- Email: [email protected]
Medication adherence in schizophrenia
Drug Discovery Today: Therapeutic Strategies
Vol. 8, No. 1–2 2011
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Treatment of schizophrenia
Medication adherence in schizophrenia David L. Roberts*, Dawn I. Velligan Department of Psychiatry, Division of Schizophrenia and Related Disorders, University of Texas Health Science Center, 7703 Floyd Curl Drive, MC 7797, San Antonio, TX 78229, United States
Antipsychotic medications enable many individuals with schizophrenia to live more rewarding and productive lives. However, this benefit hinges on patients taking medications as prescribed, and as many as half of all patients exhibit some degree of treatment non-
Section editors: Diana Kristensen – Department of Psychiatry, Hvidovre University Hospital, Brøndby, Copenhagen, Denmark Mikkel Myatt – Psykiatrisk Center Glostrup, Copenhagen University, Glostrup, Copenhagen, Denmark
adherence. The current review summarizes the results of a survey on medication nonadherence that was completed by 41 experts in the field. Results confirm the prevalence of the problem, and provide practical guidance for clinicians on measurement and management of nonadherence.
Introduction Inadequate medication adherence is common across illnesses, but in schizophrenia it can be particularly devastating to the patient and costly to society [1,2]. There are several key challenges to improving medication adherence in schizophrenia. First, there is inconsistency in how nonadherence is defined and measured. Second, although numerous reviews of adherence intervention approaches have been produced in recent years [3–5], no one or two approaches to adherence have emerged as consistently superior. Third, adherence strategies differ in their feasibility for use in routine clinical practice. To address these issues and provide recommendations for addressing medication nonadherence in schizophrenia, an expert consensus survey was conducted among 41 research experts on the topic, and responses were developed into guidelines and published in 2009 [6]. The purpose of the present review is to provide a succinct summary of these expert consensus guidelines. *Corresponding author: D.L. Roberts[4]–> ([email protected]) 1740-6773/$ ß 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2011.10.001
Summary of the guidelines The expert consensus procedure The Expert Consensus Guideline Series: Adherence Problems in Patients with Serious and Persistent Mental Illness reflect statistically aggregated survey responses from 41 experts on medication adherence in psychiatric disorders (85% of the 48 experts to whom the survey was sent). Experts were identified on the basis of their publication record. The survey, containing 39 items of mixed-response format, was developed by the guideline editors to address the following problematic issues in the research literature: defining nonadherence, describing the extent of the problem, identifying risk factors for nonadherence, assessment methods and intervention approaches. The current review provides a succinct summary of expert consensus on these issues. Although the survey addressed both schizophrenia and bipolar disorder, the current review addresses only schizophrenia-related items. For a more comprehensive discussion of the overlap between consensus and the empirical literature readers are referred to the full guidelines [6]. Topic-specific summaries of the empirical literature on schizophrenia are available elsewhere (defining and measuring nonadherence [7]; interventions to enhance adherence [3–5]).
Defining nonadherence Experts were asked how adherence should be defined to best advance research and intervention in this area. Experts identified percentage of medication taken over a period of time rather than medication gaps or cessation of treatment as the preferred 11
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
way to define adherence problems. Specifically, taking 80% of medication was considered to be an appropriate cut-off for defining adherence, with 50% as a cut-off for defining partial adherence. While defining medication nonadherence as a gap in treatment received less support as a definition, experts agreed that four days to one week of missed medication indicated nonadherence. Complete cessation of medication did not receive consensus support as a definition of nonadherence, in part because this definition was viewed to be insensitive to early evidence of nonadherence. Similarly, attitude or willingness to take medication, although viewed as an important variable, was not seen as a strong proxy measure for nonadherence, probably because there is not always a correspondence between attitudes and behaviors.
Epidemiology of adherence problems Most experts who treat schizophrenia estimated that their patients take between 51 and 70% of prescribed psychiatric medication. Only 10% judged that their patients took 80– 100% of their medications (the consensus definition for fully adherent). The editors note that these data are relatively consistent with the empirical literature and reflect an increased assessment of nonadherence compared to an earlier expert consensus survey. This may indicate growing awareness of the problem of nonadherence among mental health professionals.
Factors that affect adherence Experts were asked to rate the importance of a range of potential factors that affect adherence. Factors that were judged to play the greatest role in causing nonadherence were: Poor insight into having an illness, distress associated with persistent side effects (or fear of potential side effects), limited efficacy of medication with continued symptoms, and believing medications are no longer needed. Also highly rated were, ongoing substance use problems, cognitive deficits, lack of social support to assist with medication-taking and practical problems (e.g. transportation, financial problems). Factors rated as somewhat important were problems with therapeutic alliance, lack of daily routines, complexity of treatment regimen, medication attitudes of significant others and stigma associated with mental illness and medication. The editors note that these ratings generally converge with the self-report literature on factors affecting adherence in serious mental illness. However, they note that experts in the present survey attributed more importance to side effects than do patients in most surveys. That said, when asked to rate the specific side effects that most effect adherence, experts agreed with patient surveys in highlighting the importance of weight gain (especially in women) and cognitive side effects of medications. The experts also identified excessive sedation, akathisia, sexual dysfunction (especially in men) and parkinsonian symptoms as side effects that contribute to medication nonadherence. 12
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Vol. 8, No. 1–2 2011
As noted above, the experts identified limited medication efficacy and continued symptoms as a contributor to nonadherence. In follow-up questions, they endorsed both persistent negative symptoms and persistent positive symptoms as specific contributors to nonadherence. Negative symptoms can diminish adherence by decreasing initiative to take mediation or inducing apathy regarding the importance of medication. Positive symptoms may decrease adherence through the content of delusions or hallucinations. For example, a patient may believe his medications are poisoning him or may hear voices that tell him not to take medication. It is also true that the presence of persisting positive symptoms may indicate to the patient that medication is not helpful, leading to problems with adherence. The experts did not endorse a strong role for depressive symptoms in contributing to nonadherence in schizophrenia.
Methods for measuring adherence To optimize treatment it is necessary to know whether patients are actually receiving the treatment prescribed. As noted above, it is difficult for prescribers to determine whether poor treatment response is due to inadequate medication or to treatment nonadherence. Thus, methods for measuring adherence are of utmost importance. Adherence is most commonly measured using subjective methods, including patient self-report and physician judgment [7]. Unfortunately, despite being convenient, these methods are known to have poor validity, and typically overestimate level of adherence. Objective measures of adherence include pill counts, pharmacy records, plasma concentrations and electronic monitors. Although typically more valid than subjective report, estimates derived from these methods are also vulnerable to error and should be interpreted carefully. Moreover, most objective measures are less feasible for routine clinical use (e.g. blood plasma concentrations and electronic monitors). The research literature provides limited guidance on how measurement might best be addressed in routine clinical practice. The expert consensus panel was asked to judge the usefulness of a range of assessment methods for nonadherence (‘useful,’ ‘sometimes useful’ or ‘not useful’) as well as the frequency with which each of these methods is used in general clinical practice (‘very frequently,’ ‘frequently,’ ‘somewhat frequently’ or ‘rarely’). The only method judged to be used very frequently was that of asking patients about their adherence behavior (e.g. Are you taking your medication? How much do you take?). The panel judged this approach to be ‘sometimes useful.’ The panel estimated that the second most common method of adherence assessment generally employed (used ‘frequently’) is to ask patients about any problems that they have been having or that they anticipate having with taking medications. They judged this method to be more useful than just asking about adherence behavior.
Vol. 8, No. 1–2 2011
Thus, it may be more important for practicing clinicians to elicit the problems anticipated with taking medications rather than just asking about adherence behavior. Other methods that were rated as ‘useful’ but which are employed less frequently, probably because they are less convenient, were: obtaining patient’s permission to ask family or care provider about adherence, obtaining medication plasma level, having patients bring in medication supply for review and/or pill count, pharmacy refill record review, technological tools (e.g. ‘smart pill’ bottles) and asking about attitudes toward medication. In addition to asking the patient about adherence behavior, other methods that were judged to be ‘sometimes useful’ were consultation with other treatment team members and using standardized self-report instruments. One self-report instrument that is easy to use, publicly available and has shown promising psychometric properties is the Brief Adherence Rating Scale (BARS [8]). Finally, use of symptom levels to estimate adherence was judged to be ‘not useful.’ It may be important for clinicians to avoid this type of backward reasoning (i.e. the patient must not be adherent because they are not doing well). The expert panel judged that although it is most important to assess patients’ adherence behavior, it is also valuable to assess patients’ attitudes toward taking medication. Assessing patients’ attitudes can bring to prescribers’ attention important modifiable factors that may be hindering adherence, including inaccurate, myth-based beliefs about medication. In discussing medication clinicians should attend carefully to how they ask questions, avoiding sounding authoritarian or punitive, making clear that it is OK for the patient to disagree, showing willingness to be flexible, and keeping in mind that one’s relationship with the patient can play a key role in both adherence and accurate assessment of adherence [9]. The full Guidelines include a section providing extensive, concrete guidance on how to organize and carry out adherence discussions. Goals and techniques for assessment discussions are provided along with topically organized suggestions for specific prompts and phrasing. This includes prompts for identifying obstacles to adherence which are organized based on factors that affect adherence (i.e. attitudes and past behaviors, comorbidity and symptom severity, demographic factors, environmental factors, cognitive impairment, medication-related factors, factors in the therapeutic relationship, family factors and factors related to the service delivery system).
Frequency and duration of adherence assessment The expert panel was asked to recommend the optimal frequency of adherence assessment and the amount of time that should be spent conducting assessments across a range of hypothetical clinical situations. The panel recommended that adherence be assessed more frequently and for longer duration among patients who do not appear to be responding
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
to medication and for whom nonadherence is a known problem. Specifically, the panel recommended assessing adherence at least weekly for 10–30 min in these patient groups. For a patient who is new to the clinician but appeared adherent at initial evaluation, the panel recommended monthly, 5– 10 min adherence assessment. Lastly, for patients who are well known and regularly adherent, assessment may be conducted monthly for 5 min. It is noteworthy that these guidelines may not be practical within the realities of community mental health service provision in which some patients may only be seen briefly every three months.
Strategies for improving adherence A wide range of intervention approaches have been developed to enhance medication adherence in severe psychiatric disorders. Many of these approaches employ services-level and multi-faceted interventions, such as assertive community treatment (ACT), which cannot feasibly be initiated by an individual prescriber in clinical practice. To maximize the clinical utility of the Guidelines, survey questions were designed to elicit expert advice regarding intervention approaches that could plausibly be initiated by individual clinicians. Experts were asked to rate the utility of a range of strategies for addressing specific factors that contribute to adherence problems on a scale of 1 (lowest) to 9 (highest). Strategies were designated as ‘first-line’ if they were the highest rated strategy for addressing a specific factor and if the 95% confidence interval for their mean rating extended above 6.5 on the 9-point scale. Strategies were designated as ‘second-line’ if the 95% confidence interval extended above 3.5. Table 1 summarizes expert consensus regarding first-line and high second-line strategies for addressing specific factors that contribute to poor medication adherence. For some contributing factors, no strategies were identified as first-line, possibly reflecting limited available evidence on the topic. If a strategy received a rating of 9 by more than 50% of experts it was considered an ‘intervention of choice.’ In Table 1, first-line factors are indicated by bold and interventions of choice by bold and italics. The expert panel was asked about the appropriateness of prescribing alternative medications for patients who refuse primary antipsychotic medication. The experts recommended that clinicians continue ongoing psychotherapy with such patients and consider the use of anxiolytics or antidepressants if appropriate to the presenting symptoms. Experts cautioned against the use of stimulants and antidepressants for patients at risk of mania, and did not recommend the use of natural/ vitamin treatment or Modafanil as promising alternatives to maintenance antipsychotic treatment.
Use of long-acting injectable antipsychotics Experts were asked several questions regarding the use of long-acting injectable antipsychotics as a strategy to promote www.drugdiscoverytoday.com
13
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
Vol. 8, No. 1–2 2011
Table 1. Strategies to improve medication adherence based on contributing factors.a Contributing factor
Psychosocial/programmatic strategy
Pharmacological strategy
Lack of insight
Medication monitoring environmental supports Patient psychoeducation More frequent/longer visits if possible CBT Family-focused therapy
Switch to a long-acting antipsychotic
Concern about stigma
Patient psychoeducation CBT Family-focused therapy
No change in medication; intensify psychosocial interventions
Substance use
Patient psychoeducation Involuntary outpatient commitment Medication monitoring/environmental supports Integrated dual diagnosis treatment program
Switch to a long-acting antipsychotic No change in medication; intensify psychosocial interventions
Persistent symptoms
Symptom and side effect monitoring Medication monitoring/environmental supports More frequent and/or longer visits if possible CBT
Increase dose of current antipsychotic Switch to a long-acting antipsychotic or a different oral antipsychotic
Logistic problems
Social work targeting logistic problems Medication monitoring/environmental supports
Simplify medication regimen Switch to a long-acting antipsychotic No change in medication; intensify psychosocial interventions
Lack of routines
Medication monitoring/environmental supports Social work targeting logistic problems Interpersonal and social rhythm therapy
Simplify medication regimen Switch to a long-acting antipsychotic No change in medication; intensify psychosocial interventions
Cognitive deficits
Medication monitoring/environmental supports Social work targeting logistic problems Symptom and side effect monitoring
Simplify medication regimen
Persistent side effects
Symptom and side effect monitoring
Decrease dose of current antipsychotic Switch to a different oral antipsychotic
Poor therapeutic alliance
More frequent and/or longer visits if possible Patient psychoeducation Compliance therapy Medication monitoring/environmental supports
No change in medication; intensify psychosocial interventions
Lack of family and social support
Family-focused therapy Social work targeting logistic problems Medication monitoring/environmental supports
No change in medication; intensify psychosocial interventions Switch to a long-acting antipsychotic Simplify medication regimen
Bold = first-line strategy; Italics = strategy of choice. a Adapted with permission from Velligan et al. [6].
adherence. The panel strongly endorsed the view that such agents may be useful for a wide range of patients for whom adherence with oral treatment has been problematic. This approach was considered a first-line treatment. In particular, they recommended this approach among patients who have done well with depot medication in the past, who are under involuntary outpatient commitment, and who chronically relapse on oral medication. The panel indicated that particular strengths of depot medication include immediate recognition of nonadherence, recognition of poor symptom response to medication, reduced risk of relapse, convenience for the patient, and short-term maintenance of medication in system after a missed dose. The panel indicated that barriers to the use of long-acting injectables include inability to immediately discontinue medication in the case of problematic side effects, 14
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frequency of injections (e.g. every two weeks for long-acting risperidone), difficulties with reimbursement and negative attitudes toward injectables by patients. Notably, two recent studies contradict this last barrier in suggesting that firstepisode patients may be more amenable to injectables than assumed by care providers [10,11].
Working with families The panel was asked to rate strategies for working with family members who contact clinicians about adherence problems in a relative with schizophrenia. The panel most supported four approaches. First, ‘ask the patient if you could invite family members to the next appointment or visit them at home to see how everyone is coping (without reporting the call).’ Second, ‘advise family against putting medication in
Vol. 8, No. 1–2 2011
the food and tell them it is not a good idea to medicate someone without their knowledge.’ Third, ‘use what the family has told you to construct questions that are likely to elicit the same information from the patient.’ Fourth, ‘refer the parents to the National Alliance on Mental Illness for advice.’
Outpatient commitment and involuntary hospitalization There was not consensus on the use of outpatient commitment as an adherence strategy. Of the 41 experts, 55% gave it a first-line rating (i.e. above 6.5 on a 9-point scale) while 15% gave it third-line rating (below 3.5). The panel identified several problems with this approach, including: inconsistent criteria for implementation, inconsistent willingness of courts and law enforcement to enforce requirements, difficulty obtaining commitment orders due to paperwork and poor system integration, potential for negative effect of therapeutic alliance (i.e. perception as coercive), short-term effectiveness and inconsistent quality of care.
Conclusions This review has summarized expert consensus regarding identification, assessment and intervention for medication adherence problems among patients with schizophrenia. By and large, expert opinion agrees with the empirical research literature regarding the core features of this clinical problem and how it is best managed. First, nonadherence is a widespread problem that is caused by an array of factors that may differ substantially across individuals. Key contributing factors exist at the level of the patient (e.g. poor insight, symptoms, cognitive deficits), the environment (e.g. logistical problems, low family support) and the service system (e.g. poor communication within the treatment team). Second, thoughtful measurement of adherence is important; patient and clinician judgment are often inaccurate and objective measurement approaches are accompanied by important limitations to accuracy and/or feasibility. Third, the utility of different strategies for enhancing adherence depends on the factors that are causing and maintaining nonadherence.
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
Expert consensus and the empirical literature point to some firm conclusions. Regarding assessment of adherence, clinicians should use multiple sources of information, including at least one objective tool, such as pharmacy refill record or blood plasma level. Regarding intervention, although poor insight and negative attitudes toward medication are likely contributors to nonadherence in many cases, psychotherapeutic strategies aimed at changing attitudes toward medication have not received strong support. By contrast, there is clearer support for interventions that remove logistical barriers and provide environmental supports; these strategies may be particularly useful for patients with cognitive and motivational deficits (reviewed in [4]).
References 1 Terkelsen, K.G. and Menikoff, A. (1995) Measuring the costs of schizophrenia. Implications for the post-institutional era in the US. Pharmacoeconomics 8, 199–222 2 Weiden, P.J. and Olfson, M. (1995) Cost of relapse in schizophrenia. Schizophrenia Bull. 21, 419–429 3 Nose, M. et al. (2003) Clinical interventions for treatment non-adherence in psychosis: meta-analysis. Br. J. Psychiatry 183, 197–206 4 Roberts, D.L., et al. Interventions to improve oral medication adherence in psychosis: the role of adherence measurement. Neuropsychiatry (in press) 5 Zygmunt, A. et al. (2002) Interventions to improve medication adherence in schizophrenia. Am. J. Psychiatry 159, 1653–1664 6 Velligan, D.I. et al. (2009) The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J. Clin. Psychiatry 70 (Suppl. 4), 1–46 7 Velligan, D.I. et al. (2006) Defining and assessing adherence to oral antipsychotics: a review of the literature. Schizophrenia Bull. 32, 724–742 8 Byerly, M.J. et al. (2008) The Brief Adherence Rating Scale (BARS) validated against electronic monitoring in assessing the antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. Schizophrenia Res. 100, 60–69 9 Weiden, P.J. (2007) Understanding and addressing adherence issues in schizophrenia: from theory to practice. J. Clin. Psychiatry 68 (Suppl. 14), 14–19 10 Emsley, R. et al. (2008) J. Clin. Psychopharmacol. 28, 210–213 11 Weiden, P.J. et al. (2009) A randomized controlled trial of long-acting injectable risoperidone vs continuation on oral atypical antipsychotics for first-episode schizophrenia patients: initial adherence outcome. J. Clin. Psychiatry 70, 1397–1406
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Vol. 8, No. 1–2 2011
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Treatment of schizophrenia
Medication adherence in schizophrenia David L. Roberts*, Dawn I. Velligan Department of Psychiatry, Division of Schizophrenia and Related Disorders, University of Texas Health Science Center, 7703 Floyd Curl Drive, MC 7797, San Antonio, TX 78229, United States
Antipsychotic medications enable many individuals with schizophrenia to live more rewarding and productive lives. However, this benefit hinges on patients taking medications as prescribed, and as many as half of all patients exhibit some degree of treatment non-
Section editors: Diana Kristensen – Department of Psychiatry, Hvidovre University Hospital, Brøndby, Copenhagen, Denmark Mikkel Myatt – Psykiatrisk Center Glostrup, Copenhagen University, Glostrup, Copenhagen, Denmark
adherence. The current review summarizes the results of a survey on medication nonadherence that was completed by 41 experts in the field. Results confirm the prevalence of the problem, and provide practical guidance for clinicians on measurement and management of nonadherence.
Introduction Inadequate medication adherence is common across illnesses, but in schizophrenia it can be particularly devastating to the patient and costly to society [1,2]. There are several key challenges to improving medication adherence in schizophrenia. First, there is inconsistency in how nonadherence is defined and measured. Second, although numerous reviews of adherence intervention approaches have been produced in recent years [3–5], no one or two approaches to adherence have emerged as consistently superior. Third, adherence strategies differ in their feasibility for use in routine clinical practice. To address these issues and provide recommendations for addressing medication nonadherence in schizophrenia, an expert consensus survey was conducted among 41 research experts on the topic, and responses were developed into guidelines and published in 2009 [6]. The purpose of the present review is to provide a succinct summary of these expert consensus guidelines. *Corresponding author: D.L. Roberts[4]–> ([email protected]) 1740-6773/$ ß 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2011.10.001
Summary of the guidelines The expert consensus procedure The Expert Consensus Guideline Series: Adherence Problems in Patients with Serious and Persistent Mental Illness reflect statistically aggregated survey responses from 41 experts on medication adherence in psychiatric disorders (85% of the 48 experts to whom the survey was sent). Experts were identified on the basis of their publication record. The survey, containing 39 items of mixed-response format, was developed by the guideline editors to address the following problematic issues in the research literature: defining nonadherence, describing the extent of the problem, identifying risk factors for nonadherence, assessment methods and intervention approaches. The current review provides a succinct summary of expert consensus on these issues. Although the survey addressed both schizophrenia and bipolar disorder, the current review addresses only schizophrenia-related items. For a more comprehensive discussion of the overlap between consensus and the empirical literature readers are referred to the full guidelines [6]. Topic-specific summaries of the empirical literature on schizophrenia are available elsewhere (defining and measuring nonadherence [7]; interventions to enhance adherence [3–5]).
Defining nonadherence Experts were asked how adherence should be defined to best advance research and intervention in this area. Experts identified percentage of medication taken over a period of time rather than medication gaps or cessation of treatment as the preferred 11
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
way to define adherence problems. Specifically, taking 80% of medication was considered to be an appropriate cut-off for defining adherence, with 50% as a cut-off for defining partial adherence. While defining medication nonadherence as a gap in treatment received less support as a definition, experts agreed that four days to one week of missed medication indicated nonadherence. Complete cessation of medication did not receive consensus support as a definition of nonadherence, in part because this definition was viewed to be insensitive to early evidence of nonadherence. Similarly, attitude or willingness to take medication, although viewed as an important variable, was not seen as a strong proxy measure for nonadherence, probably because there is not always a correspondence between attitudes and behaviors.
Epidemiology of adherence problems Most experts who treat schizophrenia estimated that their patients take between 51 and 70% of prescribed psychiatric medication. Only 10% judged that their patients took 80– 100% of their medications (the consensus definition for fully adherent). The editors note that these data are relatively consistent with the empirical literature and reflect an increased assessment of nonadherence compared to an earlier expert consensus survey. This may indicate growing awareness of the problem of nonadherence among mental health professionals.
Factors that affect adherence Experts were asked to rate the importance of a range of potential factors that affect adherence. Factors that were judged to play the greatest role in causing nonadherence were: Poor insight into having an illness, distress associated with persistent side effects (or fear of potential side effects), limited efficacy of medication with continued symptoms, and believing medications are no longer needed. Also highly rated were, ongoing substance use problems, cognitive deficits, lack of social support to assist with medication-taking and practical problems (e.g. transportation, financial problems). Factors rated as somewhat important were problems with therapeutic alliance, lack of daily routines, complexity of treatment regimen, medication attitudes of significant others and stigma associated with mental illness and medication. The editors note that these ratings generally converge with the self-report literature on factors affecting adherence in serious mental illness. However, they note that experts in the present survey attributed more importance to side effects than do patients in most surveys. That said, when asked to rate the specific side effects that most effect adherence, experts agreed with patient surveys in highlighting the importance of weight gain (especially in women) and cognitive side effects of medications. The experts also identified excessive sedation, akathisia, sexual dysfunction (especially in men) and parkinsonian symptoms as side effects that contribute to medication nonadherence. 12
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Vol. 8, No. 1–2 2011
As noted above, the experts identified limited medication efficacy and continued symptoms as a contributor to nonadherence. In follow-up questions, they endorsed both persistent negative symptoms and persistent positive symptoms as specific contributors to nonadherence. Negative symptoms can diminish adherence by decreasing initiative to take mediation or inducing apathy regarding the importance of medication. Positive symptoms may decrease adherence through the content of delusions or hallucinations. For example, a patient may believe his medications are poisoning him or may hear voices that tell him not to take medication. It is also true that the presence of persisting positive symptoms may indicate to the patient that medication is not helpful, leading to problems with adherence. The experts did not endorse a strong role for depressive symptoms in contributing to nonadherence in schizophrenia.
Methods for measuring adherence To optimize treatment it is necessary to know whether patients are actually receiving the treatment prescribed. As noted above, it is difficult for prescribers to determine whether poor treatment response is due to inadequate medication or to treatment nonadherence. Thus, methods for measuring adherence are of utmost importance. Adherence is most commonly measured using subjective methods, including patient self-report and physician judgment [7]. Unfortunately, despite being convenient, these methods are known to have poor validity, and typically overestimate level of adherence. Objective measures of adherence include pill counts, pharmacy records, plasma concentrations and electronic monitors. Although typically more valid than subjective report, estimates derived from these methods are also vulnerable to error and should be interpreted carefully. Moreover, most objective measures are less feasible for routine clinical use (e.g. blood plasma concentrations and electronic monitors). The research literature provides limited guidance on how measurement might best be addressed in routine clinical practice. The expert consensus panel was asked to judge the usefulness of a range of assessment methods for nonadherence (‘useful,’ ‘sometimes useful’ or ‘not useful’) as well as the frequency with which each of these methods is used in general clinical practice (‘very frequently,’ ‘frequently,’ ‘somewhat frequently’ or ‘rarely’). The only method judged to be used very frequently was that of asking patients about their adherence behavior (e.g. Are you taking your medication? How much do you take?). The panel judged this approach to be ‘sometimes useful.’ The panel estimated that the second most common method of adherence assessment generally employed (used ‘frequently’) is to ask patients about any problems that they have been having or that they anticipate having with taking medications. They judged this method to be more useful than just asking about adherence behavior.
Vol. 8, No. 1–2 2011
Thus, it may be more important for practicing clinicians to elicit the problems anticipated with taking medications rather than just asking about adherence behavior. Other methods that were rated as ‘useful’ but which are employed less frequently, probably because they are less convenient, were: obtaining patient’s permission to ask family or care provider about adherence, obtaining medication plasma level, having patients bring in medication supply for review and/or pill count, pharmacy refill record review, technological tools (e.g. ‘smart pill’ bottles) and asking about attitudes toward medication. In addition to asking the patient about adherence behavior, other methods that were judged to be ‘sometimes useful’ were consultation with other treatment team members and using standardized self-report instruments. One self-report instrument that is easy to use, publicly available and has shown promising psychometric properties is the Brief Adherence Rating Scale (BARS [8]). Finally, use of symptom levels to estimate adherence was judged to be ‘not useful.’ It may be important for clinicians to avoid this type of backward reasoning (i.e. the patient must not be adherent because they are not doing well). The expert panel judged that although it is most important to assess patients’ adherence behavior, it is also valuable to assess patients’ attitudes toward taking medication. Assessing patients’ attitudes can bring to prescribers’ attention important modifiable factors that may be hindering adherence, including inaccurate, myth-based beliefs about medication. In discussing medication clinicians should attend carefully to how they ask questions, avoiding sounding authoritarian or punitive, making clear that it is OK for the patient to disagree, showing willingness to be flexible, and keeping in mind that one’s relationship with the patient can play a key role in both adherence and accurate assessment of adherence [9]. The full Guidelines include a section providing extensive, concrete guidance on how to organize and carry out adherence discussions. Goals and techniques for assessment discussions are provided along with topically organized suggestions for specific prompts and phrasing. This includes prompts for identifying obstacles to adherence which are organized based on factors that affect adherence (i.e. attitudes and past behaviors, comorbidity and symptom severity, demographic factors, environmental factors, cognitive impairment, medication-related factors, factors in the therapeutic relationship, family factors and factors related to the service delivery system).
Frequency and duration of adherence assessment The expert panel was asked to recommend the optimal frequency of adherence assessment and the amount of time that should be spent conducting assessments across a range of hypothetical clinical situations. The panel recommended that adherence be assessed more frequently and for longer duration among patients who do not appear to be responding
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
to medication and for whom nonadherence is a known problem. Specifically, the panel recommended assessing adherence at least weekly for 10–30 min in these patient groups. For a patient who is new to the clinician but appeared adherent at initial evaluation, the panel recommended monthly, 5– 10 min adherence assessment. Lastly, for patients who are well known and regularly adherent, assessment may be conducted monthly for 5 min. It is noteworthy that these guidelines may not be practical within the realities of community mental health service provision in which some patients may only be seen briefly every three months.
Strategies for improving adherence A wide range of intervention approaches have been developed to enhance medication adherence in severe psychiatric disorders. Many of these approaches employ services-level and multi-faceted interventions, such as assertive community treatment (ACT), which cannot feasibly be initiated by an individual prescriber in clinical practice. To maximize the clinical utility of the Guidelines, survey questions were designed to elicit expert advice regarding intervention approaches that could plausibly be initiated by individual clinicians. Experts were asked to rate the utility of a range of strategies for addressing specific factors that contribute to adherence problems on a scale of 1 (lowest) to 9 (highest). Strategies were designated as ‘first-line’ if they were the highest rated strategy for addressing a specific factor and if the 95% confidence interval for their mean rating extended above 6.5 on the 9-point scale. Strategies were designated as ‘second-line’ if the 95% confidence interval extended above 3.5. Table 1 summarizes expert consensus regarding first-line and high second-line strategies for addressing specific factors that contribute to poor medication adherence. For some contributing factors, no strategies were identified as first-line, possibly reflecting limited available evidence on the topic. If a strategy received a rating of 9 by more than 50% of experts it was considered an ‘intervention of choice.’ In Table 1, first-line factors are indicated by bold and interventions of choice by bold and italics. The expert panel was asked about the appropriateness of prescribing alternative medications for patients who refuse primary antipsychotic medication. The experts recommended that clinicians continue ongoing psychotherapy with such patients and consider the use of anxiolytics or antidepressants if appropriate to the presenting symptoms. Experts cautioned against the use of stimulants and antidepressants for patients at risk of mania, and did not recommend the use of natural/ vitamin treatment or Modafanil as promising alternatives to maintenance antipsychotic treatment.
Use of long-acting injectable antipsychotics Experts were asked several questions regarding the use of long-acting injectable antipsychotics as a strategy to promote www.drugdiscoverytoday.com
13
Drug Discovery Today: Therapeutic Strategies | Treatment of schizophrenia
Vol. 8, No. 1–2 2011
Table 1. Strategies to improve medication adherence based on contributing factors.a Contributing factor
Psychosocial/programmatic strategy
Pharmacological strategy
Lack of insight
Medication monitoring environmental supports Patient psychoeducation More frequent/longer visits if possible CBT Family-focused therapy
Switch to a long-acting antipsychotic
Concern about stigma
Patient psychoeducation CBT Family-focused therapy
No change in medication; intensify psychosocial interventions
Substance use
Patient psychoeducation Involuntary outpatient commitment Medication monitoring/environmental supports Integrated dual diagnosis treatment program
Switch to a long-acting antipsychotic No change in medication; intensify psychosocial interventions
Persistent symptoms
Symptom and side effect monitoring Medication monitoring/environmental supports More frequent and/or longer visits if possible CBT
Increase dose of current antipsychotic Switch to a long-acting antipsychotic or a different oral antipsychotic
Logistic problems
Social work targeting logistic problems Medication monitoring/environmental supports
Simplify medication regimen Switch to a long-acting antipsychotic No change in medication; intensify psychosocial interventions
Lack of routines
Medication monitoring/environmental supports Social work targeting logistic problems Interpersonal and social rhythm therapy
Simplify medication regimen Switch to a long-acting antipsychotic No change in medication; intensify psychosocial interventions
Cognitive deficits
Medication monitoring/environmental supports Social work targeting logistic problems Symptom and side effect monitoring
Simplify medication regimen
Persistent side effects
Symptom and side effect monitoring
Decrease dose of current antipsychotic Switch to a different oral antipsychotic
Poor therapeutic alliance
More frequent and/or longer visits if possible Patient psychoeducation Compliance therapy Medication monitoring/environmental supports
No change in medication; intensify psychosocial interventions
Lack of family and social support
Family-focused therapy Social work targeting logistic problems Medication monitoring/environmental supports
No change in medication; intensify psychosocial interventions Switch to a long-acting antipsychotic Simplify medication regimen
Bold = first-line strategy; Italics = strategy of choice. a Adapted with permission from Velligan et al. [6].
adherence. The panel strongly endorsed the view that such agents may be useful for a wide range of patients for whom adherence with oral treatment has been problematic. This approach was considered a first-line treatment. In particular, they recommended this approach among patients who have done well with depot medication in the past, who are under involuntary outpatient commitment, and who chronically relapse on oral medication. The panel indicated that particular strengths of depot medication include immediate recognition of nonadherence, recognition of poor symptom response to medication, reduced risk of relapse, convenience for the patient, and short-term maintenance of medication in system after a missed dose. The panel indicated that barriers to the use of long-acting injectables include inability to immediately discontinue medication in the case of problematic side effects, 14
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frequency of injections (e.g. every two weeks for long-acting risperidone), difficulties with reimbursement and negative attitudes toward injectables by patients. Notably, two recent studies contradict this last barrier in suggesting that firstepisode patients may be more amenable to injectables than assumed by care providers [10,11].
Working with families The panel was asked to rate strategies for working with family members who contact clinicians about adherence problems in a relative with schizophrenia. The panel most supported four approaches. First, ‘ask the patient if you could invite family members to the next appointment or visit them at home to see how everyone is coping (without reporting the call).’ Second, ‘advise family against putting medication in
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the food and tell them it is not a good idea to medicate someone without their knowledge.’ Third, ‘use what the family has told you to construct questions that are likely to elicit the same information from the patient.’ Fourth, ‘refer the parents to the National Alliance on Mental Illness for advice.’
Outpatient commitment and involuntary hospitalization There was not consensus on the use of outpatient commitment as an adherence strategy. Of the 41 experts, 55% gave it a first-line rating (i.e. above 6.5 on a 9-point scale) while 15% gave it third-line rating (below 3.5). The panel identified several problems with this approach, including: inconsistent criteria for implementation, inconsistent willingness of courts and law enforcement to enforce requirements, difficulty obtaining commitment orders due to paperwork and poor system integration, potential for negative effect of therapeutic alliance (i.e. perception as coercive), short-term effectiveness and inconsistent quality of care.
Conclusions This review has summarized expert consensus regarding identification, assessment and intervention for medication adherence problems among patients with schizophrenia. By and large, expert opinion agrees with the empirical research literature regarding the core features of this clinical problem and how it is best managed. First, nonadherence is a widespread problem that is caused by an array of factors that may differ substantially across individuals. Key contributing factors exist at the level of the patient (e.g. poor insight, symptoms, cognitive deficits), the environment (e.g. logistical problems, low family support) and the service system (e.g. poor communication within the treatment team). Second, thoughtful measurement of adherence is important; patient and clinician judgment are often inaccurate and objective measurement approaches are accompanied by important limitations to accuracy and/or feasibility. Third, the utility of different strategies for enhancing adherence depends on the factors that are causing and maintaining nonadherence.
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Expert consensus and the empirical literature point to some firm conclusions. Regarding assessment of adherence, clinicians should use multiple sources of information, including at least one objective tool, such as pharmacy refill record or blood plasma level. Regarding intervention, although poor insight and negative attitudes toward medication are likely contributors to nonadherence in many cases, psychotherapeutic strategies aimed at changing attitudes toward medication have not received strong support. By contrast, there is clearer support for interventions that remove logistical barriers and provide environmental supports; these strategies may be particularly useful for patients with cognitive and motivational deficits (reviewed in [4]).
References 1 Terkelsen, K.G. and Menikoff, A. (1995) Measuring the costs of schizophrenia. Implications for the post-institutional era in the US. Pharmacoeconomics 8, 199–222 2 Weiden, P.J. and Olfson, M. (1995) Cost of relapse in schizophrenia. Schizophrenia Bull. 21, 419–429 3 Nose, M. et al. (2003) Clinical interventions for treatment non-adherence in psychosis: meta-analysis. Br. J. Psychiatry 183, 197–206 4 Roberts, D.L., et al. Interventions to improve oral medication adherence in psychosis: the role of adherence measurement. Neuropsychiatry (in press) 5 Zygmunt, A. et al. (2002) Interventions to improve medication adherence in schizophrenia. Am. J. Psychiatry 159, 1653–1664 6 Velligan, D.I. et al. (2009) The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J. Clin. Psychiatry 70 (Suppl. 4), 1–46 7 Velligan, D.I. et al. (2006) Defining and assessing adherence to oral antipsychotics: a review of the literature. Schizophrenia Bull. 32, 724–742 8 Byerly, M.J. et al. (2008) The Brief Adherence Rating Scale (BARS) validated against electronic monitoring in assessing the antipsychotic medication adherence of outpatients with schizophrenia and schizoaffective disorder. Schizophrenia Res. 100, 60–69 9 Weiden, P.J. (2007) Understanding and addressing adherence issues in schizophrenia: from theory to practice. J. Clin. Psychiatry 68 (Suppl. 14), 14–19 10 Emsley, R. et al. (2008) J. Clin. Psychopharmacol. 28, 210–213 11 Weiden, P.J. et al. (2009) A randomized controlled trial of long-acting injectable risoperidone vs continuation on oral atypical antipsychotics for first-episode schizophrenia patients: initial adherence outcome. J. Clin. Psychiatry 70, 1397–1406
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