Interventions to improve adherence to antipsychotic medication in patients with schizophrenia–A review of the past decade

European Psychiatry 27 (2012) 9–18

Review

Interventions to improve adherence to antipsychotic medication in patients with schizophrenia–A review of the past decade E. Barkhof a,*, C.J. Meijer a, L.M.J. de Sonneville b, D.H. Linszen a, L. de Haan a a b

Department of Psychiatry, Academic Medical Centre, Meibergdreef 5, 1105 AZ Amsterdam, The Netherlands Department of Clinical Child and Adolescent Studies, Leiden University, Leiden, The Netherlands

A R T I C L E I N F O

A B S T R A C T

Article history: Received 24 September 2010 Received in revised form 16 January 2011 Accepted 6 February 2011 Available online 10 May 2011

Objective: Nonadherence to antipsychotic medication is highly prevalent in patients with schizophrenia and has a deleterious impact on the course of the illness. This review seeks to determine the interventions that were examined in the past decade to improve adherence rates. Method: The literature between 2000 and 2009 was searched for randomized controlled trials which compared a psychosocial intervention with another intervention or with treatment as usual in patients with schizophrenia. Results: Fifteen studies were identified, with a large heterogeneity in design, adherence measures and outcome variables. Interventions that offered more sessions during a longer period of time, and especially those with a continuous focus on adherence, seem most likely to be successful, as well as pragmatic interventions that focus on attention and memory problems. The positive effects of adapted forms of Motivational Interviewing found in earlier studies, such as compliance therapy, have not been confirmed. Conclusion: Nonadherence remains a challenging problem in schizophrenia. The heterogeneity of factors related to nonadherence calls for individually tailored approaches to promote adherence. More evidence is required to determine the effects of specific interventions. ß 2011 Elsevier Masson SAS. All rights reserved.

Keywords: Adherence Antipsychotics Intervention studies Review of the literature Schizophrenia

1. Introduction Antipsychotic medication is held to be the cornerstone in the treatment of patients with schizophrenia. Antipsychotics are effective in reducing psychotic symptoms, in preventing psychotic relapses in maintenance therapy and in improving psychosocial functioning [33]. Although some patients turn out to be treatmentresistant to all antipsychotic medication, an effective antipsychotic can be found among the available medications for the majority of patients [15]. The overall efficacy of antipsychotic medication in comparative trials seems evident. However, the grim reality we face is that the actual effectiveness of antipsychotics, for example when we look at relapse rates in naturalistic studies, is much lower than would be concluded from medication trials [62]. This efficacyeffectiveness gap may be largely due to adherence problems with antipsychotic treatment [22]. Nonadherence is highly prevalent in patients with schizophrenia. Reviews of the literature report very divergent rates of nonadherence, ranging from 20% up to 89% [113]. The overall rate of nonadherence to antipsychotics is estimated roughly at 50%

* Corresponding author. Tel.: +31 20 8913500; fax: +31 20 8913702. E-mail address: [email protected] (E. Barkhof). 0924-9338/$ – see front matter ß 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2011.02.005

[55]. The median rate of nonadherence during the first two years following a psychotic episode is 55% [30], and in first episode patients this leads to a five times higher chance of readmission within a year [86]. This rate may even be an underestimation, as it does not account for patients who refuse medication from the start or drop out of follow-up studies [115]. The consequences of nonadherence can be devastating, for patients and their families in terms of personal suffering, hospitalization, reduced quality of life as well as for society in general due to loss of income and direct costs of healthcare [109]. When looking at the problem of nonadherence, the divergent rates reported in studies may partly reflect methodological obstacles. One such obstacle concerns the difficulty to reliably measure whether a patient is taking medication or not. In many studies, self-report measures are used. In general, adherence self-reports have proved to be unreliable, as they are likely to be inaccurate and tend to overestimate actual levels of adherence [17,105]. Pill counts are considered more reliable indicators of adherence, but still offer no proof that the medication is actually taken. The measuring of serum levels is a more direct method, but this often forms an obstacle for patients who are reluctant to cooperate with blood samples. Moreover, nonadherence is not an ‘all or nothing’ phenomenon. Partial adherence or changing adherence over time

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frequently occurs. At first glance partial adherence seems to be a more limited problem compared to complete nonadherence. Research, however, shows that even partial nonadherence is associated with an increase in hospitalization rates and hence with poorer outcomes, proportional to increasing days of nonadherence [64,110]. This review aims at providing a comprehensive overview of the available data on interventions designed to improve adherence to medication in schizophrenia. Following an overview of the possible causes of nonadherence, we will first give a summary of the research findings published before 2000, based on two previous reviews [26,115]. Subsequently we will review the studies on interventions for improving adherence to antipsychotic medication in patients with schizophrenia published between 2000 and 2009. 2. Factors influencing (non-) adherence Why do patients stop taking their antipsychotic medication, when there is clear evidence that in all likelihood doing so will lead to an unfavorable outcome? On the other hand, one might ask why patients do take their medication, as it appears to be difficult for anyone (including health care professionals themselves) to adhere to a treatment, such as complying fully with the completion of an antibiotic therapy, once the acute symptoms of an infection have disappeared. The Health Belief model [5,78] proposes that a person is willing to comply with a treatment when one realizes that one’s health is at risk and one is ready to act on that threat, and when the perceived benefits of a proposed treatment outweigh the costs of that treatment. For patients with schizophrenia, there are several factors that may play an important part in this intriguing process. From a therapeutic perspective it is most interesting to focus on modifiable factors influencing adherence to antipsychotic medication. 2.1. Illness awareness, insight into illness and general beliefs Several studies and reviews report that patients with a low degree of illness awareness and insight into their illness are more likely to show poor adherence to treatment [1,30,55]. Also, general beliefs and attitudes towards health and taking medication, based on previous experiences, cultural factors and socioeconomic status, are associated with adherence [56]. These factors might contribute to the fact that the younger the age, the earlier the age of onset of schizophrenia and the shorter the duration of illness, the poorer the adherence rates are. 2.2. Psychopathology Psychotic symptoms, especially paranoid and grandiose delusions have been found to be negatively associated with adherence [30], although not all studies on this issue show consistent results [56]. Cognitive impairment as a cause for nonadherence yielded inconsistent results in earlier studies [30], whereas more recent research revealed that basic cognitive deficits like attention and memory deficits are related to a patient’s difficulty in managing medications [28,50]. Although negative symptoms intuitively interfere with adequate adherence and are mentioned in the literature in this respect [74], no data are as yet available to support this hypothesis. 2.3. Medication related aspects Efficacy of antipsychotic medication is intricately related to adherence. The antipsychotic effect reduces psychopathology,

thereby improving adequate logic reasoning, required for insight into illness. A good response to antipsychotic medication is positively related to adherence, which is clearly demonstrated in numerous studies. However, in the case of nonadherence, it seems hard to determine whether lack of efficacy of medication causes nonadherence, or that nonadherence itself leads to persistence of psychotic symptoms. In other words: is it the cause or the consequence? Another factor regarding medication and adherence are medication side effects. Clearly, side effects are strongly and negatively correlated to adherence. With the first generation antipsychotics especially extrapyramidal side effects are reported [87,108], but also neuroleptic dysphoria may play a role [23,102]. With the second-generation antipsychotics, sedation and weight gain are associated with nonadherence [76]. In studies comparing first and second-generation antipsychotics, the latter show small advantages in tolerability and relapse rates. However these advantages are not (directly) associated with differences in adherence rates [61]. Therefore it appears that in order to improve adherence, the choice of drug should be dependent on the patient’s individual attitude and response towards medication. A third factor concerns the route of administration and dosing strategies. On the one hand low dosing may result in fewer side effects; however, very low doses may lead to sub-optimal efficacy. Reducing the dosing frequency to once-daily regimens has been demonstrated to improve adherence rates [24,38]. The use of depot medication has shown to be effective in preventing nonadherence in studies with a follow-up of 1–7 years [85]. Also, the one-year relapse rate for patients using depot medication was significantly reduced, compared to the relapse rate of patients receiving oral medication [90]. Depot medication appears particularly suitable to prevent covert nonadherence, as nonadherence is directly noticeable by depot refusal and/or no-show on physician appointments, which enables the treating physician to act on this. Nevertheless, some studies show that even with depot medication, nonadherence rates remain relatively high [13,103]. Although randomized controlled data comparing adherence to depot and oral antipsychotics are scarce due to methodological problems, the available data have led to recommendations in several guidelines for the use of depot medication for patients with known recent medication nonadherence [60]. 2.4. Therapeutic alliance It has been demonstrated that a good therapeutic alliance is associated with better adherence rates [32]. Presumably related to this, better adherence rates are also predicted by adequate discharge planning and maintaining contact with outpatients [56,66]. 2.5. Environmental factors Social support and in particular the support of family or friends in assisting with medication taking, as well as stability of living conditions, show some positive association with adherence [30,56]. 2.6. Substance abuse Substance abuse is highly prevalent in patients with schizophrenia and is strongly associated with nonadherence, leading to a 13-fold increased risk of patients with schizophrenia and substance abuse to be non-adherent, in comparison with patients who do not use substances [51].

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3. Research in the period 1980–1999 Table 1 shows the 47 studies published between 1980 and 1999, examined in two previous reviews covering interventions to improve adherence to antipsychotic medication [26,115]. Though these two reviews are comparable in design and search strategy, Dolder et al. [26] incorporated 21 studies, whereas

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Zygmunt et al. [115] incorporated 40 studies, using somewhat broader criteria. General conclusions were that interventions, which applied only psychoeducational strategies without adjunctive components such as family involvement or behavioural management, were least successful in improving adherence to antipsychotic medication. Although psychoeducation did seem to enhance knowledge

Table 1 Studies 1980–1999. Target of intervention

Studies

Results

Individual interventions

Randomized trials Boczkowski et al. [8] MacPherson et al. [68] Streicker et al. [96] Frank and Gunderson [32] Hayward et al. [42] Kemp et al. [53,54]

Behavioural training > Psychoeducation > TAU 3 sessions psychoeducation (PE) = 1 session PE = TAU Psychoeducation = TAU Psychotherapy focussing on therapeutic alliance > TAU Medication self-management > TAU Compliance therapy > non-specific counselling

Group interventions

Family interventions

Randomized trials Malm et al. [69] Brown et al. [12] Eckman et al. [27] Atkinson et al. [2] Non-randomized trials Seltzer et al. [91] Battle et al. [4] Randomized trials Strang et al. [95]; Falloon et al. [29] Leff et al. [57] Leff et al. [58,59] Tarrier [97] Glick et al. [34] Xiang et al. [111] Xiong et al. [112] Zhang et al. [114] McFarlane et al. [67] Razali and Yahya [83] Telles et al. [98] Schooler et al. [89] Razali et al. [84]

Community interventions

Randomized trials Stein and Test [94] Bond et al. [9] Modrcin [73] Bush et al. [16] Ford et al. [31] Solomon and Drain [92] Non-Randomized trials Bond et al. [10] Bigelow et al. [7] Bond et al. [11] Sands and Cnaan [88] Dixon et al. [25]

Mixed-modality interventions

Randomized trials Hogarty et al. [44,45] Kelly and Scott [52] Guimon et al. [40] Herz [43] Linszen et al. [65] Hornung et al. [47,48]; Buchkremer et al. [14]

Hogarty et al. [46] Azrin and Teichner [3] Merinder et al. [71] Adapted from: Zygmunt et al. [115]; Dolder et al. [26].

Dynamic therapy = social skills training Psychoeducation = TAU Group behavioural intervention > TAU Psychoeducation = waiting list Psychoeducation > TAU Psychoeducation (PE) daily = PE weekly = TAU

Behavioural management > intensive case management Social interventions = TAU Psychoeducation (PE) + family therapy = PE + relatives group Behavioural enactive group = behavioural symbolic therapy = psychoeducation = TAU Family intervention = TAU Psychoeducation > TAU Psychoeducation + multiple family groups = TAU Psychoeducation + multiple family groups = TAU Multiple family psychoeducation (PE) = single family PE Behavioural family therapy > TAU Behavioural management = TAU Supportive treatment = family management/problem solving Behavioural intervention + medication > behavioural Intervention

Assertive community treatment > TAU Assertive community treatment = TAU Strengths case management = TAU Assertive community treatment > TAU Intensive case management > TAU Intensive consumer case management = intensive case management Assertive community treatment (ACT) + crisis house = ACT + purchased house Assertive community treatment = TAU Assertive community treatment = educational supportive reference groups = standard case management Assertive community treatment > Intensive case management Assertive community treatment > TAU

Family treatment + education = social skills training = family treatment + social skills traning > TAU In-home behavioural interventions = home and clinic intervention > clinic intervention only = TAU Patient + family group therapy > TAU Individual + multifamily groups > TAU Individual psychosocial + behavioural family intervention = individual psychosocial intervention Psychoeducation = psychoeducation + cognitive therapy = psychoeducation + relatives group = psychoeducation + cognitive therapy + relatives group = non-specific leisure-time group Personal therapy = family psychoeducation = personal therapy + family therapy = supportive therapy Patient + family behavioural intervention = patient behavioural intervention > psychoeducation Family + patient Psychoeducation = TAU

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about illness and medication and may be important, it is not sufficient to raise adherence rates. Interventions using cognitive techniques directed at attitudes towards medication showed favorable results, as well as behavioural interventions. Family therapy programs showed no considerable effect, unless they were accompanied by behavioural components. The lack of effectiveness of family programs may in part be accounted for by the fact that patients in family studies already tended to be more adherent at baseline, probably because of the family involvement, making it difficult to detect an increase in adherence. Interventions that were specifically designed to improve adherence were more successful than programs that intended to address a wider range of clinical problems, which suggests that a more intensive and focused approach is required to improve adherence rates. Here as well, a ceiling effect may play a role, as most of the studies using specific interventions included more non-adherent patients, allowing for a possibly greater improvement. The majority of studies that used an integrated approach, combining several interventions to improve adherence, such as cognitive behavioural techniques, family interventions and community based interventions, showed positive results. Of the less specific intervention programs, which were not exclusively designed to target adherence, assertive community treatment and intensive case management seemed to be positive exceptions, showing promising results in promoting adherence. Interventions with a greater number of therapeutic sessions and a longer duration tended to produce greater improvement in adherence to antipsychotic medication. Several studies with negative results were relatively short in duration, which pleads for more prolonged interventions or the use of booster sessions to reinforce and consolidate gains made during short-term, more intense interventions. Several studies included only a limited number of participants. Studies including more participants had a higher chance of showing improvement in adherence rates, which suggests that adequate sample sizes and thus sufficient power are obviously essential to determine the value of an intervention for improving adherence. 4. Method The review focuses on studies examining interventions to improve adherence to antipsychotic medication in patients with schizophrenia, published in English between 2000 and 2009. An electronic search was conducted using Medline, PsychLIT, EMBASE and CINAHL, with combinations of the keywords schizophrenia; psychosis; adherence; compliance; intervention; therapy; program; randomized; controlled; trial. The selection criteria were as follows: (1) a randomized controlled design, comparing a psychosocial intervention, at least partially aimed at improving adherence with another intervention or a control condition. A psychosocial intervention is regarded a therapeutic intervention which is non-pharmacological in nature; (2) a sample of patients who were diagnosed with a schizophrenia spectrum disorder; (3) a measure of adherence to antipsychotic medication as a primary or secondary outcome. The search was supplemented by crosschecking the references of the articles found in the electronic search. 5. Results Fifteen randomized controlled studies published between 2000 and 2009 met the inclusion criteria, as shown in Table 2.

5.1. Individual interventions In the last decade, seven adherence intervention studies directed at the individual patient were performed, of which three showed positive results. The purpose of four studies of these studies was to investigate the effects of compliance therapy, while trying to replicate earlier positive results by Kemp et al. [53,54]. Compliance therapy builds on cognitive behavioural therapy combined with motivational interviewing [72]. A study by O’Donnel et al. [77] failed to replicate the positive effect of compliance therapy in a study with a similar design as the original study by Kemp et al. [53,54]. Compliance therapy was slightly modified into adherence therapy in one study [37], with a small increase in the number of sessions (two extra sessions) and a more individually tailored structure. This large European trial [37], including 409 patients in four countries, did not find any differences between adherence therapy and a control group receiving an individual intervention of health education, neither where the primary outcome quality of life, nor where rates of patient-reported medication adherence were concerned. Another adaptation of compliance therapy is called adherencecoping-education (ACE), which aims at enhancing insight and at promoting treatment adherence in early psychosis patients. In a pilot study [100] this intervention, consisting of 14 individual sessions, was tested against supportive therapy. In a sample of 19 participants, perceived need for treatment and benefits of medication appeared to be better in patients with ACE shortly after intervention, compared to controls. No direct adherence rates were available and follow-up results are awaited. Four studies focused on specific support for cognitive impairments, based on the assumption that nonadherence in patients with schizophrenia may be partly due to difficulties in e.g. attention and memory. Reminders with SMS text messages in one study [80] did not lead to better adherence, but a specific cognitive adaptation training (CAT) did show positive results [106]. CAT uses environmental supports such as signs, checklists, alarms and the organizing of a patient’s belongings in order to cue and sequence adaptive behavior. An extensive intervention (full-CAT) tackling several aspects of functioning was compared with cognitive adaptation focusing on medication only (Pharm-CAT) and with a control group receiving treatment as usual, in a randomized trial with 105 participants. The intervention was carried out for a period of 9 months with a follow-up period of 6 months. It resulted in a significantly better adherence to medication for both intervention groups, as measured by unannounced pill counts. Average adherence rates were roughly 80% in the intervention groups during the 15 months of the intervention and follow-up, compared to 60% in the treatment as usual. The percentage of relapse for both intervention groups was 35% against 81% for the control group. This effect was maintained for 6 months after the intervention was completed. Outcomes of social and occupational functioning improved only with full-CAT, with a deterioration after the intervention stopped, suggesting that these aspects probably ask for continued intervention. A relatively small study [6] reports a positive effect of a telephone-nursing intervention (TIPS). This intervention comprises weekly calls by psychiatric nurses, trained to help patients with problem solving, offering reminders and coping alternatives with regard to common medication adherence barriers. Overall adherence rates during the 3 months of the study were 80% in the intervention group, versus 60,1% in the control group, as measured in 3-monthly pill counts in an outpatient sample of 29 participants. The fourth study to compensate for attention and memory problems used a pharmacy-based intervention, called Meds-Help intervention [101]. In a randomized controlled trial with 118 participants of which 67% had a schizophrenia spectrum disorder,

Table 2 Studies 2000–2009. Study

Design

Adherence measure

Duration of intervention

Follow-up time

Adherence outcome

Individual interventions

Gray [35]

n = 44. Intervention group: psychoeducation. Control group: TAU n = 56. Intervention group: compliance therapy. Control group: non-specific therapy n = 409. Intervention group: adherence therapy. Control group: health education n = 95. Intervention group 1: full cognitive adaptation training. Group 2: partial cognitive adaptation training (directed only at medication). Control group: TAU n = 24. Intervention group: adherencecoping-education (ACE). Control group: TAU n = 62. Intervention group: SMS text messages, with individualised prompts. Control group: waiting list n = 118. Intervention group: pharmacybased intervention. Control group: TAU n = 29. Intervention group: telephone intervention by nurses (TIPS) directed at problem solving

Self-report

3 weekly sessions

2 months

Psychoeducation = TAU

Self-, clinician- & carer-report

5 weekly sessions

12 months

Compliance therapy = control

Self-report

8 weekly sessions

12 months

Adherence therapy = control

Unannounced pill counts and pharmacy records

39 weekly sessions

9 + 6 months

Full-CAT and Pharm-CAT > TAU

Self-report

6 weekly + 8 biweekly sessions

6 months

ACE > TAU on perceived need for and benefit of treatment

Self-report

Prompts during 7 weeks

21 weeks

SMS group = waiting list on adherence rates

Pharmacy records, self-report and blood test Pill counts

12 months

12 months

Pharmacy-based intervention > TAU

3 months

3 months

TIPS > TAU

n = 72. Training of 52 nurses. Intervention group: medication management training. Control group: TAU n = 349. Training of nurses of 3 out of 6 VA networks. Intervention group: guideline implementation and patient-tailoring strategies. Control group: TAU

Self-report

Unknown

6 months

Medication management > TAU

Self-report and medical record

> 4 sessions in 6 months

6 months

Enhanced strategy > TAU

n = 326. Intervention group 1: family psychoeducation + depot medication. Intervention group 2: depot medication. Control group: TAU n = 101. Intervention group: family education. Control group: TAU

Clinician-report

9 monthly sessions + 3 multiple family workshops

9 months

Family psychoeducation + depot > depot-only > TAU

Self-report

9 months

Family education = TAU on adherence rates

Chan et al. [18]

N = 73. Intervention group: family psychoeducation

Self-report

36 hours during admission + 3 monthly sessions after discharge 10 weekly sessions

12 months

Family psychoeducation > TAU

Petersen et al. [79]

n = 547. (OPUS trial) Intervention group: integrated treatment (ACT + family involvement + social skills training. Control group: TAU n = 50. Intervention group: integrated treatment (intensive case management + family psychoeducation + social skills training + individual cognitive behavioural therapy

Clinician-report

24 months

Integrated treatment > TAU

24 months

Integrated treatment = TAU

O’Donnel et al. [77]

Gray et al. [37]

Velligan et al. [106]

Uzenoff et al. [100]

Peijnenborg et al. [80]

Valenstein et al. [101]

Beebe et al. [6]

Community interventions

Gray et al. [36]

Hudson et al. [49]

Family interventions

Ran et al. [82]

Li & Arthur [63]

Mixed-modality interventions

Morken et al. [75]

Self-report, controlled by (not routinely) clinician-report and plasma levels

2-weekly multiple family sessions for 18 months + social skills training in groups; unknown frequency 8 weekly family sessions + 22 monthly sessions + frequent individual sessions, on PRN-basis

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Intervention type

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the intervention group received unit-of-dose packaging for all the medication they were taking and a packaging education session; refill reminders were mailed 2 weeks before the scheduled refill dates. Also, clinicians received notification when a patient failed to collect his antipsychotic prescriptions. Statistically significant improvements in medication possession rates (MPR) were observed in the intervention group after 6 and 12 months, compared with a control group that received care as usual. When a more stringent measure of adherence was used, by combination of a MPR of greater than 80% with a positive subjective assessment of adherence and a blood test indicating the presence of some antipsychotics, 50% of the intervention group fulfilled the criteria of adherence after 6 months versus 17% in the control group. 5.2. Family interventions After 2000, four studies were carried out using family interventions, all conducted in China. One study [19] provides no data on actual adherence rates. Of the three remaining studies, two showed positive results on adherence to medication. In a rural area in China, Ran et al. [82] carried out a cluster randomized trial with 357 participants, in which three groups were compared. Both intervention groups received depot medication. One intervention group received in addition a monthly psychoeducational family intervention, in which patients were encouraged to participate, 3monthly multiple family sessions and crisis family interventions when necessary. After 9 months, 35% of patients in the combined treatment group maintained regular treatment, in comparison with 32% in the depot-only group and 5% in the control group. The numbers of patients who did not comply with treatment at all were 2% in the combined group, 27% in the depot group and 50% in the control group, with accordingly increasing rates of relapse. Chan et al. [18] investigated a psychoeducational program for patients and their family caregivers in the urban area of Hong Kong. Seventy-three patients were included and the intervention consisted of 10 family sessions of psychoeducation within a period of 3 months, which was compared with routine care. One month after completion of the interventions, and again 6 months later, significant differences in favor of the intervention group were reported on adherence to medication, as measured by the Rating Of Medication Influences scale (ROMI), yet these were not sustained after 12 months of follow-up. The same effect was found for illness insight. Also, family burden and self-efficacy on the part of the family initially ameliorated, but this effect was not sustained after 12$months either. 5.3. Community interventions Two studies in the last decade focused specifically on training of psychiatric nurses. Gray et al. [36] examined in a randomized controlled cluster trial a medication management training package for Community Mental Health Nurses. Half of the 52 participating nurses received the training package, consisting of side effects management as well as training in effective treatment strategies for schizophrenia. The other half of the group of nurses received no training and delivered treatment as usual. At the follow-up after 12 months, 29 patients treated by the trained nurses improved significantly in adherence rates, on a clinician rating scale as used in the study by Kemp et al. [53] and on patient attitudes towards medication, as well as on symptomatology, compared with a group of 24 patients receiving care from the non-trained nurses. In a comparable study [49] six US Department of Veteran Affairs medical centers received basic guideline implementation strategies for the treatment of schizophrenia. Three of the six medical centers received an enhanced implementation strategy, in which physicians were trained to prescribe guideline-concordant. In

addition, a research nurse identified barriers of adherence in patients. The nurses were trained in a protocol designed to assess medication adherence, strategies to maintain contact with the patients and provide feedback to the physician about adherence (barriers) and treatment preferences. Patients enrolled at the sites receiving the enhanced intervention, appeared almost twice as likely to be adherent at the follow-up after 6 months, as measured by patient report and chart reviews. 5.4. Mixed-modality interventions Two studies examined integrated treatments, one of which showed a positive result. This regards the Danish OPUS trial [79], a large randomized clinical trial for first episode psychosis patients. The study investigated an integrated treatment, encompassing assertive community treatment, family involvement and social skills training and compared it to treatment as usual. Adherence was only indirectly measured by participation in the treatment program, which showed significant differences after a follow-up of one year. Discontinuation of treatment for more than a month occurred in 8% of patients in the intervention group, against 22% in the control group. The percentage of patients stopping treatment in spite of necessity was 3% versus 15% in the control group, and the number of patients not making any outpatient visits 4% versus 15%. At a two-year follow-up, these differences were smaller and no longer significant for the groups stopping treatment or those discontinuing treatment for more than a month. In the intervention group also positive and negative symptomatology as well as substance abuse outcomes were significantly more favorable compared to treatment as usual; these results were maintained at two years follow-up. 6. Discussion From the studies between 1980 and 1999 can be concluded that psychoeducational interventions show little effect on adherence, unless they are accompanied by behavioural and cognitive interventions that aim directly at medication attitudes and adherence behaviour. In general, combined interventions and a longer duration of interventions were associated with favorable outcomes. Compliance therapy, consisting of a combination of motivational interviewing and cognitive behavioural therapy, raised high expectations, as it appeared an effective strategy in a clinical population and maintained a superior effect over supportive therapy after 18 months [53,54]. In the period after 2000, 16 studies were published that met the inclusion criteria of this review. Three studies [37,70,77] elaborated on the apparent success of compliance therapy, but the expectations have not yet been fulfilled. A direct replication of the study by Kemp et al. [53,54], using the same intervention and a similar study population, was undertaken by O’Donnell et al. [77], yielding no difference in adherence rates between four to six sessions of compliance therapy and a control condition. Practically the same intervention, with an extended duration of six to eight sessions, renamed adherence therapy because of the negative connotation of the word compliance, was tested in a large European multicenter study [37], but yielded no differences either on adherence rates after one year. Only a small study in Thailand [70] found a modest effect of Adherence Therapy, but was not included in this review, as no direct adherence measures were applied. A possible explanation for these overall negative findings might be that the initial adherence rates of participants in these studies were moderate, leaving less room for amelioration, although even a subgroup with low adherence rates at baseline in the study by Gray et al. [37] did not seem to benefit from the

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intervention. Another factor that might have had a negative influence was the fact that the intervention was given during a relative short period by a therapist who was not a member of the treating staff, which might have diluted the actual effect. Supporting this assumption, the two studies focusing on training case-managers (nurses) in medication management [36] and patient-tailoring strategies and guideline implementation [49], did show positive results on medication adherence in the patients they treated. An evaluation of a medication management training program for community mental health professionals [41], not included in this review as it used no direct measure of adherence, found a positive effect on service user involvement in treatment. These findings might indicate how important the continuation of managing of adherence issues is, or how important it is that interventions aimed at promoting adherence are undertaken by the actual treating caregiver, though it is likely that a combination of these is essential. With regard to the duration of the intervention, Uzenoff et al. [100] showed in a preliminary trial that expanding the number of interventions of adherence therapy over a longer period of time, combined with a focus on coping strategies called adherencecoping-education therapy, leads to favorable outcomes in patients following a first psychotic episode. The timing of the intervention may also play an important role and might therefore account for certain differences in effect of the interventions. However, timing of the intervention could not be identified as a predictor for success from our review. Some studies [49,79] only offered the intervention early on in the treatment after a relapse, thus with subjects in an instable phase of their disorder, whereas other studies also included more stabilized patients [18,37,100]. This may, however, turn both ways; relatively stable patients will be more capable to benefit of certain psychosocial interventions, while on the other hand the baseline adherence levels in such a group are generally higher, with less opportunity for improvement of adherence levels. Also, in the past decade attention was given to compensation for cognitive deficits in patients with schizophrenia, using environmental supports such as checklists, signs and electronic cuing devices. From the four studies included in this review, reminders with SMS text messaging to support medication taking [80] did not lead to better adherence, but a telephone intervention by nurses [6] and especially Cognitive Adaptation Training [106] did show promising results, as well as a pharmacy-based intervention [101]. Supporting patients in collecting their antipsychotic prescriptions and behavioural techniques to facilitate taking medication clearly have a positive influence on adherence behavior. This is in agreement with findings in studies regarding patients suffering from other chronic medical disorders [21], who have comparable nonadherence rates. This suggests that all patients with chronic conditions and poor adherence could benefit from reducing access barriers by the use of pharmacy-based interventions and concrete problem-solving interventions accompanied by technical aids. Whether this effect is irrespective of the underlying nature of the disease remains an open question, but it sheds an interesting light on the causes of nonadherence in schizophrenia spectrum disorders. It could be hypothesized that if patients with other chronic conditions benefit from these supportive measures, patients with schizophrenia in particular are in need of these measures, as cognitive problems are highly prevalent in schizophrenia. Another initiative involving communication technology, not included in this review, aims at detecting prodromal symptoms of relapse; it uses a short questionnaire for patients and caregivers by a weekly SMS text message to make an early intervention possible. It shows promising results in an open study [93], but needs to be tested in a randomized controlled trial.

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In line with the findings in the studies before 2000, studies in the past decade that offered more sessions during a longer period of time were more likely to be successful. Possibly due to the prolonged duration of interventions, in the past decade family interventions showed positive results, unlike the studies before 2000. Of the interventions whose purpose it was not only to raise adherence in the individual patient, but encompassed other treatment targets as well, both the two community interventions, two out of three family interventions and one of the two mixedmodality interventions showed positive results, which suggests that a wider range of targets may be needed to promote adherence to medication, such as resuming rewarding life roles and regaining functional capacities. Given the fact that impaired illness insight is an important contributing factor to nonadherence, the wider range of targets possibly explains why, even when insight is not ameliorated, these comprehensive interventions may be of benefit, as they link medication adherence to the achievement of functional goals. However, the variety in targets and outcome variables in these studies, make it difficult to define what components are specifically relevant to raise adherence rates for patients with schizophrenia, and whether there are subgroups of patients who need different approaches in dealing with adherence problems. Further elaborating on this, a recent expert consensus guideline [107] proposes the use of strategies targeted at specific types of adherence problems, thereby developing an individually tailored approach to promote adherence. This appears to be a promising direction, which will require regular updates and input of ongoing initiatives to more elaborately specify the relevance of specific interventions for specific problems and for certain subgroups of patients. It means that there is a great demand for more studies on this multifaceted problem, especially considering the methodological problems researchers face when measuring the effectiveness of adherence interventions, given the heterogeneity of the population and the large number of possible influencing factors. This calls for large well-powered studies targeting specific interventions. Yet another interesting approach is offered in an outline by Priebe et al. [81], who are currently undertaking a study to investigate the effect of a financial incentive to raise adherence rates. Inspired by the positive effect of financial incentives in patients with substance abuse, an earlier small open label study in the UK [20] in assertive outreach teams showed an amelioration of medication adherence in four out of five patients, in a mixed population with mental health problems and substance abuse. The use of financial incentives raises some ethical considerations because of the risk of financial dependency, increasing financial demands and/or extortion [81]. However, financial incentives have proven earlier to be successful in other medical areas, such as enhancing adherence to medication for tuberculosis and hypertension, as well as adherence to dental care or a weight management program [39]. There are some limitations to interpretation of the studies included in this review. As mentioned earlier, a number of the interventions were not specifically designed to improve only adherence, but also to address a wider range of targets and subsequent outcome variables. This makes it difficult to determine which components are essential to improve adherence rates in these studies. Furthermore, the included studies are heterogeneous in design and in the adherence measures that were used, which makes it difficult to compare the outcomes and draw general conclusions. Another limitation is the publication bias. In pharmacological studies [99], negative results are less likely to be published than positive results. This may also be the case here and may lead to overestimation of certain effects. Finally, measuring adherence, in particular in patients with schizophrenia, remains

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very challenging. It is clear that indirect or subjective measures of adherence (self-report, clinician-report, caregiver-report) are less reliable than direct or objective measures (such as pill counts, electronic devices (MEMS), electronic refill records, assays of medication levels in blood or urine samples). Subjective reports systematically tend to overestimate adherence [104]. In order to include a representative patient population, the wish for accuracy on this matter, for research purposes, must be outweighed against the apparent reluctance to cooperate with more ‘invasive’ research measures (such as blood samples) in patients with schizophrenia and adherence problems. All the same, some conclusions can be drawn from this review. Firstly, interventions that are longer in duration and offer more sessions, and especially interventions that provide continuous focus on adherence, tend to be more successful at improving adherence than interventions of short duration. Secondly, the use of problem-solving interventions accompanied by technical aids, including pharmacy-based interventions, is clearly promising; they appear to ameliorate adherence in all chronic conditions, including schizophrenia. Thirdly, the positive effects of adapted forms of motivational interviewing found in earlier studies, such as compliance therapy, have not yet been confirmed. Finally, it appears that the heterogeneity of factors related to nonadherence calls for individually tailored approaches to promote adherence. As it is recognized that nonadherence contributes enormously to poor outcome, substantial work needs still to be done. Acknowledging that the problem has to be dealt with on a structural and consistent basis is the first step. More evidence and exploration of the validity and effectiveness of specific interventions aimed at improving adherence is required to raise the standard of care and clinical outcome for patients with schizophrenia. Conflict of interest statement The authors declare that they have no conflicts of interest concerning this article. References [1] Agarwal MR, Sharma VK, Kishore Kumar KV, Lowe D. Non-compliance with treatment in patients suffering from schizophrenia: a study to evaluate possible contributing factors. Int J Soc Psychiatry 1998;44(2):92–106. [2] Atkinson JM, Coia DA, Gilmour WH, et al. The impact of education groups for people with schizophrenia on social functioning and quality of life. Br J Psychiatry 1996;168:199–204. [3] Azrin NH, Teichner G. Evaluation of an instructional program for improving medication compliance for chronically mentally ill outpatients. Behav Res Ther 1998;36:849–61. [4] Battle EH, Halliburton A, Wallston KA. Self-medication among psychiatric patients and adherence after discharge. J Psychosoc Nurs Ment Health Serv 1982;20:21–8. [5] Becker MH, Maimon LA. Sociobehavioural determinants of compliance with health and medical care recommendations. Med Care 1975;13:10–24. [6] Beebe LH, Smith K, Crye C, et al. Telenursing intervention increases psychiatric medication adherence in schizophrenia outpatients. J Am Psychiatr Nurses Assoc 2008;14(3):217–24. [7] Bigelow DA, McFarland BH, Gareau MJ, Young DJ. Implementation and effectiveness of a bed reduction project. Community Ment Health J 1991;27:125–33. [8] Boczkowski JA, Zeichner A, DeSanto N. Neuroleptic compliance among chronic schizophrenic outpatients: an intervention outcome report. J Consult Clin Psychiatry 1985;53:666–71. [9] Bond GR, Miller LD, Krumwied RD, Ward RS. Assertive case management in three CMHCs: a controlled study. Hosp Community Psychiatry 1988;39: 411–8. [10] Bond GR, Witheridge TF, Wasmer D, et al. A comparison of two crisis housing alternatives to psychiatric hospitalization. Hosp Community Psychiatry 1989;40:177–83. [11] Bond GR, McDonel EC, Miller LD, Pensec M. Assertive community treatment and reference groups: an evaluation of their effectiveness for young adults with serious mental illness and substance abuse problems. Psychosoc Rehabil J 1991;15:30–43.

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