Effectiveness of adherence therapy to improve medication adherence for patients diagnosed with schizophrenia within the context of community-based mental health care: A systematic review

Aim

The purpose of this systematic research was to assess effective adherence therapy in improving medication adherence among patients diagnosed with schizophrenia in both inpatient and community settings.

Search strategy

This systematic review followed the guidelines established by PRISMA (Page et al., 2021) and was registered in the PROSPERO database (ID: CRD420261416466). Using the PICOS framework (P-population, I-intervention, C-comparison, O-outcomes, S-study design), research questions and eligibility criteria for inclusion were defined. A three-step search strategy was employed to identify published and unpublished studies published in English from 2010 to 2023:

Inclusion criteria

Studies were included in this review if they met the following criteria: (i) participants were adults aged 18 years and older diagnosed with schizophrenia spectrum disorders; (ii) the primary objective of the study was to investigate the effectiveness of adherence therapy (AT) in improving medication adherence; (iii) participants were either hospitalized (inpatients) or living in the community (outpatients) ; (iv) the study design was a randomized controlled trial (RCT) examining medication adherence among patients with schizophrenia; (v) the intervention specifically involved any modality of adherence therapy aimed at enhancing medication adherence; and (vi) The study was published in English between 2010 and 2023. Opinion pieces, literature reviews, and editorials were excluded from this review.

Screening and selection of included studies

The screening procedures involved two authors who independently evaluated all relevant search results based on titles and abstracts. Articles meeting the predetermined inclusion criteria proceeded to full-text review, during which the same authors independently assessed complete publications using a standardized template adapted from the Cochrane Review data collection form. Any disagreements between the two authors were first addressed through careful discussion and consideration. If consensus could not be reached, a third author was consulted to resolve the differences. Duplicate articles and studies not meeting the inclusion criteria were excluded from the analysis.

Quality assessment of included studies

Two reviewers independently assessed the quality of the included randomized controlled trials (RCTs). The reporting quality of the RCTs was evaluated using the Consolidated Standards of Reporting Trials (CONSORT) checklist to ensure transparency and completeness in reporting key trial elements. To assess the risk of bias in the RCTs, the Cochrane RoB 2 tool was applied, as recommended by the Cochrane Handbook (Sterne et al., 2019). This tool evaluates potential sources of bias across five domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. Each study was assigned an overall risk of bias judgment based on these assessments. Disagreements between reviewers were resolved through discussion or consultation with a third reviewer.

Data extraction

Studies that had previously been identified for this review were used to extract data, which was done using a specifically designed electronic data extraction sheet. Included in the extracted data were identifying information on the study (title, year published), where the study was performed (country), what primary and secondary outcomes were measured, what instruments were used to collect data, what study design was employed, what intervention(s) were delivered and for how long, the size of the population/sample in the study, limitations identified in the study, and the study findings related to the review questions and specific objectives. The authors of the primary literature were contacted to help us find out whether they could provide additional information or clarify any unclear information. We selected a total of ten RCTs that met our pre-established criteria. A systematic research methodology has been employed to collect articles for the present study. This methodology can be found in Figure 1 (the PRISMA Flow Diagram), which illustrates the process of identifying and selecting research. Each of the selected studies was evaluated against specific, predetermined inclusion criteria (i.e. relevance) before it was included in the subsequent analysis. Therefore, it is necessary to evaluate your own research against these criteria when developing your analysis. Researcher 1 was assigned the task of performing the first assessment of each of the studies identified as potentially relevant to the present study. A total of 480 studies were identified as possibly relevant to the present study by this process. Of these, ten studies were ultimately selected for inclusion in the final review of the current research due to their appropriateness. A summary of the included studies is presented in Table 1.

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Figure 1.

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources.

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Table 1.

Summary of RCT studies.

Author & country	Outcome measures	Data collection instrument	Intervention/duration	Population, sample size, and settings	Limitations	Study findings
Staring et al. (2010) Netherlands	Service engagement and medication adherence	The SES Subscale Medication Compliance	The study compared the outcomes of two treatment conditions – treatment adherence therapy (TAT) vs. treatment as usual (TAU). At baseline (T0), at the end of the 6-month treatment (T1), and at 6-month follow-up (T2).	109 outpatients	The small sample size limited the power to detect treatment effects on secondary outcomes and mediators. The people who refused to participate in the study were engaging less with services than those included.	Treatment adherence therapy v. TAU significantly benefited service engagement (Cohen’s d = 0.48) and medication adherence (Cohen’s d = 0.43). Results remained significant at 6-month follow-up for medication adherence.
Anderson et al. (2010) The United States	Medication adherence	The Personal Evaluation of Transitions in Treatment.	Participants were randomly allocated to receive eight weekly sessions of adherence therapy or continue with their treatment as usual (TAU). Patients were assessed at baseline and follow-up (after therapy completion).	Twenty-six patients (12 experimental and 14 controls)	The small sample size made the study underpowered and increased the risk of type II errors; The possibility of outliers in a sample, this size skewed the data. Selection bias, considering the high rate of refusal to participate and the possibility of those who agreed already were more medication adherent.	Patients receiving adherence therapy did not significantly improve in overall psychiatric symptomatology (change in PANSS total scores: AT: −10.2, TAU: −8.6; mean difference, −1.6; P = ns) or with medication adherence (AT: −2.8, TAU 1.5; P = ns) compared with the TAU group at follow up.
Barkhof et al. (2013) Netherlands	Medication adherence and hospitalization rate	The Medication Adherence Questionnaire (MAQ)	Participants received an adapted form of motivational interview (MI) or an active control intervention, health education (HE). Both interventions consisted of 5–8 sessions, which patients received in adjunction to the care as usual. Patients were assessed at baseline and six and 12-month follow-up.	The study included 114 patients who experienced a psychotic relapse due to medication nonadherence in the past year	The small sample size limited the study’s generalization. Therapists performed both motivation interviews and health education who were not otherwise involved in the treatment of patients to ensure treatment integrity of the interventions.	The results showed that motivational interview did not improve medication adherence in previously nonadherent patients who experienced a psychotic relapse.
Chien et al. (2015) China	Medication adherence, symptom severity, insight into treatment	Adherence Rating Scale (ARS)	The intervention was in one community psychiatric nursing service. After the pre-test, the participants were randomly assigned to either an eight-session course of adherence therapy plus usual care or usual psychiatric care.	The study was conducted in a random sample of 114 participants with schizophrenia spectrum disorders	While the refusal rate in this study was very low (7%), over 50% of the patients in the outpatient clinic were found not to be eligible to participate in this study. All of the outcome measures were reported by the participants, except the level of adherence rated by the RA and community psychiatric nurses.	Adherence therapy seemed to be effective in improving medication adherence.
, Hasan et al. (2015) Jordan	Change in knowledge of schizophrenia and medication adherence	The S-CQoL	Participants aged 18 years or older with DSM-IV schizophrenia or schizoaffective disorder, and their primary caregivers, from four outpatient mental health clinics in Jordan, were randomly assigned to receive 12 weeks of a booklet form of psychoeducation, with follow-up phone calls and treatment as usual [TAU] (intervention, n = 58), or TAU (control, n = 63). Participants were assessed at baseline, immediately post-intervention (post-treatment1) and at 3 months follow-up.	121 patients with schizophrenia	Most of the outcome measures were self-reported, and this caused response bias. The small sample size. There was no blinding.	Psycho-education and TAU were more effective than TAU alone at improving participants’ knowledge, medication adherence and psychological outcomes.
Bäuml et al. (2016) Germany	Compliance ratings to bifocal psychoeducation to standard treatment	Clinical rating scales	The patients were randomized at study entry, either to bifocal psychoeducation (21), or to standard treatment (20). They were compared concerning compliance, type of medication, dosage (CPZ equivalents), motor side effects, and number of days in hospital. The average daily antipsychotic medication 2 and 7 years after index discharge was 365 and 354 CPZ units, respectively, in the intervention group (IG), but 247 and 279, respectively, in the control group (CG).	41 patients with a diagnosis of schizophrenic or schizoaffective disorder	The small sample size and the dropout rate due to refusal to continue participating in the program were high.	There was a significant reduction in medication adherence.
Chien et al. (2016) China	Medication adherence	Adherence Rating Scale (ARS)	This randomized controlled trial was conducted with 134 outpatients with schizophrenia spectrum disorders; 67 of them received a six-session adherence therapy (in addition to usual care), and 67 received usual psychiatric care alone.	134 outpatients with schizophrenia	The small sample size. All of the outcome measures were reported by the participants, except the level of adherence rated by the research assistant and community psychiatric nurse.	The adherence therapy group reported significantly greater improvements in symptom severity (p < 0.003), insight into illness/treatment (p < 0.001), functioning (p < 0.005), duration of re-hospitalizations (p < 0.005), and  medication adherence (p < 0.005) over 18 months follow-up, when compared with usual care alone.
Khalil et al. (2019) Egypt	Medication adherence, attitudes, and knowledge	Drug Attitude Inventory 10-item scale (DAI-10),	Thirty subjects with schizophrenia were selected to receive 14 sessions of a culturally adapted behavioral family psychoeducational program (BFPEP). Another 30 subjects received standard treatment as usual (STU) for 6 months.	30 subjects with schizophrenia	The small sample size. There was a large dropout of initial participants.	A psychoeducational program (BFPEP) significantly improved medication adherence.
Uslu and Buldukoglu (2020) Turkey	Medication adherence	Medication Adherence Rating Scale	Telephone Intervention Problem Solving (TIPS) was applied to the intervention group for 2 months, whereas the control group received routine care.	45 patients	There was no blinding performed when the participants were assigned to groups. The study had a pretest-posttest design and only a 2-month follow-up.	Medication adherence scores were higher in the intervention group than in the control group.
Alizioti and Lyrakos (2021) The United Kingdom	Medication adherence, stress, and anxiety	The Drug Attitudes Inventory (DAI)	The participants in the study (n = 29) were randomly allocated to either the psychoeducation group or the control group.	29 patients with schizophrenia	The small sample size. Possible bias: the two study groups were found similar at baseline in regard to clinical and demographic characteristics, as well as all other measured variables, with no needed correction	This study proposed that psychoeducation is an appropriate intervention to address a wide range of factors that compound adherence to medication and patients’ symptoms

Outcome measures

Medication adherence was measured using a variety of instruments across the included studies, including self-reported scales, clinician assessments, and objective indicators. No restrictions were placed on the method of adherence measurement to allow for a broader inclusion of studies and to reflect variability in clinical practice. Due to this heterogeneity in outcome measures, a qualitative systematic review approach was adopted.

Study selection

The research methodology of this study included a systematic strategy to extract articles. The process of locating and selecting research is depicted in Figure 1, which showcases the PRISMA flow chart. The collected studies were assessed for their relevance using predetermined inclusion criteria. The researchers conducted an initial assessment separately to determine if they met the criteria for inclusion or exclusion. A total of 480 research publications were identified as potentially relevant to the current topic. Ten papers were chosen for inclusion in the comprehensive review based on their appropriateness. The inquiry was conducted by considering three stages of data evaluation. In phase I, databases were queried to identify studies that met the predetermined criteria. The investigation focused on scientific research articles published from 2010 to 2023. A grand number of 480 papers were obtained throughout the initial phase of the project. In the second part of the investigation, the initial selection of publications was conducted by removing duplicate articles (n = 105), deleting review articles (n = 168), and excluding research articles published in languages other than English (n = 103). During Phase III, the manuscript underwent scrutiny in 94 research journals. A total of 46 studies were excluded from the analysis due to their primary focus on populations that differed from patients diagnosed with schizophrenia. Additionally, 37 articles that did not employ RCTs were excluded from the study. Furthermore, the current study used a stringent selection criterion by removing research that did not solely examine AT. As a result, ten RCTs met the established criteria for eligibility. The study selection process is presented in Figure 1.

Study characteristics

This systematic review included a total of ten randomized controlled trials (RCTs) published between 2010 and 2023 (Alizioti and Lyrakos, 2021; Anderson et al., 2010; Barkhof et al., 2013; Bäuml et al., 2016; Chien et al., 2015, 2016; Hasan et al., 2015; Khalil et al., 2019; Staring et al., 2010; Uslu and Buldukoglu, 2020). The majority of included studies (n = 9) utilized a control group receiving standard psychiatric care without additional intervention, thereby allowing for direct comparison with adherence therapy interventions. In contrast, one study employed a health education intervention as an active control condition (Barkhof et al., 2013).

Medication adherence was the primary outcome in most of the included trials, although it was assessed as a secondary outcome in a minority of studies. Notably, considerable heterogeneity was observed across studies in terms of outcome measurement tools, with no single standardized instrument consistently applied across all trials. This variability limits the direct comparability of findings and represents a key source of methodological heterogeneity within the review (Alizioti and Lyrakos, 2021; Barkhof et al., 2013; Bäuml et al., 2016; Chien et al., 2015; Khalil et al., 2019; Staring et al., 2010; Uslu and Buldukoglu, 2020).

There are multiple validated tools to assess adherence to medications prescribed. The three studies utilized the Adherence Rating Scale (ARS; Chien et al., 2015, 2016; Uslu and Buldukoglu, 2020). Additional studies utilized various self-reporting and clinician-reported tools, such as the Drug Attitudes Inventory (DAI; Alizioti and Lyrakos, 2021; Khalil et al., 2019), the compliance rating scale developed by Bäuml et al. (2016), the Medication Adherence Questionnaire (MAQ; Barkhof et al., 2013), and the Personal Evaluation of Transitions in Treatment scale (Anderson et al., 2010). Also, the study by Hasan et al. (2015) used the Schizophrenia Quality of Life Scale (S-CQoL) to assess the impact of adherence on quality of life. Additionally, the SES subscale from the Staring et al. (2010) study was also utilized to assess adherence in this trial. Overall, the diversity of outcome measures and assessment tools underscores the lack of standardization in evaluating medication adherence in schizophrenia research, which may contribute to variability in reported outcomes across studies. The characteristics of the included studies are summarized in Table 1.

Risk of bias assessment

Overall, the majority of studies exhibited a low risk of bias across all domains assessed for randomization and outcomes. A few studies had a higher risk, as indicated by Anderson et al. (2010), which was due mostly to risk in randomization and deviation from the intervention. Likewise, the study by Uslu and Buldukoglu (2020) indicated deviation from the intended intervention as a source of concern.

Most studies explained how they concealed allocation, although Anderson et al. (2010) were less clear about this. Due to the psychosocial nature of adherence therapy, no study was able to blind participants. Most studies used patient self-reported outcomes, but some used objective outcomes (Chien et al., 2015). The risk of bias assessment of the included randomized controlled trials is summarized in Table 2.

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Table 2.

Risk of Bias (RoB 2) assessment for included randomized controlled trials.

Author	Interventions	Comparison group (control condition)	Randomization process	Deviations from intended interventions	Missing outcome data	Measurement of outcome	Selection of reported results	The overall risk of biased judgment
Staring et al. (2010)	Adherence therapy	Treatment as usual (TAU)	Low	Low	Low	Low	Low	Low risk of bias
Anderson et al. (2010)	Adherence therapy	Treatment as usual (TAU)	High	High	Low	Low	High	High risk of bias
Barkhof et al. (2013)	Motivational interviewing-based adherence therapy	Treatment as usual (TAU)	Low	Low	Low	Low	Low	Low risk of bias
Chien et al. (2015)	Motivational interviewing-based adherence therapy	Routine psychiatric care	Low	Low	Low	Low	Low	Low risk of bias
, Hasan et al. (2015)	Psychoeducational intervention (Adherence therapy)	Usual care	Low	Low	Some concern	Low	Low	Low risk of bias
Bäuml et al. (2016)	Psychoeducation program (Adherence therapy)	Standard care	Low	Low	Low	Low	Some concern	Low risk of bias
Chien et al. (2016)	Adherence therapy	Routine psychiatric care	Low	Low	Some concern	Low	Low	Low risk of bias
Khalil et al. (2019)	Culturally adapted behavioral family psychoeducational program (Adherence therapy)	Standard care	Low	Low	Low	Low	Low	Low risk of bias
Uslu and Buldukoglu (2020)	Telephone intervention problem solving (Adherence therapy)	Usual care	Low	Some concerns	Low	Low	Low	Some concerns.
Alizioti and Lyrakos (2021)	Psychoeducation program (Adherence therapy)	standard care)	Low	Low	Some concerns	Low	Low	Low risk of bias

Effectiveness of adherence therapy

A meta-analysis was not conducted due to significant heterogeneity among the included studies in terms of intervention formats, outcome measures, and follow-up durations. Specifically, variations were observed in the delivery of adherence therapy (e.g. motivational interview-based, psychoeducational, or telephone-based interventions), differences in adherence measurement tools, and inconsistencies in follow-up periods. Therefore, a narrative synthesis was the most appropriate approach.

Potential biases in the review process

The quality of RCTs included in this review was generally satisfactory. Most RCTs had a low risk of bias related to randomization processes and outcome assessments, although several studies demonstrated methodological limitations. For example, Anderson et al. (2010) was judged to have a high risk of bias related to the randomization process. Likewise, Uslu and Buldukoglu (2020) had some methodological flaws. Small sample sizes, short follow-up periods, and high rates of treatment refusal or non response may have reduced levels the internal validity and generalizability of the findings.

In contrast, Chien et al. (2015) demonstrated greater methodological rigor than the other included studies. Participants were recruited using a rigorous methodology, and sa clear protocol was implemented to manage missing data during the trial. In addition, the study showed a low risk of selective reporting bias due to the adequate descriptions of participants allocation, randomization concealment, and blinding procedures for outcome assessment, where applicable in psychosocial adherence therapy interventions.

In reporting the results and making sense of the implications, the limitations in methodologies particularly the use of patient-reported outcome measures in quasiexperimental studies should be borne in mind. On the positive side, several studies used objective measures (e.g. medication adherence rates and rehospitalization) which were reassuring. There is promise associated with adherence therapy for those with schizophrenia to support better adherence. With more RCTs, of better quality, and with more poorer quality studies, the evidence will gain more weight and be more persuasive.

Limitations

This systematic review has some limitations, including the low number of RCTs found, and considerable variation in follow-up time points across studies, which may lessen the applicability of the results. In addition, different RCTs used different methods to measure patient-reported outcomes for similar clinical endpoints, therefore limiting the ability to compare the results of those studies to one another. Also, one of the studies had a sample size that was not large enough to have adequate power, potentially increasing the chance of Type II error. Furthermore, by focusing on a qualitative narrative approach, this review is limited in its ability to quantify the overall effect of adherence therapy on medication adherence while controlling for variations in interventions.

Implication for practice and research

In order to empower patients and enhance their sense of control over their illness, it is advisable to incorporate AT into their treatment plan by using the cognitive behavioral therapy (CBT) and motivational interviewing (MI) therapeutic techniques, as these approaches are integral to AT (Gray et al., 2016). The implementation of CBT and MI may lead to an improvement in patients’ overall functioning, with the emphasis on adherence becoming less significant (Gray et al., 2016; Lin et al., 2022). Further studies are needed to elucidate the mechanisms underlying the effectiveness of AT, thereby ensuring its optimal application in various contexts and identifying which sociodemographic groups may be most receptive to this intervention.