to antipsychotics in outpatients. The results indicated clinically signicant non-adherence was evident in around 50% of patients. In contrast, clinicians indicated that none of these patients were nonadherent, thus indicating signicant discrepancies in adherence estimates and electronic measures. Although electronic medication packs may provide more reliable information about medication adherence, associated costs tend to be prohibitive for use in clinical practice. Data from pill count assessment may be unreliable as patients may not necessarily be ingesting the pills after removing them from packaging or pill box (dosette) (Sajatovic et al., 2007b). Blood
measurement may also be unreliable as medication adherence for only a few days before blood testing can raise blood levels to appropriate levels (Vieta, 2005). Based on these restraints, a more reliable and practical methodology for adherence assessment may be to combine modalities such as; patients reports, caregivers reports (if congruent with family engagement and consent), and unscheduled blood monitoring. It is however unclear what weight to give each of these measures in assessing an individuals adherence status (Sajatovic et al., 2007b). It is possible that combining subjective and objective quantitative assessment with a more qualitative interview may shed more accurate light on a persons overall adherence status and provide information on different aspects of their adherence. For example, if it is selective and irregular. Despite these challenges, studies have been conducted using various denitions of adherence and measurement techniques to examine the impact of adherence status on outcome, to identify risk factors and to evaluate the effects of adjunctive psychosocial interventions. The impact of poor adherence on clinical, functional, and illness outcomes Mood stabilizers are considered to be highly effective in the treatment of clinical trial populations with bipolar disorder. However, rates of relapse in patients with bipolar disorder (even when taking mood stabilizers) are as high as 40% in the rst year, 60% in the second year, and 73% over 5 or more years (Gitlin et al., 1995). Johnson and McFarland (Johnson and McFarland, 1996) followed 1500 patients treated with lithium and reported that the mean duration of continuous lithium adherence was 76 days. Thus, the potential benets of pharmacological treatment on recovery, preventing relapse and reducing mortality are signicantly undermined by poor adherence. Studies that have examined the effects of stopping medication highlight the serious consequences of nonadherence (Keck et al., 1998; Svarstad et al., 2001). The cause and effect relationship underlying this change in adherence may be bi-directional. More specically, it may be that adherence decreases when clients are becoming unwell. Alternatively, failing to adhere to medication may lead to relapses in mood episodes (Keck et al., 1996). Suppes et al. (1991) showed that the time to a 50% failure of remission after lithium discontinuation was 5.0 months after stopping therapy. Cavanagh et al. (2004) demonstrated poorer outcomes and increased risk of relapse after acute lithium withdrawal through a review of clinical patient les over 7 years.
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Faedda et al. (1993) raise the possibility that how a medication is discontinued may be a factor that inuences relapse, and the understanding of the effect of non-adherence on outcome. They reported a greater risk of a new episode of mania after rapid rather than gradual lithium discontinuation, an effect that was even greater for depression. Baldessarini et al. (1999) have also demonstrated that rapid cessation of lithium leads to an even greater risk of relapse than not having taken the drug at all, and that within 5 months of cessation, 50% of patients have relapsed (mainly into mania). A review by Colom et al. (2005b) also reported that rapid discontinuation of lithium was associated with relapse rates of 50% in the 3 months following cessation, compared with less than 10% in people who continued taking prophylactic medication. While complete nonadherence has known impacts on outcomes, it must be noted that partial adherence also impacts risk of relapse and re-hospitalization (Scott and Pope, 2002a). Keck et al., (1998) also reported that fully adherent individuals are more likely to achieve syndromic recovery than those who are non- or partially adherent. The importance of adherence in bipolar disorder is further highlighted when considering suicide and mortality in bipolar disorder (Baldessarini et al., 2006). It is notable that untreated bipolar patients are 5 times more likely to commit suicide (Angst et al., 2005), and other deaths are also more frequent in
untreated patients (Angst et al., 2002). This implies that medication adherence has a protective effect. Adherence with mood stabilizers, particularly lithium, has been found to signicantly reduce the likelihood of attempted or completed suicide in people with bipolar disorder (Goodwin et al., 2003). For example, in a prospective 10-year follow up study of the relationship between suicidal acts and adherence to lithium in bipolar patients, Gonzalez-Pinto et al. (2006) found a 5.2 fold increased suicide rate in patients with poor adherence compared to highly adherent patients. These studies conrm the usefulness of targeting adherence to improve both clinical and safety outcomes in bipolar disorder. Identifying risk factors for adherence problems and researching possible ways to address these problems may make a difference to people with bipolar disorder and their families.
Risk factors associated with adherence issues A number of factors, some of which are amenable to change have been associated with medication nonadherence in bipolar disorder (Figure 1). These include (1) Demographic and illness related factors. (2) Knowledge, attitudes, and beliefs. (3) Treatment variables.
Figure 1. Factors that inuence adherence status
Demographic and illness related factors. Adherence problems may be linked to specic demographic factors such as age, comorbidity, social support, and gender, and may inform interventions that target adherence in these specic groups of people with bipolar disorder. For example, a recent study by Sajatovic et al. (2007c) assessed medication adherence in 44 637 patients receiving either lithium or anticonvulsant medication, using the medication possession ratio (MPR: days of supply/ 365 days). Results indicated that non-adherent patients were more likely to be younger, non-Caucasian, single, homeless, to have substance use disorders, and attend less outpatient visits compared to patients who were fully or partially adherent. Interestingly, patients receiving two mood stabilizing agents were more adherent than patients receiving 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 younger patients), was a signicant predictor of adherence to antipsychotic medications. More specically, it was reported that 61% of the older individuals were fully adherent, compared to 49.5% in younger individuals. The authors highlight that even with these gures, the patients in the older age group still experience adherence problems. This may be connected to an increased number of medications being required to treat physical comorbidity, and a decrease in cognitive ability resulting in unintentionally forgetting to take medication (Depp et al., 2007). Providing tools to prompt adherence behavior and help organize daily doses may be particularly helpful in this group of people. Studies have found conicting evidence about the link between younger age and non-adherence (Colom et al., 2005b). Colom et al. (2000) highlight that from a clinical point of view it may be wise to look out for non-adherence in refractory patients that fall in the two extremes of the lifespan, teenagers and the elderly. Comorbid substance abuse was found to be a predictor of non-adherence in both younger and older patient groups (Sajatovic et al., 2007a). In a study by Manwani et al. (2007), lifetime adherence to mood stabilizers was 65.5% for the group of people with bipolar disorder and co-occurring substance use disorders compared to 85% in those people with bipolar disorder without substance use disorders ( p < 0.05). People with bipolar disorder and comorbid substance use disorders provided different reasons for non-adherence compared to reasons provided by those without this comorbidity, highlighting the importance of addressing this specic risk factor when aiming to improve adherence. In a recent review of the treatment
adherence literature, Gaudiano et al. (2008) highlight the need to address this risk factor for non-adherence in adherence programs. Most existing psychosocial interventions exclude people with co-occurring substance use although 60% of people with bipolar disorder have a lifetime history of substance use disorders comorbidity and this is connected with worse course of bipolar illness, greater impairment, and higher suicide rates (Gaudiano et al., 2008). Other comorbid disorders that may affect adherence include psychosis (Miklowitz, 1992) and personality disorders (Colom et al., 2000). Cognitive decits in bipolar disorder do not only occur in old age. They may be present in acute mood states and euthymic bipolar patients, and there is a growing awareness of the need to nd treatments to address these decits and their impact on functioning (Burdick et al., 2007, Vieta, 2005). Helpful behavioral tools to prompt adherence may help compensate for impairment. In terms of social factors, marriage appears to be a protective factor that increases adherence (Connelly et al., 1982; Sajatovic et al., 2007b). Perceived continuity of care was also associated with adherence with consultation appointments. The role of gender on adherence is still unclear, with studies reporting conicting ndings. For example, Kessing et al. (2007) reported that woman were signicantly more likely to have poorer adherence to lithium in a naturalistic study in Denmark, whereas Sajatovic et al. (2006) did not nd gender signicant in their study of adherence to antipsychotics in veterans with bipolar disorder. The latter study reported that woman may have been under-represented in their sample. This highlights the difculty of identifying risk factors for poor adherence across studies to assess different kinds of medications. Examining adherence problems in the different phases and stages of illness may also increase understanding of high-risk times. For example, a high-risk time for adherence problems has been connected to manic symptoms, with the risk increasing with the severity of manic symptom (Keck et al., 1996). This may be linked to cognitive decits or poor insight common to this phase of illness (Colom et al., 2005b; Copeland et al., 2008). An area for future research on adherence difculties may be the depressed phase. For example, little is known about how negative cognitions or other depressive symptoms affect adherence behavior (Gaudiano et al., 2008). Adherence problems may be prevalent at specic stages in the course of illness such as prior to Late adherence when patients adhere to medication after
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experiencing repeated relapses and eventually accepting the need for medication. Late non-adherence typically occurs when a person has been taking a mood stabilizer for a few years, and begins to question the need for medication as they have been well, or to worry about the dangers of long-term use (Colom and Vieta, 2002). Knowledge, attitudes, and beliefs. Having knowledge about their illness and treatment can assist people in making informed decisions about illness management and reduce inaccurate and negative beliefs about medications. Several studies have examined the impact of knowledge, beliefs, and attitudes on medication adherence in bipolar disorder, and have found adherence to be associated with patients increased understanding of their illness and need for preventative (prophylactic) treatment. For example, Rosa et al. (2007) assessed medication adherence and its related factors using the lithium attitudes questionnaire (LAQ), lithium knowledge test (LKT), and medication adherence rating scale (MARS) in patients with bipolar disorder. They reported that patients knowledge about the disorder and medication was positively correlated with treatment adherence to lithium prophylaxis. The large Gamian-Europe/ Beam survey found an improvement in quality of life and medication adherence in people with bipolar disorder who were more informed about their illness 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 a higher perception of illness severity and stronger beliefs about the benets of treatment, contributing 43% of the variance in adherence behavior. Kleindienst and Greil (2004) showed that adherence to medication was associated with inated scores on the subscales of the Illness Concept Scale (ICS) relating to trust in medication and clinicians, and absence of negative expectations toward treatment. A recent small qualitative study also found that patients made decisions about taking medication or not based on their perceptions of the illness and treatment (Clatworthy et al., 2007). In addition to examining intentional or voluntary non-adherence they found a different risk factor for involuntary non-adherence. This unintentional non-adherence was commonly linked to forgetting especially when becoming manic. While addressing perceptions about illness and treatment is vital, exploring other aspects of non-adherence can inform additional strategies that may be needed to boost adherence. Interestingly, Clatworthy and colleagues study is intended to inform the development of a
questionnaire to assess the common illness and treatment perceptions that affect adherence status in bipolar disorder. Such a questionnaire may facilitate easier detection of these risk factors. Difculties in accepting bipolar disorder may impede adherence. Scott and Pope (2002) found that in a cohort of patients with affective disorders receiving long-term medication, three factors, denial of illness, previous non-adherence, and being prescribed a mood stabilizer for a long time, were highly predictive of partial adherence. For some people, the stigma and idea of having a chronic mental illness may deter adherence (Cochran 1984). Conversely, abnormal illness behavior, attachment to the sick role or pursuit of elevated moods and sensation seeking may also result in adherence problems (Berk et al., 2004). For some individuals, illness may become an unwitting escape from lifes demands and complexities. Interestingly, patients with a more internal locus of control may show aversion to be controlled by medication. However, the link between internal locus of control and poor adherence is controversial with studies displaying conicting results (Adams and Scott, 2000; Darling, et al., 2008). The views of signicant others such as family members and clinicians may inuence patient attitudes and beliefs about the illness and its treatment and affect adherence. Therefore, understanding the beliefs of signicant others and caregivers, and their impact on patients adherence behavior, is important (Cochran and Gitlin, 1988). Family factors including high expressed emotion and particularly over involvement have also been associated with poorer adherence and poorer overall outcomes in bipolar patients (Miklowitz et al., 1986; Perlick et al., 2004). Based on these ndings, it would be predicted that interventions that include family members as well as patients as collaborative partners may improve adherence and impact on outcomes. From a clinical point of view, understanding the patients attitudes and beliefs about the illness and treatment may indicate targets for clarifying information and discussion to improve adherence. Interestingly, Johnson and Fulford (2008) have developed a self-report scale, the Treatment Attitudes Questionnaire that assesses awareness of illness and attitudes to treatment, to help identify patients at risk of adherence problems and facilitate further research to inform treatment planning. Treatment variables. Large-scale studies of typical risk factors connected to treatment variables could ultimately inform psychosocial interventions and
clinical practice, and have a positive effect on adherence. Notably, a treatment variable that may have a protective effect on adherence is a sound therapeutic alliance. A recent study of veterans with bipolar disorder found that positive therapeutic alliance was connected to medication adherence. Clinicians encouraging regular contact with patients and patients having regular reviews of their progress were particularly important factors in self-reported adherence (Zeber et al., 2008). Strauss and Johnson (2006) reported that a strong therapeutic alliance had a positive inuence on beliefs and attitudes resulting in less negative attitudes about medication and greater acceptance of illness and improved adherence. Lingam and Scott (2002) also highlighted the importance of the therapeutic alliance, reporting that poor clinician patient interaction was four times more common with non-adherent patients compared to those who were adherent. The importance of the therapeutic alliance in adherence may apply cross culturally, as evidenced by a survey of Chinese patients, that found that the treatment alliance was more important than knowledge about treatment in sustained adherence to prophylactic lithium (Lee et al., 1992). The research by Bultman and Svarstad (2002) indicated that the benet of therapeutic relationships may extend to pharmacists, with results of their study indicating that pharmacist monitoring played 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 the clinician versus the reasons for non-adherence stated by patients. This suggests a divide between clinician and patients views on this issue, and a need for clinicians to listen to patients reasons for nonadherence and good communication to facilitate the exchange of information. Sajatovic et al. (2005) suggest that adherence is most likely when a strong collaborative relationship exists between patient and clinician. There may be utility in developing collaborative treatment plans that involve shared decision making between clinician and patient, which in turn encourages a sense of ownership of the treatment decisions, contributing to adherence. It is particularly notable that although clinicians commonly attribute their patients medication nonadherence to side effects, a large survey found that they are not a major determinant of adherence. This large survey (Morselli et al., 2003, 2004) was conducted in a national patient organization in 30 European countries. The results indicated that only 18.3% of the patients stated that side effects were the main reason for discontinuation of pharmacological treatments. The
major reasons for poor adherence that were cited included fear of being dependant on medication (30%) as well as poor medication information, and fear of long-term side effects (20.2%). Of concern, the survey found that about 35% of the patients did not receive any information on the possible side effects of the medications, and more than 50% had not received guidance on side effect management. Lack of information may have contributed to the fear of side effects. Scott and Pope (2002b) showed that fear of side effects was a stronger predictor of non-adherence rather than the side effects experienced. In contrast, earlier studies, when medication adherence was considered in the traditional medical model framework, showed a greater correlation between side effects and non-adherence in bipolar patients (Gitlin et al., 1989). On the other hand, the fact that despite having more tolerable drugs than in the past, the nonadherence gures have remained basically the same, diminishes the importance of side effects on nonadherence. Interestingly a recent study involving a web survey found that satisfaction with medication might still be worth considering. They reported that medications that improved depressive episodes and had few cognitive side effects and little weight gain were connected with improved satisfaction and adherence (Reed et al., 2007). A number of studies investigated the impact of medication class on adherence, with the focus largely on antipsychotics used in bipolar disorder. Gianfrancesco et al. (2006) compared adherence to different antipsychotics in patients with bipolar disorder. Adherence was evaluated by MPR and length of treatment episodes. This study found that adherence was higher with quetiapine than risperidone, olanzapine, or typical antipsychotics. The adherence intensities of olanzapine and ziprasidone were additionally higher than with risperidone. In addition, the treatment durations of quetiapine and risperidone were signicantly longer than with olanzapine, ziprasidone, and the typical antipsychotics, although overall study differences were small. Dolder et al. (2002) reported that outpatient veterans who received atypical antipsychotics had higher adherence rates than those who received typical ones. However, Lingam and Scott (2002) have suggested that adherence has not been improved by the introduction of newer pharmacological agents and ndings of Sajatovic et al. (2006) showed that adherence with atypical antipsychotics is still low, with just over half (51.9%) of the bipolar patients prescribed atypical antipsychotics being fully adherent, while 48.1% of the patients were either partially adherent or non-adherent. Baldessarini et al.
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(2008) found that adherence did not vary across therapeutic classes, but was rather inuenced by factors such as alcohol-dependence, youth, greater affective morbidity, various side effects, comorbid obsessive-compulsive disorder, or recovery from maniahypomania. Further studies are needed to better understand treatment adherence to different pharmacological agents used to treat bipolar disorder. Treatment adherence in bipolar disorder may be inuenced by a number of variables associated with the patient, clinician, family, illness, and treatment and many of these risk factors are amenable to intervention and could serve as clinical targets (Berk et al., 2008). It is clear that there are many risk factors that may work individually or compound with other factors to increase risk of non-adherence. This implies that risk factors may differ from person to person and form predictable clusters in certain subgroups of people with bipolar disorder. These risk factors or clusters may not only change in relation to each other and the illness, but also across time. Future research might consider exploring the links between certain types of non-adherence and particular risk factors in different subgroups of patients at different stages of treatment to establish vulnerability trends that could be addressed by adjunctive psychosocial interventions. From a clinical point of view, this plethora of risk factors highlights the importance of not just providing information to the patient but also of fostering a collaborative therapeutic relationship whereby individual reasons for nonadherence can be discussed and addressed. Psychosocial interventions for enhancing adherence A combination of pharmacotherapy and psychotherapy may be optimal for achieving positive long-term outcomes (Colom et al., 2003). Psychosocial interventions targeting adherence as a primary outcome measure range from focusing exclusively on psychoeducation about the illness and its treatment to those that utilize psycho-education plus behavioral and cognitive skills to enhance positive attitudes and adherence behaviors. Interventions that treat adherence as a secondary outcome tend to be longer and include more complex interventions with a number of illness management skills (Colom et al., 2003; Lam et al., 2005; Miklowitz et al., 2003). A common thread that links all adjunctive psychosocial studies that target adherence is psycho-education. Most interventions require the establishment of collaborative relationships with patients, clinicians, and sometimes families to enhance adherence behavior. PsychotherCopyright # 2009 John Wiley & Sons, Ltd.
apeutic approaches to adherence include approaches such as psycho- education, cognitive-behavioral therapy, family interventions, and group therapy (Table 1). Overall the studies that do exist, despite the differences in focus, types of intervention, duration and adherence measures used, point to the potential usefulness of combining pharmacotherapy with psychotherapy to improve medication adherence. Studies that target medication adherence as a primary outcome. Only a handful of studies have focused primarily on improving adherence. Peet and Harvey (1991) conducted a short psycho-education intervention aimed at improving adherence to lithium. Patients in the treatment group were given a videotaped lecture and written handout with information about lithium and follow up visits, while patients in the waiting list control group did not receive any psycho-education. People who received the education had improved knowledge about lithium at 6 weeks follow up. Interestingly, improved attitudes to lithium, rather than actual knowledge, in both the intervention and control groups, was related to improved adherence. Patients in the intervention group reported missing fewer doses of lithium compared to the control group, but this did not quite reach statistical signicance, and no differences were found between groups regarding plasma and serum RBC lithium levels. In a small controlled study (n 26), Dogan and Sabanciogullari (2003) found that giving bipolar patients a short threesession education program regarding the disorder and lithium treatment improved medication knowledge, quality of life and resulted in more regular medication use and a decrease in symptom levels at 3 months in the group that received the intervention. Some approaches have added cognitive and behavioral strategies, aiming not only to increase knowledge, but to change attitudes to treatment and foster adherence behavior. Cochran (1984) examined whether 6 weekly sessions of cognitive behavioral therapy could improve adherence. This was measured, with patients, informants and physicians reports, serum lithium levels and a composite measure including attendance at medical appointments, medication consumption and lithium levels. Results indicated a signicant improvement in patient adherence in the intervention, as opposed to the standard care group at post treatment and 6 months later on this composite measurement of adherence, as well as on physicians ratings. Patients in the intervention group were less likely to stop lithium against their doctors advice or to relapse and be hospitalized. Although this was a small study (n 28), it highlights the potential

Table 1. Interventions targeting medication adherence as a primary outcome (T) and comprehensive interventions (C) Study Cochran (1984), T No. of patients 28 Study design Randomized controlled study of six sessions of individual cognitive behavioral therapy targeting adherence. Follow up occurred post trial, 3 months and 6 months Wait list controlled study involving videotape and handout plus follow-up visit. Study conducted over 24 weeks Open pilot study of Concordance therapy (CCT): bipolar patients with self-reported problems received CCT. Psychiatric follow-up for 6 months Bipolar patients on lithium therapy were given short education program. Outcome was assessed at 3 months in treatment and control groups Randomized controlled trial of Family-focused therapy (FFT): FFT and pharmacotherapy versus crisis management (CM) and pharmacotherapy. Outcomes were assessed every 36 months for 2 years Randomized controlled trial: Standard psychiatric care plus group psycho-education versus unstructured group meetings for 21 sessions. Outcomes assessed monthly over 2-year follow up Randomized controlled trial of individual cognitive therapy (CT): bipolar patients with frequent relapse were randomized into control and CT group and followed up for 30 months Randomized controlled trial of individual cognitive therapy or treatment as usual over 12 months follow up Randomized controlled trial of 4 combinations of acute and maintenance phases of IPSRT and ICM. Quasi-experimental clinical trial, 12 group sessions with middle aged tand elderley adults,divided into 4 components (education, motivational training, medication management and symptom management) Outcome
Peet and Harvey (1991), T Scott and Tacchi (2002), T.
60 10
Dogan and Sabanciogullari (2003), T Miklowitz et al. (2003), C
26 101
Colom et al. (2003), C
120
Lam et al. (2005), C
103
Ball et al. (2006) C Frank et al. (2005) C Depp et al. (2007), T
52 175 21
Increased adherence in intervention group on some of the measures, less people terminated lithium against medical advice, less hospitalization or relapses related to poor adherence ( p 0.05) Knowledge of lithium improved in intervention group. No signicant differences in adherence as assessed by self-report or plasma and RBC levels Improvement in attitude toward lithium associated with improvement in self-reported adherence. Serum lithium levels signicantly increased after CCT (from 0.4 to 0.6, effect size 1.7) Educated group had increased medication knowledge, improved quality of life, reduced symptom level, and improved medication adherence compared to baseline 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, P 0.003). FFT group had better medication adherence than CM group Intervention group showed reduction in relapses, reduction in recurrences per person and hospitalization. Mean serum lithium levels were higher and more stable in intervention group Compared to control, CT group had better survival to bipolar or depressive episodes, higher social functioning, less mood symptoms. Improvements in self and clinician reported medication adherence Improvements in adherence did not differ between groups. There were signicantly less severe depression scores in the CT group No between group differences in adherence. There was greater time to new illness episode for those participants assigned to IPSRT in the acute phase Improvements in self-reported medication adherence, medication management ability, depressive symptoms, and selected indices of health-related quality of life
benets of short cognitive behavioral interventions targeting treatment adherence. Scott and Tacchi (2002) assessed the efcacy of six sessions of concordance therapy in improving adherence with lithium prophylaxis over 6 months in a small open pilot study of ten outpatients with bipolar disorder. Concordance therapy is a form of cognitive therapy (CT) that treats each person as an individual, and focuses on the choices that are concordant with their belief and value systems. A psycho-education component was supplemented with strategies aimed at achieving changes in attitudes to treatment in order to change adherence behavior. The concordance approach aims to develop a shared understanding between clinician and patient about bipolar disorder and its treatment and the formation of collaborative treatment goals, and has parallels with the notion of the collaborative alliance (Berk et al., 2008). This concordance encourages adherence to treatment regimens that are practical and meaningful to the patient.
Clarication of inaccurate beliefs and expectations about treatment and a problem solving approach to adherence difculties assist in personalizing medication adherence as an effective coping strategy. This pilot study showed signicant improvements in attitudes linked to improvements in self-reported adherence and serum lithium levels. A recent small pilot study (n 21) specically targeting medication adherence in middle aged and elderly adults with bipolar disorder demonstrated encouraging results for a 12 week group based intervention involving medication adherence skills training using a quasi experimental design (Depp et al., 2007). There was a high retention rate, satisfaction with the program and improvements in self-reported medication adherence, medication management ability as well as depressive symptoms and aspects of health related quality of life. The authors point out that a larger sample, follow up data and a control group is needed to evaluate this intervention more thoroughly.
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Interestingly, the reasons for non-adherence were linked directly to the skills included in the intervention such as ways to remind oneself to take medications and communication with clinicians. These reasons for nonadherence were found to be more salient for this older subgroup of people with bipolar disorder than negative attitudes, emphasizing the need for a patient centered approach to improving adherence. In summary, although these few studies have limitations in that some are pilot studies, and there is a need for larger longer term randomized controlled evaluation of interventions, they highlight the potential of relatively brief focused efforts to improve medication adherence. Such interventions may need to adopt a patient centered approach in targeting risk factors that are patient specic. Psychosocial interventions that target medication adherence as a secondary outcome. There are a number of randomized controlled studies of comprehensive adjunctive psychosocial interventions that improve outcomes in bipolar disorder (Colom et al., 2003; Lam et al., 2005; Miklowitz et al., 2003). These interventions have numerous targets besides medication adherence, including psycho-education about the illness and its treatment, identication and reduction of triggers and warning signs of illness, stress management, and regulating lifestyle and sleep. These comprehensive interventions expose the complexity of the Interacting mechanisms of action responsible for positive outcomes. Lam et al. (2005) conducted a complex randomised controlled trial of a CT intervention with 103 outpatients with bipolar disorder who had experienced frequent relapses despite pharmacological treatment. The active intervention involved an average of 14 sessions over 6 months with two booster sessions in the following 6 months, in addition to the mood stabilizers and psychiatric follow up received by the control group. Serum lithium levels were only available for about half the patients and differences between the control and intervention groups were not signicant. In the group receiving CT there were signicant improvements in patient and clinician reports of medication adherence. The positive effect on relapse reduction was signicant in the rst year of the study, but this was not sustained over the last 18 months of the study. However, when controlling for medication adherence the intervention group still had fewer days in episode, had better mood ratings, coped better with prodromes and had improved social functioning and attitudes to goal attainment over the 30 months. This study demonstrates that CT may
improve medication adherence, but there are a number of mechanisms of action that may contribute to positive outcomes. Another randomized study using a different kind of individual CT that included emotive techniques, also reported positive benets of the intervention, particularly with regard to depressive relapse, modication of dysfunctional attitudes, and some improvement in functioning (Ball et al., 2006). These benets, like the previous study, diminished with time from active treatment. Future research may usefully examine longterm adherence to psychosocial illness management skills that may lag once the impetus of the active intervention is over. Booster sessions or other factors such as family involvement may play a role in sustaining such adherence. In this CT study, there was no signicant difference in self-reported medication adherence between the groups. Scott et al. (2006) in a large study of Cognitive Behavioral Therapy (CBT), also did not nd that medication adherence was improved in the intervention group despite a specic part of the intervention being devoted to targeting dysfunctional cognitions related to treatment adherence (Scott et al., 2006). A different type of comprehensive intervention comparing Interpersonal and Social Rhythm Therapy (IPSRT) to Intensive Case Management (ICM) also found no differences in medication adherence between groups, although the group receiving (ISPRT) in the acute phase showed greater time to new illness episode (Frank et al., 2005). This conrms that other mechanisms of action, besides medication adherence may contribute to positive outcomes. Interestingly in this study, patients with medical or anxiety related comorbidity beneted more from ICM than ISPRT highlighting the role of patient variables in predicting outcomes. This is conrmed by Scott et al. (2006) who reported that patients with fewer than 12 previous episodes had less recurrences with CBT, but this was not true of those with more than 12 episodes who deteriorated with the intervention. These studies highlight the need to consider patient variables and rene the use of adjunctive psychosocial interventions for specic subgroups of people with bipolar disorder. The intervention forokagated by Miklowitz et al. (2003) includes family members together with the patient and provides psycho-education on the illness and its treatment as well as emphasizing communication skills and problem solving in the family. They compared patients assigned to either pharmacotherapy and Family-Focused Treatment (FFT, 21 sessions involving psycho-education, communication training, and problem solving skills), or pharmacotherapy with a
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less intensive crisis management intervention (two sessions of family psycho-education, and ongoing intervention support). The results indicated that over the 2-year follow up period, 45% of patients receiving FFT were fully adherent (consistent use of prescribed mood stabilizers) compared with 21% of patients who received Crisis Management. No differences were evident in partial adherence but non-adherence was about three times higher in the Crisis Management group (Miklowitz, 2006). There was evidence of signicantly greater reductions in mood symptoms and increased time to relapse in patients who received the FFT intervention compared to in the comparison group, particularly with regard to depression. Positive results on medication adherence were also reported in an earlier study of an intervention involving marital therapy and psycho-education, with a positive impact on functioning rather than symptoms (Clarkin et al., 1998). No difference was evident in an early group based intervention for partners that did not include the patients themselves (van Gent and Zwart, 1991). Thus, interventions that include family members have shown a positive inuence on medication adherence and other outcomes. They may also help to reduce suicide risk (Miklowitz and Taylor, 2006). FFT was also associated with sustained benets in terms of relapse rates and re-hospitalization in the second follow up year, once active treatment was over compared to individual psycho-education (Rea et al., 2003). A possible explanation could be the added advantage of the positive long-term inuence of families on medication adherence. However, importantly, there was no difference in medication adherence between the patients in the FFT group compared to those who received individual psycho-education in this study. This means that other explanations linked to the possible mechanisms of actions of family therapy might explain these improved outcomes, for example, involving family members in detecting and responding to warning signs of illness or reducing interpersonal stress. It is notable that improved medication adherence was considered to be one of the factors that contributed to the benecial outcomes of group psycho-education (Colom et al., 2003). In a randomized controlled trial, 120 patients with bipolar disorder were randomized to receive 21 sessions of group psycho-education or 21 sessions of non-structured group meetings in addition to standard psychiatric care. At 6-months and 2-years follow-up patients who received the psycho-education program had signicantly fewer recurrences, and an increased length of time to depressive, manic, hypomanic, and mixed episodes. Analysis of patients
that were on lithium during the study showed that patients who received group psycho-education had more optimal and stable lithium levels compared to control patients (Colom et al., 2005a). Adherence was not the sole mediator of improved outcome as participants who were already highly adherent also showed signicant improvement as a result of the psycho-education intervention. Group psychoeducation was further associated with lower relapse rates at a 5-year follow up, suggesting a sustained benet that may in part be mediated by adherence (Colom et al., 2009). The Life Goals program combined group psychoeducation with regular individual follow up and monitoring of prodromes and medication problems within a collaborative care model. Active involvement in treatment was encouraged through the collaborative relationship between patient and clinician. This program demonstrated good adherence levels to both medication and clinical attendance and reported positive results on relapse and manic symptomatology (Simon et al., 2006). However, neither the number of medication visits nor atypical antipsychotic medications was related to lower mania ratings. From this review of studies that target medication adherence as a secondary outcome, it is evident that such a holistic approach can provide a useful adjunct to pharmacological treatment and signicantly improve patient outcomes (for example, Colom et al., 2003; Miklowitz et al., 2003). More detailed attention needs to be given to the inuence of different mechanisms of action and sustaining benets over time (Lam et al., 2005). In the context of future practice, this raises questions about whether to focus on developing briefer interventions that target treatment adherence alone and to assess these in large randomized controlled trials, or to continue to promote adherence as a component of more complex interventions. People may be more amenable to addressing treatment adherence issues within a more comprehensive holistic approach that includes other areas that are meaningful and important to them, for example stress management. However, concerns about the translation of these interventions into clinical world outcomes and their cost-effectiveness need to be addressed (Scott, 2006). A possibility may be to isolate core parts of more comprehensive interventions and their applications to specic subgroups of patients with bipolar disorder to enhance real-world outcomes. On the other hand restraints on resources and costs may point to the usefulness of even briefer targeted approaches that focus exclusively on a relevant health behavior like adherence that affects clinical outcomes. Addressing
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relevant risk factors for non-adherence for particular subgroups of people with bipolar disorder within the context of briefer family, group, and individual models may signicantly improve medication adherence and other outcomes. However, notably, there is a lack of large scale randomized controlled psychosocial studies of briefer interventions targeting medication adherence to inform best practice. Studies that specically address attitudes, beliefs, and behaviors to improve medication adherence may have more chance of improving adherence than those that do not include such a specic focus. For example, Perry et al. (1999) targeted warning signs of illness (Gaudiano et al., 2008). However, to enhance adherence, this specic focus needs to be tailored to the complex needs of people with bipolar disorder, for example, people with comorbidity, and to specic adherence problems, for example, involuntary versus voluntary non-adherence (Depp et al., 2007; Frank et al., 2005; Scott et al., 2006). Perhaps, ultimately a more needs based approach relying on more sophisticated assessment of individual difculties in managing bipolar disorder may assist in matching briefer interventions to core problem areas. For example, people who are already adherent to medication might benet more at that point in time from an intervention that targets different aspects of illness management.
Improving psycho-education Psycho-education is a primary component of the collaborative model of treatment that advocates the rights of the patient to make informed decisions about their treatment (Sajatovic et al., 2007b). Psychosocial studies recognize the usefulness of psycho-education as a tool to foster adherence and other outcomes. One study demonstrated the impact of poor psychoeducation in bipolar disorder through a recent consumer survey of 223 members of the US Manic Depression fellowship (Bowskill et al., 2007). They found that people with more dissatisfaction with information about their medications reported lower adherence. High levels of dissatisfaction in this study were reported about information on potential problems related to their medications such as side effects, and how medications would affect their sex life. In addition there was dissatisfaction about information on how medicines work. While psycho-education is a potentially useful tool, to have maximum effect, a number of variables relating to the patient, the stage of illness, and the treatment
relationship may need to be considered. Targeted psycho-education about the illness, treatment, and helpful behavioral skills may assist in reducing the different aspects of non-adherence including voluntary, involuntary, partial, irregular, and selective nonadherence and abuse (Colom et al., 2005b). Clinicians may need to consider peoples current level of knowledge and different requirements for information about their medicines and that these requirements may change at different stages of treatment (Bowskill et al., 2007). Attention may also need to be given to the timing and delivery of information. For example, providing lots of information when a person is too ill to process it may overwhelm the patient, leading to information overload and anxiety. Further, information may need to be adapted to take into account cognitive decits (Depp et al., 2007). McGorry and McConville, (1999) highlight the dangers of too much information too soon, especially early in treatment for people with psychotic disorders. Insight into the reality that one has a mental illness may lead to a fall in self-concept, demoralization, and a protective denial of the illness, or the need for treatment to deal with this cognitive dissonance. Information may need to be conveyed in a way that is sensitive to these issues and employs the individuals own language and draws on their personal conceptions of illness and treatment rather than in a didactic way. Essential to this process is a good therapeutic alliance, which facilitates the optimal exchange of information between clinician and patient (Berk et al., 2008). Similarly facilitating a supportive group process or collaborative family interaction may make it easier for individuals to consider, openly question and integrate information about their illness, and to develop positive attitudes toward treatment. A group format has the advantage of peer support and cost effectiveness. Although it may not be possible to focus on each individual difference in terms of requirements of information, it may be feasible to identify people with bipolar disorder that have certain common risk factors and apply psycho-education more selectively and appropriately within these subgroups. Thus, more targeted psycho-education within a supportive collaborative therapeutic relationship and/ or group or family context may help improve real world outcomes (Scott, 2006). Research is needed to test out the advantages of this approach, perhaps by comparing it to interventions that simply provide general written information. Information on how medicines work is progressing, and may ultimately inform psycho-education and contribute to informed choices about adhering to
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medication. Advances in identifying biological changes that help explain the positive impact of adherence on outcome could assist people in understanding the rationale behind adherence and possibly have a useful place in psycho-educational interventions. Further, increasingly evidence indicates that the timing of medication in the illness course and targeting medication to the stage of the illness is another extremely important factor when considering adherence (Berk et al., 2007), particularly as studies demonstrate that earlier pharmacological intervention is associated with better outcomes (Franchini et al., 1999). There is awareness that bipolar disorder is associated with cellular atrophy and/or volumetric decreases in the brain (Shaltiel et al., 2007). In contrast, recent evidence indicates that mood stabilizing medications may protect the brain from this neuronal atrophy and degeneration (i.e., be neuroprotective). Specically, lithium has demonstrated neuroprotective properties in a number of studies (Bearden et al., 2007; Sassi et al., 2004). In adolescent bipolar disorder, mood stabilizers are associated with sparing the cortical volume loss observed in patients not on mood stabilizers (Chang et al., 2005). Evidence indicates that adherence to lithium in bipolar disorder also may prevent gray matter volume losses in bipolar disorder (Moore et al., 2000). These results, while tentative, have led to mood stabilizers now being considered neuroprotective, leading to an even greater emphasis on adherence to prevent progression of structural changes. Conveying this information may be key in enhancing adherence.
arise from more sensitive matching of interventions to particular needs and risk factors, not only for the different aspects of non-adherence but for other health behaviors that also impact on outcome. Existing comprehensive psychosocial interventions may be able to be consolidated into a brief cost-effective format or/and short stand alone interventions that target medication adherence or other health behaviors as primary targets and could be provided on an as needed basis. Large-scale effectiveness trials of more consolidated versions of existing comprehensive interventions as well as brief psychosocial interventions utilising medication adherence as a primary outcome may provide evidence on the usefulness of these approaches. This review demonstrates that clinicians working with bipolar populations should consider the vulnerability of a particular patient to the different types of non-adherence, as well as the specic risk factors for non-adherence over the course of treatment. It may be helpful to adopt a patient centered approach to the delivery of psycho-education within the context of a collaborative patientclinician alliance. This may encourage patients to get the most benets from their medications and maximize symptomatic and functional recovery. Further research into the delivery of psycho-education may facilitate these improved clinical outcomes. As our understanding about how medicines work increases, the rationale for taking them is becoming clearer, knowledge that should empower both patient and clinician in making informed treatment decisions.
ACKNOWLEDGEMENTS Francesc Colom and Eduard Vieta would like to thank the support and funding of the Spanish Ministry of Health, Instituto de Salud Carlos III, CIBER-SAM. Dr Colom is funded by the Spanish Ministry of Science and Innovation, Instituto Carlos III, through a Miguel Servet postdoctoral contract (CP08/00140) Lesley Berk was supported by the NHMRC.
CONCLUSION There is a need to explore ways of maximising medication adherence that translate into effective realworld practice. The concept of non-adherence may need to be rened to include different aspects, for example, involuntary, voluntary, irregular, and selective non-adherence. Identifying common risk factors for these specic forms of non-adherence and those that are more likely to be relevant to certain subgroups of people with bipolar disorder may assist in developing briefer targeted interventions to improve clinical outcomes. This review indicates that adjunctive psychotherapy may augment pharmacological interventions, in part by improving treatment adherence resulting in improved outcomes. The long-term cost effectiveness of complex lengthy interventions needs more research. Briefer interventions that signicantly improve outcomes may
DISCLOSURE OF INTEREST Dr. Francesc Colom has served as advisory or speaker for the following companies: Astra Zeneca, BristolMyers, Pzer Inc, Glaxo-Smith-Kline, Eli-Lilly, Sano-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,
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Novartis, Organon, Otsuka, Pzer Inc, Sano-Aventis,. Servier & UCB Pharmaceuticals.
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human psychopharmacology

Enhancing medication adherence in patients with bipolar disorder

Copyright # 2009 John Wiley & Sons, Ltd.

medication adherence in bipolar disorder

Figure 1. Factors that inuence adherence status

Copyright # 2009 John Wiley & Sons, Ltd.

Hum. Psychopharmacol Clin Exp 2010; 25: 116. DOI: 10.1002/hup

medication adherence in bipolar disorder

medication adherence in bipolar disorder

medication adherence in bipolar disorder

Peet and Harvey (1991), T Scott and Tacchi (2002), T.

Dogan and Sabanciogullari (2003), T Miklowitz et al. (2003), C

Colom et al. (2003), C

Lam et al. (2005), C

Ball et al. (2006) C Frank et al. (2005) C Depp et al. (2007), T

medication adherence in bipolar disorder

medication adherence in bipolar disorder

Copyright # 2009 John Wiley & Sons, Ltd.

Hum. Psychopharmacol Clin Exp 2010; 25: 116. DOI: 10.1002/hup

medication adherence in bipolar disorder

Copyright # 2009 John Wiley & Sons, Ltd.

Hum. Psychopharmacol Clin Exp 2010; 25: 116. DOI: 10.1002/hup

Copyright # 2009 John Wiley & Sons, Ltd.

Hum. Psychopharmacol Clin Exp 2010; 25: 116. DOI: 10.1002/hup

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