4

Department of Veterans Affairs

Health Services Research & Development Service Evidence-based Synthesis Program

Interventions to Improve 

Pharmacological Adherence among 

Adults with Psychotic Spectrum 

Disorders, Bipolar Disorder, and 

Posttraumatic Stress Disorder

November 2015

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

Portland VA Medical Center

Portland, OR

Devan Kansagara, MD, MCR, Director

Investigators:

Principal Investigator: 

Karli Kondo, PhD

Co-investigators: 

Allison Low, BA

Kazuaki Jindai, MD

Aaron Mendelson, BA

Makalapua Motu’apuaka, BA

David Mansoor, MD

Matthew Judge, MD

Devan Kansagara, MD, MCR

Michele Freeman, MPH

Daniel Hartung, PharmD, MPH
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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PREFACE

The VA Evidence-based Synthesis Program (ESP) was established in 2007 to provide timely and 

accurate syntheses of targeted healthcare topics of particular importance to clinicians, managers, and 

policymakers as they work to improve the health and healthcare of Veterans. QUERI provides funding 

for four ESP Centers, and each Center has an active University affiliation. Center Directors are 

recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based 

Practice Centers. The ESP is governed by a Steering Committee comprised of participants from VHA 

Policy, Program, and Operations Offices, VISN leadership, field-based investigators, and others as 

designated appropriate by QUERI/HSR&D.

The ESP Centers generate evidence syntheses on important clinical practice topics. These reports help: 

Develop clinical policies informed by evidence;

Implement effective services to improve patient outcomes and to support VA clinical practice

guidelines and performance measures; and

Set the direction for future research to address gaps in clinical knowledge.

The ESP disseminates these reports throughout VA and in the published literature; some evidence 

syntheses have informed the clinical guidelines of large professional organizations. 

The ESP Coordinating Center (ESP CC), located in Portland, Oregon, was created in 2009 to expand the 

capacity of QUERI/HSR&D and is charged with oversight of national ESP program operations, program 

development and evaluation, and dissemination efforts. The ESP CC establishes standard operating 

procedures for the production of evidence synthesis reports; facilitates a national topic nomination, 

prioritization, and selection process; manages the research portfolio of each Center; facilitates editorial 

review processes; ensures methodological consistency and quality of products; produces “rapid response 

evidence briefs” at the request of VHA senior leadership; collaborates with HSR&D Center for 

Information Dissemination and Education Resources (CIDER) to develop a national dissemination 

strategy for all ESP products; and interfaces with stakeholders to effectively engage the program. 

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP CC Program 

Manager, at Nicole.Floyd@va.gov. 

Recommended citation: Kondo K, Low A, Jindai K, Mendelson A, Motu'apuaka M, Mansoor D, Judge

M, Kansagara D, Freeman M, Hartung D. Interventions to Improve Pharmacological Adherence among

Adults with Psychotic Spectrum Disorders, Bipolar Disorder, and Posttraumatic Stress Disorder. VA 

ESP Project #05-225; 2015. 

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) Center located at 

the Portland VA Health Care System, Portland, OR, funded by the Department of Veterans Affairs, Veterans 

Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. The 

findings and conclusions in this document are those of the author(s) who are responsible for its contents; the 

findings and conclusions do not necessarily represent the views of the Department of Veterans Affairs or the 

United States government. Therefore, no statement in this article should be construed as an official position of the 

Department of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, 

consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or 

royalties) that conflict with material presented in the report. 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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TABLE OF CONTENTS

EXECUTIVE SUMMARY ............................................................................................................ 1

Introduction ................................................................................................................................. 1

Methods ...................................................................................................................................... 2

Data Sources and Searches ..................................................................................................... 2

Study Selection ....................................................................................................................... 2

Data Abstraction and Quality Assessment .............................................................................. 2

Data Synthesis and Analysis ................................................................................................... 3

Results ....................................................................................................................................... 3

Results of Literature Search .................................................................................................... 3

Summary of Results for Key Questions.................................................................................. 3

Discussion ................................................................................................................................. 11

Conclusions ........................................................................................................................... 12

Abbreviations Table .................................................................................................................. 12

EVIDENCE REPORT .................................................................................................................. 14

INTRODUCTION ........................................................................................................................ 14

METHODS ................................................................................................................................... 16

Topic Development ................................................................................................................... 16

Search Strategy ......................................................................................................................... 18

Study Selection ......................................................................................................................... 18

Data Abstraction ....................................................................................................................... 21

Quality Assessment ................................................................................................................... 21

Data Synthesis ........................................................................................................................... 21

Rating the Body of Evidence .................................................................................................... 21

RESULTS ..................................................................................................................................... 23

Literature Flow ......................................................................................................................... 23

Key Question 1. Adults with psychotic spectrum disorder ...................................................... 24

1a. What are the effects of medication adherence interventions on psychopharmacological 

adherence?............................................................................................................................. 24

1b. What are the effects of medication adherence interventions on long-acting injectable 

(depot) psychopharmacological adherence? ......................................................................... 41
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1c. What are the effects of medication adherence interventions on nonpsychopharmacological adherence? ...................................................................................... 41

1d. What are the effects of these interventions on patient outcomes? .................................. 44

1e. What are the harms and costs related to these interventions? ......................................... 68

Key Question 2. Adults with Bipolar Disorder ......................................................................... 71

2a. What are the effects of medication adherence interventions on psychopharmacological 

adherence?............................................................................................................................. 71

2b. What are the effects of medication adherence interventions on long-acting injectable 

(depot) psychopharmacological adherence? ......................................................................... 72

2c. What are the effects of medication adherence interventions on nonpsychopharmacological adherence? ...................................................................................... 72

2d. What are the effects of these interventions on patient outcomes? .................................. 76

2e. What are the harms and costs related to these interventions? ......................................... 77

Key Question 3. Adults with PTSD .......................................................................................... 77

SUMMARY AND DISCUSSION ................................................................................................ 82

Summary of Evidence by Key Question ................................................................................... 82

Key Question 1. .................................................................................................................... 82

Key Question 2 ..................................................................................................................... 85

Key Question 3. .................................................................................................................... 85

Limitations ................................................................................................................................ 85

Discussion ................................................................................................................................. 87

Recommendations for Future Research ................................................................................ 88

Conclusion ................................................................................................................................ 88

REFERENCES ............................................................................................................................. 90

TABLES

Table 1. Psychotic Spectrum Disorders: Summary of Medication Adherence Outcomes ......... 5

Table 2. Bipolar Disorder: Summary of Medication Adherence Outcomes ............................. 10

Table 3. PICOTS by Key Question .......................................................................................... 19

Table 4. Psychotic Spectrum Disorders: Multicomponent Behavioral Interventions Medication 

Adherence Outcomes ................................................................................................... 26

Table 5. Psychotic Spectrum Disorders: Family Intervention Medication Adherence Outcomes

 ..................................................................................................................................... 32

Table 6. Psychotic Spectrum Disorders: System and Pharmacist Medication Adherence 

Outcomes ..................................................................................................................... 36
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Table 7. Psychotic Spectrum Disorders: Other Medication Adherence Outcomes .................. 39

Table 8. Outcomes Associated with Long-acting Injectable Adherence .................................. 42

Table 9. Psychotic Spectrum Disorders: Non-psychopharmacological Medication Adherence 

Outcomes ..................................................................................................................... 43

Table 10. Psychotic Spectrum Disorders: Patient Outcomes ................................................... 47

Table 11. Costs Associated with Medication Adherence Interventions ................................... 69

Table 12. Bipolar Disorder: Medication Adherence Outcomes ............................................... 73

Table 13. Bipolar Disorder: Patient Outcomes ......................................................................... 78

Table 14. Psychotic Spectrum Disorders: Summary of Medication Adherence Outcomes ..... 83

Table 15. Bipolar Disorder: Summary of Medication Adherence Outcomes ........................... 86

FIGURES

Figure 1. Analytic Framework .................................................................................................. 17

Figure 2. Literature Flow Chart ................................................................................................ 23

APPENDIX A. Technical Expert Panel........................................................................................ 95

APPENDIX B: Search Strategies ................................................................................................. 97 

APPENDIX C. Study Selection: Inclusion/Exclusion Criteria for Title/Abstract Review ........ 115

APPENDIX D. Study Selection: Inclusion/Exclusion Criteria for Full-text Review ................. 117

APPENDIX E. Medication Adherence Outcome Measures ....................................................... 118

APPENDIX F. Patient Outcome Measures ................................................................................ 119

APPENDIX G. Risk of Bias: Trials ............................................................................................ 121 

APPENDIX H. Risk of Bias: Observational Studies .................................................................. 125 

APPENDIX I. Peer Review Comments/Author Responses ....................................................... 127

 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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EXECUTIVE SUMMARY

INTRODUCTION

Non-adherence to medication is a serious problem in the United States (US). It is associated with 

increased emergency department visits and hospitalizations, higher costs of care, and greater 

mortality. For patients with serious mental illness, including schizophrenia and other psychotic 

spectrum disorders, bipolar disorder, and posttraumatic stress disorder (PTSD), adherence to 

psychopharmacological and/or non-psychopharmacological medications is an important concern.

There are a wide range of interventions for medication adherence. Interventions that target 

patients include psychosocial and behavioral interventions, including cognitive behavioral 

therapy (CBT) and Motivational Interviewing (MI), shared decision-making, customized 

adherence enhancement (CAE), Adherence and Compliance Therapies, and interventions 

involving family members. Other interventions target providers, such as provider education and 

training in MI. Interventions at the organization level may involve system-level interventions, 

such as financial incentives or reducing economic barriers through cost sharing; blister 

packaging for improving patient recall and tracking; and care coordination. Other interventions 

implemented at the organizational level include information and communication technology, 

such as electronic monitoring (e-monitoring), refill reminders via telephone or short message 

service (SMS); or other strategies, A recent review of interventions for medication adherence in 

patients with chronic illness found that educational interventions and case management were 

consistent in improving adherence across different clinical conditions, as were clinical 

reminders, pharmacist-led multicomponent approaches, and reducing out of pocket expenses for 

patients. This review examined interventions for medication adherence in patients with 

depression, but did not include other serious mental illnesses. 

The goal of this report is to synthesize evidence examining the effectiveness of interventions to 

improve medication adherence in patients with psychotic spectrum disorders, bipolar disorder, 

and PTSD; the effect of these interventions on patient outcomes; and the related costs and any 

associated intervention specific harms. The key questions used to guide our report are: 

KQ1. In adults with psychotic spectrum disorders:

a. What are the effects of medication adherence interventions on psychopharmacological

adherence?

b. What are the effects of medication adherence interventions on long-acting injectable 

(depot) psychopharmacological adherence?

c. What are the effects of medication adherence interventions on

non-psychopharmacological adherence?

d. What are the effects of these interventions on patient outcomes?

e. What are the harms and costs related to these interventions?

KQ2. In adults with bipolar disorder:

a. What are the effects of medication adherence interventions on psychopharmacological

adherence?
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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b. What are the effects of medication adherence interventions on long-acting injectable 

(depot) psychopharmacological adherence?

c. What are the effects of medication adherence interventions on 

non-psychopharmacological adherence?

d. What are the effects of these interventions on patient outcomes?

e. What are the harms and costs related to these interventions?

KQ3. In adults with posttraumatic stress disorder (PTSD):

a. What are the effects of medication adherence interventions on psychopharmacological

adherence?

b. What are the effects of medication adherence interventions on 

non-psychopharmacological adherence?

c. What are the effects of these interventions on patient outcomes?

d. What are the harms and costs related to these interventions?

METHODS

Data Sources and Searches

To identify relevant studies, we searched MEDLINE®, PubMed, PsycINFO©, Embase®, 

CINAHL©, and the Cochrane Library (Ovid EBM Reviews: Cochrane Central Register of 

Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews 

of Effects, Health Technology Assessment, and NHS Economic Evaluation Database) from 

database inception through January 2015. We also searched ClinicalTrials.gov, the World Health 

Organization’s International Clinical Trials Registry Platform (ICTRP), ISRCTN Registry, 

Conference Papers Index, and Dissertations & Theses Global, and searched the bibliographies of 

included studies for additional relevant citations. 

Study Selection

Criteria for population, interventions, comparators, outcomes, timing, and setting (PICOTS)

were developed in collaboration with our stakeholders and Technical Expert Panel. We included 

only studies with adult populations in general mental health settings (both inpatient and 

outpatient) that reported both an objective measure of adherence or validated subjective measure 

of adherence and a patient outcome measure. Studies conducted in forensic settings with 

incarcerated participants were excluded due to limited applicability. Two independent reviewers 

assessed all articles for inclusion, with discrepancies resolved through discussion or consultation 

with a third reviewer. 

Data Abstraction and Quality Assessment

One investigator abstracted data into a customized Systematic Review Data Repository (SRDR) 

database, which was then reviewed for accuracy by a second investigator. Study quality was dual 

rated using risk of bias (ROB) assessment criteria based on the guidance and tools developed for 

the Agency for Healthcare Research and Quality’s (AHRQ) Evidence-based Practice Centers 

(EPC), with any disagreements resolved through discussion or a third reviewer. 
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Data Synthesis and Analysis

We qualitatively synthesized the literature for each key question/clinical population. We 

compiled evidence tables of study characteristics, and analyzed individual study findings to draw 

conclusions. We assessed the overall strength of evidence for outcomes using a method 

developed for AHRQ’s EPCs.

RESULTS

Results of Literature Search 

From 7,944 titles and abstracts we identified 152 potentially relevant studies. After full-text 

review, we excluded 127 studies for a total of 24 included studies from 25 publications. Of the 

518 clinical trial protocols identified by our search of trial registry websites, one study met 

inclusion criteria; however, this study and all data reported on ClinicalTrials.gov are represented 

in an included publication. We identified 21 articles (20 primary studies) for Key Question 1, 4

primary studies for Key Question 2, and no primary studies for Key Question 3. 

Summary of Results for Key Questions

Key Question 1. In adults with psychotic spectrum disorders:

a. What are the effects of medication adherence interventions on psychopharmacological 

adherence?

Multicomponent Behavioral Interventions: Findings of the 7 included studies are mixed, with 

insufficient evidence from which to draw firm conclusions. Of the 4 studies examining 

Compliance Therapy, an intervention described in the 1997 manual by Kemp et al, one study 

found improved adherence at one month, but no differences by 6 months follow-up; another 

study found significantly greater adherence up to 18 months, and the other 2 studies found no 

significant differences between the Compliance Therapy and control groups, and no 

improvement in adherence in either group. Two studies of Adherence Therapy, an intervention 

based on Compliance Therapy, found no benefit over comparators. The seventh multicomponent 

behavioral intervention compared CBT to psychoeducation, with MI in both arms, and found no 

difference between groups at any time point. 

Interventions Involving Family Members: The 3 studies examining interventions involving 

family members show a generally positive effect, with low strength of evidence. Caution in 

interpretation and generalization is advised due to the limited number of studies, the 

heterogeneity among the interventions, and mixed findings. Two studies found family 

interventions to be more effective than usual care, and one study found no significant difference 

when controlling for time.

System-level Intervention: One study found that although adherence associated with a systemlevel intervention was better as compared to Compliance Therapy, the differences were not 

significant. There is insufficient evidence to determine the efficacy of system-level interventions.

Pharmacist-led Interventions: One study found no difference between a pharmacist-led 

intervention and usual care. There is insufficient evidence regarding the efficacy of pharmacistled interventions. 
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Technology Interventions: The 4 included studies provide low strength of evidence showing a 

positive effect associated with technology interventions. Two RCTs compared e-monitoring 

using smart pill containers/dispensers to a variety of comparators. One study, which examined emonitoring both as an intervention and a measure of adherence, reported a significant effect of 

the e-monitoring intervention as assessed by pill counts and no effect as assessed by emonitoring; a second study found adherence in the e-monitoring group to be significantly higher 

than both pill counts by a pharmacist and self-report. The third study compared a telephone and 

SMS intervention to telephone only and SMS only. Results indicated that although adherence 

was better in the group receiving both phone and SMS, differences were not significant, nor did 

adherence improve significantly for any of the groups over the duration of the study. The fourth 

study compared daily SMS to usual care, and found significantly better adherence in the 

intervention group both at the end of the active phase (3 months) and at 6-months follow-up.

Other Interventions: The 4 studies examining other interventions for medication adherence 

provided insufficient evidence from which to draw conclusions. One study of MI found no 

significant differences between the intervention group and controls. Similarly, no difference was 

found in adherence for a shared decision making intervention compared with usual care. Two 

studies examined Cognitive Adaptation Training and/or the medication adherence components of 

Cognitive Adaptation Training alone, with one study concluding no difference between standard 

Cognitive Adaptation Training and the use of only the medication adherence components (with 

significant benefit of both as compared with usual care), and one study that found no difference 

between the medication adherence components of Cognitive Adaptation Training and emonitoring. 

b. What are the effects of medication adherence interventions on long-acting injectable (depot) 

psychopharmacological adherence?

The 2 studies of interventions for medication adherence in patients prescribed depot

antipsychotics found limited evidence of a positive effect; however, there is insufficient evidence 

from which to draw firm conclusions. One study of patients prescribed a depot antipsychotic 

included an intervention for family members, psychoeducation, and early warning sign detection. 

Results indicated better adherence as compared with controls up to 24 months. The second study 

included depot in combination with a customized multicomponent behavioral intervention, and 

found significantly better adherence through 25 weeks. 

c. What are the effects of medication adherence interventions on non-psychopharmacological 

adherence?

One study examined the effect of an intervention for medication adherence on nonpsychopharmacological adherence and provides insufficient evidence from which to draw 

conclusions. The study compared a telephone plus SMS intervention to telephone or text only. 

There was no significant difference between groups. 
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Table 1. Psychotic Spectrum Disorders: Summary of Medication Adherence Outcomes

Type of 

Intervention

Study Design 

(Combined N) Findings

Strength of 

Evidence Comments

Behavioral 

Multicomponent - 

Adherence 

Therapy

2 RCTs (N = 370) Mixed findings: one study (low ROB) reported better adherence compared to 

usual care on the MAQ and SAI-C at 12 months, and the other (low ROB) 

reporting no difference from usual care on the CDR, DAI-30, and MARS at 12 

weeks post-discharge.

Insufficient Evidence from only 2 

studies, with mixed 

findings.

Behavioral 

Multicomponent - 

Compliance 

Therapy

2 RCTs (N = 130)

1 NRCT (N = 70)

1 Prospective Cohort 

(N = 30)

Mixed findings: better MARS scores with Compliance Therapy at 1 month but 

not 6 months in 1 study (high ROB); better DAI and compliance scores as 

compared with routine management plus supportive counseling through 18 

month follow in 1 study (high ROB); no benefit to Compliance Therapy up to 6 

months in 2 studies (compared to nonspecific counseling and Compliance 

Therapy; moderate ROB).

Insufficient Inconsistent findings 

among 4 studies. Risk 

of bias due to study 

design.

Other Behavioral 

Multicomponent

1 RCT (N = 88) No difference between group cognitive behavioral therapy (CBT) plus MI and 

group psychoeducation plus MI (moderate ROB).

Insufficient Evidence from only 

one study.

Depot plus 

Behavioral 

Multicomponent

1 Trial (randomization 

unclear) (N = 57)

1 Prospective Cohort 

(N = 30)

Findings indicated improved adherence related to the use of depot antipsychotic

injections plus a behavioral multicomponent intervention (compared to usual 

care or no comparator) as measured by injection visits up to one year, and 

injection visits, TRQ, Morisky scale, DAI, and AMQ up to 25 weeks (moderate 

ROB).

Insufficient Heterogeneity among 

interventions; risk of 

bias due to study 

design.

Family 

Intervention 

3 RCTs (N = 449) Better adherence with family interventions as measured by clinician rating/blood 

plasma and pharmacy records/family-report as compared to usual care in 2 

studies (moderate ROB). No difference when controlling for time in a 3rd study 

examining a culturally modified family intervention as compared to the standard 

family intervention and monthly sessions (moderate ROB). 

Low Heterogeneity among 

interventions.

System-level 

Intervention

1 NRCT (N = 70) Nonsignificant trend towards better adherence for the system-level intervention, 

compared with Compliance Therapy (moderate ROB).

Insufficient Evidence from only 

one study.

Pharmacist-led 1 Prospective Cohort 

w/post hoc 

comparison

(N = 30)

No significant difference over time or between groups (high ROB). Insufficient Evidence from only 

one study; potential 

risk of bias due to 

study design flaws.

Technology 

Interventions

4 RCTs (N = 434) Mixed findings on e-monitoring/MEMS: better adherence in one study as 

compared to pill counts and self-reported adherence (high ROB), conflicting 

results in 1 study as compared to a pharmacy based intervention and usual care 

(low ROB). Telephone plus SMS resulted in nonsignificant adherence 

improvement vs telephone or SMS alone (moderate ROB); SMS alone resulted 

in significantly better adherence than usual care (moderate ROB). 

Low Mixed findings and 

heterogeneous 

interventions. 
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Type of 

Intervention

Study Design 

(Combined N) Findings

Strength of 

Evidence Comments

Motivational 

Interviewing (MI)

1 RCT (N = 114) One study found no benefit to MI over usual care as measured by the MAQ or 

DAI (low ROB). 

Insufficient Evidence from only 

one study

Cognitive 

Adaptation

Training (CAT)

2 RCTs (N = 240) One study found that both CAT and Pharm-CAT resulted in better adherence 

than usual care, with no difference between the 2 (moderate ROB). The second 

study comparing Pharm-CAT to e-monitoring reported mixed results (low ROB). 

Insufficient Evidence from 2 

studies that used 

different 

comparators.

Shared Decision 

Making

1 RCT (N = 107) One study found no benefit to a shared decision making over usual care as 

measured by the MARS and plasma levels (high ROB).

Insufficient Evidence from only 

one single study.

Note. Studies comparing interventions may be accounted for more than once. 

Abbreviations: AMQ = Attitude towards Medication Questionnaire; CAT = Cognitive Adaptation Training; CBT = Cognitive behavioral therapy; CDR = 

Concentration to Dose Ratio; DAI = Drug Attitude Inventory; e-Monitoring = Electronic monitoring; MAQ = Medication Adherence Questionnaire; MARS = 

Medication Adherence Rating Scale; MEMS = Medication Event Monitoring System; MI = Motivational Interviewing; NRCT = Non-randomized controlled 

trial; ROB = Risk of bias; SAI-C = Schedule for the Assessment of Insight - C; SMS = Short message service; TRQ = Tablet Routine Questionnaire.
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d. What are the effects of these interventions on patient outcomes?

Positive and Negative Symptom Severity: Findings related to positive and negative symptom 

severity were mixed, and insufficient from which to draw conclusions. Four studies evaluated the 

effect of interventions for medication adherence in patients along the psychotic spectrum on 

positive and negative symptoms. One study of an intervention involving family members

resulted in a significant improvement in positive and negative symptoms. Another study 

examining SMS reminder messages resulted in significantly fewer negative symptoms. No other 

significant differences were found.

Overall Symptom Severity: Findings related to overall symptom severity were mixed and 

insufficient from which to form conclusions. Of the 17 studies examining overall symptom 

severity, 4 of 9 studies reported better total symptom severity as measured by the Positive and 

Negative Syndrome Scale (PANSS), 2 of 8 studies reported better score on the Brief Psychiatric 

Rating Scale (BPRS), and 2 of 3 studies reported better Clinical Global Impression scale (CGI) 

scores associated with the intervention.

Quality of Life: Findings from the 4 studies examining quality of life generally indicated no 

improvement associated with medication adherence interventions; however, given the 

heterogeneity of the interventions and limited evidence, the evidence is insufficient to form 

conclusions. Of the 4 studies, one study of an intervention involving SMS reminder messages 

resulted in better quality of life scores at the end of the intervention (3 months) but not at the 6-

months follow-up. 

Functional Impairment: Findings from the 10 studies examining functional impairment are 

mixed, and insufficient from which to form conclusions. Two studies found a positive effect on 

improving functional impairment associated with interventions involving family members, and 

functional impairment was improved in participants prescribed depot injections along with CAE. 

One of 3 studies examining Compliance Therapy reported greater functional improvement 

associated with the intervention, and one of 2 studies examining Cognitive Adaptation Training 

reported higher functioning associated with both standard Cognitive Adaptation Training and the 

use of only the medication adherence components, as compared to usual care at 3 and 6 months, 

with no difference thereafter.

Time to First Readmission/Hospitalization: Findings from the 10 studies examining time to first 

readmission or hospitalization are mixed and provide insufficient evidence from which to draw 

conclusions. Three studies examining interventions involving family members showed a positive 

effect of the intervention on hospital admissions and/or time to readmission or hospitalization. A 

system-level intervention resulted in a longer time to readmission as compared with Compliance 

Therapy, with 2 other studies also finding no effect of Compliance Therapy on 

readmission/hospitalization.

Time Spent in the Hospital: Three studies examined time spent in the hospital, and the evidence 

is insufficient from which to draw conclusions. Findings were mixed, with only one study of a 

family intervention reporting a shorter stay associated with the intervention. 

Time to Relapse: The 2 studies examining time to relapse reported better outcomes associated 

with the intervention, with longer time to relapse associated with a family intervention, and both 
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standard Cognitive Adaptation Training and the use of only the medication adherence 

components, as compared to usual care.

Side Effects: One study compared a system-level intervention to Compliance Therapy and 

examined side effects related to psychopharmacological interventions, and found fewer side 

effects associated with Compliance Therapy.

e. What are the harms and costs related to these interventions?

Two studies examined costs associated with interventions to improve medication adherence in 

patients along the psychotic spectrum. One study found no difference between Compliance 

Therapy and routine management with supportive counseling, and the second study found a 

higher average cost per patient associated with the adherence components of Cognitive 

Adaptation Training as compared to e-monitoring. 

Key Question 2. In adults with bipolar disorder:

a. What are the effects of medication adherence interventions on psychopharmacological

adherence?

The 4 studies meeting inclusion criteria for Key Question 2 provide limited evidence regarding 

the effectiveness of interventions for medication adherence in patients with bipolar disorder. 

Three of the 4 studies found a positive effect on psychopharmacological adherence associated 

with an adherence intervention, with high rates of attrition in the one study reporting no effect. 

Despite evidence suggesting a generally positive effect, the strength of the evidence is 

insufficient due to the fact that the interventions were heterogeneous, sample sizes were small, 

and external validity questionable because 2 studies showing a positive effect were conducted in 

Iran (see Table 2). 

d. What are the effects of these interventions on patient outcomes?

Depression: Findings of the 3 studies examining the effect of medication adherence interventions 

on depressive symptomology are mixed and provide insufficient evidence from which to draw 

conclusions. Of the 3 included studies, one study examining an individual psychoeducation 

intervention found a positive effect on depression associated with the intervention. A second 

study found that CAE resulted in significantly improved depression scores, but only at 6 months, 

while the third study showed no effect.

Mania: Findings of the 3 studies examining the effect of medication adherence interventions on 

mania are mixed and provide insufficient evidence from which to draw conclusions. Of the 3 

included studies, 2 showed significant effects on mania-related outcomes. One study examining 

an individual psychoeducation intervention found a positive effect on mania symptoms 

associated with the intervention. A second study of CAE found no difference in mania scores at 

3 months, but mania scores were significantly lower at 6 months.

Functional Impairment: Similar to results examining depression and mania, 2 of 3 studies 

reporting functional impairment outcomes in patients with bipolar disorder reported positive 

effects. One study reported a positive effect on improving functional impairment associated with 

a group psychoeducation intervention, and a second study (examining CAE) found no 

improvement between baseline and 3 months, but did report improved function at 6 months. 
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Single studies examined symptom severity, positive and negative affect, quality of life, and 

hospital readmissions. One study found no improvement associated with CAE on symptom 

severity at 3 months, with significant improvements by 6-months follow-up. Positive and 

negative affective symptoms improved significantly from baseline at both 3 and 6 months. 

Another study found significantly higher quality of life scores and fewer hospital readmissions 

over an 18-month period associated with an individual psychoeducation intervention. 

No studies were identified examining the effect of medication adherence interventions on longacting injectable (depot) psychopharmacological adherence (Key Question 2b), nonpsychopharmacological adherence (Key Question 2c), or reporting harms or costs associated 

with the intervention (Key Question 2e).

Key Question 3. In adults with PTSD:

We identified no studies meeting inclusion criteria for Key Question 3. 
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Table 2. Bipolar Disorder: Summary of Medication Adherence Outcomes

Type of Intervention

Study Design 

(Combined N) Findings

Strength of 

Evidence Comments

Psychoeducation 

(individual/group) 

1 RCT (N = 

108)

1 NRCT (N = 

45)

Both individual and group psychoeducation 

resulted in better medication adherence than 

pharmacotherapy alone or pharmacotherapy 

with standard psychotherapy (moderate 

ROB).

Insufficient Evidence from only 2 studies, external validity 

due to setting

Psychoeducation plus 

problem solving

1 RCT (N = 

164)

There was no improvement in medication 

adherence associated with the intervention as 

compared to usual care (moderate ROB).

Insufficient Evidence from only one study. Only 75% of 

the intervention group and 81% of the control 

group participated in baseline plus one other 

assessment, and only 49% of the intervention 

group participated in most or all of the group 

sessions, with 37% never participating.

Customized Behavioral 

Multicomponent 

(psychoeducation, substance 

use/modified MET, provider 

communication, medication 

management)

1 Prospective 

Cohort (N = 43)

Customized adherence enhancement (CAE)

was associated with better adherence and 

attitudes towards medication at 3 and 6 

months (moderate ROB). 

Insufficient Evidence from only one study; risk of bias due 

to study design.

Abbreviations: CAE = Customized adherence enhancement; MET = Motivational Enhancement Therapy; NRCT = Non-randomized controlled trial; RCT = 

Randomized controlled trial; ROB = Risk of bias.
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DISCUSSION 

We found 24 studies in 25 publications with the potential to inform policies and practices related 

to medication adherence in patients with severe mental illness in the VHA. Twenty studies 

(reported in 21 articles) examined patients with psychotic spectrum disorders, and 4 studies were

in patients with bipolar disorder. We identified no studies examining patients with PTSD. The 

interventions designed to improve medication adherence across Key Questions 1 and 2 differed 

widely, with very few studies evaluating the same specific interventions. Despite a variety of 

interventions designed to increase psychopharmacological adherence, study limitations (eg, 

differences in population and setting, heterogeneity among studies, a wide range of comparators, 

and the challenge of evaluating complex interventions), as well as concerns regarding

applicability to the VHA, preclude us from drawing strong conclusions. 

There is limited evidence that the involvement of family members, the use of technology (eg, emonitoring, SMS, telephone), and the combination of a depot antipsychotic and another 

intervention may be effective in improving adherence. However, these findings must be 

interpreted with caution, given the heterogeneity among interventions, the difficulty in 

determining the contribution of the depot antipsychotic versus the adherence intervention, the 

methodological limitations and the lack of consistent replication of any specific intervention. 

With the exception of interventions involving technology and system-level interventions, many 

interventions include behavioral or other techniques (eg, MI) that are flexible and designed to 

adapt to different settings and patients. While these techniques have been found effective in the 

treatment of other mental health conditions (eg, anxiety, depression, substance abuse), additional 

research of standardized interventions designed to improve medication adherence is needed to 

replicate findings across settings and populations in order to better understand their effect on 

adherence and patient outcomes. Similarly, many of the included studies compare interventions 

for medication adherence to usual care, rather than an active comparator. Given the population 

and the nature of mental illness, it is possible that the lack of active controls may result in more 

frequent provider interaction for the intervention group than for those receiving usual care. More 

frequent contact alone has the potential to result in improved outcomes, and it is impossible to 

ascertain whether any effect was due to the intervention or to increased attention. Finally, 

sampling bias may exist related to baseline differences in the adherence of individuals selected to 

enroll in studies examining interventions designed to improve medication adherence and those 

who do not – particularly in studies examining long-acting injectable depot antipsychotics.

An additional challenge in accurately assessing the body of research examining medication 

adherence is the wide range of methods used to assess adherence. We limited our inclusion to 

studies that assessed adherence using an objective measure such as blood plasma concentration 

levels, pill counts, e-monitoring/MEMS caps, or using a validated adherence scale.1

 For studies 

using multiple adherence measures, it was not uncommon for the determination of adherence to 

be incongruent, leading to questions related to the validity of commonly used and validated 

objective and subjective measures. 

There is a paucity of research examining the effect of medication adherence interventions on 

non-psychopharmacological interventions. Given the risk of comorbid health conditions (eg, 

diabetes, hypertension) in persons with serious mental illness, future research should evaluate the 

impact of adherence interventions aimed at prevalent comorbid non-psychiatric conditions. 
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Furthermore, we identified no studies evaluating the potential harms that may result from these 

interventions. Despite the fact that the potential for harm appears to be low as compared to the 

risks associated with both the use of, and non-adherence to, prescribed medication, research 

documenting relative risk is warranted. Similarly, very few studies evaluated differential effects 

in subpopulations. It is important to understand whether both the benefits and potential harms 

differ by subgroup or clinical subpopulation and whether one type of intervention may be more 

effective than others for a given population or setting. 

We identified no studies examining interventions to improve medication adherence in patients 

with PTSD. Although trauma processing therapies are often the first line of treatment for patients 

with PTSD, pharmacological interventions are commonly used as adjunctive therapy to alleviate 

associated symptoms and to treat comorbid conditions. There is limited evidence to suggest that 

adherence to medication is poor in Veterans with PTSD who are taking medication. Thus, future 

research is warranted to determine whether improvements in adherence in this population can be 

achieved through the use of interventions, or by adapting interventions developed for other 

patient populations. 

Conclusions

Findings from the studies examining interventions to improve medication adherence in patients 

with psychotic spectrum disorders are mixed and evaluate a wide range of heterogeneous 

interventions. Sample sizes were generally small, studies often lacked an active comparison 

group, and there was wide variation in how adherence was measured among studies. There is 

limited evidence to support improved adherence associated with interventions involving family 

members, those involving technology, and those combining a depot antipsychotics with another 

intervention. Findings were mixed regarding the effectiveness of multicomponent behavioral 

interventions, with no support for Adherence or Compliance Therapies. In addition, no clear 

evidence exists to support conclusions regarding the effect of medication adherence interventions 

on patient outcomes. Very few studies examined interventions for medication adherence in 

patients with bipolar disorder, and while in general there appears to be a positive effect of these 

interventions on adherence in this population, interventions were heterogeneous and more 

research is needed. No studies were found examining PTSD populations. For all populations, 

methodologically rigorous replication studies of standardized treatments using objective or 

validated subjective measures of adherence are needed to confirm preliminary results, as is 

research examining the costs and potential harms associated with the wide array of interventions 

designed to improve medication adherence.

ABBREVIATIONS TABLE

Abbreviation Term

AHRQ Agency for Healthcare Research and Quality

AMQ Attitude towards Medication Questionnaire

BPRS Brief Psychiatric Rating Scale 

BPRS–E Brief Psychiatric Rating Scale – Expanded

CAE Customized Adherence Enhancement

CAT Cognitive Adaptation Training

CBT Cognitive Behavioral Therapy

CDR Concentration to Dose Ratio

CGI Clinical Global Impression
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CGI-BP Clinical Global Impression – Bipolar scale

CGI-SGH Clinical Global Impression – Schizophrenia scale

CI Confidence Interval

DAI Drug Attitude Inventory

e-monitoring electronic-monitoring

EPC Evidence-based Practice Centers

EQ-5D EuroQoL

ES Effect size

GAF Global Assessment of Functioning

GAS Global Assessment Scale

HAM-D Hamilton Depression Rating Scale 

LEE Level of Expressed Emotion

LGP Life Goals Program

M Mean

MAQ Medication Adherence Questionnaire

MARS Medication Adherence Rating Scale

MDN Median

MEMS Medication Event Monitoring System

MET Motivational Enhancement Therapy

MI Motivational Interviewing

MM Med-eMonitor

NA Not applicable

NRCT Non-randomized controlled trial

NS Not significant

PANSS Positive and Negative Syndrome Scale

PICOTS Population, interventions, comparators, outcomes, timing, and setting 

PTSD Posttraumatic stress disorder

QLF Quality of Life Scale

RCT Randomized controlled trial

ROB Risk of Bias

SAI Schedule for Assessment of Insight

SAI-C Schedule for the Assessment of Insight - C

SAI-E Schedule for Assessment of Insight- Expanded

SD Standard deviation

SE Standard error

SF-36 Short Form Health Survey

SMS Short message service

SOFAS Social and Occupational Functioning Scale

SRDR Systematic Review Data Repository

SWN Subjective Well-being on Neuroleptic Treatment Scale

TIPS Telephone Intervention Problem Solving for Schizophrenia

TRQ Tablet Routine Questionnaire

VA Veterans Affairs

VHA Veterans Health Administration

WHOQOL-BREF World Health Organization Quality of Life instrument – Abbreviated version

WSRT Wilcoxon signed-rank test

YMRS Young Mania Rating Scale 
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EVIDENCE REPORT

INTRODUCTION 

Non-adherence to medication is a serious problem in the United States (US). It is associated with 

increased emergency department visits and hospitalizations,2-7 higher costs of care,2,6,7 and 

greater mortality.8,9

 For patients with serious mental illness, including schizophrenia and other 

psychotic spectrum disorders, bipolar disorder, and posttraumatic stress disorder (PTSD), 

adherence to psychopharmacological and/or non-psychopharmacological medications is an 

important concern. While some similarities exist, in general, these 3 populations are largely 

distinct in the factors associated with medication non-adherence and related outcomes, with 

some overlap in the interventions used to increase adherence. 

For individuals with schizophrenia and other psychotic spectrum disorders, antipsychotic 

medications are a primary focus of treatment.10 Among people with schizophrenia, adherence to 

antipsychotic medication is estimated to be between roughly 25%11,12 to 50%13; in a study of 

patients with schizophrenia or schizoaffective disorder in the Veterans Affairs (VA) system, an 

adherence rate of 60% was reported.14 Wide variation exists in reported adherence rates, and 

largely depend on the length of time examined and the method used to measure adherence.15

Factors related to non-adherence in individuals with psychotic spectrum disorders may include 

patient-level factors such as lack of awareness or insight into the illness, negative attitudes 

towards medication,15,16 comorbid substance use, and cognitive impairment; demographic factors 

such as younger age, male gender, and lower socioeconomic status; relationship factors such as a 

poor therapeutic alliance and poor social support; and system-level factors such as co-pays, 

medication supervision, and access to mental healthcare providers.16 In addition to poor 

adherence to antipsychotic medications, individuals with schizophrenia and other psychotic 

spectrum disorders may be prone to poor adherence to medications prescribed for comorbid 

conditions, with one study reporting similar adherence rates for psychopharmacologic and nonpsychopharmacologic therapies,17 and another study using VA data reporting a higher rate of 

non-adherence to oral hypoglycemic medications among Veterans with schizophrenia than 

without.18

Similar to individuals along the psychotic spectrum, psychopharmacological medications (eg, 

antipsychotics and mood stabilizers) are the first line of treatment for patients with bipolar 

disorder,19 with reported rates of adherence between 30%-57%.20-22 Studies conducted in VA 

settings reported an adherence rate of 51.9%.16,23 While many of the factors associated with nonadherence to antipsychotic medications – such as lack of insight into illness, comorbid substance 

use, cognitive function, and a poor therapeutic alliance – are similar to those found in individuals 

with psychotic spectrum disorders, other factors are more specific to patients with bipolar 

disorder, such as being unmarried, female, and homeless, having an external locus of control (eg, 

events are controlled by external factors rather than their own actions), having more suicide 

attempts, and receiving less-intensive psychopharmacologic treatments.23

Unlike patients with psychotic spectrum disorders or bipolar disorder, for individuals with 

PTSD, trauma processing therapy is often the first line of treatment.24 Pharmacologic treatment 

is also used to treat PTSD, including serotonergic antidepressants, adrenergic receptor 

antagonists such as prazosin, second-generation antipsychotics, and anticonvulsants.24 For 
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patients with PTSD, in addition to pharmacologic treatment for PTSD symptoms, non-adherence 

to medications for comorbid disorders may be a particular concern, with studies reporting higher 

rates of non-adherence to medications for cardiovascular disease.25,26 While few studies examine 

medication adherence rates in patients with PTSD, one study of individuals discharged from a 

VA PTSD treatment program reported that 66% were non-adherent during the 12 months 

following discharge. A second study of Veterans stated that 12% of participants reported not 

taking their medication, 41% reported forgetting to take their medication, and 24% reported 

skipping medication.26,27

Current measures of medication adherence vary widely, with a broad range of inherent 

limitations, often related to validity or cost. Objective measures of adherence include observed 

intake, pill counts, electronic monitoring (e-monitoring), administrative pharmacy claims, and 

blood plasma concentration levels; subjective measures include patient report, self-reported 

scales, patient diaries, reports by caregivers or case managers, and clinician’s views on 

adherence based on therapeutic response.28-30 

Due to the extensiveness of medication non-adherence and its severe health consequences for 

patients with severe mental illness, many interventions have been developed to try to combat this 

problem. Interventions for medication adherence include patient-level interventions such as 

Adherence and Compliance Therapies; adherence skills trainings; psychosocial and behavioral 

interventions, including cognitive behavioral therapy (CBT) and Motivational Interviewing (MI), 

shared decision-making, customized adherence enhancement (CAE), and interventions involving 

family members. Provider-level interventions include provider education and training in MI. 

System-level interventions include financial incentives; methods related to information and 

communication technology (eg, phone follow-up, electronic reminder systems, e-Health 

interventions, refill reminders); reducing economic barriers (eg, cost-sharing, reducing co-pays); 

blister or unit dose packaging; case management or care coordination; and simplified dosing or 

dosing frequency strategies, including long-acting injectables. A recent review of interventions 

for medication adherence in patients with chronic illness found that educational interventions and 

case management were consistent in improving adherence across different clinical conditions, as 

were clinical reminders, pharmacist-led multicomponent approaches, and reducing out of pocket 

expenses for patients.31 While this review did examine interventions for medication adherence in 

patients with depression, it did not include other serious mental illnesses. 

The goal of this evidence report is to summarize the current evidence examining the 

effectiveness of interventions to improve medication adherence in patients with psychotic 

spectrum disorders, bipolar disorder, and PTSD, the effect of these interventions on patient 

outcomes, as well as the related costs and any associated intervention specific harms. As the 

Veterans Health Administration (VHA) continues to strive to provide high quality care, a better 

understanding of adherence interventions for these distinct populations will help to aid the VA in 

determining the programs and policies most appropriate for improving Veterans’ health.
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METHODS 

TOPIC DEVELOPMENT

This topic was submitted to the ESP Coordinating Center by Anthony Morreale, PharmD, MBA, 

BCPS, FASHP, Assistant Chief Consultant for Clinical Pharmacy Services and Health Services 

Research, in the VA Office of Pharmacy Benefits Management Services. We further refined the 

scope and key questions for this topic through a preliminary search of peer-reviewed literature, 

and in concert with internal partners and investigators, Dr. Morreale, and a Technical Expert 

Panel comprised of both VA and non-VA experts (Appendix A). The key questions for the 

review are as follows:

KQ1. In adults with psychotic spectrum disorders:

a. What are the effects of medication adherence interventions on psychopharmacological

adherence?

b. What are the effects of medication adherence interventions on long-acting injectable 

(depot) psychopharmacological adherence?

c. What are the effects of medication adherence interventions on 

non-psychopharmacological adherence?

d. What are the effects of these interventions on patient outcomes? 

e. What are the harms and costs related to these interventions? 

KQ2. In adults with bipolar disorder:

a. What are the effects of medication adherence interventions on psychopharmacological

adherence?

b. What are the effects of medication adherence interventions on long-acting injectable 

(depot) psychopharmacological adherence?

c. What are the effects of medication adherence interventions on 

non-psychopharmacological adherence?

d. What are the effects of these interventions on patient outcomes? 

e. What are the harms and costs related to these interventions? 

KQ3. In adults with posttraumatic stress disorder (PTSD): 

a. What are the effects of medication adherence interventions on psychopharmacological

adherence?

b. What are the effects of medication adherence interventions on 

non-psychopharmacological adherence?

c. What are the effects of these interventions on patient outcomes? 

d. What are the harms and costs related to these interventions? 

Our approach was guided by the analytic framework shown in Figure 1.
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Figure 1. Analytic Framework: Interventions for Medication Adherence in Adults with Psychotic Spectrum Disorders, Bipolar 

Disorder, and Posttraumatic Stress Disorder

Abbreviations: HbA1c = Glycated hemoglobin; PTSD = Posttraumatic Stress Disorder. 
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SEARCH STRATEGY

A search strategy was developed in consultation with a research librarian, and was peer reviewed 

by a second research librarian using the instrument for Peer Review of Search Strategies 

(PRESS).32,33 We conducted a primary review of the literature by systematically searching, 

reviewing, and analyzing the scientific evidence as it pertains to the key questions from database 

inception to January 27, 2015. To identify relevant articles, we searched MEDLINE®, PubMed, 

PsycINFO©, Embase®, CINAHL©, and the Cochrane Library (Ovid EBM Reviews: Cochrane 

Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of 

Abstracts of Reviews of Effects, Health Technology Assessment, and NHS Economic Evaluation 

Database). In addition, we evaluated the bibliographies of included primary studies and any 

relevant systematic or nonsystematic reviews that were identified. To identify studies not 

published in peer-reviewed journals, we searched ClinicalTrials.gov, the World Health 

Organization’s International Clinical Trials Registry Platform (ICTRP), ISRCTN Registry, 

Conference Papers Index, and Dissertations & Theses Global. The complete search strategy is 

provided in Appendix B.

STUDY SELECTION

Criteria for population, interventions, comparators, outcomes, timing, and setting (PICOTS)

were developed in collaboration with our stakeholders and Technical Expert Panel, and are

provided in Table 3. We included only studies with adult populations examining interventions 

designed to improve medication adherence in general mental health settings (both inpatient and 

outpatient) that reported both a patient outcome measure and an objective or validated subjective 

measure of adherence.1 Studies set in forensic settings with incarcerated participants were 

excluded due to limited applicability (eg, including increased supervision, medication 

distribution). Eligible study designs included randomized controlled trials (RCTs) or 

methodologically rigorous observational studies, including before/after studies with at least 3 

time points and that completed analyses that controlled for time. Using pre-specified 

inclusion/exclusion criteria (Appendix C), 2 independent reviewers reviewed titles and abstracts 

using Abstrackr34 and agreed on a final inclusion/exclusion decision for 10% of the search yield, 

with the remaining 90% decided by a single reviewer. Clinical trials were reviewed for inclusion 

according to the same pre-specified inclusion criteria by the primary investigator. At the full-text 

screening stage, 2 independent reviewers assessed all articles for inclusion (Appendix D). 

Discordant results were resolved through discussion or consultation with a third if discrepancies 

could not be resolved between the first 2 reviewers. Articles meeting eligibility criteria were

included for data abstraction. 
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Table 3. PICOTS by Key Question 

Key 

Question

KQ1. In patients with psychotic spectrum disorders: 

a. What are the effects of medication adherence 

interventions on psychopharmacological

adherence?

b. What are the effects of medication adherence 

interventions on long-acting injectable (depot) 

psychopharmacological adherence?

c. What are the effects of medication adherence 

interventions on non-psychopharmacological

adherence?

d. What are the effects of these interventions on 

patient outcomes?

e. What are the harms and costs related to these 

interventions?

KQ2. In patients with bipolar disorder:

a. What are the effects of medication 

adherence interventions on 

psychopharmacological adherence?

b. What are the effects of medication 

adherence interventions on long-acting

injectable (depot) psychopharmacological

adherence?

c. What are the effects of medication 

adherence interventions on nonpsychopharmacological adherence?

d. What are the effects of these interventions 

on patient outcomes?

e. What are the harms and costs related to 

these interventions?

KQ3. In patients with posttraumatic 

stress disorder (PTSD): 

a. What are the effects of medication 

adherence interventions on 

psychopharmacological adherence?

b. What are the effects of medication 

adherence interventions on nonpsychopharmacological adherence?

c. What are the effects of these 

interventions on patient outcomes?

d. What are the harms and costs 

related to these interventions?

Populations Adults with psychotic spectrum disorders Adults with bipolar disorder Adults with PTSD

Intervention Studies where the primary outcomes include medication adherence, including: 

§ Patient-level interventions specifically designed to address medication adherence, such as: Compliance or Adherence Therapies, 

adherence skills training, psychosocial interventions (eg, psychoeducation, behavioral interventions, MI, cognitive interventions), 

customized adherence enhancement, family-supervised treatment, shared decision-making

or

§ Provider-level interventions specifically designed to address medication adherence, such as provider education, and training in MI

or

§ Systems-level interventions specifically designed to address medication adherence, such as: financial incentives, information and 

communication technology (eg, follow-up by phone, electronic reminder systems), reduction of economic barriers to adherence (eg, 

reducing copayments or prescription cost, cost-sharing), blister or unit-dose packaging, augmented pharmacy services, internet-based or 

eHealth interventions, simplified dosing or dosing frequency strategies, long-acting injectables (depot), case management or care 

coordination (eg, assertive community treatment, nurse-facilitated enhanced-treatment)

Comparator Other active interventions

No treatment

Usual care 

Studies with no comparison group only if outcome data are provided for baseline and at least 2 additional time points

Outcomes Medication adherence:

§ Measured objectively (eg, medication container with electronic monitoring [eg, MEMS], pill counts, biological markers, observed intake, 

medication possession ratio, medication plasma level, electronic ingestible event marker)

§ Measured subjectively by a validated patient self-report scale or measure (eg, Morisky Medication Adherence Scales [MMAS-8, MMAS4 or MAQ]). See Nguyen et al for a list of validated measures.1
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Patient outcomes:

§ Intermediate patient outcomes (HbA1c, blood pressure, lipids), clinical outcomes (mortality, morbidity), quality of life, patient 

satisfaction, health care utilization, quality of care, hospitalization, suicide/attempts, institutionalization, functional status, other.

Costs

Exclude: Medication adherence not the primary outcome –OR– Patient self-report, caregiver report, case manager report, clinician’s view based 

on therapeutic response, and other non-validated subjective outcomes.

Timing Short- and long-term outcomes

Study 

Design

RCTs; Methodologically rigorous observational studies (case control/cohort studies) that adjust for important confounders, and if no comparison 

group exists, data must be provided for baseline and at least 2 additional time points with analyses examining the trend and controlling for time. 
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DATA ABSTRACTION

Data from published reports were abstracted into a customized Systematic Review Data 

Repository (SRDR)35 database by one investigator (among KK, DH, KJ, AM, AL) and confirmed

by a second reviewer. From each study, we abstracted the following where available: study design, 

objectives, setting, population characteristics (including sex, age, race/ethnicity, diagnosis), subject 

eligibility and exclusion criteria, number of subjects, years of enrollment, duration of follow-up, 

the study and comparator interventions, important co-interventions, medication/class, number of 

medications, medication adherence outcomes, medication adherence thresholds, clinical outcomes, 

implementation factors, and harms. 

QUALITY ASSESSMENT

Two reviewers (among KK, DH, KJ, AM, AL, MM) independently assessed the quality of each 

study using the risk of bias (ROB) assessment criteria developed for a recent high-quality 

comparative effectiveness review examining medication adherence interventions that did not 

address the populations included in this report.31 This report followed the guidance and tools 

developed for the Agency for Healthcare Research and Quality’s (AHRQ) Evidence-based 

Practice Centers (EPC), and allows for the assessment of ROB for a wide range of study 

designs.36,37 Disagreements were resolved through discussion with a third reviewer evaluating 

methodological quality if consensus could not be reached between the first 2 reviewers. Each study 

was given an overall summary assessment of low, medium, high, or unclear ROB (Appendices G

& H):

36

Low ROB = We have confidence that the results represent the true treatment effect. The 

study reporting is adequate to judge that no major or minor sources of bias are likely to 

influence results. 

Medium ROB = We have some confidence that the results represent the true treatment 

effect. The study is susceptible to some bias, but the problems are not sufficient to 

invalidate the results.

High ROB = We have low confidence that results represent the true treatment effect. The 

study has significant flaws that imply biases of various types that may invalidate its results; 

these may arise from serious errors in conduct, analysis, or reporting, large amounts of 

missing information, or discrepancies in reporting.

Unclear ROB = The study is missing information, making it difficult to assess limitations 

and potential problems. 

DATA SYNTHESIS

We summarized the primary literature by abstracting relevant data and qualitatively synthesizing 

the literature for each key question/clinical population. Due the heterogeneity in the literature, a 

meta-analysis was not performed. We constructed evidence tables outlining study characteristics, 

organized by key question, and analyzed individual study findings to draw conclusions. 

RATING THE BODY OF EVIDENCE

We assessed the overall strength of evidence for outcomes using a method developed for AHRQ’s 

EPCs.38 The AHRQ EPC method considers study limitations, directness, consistency, precision, 
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and reporting bias to classify the strength of evidence for individual outcomes independently for 

randomized controlled trials and observational studies, with supplemental domains of doseresponse association, plausible confounding that would decrease the observed effect, and strength 

of association, as well as separate guidance for applicability as follows:39

High = We are very confident that the estimate of effect lies close to the true effect for this 

outcome. The body of evidence has few or no deficiencies. We believe that the findings are 

stable; in other words, another study would not change the conclusions. 

Moderate = We are moderately confident that the estimate of effect lies close to the true 

effect for this outcome. The body of evidence has some deficiencies. We believe that the 

findings are likely to be stable, but some doubt remains.

Low = We have limited confidence that the estimate of effect lies close to the true effect 

for this outcome. The body of evidence has major or numerous deficiencies (or both). We 

believe that additional evidence is needed before concluding either that the findings are 

stable or that the estimate of effect is close to the true effect.

Insufficient = We have no evidence, we are unable to estimate an effect, or we have no 

confidence in the estimate of effect for this outcome. No evidence is available or the body 

of evidence has unacceptable deficiencies, precluding reaching a conclusion
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RESULTS 

Our search of electronic databases, bibliographies, and other sources resulted in a total of 7,944 

studies. After title and abstract review, 152 were selected for full-text review. Upon review of the 

full-text articles, we excluded 127 citations for a total of 24 included studies from 25 publications. 

Additionally, a search of the ClinicalTrials.gov online trial registry identified 518 clinical trials, 

and one study met inclusion criteria;40 however, this study and all data reported on 

ClinicalTrials.gov are represented in an included publication.41 We identified 21 articles (20 

individual primary studies) for Key Question 1, 4 primary studies for Key Question 2, and no 

primary studies for Key Question 3. 

LITERATURE FLOW 

Figure 2 shows the citation yield from electronic database searches and other sources, numbers for 

exclusions at the abstract and full-text phases, and the final yield of included studies delineated by 

key question. 

Figure 2. Literature Flow Chart

Search results: 

7,944 references*

Pulled for full-text review: 

152 references

Included studies: 24 (from 

25 publications)

Excluded = 7,792 references

Excluded = 127 references

KQ 1 (psychotic 

spectrum 

disorders):

20 studies (from 21 

publications)

* 7,895 were identified through database searches (Appendix B), and an additional 49 were identified from 

the bibliographies of relevant systematic reviews and primary studies.

KQ 2 (bipolar 

disorder):

4 studies

KQ 3

(posttraumatic 

stress disorder):

0 studies
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KEY QUESTION 1. ADULTS WITH PSYCHOTIC SPECTRUM DISORDER

We identified 21 articles meeting inclusion criteria for patients along the psychotic spectrum, with 

20 independent studies reporting medication adherence outcomes, and one article42 reporting a cost 

analysis of another included study.43 Seven studies examined multicomponent behavioral 

interventions;43-49 3 studies examined interventions involving family members;50-52 one study 

examined a system-level intervention;49 one study examined a pharmacist-led intervention;53 4 

studies examined technology interventions (Medication Event Monitoring System [MEMS], 

telephone, short message service [SMS]);54-57 and 4 studies examined other interventions such as 

MI (1 study),58 shared decision-making (1 study),59 and environmental supports (2 studies).57,60

Two studies examined the combination of depot antipsychotics and an intervention designed to 

increase medication adherence,61,62 one study reported the intervention effect on nonpsychopharmacologic medications,54 and 2 studies reported outcomes related to costs.42,57 Study 

details are found in Tables 4-11. 

Studies were conducted in community mental health outpatient settings (12 studies) and in 

hospitals with inpatients (4 studies), with other interventions spanning pre- and post-discharge 

periods (3 studies), and one multi-site study that included both inpatient and outpatient settings. 

Six studies were conducted in the US and 12 were conducted in Europe, with one study conducted 

in South Korea, and another in Mexico. The included studies measured adherence using objective 

measures such as e-monitoring/MEMS, pill counts, and blood plasma concentration levels;

validated scales measuring adherence such as the Medication Adherence Questionnaire (MAQ),

the Medication Adherence Rating Scale (MARS), and the Drug Attitude Inventory (DAI), which 

has been shown to correlate with other measures of adherence;1 and a variety of other measures of 

adherence, some of which used multiple sources. The patient outcomes most frequently reported 

were positive and negative symptoms, symptom severity, functional impairment, and time to first 

readmission or hospitalization. Commonly used measures included the Positive and Negative 

Syndrome Scale (PANSS), the Clinical Global Impression scale (CGI), the Brief Psychiatric 

Rating Scale (BPRS), and the Global Assessment of Functioning (GAF). Tables 4-11 provide 

study detail, and a brief description of adherence and patient outcome measures are provided in 

Appendices E and F. 

1a. What are the effects of medication adherence interventions on 

psychopharmacological adherence?

Multicomponent Behavioral Interventions

Summary: Findings of the included studies are mixed, and there is no consistent evidence from 

which to draw conclusions about the efficacy of multicomponent behavioral interventions on 

pharmacological adherence. Table 4 provides study detail.

Details: There are a wide range of behavioral interventions targeting medication adherence, 

including functional analysis (eg, identifying the antecedents to specific behaviors), positive 

reinforcement, relaxation techniques. CBT combines behavioral interventions with the 

identification and challenging of cognitive distortions (eg, overgeneralization, black and white 

thinking). Other interventions commonly combined into multicomponent interventions include 

psychoeducation and MI, a non-confrontational goal-oriented style focused on overcoming 

ambivalence related to behavior change. Compliance Therapy is a multicomponent intervention 

first studied by Hayward et al in 199563 and described fully in a manual by Kemp et al in 199764
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that combines MI, cognitive, and psychoeducation approaches targeting psychotic symptoms, 

focusing on illness and treatment history, beliefs and understanding of the illness, and ambivalence 

towards treatment and stigma. Adherence Therapy65 is a manualized intervention that builds on 

Compliance Therapy, and is a patient-centered cognitive behavioral approach incorporating MI

and emphasizing joint decision-making, medication problem solving, exploring ambivalence, and 

the discussion of beliefs and concerns about medication.

We identified 7 studies (2 high ROB,43,45 3 moderate ROB,44,47,49 2 low ROB46,48) examining 

multicomponent behavioral interventions, of which 2 examined Adherence Therapy. The first was 

an RCT examining clinically unstable outpatients and found that over a period of 12 months, there 

was no difference between Adherence Therapy and the health education controls.46 The second 

study, also an RCT, included 5 sessions while participants were inpatients, and 3 sessions after 

release. At 12 weeks post-discharge, there was no difference in medication adherence between the 

Adherence Therapy group and controls.48

Four studies examined Compliance Therapy with mixed findings. A prospective cohort study 

conducted in a community setting found a significant improvement in adherence between baseline 

and the end of treatment (1 month) as assessed using the MARS; however, there was no significant 

improvement by 6 months follow-up, and no significant improvement as assessed using MEMS at 

either time point.

45 An RCT of inpatients compared Compliance Therapy to supportive counseling, 

and found significantly better adherence in the Compliance Therapy group at discharge, with 

differences between the 2 groups continuing through the 18-month follow-up period.

43 Two 

studies however, found no significant improvement in medication adherence associated with 

Compliance Therapy.

47,49

Finally, one RCT of inpatients compared group CBT with MI to group psychoeducation with MI 

and found no difference between groups at 24 months follow-up.

44 Table 4 provides study detail. 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Table 4. Psychotic Spectrum Disorders: Multicomponent Behavioral Interventions Medication Adherence Outcomes

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Adherence Therapy

Gray et al,

200646

G1: 204

G2: 205

Adults with 

clinically 

unstable 

schizophrenia 

requiring 

antipsychotic 

medication for ≥ 

1 year postbaseline.

Outpatient 

settings in the 

Netherlands, 

Germany, 

England, and 

Italy

G1: Usual care plus Adherence Therapy 

(AT), a brief cognitive behavioral approach 

focused on joint decision making including: 

assessments, medication problem solving, a 

medication timeline, exploring ambivalence, 

discussing beliefs and concerns about 

medication, medication in the future

G2: Usual care plus didactic health 

education 

Eight 

individual 30- 

to 50-minute 

weekly 

sessions

MAQ

M(SD)

G1 (N = 172): 2.98 

(1.24)

G2 (N = 194): 2.97 

(1.20)

12 Months:

M(SD)

G1 (N = 172): 3.20 (1.07)

G2 (N = 194): 3.33 (1.02)

Difference between groups (all available cases): -

0.13 (CI, -0.35 to 0.08), P = .23

Difference between groups (complete cases): -

0.15 (CI, -0.34 to 0.05), P = .15

SAI-C

M(SD)

G1 (N = 173): 5.04 

(1.39)

G2 (N = 189): 4.73 

(1.63)

12 Months:

M(SD)

G1 (N = 173): 5.22 (1.57)

G2 (N = 189): 5.03 (1.55)

Difference between groups (all available cases): 

0.19 (CI, -0.12 to 0.52), P = .24

Difference between groups (complete cases): -

0.16 (CI, -0.32 to 0.29), P = .92

Schulz et al,

201348

G1: 93

G2: 105

Adults diagnosed 

with a 

schizophrenic 

disorder (without 

comorbid 

disorders) 

recently 

G1: Usual care plus Adherence Therapy 

(AT), a brief cognitive behavioral approach 

focused on joint decision making including: 

assessments, medication problem solving, a 

medication timeline, exploring ambivalence, 

discussing beliefs and concerns about 

medication, medication in the future

Eight 

individual 

sessions, 5 as 

an inpatient, 

additional 3 

after 

discharge. 

CDR (blood serum)

M(SD)

G1 (N = 54): 3.83(6.80)

G2 (N = 39): 4.19(5.79)

12 Weeks Post Discharge 

M(SD)

G1 (N = 54): 3.34(5.36

G2 (N = 39): 6.36(10.56)

F = 2.29, P = NS
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

discharged and 

prescribed 

antipsychotic 

medication with 

a 

recommendation 

of treatment for a 

least one year 

following

discharge.

Hospitals in 

Germany (3) and 

Switzerland

G2: Usual care followed national guidelines 

for the treatment of schizophrenia and 

generally included medication, 

psychotherapy, occupational therapy, and 

psychoeducation.

DAI-30

M(SD)

G1 (N = 69): 

22.46(6.83)

G2 (N = 46): 

22.70(6.69)

12 Weeks Post Discharge

M(SD)

G1 (N = 69): 22.70(6.59)

G2 (N = 69): 22.83(5.89)

Difference = -.13, F = .039, P = NS

MARS

M(SD)

G1 (N = 69): 7.55(2.07)

G2 (N = 46): 7.46(1.73)

12 Weeks Post Discharge

M(SD)

G1 (N = 69): 7.74(2.01)

G2 (N = 46): 7.65(1.87)

Difference = 0. F not reported. 

Compliance Therapy64

Byerly et al,

200545

G1: 30

Adults diagnosed 

with 

schizophrenia or 

schizoaffective 

disorder taking 

only one oral 

antipsychotic, 

and who had 

been admitted to 

a psychiatric 

ward or 

emergency 

department for 

psychiatric 

purposes within

2 years. 

Community 

mental health

G1: Compliance Therapy is a combination 

of MI, cognitive, and psychoeducation 

approaches targeting psychotic symptoms, 

focusing on illness and treatment history, 

beliefs and understanding of the illness, and 

ambivalence towards treatment and stigma. 

Four to 6 

individual 

face-to-face 

30- to 60-

minute 

sessions over 

the period of 

a month.

MEMS

NR

1 Month

G1: 4% decline (P = 

.12)

6 Month

G1: Adherence increased 

by .19 each month from 

Months 1-6 (P = .83)

Diagnosis of 

schizoaffective 

disorder was 

associated with a 

larger decrease in 

adherence between 

months -1 and +1 

(HLM, P = .03)

Greater insight at 

baseline was associated 

with a greater increase in 

adherence in months 2-6 

(HLM, P<.01) 

MARS

NR

1 Month

G1: 8.9% increase (P

= .04)

6 Months

G1: 1.4% decline per 

month in months 2-6 (P

= .07)

DAI

NR

3 Month

G1: 15.2% increase (P

= .15)

6 Months

G1: .5% decrease (P = 

.81)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Kemp et al,

199843

G1: 39

G2: 35

Adult inpatients 

with psychotic 

disorders 

Hospital in 

England

G1: Routine management plus Compliance 

Therapy, a combination of MI, cognitive, 

and psychoeducation approaches targeting 

psychotic symptoms, focusing on illness 

and treatment history, beliefs and 

understanding of the illness, and 

ambivalence towards treatment and stigma. 

G2: Routine management plus supportive 

counseling (no medication issues addressed)

Four to 6 

individual 

face-to-face 

sessions (M = 

4.7) lasting 

20-60 

minutes twice 

weekly

DAI

M(SD)

G1 (N = 39): 45.3(6.8)

G2 (N = 35): 44.1(7.7)

At Discharge

M(SD)

G1 (N = 39): 52.0(5.9) 

G2 (N = 35): 45.7(8.5)

1 Month

M(SD)

G1 (f35): 50.1(6.3) G2 

(N = 28): 44.4(8.1)

6 Months

M(SD)

G1 (N = 18): 50.4(7.4)

G2 (N = 14): 41.9(5.9)

12 Months

M(SD)

G1 (N = 28): 49.5(6.9) 

G2 (N = 16): 44.6(7.5)

18 Months

M(SD)

G1 (N = 16): 50.9(6.2) 

G2 (N = 13): 48.2(8.5)

Advantage of Compliance Therapy (95% CI 2.5-

7.2). Compliance Therapy group had more 

favorable scores immediately post-treatment and 

this advantage was retained over all postintervention assessments, with a mean difference 

of 15.6%.

Compliance (Kemp) 

rated by multiple 

sources including 

primary nurse

M(SD)

G1 (N = 39): 3.7(1.2) 

G2 (N = 35): 4.1(1.2)

At Discharge:

M(SD)

G1 (N = 39): 5.5(0.8) 

G2 (N = 35): 4.3(1.4)

3 Months:

M(SD)

G1 (N = 38): 5.7(1.3) 

G2 (N = 34): 3.8(2.1)

6 Months:

M(SD)

G1 (N = 36): 5.7(1.8) 

G2 (N = 33): 3.5(1.9)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

12 Months:

M(SD)

G1 (N = 35): 5.5(1.8) 

G2 (N = 31): 3.6(2.1)

18 Months:

M(SD)

G1 (N = 25): 5.6(1.7) 

G2 (N = 23): 4.2(2.3)

There was a significant advantage for the Compliance Therapy group at 

discharge, and this was maintained throughout post-treatment.

AMQ

M(SD)

G1 (N = 39): 14.8(3.9) 

G2 (N = 35): 14.0(6.4)

At Discharge:

M(SD)

G1 (N = 39): 19.4(3.7) 

G2 (N = 35): 14.9(6.1)

P = Significant (NR)

NR

O’Donnell et 

al, 200347

G1: 28

G2: 28

Adults 65 and 

under with a 

diagnosis of 

schizophrenia 

and an IQ>80 

recently admitted 

to the hospital. 

Hospital in 

Ireland

G1: Compliance Therapy, a combination of 

MI, cognitive, and psychoeducation 

approaches targeting psychotic symptoms, 

focusing on illness and treatment history, 

beliefs and understanding of the illness, and 

ambivalence towards treatment and stigma. 

G2: Nonspecific counseling 

Five 

individual 

face-to-face

sessions 

lasting 30-60 

minutes. 

DAI

M(SD)

G1 (N = 28): 50(8)

G2 (N = 28): 50(7)

1 Year:

M(SD)

G1: 51.3(8.2)

G2: 53.4(6.2)

Difference = -2.1(95% CI, -6.3 to 2.1), P = .32

4-point self-report scale 

and adjusted by key 

informants

G1 (N = 23): 8/23 

(35%)

G2 (N = 21): 4/21 

(19%)

1 Year:

G1: 12/28

G2: 15/28

OR = .65 (95% CI .197 to 2.123)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Skarsholm et 

al, 201449

G1: 30

G2: 40

Adult inpatients 

close to 

discharge 23-70 

with a diagnosis 

of schizophrenia 

or 

schizoaffective 

disorder under 

the care of a 

community 

mental health 

team. 

Community 

mental health in 

Denmark

G1: System-Oriented Intervention included 

providing a brochure and questionnaire on 

antipsychotic treatment as a basis for 

conversation between participant/provider, a 

screening form for identification of 

compliance problems as the basis for 

participant/nurse conversation, a reminder 

box that contained medicine cards, dosage 

boxes, electronic alarm systems, medication 

reconciliation, adherence to clinical 

guidelines 

G2: Compliance Therapy, a combination of 

MI, cognitive, and psychoeducation 

approaches targeting psychotic symptoms, 

focusing on illness and treatment history, 

beliefs and understanding of the illness, and 

ambivalence towards treatment and stigma. 

G1: NA

G2: Six 

individual 

face-to-face

sessions and

3 booster 

sessions 30-

45 minutes in 

length.

Compliance based on 

self-report, DAI, 

appointment keeping, 

PANSS G-12 

NR

6 Months:

Difference in compliance score from baseline to 

follow-up, LOCF:

G1: (N = 40): 0.400, 95% CI (−.174 to 0.974), 

P<0.05 

G2: (N = 30): 1.103, 95% CI (.434 to 1.733), 

P>0.05 

Difference between intervention groups, 

coefficient:

Regression, MI: 0.476 (SE 0.362, CI -0.247 to 

1.120), P = 0.193

Other Multicomponent Behavioral Intervention

Bechdolf et 

al, 200544

G1: 40

G2: 48

Adult inpatients 

18-64 years who 

met criteria for a 

schizophrenic or 

related disorder

Hospital in 

Germany

G1: Group CBT included MI, coping 

strategies, problem solving, relapse 

prevention, and focused on the treatment of 

auditory hallucinations and delusions, 

associated symptoms, relapse prevention, 

and med adherence. 

G2: Group psychoeducation focused on 

improvements in medication compliance 

and rehospitalization rates and included MI

G1: 16 group 

sessions over 

8 weeks 

lasting 60-90 

minutes.

G2: 8 

sessions in 8 

weeks lasting 

60-90 

minutes

Compliance (similar to 

Kemp) w/corroboration 

with key informants

M(SD)

G1 (N = 40): 3.9(.3)

G2 (N = 48): 3.77(.5)

Post-treatment:

M(SD)

G1 (N = 37): 3.9(.3)

G2 (N = 43): 3.7(.6)

24 Months:

M(SD)

G1 (N = 16): 3.4(.7)

G2 (N = 25): 2.9(1.1)

F = 1.31, P = .26

Note. Studies were conducted in the US unless otherwise specified. Brief descriptions of medication adherence assessments are reported in Appendix E. 

Abbreviations: AMQ = Attitude towards Medication Questionnaire; CBT = Cognitive behavioral therapy; CDR = Concentration to Dose Ratio; CI = Confidence Interval; DAI = 

Drug Attitude Inventory; M = Mean; MAQ = Medication Adherence Questionnaire; MARS = Medication Adherence Rating Scale; MEMS = Medication Event Monitoring 

System; PANSS = Positive and Negative Syndrome Scale; SAI-C = Schedule for the Assessment of Insight – C; SD = Standard deviation. 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Interventions Involving Family Members

Summary: Findings of the included studies show a generally positive effect associated with 

interventions for medication adherence involving family members.

Details: Interventions involving family members are often conducted in group settings, and often 

include psychoeducation, support for families, behavioral problem solving, and crisis 

management.66

Three RCTs (all moderate ROB) meeting inclusion criteria examined the effect of interventions 

involving family members.50-52 Two studies included both an individual and a family component, 

with individual treatment conducted in a group setting.51,52 Two studies involved interventions 

that included both the participant and family together,50,52 with one study including a group 

intervention for relatives only.51 Two studies found family interventions to be more effective 

than usual care,51,52 and one study found no significant difference when controlling for time.50

Table 5 provides study detail. 
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Table 5. Psychotic Spectrum Disorders: Family Intervention Medication Adherence Outcomes

Study;

N per Group Sample and Setting Intervention Groups Intervention Intensity Measure; Baseline First Follow-up Additional Follow-ups

Kopelowicz et 

al, 201250

G1: 64

G2: 54

G3: 60

Adults 18-50 of 

Mexican origin and 

fluent Spanish speaker 

with a diagnosis of 

schizophrenia or 

schizoaffective 

disorder who had been 

without antipsychotic 

medication for at least 

one week in the past 

month without 

authorization, and 

lived with their family 

of origin with a 

relative willing to 

participate in family 

treatment. 

Community mental 

health

G1: Usual care plus Multifamily 

group – Adapted, a culturally 

modified version of multifamily 

group therapy, a behavioral 

family treatment combining 

psychoeducation and skills 

training.

G2: Multifamily group – 

Standard plus usual care

G3: Usual care

G1: Three individual family 

joining sessions, a 6 hour 

multifamily workshop, and 

twenty-one 90-minute 

multifamily group sessions 

twice a month.

G2: Same as G1

G3: Monthly 20-minute 

sessions or more if 

participant was unstable.

Clinician assessed, 

self-report, family 

report, pharmacy 

data

NR

4 Months:

Estimated from 

graph

% Compliant 

G1: 30%

G2: 27%

G3: 25%

More 

participants G1 

were fully 

adherent than 

those in G3 

(P<0.01).

8 Months:

Estimated from graph

% Compliant 

G1: 46%

G2: 27%

G3: 22%

G1 was significantly better than G2 

(P = .03), 

12 Months:

Estimated from graph

% Compliant 

G1: 52%

G2: 32%

G3: 25%

G1 was significantly better than G2 

(P = .04).

18 Months:

Estimated from graph

% Compliant 

G1: 43%

G2: 20%

G3: 16%

G1 was significantly better than G2 

(P = .01).

24 Months:

Estimated from graph

% Compliant 

G1: 33%

G2: 23%

G2: 11%

P = NS
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group Sample and Setting Intervention Groups Intervention Intensity Measure; Baseline First Follow-up Additional Follow-ups

Across the 24 months of the study (12 months of treatment and 12 months of 

follow-up), there were significant main effects of treatment on adherence for 

group (F[2,172] = 6.41, P = .003) and for time (F[4,172] = 3.5, P = .009), but 

not the group X time interaction (F[8,171] = 1.4, P = .22)., and There was no 

significant difference at any point between the G2 and G3.

Pitschel-Walz 

et al, 200651

G1: 102

G2: 92

Adults 18-65 with a 

diagnosis of 

schizophrenia or 

schizoaffective 

disorder

Inpatient wards in 

Germany

G1: Patients psychoeducation 

group focused on symptoms, 

etiology, acute treatment, relapse 

prevention, psychosocial 

treatment, and coping strategies. 

Family psychoeducation group 

focused on the same as patients, 

and how they could best support 

patient. 

G2: Usual care

G1: Patient groups were

eight 60-minute sessions, 

with 1-4 weekly, then 5-8 

monthly. Relative groups 

were 8 bi-weekly 90-minute 

sessions. 

Clinician assessed, 

plasma verified

NR

Discharge

% Very 

Good/Good 

Compliance

G1: 85, 69/81

G2: 81, 64/79

P = NS

12 Months:

% Very Good/Good Compliance

G1: 80, 65/81

G2: 58, 46/79

P<.01

24 Months:

% Very Good/Good Compliance

G1: 80, 53/73

G2: 55, 34/64

P<.01

Valencia et al,

201052

G1: 41

G2: 36

Adult outpatients with 

a diagnosis of 

schizophrenia who 

were adherent to their 

medication and 

clinically stable

Community mental 

health in Mexico

G1: Group/family psychosocial 

skills including medication, 

decision making, relapse 

prevention, avoiding drug and 

alcohol, friendships, improving 

family relations + usual care

G2: Usual care

G1: Patients – 90-minute 

group session weekly – 40 

total sessions in 12 months. 

Family + patient – 5 

sessions

G2: 20 minute monthly 

appointments

Pharmacy data, 

family report

NR

End of Treatment:

Adherence = 90% adherent

G1: 91.5% 

G2: 77.8% 

P<.05

Note. Studies were conducted in the US unless otherwise specified. Brief descriptions of medication adherence assessments are reported in Appendix E. 

Abbreviations: NR = Not reported; NS = Not significant.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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System-level Interventions

Summary: There is insufficient evidence regarding the efficacy of system-level interventions to 

improve medication adherence. 

Details: System-level interventions include policies implemented at the system-level for all 

patients meeting predefined criteria, and may include screening, education, and other 

interventions.

One included RCT (moderate ROB) compared a system-level intervention to Compliance 

Therapy.

49 The system-level intervention included a brochure and questionnaire on antipsychotic 

treatment as a basis for conversation between participant/provider, a screening form for 

identification of compliance problems as the basis for participant/nurse conversation, a reminder 

box that contained medicine cards, dosage boxes, electronic alarm systems, medication 

reconciliation, and the requirement that providers adhere to clinical guidelines. Although the 

system-level group showed better adherence outcomes, differences were not significant. Table 6

provides study detail.

Pharmacist-led Interventions

Summary: Findings of the included studies are insufficient to determine the efficacy of 

pharmacist-led interventions. 

Details: Pharmacist-led interventions are often brief interventions focused on education specific 

to medication, including the benefits, side effects, and potential consequences for discontinuing 

medication. 

We identified one study (high ROB) examining a pharmacist-led intervention, which involved a 

group session that included a question and answer session about medication, rationale, risks of 

stopping, side effects, risk/benefit evaluations.53 One session focused on antipsychotics, the 

second session focused on mood stabilizers. There was no significant difference between the 

pharmacist-led intervention and usual care. Table 6 provides study detail. 

Technology Interventions

Summary: Findings of the included studies show a generally positive effect, with low strength 

of evidence.

Details: Technology interventions vary, and may include SMS or telephone reminders, emonitoring using a variety of platforms, including MEMS caps, which record the time and date 

each time the cap is opened.54

We identified 4 studies (one high ROB,55 2 moderate ROB,54,56 one low ROB57) examining 

technology interventions to improve psychopharmacologic adherence. Two RCTs compared emonitoring to a variety of comparators.

55,57 One study found significantly better adherence when 

assessed using the e-monitor as compared with usual care, but not as assessed by pill counts.57

The second study, which examined e-monitoring both as an intervention and a measure of 

adherence, compared adherence measured by e-monitoring, pill counts, and self-report using a 

validated scale, and found adherence in the e-monitoring group to be significantly higher than 

both pill counts by a pharmacist and self-report.55 The third study compared a telephone and 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

35

SMS intervention to telephone only and SMS only. Results indicated that although adherence 

was better in the group receiving both phone and SMS, the differences were not significant, nor 

did adherence improve significantly for any of the groups over the duration of the study.54 The 

fourth study compared daily SMS to usual care, and found significantly better adherence in the 

intervention group both at the end of the active phase (3 months) and at 6-months follow-up.56

Table 6 provides more details about the included studies.

Other Interventions

Summary: Findings are insufficient to evaluate the efficacy of other interventions for 

psychopharmacologic adherence in patients along the psychotic spectrum. 

Details: Four studies (one high ROB,

59 one moderate ROB,60 2 low ROB57,58) examined other 

interventions for medication adherence for people along the psychotic spectrum. Included studies 

examined MI, shared decision making, and Cognitive Adaptation Therapy (CAT). One study 

examined an MI intervention targeting positive and negative symptoms and cognitive deficits.58

Results indicated no significant difference between the intervention and comparison group, with 

better adherence in patients prescribed depot antipsychotics regardless of group. A second study 

examined a shared decision intervention that included a shared decision aid booklet covering 

pros/cons of medication, psychoeducation, and a treatment agreement with their clinician.59 No 

difference in adherence was found as compared to usual care. Two studies examined CAT, an 

intervention focused on individualized strategies and environmental supports – one comparing 

standard CAT to the medication adherence component of CAT alone (Pharm-CAT) and usual 

care,60 and the other comparing Pharm-CAT to e-monitoring and usual care.57 Results indicated 

no difference between CAT and Pharm-CAT, and that both CAT and Pharm-CAT resulted in 

better adherence than usual care through 15 months as evaluated by pill counts. The study also 

found CAT, but not Pharm-CAT, to be better than usual care over 15 months as evaluated by 

pharmacy refill rates.60 There were no differences between Pharm-CAT and e-monitoring over 3 

months as assessed using the e-monitor, and Pharm-CAT was associated with better adherence 

than e-monitoring alone or usual care as assessed by pill counts.57 Table 7 provides more detail.
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Table 6. Psychotic Spectrum Disorders: System and Pharmacist Medication Adherence Outcomes

Study;

N per Group Sample and Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

System-level Interventions

Skarsholm et 

al, 201449

G1: 30

G2: 40

Adult inpatients close 

to discharge 23-70 

with a diagnosis of 

schizophrenia or 

schizoaffective 

disorder under the 

care of a community 

mental health team. 

Community mental 

health in Denmark

G1: System-Oriented Intervention 

included providing a brochure and 

questionnaire on antipsychotic 

treatment as a basis for 

conversation between 

participant/provider, a screening 

form for identification of 

compliance problems as the basis 

for participant/nurse conversation, 

a reminder box that contained 

medicine cards, dosage boxes, 

electronic alarm systems, 

medication reconciliation, 

adherence to clinical guidelines 

G2: Compliance Therapy, a 

combination of MI, cognitive, and 

psychoeducation approaches 

targeting psychotic symptoms, 

focusing on illness and treatment 

history, beliefs and understanding 

of the illness, and ambivalence 

towards treatment and stigma. 

G1: NA

G2: Six 

individual 

face-to-face

sessions and

3 booster 

session 30-

45 minutes in 

length.

Compliance Scale 

– self-report, DAI, 

PANSS G12

NR

6 Months:

Difference in compliance score from baseline to followup, LOCF:

G1: (N = 40): 0.400, 95% CI (-.174 to 0.974), P<0.05 

G2: (N = 30): 1.103, 95% CI (.434 to 1.733), P>0.05 

Difference between intervention groups, coefficient:

Regression, MI: 

0.476 (SE 0.362, CI -0.247 to 1.120), P = 0.193

Pharmacy Interventions

Kavanagh et 

al, 200353

G1: 15

G2: 15

Adults diagnosed 

with psychotic 

disorders who were 

inpatients in a 

psychiatric ward.

Hospital in London

G1: Pharmacist-led group 

including Q & A about 

medication, rationale, risks of 

stopping, side effects, risk/benefit 

evaluations. One session focused 

on antipsychotics, the second 

session focused on mood 

stabilizers + usual care.

G2: Usual care

G1: Two 

one-hour 

group 

sessions on 

consecutive 

weeks.

Compliance 

(Kemp), nurse 

assessed

M(SD)

G1 (N = 15): 

4.60(1.30)

G2 (N = 15): 

4.47(1.19)

Post Session and 2 Weeks Follow-up:

There were no significant differences between groups, 

over time, nor an interaction. 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group Sample and Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Technology Interventions (e-Monitoring, SMS, Phone)

Beebe et al,

201454

G1: 10

G2: 10

G3: 10

Adults 21-68 with a 

diagnosis of 

schizophrenia or 

schizoaffective 

disorder receiving 

outpatient care.

Community mental 

health

G1: TIPS + Text. TIPS is a 

manualized intervention providing 

weekly telephone support 

addressing taking medication, 

attending appointments, coping 

with symptoms, abstaining from 

alcohol and other drugs, and 

getting along with others. 

G2: TIPS only

G3: Text only – text format of the 

TIPS protocol. Texts were 

delivered daily

G1: Weekly 

phone calls 

and daily 

texts for 3 

months

G2: Weekly 

phone calls 

for 3 months

G3: Daily 

text 

messages for

3 months

Home pill counts 

or % of injections

M(SD)

NR

1 Month:

M(SD)

Month 1:

G1 (N = 10): 84.2(22.4) 

G2 (N = 10): 72(33.7)

G3 (N = 10): 72(20.1)

2 Months:

M(SD)

G1 (N = 10): 87.5(13.0) 

G2 (N = 10): 70.1(33.2)

G3 (N = 8): 83.9(18.0)

3 Months:

M(SD)

G1 (N = 10): 81.1(25.5) 

G2 (N = 10): 71.5(26.6)

G3 (N = 8): 80.9(16.3)

There was no significant Group x Time interaction for psychiatric medication 

adherence, F(4,26) = 1.24, P = .31). Nevertheless, findings were in the 

predicted direction: Mean psychiatric adherence scores for G1 were higher 

than both G2 (by an average of 5.3%) and G3 (by an average of 13%) at 

months 1, 2, 3. A post hoc analysis revealed that the power to examine 

psychiatric medication adherence was 34%.

Frangou et al,

200555

G1: 36

G2: 36

G3: 36

Adult outpatients 18-

64 with a diagnosis 

of schizophrenia who 

had at least 2 

admissions in 

preceding 12 months, 

and prescribed oral 

medication.

Community mental 

health in London

G1: e-monitoring (MEMS) –

medication dispenser that recorded 

access and transmitted data via the 

@HOME platform. Staff was 

alerted if participant took less than 

prescribed amount.

G2: Pill counting by pharmacists 

at study visits

G3: Self-report of adherence using 

Morisky scale.

G1: eMonitoring

G2: 

Pharmacist

G3: Selfreport

See Groups

NR

8 weeks

M%(SD)

G1 (N = 36): 92.3(4.8) 

G2 (N = 36): 78.5(14)

G3 (N = 36): 75.3(27.6)

P = .0001, 

G1 significantly better than G2 (P = .001) and G3 (P = 

.007)

Montes et al,

201256

G1: 100

G2: 154

Adult outpatients 18-

65 with a diagnosis 

of schizophrenia who 

were clinically stable, 

prescribed a single 

antipsychotic, and 

G1: Daily SMS reminders to take 

their medication, “Please 

remember to take your 

medication.” + usual care

G2: Usual care

G1: Daily 

SMS for 3 

months

MAQ

M(95% CI)

G1 (N = 100): 

2.2(2.02 to 2.38)

G2 (N = 154): 

3 Months:

Mean changes M(95% CI)

G1: -1.0(-1.02 to -.98)

G2: -.7(-.72 to -.68)

P = .02

6 Months:

Mean changes M(95% CI)

G1: -1.1(-1.12 to -1.08)

G2: -.8(-.81 to -.78)

P = .04
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group Sample and Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

one affirmative 

answer on the MAQ

Community mental 

health in Spain

2.2(2.06 to 2.34)

Velligan et al,

201357

G1: 47

G2: 48

G3: 47

Adults 18-60 

diagnosed with 

schizophrenia or 

schizoaffective 

disorder treated with 

oral antipsychotic(s) 

who had missed at 

least one dose in the 

previous week.

Community mental 

health

G1: Pharm-CAT consists of 

manualized individualized 

strategies and environmental 

supports targeting medication 

adherence

G2: Med-eMonitor (MM) is a 

smart pill container capable of 

cueing and warning patients, 

recording side effect complaints,

alerting staff of failure to take 

medication as prescribed.

G3: Usual care

G1: Home 

visits 30 

minutes long 

weekly for 9 

months.

G2: MM 

support and 

phone 

contact as 

needed.

MEMS

NA

Aggregated 3 Month:

Mixed-effects regression model yielded a significant 

treatment group for group (F[2m 365] = 47.29, P<.0001). 

Time and group X time effects were nonsignificant.

G1 and G2 were significantly better than G3 at all time 

points through treatment and follow-up (P’s<.0001). 

There was no significant difference between G1 and G2.

Pill Counts

NA

Aggregated 3 Month:

The mixed-effects regression model yielded a significant 

main effect of group (F[2, 116] = 7.83, P<.0001). Time 

and group X time effects were nonsignificant.

G1 had higher adherence by pill count (91%) than either 

G2 (86%, t[116] = 2.05, P = .04) or G3 (80%, t[115] = 

3.95, P = .0001).

DAI

M(95% CI)

G1 (N = 100): 

3.4(2.49 to 4.31)

G2 (N = 154): 

3.1(2.43 to 3.77)

3 Months:

Mean changes M(95% CI)

G1: 2.0(1.94 to 2.06)

G2: .4(.35 to .45)

P = .0003

6 Months:

Mean changes M(95% CI)

G1: 2.3(2.24 to 2.36)

G2: .9(.85 to .95)

P = .002

Note. Studies were conducted in the US unless otherwise specified. Brief descriptions of medication adherence assessments are reported in Appendix E. 

Abbreviations: CAT = Cognitive Adaptation Training; CI = Confidence Interval; DAI = Drug Attitude Inventory; M = Mean; MAQ = Medication Adherence 

Questionnaire; MEMS = Medication Event Monitoring System; MM = Med-eMonitor; PANSS = Positive and Negative Syndrome Scale; SD = Standard 

deviation; TIPS = Telephone Intervention Problem Solving for Schizophrenia. 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Table 7. Psychotic Spectrum Disorders: Other Medication Adherence Outcomes

Study;

N per Group Sample and Setting

Intervention

Groups

Intervention 

Intensity

Measure; 

Baseline First Follow-up Additional Follow-ups

Motivational Interviewing(MI)

Barkhof et al,

201358

G1: 55

G2: 59

Adults with 

schizophrenia or 

schizoaffective 

disorder with a 

psychotic relapse or 

deterioration 

following nonadherence to 

antipsychotics, who 

have resumed 

antipsychotics with 

some clinical 

improvement.

Three sites - 

Inpatient and 

outpatients in 

Amsterdam

G1: A manualized MI 

intervention based on 

negative symptoms, 

positive symptoms, 

cognitive deficits.

G2: Health education on 

general health topics.

Eight individual 

20- to 45-

minute sessions 

over 26 weeks.

MAQ

M(SD)

G1 (N = 30): 

3.00(1.34)

G2 (N = 32): 

3.13(1.24)

26 Weeks: M(SD)

G1 (N = 30): 3.34(0.99)

G2 (N = 32): 3.13(1.12)

P = .34

6 Months: M(SD)

G1 (N = 30): 2.97(1.42)

G2 (N = 32): 3.38(1.11)

P = .21

There was a significant interaction between MAQ and route of 

medication administration, suggesting higher adherence rates 

when using depot medication and received MI, F(1, 59) = 4.53, 

P = .037, η2 = .14.

DAI

M(SD)

G1(N = 30): 

6.86(2.18)

G2 (N = 32):

6.03(2.30)

26 Weeks: M(SD)

G1(N = 30): 6.86(2.50)

G2 (N = 32): 6.38(1.98)

P = .72

6 Months: 

M(SD)

G1(N = 30): 6.89(2.39)

G2 (N = 32): 6.67(2.52)

P = .70

There was a trend level interaction between DAI and age group: 

F(1,49) = 3.93, P = 05, η2 = 0.07, suggesting that participants 

≤35 years showed more favorable attitudes toward medication 

at 6 months follow-up when they received MI vs HE.

Shared Decision-making

Hamann et 

al, 200759

G1: 39

G2: 47

Adult inpatients 18-

65 with a diagnosis 

of schizophrenia or 

schizophreniform 

disorder

Hospital in Germany

G1: Shared decision aid 

booklet covering 

pros/cons of medication, 

psychoeducation, 

treatment agreement with 

clinician + usual care

G2: Usual care

G1: Decision 

aid session with 

nurse and extra 

planning talk 

with 

psychiatrist

MARS and 

blood plasma

NR

6 Months:

#(%) Good Compliance

G1 (N = 39): 16(41)

G2 (N = 47): 26(55)

P = NS

18 Months:

#(%) Good Compliance

G1 (N = 30): 18(60)

G2 (N = 38): 22(58)

P = NS

Cognitive Adaptation Therapy (CAT)

Velligan et 

al, 200860

G1: 37

Adult outpatients 

18-60 diagnosed 

with schizophrenia 

and prescribed an 

G1: CAT consists of 

manualized 

individualized strategies 

and environmental 

G1: Individual 

face-to-face

weekly visits 

lasting 30-45 

Unannounced 

Home Pill 

Counts

3 Months: 

G1 vs G3: P = .04

G2 vs G3: P = .05

15 Months:
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

40

Study;

N per Group Sample and Setting

Intervention

Groups

Intervention 

Intensity

Measure; 

Baseline First Follow-up Additional Follow-ups

G2: 32

G3: 29

oral antipsychotic

Community mental 

health

supports designed to 

include medication 

adherence, grooming, and 

activities of daily living

G2: Pharm-CAT 

consisted of only the 

medication adherence 

components of CAT

G3: Usual care

minutes for 9 

months

G2: Same as 

G1, but sessions 

were generally 

shorter

NA G2 vs G3: P = .002

All other time points:

G1 vs G3: P = .001

G2 vs G3: P = .0001

G1 vs G2 at all time points: P = NS

All effect sizes >1 for G1 and G2 at 6 months and after.

Pharmacy 

Refill Rates

NA

15 Months:

Mixed effects regression main effect for group: F(2, 105) = 

3.93, P<.02

No significant effect for time or group X time.

G1 significantly more adherent than G3.

Velligan et 

al, 201357

G1: 47

G2: 48

G3: 47

Adults 18-60 

diagnosed with 

schizophrenia or 

schizoaffective 

disorder treated with 

oral antipsychotic(s) 

who had missed at 

least one dose in the 

previous week.

Community mental 

health

G1: Pharm-CAT consists 

of manualized 

individualized strategies 

and environmental 

supports targeting 

medication adherence

G2: Med-eMonitor (MM) 

is a smart pill container 

capable of cueing and 

warning patients, 

recording side effect 

complaints, alerting staff 

of failure to take 

medication as prescribed.

G3: Usual care

G1: Home visits 

30 minutes long 

weekly for 9 

months.

G2: MM 

support and 

phone contact 

as needed.

MEMS

NA

Aggregated 3 Months:

Mixed-effects regression

model yielded a significant treatment group for group 

(F[2m 365] = 47.29, P<.0001). Time and group X time effects 

were nonsignificant.

G1 and G2 were significantly better than G3 at all time points 

through treatment and follow-up (P’s<.0001). 

There was no significant difference between G1 and G2.

Unannounced 

Home Pill 

Counts

NA

Aggregated 3 Months:

The mixed-effects regression model yielded a significant main 

effect of group (F[2, 116] = 7.83, P<.0001). Time and group X 

time effects were nonsignificant.

G1 had higher adherence by pill count: (91%) than either G2 

(86%, t[116] = 2.05, P = .04) or G3 (80%, t[115] = 3.95, P = 

.0001).

Note. Studies were conducted in the US unless otherwise specified. Brief descriptions of medication adherence assessments are reported in Appendix E. 

Abbreviations: CAT = Cognitive Adaptation Training; CI = Confidence Interval; DAI = Drug Attitude Inventory; M = Mean; MAQ = Medication Adherence 

Questionnaire; MARS = Medication Adherence Rating Scale; MEMS = Medication Event Monitoring System; MM = Med-eMonitor; SD = Standard deviation.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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1b. What are the effects of medication adherence interventions on long-acting 

injectable (depot) psychopharmacological adherence?

Two studies (both moderate ROB) examined interventions targeting people along the psychotic 

spectrum using long-acting injectable (depot) antipsychotics, and both reported improved 

adherence.61,62 The first study was an RCT of outpatients prescribed depot antipsychotics 

receiving an intervention that included psychoeducation, early warning sign detection, and 

family education. Results indicated better adherence for the intervention group versus usual care

at both the end of the intervention phase (12 months) and at 24-months follow-up.

61 The second 

study was a prospective cohort study of homeless outpatients in a community setting receiving 

depot plus CAE, a manualized individual multicomponent behavioral intervention consisting of 4 

modules (psychoeducation, substance use/modified Motivational Enhancement Therapy [MET], 

provider communication, medication management).62 CAE is customized based on an 

assessment at baseline to identify each patient’s adherence vulnerabilities and reasons for nonadherence, with one to 4 of the modules assigned based on the results of the assessment. Results 

indicated significantly improved adherence through 25 weeks. Table 8 provides more detail.

1c. What are the effects of medication adherence interventions on nonpsychopharmacological adherence?

One RCT (moderate ROB) examined the effect of an intervention for medication adherence on 

non-psychopharmacological adherence in patients along the psychotic spectrum.54 The 

intervention was a technology intervention comparing telephone and SMS to telephone or SMS

alone. There was no significant difference between groups. Table 9 provides study detail. 
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Table 8. Outcomes Associated with Long-Acting Injectable Adherence

Study;

N per Group Sample and Setting

Intervention

Groups

Intervention 

Intensity

Measure; 

Baseline First Follow-up Additional Follow-ups

Lee et al,

201061

G1: 24

G2: 33

Participants were 

outpatients between 17-

60 years old, diagnosed 

with schizophrenia or 

schizoaffective 

disorder, and prescribed 

treatment with a longacting injectable 

antipsychotic (depot). 

Community mental 

health in Korea

G1: Psychosocial 

Intervention for 

Relapse Prevention 

for depot; included 

psychoeducation, 

early warning sign 

detection, family 

education with 

biweekly 

intervention + usual 

care.

G2: Usual care

G1: 60-minute 

sessions 

monthly for 12 

months

Biweekly 

injection visits

NA

12 Months:

M%(SD)

G1 (N = 21): 94.6(12.2)

G2 (N = 25): 75.9(22.2)

t(45) = 3.5, P<.01

24 Months:

M%(SD)

G1 (N = 21): 92.1(16.5)

G2 (N = 25): 74.2(26.6)

t(45) = 2.7, P<.01

Sajatovic et al,

201362

G1: 30

Adults 18+ with a 

diagnosis of 

schizophrenia or 

schizoaffective disorder 

who had missed 20%+ 

of prescribed 

antipsychotics and were 

homeless within the 

past 12 months.

Community-based 

mental health

G1: Depot + CAE is 

a manualized 

individual 

behavioral 

intervention that 

consists of 4 

modules 

(psychoeducation, 

substance 

use/modified MET, 

provider 

communication, 

medication 

management). CAE 

is customized based 

on an assessment at 

baseline, with one to

4 modules assigned.

Eight monthly, 

in-person, 30- 

to 40-minute 

sessions 

TRQ

Screening:

M(SD)

Past Week:

G1: 57.2(33.2)

Past Month:

G1: 46.1(31.2)

Week 13:

M(SD), Change from Baseline (95% CI)

Past Week:

G1 (N = 10): 12.4(17.3), -42.9 (-60.6 to -

25.2)

Past Month:

G1 (N = 10): 8.2(11.6), -36.3(-52.9 to -

19.8)

Week 25:

M(SD), Change from Baseline (95% CI)

Past Week:

G1 (N = 10): 13.9(31.4), -38.9(-75.7 to -

2.0)

Past Month:

G1 (N = 10): 10.1(16.7), -29.6(-54.3 to -

4.8)

Past Week: P = .047

Past Month: P = .028

Morisky Scale

M(SD)

G1 (N = 30): 

2.5(1.2)

Week 13:

M(SD)

G1 (N = 30): 1.4(1.3)

Week 25:

M(SD)

G1 (N = 30):1.4(1.6)

P = .001

Injection 

Frequency

NA

Week 13:

M(SD)

G1 (N = 29): 83(35)

Week 25:

M(SD)

G1 (N = 29): 76(35)

Note. Studies were conducted in the US unless otherwise specified. Brief descriptions of medication adherence assessments are reported in Appendix E. 

Abbreviations: CAE = Customized adherence enhancement; M = Mean; MET = Motivational Enhancement Therapy; NA = Not applicable; SD = Standard deviation; TRQ = 

Tablet Routine Questionnaire.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Table 9. Psychotic Spectrum Disorders: Non-Psychopharmacological Medication Adherence Outcomes

Study;

N per 

Group Sample and Setting Intervention Groups

Intervention 

Intensity

Measure; 

Baseline

First 

Follow-up Additional Follow-ups

Beebe et 

al, 201454 

G1: 10

G2: 10

G3: 10

Adults 21-68 with a 

diagnosis of 

schizophrenia or 

schizoaffective 

disorder receiving 

outpatient care.

Community mental 

health

G1: TIPS + Text. TIPS is a 

manualized intervention providing 

weekly telephone support 

addressing taking medication, 

attending appointments, coping with 

symptoms, abstaining from alcohol 

and other drugs, and getting along 

with others. 

G2: TIPS only

G3: Text only – text format of the 

TIPS protocol. Texts were delivered 

daily

G1: Weekly phone 

calls and daily texts 

for 3 months

G2: Weekly phone 

calls for 3 months

G3: Daily text 

messages for 3 

months

Home pill 

counts or 

percentage of 

injections 

received vs 

prescribed for 

depot

NR

1 Month:

M(SD)

G1 (N = 7): 

82.1(19.9)

G2 (N = 7): 

73.1(21.8)

G3 (N = 6): 

82.2(26.5)

2 Months:

M(SD)

G1 (N = 8): 86.6(7.6)

G2 (N = 6): 58.5(27.2)

G3 (N = 5): 69.4(33.9)

3 Months:

M(SD)

G1 (N = 8): 76.9(20.9) 

G2 (N = 6): 69.3(24.9)

G3 (N = 5): 70.2(27.2)

Mean non-psychiatric medication adherence scores for G1 

were higher (by an average of 11.9%) than G3 at 2 of the 3 

follow-ups, and higher than G2 (by an average of 14.9%) 

months 1, 2, 3. Post hoc analysis revealed that the power to 

examine non-psychiatric medication adherence was 25%.

Note. Studies were conducted in the US unless otherwise specified. Brief descriptions of medication adherence assessments are reported in Appendix E. 

Abbreviations: M = Mean; NR = Not reported; SD = Standard deviation; SMS = Short message service; TIPS = Telephone Intervention Problem Solving for 

Schizophrenia.
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1d. What are the effects of these interventions on patient outcomes?

Twenty included studies examined a wide range of patient outcomes, including symptom 

severity, quality of life, functional impairment, insight, time to first readmission/hospitalization, 

time spent in the hospital, and time to relapse. Patient outcome scales are described in Appendix

F.

Symptom Severity

Seventeen studies examined the effect of interventions for medication adherence on positive (eg, 

delusions, hallucinations, disorganized speech or behavior), negative (eg, reduced emotional 

responsiveness, speech, movement, socialization, motivation), or total symptom severity in 

patients along the psychotic spectrum. 

Positive Symptoms

Four studies evaluated positive symptoms using PANSS or CGI. Interventions included MI,58 a 

multicomponent behavioral intervention,44 an intervention involving family,52 and SMS 

reminders.

56 Only the family intervention resulted in a significant decrease in positive 

symptoms.52 See Table 10 for more detail. 

Negative Symptoms

Four studies evaluated negative symptoms using the PANSS scale or CGI, and findings 

associated with the interventions were mixed. Interventions included MI,58 a multicomponent 

behavioral intervention,44 an intervention involving family,52 and SMS reminders.56

The group family intervention resulted in a significant decrease in negative symptoms as 

assessed by the PANSS at 12 months; however, there was no significant difference as assessed 

by the CGI negative symptom scale at 3 months. SMS reminder messages were associated with a 

greater degree of change at 3 months and a decrease in severity of negative symptoms at 6 

months.56 No other interventions were associated with a decrease in negative symptoms. Table 

10 provides more detail. 

Overall Symptom Severity

Seventeen studies evaluated total symptom severity using the PANSS, CGI, or BPRS, with 

mixed findings associated with the intervention. Of the 10 studies reporting PANSS 

scores,

44,45,47-49,52,55,58,61,62 four48,52,55,62 reported significantly fewer symptoms associated with the 

intervention, including depot plus a customized multicomponent behavioral intervention at 25 

weeks,62 a group family intervention,52 Adherence Therapy at 12-weeks post-discharge,48 and emonitoring and pill counts as compared with self-reported adherence. MI did not reduce 

symptom severity for the full sample; however, it was associated with greater general symptom 

score reductions in women.58

Nine studies assessed symptoms using the BPRS,43,46,50,51,53,54,57,59,60,62 with 2 reporting better 

scores associated with the intervention. The first study, a study of homeless outpatients included 

depot plus a customized multicomponent behavioral intervention and reported improved scores 

at 13 and 25 weeks.62 The second study compared family psychoeducation to usual care, with 

better BPRS scores for the intervention group at 12 and 24 months.51 The other 6 studies did not 

find a difference in BPRS scores between groups.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

45

Three studies reported CGI scores,55,59,62 with e-monitoring55 (at 8 weeks) and depot plus a 

customized multicomponent behavioral intervention for homeless participants62 reporting better 

scores at 13 and 25 weeks. Table 10 reports study detail.

Quality of Life

Four studies46,47,49,56 evaluated the effect of the interventions on quality of life, with no 

improvements associated with Adherence Therapy,

46 Compliance Therapy,47,49 or a system-level

intervention.49 However, daily SMS reminders as compared with usual care resulted in better 

quality of life scores at the end of the intervention (3 months), but not at 6 months follow-up.

56

Table 10 reports study detail.

Functional Impairment

Eleven studies evaluated functional impairment using the GAF, Global Assessment Scale (GAS), 

or the Social and Occupational Functioning Scale (SOFAS).43,47-49,51,52,57,59-62 The studies 

reported mixed findings, with some showing no effect and others a positive effect of medication 

adherence interventions on functional impairment. The 2 studies comparing interventions 

involving family members to usual care found the intervention group to be less impaired,51,52 as 

did one study of depot plus CAE.62 However, no improvement or group differences were found 

in studies examining Adherence Therapy,

48 e-monitoring,57 a system-level intervention,49 and 

shared decision-making.59 Results of the 3 studies examining Compliance Therapy were mixed, 

with 2 studies reporting no effect of Compliance Therapy on functional impairment,47,49 and one 

study reporting improvement in functional impairment associated with Compliance Therapy as 

compared to routine management and supportive counseling for up to 18 months.43 Similar 

results were found for studies examining CAT and Pharm-CAT, with one study reporting no 

improvement over time and as compared to e-monitoring,57 and a second study reporting higher 

functioning for CAT versus Pharm-CAT and usual care.60 Higher functioning was associated 

with Pharm-CAT as compared to usual care at 3 and 6 months, with no difference thereafter. 

Table 10 reports study detail.

Time to First Readmission/Hospitalization

The 10 studies examining time to first readmission or hospitalization reported mixed findings 

associated with interventions to improve medication adherence. Three studies comparing 

interventions involving family members to usual care reported significantly fewer admissions or 

longer time to readmission/hospitalization associated with the family intervention.50-52 One study 

comparing a system-level intervention to Compliance Therapy found that over one year, the 

system-level intervention resulted in longer time to readmission.49 Two other studies examining 

Compliance Therapy43,47 found that the intervention had no effect on readmission/

hospitalization, nor did MI,58 depot plus CAE,62 or shared decision making.59 Table 10 provides 

more detail. 

Time Spent in the Hospital 

Three studies examined whether the interventions aimed at improving medication adherence had 

any effect on time spent in the hospital. Neither Compliance Therapy43 nor a group 

multicomponent behavioral intervention44 was associated with shorter stays; however, a family 

intervention was associated with fewer days in the hospital after rehospitalization at 24 months.51

Table 10 provides study detail.
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Time to Relapse

The 2 studies examining time to relapse reported better outcomes associated with the 

intervention, with longer time to relapse associated with a family intervention,52 as well as both 

CAT and Pharm-CAT as compared to usual care.60 Table 10 provides study detail. 

Side Effects

One study compared a system-level intervention to Compliance Therapy and examined side 

effects (eg, psychic, neurological, autonomic) related to psychopharmacological interventions, 

and found fewer side effects associated with Compliance Therapy. Table 10 reports study detail.
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Table 10. Psychotic Spectrum Disorders: Patient Outcomes

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Adherence Therapy

Gray et al,

200646

G1: 204

G2: 205

Adults with 

clinically 

unstable 

schizophrenia 

requiring 

antipsychotic 

medication for ≥ 

1 year postbaseline.

G1: Usual care plus 

Adherence Therapy (AT), 

a brief cognitive 

behavioral approach 

focused on joint decision 

making including: 

assessments, medication 

problem solving, a 

medication timeline, 

exploring ambivalence, 

discussing beliefs and 

concerns about 

medication, medication in 

the future

G2: Usual care plus 

didactic health education 

Eight 

individual 30- 

to 50-minute 

weekly 

sessions

BPRS–E 

M(SD)

G1 (N = 175): 45.96 (13.23)

G2 (N = 196): 44.31 (12.79)

12 Months:

M(SD)

G1 (N = 175): 38.11 (11.33)

G2 (N = 196): 37.34 (9.79)

Difference between groups (all available cases): 0.77 

(CI, -1.39 to 2.93), P = .48

Difference between groups (complete cases): 0.13 (CI, -

1.84 to 2.09), P = .90

SF-36 

M(SD)

G1 (N = 175): 38.34 (10.89)

G2 (N = 192): 40.12 (12.25)

12 Months:

M(SD)

G1 (N = 175): 40.24 (11.97)

G2 (N = 192): 41.32 (11.49)

Difference between groups (all available cases): -1.08 

(CI, -3.49 to 1.33), P = .38

Difference between groups (complete cases): -0.40 (CI, 

-2.56 to 1.76), P = .72

Sensitivity analysis confirmed the findings.

Schulz et al,

201348

G1: 93

G2: 105

Adults diagnosed 

with a 

schizophrenic 

disorder (without 

comorbid 

disorders), who 

were recently 

discharged and 

prescribed 

antipsychotic 

medication with 

a 

G1: Usual care plus

Adherence Therapy (AT), 

a brief cognitive 

behavioral approach 

focused on joint decisionmaking including: 

assessments, medication 

problem solving, a 

medication timeline, 

exploring ambivalence, 

discussing beliefs and 

concerns about 

Eight 

individual 

sessions, 5 as 

an inpatient, 

additional 3 

after 

discharge. 

PANSS 

M(SD)

G1 (N = 63): 48.32(13.83)

G2: (N = 42): 49.33(14.74)

12 Weeks Post Discharge 

M(SD)

G1 (N = 63): 44.13(10.67)

G2 (N = 42): 50.29(13.67)

Difference = -6.16, F = 6.19, P<.05

GAF 

M(SD)

G1 (N = 67): 67.05(12.17)

G2 (N = 46): 64.2(13.49)

12 Weeks Post Discharge 

M(SD)

G1 (N = 67): 72.51(11.52)

G2 (N = 46): 67.15(13.81)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

48

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

recommendation 

of treatment for a 

least one year 

following 

discharge.

Hospitals in 

Germany (3) and 

Switzerland

medication, medication in 

the future

G2: Usual care followed 

national guidelines for the 

treatment of schizophrenia 

and generally included 

medication, 

psychotherapy, 

occupational therapy, and 

psychoeducation.

Difference = 5.4, F = .039, P = NS

Compliance Therapy64

Byerly et al,

200545

G1: 30

Adults diagnosed 

with 

schizophrenia or 

schizoaffective 

disorder taking 

only one oral 

antipsychotic, 

and who had 

been admitted to 

a psychiatric 

ward or 

emergency 

department for 

psychiatric 

purposes within

2 years. 

Community 

mental health

G1: Compliance Therapy 

is a combination of MI, 

cognitive, and 

psychoeducation 

approaches targeting 

psychotic symptoms, 

focusing on illness and 

treatment history, beliefs 

and understanding of the 

illness, and ambivalence 

towards treatment and 

stigma. 

Four to 6 

individual 

face-to-face 

30- to 60-

minute 

sessions over 

the period of 

a month.

PANSS

M(SD)

G1: 71.6(17.8) Range 38-105

3 Months

G1: .8% increase (P = .59)

6 Months

G1: .4% decrease (P = .33)

Kemp et al,

199843

G1: 39

G2: 35

Adult inpatients 

with psychotic 

disorders 

Hospital in 

England

G1: Routine management 

plus Compliance Therapy, 

a combination of MI, 

cognitive, and 

psychoeducation 

approaches targeting 

psychotic symptoms, 

Four to 6 

individual 

face-to-face 

sessions (M = 

4.7) lasting 

20-60 

minutes twice 

BPRS

M(SD)

Full: 

G1 (N = 39): 59.6(14.9) 

G2 (N = 35): 55.7(13.6)

At Discharge

M(SD)

Full:

G1 (N = 39): 37.6(10.1) 

G2 (N = 35): 37.4(8.5)

6 Months

M(SD)

7-item:

G1 (N = 36): 14.5(7.2) 

G2 (N = 31): 16.7(6.9)

12 Months
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

49

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

focusing on illness and 

treatment history, beliefs 

and understanding of the 

illness, and ambivalence 

towards treatment and 

stigma. 

G2: Routine management 

plus supportive counseling 

(no medication issues 

addressed)

weekly 7-item:

G1 (N = 39): 20.3(7.6) 

G2 (N = 35): 19.2(6.6)

P = Significant (NR)

7-item:

G1 (N = 39): 12.6(5.8) 

G2 (N = 35): 11.7(3.3)

M(SD)

7-item:

G1 (N = 35): 13.8(6.3) 

G2 (N = 28): 15.3(6.2)

18 Months

M(SD)

7-item:

G1 (N = 25): 12.5(5.6) 

G2 (N = 20): 14.8(4.1)

There was a significant effect on the 7-item measure, 

but no significant effect when accounting for time. 

GAF 

M(SD)

G1 (N = 39): 36.8(9.5) 

G2 (N = 35): 37.7(8.9)

At Discharge

M(SD)

G1 (N = 39): 49.7(13.2) 

G2 (N = 35): 47.9 11.2)

3 Months:

M(SD)

G1 (N = 37): 54.0(17.3) 

G2 (N = 33): 44.5(10.4)

6 Months:

M(SD)

G1 (N = 36): 55.9(17.5) 

G2 (N = 31): 43.3(10.6)

12 Months:

M(SD)

G1 (N = 35): 57.9(16.6) 

G2 (N = 30): 44.4(14.8)

18 Months:

M(SD)

G1 (N = 25): 62.8(18.4) 

G2 (N = 23) 48.3(14.5)

There was a significant treatment effect and a significant 

time x treatment effect with the intervention group 

showing greater improvement.

SAI-E At Discharge: 6 Months:
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

50

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

M(SD)

G1 (N = 39): 39.7(19.7) 

G2 (N = 35): 35.4(28.5)

M(SD)

G1 (N = 39): 63.0(23.6) 

G2 (N = 35) 40.6(31.2)

M(SD)

G1 (N = 34): 62.6(23.5) 

G2 (N = 29): 41.9(30.8)

12 Months:

M(SD)

G1 (N = 30): 63.4(25.5) 

G2 (N = 20): 42.6(36.5)

18 Months:

M(SD)

G1 (N = 16): 70.7(24.4) 

G2 (N = 15): 55.3(42.5)

Patients who received Compliance Therapy had 

significant greater insight and retained this over the 

follow-up period with a mean difference of 18.8% on 

the insight scale. 

Time to Readmission 

NA

NA 18 Months:

G1 30% 

G2 52%

Hazard Ratio = 2.2 (95% 

CI 1.16 to 4.18) for G2 

relative to G1

Time Spent in the Hospital

NA

M(SD)

G1 41.7(75.5) 

G2 61.6(90.8)

Mann-Whitney U test P = 

.208

NA

O’Donnell et 

al, 200347

G1: 28

G2: 28

Adults 65 and 

under with a 

diagnosis of 

schizophrenia 

and an IQ >80 

recently admitted 

G1: Compliance Therapy, 

a combination of MI, 

cognitive, and 

psychoeducation 

approaches targeting 

psychotic symptoms, 

Five 

individual 

face-to-face

sessions 

lasting 30-60 

minutes. 

PANSS 

M(SD)

G1 (N = 28): 71(22)

G2 (N = 28): 66(17)

1 Year:

M(SD)

G1: 58.2(17)

G2: 2.1(21)

NA
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

51

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

to the hospital. focusing on illness and 

treatment history, beliefs 

and understanding of the 

illness, and ambivalence 

towards treatment and 

stigma. 

G2: Nonspecific 

counseling 

Difference = 6.1 (95% CI, 

− 4.7 to 16.9), P = .26

SAI 

M(SD)

G1 (N = 28): 9(4)

G2 (N = 28): 9(4)

1 Year:

M(SD)

G1: 9.9(4.1)

G2: 10.4(2.8)

Difference = -.5 (95% CI, 

− 2.4 to 1.5), P = .65

NA

GAF 

M(SD)

G1 (N = 28): 36(14)

G2 (N = 28): 31(12)

1 Year:

M(SD)

G1: 52.7(17.8)

G2: 56.9(25.3)

Difference = -4.2 (95% CI, 

16.8 to 8.4), P = .50

NA

QLF 

M(SD)

G1 (N = 28): 67(22)

G2 (N = 28): 66(22)

1 Year:

M(SD)

G1: 71.8(21)

G2: 75.2(25)

Difference = -3.4 (95% CI, 

− 16.6 to 9.9), P = .61

NA

Occupancy of hospital beds

NA

1 Year:

M(SD)

G1: 26(45)

G2: 33(57)

Difference = -7 (95% CI, − 

35 to 21), P = .61

2 Years:

M(SD)

G1: 43(60)

G2: 50(70)

Difference = -7 (95% CI, − 

42 to 28), P = .69

Time to first rehospitalization

NA

M

G1: 440 days (95% CI, 346 to 534)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

52

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

G2: 482 days (95% CI, 378 to 586)

P = NS

Skarsholm et 

al, 201449

G1: 30

G2: 40

Adult inpatients 

close to 

discharge 23-70 

with a diagnosis 

of schizophrenia 

or 

schizoaffective 

disorder under 

the care of a 

community 

mental health 

team. 

Community 

mental health in 

Denmark

G1: System-Oriented 

Intervention included 

providing a brochure and 

questionnaire on 

antipsychotic treatment as 

a basis for conversation 

between 

participant/provider, a 

screening form for 

identification of 

compliance problems as 

the basis for 

participant/nurse 

conversation, a reminder 

box that contained 

medicine cards, dosage 

boxes, electronic alarm 

systems, medication 

reconciliation, adherence 

to clinical guidelines 

G2: Compliance Therapy, 

a combination of MI, 

cognitive, and 

psychoeducation 

approaches targeting 

psychotic symptoms, 

focusing on illness and 

treatment history, beliefs 

and understanding of the 

illness, and ambivalence 

towards treatment and 

stigma. 

G1: NA

G2: Six 

individual 

face-to-face

sessions and 3 

booster 

sessions 30-

45 minutes in 

length.

PANSS

NR

6 Months:

LOCF: 

G1 (N = 30): 22 

G2 (N = 40): 26 

P = .036 (adjusted for baseline score, P = .001)

Estimate of difference by regression: 4.93, 95% CI 

(−7.835 to −2.015)

MI: 

−4.478 (CI −9.259 to 0.403), P = .072 (adjusted for 

baseline score)

GAF 

Median (10; 90th percentile)

G1 (N = 30): 33(25, 45)

G2 (N = 40): 33(25, 40)

6 Months:

P = NS (MI and LOCF)

SWN

NR

6 Months:

P = NS (MI and LOCF)

Time to first readmission

NA

Kaplan-Meier survival proportion estimated from graph:

100 days follow-up:

G1 (N = 30): 0.9

G2 (N = 40): 0.7

200 days follow-up:

G1 (N = 30): 0.7

G2 (N = 40): 0.5

300 days follow-up:

G1 (N = 30): 0.6

G2 (N = 40): 0.4

365 days follow-up:
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

53

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

G1 (N = 30): 0.55

G2 (N = 40): 0.35

P = .049

Occupancy of hospital beds

NA

12 Months:

P = NS

System-level Interventions

Skarsholm et 

al, 201449

G1: 30

G2: 40

Adult inpatients 

close to 

discharge 23-70 

with a diagnosis 

of schizophrenia 

or 

schizoaffective 

disorder under 

the care of a 

community 

mental health 

team. 

Community 

mental health in 

Denmark

G1: System-Oriented 

Intervention included 

providing a brochure and 

questionnaire on 

antipsychotic treatment as 

a basis for conversation 

between 

participant/provider, a 

screening form for 

identification of 

compliance problems as 

the basis for 

participant/nurse 

conversation, a reminder 

box that contained 

medicine cards, dosage 

boxes, electronic alarm 

systems, medication 

reconciliation, adherence 

to clinical guidelines 

G2: Compliance Therapy, 

a combination of MI, 

cognitive, and 

psychoeducation 

approaches targeting 

psychotic symptoms, 

focusing on illness and 

treatment history, beliefs 

G1: NA

G2: Six 

individual 

face-to-face

sessions and 3 

booster 

sessions 30-

45 minutes in 

length.

PANSS

NR

6 Months:

LOCF: 

G1 (N = 30): 22 

G2 (N = 40): 26 

P = .036 (adjusted for baseline score, P = .001)

Estimate of difference by regression: 4.93, 95% CI 

(−7.835 to −2.015)

MI: 

−4.478 (CI −9.259 to 0.403), P = .072 (adjusted for 

baseline score)

GAF 

Median (10; 90th percentile)

G1 (N = 30): 33(25, 45)

G2 (N = 40): 33(25, 40)

6 Months:

P = NS (MI and LOCF)

SWN

NR

6 Months:

P = NS (MI and LOCF)

Time to first readmission

NA

Kaplan-Meier survival proportion estimated from graph:

100 days follow-up:

G1 (N = 30): 0.9

G2 (N = 40): 0.7

200 days follow-up:

G1 (N = 30): 0.7
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

54

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

and understanding of the 

illness, and ambivalence 

towards treatment and 

stigma. 

G2 (N = 40): 0.5

300 days follow-up:

G1 (N = 30): 0.6

G2 (N = 40): 0.4

365 days follow-up:

G1 (N = 30): 0.55

G2 (N = 40): 0.35

P = .049

Occupancy of hospital beds

NA

12 Months:

P = NS

UKU – Side Effects

NA

6 Months:

#(%)

G1 (N = 30): 21(70%)

G2 (N = 40): 17(43%)

P = .03

Other Multicomponent

Bechdolf et 

al, 200544

G1: 40

G2: 48

Adult inpatients 

18-64 years who 

met criteria for a 

schizophrenic or 

related disorder

Hospital in 

Germany

G1: Group CBT included 

MI, coping strategies, 

problem solving, relapse 

prevention, and focused on 

the treatment of auditory 

hallucinations and 

delusions, associated 

symptoms, relapse 

prevention, and med 

adherence. 

G2: Group 

psychoeducation focused 

on improvements in 

medication compliance 

and rehospitalization rates 

and included MI

G1: 16 group 

sessions over 

8 weeks 

lasting 60-90 

minutes.

G2: 8 

sessions in 8 

weeks lasting 

60-90 

minutes

PANSS

M(SD)

Positive Scale:

G1 (N = 40): 14.7(4.9)

G2 (N = 48): 14.4(5.1)

Negative Scale:

G1 (N = 4): 16.5(6.1)

G2 (N = 48): 15.5(6.0)

General Score:

G1 (N = 48): 33.7(9.1)

G2 (N = 40): 29.6(7.6)

Post-treatment:

M(SD)

Positive Score:

G1 (N = 37): 13.34.8)

G2 (N = 43): 10.4(2.1)

Negative Score:

G1 (N = 37): 13.9(4.5)

G2 (N = 43): 12.5(5.2)

General Score:

G1 (N = 38): 31.7(9.9)

G2 (N = 43): 24.1(4.9)

24 Months:

M(SD)

Positive Scale: 

G1 (N = 16): 13.5(5.6)

G2 (N = 25): 13.5(6.5)

F = .5, P = .49

Negative Scale:

G1 (N = 16): 13.7(5.0)

G2 ( N = 25): 14.5(6.3)

F = .001, P = .94

General Score:

G1 (N = 16): 28.1(6.3)

G2 (N = 25): 26.4(6.9)

F = .29, P = .50
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

55

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Rehospitalization rates

NA

NA 24 Months:

No(%)

G1 (N = 16): 6(37.5%)

G2 (N = 27): 16(59.3%)

χ

2 = 2.50, P = .114

Length of hospitalization

NA

At Discharge:

G1: 92 days

G2: 163 days

Mann–Whitney U = 31.5, 

P = .224

NA

Lee et al,

201061

G1: 24

G2: 33

Participants were 

outpatients 

between 17-60 

years old, 

diagnosed with 

schizophrenia or 

schizoaffective 

disorder, and 

prescribed 

treatment with a 

long-acting 

injectable 

antipsychotic 

(depot). 

Community 

mental health in 

Korea

G1: Psychosocial 

Intervention for Relapse 

Prevention for depot; 

included psychoeducation, 

early warning sign 

detection, family education 

with biweekly intervention 

+ usual care.

G2: Usual care

G1: 60-

minute 

sessions 

monthly for 

12 months

PANSS 

M(SD)

G1 (N = 21): 61(11)

G2 (N = 25): 58.7(7.7)

Both groups experienced significant decreases (P<.01) 

over time, with no significant difference between 

groups. 

CGI –SGH

M(SD)

G1 (N = 21): 4.1(.5)

G2 (N = 25): 4.0(1.2)

Both groups experienced significant decreases (P<.01) 

over time, with no significant difference between 

groups.

GAF 

M(SD)

G1 (N = 21): 46.4(9.8)

G2 (N = 25): 45.8(14.3)

Both groups experienced significant decreases (P<.01) 

over time, with no significant difference between 

groups.

Relapse – increases to 

moderately severe PANSS 

positive score or GAF of 30 or 

less

NA

12 Months:

N(%)

G1 (N = 21): 2(9)

G2 (N = 25): 10(45)

P<.01

24 Months:

N(%)

G1 (N = 21): 5(24)

G2 (N = 25): 12(48)

P = .04

Injection discontinuation - Over 24 Months:
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

56

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

declined to take further 

injections/ preferred oral 

medication, or when the patient 

no longer visited the hospital

NA

N(%)

G1 (N = 21): 5(23)

G2 (N = 25): 18(68)

χ

2

(1) = 13.0, P<.01

Treatment discontinuation - no 

longer visited the hospital for 

treatment

NA

Over 24 Months:

N(%)

G1 (N = 21): 3(14)

G2 (N = 25): 11(28)

χ

2

(1) = 6.0, P = .01

Sajatovic et 

al, 201362

G1: 30

Adults 18+ with 

a diagnosis of 

schizophrenia or 

schizoaffective 

disorder who had 

missed 20%+ of 

prescribed 

antipsychotics 

and were 

homeless within 

the past 12 

months.

Communitybased mental 

health

G1: Depot + CAE is a 

manualized individual 

behavioral intervention 

that consists of 4 modules 

(psychoeducation, 

substance use/modified 

MET, provider 

communication, 

medication management). 

CAE is customized based 

on an assessment at 

baseline, with one to 4 

modules assigned.

Eight 

monthly, inperson, 30- to 

40-minute 

sessions 

BPRS 

M(SD)

G1 (N = 30): 47.1(11.5)

13 Weeks:

M(SD)

G1 (N = 30): 34.0(9.0)

25 Weeks:

M(SD)

G1 (N = 30): 32.8(10.0)

P<.001

PANSS

M(SD)

G1 (N = 13): 78.2(26.6)

Week 13:

NR

Week 25:

M(SD)

G1 (N = 13): 51.8(16.7)

P = .005

SOFAS 

M(SD)

G1 (N = 19): 47.9(8.0)

13 Weeks:

NR

25 Weeks:

M(SD)

G1 (N = 19): 59.3(9.8)

P<.001

CGI –SGH 

M(SD)

G1 (N = 18): 4.6(.9)

13 Weeks:

M(SD)

G1 (N = 18): 3.5(.8)

25 Weeks:

M(SD)

G1 (N = 18): 3.3(.8)

P<.001

Psychiatric hospitalizations 

M(SD)

G1 (N = 17): 1.0(3.0)

13 Weeks:

NR

25 Weeks:

M(SD)

G1 (N = 17): 0.1(.3)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

57

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

P = .13

Medical hospitalizations 

M(SD)

G1 (N = 17): 0.1(.3)

13 Weeks:

NR

25 Weeks:

M(SD)

G1 (N = 17): 0.3(.7)

P = .66

Family Interventions

Kopelowicz 

et al, 201250

G1: 64

G2: 54

G3: 60

Adults 18-50 of 

Mexican origin 

and fluent 

Spanish speaker 

with a diagnosis 

of schizophrenia 

or 

schizoaffective 

disorder who had 

been without 

antipsychotic 

medication for at 

least one week in 

the past month 

without 

authorization, 

and lived with 

their family of 

origin with a 

relative willing 

to participate in 

family treatment. 

Community 

mental health

G1: Usual care plus 

Multifamily group – 

Adapted, a culturally 

modified version of 

multifamily group therapy, 

a behavioral family 

treatment combining 

psychoeducation and skills 

training.

G2: Multifamily group – 

Standard plus usual care

G3: Usual care

G1: Three 

individual 

family joining 

sessions, a 6-

hour 

multifamily 

workshop, 

and twentyone 90-

minute 

multifamily 

group 

sessions twice 

a month.

G2: Same as 

G1

G3: Monthly 

20-minute 

sessions or 

more if 

participant 

was unstable.

BPRS

NR

At the end of treatment (12 months after baseline), all 3 

groups improved significantly on the BPRS relative to 

baseline, but there was no group X time difference 

(F[2,171] = 1.14,P = .32). There was no significant 

change in BPRS scores between the end of treatment 

and the 24-month follow-up in any of the 3 treatment 

groups. 

Time to Hospitalization 

NR

4 Months:

Estimated from graph

G1: 75%

G2: 60%

G3: 60%

8 Months:

Estimated from graph 

G1: 72%

G2: 48%

G3: 45%

12 Months:

Estimated from graph 

G1: 62%

G2: 45%

G2: 35%

18 Months:

Estimated from graph 

G1: 63%

G2: 38%

G3: 29%

24 Months: 

Estimated from graph

G1: 61%

G2: 34%
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

58

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

G3: 30%

The overall test for group differences in time to first hospitalization (log-rank χ

2 = 13.3, P

= .001). Follow-up comparisons using proportional hazard regression indicated that G1 

participants had longer time to first hospitalization than G2 (χ

2 = 6.3, P = .01) and G3 (χ2

= 8.7, P = .003). Across the entire follow-up period, hospitalization was less likely for 

those in Multifamily group – Adapted (39%) than for those in Multifamily group – 

Standard (66%, χ

2 = 8.2, P = .004) or TAU (70.2%, χ2 = 11.3, P<.001), with no 

differences between G2 and G3.

Tests of regression show significant direct paths from treatment to hospitalization (B = 

-0.29, SE = 0.07, t = -3.88, P<.001), and with significant paths from G1 to adherence (B = 

0.91, SE = 0.26, t = 3.53, P<.001), and G1 as a mediator between adherence and 

hospitalization (Sobel test = 2.92, SE = 0.033, P = .004). 

PitschelWalz et al,

200651

G1: 102

G2: 92

Adults 18-65 

with a diagnosis 

of schizophrenia 

or 

schizoaffective 

disorder

Impatient wards 

in Germany

G1: Patients 

psychoeducation group 

focused on symptoms, 

etiology, acute treatment, 

relapse prevention, 

psychosocial treatment, 

and coping strategies. 

Relative psychoeducation 

group focused on the same 

as patients, and how they 

could best support patient. 

G2: Usual care

G1: Patient 

groups were

eight 60-

minute 

sessions, with 

1-4 weekly, 

then 5-8 

monthly. 

Relative

groups were 

eight biweekly 90-

minute 

sessions. 

GAS 

M 

G1: 49

G2: 51

Discharge:

M 

G1: 67

G2: 64

P = NS

12 Months:

M 

G1: 78

G2: 68

P<.001

24 Months:

M 

G1: 75

G2: 66

P<.01

BPRS 

M 

G1: 41

G2: 38

P = NS

Discharge:

M 

G1: 30

G2: 31

P = NS

12 Months:

M 

G1: 26

G2: 32

P<.001

24 Months:

M 

G1: 28

G2: 34

P<.01

Rehospitalization within the NA 12 Months:
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

first 2 years and days in the 

hospital

NA

# M(SD), Days M(SD)

G1: .3(.7), 12(46.6)

G2: .6(.8), 30(54.4)

P = NS

24 Months: 

# M(SD), Days M(SD)

G1: .6(1.1), 39(90.4)

G2: 1.1(1.4), 78(127.2)

#: P = .031 

Days: P = .034

Valencia et 

al, 201052

G1: 47

G2: 36

Adult outpatients 

with a diagnosis 

of schizophrenia 

who were 

adherent to their 

medication and 

clinically stable

Community 

mental health in 

Mexico

G1: Group/family (plus 

individual component) 

psychosocial skills 

psychoeducation including 

medication, decision 

making, relapse 

prevention, avoiding drug 

and alcohol, friendships, 

improving family relations 

+ usual care

G2: Usual care

G1: Patients –

90-minute 

group session 

weekly – 40 

total sessions 

in 12 months. 

Family + 

patient – 5 

sessions

G2: 20-

minute 

monthly 

appointments

GAF 

M(SD)

G1 (N = 47): 42.4(5.9)

G2 (N = 36): 42.7(6.1)

End of Treatment (12 Months): 

M(SD)

G1 (N = 47): 57.6(9.4)

G2 (N = 36): 44.3(9.0)

There was a significant main effect for time (P<.001) 

and group (P<.01), and group X time (P<.01)

PANSS

M(SD)

Total: 

G1 (N = 47): 87.0(44.5)

G2 (N = 36): 76.4(35.5)

Positive:

G1 (N = 47): 19.1(12.3)

G2 (N = 36):15.8(9.6)

Negative:

G1 (N = 47): 23.2(12.1)

G2 (N = 36): 20.6(9.8)

General Psychopathology: 

G1 (N = 47): 44.8(21.7)

G2 (N = 36): 40.1(17.5)

End of Treatment (12 Months): 

M(SD)

Total:

G1 (N = 47): 51.8(12.1)

G2 (N = 36): 57.3(17.7

Positive: 

G1 (N = 47): 8.6(2.4)

G2 (N = 36): 11.4(4.7)

Negative:

G1 (N = 47): 11.2(5.2)

G2 (N = 36): 14.9(6.6)

General Psychopathology:

G1 (N = 47): 22.0(5.6)

G2 (N = 36): 30.9(8.9)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

There was a significant main effect for time for all 

scales and total (all Ps<.001). There was a significant 

group X time interaction: 

Total: P<.001

Positive: P<.01

Negative: P<.001

General Psychopathology: P<.01

LEE 

M(SD)

G1 (N = 44): 62.32(12.31)

G2 (N = 34): 64.71(13.2)

End of Treatment (12 Months): 

M(SD)

G1 (N = 44): 58.59

G2 (N = 34): 62.0(10.95)

P<.05

Rehospitalization 

NA

End of Treatment (12 Months): 

G1: 2.1%

G2: 14%

P<.05

Relapse - defined as a 

significant exacerbation of 

psychotic symptoms with at 

least a 25% increase on the 

PANSS total score from 

baseline 

NA

End of Treatment (12 Months): 

G1: 12.8%

G2: 33.3%

P<.05

Motivational Interviewing(MI)

Barkhof et al,

201358

G1: 55

G2: 59

Adults with 

schizophrenia or 

schizoaffective 

disorder with a 

psychotic relapse 

or deterioration 

following nonG1: A manualized MI 

intervention based on 

negative symptoms, 

positive symptoms, 

cognitive deficits.

G2: Health education on 

Eight 

individual 20- 

to 45-minute 

sessions over 

26 weeks.

Hospitalized 

# M(SD)

G1 (N = 55): 24(44%)

G2 (N = 59): 25(44%)

26 Weeks:

# M(SD)

G1 (N = 45): 17(38)

G2 (N = 49): 19(39%)

6 Months:

# M(SD)

G1 (N = 45): 12(27%)

G2 (N = 48): 19(40)

There were no significant differences by intervention at any time point.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

61

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

adherence to 

antipsychotics, 

who have 

resumed 

antipsychotics 

with some 

clinical 

improvement.

3 sites - Inpatient 

and outpatients 

in Amsterdam

general health topics. In participants 35 and under, fewer in the MI group (3/21, 14% vs 11/22, 50%) were 

hospitalized over the 6-month period (P = .012) 

PANSS 

M(SD)

Total Score:

G1 (N = 30): 72(17.9)

G2 (N = 32): 72(17.5)

Positive Symptoms:

G1 (N = 30): 16.2(5.87)

G2 (N = 32): 17.2(6.69

Negative Symptoms:

G1 (N = 30): 18.7(5.8)

G2 (N = 32): 19.1(6.56)

General Symptoms:

G1 (N = 30): 37.7(9.74)

G2 (N = 32): 35.8(8.28)

26 Weeks:

M(SD)

Total Score:

G1 (N = 30): 65.6(22.0)

G2 (N = 32): 63.5(16.9)

Positive Symptoms: 

G1 (N = 30): 15.2(6.29)

G2 (N = 32): 15.0(6.05)

Negative Symptoms:

G1 (N = 30): 16.0(5.83)

G2 (N = 32): 16.4(6.53)

General Symptoms:

G1 (N = 30): 35.4(12.98)

G2 (N = 32): 32.2(7.07)

6 Months:

M(SD)

Total Score:

G1 (N = 30): 64.0(30.3)

G2 (N = 32): 66.2(16.7)

Positive Symptoms:

G1 (N = 30): 15.7(8.84)

G2 (N = 32): 15.9(6.32)

Negative Symptoms: 

G1 (N = 30): 16.2(7.31)

G2 (N = 32): 17.3(6.66)

General Symptoms:

G1 (N = 30): 32.1(14.33)

G2 (N = 32): 32.2(7.89)

For all subscales P = NS

There was no significant interaction between type of intervention and time (P = .68), with 

a large effect for time with both groups showing reductions in the severity of psychopathology (F(2, 110) = 5.59, P = .005, but no differences between interventions (P = .99). 

Female patients showed a larger decrease than males in reduction of general PANSS 

symptoms in G1 (Δ 7.9, SD = 4.0) compared with the HE group (Δ 3.4, SD = 2.4); t (11)

= −2.40, P = .035.

Shared Decision-making

Hamann et 

al, 200759

G1: 39

G2: 47

Adult inpatients 

18-65 with a 

diagnosis of 

schizophrenia or 

schizophreniform 

disorder

Hospital in 

G1: Decision aid booklet 

covering pros/cons of 

medication, 

psychoeducation, 

interventions + usual care

G2: Usual care

G1: Decision 

aid session 

with nurse 

and extra 

planning talk 

with 

psychiatrist

CGI 

NR

NR 18 Months:

M(SD)

G1 (N = 35): 4.0(1.5)

G2 (N = 40): 4.1(1.4)

P = NS

GAF NR 18 Months:

M(SD)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

62

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Germany NR

G1 (N = 30): 54.7(16.5)

G2 (N = 37): 51.0(18.5)

P = NS

Rehospitalization 

NA

6 Months:

#(%)

G1 (N = 36): 8(22)

G2 (N = 37): 8(22)

P = NS

18 Months:

#(%)

G1 (N = 38): 20(53)

G2 (N = 41): 19(46)

P = NS

In a backwards stepwise regression, having received the 

intervention showed a positive trend (OR = .19, P = .08) 

in the direction of fewer hospitalizations.

Cognitive Adaptation Therapy (CAT)

Velligan et 

al, 200860

G1: 37

G2: 32

G3: 29

Adult outpatients 

18-60 diagnosed 

with 

schizophrenia 

and prescribed an 

oral 

antipsychotic

Community 

mental health

G1: CAT consists of 

manualized individualized 

strategies and 

environmental supports 

designed to include 

medication adherence, 

grooming, and activities of 

daily living

G2: Pharm-CAT consisted 

of only the medication 

adherence components of 

CAT

G3: Usual care

G1: 

Individual 

face-to-face

weekly visits 

lasting 30-45 

minutes for 9 

months

G2: Same as 

G1, but 

sessions were 

generally 

shorter

BPRS–E 

NR

Results of a mixed-effects regression model with the 

base- line symptom scores used as covariates yielded no 

significant main effects or interactions (all Ps>.09).

Relapse – index based on BPRS 

psychosis items, suicidality, 

hospitalization, inability to care 

for self unsupervised 

NR

The time to relapse differed by group (χ 2

(2) = 11.09; 

P<.004).

G1 vs G3: χ

2 = 8.29; P<.004 

G2 vs G3: χ

2 = 8.20; P<.005, respectively). 

Over 65% of patients in G1 and G2 survived the 15 

months without a relapse vs only 19% of G3. There 

were no differences between G1 and G2.

SOFAS 

NR

G2 was higher functioning than G3 at 3 and 6 months 

(P's<.05) but not at any time point thereafter. 

G1 was significantly higher functioning than G3 at all 

assessment points during the treatment period (all 

P's<.0001), and significantly better than G1 in the first 3 

months of follow-up (P<.0001), but there was only a 

nonsignificant positive trend by the end of 6-month 

follow-up. 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

63

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

G1 was significantly better than G2 at all time points 

(P's <.0004) with the exception of the 6-month followup.

Effect sizes for G1 were large during the treatment 

phase and moderate 6 months after withdrawal of home 

visits. The effect size for G2 was small. 

Velligan et 

al, 201357

G1: 47

G2: 48

G3: 47

Adults 18-60 

diagnosed with 

schizophrenia or 

schizoaffective 

disorder treated 

with oral 

antipsychotic(s) 

who had missed 

at least one dose 

in the previous 

week.

Community 

mental health

G1: Pharm-CAT consists 

of manualized 

individualized strategies 

and environmental 

supports targeting 

medication adherence

G2: Med-eMonitor (MM) 

is a smart pill container 

capable of cueing and 

warning patients, 

recording side effect 

complaints, alerting staff 

of failure to take 

medication as prescribed.

G3: Usual care

G1: Home 

visits 30 

minutes long 

weekly for 9 

months.

G2: MM 

support and 

phone contact 

as needed.

Hospital and emergency 

services contact

NA

There were no differences between groups

(χ2 = 0.53, P = .77). 

BPRS–E There were no significant main effects or interactions 

(all P values >.09).

SOFAS There were no significant main effects or interactions 

(all P values >.09). 

Pharmacy Interventions

Kavanagh et 

al, 200353

G1: 15

G2: 15

Adults diagnosed 

with psychotic 

disorders who 

were inpatients 

in a psychiatric 

ward.

Hospital in

London

G1: Pharmacist-led 

psychoeducation group 

including Q & A about 

medication, rationale, risks 

of stopping, side effects, 

risk/benefit evaluations. 

One session focused on 

antipsychotics, the second 

session focused on mood 

stabilizers + usual care.

G2: Usual care

G1: Two onehour group 

sessions on 

consecutive 

weeks.

SAI-E 

M(SD)

G1 (N = 15): 3.60(4.88)

G2 (N = 15): 2.67(5.81)

P = NS

Post Session and 2 Weeks Follow-up:

There was no main effect.

BPRS 

M(SD)

G1 (N = 15): 36.47(2.77)

G2 (N = 15): 28.87(4.05)

F = 11.843, P = .004

Post Session and 2 Weeks Follow-up:

There was no main effect of time and no significant time 

X group interaction.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

64

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Technology Interventions (e-Monitoring, SMS, Phone)

Beebe et al,

201454

G1: 10

G2: 10

G3: 10

Adults 21-68 

with a diagnosis 

of schizophrenia 

or 

schizoaffective 

disorder 

receiving 

outpatient care.

Community 

mental health

G1: TIPS + Text. TIPS is a 

manualized intervention 

providing weekly 

telephone support 

addressing taking 

medication, attending 

appointments, coping with 

symptoms, abstaining from 

alcohol and other drugs, 

and getting along with 

others. 

G2: TIPS only

G3: Text only – text 

format of the TIPS 

protocol. Texts were 

delivered daily

G1: Weekly 

phone calls 

and daily 

texts for 3 

months

G2: Weekly 

phone calls 

for 3 months

G3: Daily text 

messages for

3 months

BPRS 

M(SD)

G1 (N = 10): 37.7(6.1)

G2 (N = 10): 50.1(11.7)

G3 (N = 10): 41.3(5.2)

1 Month:

M(SD)

G1 (N = 10): 38.2(11.9) 

G2 (N = 10): 38.5(9.1)

G3 (N = 10): 31.8(9.7)

2 Months:

M(SD)

G1 (N = 10): 36.8(10.9) 

G2 (N = 10): 47.6(9.5)

G3 (N = 8): 46.5(10.9)

3 Months:

M(SD)

G1 (N = 10): 35.8(12.8) 

G2 (N = 10): 41.7(12.4)

G3 (N = 8): 44.5(11.6)

Analyses yielded a statistically significant main effect for group (F (4,26) = 4.2, P = .005, 

with mean G1 scores lower than G3 (average mean difference of 9.2 points) at 2 of 3 postintervention measurement points. Mean G1 scores were lower than G2 scores (average 

mean difference of 5.7 points) at months 1, 2, 3. 

Frangou et al,

200555

G1: 36

G2: 36

G3: 36

Adult outpatients 

18-64 with a 

diagnosis of 

schizophrenia 

who had at least

2 admissions in 

preceding 12 

months, and 

prescribed oral 

medication.

Community 

mental health in 

London

G1: e-monitoring (MEMS) 

– provided with a 

medication dispenser that 

recorded access and 

transmitted data via the 

@HOME platform. Staff 

was alerted if participant 

took less than prescribed 

amount.

G2: Pill counting by 

pharmacists at study visits

G3: Self-report of 

adherence using Morisky 

scale.

G1: 

eMonitoring

G2: 

Pharmacist

G3: Selfreport

CGI –SGH 

M(SD)

G1 (N = 36): 3.1(1)

G2 (N = 36): 3.0(1.1)

G3 (N = 36): 3.1(1)

8 Weeks:

M(SD)

G1 (N = 36): 2.1(1.6)

G2 (N = 36): 2.5(1)

G3 (N = 36): 3.3(1.2)

P = .008, 

G1 significantly better than G2 (P = .04) and G3 (P = 

.01). G2 also significantly better than G3 (P = .05)

PANSS 

M(SD)

G1 (N = 36): 43(14.9)

G2 (N = 36): 43.4(15.5)

G3 (N = 36): 46.6(15.9)

8 Weeks:

M(SD)

G1 (N = 36): 28.1(2)

G2 (N = 36): 28.3(13.1)

G3 (N = 36): 42.7(21.4)

P = .004, 

G3 less improved compared to G1 (P = .04) and G2 (P
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

65

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

= .008). No difference between G1 and G2 

Resource utilization – total 

number of psychiatric and CPN 

contacts, and emergency visits 

M(SD)

Psychiatric:

G1 (N = 36): 2.1(.7)

G2 (N = 36): 2.2(.8)

G3 (N = 36): 2.2(1.2)

CPN:

G1 (N = 36): 8.5(2.6)

G2 (N-36): 8.5(2.1)

G3 (N = 36): 8.3(2.7)

Emergency department visits: 

G1 (N = 36): .6(.7)

G2 (N = 36): .5(.6)

G3 (N = 36): .5(.8)

8 Weeks:

M(SD)

Psychiatric:

G1 (N = 36): 1.7(.6)

G2 (N = 36): 2.1(.6)

G3 (N = 36): 2.2(.8)

CPN: 

G1 (N = 36): 7.4(1.2)

G2 (N = 36): 8.0(1.6)

G3 (N = 36): 8.1(2.0)

Emergency department visits : 

G1 (N = 36): .1(.3)

G2 (N = 36): .9(.9)

G3 (N = 36): .8(1.0)

MANOVA: P = .002

Significantly fewer psychiatric and emergency 

department visits for G1 (G2, P = .01; G3, P = .0001).

Montes et al,

201256

G1: 100

G2: 154

Adult outpatients 

18-65 with a 

diagnosis of 

schizophrenia 

who were 

clinically stable, 

prescribed a 

single

antipsychotic, 

and one 

affirmative 

answer on the 

MAQ

Community 

mental health in 

G1: Daily SMS reminders 

to take their medication, 

“Please remember to take 

your medication.” + usual 

care

G2: Usual care

G1: Daily 

SMS for 3 

months

CGI –SGH 

M(95% CI)

Severity:

Positive:

G1 (N = 100): 2.5(2.24 to 2.76)

G2 (N = 154): 2.8(2.61 to 2.99)

Negative:

G1 (N = 100): 3.3(3.06 6o 3.54)

G2 (N = 154): 3.4(3.22 to 3.58)

Depressive:

G1 (N = 100): 2.3(2.06 to 2.54)

G2 (N = 154): 2.3(2.11 to 2.49)

3 Months:

Mean changes M(95% CI)

Severity:

Positive:

G1: -.4(-.42 to -.38)

G2: -.3(-.32 to -.28)

P = .26

Negative:

G1: -.4(-.42 to -.38)

G2: -.3(-.32 to -.28)

P = .16

Depressive:

G1: -.2(.22 to -.18)

6 Months:

Mean changes M(95% CI)

Severity: 

Positive:

G1: 3(-.32 to -.28)

G2: 3(-.32 to -.28)

P = .89

Negative:

G1: -.6(-.62 to -.58)

G2: 3(-.32 to -.28)

P = .03

Depressive:

G1: -.2(.22 to -.18)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

66

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Spain Cognitive:

G1 (N = 100): 2.8(2.58 to 3.02)

G2 (N = 154): 3.0(2.84 to 3.16)

Global: 

G1 (N = 100): 3.0(2.78 to 3.22)

G2 (N = 154): 3.2(3.06 to 3.34)

Degree of Change: 

NR

G2: -.1(-.12 to -.08)

P = .09

Cognitive:

G1: -.4(-.42 to -.38)

G2: -.3(-.32 to -.28)

P = .13

Global:

G1: -.5(-.52 to -.48)

G2: -.3(-.32 to -.28)

P = .11

Degree of Change:

Positive:

G1: 3.2(3.0 to 3.4)

G2: 3.4(3.24 to 3.56)

P = .1 

Negative:

G1: 3.3(3.10 to 3.50)

G2: 3.5(3.36 to 3.64)

P = .02

Depressive:

G1: 3.3(3.10 to 3.50)

G2: 3.5(3.34 to 3.66)

P = .07

Cognitive:

G1: 3.3(3.12 to 3.48)

G2: 3.6(3.46 to 3.74)

P = .01

Global:

G1: 3.2(3.02 to 3.38)

G2: 3.5(3.36 to 3.64)

P = .012

G1: -.1(-.11 to -.08)

P = .35

Cognitive:

G1: -.4(-.42 to -.38)

G2: -.3(-.32 to -.28)

P = .48

Global:

G1: -.5(-.52 to -.48)

G2: -.4(-.42 to -.38)

P = .48

Degree of Change: 

Positive:

G1: 3.4(3.38 to 3.42)

G2: 3.3(3.14 to 3.46)

P = .63

Negative:

G1: 3.4(3.38 to 3.42)

G2: 3.4(3.24 to 3.56)

P = .82

Depressive:

G1: 3.4(3.38 to 3.42)

G2: 3.4(3.22 to 3.58)

P = .88

Cognitive:

G1: 3.5(3.48 to 3.52)

G2: 3.5(3.34 to 3.66)

P = .8 

Global:

G1: 3.3(3.10 to 3.50)

G2: 3.5(3.32 to 3.68)

P = .32

EQ-5D 3 Months: 6 Months:
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

67

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

M(95% CI)

G1 (N = 100): 65.9(62.5 to 

69.2)

G2 (N = 154): 64.3(61.7 to 

66.8)

Mean changes M(95% CI)

G1: 6.6(6.3 to 6.8)

G2: 3.1(2.91 to 3.29)

P = .03

Mean changes M(95% CI)

G1: 6.1(5.84 to 5.36)

G2: 5.6(5.42 to 5.78)

P = .75

Velligan et 

al, 201357

G1: 47 

G2: 48

G3: 47

Adults 18-60 

diagnosed with 

schizophrenia or 

schizoaffective 

disorder treated 

with oral 

antipsychotic(s) 

who had missed 

at least one dose 

in the previous 

week.

Community 

mental health

G1: Pharm-CAT consists 

of manualized 

individualized strategies 

and environmental 

supports targeting 

medication adherence

G2: Med-eMonitor (MM) 

is a smart pill container 

capable of cueing and 

warning patients, 

recording side effect 

complaints, alerting staff 

of failure to take 

medication as prescribed.

G3: Usual care

G1: Home 

visits 30 

minutes long 

weekly for 9 

months.

G2: MM 

support and 

phone contact 

as needed.

Hospital and emergency 

services contact

NA

There were no differences between groups

(χ2 = 0.53, P = .77). 

BPRS–E There were no significant main effects or interactions 

(all P values >.09).

SOFAS There were no significant main effects or interactions 

(all P values >.09). 

Note. Studies were conducted in the US unless otherwise specified. Studies comparing interventions may be represented in the table more than once. Brief 

descriptions of patient outcome assessments are reported in Appendix F.

Abbreviations: BPRS = Brief Psychiatric Rating Scale ; BPRS–E = Brief Psychiatric Rating Scale – Expanded; CAE = Customized adherence enhancement; CAT = 

Cognitive Adaptation Training; CBT = Cognitive behavioral therapy; CGI = Clinical Global Impression scale; CGI-SGH = Clinical Global Impression – 

Schizophrenia scale; EQ-5D = EuroQoL; GAF = Global Assessment of Functioning; GAS = Global Assessment Scale; LEE = Level of Expressed Emotion; M = 

Mean; MAQ = Medication Adherence Questionnaire; MET = Motivational Enhancement Therapy; MM = Med-eMonitor; PANSS = Positive and Negative Syndrome 

Scale; QLF = Quality of Life Scale; SAI = Schedule for Assessment of Insight; SAI-E = Schedule for Assessment of Insight- Expanded; SD = Standard deviation; 

SF-36 = Short Form Health Survey; SOFAS = Social and Occupational Functioning Scale; SWN = Subjective Well-being on Neuroleptic Treatment Scale; TIPS = 

Telephone Intervention Problem Solving for Schizophrenia.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

68

1e. What are the harms and costs related to these interventions?

Two studies evaluated costs related to interventions to improve medication adherence in patients 

along the psychotic spectrum.42,57 The first study compared the costs related to the frequency and 

duration of service contacts for Compliance Therapy as compared with routine management and 

supportive counseling.1 Results indicated no difference in costs between the 2 interventions, and 

a positive relationship between costs and adherence for both groups (ie, regardless of 

intervention, better adherence was related to more contact).42 The second study2 compared 

Pharm-CAT to e-monitoring and usual care, and found that the average costs of treatment per 

patients were higher (significance not reported) for participants in the Pharm-CAT group as 

compared to e-monitoring.57 Table 11 reports study detail.

No studies reported harms specific to an intervention. 

 1 Healey et al (1998)42 found significantly better adherence associated with CT.

2 Velligan et al (2008)60 found no difference in adherence when comparing pharm-CAT to e-monitoring, with both 

groups significantly more adherent than usual care.
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Table 11. Costs Associated with Medication Adherence Interventions

Study; 

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure 

(range, 

direction) Source Baseline First Follow-up

Additional 

Follow-ups

Healey et al,

199842

G1: 39

G2: 35

Adult inpatients 

with psychotic 

disorders 

Hospital in 

England

G1: Routine management 

plus Compliance Therapy, 

a combination of MI, 

cognitive, and 

psychoeducation 

approaches targeting 

psychotic symptoms, 

focusing on illness and 

treatment history, beliefs 

and understanding of the 

illness, and ambivalence 

towards treatment and 

stigma. 

G2: Routine management 

plus supportive 

counseling (no medication 

issues addressed)

Four to 6 

individual faceto-face sessions 

(M = 4.7) 

lasting 20-60 

minutes twice 

weekly

Client Service 

Receipt 

Inventory 

(CSRI), which 

measures the 

frequency and 

duration of 

service 

contacts. 

Self-report 

information, 

supplemented 

case note and 

agency data, 

including 

hospital 

admission 

records

3 months preentry: 

£ Mean/MDN 

(SD)

G1 (N = 37): 

113/27 (184) 

G2 (N = 35): 

188/42 (131)

6 Months: 

£ Mean/

MDN(SD)

G1 N = 36):

187/49 (292) 

G2 (N = 34): 

252/230(234)

P = .146

12 Months: 

£ Mean/

MDN(SD) 

G1 (N = 33): 

232/161 (281) 

G2 (N = 34) 

177/230(278)

P = .216

18 Months:

£ Mean/

MDN(SD)

G1 (N = 24): 

239/161(281) 

G2 (N = 21): 

326/146(404)

P = .468

When comparing 

Months 1-18:

£ Mean/

MDN(SD)

G1 (N = 23): 

175/146(148) 

G2 (N = 18) 

193/152(222)

P = .920
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study; 

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure 

(range, 

direction) Source Baseline First Follow-up

Additional 

Follow-ups

Statistically significant positive correlations were 

found for the entire sample between (a) costs and 

changes in compliance, and (b) costs and changes in 

insight between one and 6 months. When the

Compliance Therapy and control groups were analyzed 

separately, neither revealed an obvious efficiency 

advantage in terms of translating service inputs into 

subject outcomes.

A positive association was found for G1 between 

change in compliance and costs over 1-6 months (P = 

.004) and change in insight and costs over the same 

period (P = .022). The only other significant 

correlation was between residual costs and change in 

compliance in the control group over the 7-12 month 

period (P = .023). 

Velligan et al,

201357

G1: 47

G2: 48

G3: 47

Adults 18-60 

diagnosed with 

schizophrenia or 

schizoaffective 

disorder treated 

with oral 

antipsychotic(s) 

who had missed at 

least one dose in 

the previous 

week.

Community 

mental health

G1: Pharm-CAT consists 

of manualized 

individualized strategies 

and environmental 

supports targeting 

medication adherence

G2: Med-eMonitor (MM) 

is a smart pill container 

capable of cueing and 

warning patients, 

recording side effect 

complaints, alerting staff 

of failure to take 

medication as prescribed.

G3: Usual care

G1: Home visits 

30 minutes long 

weekly for 9 

months.

G2: MM 

support and 

phone contact 

as needed.

Average cost of 

treatment per 

patient per 

month included 

mileage for 

home visits, 

monitor, web 

support, PharmCAT staff and 

supplies.

Multiple NA Average cost of treatment per patient 

per month

G1: $180

G2: $130

Note. Studies were conducted in the US unless otherwise specified. Brief descriptions of patient outcome assessments are reported in Appendix F.

Abbreviations: CAT = Cognitive Adaptation Training; MDN = Median; MI = Motivational interviewing; MM = Med-eMonitor.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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KEY QUESTION 2. ADULTS WITH BIPOLAR DISORDER

We identified 4 studies (all moderate ROB) meeting inclusion criteria for patients with Type I or 

Type II bipolar disorder.41,67-69 All 4 studies examined interventions that included 

psychoeducation. One study examined the addition of individual psychoeducation to 

psychotherapy,68 another examined group psychoeducation alone,69 and the third examined the 

Life Goals Program,

67 which includes psychoeducation and individualized problem solving skills

with a focus on self-management. The fourth study evaluated CAE, a customized behavioral 

multicomponent intervention in which participants were assigned to one to 4 modules 

(psychoeducation, substance use/modified MET, provider communication, medication 

management) based on an assessment at baseline.41

Two of the 4 studies were conducted in Iran (one in an outpatient hospital clinic and the other in 

private and university clinics), with the other 2 conducted in community mental health clinics in 

the US. Studies assessed adherence using the MARS, the DAI, pill counts, and other measures. 

Common patient outcomes reported were severity of depression, mania, and functional 

impairment, as assessed by the Hamilton Depression Rating Scale (HAM-D), the Young Mania 

Rating Scale (YMRS), and the GAF. Appendices E and F provide brief descriptions of adherence 

and patient outcome assessment tools. 

2a. What are the effects of medication adherence interventions on 

psychopharmacological adherence?

Four studies examined interventions designed for psychopharmacological adherence. Two 

studies conducted in Iran examined psychoeducation alone, with one study focusing on 

individual sessions,68 and the other focusing on a group intervention.69 The first study 

randomized participants to standard psychotherapy plus individual psychoeducation (intervention 

group) or standard psychotherapy alone (control group), both of which included 8 weekly 

sessions followed by monthly question and answer sessions by phone for a total of 18 months.68

The study evaluated the effect of the interventions on adherence using the MARS, and results 

indicated significantly better adherence in the intervention group at 6, 12, and 18 months (P = 

.008). Table 12 provides more detail. 

In the second study participants were allocated to one of 3 groups – group psychoeducation, 

supportive group psychotherapy (placebo), or medication only (control).69 The intervention 

group received weekly 90-minute sessions over a period of 9 weeks, with medication adherence 

assessed using the MARS at 3 and 6 months. Data from this study indicated better adherence in 

the intervention group as compared to both placebo and control (F(2, 31) = 55.09, P = .0001). 

Table 12 provides more detail. 

The third study was an RCT evaluating the effect of the Life Goals Program,

70 a manualized 

structured group psychotherapy program focused on psychoeducation and individual application 

of problem solving skills.67 Participants were randomized to either the Life Goals Program plus

usual care (medication management, counseling, access to social services and case management), 

or usual care alone. The Life Goals Program consists of 2 phases. Phase I included 6 weekly 

group (6-8 members) sessions and targets issues related to medication adherence, with Phase II

comprised of ongoing monthly group sessions focused on functional goal attainment. 

Participants were enrolled in Phase I, and encouraged to attend Phase II. Medication adherence 

was assessed at baseline and at 3, 6, and 12 months using the DAI, which assesses attitudes 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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towards psychotropic medication, and has been shown to correlate significantly with validated 

measures of medication adherence.1 Participants were also asked to provide an estimate of their 

adherence to all psychopharmacological medications combined. Data from this study indicated

no significant difference between groups. However, there was a large amount of missing data 

(only 75% of the intervention group and 81% of the control group participated in baseline plus 

one other assessment) and only 49% of the intervention group participated in most or all of the 

group sessions, with 37% never participating. The authors conducted a secondary analysis 

comparing those who had participated in 4 to 6 sessions, those participating in 1 to 2 sessions, 

and those never attending a group session. Results of the secondary analysis indicated a 

difference in the effect of the intervention between those participating in 4 to 6 sessions (effect 

size = .59), and those participating in 1-2 (effect size = .16), and no sessions (effect size = .07). 

Table 12 provides more detail. 

The fourth study was a cohort study evaluating the effect of CAE delivered over 4 weekly, 

individual, 60-minute sessions and up to 2 follow-up telephone sessions over a 6-week period.41

The DAI, the Morisky Scale, the Tablet Routine Questionnaire (TRQ) for both the previous 

week and the previous month, and pill counts were used to assess medication adherence 

outcomes at 6 weeks, 3 months, and 6 months. Findings indicated better DAI scores at both 6

weeks (P = .005) and at 6 months (P = .001), and better treatment adherence according to the 

Morisky Scale at 6 months (P = .001). Table 12 provides more detail. 

2b. What are the effects of medication adherence interventions on long-acting 

injectable (depot) psychopharmacological adherence?

We identified no studies examining medication adherence interventions for long-acting 

injectable (depot) psychopharmacological adherence. 

2c. What are the effects of medication adherence interventions on nonpsychopharmacological adherence?

We identified no studies examining medication adherence interventions for nonpsychopharmacological adherence. 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Table 12. Bipolar Disorder: Medication Adherence Outcomes 

Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

Psychoeducation (Individual)

Javadpour et 

al, 201368

G1: 54

G2: 54

Adults 18-60 

with a history of 

at least 2 episodes 

of relapse in the 

past 2 or 3 

episodes in the 

last 5 years.

Outpatient 

psychology clinic 

in a hospital in 

Iran

G1: Standard 

psychotherapy plus 

individual 

psychoeducation about 

bipolar disorder and 

medication, and a question 

and answer session by 

telephone.

G2: Standard 

psychotherapy

Eight 50-

minute faceto-face

weekly 

sessions, 

followed by 

monthly 10-

minute 

phone calls 

for 18 

months.

MARS

NR

6 months: 

M 

G1: 7.93 

G2: 4.70

12 months:

M 

G1: 7.80

G2: 4.00

18 months:

M 

G1: 7.91

G2: 3.73

Group Difference: P = .008

Psychoeducation (Group)

Bahredar, et 

al, 201469

G1: 15

G2: 15

G3: 15

Adults 18 to 50 

with type I 

bipolar disorder 

experiencing 

euthymic mood. 

Private and 

university clinics 

in Iran

G1: Pharmacotherapy plus 

group psychoeducation

about BD and medication. 

G2: Pharmacotherapy plus 

supportive psychotherapy 

(placebo)

G3: Pharmacotherapy only

Nine 90-

minute 

weekly 

group 

sessions. 

MARS

M(SD) 

G1 (N = 15): 6.27 

(0.88) 

G2 (N = 15): 6.47 

(0.52)

G3 (N = 15): 6.53 

(0.64)

3 months:

M(SD) 

G1 (N = 15): 8.33 (0.65) 

G2 (N = 15): 4.91 (0.54) 

G3 (N = 15): 5.08 (0.79)

6 months:

M(SD) 

G1 (N = 15): 7.92 (1.38) 

G2 (N = 15): 4.36 (0.67)

G3 (N = 15): 4.33 (0.49)

Group Difference: F(2,31) = 55.09, P = .0001

Other Multicomponent Behavioral Interventions

Sajatovic et al,

200967

G1: 84

G2: 80

Adults with Type 

I or Type II 

bipolar disorder 

with >2 years 

since first BD 

episode. 

Communitybased mental 

health

G1: Treatment as usual 

plus Life Goals Program 

(LGP), a manualized group 

psychotherapy program 

that includes education and 

individualized problem 

solving to promote illness 

self-management.

G2: Treatment as usual 

(medication management 

Six weekly 

group 

sessions

DAI

M(SD) 

G1 (N = 73): 7.18 

(2.42)

G2 (N = 69): 7.52 

(2.07)

3 months:

M(SD) 

G1 (N = 53): 8.06 (1.81)

G2 (N = 56): 7.50 (2.22)

6 months:

M(SD) 

G1 (N = 45): 8.20 (1.75)

G2 (N = 45): 7.51 (2.27)

12 months:

M(SD) 

G1 (N = 34): 8.27 (1.90)

G2 (N = 30): 7.93 (1.86)

Group Difference: P = NS
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

by a psychiatrist, 

psychosocial therapy and 

counseling by mental 

health clinicians and 

access to social services or 

case management)

Secondary analysis examining DAI by group session 

attendance found ES = .59 for those attending 4-6 

sessions, ES = .16 for those attending 1-2 sessions, and 

ES = .07 for those never attending session.

Self-reported treatment 

adherence behaviors

M(SD) 

G1 (N = 84): 79.46 

(32.04)

G2 (N = 80): 82.19 

(30.34)

3 months:

M(SD) 

G1 (N = 62): 83.87 

(28.66)

G2 (N = 61): 81.15 

(32.49)

6 months:

M(SD) 

G1 (N = 51): 90.20 (22.40)

G2 (N = 55): 77.27 (35.12)

12 months:

M(SD) 

G1 (N = 41): 95.73 (11.04)

G2 (N = 39): 81.08 (30.85)

Group Difference: P = NS

A mixed model repeated measures analysis found a trend (P = .56) that more time 

in any treatment predicted more positive attitudes towards medication

Sajatovic et al,

201241

G1: 43

Adults with Type 

I or Type II 

bipolar disorder 

and poor 

adherence, with 

>2 years since 

first BD episode. 

Communitybased mental 

health

G1: Customized adherence 

enhancement (CAE) is a 

manualized individual 

behavioral intervention 

consisting of 4 modules 

(psychoeducation, 

substance use/modified 

MET, provider 

communication, 

medication management). 

CAE is customized based 

on an assessment at 

baseline, with one to 4 

modules assigned.

Four weekly, 

in-person, 

60-minute 

sessions and 

up to 2 

follow-up 

telephone 

sessions over 

a 6 week 

period.

DAI

M(SE), MDN

G1: 6.5 (0.3), 7.0 

Six Weeks:

M(SE), MDN

G1: 7.5 (0.3), 8.0

3 Months:

M(SE), MDN

G1: 7.8 (0.4), 8.0

WSRT Z = 2.815, 

P = .005

6 Months:

M(SD), MDN

G1: 8.1 (0.4), 9.0 

t(30) = 4.252, P<.001

Morisky Scale

M(SE), MDN

G1: 3.0 (0.2), 3.0

6 Months:

M(SE), MDN

G1: 1.3 (0.3),1.0

WSRT Z = -3.923, P<.001

TRQ

M% (SE), MDN

Previous Week: 

6 Weeks:

M% (SE), MDN

Previous Week:

3 Months:

M% (SE), MDN

Previous Week: 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure;

Baseline First Follow-up Additional Follow-ups

G1: 48.0 (4.8), 43.0

Previous Month:

G1: 51.4 (4.1), 43.0

G1: 23.5 (5.1), 14.0

Previous Month:

G1: 20.7 (4.2), 14.0

G1 (N = 33): 24.0 (6.4), 0 

WSRT Z = -3.054, P = 

.002

Previous Month: 

G1 (N = 33): 21.4 (5.6), 0 

WSRT Z = -3.753, P<.001

6 Months:

M% (SE), MDN

Previous Week:

G1 (N = 28): 25.2 (6.8), 

3.5 

WSRT Z = -2.561, P = .01 

Previous Month:

G1 (N = 28): 21.3 (5.5), 

7.0 

WSRT Z = -3.679, P<.001

Longitudinal mixed models for both the previous month and the previous week as 

dependent variables were fit. The fixed effect of time was statistically significant 

for TRQ adherence for both the previous month (P<.001) and previous week (P = 

.002), indicating improved adherence over time.

Pill Counts

M% (SE), MDN

57.6 (7.6), 47.0

Six Weeks:

M% (SE), MDN

58.8 (20.7), 72.0

3 Months:

M% (SE), MDN

38.0 (19.2), 29.0

6 Months:

M% (SE), MDN

35.3 (9.9), 27.5

Only one-third of participants provided pill bottles, with only 2 participants at 

baseline and 3-months, and one participant at baseline and 6-months.

Note. Studies were conducted in the US unless otherwise specified. Brief descriptions of medication adherence assessments are reported in Appendix E. 1 Only 75% of the intervention group and 81% of the control group participated in baseline plus one other assessment, and only 49% of the intervention group 

participated in most or all of the group sessions, with 37% never participating.

Abbreviations: CAE = Customized adherence enhancement; DAI = Drug Attitude Inventory; ES = Effect size; MARS = Medication Adherence Rating Scale; M = 

Mean; MDN = Median; SD = Standard deviation; SE = Standard error; TRQ = Tablet Routine Questionnaire; WSRT = Wilcoxon signed-rank test.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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2d. What are the effects of these interventions on patient outcomes?

The 4 studies meeting inclusion criteria for medication adherence outcomes in patients with 

bipolar disorder also reported data related to patient outcomes, including quality of life, 

depression, mania, functional impairment, global functioning/severity, positive and negative 

affective symptoms, and hospital readmissions. Appendix F provides a summary of the included 

patient outcome scales.

Quality of Life

One study, which evaluated the addition of 8 weekly individual psychoeducation sessions and 

short telephone contact for 18 months compared to standard psychotherapy, assessed quality of 

life using the World Health Organization Quality of Life instrument (WHOQOL-BREF) at 

baseline, 6, 12, and 18 months.68 The WHOQOL-BREF includes the domains of physical health, 

mental health, social health, and the environment, and results indicated that mean scores (all time 

points combined) for the intervention group were significantly higher than the comparison group 

along all of the domains, indicating better quality of life (P = .000). Table 13 provides more 

detail.

Depression

Three studies assessed depression using the HAM-D.41,67,68 Data from the first study, which 

assessed the addition of individual psychoeducation sessions in participants who had experienced 

at least 2 episodes of relapse in the past 2 years or had a history of 3 episodes in the past 5 years 

(intervention group baseline mean [M] = 4.24), found significantly lower scores in the 

intervention group at 6, 12, and 18 months (P = .000).68 The second study, which evaluated the 

CAE in bipolar participants with poor adherence, found that while there was no significant 

difference from baseline to 3 months (M[SE] = 16.2[1.2], P = .246), as compared to baseline, 

HAM-D scores were significantly lower at 6 months (M[SE] = 15.3[1.6], P = .044).41

The third study compared the Life Goals Program, a group psychotherapy program including 

psychoeducation and individualized problem-solving, to treatment as usual (intervention group 

baseline M[SD] = 19.98[11.45]), and found no significant differences at 3, 6, and 12 months.67

However, a mixed model repeated measures analysis found a trend (P = .056) indicating that 

higher baseline HAM-D scores predicted more negative attitudes towards medications over time 

regardless of intervention. In this study, only 49% of the intervention group participated in most 

or all of the group sessions, and 37% never attended a group session. See Table 13 for more 

detail. 

Mania

Three included studies assessed mania.41,67,68 Using the Bech Rafaelsen Mania Scale, one study68

assessed the addition of individual psychoeducation versus standard psychotherapy versus 

standard psychotherapy alone and found significantly lower mean mania scores at 6, 12, and 18 

months (P = .000). Similar to findings for depression, another study41 found that while CAE 

resulted in no significant differences from baseline to 3 months (P = .101) on the YMRS, mania 

scores were significantly lower at 6 months (M[SE] = 9.6[1.0]) as compared with baseline 

(M[SE] = 14.2[1.2], P = .002). Also similar to findings for depression outcomes, a study67

comparing the Life Goals Program group to participants receiving usual care found no difference 

in YMRS scores. Table 13 provides more detail. 
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Functional Impairment

Three included studies examined outcomes related to functional impairment, 2 of which used the 

GAF,41,69 with one utilizing the predecessor to the GAF, the GAS.

67 One study compared group 

psychoeducation to a placebo group receiving supportive psychotherapy, and to a control group 

composed of participants experiencing euthymic mood.69 GAF scores for all 3 groups were 

similar at baseline. Findings indicated that while there was no difference between the placebo 

and control groups, GAF scores for the intervention group were significantly higher than both 

placebo and control at 3 and 6 months (P = .0001), indicating higher levels of functioning.

Similar to other patient outcomes associated with CAE, there was no significant difference in 

functional impairment between baseline (M[SE] = 51.6[1.2]) and 3 months (M[SE] = 55.7[1.3], 

P = .072), but a significant improvement was observed from baseline to 6 months follow-up

(M[SE] = 58.0[1.7], P = .001).41 Similarly, there was no difference between the Life Goals 

Program group and usual care at 3, 6, and 12 months.67 See Table 13 for more detail. 

Global Functioning/Severity – Bipolar Disorder

One study examined the severity of depressive and manic episodes and the degree of change 

from the immediately preceding phase and from the worst phase of illness using the Clinical 

Global Impression scale for use in bipolar illness (CGI-BP), and found that CAE resulted no 

improvement between baseline (M[SE] = 4.4[.16]) and 3 months (M[SE] = 3.9[.21], P = .072), 

with significant improvement from baseline to 6-months follow-up (M[SE] = 3.6[.24], P = 

.001).41 See Table 13 for more detail. 

Positive and Negative Affective Symptoms

One study assessed positive and negative affective symptoms using the BPRS.

41 Unlike other 

patient outcomes associated with CAE, there was significant improvement from baseline (M[SE]

= 43.6[1.8]) to both 3-months (M[SE] = 37.3[2.1], P = .003) and 6-months follow-up (M[SE] = 

36.1[2.3], P = .001). Table 13 provides more detail. 

Hospital Readmissions

One study examined hospital records to evaluate whether individual psychoeducation in addition 

to standard psychotherapy was associated with fewer hospital readmissions. Data indicated that 

over the 18-month study period, fewer participants in the intervention group were readmitted to 

the hospital as compared with participants receiving standard psychotherapy alone (.22% versus

1.41%, P = .000). See Table 13 for more detail. 

2e. What are the harms and costs related to these interventions?

We identified no studies addressing the harms or costs of interventions for medication adherence 

in patients with bipolar disorder. 

KEY QUESTION 3. ADULTS WITH PTSD

We identified no studies examining medication adherence interventions for patients with PTSD. 
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Table 13. Bipolar Disorder: Patient Outcomes 

Study;

N per 

Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure; 

Baseline First Follow-up Additional Follow-ups

Psychoeducation (Individual)

Javadpour 

et al, 201368

G1: 54

G2: 54

Adults 18-60 

with a history 

of at least 2 

episodes of 

relapse in the 

past 2 or 3 

episodes in 

the last 5 

years.

Outpatient 

psychology 

clinic in a 

hospital in 

Iran

G1: Standard 

psychotherapy plus 

individual 

psychoeducation about 

bipolar disorder and 

medication, and a 

question and answer 

session by telephone.

G2: Standard 

psychotherapy

Eight 50-

minute faceto-face weekly 

sessions, 

followed by 

monthly 10-

minute phone 

calls for 18 

months.

WHOQOL-BREF 

NR

Mean of Baseline + 6, 12, 18 months

Physical Health: 

G1: 63.81

G2: 53.25

Mental Health: 

G1: 66.65

G2: 54.29

Social Health:

G1: 74.07

G2: 51.68

Environment:

G1: 65.05

G2: 48.93

Group Difference: P = .000 (all domains)

Recurrence of depression 

(HAM-D >7)

M

G1: 4.24

G2: 5.22

6 months: 

M 

G1: 6.27

G2: 10.19

12 months: 

M

G1: 6.04

G2: 11.19

18 months: 

M 

G1: 5.78

G2: 11.19

Group Difference: P = .000

Recurrence of mania 

(Bech Rafaelsen Mania 

Scale >9)

M 

6 months:

M 

G1: 4.64

G2: 8.83

12 months: 

M

G1: 4.88

G2: 9.95
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Study;

N per 

Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure; 

Baseline First Follow-up Additional Follow-ups

G1: 4.18

G2: 4.34

18 months: M

G1: 4.08

G2: 7.29

Group Difference: P = .000

Hospital readmission 

0 

M over 18 months

G1: 0.22

G2: 1.41

P = .000

Psychoeducation (Group)

Bahredar, 

et al, 201469

G1: 15

G2: 15

G3: 15

Adults 18 to 

50 with type I 

bipolar 

disorder 

experiencing 

euthymic 

mood

Private and 

University 

Clinics in Iran

G1: Pharmacotherapy 

plus group 

psychoeducation about 

BD and medication. 

G2: Pharmacotherapy 

plus supportive 

psychotherapy (placebo)

G3: Pharmacotherapy 

only

Nine 90-

minute weekly 

sessions. 

GAF

M(SD) 

G1 (N = 15): 56.6 (3.58)

G2 (N = 15): 56.67 (4.5) 

G3 (N = 15): 56.27 (3.17)

3 months:

M(SD) 

G1 (N = 15): 64.83 (1.9) 

G2 (N = 15): 56.27 (3.6) 

G3 (N = 15): 55.25 

(3.91)

6 months:

M(SD) 

G1 (N = 15): 64.17 (2.12) 

G2 (N = 15): 56.0 (4.36) 

G3 (N = 15): 54.17 (5.08) 

Group Difference: F(2,31) = 90.93, P = .0001

Other Multicomponent

Sajatovic et 

al, 200967

G1: 84

G2: 80

Adults with 

Type I or 

Type II 

bipolar 

disorder.

Communitybased mental 

health

G1: Treatment as usual 

plus Life Goals Program 

(LGP), a manualized 

group psychotherapy 

program that includes 

education and 

individualized problemsolving to promote 

illness and selfmanagement.

G2: Treatment as usual 

(medication management 

Six weekly 

group sessions

HAM-D

M(SD)

G1 (N = 83): 19.98 

(11.45)

G2 (N = 80): 17.08 

(10.99)

3 months:

M(SD)

G1 (N = 63): 16.30 

(9.68)

G2 (N = 65): 15.85 

(10.52)

6 months: 

M(SD)

G1 (N = 51): 16.35 (10.18

G2 (N = 55): 15.96 

(12.47)

12 month: 

M(SD)

G1 (N = 41): 16.02 (11. 

73)

G2 (N = 39): 14.39 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per 

Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure; 

Baseline First Follow-up Additional Follow-ups

by a psychiatrist, 

psychosocial therapy and 

counseling by mental 

health clinicians and 

access to social services 

or case management)

(10.87) 

Group Difference: P = NS

A mixed model repeated measures analysis found a 

trend (P = .056) that higher baseline HAM-D scores 

predicted more negative attitudes towards 

medications over time regardless of intervention.

YMRS 

M(SD)

G1 (N = 84): 7.30 (5.41)

G2 (N = 80): 7.58 (5.44)

3 months:

M(SD)

G1 (N = 63): 6.14 (4.85)

G2 (N = 65): 8.02 (5.38)

6 months: 

M(SD)

G1 (N = 51): 6.78 (5.36)

G2 (N = 55): 7.69 (6.26)

12 months:

M(SD)

G1 (N = 41): 5. 85 (4.74)

G2 (N = 39): 7.15 (5.60

Group Difference: P = NS

GAS 

M(SD)

G1 (N = 83): 56.53 

(12.43)

G2 (N = 78): 58.22 (N = 

12.00)

3 months:

M(SD)

G1 (N = 61): 60.10 

(11.63)

G2 (N = 61): 59.05 

(12.44)

6 months:

M(SD)

G1 (N = 46): 61.72 

(12.76)

G2 (N = 53): 62.19 

(14.42)

12 months:

G1 (N = 40): 63.70 

(12.66)

G2 (N = 39): 64.51 

(15.90)

Group Difference: P = NS

Sajatovic et 

al, 201241

G1: 43

Adults with 

Type I or 

Type II 

bipolar 

disorder and 

poor 

G1: Customized 

adherence enhancement 

(CAE) is a manualized 

individual behavioral 

intervention consisting of

4 modules 

Four weekly, 

in-person, 60-

minute 

sessions and 

up to 2 followup telephone 

BPRS 

M(SE), MDN

G1: 43.6 (1.8), 42.5

3 Months:

M(SE), MDN

G1: 37.3 (2.1), 36.0

WSRT Z = -2.931, P = 

.003

6 Months:

M(SE), MDN

G1: 36.1 (2.3), 36.0 

WSRT Z = -3.267, P = 

.001
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Study;

N per 

Group

Sample and 

Setting Intervention Groups

Intervention 

Intensity

Measure; 

Baseline First Follow-up Additional Follow-ups

adherence, 

with >2 years 

since first BD 

episode. 

Communitybased mental 

health

(psychoeducation, 

substance use/modified 

MET, provider 

communication, 

medication 

management). CAE is 

customized based on an 

assessment at baseline, 

with one to 4 modules 

assigned.

sessions over a 

6-week period.

CGI-BP 

M(SE), MDN

G1: 4.4 (0.16), 4.0

3 Months:

M(SE), MDN

G1: 3.9 (0.21), 4.0 

t(31) = -1.717, P = .096

6 Months:

M(SE), MDN

G1: 3.6 (0.24), 3.0 

t(29) = -3.657, P = .001

GAF 

M(SE), MDN

G1: 51.6 (1.2), 51.0 

3 Months:

M(SE), MDN

G1: 55.7 (1.3), 51.0 

WSRT Z = 1.797, P = 

.072

6 Months:

M(SE), MDN

G1: 58.0 (1.7), 60.0

t(29) = 3.671, P = .001

HAM-D 

M(SE), MDN

G1: 17.8 (1.1), 18.5 

3 Months:

M(SE), MDN

G1: 16.2 (1.2), 16.0 

t(31) = -1.182, P = .246

6 Months:

M(SE), MDN

G1: 15.3 (1.6), 15.0 

WSRT Z = -2.010, P = 

.044

YMRS 

M(SE), MDN

G1: 14.2 (1.2), 14.0

3 Months:

M(SE), MDN

G1: 11.2 (1.4), 9.0 

WSRT Z = -1.638, P = 

.101

6 Months:

M(SE), MDN

G1: 9.6 (1.0), 9.0

t(29) = -3.404, P = .002

Note. Studies were conducted in the US unless otherwise specified. Brief descriptions of patient outcome assessments are reported in Appendix F. 1 Only 75% of the intervention group and 81% of the control group participated in baseline plus one other assessment, and only 49% of the intervention group 

participated in most or all of the group sessions, with 37% never participating.

Abbreviations: BPRS = Brief Psychiatric Rating Scale; CAE = Customized adherence enhancement; CGI-BP = Clinical Global Impression – Bipolar scale; GAF

= Global Assessment of Functioning; GAS = Global Assessment Scale; HAM-D = Hamilton Depression Rating Scale; MET = Motivational Enhancement 

Therapy; WSRT = Wilcoxon signed-rank test.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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SUMMARY AND DISCUSSION

We reviewed 7,944 titles and abstracts from the search of electronic databases, bibliographies, 

and other sources, and 152 were identified as potentially relevant. Upon full-text review, we 

excluded 127 studies for a total of 24 included studies from 25 publications. Of the 518 clinical 

trials identified by our search of trial registry websites, one study met inclusion criteria;40

however, this study and all data reported on ClinicalTrials.gov are represented in an included 

publication.41 We identified 21 articles (20 primary studies) for Key Question 1, 4 primary 

studies for Key Question 2, and no primary studies for Key Question 3. 

SUMMARY OF EVIDENCE BY KEY QUESTION

Key Question 1. In adults with psychotic spectrum disorders:

Overall there is insufficient evidence from which to draw conclusions about the effectiveness of 

interventions to improve medication adherence in patients with psychotic spectrum disorders. 

Interventions vary widely, with included studies evaluating multicomponent behavioral 

interventions, interventions involving family members, interventions involving technology, 

pharmacist-led interventions, system-level interventions, and others. Overall, findings are mixed. 

However, there is low strength of evidence that interventions involving family members, and 

those involving technology, such as e-monitoring or daily reminder messages may result in 

improved psychopharmacological adherence; this indicates that additional evidence is needed 

before concluding either that the findings are stable or that the estimate of effect is close to the 

true effect. Table 14 provides additional detail. 

There is limited evidence of the effectiveness of depot antipsychotics in combination with a 

medication adherence intervention, with studies reporting better adherence associated with a 

psychosocial intervention in patients prescribed a depot antipsychotic as compared with controls, 

and improved adherence in a homeless population associated with the prescription of depot and a 

customized multicomponent behavioral intervention. However, despite evidence suggesting a 

positive effect, the wide differences in the interventions, small sample sizes, the potential for 

sampling bias in populations prescribed depot antipsychotics, and lack of methodological rigor 

preclude drawing firm conclusions.

Only one study measured non-psychopharmacological adherence, and found no benefit 

associated with telephone and/or SMS support. 

There is no clear evidence of the effect of medication adherence interventions on patient 

outcomes. Findings reported for positive, negative, and overall symptom severity are mixed, and 

there is little support that these interventions improve quality of life. Findings related to 

functional impairment are also mixed; however, there is limited evidence that interventions 

involving family members and those including the use of a depot antipsychotic may result in 

improved functioning. Similarly, while it is unclear whether medication adherence interventions 

in general are effective in reducing hospitalizations, the time to first hospital readmission, or time 

spent in the hospital, 2 studies reported a positive effect of interventions on time to relapse, and 

limited evidence suggests that in general, interventions involving family members may result in 

better patient outcomes. 
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Table 14. Psychotic Spectrum Disorders: Summary of Medication Adherence Outcomes 

Type of 

Intervention

Study Design 

(Combined N) Findings

Strength of 

Evidence Comments

Behavioral 

Multicomponent - 

Adherence 

Therapy

2 RCTs (N = 370) Mixed findings: one study (low ROB) reported better adherence compared to 

usual care on the MAQ and SAI-C at 12 months, and the other (low ROB) 

reporting no difference from usual care on the CDR, DAI-30, and MARS at 12 

weeks post-discharge.

Insufficient Evidence from only 2 

studies, with mixed 

findings.

Behavioral 

Multicomponent - 

Compliance 

Therapy

2 RCTs (N = 130)

1 NRCT (N = 70)

1 Prospective Cohort 

(N = 30)

Mixed findings: better MARS scores with Compliance Therapy at 1 month but 

not 6 months in 1 study (high ROB); better DAI and compliance scores as 

compared with routine management plus supportive counseling through 18 

month follow in 1 study (high ROB); no benefit to Compliance Therapy up to 6 

months in 2 studies (compared to nonspecific counseling and Compliance 

Therapy; moderate ROB).

Insufficient Inconsistent findings 

among 4 studies. Risk 

of bias due to study 

design.

Other Behavioral 

Multicomponent

1 RCT (N = 88) No difference between group cognitive behavioral therapy (CBT) plus 

Motivational Interviewing (MI) and group psychoeducation plus MI (moderate 

ROB).

Insufficient Evidence from only 

one study.

Depot plus 

Behavioral 

Multicomponent

1 Trial (randomization 

unclear) (N = 57)

1 Prospective Cohort 

(N = 30)

Findings indicated improved adherence related to the use of depot antipsychotics 

plus a behavioral multicomponent intervention (compared to usual care or no 

comparator) as measured by injection visits up to one year, and injection visits, 

TRQ, Morisky scale, DAI, and AMQ up to 25 weeks (moderate ROB).

Insufficient Heterogeneity among 

interventions; risk of 

bias due to study 

design.

Family 

Intervention 

3 RCTs (N = 449) Better adherence with family interventions as measured by clinician rating/blood 

plasma and pharmacy records/family-report as compared to usual care in 2 

studies (moderate ROB). No difference when controlling for time in a third study 

examining a culturally modified family intervention as compared to the standard 

family intervention and monthly sessions (moderate ROB). 

Low Heterogeneity among 

interventions.

System-level 

Intervention

1 NRCT (N = 70) Nonsignificant trend towards better adherence for the system-level intervention, 

compared with Compliance Therapy (moderate ROB).

Insufficient Evidence from only 

one study.

Pharmacist-led 1 Prospective Cohort 

w/post hoc 

comparison

(N = 30)

No significant difference over time or between groups (high ROB). Insufficient Evidence from only 

one study; potential 

risk of bias due to 

study design flaws.

Technology 

Interventions

4 RCTs (N = 434) Mixed findings on e-monitoring/MEMS: better adherence in 1 study as 

compared to pill counts and self-reported adherence (high ROB), conflicting 

results in 1 study as compared to a pharmacy based intervention and usual care 

(low ROB). Telephone plus SMS resulted in nonsignificant adherence 

improvement vs telephone or SMS alone (moderate ROB); SMS alone resulted 

in significantly better adherence than usual care (moderate ROB). 

Low Mixed findings and 

heterogeneous 

interventions. 
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Type of 

Intervention

Study Design 

(Combined N) Findings

Strength of 

Evidence Comments

Motivational 

Interviewing (MI)

1 RCT (N = 114) One study found no benefit to MI over usual care as measured by the MAQ or 

DAI (low ROB). 

Insufficient Evidence from only 

one study.

Cognitive 

Adaptation 

Training (CAT)

2 RCTs (N = 240) One study found that both CAT and Pharm-CAT resulted in better adherence 

than usual care, with no difference between the 2 (moderate ROB). The second 

study comparing Pharm-CAT to e-monitoring reported mixed results (low ROB). 

Insufficient Evidence from 2 

studies that used 

different 

comparators.

Shared Decision 

Making

1 RCT (N = 107) One study found no benefit to a shared decision-making over usual care as 

measured by the MARS and plasma levels (high ROB).

Insufficient Evidence from only 

one single study.

Note. Studies comparing interventions may be accounted for more than once. 

Abbreviations: AMQ = Attitude towards Medication Questionnaire; CAT = Cognitive Adaptation Training; CBT = Cognitive Behavioral Therapy; CDR = 

Concentration to Dose Ratio; DAI = Drug Attitude Inventory; MAQ = Medication Adherence Questionnaire; MARS = Medication Adherence Rating Scale; 

MEMS = Medication Event Monitoring System; MI = Motivational Interviewing; NRCT = Non-randomized controlled trial; ROB = Risk of bias; SAI-C = 

Schedule for the Assessment of Insight - C; TRQ = Tablet Routine Questionnaire.
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Key Question 2. In adults with bipolar disorder:

The 4 studies meeting inclusion criteria for Key Question 2 provide limited evidence of the 

effectiveness of interventions for medication adherence in patients with bipolar disorder. Three 

of the 4 studies found a positive effect on psychopharmacological adherence associated with an 

adherence intervention, with high rates of attrition in the one study reporting no effect. Despite 

evidence suggesting a generally positive effect, the strength of the evidence is insufficient and 

thus precludes drawing conclusions, due to the fact that the interventions were heterogeneous, 

sample sizes were small, and 2 studies showing a positive effect were conducted in Iran, calling 

into question applicability (see Table 15). 

There is no clear evidence to support conclusions regarding the effect of interventions for 

improving medication adherence on patient outcomes. Findings related to depression, mania, and 

functional impairment were mixed, and despite limited evidence supporting improvement, the 

lack of high quality studies, heterogeneity of the interventions, and setting preclude the ability to 

draw conclusions. 

Key Question 3. In adults with PTSD:

We identified no studies meeting inclusion criteria for Key Question 3. 

LIMITATIONS

Our review has a number of limitations. Despite restricting included studies to randomized and 

non-randomized controlled trials and observational studies that controlled for important 

confounding variables and included either a comparison group or examined a trend controlling 

for time (see Table 3), we rated only 4 of the 25 included studies (all 4 were trials) as highquality studies with a low risk of bias,

46,48,57,58 with 442,43,55,59 of the 19 trials and 245,53 of the 6 

observational studies determined to have a high risk of bias. In many studies, sample sizes were 

small, bringing into question statistical power. While it would have been ideal to overcome the 

issue of power by combining studies quantitatively, heterogeneity between studies precluded us 

from doing so. Studies included in this review evaluate a wide range of interventions in a variety 

of settings, with vast differences in intervention characteristics and implementation; specific 

interventions were rarely examined in more than one study. Furthermore, a wide range of 

measures were used to assess medication adherence, ranging from objective measures to 

validated short self-report scales, which often found different results even within the same study. 

Finally, although we did conduct a search for grey literature, we were unable to conduct a formal 

assessment of publication bias. 
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Table 15. Bipolar Disorder: Summary of Medication Adherence Outcomes

Type of Intervention Study Design;

(Combined N) 

Findings Strength of 

Evidence

Comments

Psychoeducation 

(individual/group) 

1 RCT (N = 108)

1 NRCT (N = 45)

Both individual and group 

psychoeducation resulted in better 

medication adherence 

pharmacotherapy alone or 

pharmacotherapy with standard 

psychotherapy (moderate ROB). 

Insufficient Evidence from only 2 studies, external 

validity due to setting. 

Psychoeducation plus 

problem solving

1 RCT (N = 164) There was no improvement in 

medication adherence associated 

with the intervention as compared 

to usual care (moderate ROB).

Insufficient Evidence from only one study. Only 75% of 

the intervention group and 81% of the 

control group participated in baseline plus 

one other assessment, and only 49% of the 

intervention group participated in most or all 

of the group sessions, with 37% never 

participating.

Customized Behavioral 

Multicomponent 

(psychoeducation, 

substance use/modified 

MET, provider 

communication, 

medication 

management)

1 Prospective Cohort (N = 

43)

Customized adherence 

enhancement (CAE) was 

associated with better adherence 

and attitudes towards medication 

at 3 and 6 months (moderate 

ROB). 

Insufficient Evidence from only one study; risk of bias 

due to study design.

Abbreviations: CAE = Customized adherence enhancement; MET = Motivational Enhancement Therapy; NRCT = Non-randomized controlled trial; RCT = 

Randomized controlled trial; ROB = Risk of bias. 
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DISCUSSION

We found 24 studies in 25 publications with the potential to inform policies and practices related 

to medication adherence in patients with severe mental illness in the VHA. Twenty studies 

(reported in 21 articles) examined patients with psychotic spectrum disorders, and 4 studies were

in patients with bipolar disorder. We identified no studies examining patients with PTSD. The 

interventions designed to improve medication adherence across Key Questions 1 and 2 differed 

widely, with very few studies evaluating the same specific interventions. Despite a variety of 

interventions designed to increase psychopharmacological adherence, study limitations (eg, 

differences in population and setting, heterogeneity among studies, a wide range of comparators, 

and the challenge of evaluating complex interventions), as well as concerns regarding 

applicability to the VHA, preclude us from drawing strong conclusions.

There is limited evidence that the involvement of family members, the use of technology (eg, emonitoring, SMS, telephone), and that the combination of a depot antipsychotic and another 

intervention may be effective in improving adherence. However, these findings must be 

interpreted with caution, given the heterogeneity among interventions, the difficulty in 

determining the contribution of the depot antipsychotic versus the adherence intervention, the 

methodological limitations, and the lack of consistent replication of any specific intervention. 

With the exception of interventions involving technology and system-level interventions, many 

interventions include behavioral or other techniques (eg, MI) that are flexible and designed to 

adapt to different settings and patients. While these techniques have been found effective in the 

treatment of other mental health conditions (eg, anxiety, depression, substance abuse), additional 

research of standardized interventions designed to improve medication adherence is needed to 

replicate findings across settings and populations in order to better understand their effect on 

adherence and patient outcomes. Similarly, many of the included studies compare interventions 

for medication adherence to usual care, rather than an active comparator. Given the population 

and the nature of mental illness, it is possible that the lack of active controls may result in more 

frequent provider interaction for the intervention group than for those receiving usual care. More

frequent contact alone has the potential to result in improved outcomes, and it is impossible to 

ascertain whether any effect was due to the intervention or to increased attention. Finally, 

sampling bias may exist related to baseline differences in the adherence of individuals selected to 

enroll in studies examining interventions designed to improve medication adherence and those 

who do not – particularly in studies examining long acting injectable depot antipsychotics.

An additional challenge in accurately assessing the body of research examining medication 

adherence is the wide range of methods used to assess adherence. We limited our inclusion to 

studies that assessed adherence using an objective measure such as blood plasma concentration 

levels, pill counts, e-monitoring/MEMS caps, or using a validated adherence scale.1 For studies 

using multiple adherence measures, it was not uncommon for the determination of adherence to 

be incongruent, leading to questions related to the validity of commonly used and validated 

objective and subjective measures. 

There is a paucity of research examining the effect of medication adherence interventions on 

non-psychopharmacological interventions. Given the risk of comorbid health conditions (eg, 

diabetes, hypertension) in persons with serious mental illness, future research should evaluate the 

impact of adherence interventions aimed at prevalent comorbid non-psychiatric conditions.
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Furthermore, we identified no studies evaluating the potential harms that may result from these 

interventions. Despite the fact that the potential for harm appears to be low as compared to the 

risks associated with both the use of and non-adherence to prescribed medication, research 

documenting relative risk is warranted. Similarly, very few studies evaluated differential effects 

in subpopulations. It is important to understand whether both the benefits and potential harms 

differ by subgroup or clinical subpopulation and whether one type of intervention may be more 

effective than others for a given population or setting.

We identified no studies examining interventions to improve medication adherence in patients 

with PTSD. Although trauma processing therapies are often the first line of treatment for patients 

with PTSD, pharmacological interventions are commonly used as adjunctive therapy to alleviate 

associated symptoms and to treat comorbid conditions. There is limited evidence to suggest that 

adherence to medication is poor in Veterans with PTSD who are taking medication. Therefore, 

future research is warranted to determine whether improvements in adherence in this population 

can be achieved through the use of interventions, or by adapting interventions developed for 

other patient populations.

Recommendations for Future Research

Interventions to improve medication adherence in patients with psychotic spectrum disorders and 

bipolar disorder warrant further investigation, particularly in the form of well-designed RCTs 

with active comparators of adequate sample size and duration. Furthermore, few studies examine 

the same intervention, and replication is needed in order to draw conclusions about the 

effectiveness of a specific program. Several small studies suggest the effectiveness of some of 

the interventions (eg, interventions including family members). However, many of the 

interventions are multicomponent and complex, differ widely in their components and 

implementation, and thus research evaluating standardized interventions is needed. 

Research evaluating the effectiveness of interventions to improve medication adherence in 

patients with PTSD is lacking and needed. For all populations examined in this report, future 

research is needed to evaluate the effect of these interventions on non-psychopharmacological 

interventions. In addition, future studies should examine potential adverse events associated with 

medication adherence interventions. Objective measures should be used to measure medication 

adherence, and the identification and validation of a gold-standard assessment tool for 

medication adherence is warranted. Finally, more research is necessary to determine the cost 

effectiveness and feasibility of interventions for medication adherence in the VHA.

CONCLUSION

Findings from the studies examining interventions to improve medication adherence in patients 

with psychotic spectrum disorders are mixed and evaluate a wide range of heterogeneous 

interventions. Sample sizes were generally small, studies often lacked an active comparison 

group, and there was wide variation in how adherence was measured among studies. There is 

limited evidence to support improved adherence associated with interventions involving family 

members, those involving technology, and those combining a depot antipsychotics with another 

intervention. Findings were mixed regarding the effectiveness of multicomponent behavioral 

interventions, with no support for Adherence or Compliance Therapies. In addition, no clear 

evidence exists to support conclusions regarding the effect of medication adherence interventions 

on patient outcomes. Very few studies examined interventions for medication adherence in 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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patients with bipolar disorder, and while in general there appears to be a positive effect of these 

interventions on adherence in this population, interventions were heterogeneous and more 

research is needed. No studies were found examining PTSD populations. For all populations, 

methodologically rigorous replication studies of standardized treatments using objective or 

validated subjective measures of adherence are needed to confirm preliminary results, as is 

research examining the costs and potential harms associated with the wide array of interventions 

designed to improve medication adherence.
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Healthcare Research and Quality (AHRQ Publication No. 12-EHC068-EF); 2012.

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Health; 2008.

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Confounding in Observational Studies of Interventions or Exposures: Further 

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Quality; Methods Research Report (AHRQ Publication No. 13-EHC106-EF); 2012.

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Assessing Health Care Interventions for the Effective Health Care Program of the 

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39. Atkins D, Chang S, Gartlehner G, et al. Assessing the Applicability of Studies When 

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11-EHC019-EF); 2011.

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enhancement (CAE) therapy in bipolar disorder. Bipolar Disord. May 2012;14(3):291-

300.

42. Healey A, Knapp M, Astin J, et al. Cost-effectiveness evaluation of compliance therapy 

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43. Kemp R, Kirov G, Everitt B, Hayward P, David A. Randomised controlled trial of 

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45. Byerly MJ, Fisher R, Carmody T, Rush A. A Trial of Compliance Therapy in Outpatients 

With Schizophrenia or Schizoaffective Disorder. J Clin Psychiatry. Aug 2005;66(8):997-

1001.

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European multicentre randomised controlled trial. Br J Psychiatry. Dec 2006;189:508-

514.

47. O'Donnell C, Donohoe G, Sharkey L, et al. Compliance therapy: a randomised controlled 

trial in schizophrenia. BMJ: British Medical Journal. Oct 2003;327(7419):834.

48. Schulz M, Gray R, Spiekermann A, Abderhalden C, Behrens J, Driessen M. Adherence 

therapy following an acute episode of schizophrenia: A multi-centre randomised 

controlled trial. Schizophr Res. May 2013;146(1-3):59-63.

49. Skarsholm H, Stoevring H, Nielsen B. Effect of a system-oriented intervention on 

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50. Kopelowicz A, Zarate R, Wallace CJ, Liberman RP, Lopez SR, Mintz J. The ability of 

multifamily groups to improve treatment adherence in Mexican Americans with 

schizophrenia. Arch Gen Psychiatry. Mar 2012;69(3):265-273.

51. Pitschel-Walz G, Bauml J, Bender W, Engel RR, Wagner M, Kissling W. 

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Adherence in Patients with Schizophrenia. Telemedicine and e-Health. Dec 

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57. Velligan D, Mintz J, Maples N, et al. A randomized trial comparing in person and 

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2013;39(6):1242-1251.

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supports to improve medication adherence and outcomes in schizophrenia. Schizophr 

Bull. May 2008;34(3):483-493.

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prevention in patients with schizophrenia receiving risperidone via long-acting injection. 

Psychiatry Res. Feb 2010;175(3):195-199.

62. Sajatovic M, Levin J, Ramirez LF, et al. Prospective trial of customized adherence 

enhancement plus long-acting injectable antipsychotic medication in homeless or recently 

homeless individuals with schizophrenia or schizoaffective disorder. J Clin Psychiatry. 

Dec 2013;74(12):1249-1255.

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68. Javadpour A, Hedayati A, Dehbozorgi G-R, Azizi A. The impact of a simple individual 

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bipolar disorder patients. Asian J Psychiatr. Jun 2013;6(3):208-213.

69. Bahredar MJ, Asgharnejad Farid AA, Ghanizadeh A, Birashk B. The efficacy of psychoeducational group program on medication adherence and global functioning of patients 

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Goals Program (2nd ed.). New York, NY: Springer Publishing Co; US; 2003.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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APPENDIX A. TECHNICAL EXPERT PANEL

Jennifer Bean, Pharm.D (VA)

Clinical Pharmacy Specialist (Psychiatry and Pharmacotherapy), VA Tennessee Valley Healthcare System

Joyce Cramer (former VA) 

Medical Research Consultant

Associate Research Scientist in Psychiatry, Yale University Department of Psychiatry, retired

West Haven VA Medical Center, retired

Colin Depp, PhD (VA) 

Associate Professor of Psychiatry, University of California, San Diego

Staff Psychologist, VA San Diego Health Care System

Walid Gellad, MD, MPH (VA) 

Core Investigator, Center for Health Equity Research and Promotion

Staff Physician, VA Pittsburgh Healthcare System

Assistant Professor of Medicine, University of Pittsburgh School of Medicine

Assistant Professor of Health Policy and Management, University of Pittsburgh Graduate School of Public Health

Jennifer Houser, Pharm.D (VA) 

Clinical Pharmacy Specialist (Mental Health), William Jennings Bryan Dorn VA Medical Center

Teresa Hudson, Pharm.D, PhD (VA) 

Associate Director, Division of Health Services Research, Psychiatric Research Institute, University of Arkansas for 

Medical Sciences School of Medicine

Associate Director, VA Health Services Research & Development Center for Mental Healthcare and Outcomes 

Research, Central Arkansas Veterans Healthcare System

Judith Hyatt, Pharm.D (VA) 

Clinical Pharmacist (Psychiatry and Pharmacotherapy) VA Western New York Healthcare System

Martha Sajatovic, MD 

Professor of Psychiatry and of Neurology, University Hospitals Case Medical Center

Willard Brown Chair in Neurological Outcomes Research

Director, Neurological and Behavioral Outcomes Center

Todd Semla, Pharm.D, MS (VA)

National Pharmacy Benefits Management (PBM) Clinical Pharmacy Program Manager - Mental Health & Geriatrics

Clinical Pharmacy Specialist (Psychiatry and Geriatrics)

Marcia Valenstein, MD, MS (VA)

Staff Psychiatrist, VA Ann Arbor Healthcare System

Senior Research Scientist, VA Health Services Research and Development Service and the Serious Mental Illness 

Treatment Research and Evaluation Center (SMITREC), VA Ann Arbor Healthcare System

Professor of Psychiatry, University of Michigan

Dawn Velligan, PhD

Director, Division of Community Recovery, Research and Training

Professor of Psychiatry, Henry B. Dielmann Chair, University of Texas Health Science Center, San Antonio

Corrine Voils, PhD (VA) 

Research Health Science Specialist, Durham Center for Health Services Research in Primary Care, VA Health 

Sciences Research and Development Service

Social Psychologist, Durham VA Medical Center

Professor of Medicine, Division of General Internal Medicine, Duke University Medical Center

Daina Wells, Pharm.D. (VA)
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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Program Manager, Academic Detailing Program at the Department of Veterans Affairs

VACO Pharmacy Benefits Management

Clinical Pharmacist (Psychiatry and Pharmacotherapy)

John Zeber, PhD, MHA (VA)

Co-director, Health Outcomes Core, Center for Applied Health Research, Internal Medicine

Investigator, Central Texas Veterans Healthcare System

Associate Professor, Texas A&M Health Science Center College of Medicine

Member, International Society for Pharmacoepidemiology Outcomes Research (ISPOR) and ISPOR National 

Working Group on Medication Compliance
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APPENDIX B: SEARCH STRATEGIES

DATABASE STRATEGY

Medline - Ovid

PubMed [publisher] segment – National Library of Medicine

EMBASE – Elsevier.com

PsycINFO – Ovid

Cochrane Library (Ovid EBM Reviews): Cochrane Central Register of Controlled Trials; 

Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effects; 

Health Technology Assessment; NHS Economic Evaluation Database 

CINAHL - EBSCOHost

Conference Papers Index - ProQuest 

Dissertations & Theses - ProQuest 

GREY LITERATURE STRATEGY

ClinicalTrials.gov - http://www.clinicaltrials.gov

WHO ICTRP - http://apps.who.int/trialsearch/

ISRCTN Registry - http://www.isrctn.com/

INDIVIDUAL DATABASE SEARCH STRATEGIES

Ovid MEDLINE(R) and Ovid OLDMEDLINE(R) 1946 to January Week 3 2015, 

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations January 27, 2015 

Date Searched: January 29, 2015 

1 Medication Adherence/ 8162 

2 Patient Compliance/ 47223 

3 Medication Reconciliation/ 379 

4 Medication Therapy Management/ 740 

5 Treatment Refusal/ 10659 

6 

(((medication* or pharmaceutical* or drug* or pharmacotherap* or regimen* or therap* or treat* or 

prophylaxis or psychotropic or psychopharmac* or pharmacolog* or antipsychot* or anti-psychot* or 

neuroleptic* or mood stabilizer* or antiepileptic* or anti-epileptic* or anticonvulsant* or anticonvulsant* or poor* or patient* or client* or refus*) adj3 (adheren* or non-adheren* or 

nonadheren* or complian* or non-complian* or noncomplian* or persist* or non-persist* or 

nonpersist* or reconciliat*)) or medication therapy management).ti,ab. 

83952 

7 or/1-6 128965 

8 Psychotic Disorders/ 32480 

9 Schizophrenia/ 82350 

10 Schizophrenia, catatonic/ 529 

11 Schizophrenia, disorganized/ 505 

12 Schizophrenia, paranoid/ 3674 

13 Shared Paranoid Disorder/ 283 

14 Schizoid Personality Disorder/ 565 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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15 Schizotypal Personality Disorder/ 2198 

16 Affective disorders, psychotic/ 2105 

17 Bipolar Disorder/ 31621 

18 Cyclothymic Disorder/ 517 

19 Stress disorders, traumatic/ 471 

20 Combat Disorders/ 2589 

21 Stress disorders, post-traumatic/ 21646 

22 Stress disorders, traumatic, acute/ 316 

23

(psychotic or schizotyp* or schizophren* or schizoid* or schizoaffective or bipolar or mania* or 

hypomania* or hypo-mania* or manic or cyclothymic or PTSD or post-traumatic stress or 

posttraumatic stress or ((severe* or serious* or chronic* or persistent*) adj mental* ill*)).ti,ab. 

177009 

24 or/8-23 225382 

25 Policy Making/ 12464 

26 Public Policy/ 28025 

27 "State Health Planning and Development Agencies"/ 186 

28 Insurance Claim Review/ 4595 

29 "Medicare Part D"/ 603 

30 Medicaid/ 19453 

31 Health Services Accessibility/ 52115 

32 Health Policy/ 51267 

33 "Formularies as Topic"/ 1787 

34 Community Pharmacy Services/ 2925 

35 Cost-sharing/ 1993 

36 "Health Benefit Plans, Employee"/ 9199 

37 "Insurance, Pharmaceutical Services"/ 3574 

38 Managed Care Programs/ 23432 

39 "Health Maintenance Organizations"/og 3495 

40 "Primary Health Care"/ec, og 13631 

41 Prescription Drugs/ 3113 

42 Polypharmacy/ 2516 

43 Drug Costs/ 12338 

44 Drug Packaging/ 4272 

45 Health Services Research/ 31057 

46 Medical Indigency/ 3480 

47 Program Development/ 23021 

48 Disease Management/ 12378 

49 "Pharmacy Service, Hospital"/ 9942 

50 "Drug Administration Schedule"/ 85246 

51 (intervention or interventions or program* or reduce or reduction or patient-level* or system-level* 

or policy-level* or provider* or strateg* or enhanc* or improv* or increas* or device* or pill* or 12030466
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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packag* or policy or policies or benefit* or insurance or insured or contain* or co-pay* or copay* or 

cost* or pharmacy* or pharmacies* or pharmacist* or pharmacologist* or remind* or refill* or refill* or inject* or depot* or LAI or dosing or tele* or email* or text* or virtual* or computer* or 

electronic* or internet or ehealth or online or interactive* or interdisciplinary or inter-disciplinary or 

technolog* or monitor* or record* or data* or manag* or self-manag* or counsel* or therap* or 

alliance or coordinat* or co-ordinat* or communicat* or cognitive or interview* or psychosocial or 

psycho-social or multicomponent or multi-component or support* or tailor* or coach* or diary or 

diaries or behavioral or behavioural or family* or families* or peer* or communit* or decision* or 

educat* or psychoeducation* or psychoeducation* or train* or incentiv* or facilitat* or supervised 

treatment in out-patients for schizophren* or STOPS or ((reduc* or remov*) adj2 barrier*) or "30-

day Adherence Question" or "5-item Questionnaire" or "Adherence Attitude Inventory" or 

"Adherence Question" or "Adherence Questionnaire" or "Adherence Self-Report Questionnaire" or 

ASRQ or "Adherence Starts with Knowledge-12" or ASK-12 or "Adherence Starts with Knowledge20" or ASK-20 or "Adherence to Refills and Medications Scale" or "Adherence Visual Analogue 

Scale" or "Beliefs about Medicines Questionnaire" or "Beliefs and Behaviour Questionnaire" or -

"Beliefs and Behavior Questionnaire" or "Brief Adherence Rating Scale" or "Brief Evaluation of 

Medication Influences and Beliefs" or BEMIB or "Brief Medication Questionnaire" or "Brooks 

Medication Adherence Scale" or BMAS or "Centre for Adherence Support Evaluation" or "CASE 

Adherence Index" or "CASE Index" or "Compliance Questionnaire Rheumatology" or "Drug 

Attitude Inventory" or "Hill-Bone Compliance Scale" or "Immunosuppressant Therapy Adherence 

Scale" or ITAS or "Maastricht Utrecht Adherence in Hypertension Questionnaire" or MUAH or 

"Medication Adherence Assessment Tool" or MAAT or "Medication Adherence Questionnaire" or 

MAQ or "Medication Adherence Reasons Scale" or "Medication Adherence Report Scale*" or 

"Medication Adherence Self-Efficacy Scale" or MASES or "Medication Adherence Self-Efficacy 

Scale Revised" or MASES-R or "Morisky Medication Adherence Scale" or MMAS or "Modified 

Morisky Scale" or MMS or Morisky-8 or MMS-8 or Morisky-4 or MMS-4 or "Osteoporosis-Specific 

Morisky Medication Adherence Scale" or OS-MMAS or "Reported Adherence to Medicine Scale" or 

"Self-Reported Adherence Questionnaire" or SERAD or "Simplified Medication Adherence 

Questionnaire" or SMAQ or "Stages of Change for Adherence" or SOCA or "The Patterns of Asthma 

Medication Use Questionnaire" or "The Self-Efficacy for Appropriate Medication Use Scale").ti,ab. 

52 or/25-51 12133327

53 and/7,24,52 4722 

54 remove duplicates from 53 4705 

55 animals/ not humans/ 3879816 

56 54 not 55 4675 

57 limit 56 to "all child (0 to 18 years)" 753 

58 limit 57 to "all adult (19 plus years)" 654 

59 57 not 58 99 

60 56 not 59 4576 

61 limit 60 to (comment or editorial or letter) 93 

62 60 not 61 4483 

63 limit 62 to english language 4057 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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PubMed - [Publisher subset search] 

http://www.ncbi.nlm.nih.gov/pubmed/ 

Date Searched: January 29, 2015 

#6 Search ((((((((medication*[Title/Abstract] OR pharmaceutical*[Title/Abstract] OR drug*[Title/Abstract] 

OR pharmacotherap*[Title/Abstract] OR regimen*[Title/Abstract] OR therap*[Title/Abstract] OR 

treat*[Title/Abstract] OR prophylaxis[Title/Abstract] OR psychotropic[Title/Abstract] OR 

psychopharmac*[Title/Abstract] OR pharmacolog*[Title/Abstract] OR antipsychot*[Title/Abstract] OR 

anti-psychot*[Title/Abstract] OR neuroleptic*[Title/Abstract] OR mood stabilizer*[Title/Abstract] OR 

antiepileptic*[Title/Abstract] OR anti-epileptic*[Title/Abstract] OR anticonvulsant*[Title/Abstract] OR 

anti-convulsant*[Title/Abstract] OR poor*[Title/Abstract] OR patient*[Title/Abstract] OR

client*[Title/Abstract] OR refus*[Title/Abstract])) AND (adheren*[Title/Abstract] OR nonadheren*[Title/Abstract] OR nonadheren*[Title/Abstract] OR complian*[Title/Abstract] OR noncomplian*[Title/Abstract] OR noncomplian*[Title/Abstract] OR persist*[Title/Abstract] OR nonpersist*[Title/Abstract] OR nonpersist*[Title/Abstract] OR reconciliat*[Title/Abstract])) AND publisher 

[sb])) OR ((medication therapy management[Title/Abstract]) AND publisher [sb]))) AND 

(((psychotic[Title/Abstract] OR schizotyp*[Title/Abstract] OR schizophren*[Title/Abstract] OR 

schizoid*[Title/Abstract] OR schizoaffective[Title/Abstract] OR bipolar[Title/Abstract] OR 

mania*[Title/Abstract] OR hypomania*[Title/Abstract] OR hypo-mania*[Title/Abstract] OR 

manic[Title/Abstract] OR cyclothymic[Title/Abstract] OR PTSD[Title/Abstract] OR post-traumatic 

stress[Title/Abstract] OR posttraumatic stress[Title/Abstract] OR severe* mental* ill*[Title/Abstract] 

OR serious* mental* ill*[Title/Abstract] OR chronic* mental* ill*[Title/Abstract] OR persistent* 

mental* ill*[Title/Abstract])) AND publisher [sb])) AND (((intervention[Title/Abstract] OR 

interventions[Title/Abstract] OR program*[Title/Abstract] OR reduce[Title/Abstract] OR 

reduction[Title/Abstract] OR patient-level*[Title/Abstract] OR system-level*[Title/Abstract] OR policylevel*[Title/Abstract] OR provider*[Title/Abstract] OR strateg*[Title/Abstract] OR 

enhanc*[Title/Abstract] OR improv*[Title/Abstract] OR increas*[Title/Abstract] OR 

device*[Title/Abstract] OR pill*[Title/Abstract] OR packag*[Title/Abstract] OR policy[Title/Abstract] 

OR policies[Title/Abstract] OR benefit*[Title/Abstract] OR insurance[Title/Abstract] OR 

insured[Title/Abstract] OR contain*[Title/Abstract] OR co-pay*[Title/Abstract] OR 

copay*[Title/Abstract] OR cost*[Title/Abstract] OR pharmacy*[Title/Abstract] OR 

pharmacies*[Title/Abstract] OR pharmacist*[Title/Abstract] OR pharmacologist*[Title/Abstract] OR 

remind*[Title/Abstract] OR refill*[Title/Abstract] OR re-fill*[Title/Abstract] OR inject*[Title/Abstract] 

OR depot*[Title/Abstract] OR LAI[Title/Abstract] OR dosing[Title/Abstract] OR tele*[Title/Abstract] 

OR email*[Title/Abstract] OR text*[Title/Abstract] OR virtual*[Title/Abstract] OR 

computer*[Title/Abstract] OR electronic*[Title/Abstract] OR internet[Title/Abstract] OR 

ehealth[Title/Abstract] OR online[Title/Abstract] OR interactive*[Title/Abstract] OR 

interdisciplinary[Title/Abstract] OR inter-disciplinary[Title/Abstract] OR technolog*[Title/Abstract] OR 

monitor*[Title/Abstract] OR record*[Title/Abstract] OR data*[Title/Abstract] OR 

manag*[Title/Abstract] OR self-manag*[Title/Abstract] OR counsel*[Title/Abstract] OR 

therap*[Title/Abstract] OR alliance[Title/Abstract] OR coordinat*[Title/Abstract] OR coordinat*[Title/Abstract] OR communicat*[Title/Abstract] OR cognitive[Title/Abstract] OR 

interview*[Title/Abstract] OR psychosocial[Title/Abstract] OR psycho-social[Title/Abstract] OR 

multicomponent[Title/Abstract] OR multi-component[Title/Abstract] OR support*[Title/Abstract] OR 

tailor*[Title/Abstract] OR coach*[Title/Abstract] OR diary[Title/Abstract] OR diaries[Title/Abstract] 

OR behavioral[Title/Abstract] OR behavioural[Title/Abstract] OR family*[Title/Abstract] OR 

families*[Title/Abstract] OR peer*[Title/Abstract] OR communit*[Title/Abstract] OR 

decision*[Title/Abstract] OR educat*[Title/Abstract] OR psychoeducation*[Title/Abstract] OR 

psychoeducation*[Title/Abstract] OR train*[Title/Abstract] OR incentiv*[Title/Abstract] OR 

"facilitat*[Title/Abstract] OR supervised treatment in out-patients for schizophren*"[Title/Abstract] OR 

STOPS[Title/Abstract] OR reduc* barrier*[Title/Abstract] OR remov* barrier*[Title/Abstract] OR "30-

day Adherence Question"[Title/Abstract] OR "5-item Questionnaire"[Title/Abstract] OR "Adherence 

Attitude Inventory"[Title/Abstract] OR "Adherence Question"[Title/Abstract] OR "Adherence 

Questionnaire"[Title/Abstract] OR "Adherence Self-Report Questionnaire"[Title/Abstract] OR 

ASRQ[Title/Abstract] OR "Adherence Starts with Knowledge-12"[Title/Abstract] OR ASK12[Title/Abstract] OR "Adherence Starts with Knowledge-20"[Title/Abstract] OR ASK4
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

101

20[Title/Abstract] OR "Adherence to Refills[Title/Abstract] AND Medications Scale"[Title/Abstract] 

OR "Adherence Visual Analogue Scale"[Title/Abstract] OR "Beliefs about Medicines 

Questionnaire"[Title/Abstract] OR "Beliefs[Title/Abstract] AND Behaviour 

Questionnaire"[Title/Abstract] OR "Beliefs[Title/Abstract] AND Behavior 

Questionnaire"[Title/Abstract] OR "Brief Adherence Rating Scale"[Title/Abstract] OR "Brief 

Evaluation of Medication Influences[Title/Abstract] AND Beliefs"[Title/Abstract] OR 

BEMIB[Title/Abstract] OR "Brief Medication Questionnaire"[Title/Abstract] OR "Brooks Medication 

Adherence Scale"[Title/Abstract] OR BMAS[Title/Abstract] OR "Centre for Adherence Support 

Evaluation"[Title/Abstract] OR "CASE Adherence Index"[Title/Abstract] OR "CASE 

Index"[Title/Abstract] OR "Compliance Questionnaire Rheumatology"[Title/Abstract] OR "Drug 

Attitude Inventory"[Title/Abstract] OR "Hill-Bone Compliance Scale"[Title/Abstract] OR 

"Immunosuppressant Therapy Adherence Scale"[Title/Abstract] OR ITAS[Title/Abstract] OR 

"Maastricht Utrecht Adherence in Hypertension Questionnaire"[Title/Abstract] OR 

MUAH[Title/Abstract] OR "Medication Adherence Assessment Tool"[Title/Abstract] OR 

MAAT[Title/Abstract] OR "Medication Adherence Questionnaire"[Title/Abstract] OR 

MAQ[Title/Abstract] OR "Medication Adherence Reasons Scale"[Title/Abstract] OR "Medication 

Adherence Report Scale*"[Title/Abstract] OR "Medication Adherence Self-Efficacy 

Scale"[Title/Abstract] OR MASES[Title/Abstract] OR "Medication Adherence Self-Efficacy Scale 

Revised"[Title/Abstract] OR MASES-R[Title/Abstract] OR "Morisky Medication Adherence 

Scale"[Title/Abstract] OR MMAS[Title/Abstract] OR "Modified Morisky Scale"[Title/Abstract] OR 

MMS[Title/Abstract] OR Morisky-8[Title/Abstract] OR MMS-8[Title/Abstract] OR Morisky4[Title/Abstract] OR MMS-4[Title/Abstract] OR "Osteoporosis-Specific Morisky Medication 

Adherence Scale"[Title/Abstract] OR OS-MMAS[Title/Abstract] OR "Reported Adherence to Medicine 

Scale"[Title/Abstract] OR "Self-Reported Adherence Questionnaire"[Title/Abstract] OR 

SERAD[Title/Abstract] OR "Simplified Medication Adherence Questionnaire"[Title/Abstract] OR 

SMAQ[Title/Abstract] OR "Stages of Change for Adherence"[Title/Abstract] OR SOCA[Title/Abstract] 

OR "The Patterns of Asthma Medication Use Questionnaire"[Title/Abstract] OR "The Self-Efficacy for 

Appropriate Medication Use Scale"[Title/Abstract])) AND publisher [sb])

#5 Search ((intervention[Title/Abstract] OR interventions[Title/Abstract] OR program*[Title/Abstract] OR 

reduce[Title/Abstract] OR reduction[Title/Abstract] OR patient-level*[Title/Abstract] OR systemlevel*[Title/Abstract] OR policy-level*[Title/Abstract] OR provider*[Title/Abstract] OR 

strateg*[Title/Abstract] OR enhanc*[Title/Abstract] OR improv*[Title/Abstract] OR 

increas*[Title/Abstract] OR device*[Title/Abstract] OR pill*[Title/Abstract] OR 

packag*[Title/Abstract] OR policy[Title/Abstract] OR policies[Title/Abstract] OR 

benefit*[Title/Abstract] OR insurance[Title/Abstract] OR insured[Title/Abstract] OR 

contain*[Title/Abstract] OR co-pay*[Title/Abstract] OR copay*[Title/Abstract] OR 

cost*[Title/Abstract] OR pharmacy*[Title/Abstract] OR pharmacies*[Title/Abstract] OR 

pharmacist*[Title/Abstract] OR pharmacologist*[Title/Abstract] OR remind*[Title/Abstract] OR 

refill*[Title/Abstract] OR re-fill*[Title/Abstract] OR inject*[Title/Abstract] OR depot*[Title/Abstract] 

OR LAI[Title/Abstract] OR dosing[Title/Abstract] OR tele*[Title/Abstract] OR email*[Title/Abstract] 

OR text*[Title/Abstract] OR virtual*[Title/Abstract] OR computer*[Title/Abstract] OR 

electronic*[Title/Abstract] OR internet[Title/Abstract] OR ehealth[Title/Abstract] OR 

online[Title/Abstract] OR interactive*[Title/Abstract] OR interdisciplinary[Title/Abstract] OR interdisciplinary[Title/Abstract] OR technolog*[Title/Abstract] OR monitor*[Title/Abstract] OR 

record*[Title/Abstract] OR data*[Title/Abstract] OR manag*[Title/Abstract] OR selfmanag*[Title/Abstract] OR counsel*[Title/Abstract] OR therap*[Title/Abstract] OR 

alliance[Title/Abstract] OR coordinat*[Title/Abstract] OR co-ordinat*[Title/Abstract] OR 

communicat*[Title/Abstract] OR cognitive[Title/Abstract] OR interview*[Title/Abstract] OR 

psychosocial[Title/Abstract] OR psycho-social[Title/Abstract] OR multicomponent[Title/Abstract] OR 

multi-component[Title/Abstract] OR support*[Title/Abstract] OR tailor*[Title/Abstract] OR 

coach*[Title/Abstract] OR diary[Title/Abstract] OR diaries[Title/Abstract] OR 

behavioral[Title/Abstract] OR behavioural[Title/Abstract] OR family*[Title/Abstract] OR 

families*[Title/Abstract] OR peer*[Title/Abstract] OR communit*[Title/Abstract] OR 

decision*[Title/Abstract] OR educat*[Title/Abstract] OR psychoeducation*[Title/Abstract] OR 

psychoeducation*[Title/Abstract] OR train*[Title/Abstract] OR incentiv*[Title/Abstract] OR 

"facilitat*[Title/Abstract] OR supervised treatment in out-patients for schizophren*"[Title/Abstract] OR 

4569
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

102

STOPS[Title/Abstract] OR reduc* barrier*[Title/Abstract] OR remov* barrier*[Title/Abstract] OR "30-

day Adherence Question"[Title/Abstract] OR "5-item Questionnaire"[Title/Abstract] OR "Adherence 

Attitude Inventory"[Title/Abstract] OR "Adherence Question"[Title/Abstract] OR "Adherence 

Questionnaire"[Title/Abstract] OR "Adherence Self-Report Questionnaire"[Title/Abstract] OR 

ASRQ[Title/Abstract] OR "Adherence Starts with Knowledge-12"[Title/Abstract] OR ASK12[Title/Abstract] OR "Adherence Starts with Knowledge-20"[Title/Abstract] OR ASK20[Title/Abstract] OR "Adherence to Refills[Title/Abstract] AND Medications Scale"[Title/Abstract] 

OR "Adherence Visual Analogue Scale"[Title/Abstract] OR "Beliefs about Medicines 

Questionnaire"[Title/Abstract] OR "Beliefs[Title/Abstract] AND Behaviour 

Questionnaire"[Title/Abstract] OR "Beliefs[Title/Abstract] AND Behavior 

Questionnaire"[Title/Abstract] OR "Brief Adherence Rating Scale"[Title/Abstract] OR "Brief 

Evaluation of Medication Influences[Title/Abstract] AND Beliefs"[Title/Abstract] OR 

BEMIB[Title/Abstract] OR "Brief Medication Questionnaire"[Title/Abstract] OR "Brooks Medication 

Adherence Scale"[Title/Abstract] OR BMAS[Title/Abstract] OR "Centre for Adherence Support 

Evaluation"[Title/Abstract] OR "CASE Adherence Index"[Title/Abstract] OR "CASE 

Index"[Title/Abstract] OR "Compliance Questionnaire Rheumatology"[Title/Abstract] OR "Drug 

Attitude Inventory"[Title/Abstract] OR "Hill-Bone Compliance Scale"[Title/Abstract] OR 

"Immunosuppressant Therapy Adherence Scale"[Title/Abstract] OR ITAS[Title/Abstract] OR 

"Maastricht Utrecht Adherence in Hypertension Questionnaire"[Title/Abstract] OR 

MUAH[Title/Abstract] OR "Medication Adherence Assessment Tool"[Title/Abstract] OR 

MAAT[Title/Abstract] OR "Medication Adherence Questionnaire"[Title/Abstract] OR 

MAQ[Title/Abstract] OR "Medication Adherence Reasons Scale"[Title/Abstract] OR "Medication 

Adherence Report Scale*"[Title/Abstract] OR "Medication Adherence Self-Efficacy 

Scale"[Title/Abstract] OR MASES[Title/Abstract] OR "Medication Adherence Self-Efficacy Scale 

Revised"[Title/Abstract] OR MASES-R[Title/Abstract] OR "Morisky Medication Adherence 

Scale"[Title/Abstract] OR MMAS[Title/Abstract] OR "Modified Morisky Scale"[Title/Abstract] OR 

MMS[Title/Abstract] OR Morisky-8[Title/Abstract] OR MMS-8[Title/Abstract] OR Morisky4[Title/Abstract] OR MMS-4[Title/Abstract] OR "Osteoporosis-Specific Morisky Medication 

Adherence Scale"[Title/Abstract] OR OS-MMAS[Title/Abstract] OR "Reported Adherence to Medicine 

Scale"[Title/Abstract] OR "Self-Reported Adherence Questionnaire"[Title/Abstract] OR 

SERAD[Title/Abstract] OR "Simplified Medication Adherence Questionnaire"[Title/Abstract] OR 

SMAQ[Title/Abstract] OR "Stages of Change for Adherence"[Title/Abstract] OR SOCA[Title/Abstract] 

OR "The Patterns of Asthma Medication Use Questionnaire"[Title/Abstract] OR "The Self-Efficacy for 

Appropriate Medication Use Scale"[Title/Abstract])) AND publisher [sb]

#4 Search ((psychotic[Title/Abstract] OR schizotyp*[Title/Abstract] OR schizophren*[Title/Abstract] OR

schizoid*[Title/Abstract] OR schizoaffective[Title/Abstract] OR bipolar[Title/Abstract] OR 

mania*[Title/Abstract] OR hypomania*[Title/Abstract] OR hypo-mania*[Title/Abstract] OR 

manic[Title/Abstract] OR cyclothymic[Title/Abstract] OR PTSD[Title/Abstract] OR post-traumatic 

stress[Title/Abstract] OR posttraumatic stress[Title/Abstract] OR severe* mental* ill*[Title/Abstract] 

OR serious* mental* ill*[Title/Abstract] OR chronic* mental* ill*[Title/Abstract] OR persistent* 

mental* ill*[Title/Abstract])) AND publisher [sb]

608

#3 Search (((((medication*[Title/Abstract] OR pharmaceutical*[Title/Abstract] OR drug*[Title/Abstract] 

OR pharmacotherap*[Title/Abstract] OR regimen*[Title/Abstract] OR therap*[Title/Abstract] OR 

treat*[Title/Abstract] OR prophylaxis[Title/Abstract] OR psychotropic[Title/Abstract] OR 

psychopharmac*[Title/Abstract] OR pharmacolog*[Title/Abstract] OR antipsychot*[Title/Abstract] OR 

anti-psychot*[Title/Abstract] OR neuroleptic*[Title/Abstract] OR mood stabilizer*[Title/Abstract] OR 

antiepileptic*[Title/Abstract] OR anti-epileptic*[Title/Abstract] OR anticonvulsant*[Title/Abstract] OR 

anti-convulsant*[Title/Abstract] OR poor*[Title/Abstract] OR patient*[Title/Abstract] OR 

client*[Title/Abstract] OR refus*[Title/Abstract])) AND (adheren*[Title/Abstract] OR nonadheren*[Title/Abstract] OR nonadheren*[Title/Abstract] OR complian*[Title/Abstract] OR noncomplian*[Title/Abstract] OR noncomplian*[Title/Abstract] OR persist*[Title/Abstract] OR nonpersist*[Title/Abstract] OR nonpersist*[Title/Abstract] OR reconciliat*[Title/Abstract])) AND publisher 

[sb])) OR ((medication therapy management[Title/Abstract]) AND publisher [sb])

6556

#2 Search (medication therapy management[Title/Abstract]) AND publisher [sb] 20
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

103

#1 Search (((medication*[Title/Abstract] OR pharmaceutical*[Title/Abstract] OR drug*[Title/Abstract] OR 

pharmacotherap*[Title/Abstract] OR regimen*[Title/Abstract] OR therap*[Title/Abstract] OR 

treat*[Title/Abstract] OR prophylaxis[Title/Abstract] OR psychotropic[Title/Abstract] OR 

psychopharmac*[Title/Abstract] OR pharmacolog*[Title/Abstract] OR antipsychot*[Title/Abstract] OR 

anti-psychot*[Title/Abstract] OR neuroleptic*[Title/Abstract] OR mood stabilizer*[Title/Abstract] OR 

antiepileptic*[Title/Abstract] OR anti-epileptic*[Title/Abstract] OR anticonvulsant*[Title/Abstract] OR 

anti-convulsant*[Title/Abstract] OR poor*[Title/Abstract] OR patient*[Title/Abstract] OR 

client*[Title/Abstract] OR refus*[Title/Abstract])) AND (adheren*[Title/Abstract] OR nonadheren*[Title/Abstract] OR nonadheren*[Title/Abstract] OR complian*[Title/Abstract] OR noncomplian*[Title/Abstract] OR noncomplian*[Title/Abstract] OR persist*[Title/Abstract] OR nonpersist*[Title/Abstract] OR nonpersist*[Title/Abstract] OR reconciliat*[Title/Abstract])) AND publisher 

[sb]

6539

Ovid PsycINFO 1806 to January Week 4 2015 

Date searched: January 29, 2015 

1 (((medication* or pharmaceutical* or drug* or pharmacotherap* or regimen* or therap* or treat* or 

prophylaxis or psychotropic or psychopharmac* or pharmacolog* or antipsychot* or anti-psychot* or 

neuroleptic* or mood stabilizer* or antiepileptic* or anti-epileptic* or anticonvulsant* or anticonvulsant* or poor* or patient* or client* or refus*) adj3 (adheren* or non-adheren* or nonadheren* 

or complian* or non-complian* or noncomplian* or persist* or non-persist* or nonpersist* or 

reconciliat*)) or medication therapy management or treatment refusal).ti,ab.

18146 

2 psychosis/ or acute psychosis/ or affective psychosis/ or alcoholic psychosis/ or capgras syndrome/ or 

childhood psychosis/ or chronic psychosis/ or experimental psychosis/ or hallucinosis/ or "paranoia 

(psychosis)"/ or postpartum psychosis/ or reactive psychosis/ or senile psychosis/ or toxic psychoses/

24899 

3 schizophrenia/ or acute schizophrenia/ or catatonic schizophrenia/ or paranoid schizophrenia/ or 

process schizophrenia/ or "schizophrenia (disorganized type)"/ or schizophreniform disorder/ or 

undifferentiated schizophrenia/ or Folie A Deux/

73717 

4 exp Schizoid Personality Disorder/ 608 

5 schizotypal personality disorder/ or schizotypy/ 1533 

6 bipolar disorder/ or cyclothymic personality/ 20400 

7 mania/ or hypomania/ 5245 

8 posttraumatic stress disorder/ 22851 

9 acute stress disorder/ 463 

10 (psychotic or schizotyp* or schizophren* or schizoid* or schizoaffective or bipolar or mania* or 

hypomania* or hypo-mania* or manic or cyclothymic or PTSD or post-traumatic stress or 

posttraumatic stress or ((severe* or serious* or chronic* or persistent*) adj mental* ill*)).ti,ab.

184993 

11 or/2-10 196933 

12 exp Policy Making/ or exp Government Policy Making/ or exp Health Care Services/ or exp Public 

Health Services/ or exp Mental Health Services/ or exp Health Education/ or exp Mental Health 

Programs/ or exp Public Health/ or exp Health Care Policy/ or exp Government Agencies/

167408 

13 health insurance/ or employee health insurance/ or fee for service/ or health maintenance 

organizations/ or medicaid/ or medicare/ or "underinsured (health insurance)"/ or "uninsured (health 

insurance)"/ or managed care/

9796 

14 exp Primary Health Care/ 13140 

15 exp Prescription Drugs/ 2777 

16 exp Polypharmacy/ 816 

17 health care costs/ 7325 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

104

18 exp Program Development/ 7372 

19 exp Disease Management/ 4344 

20 pharmacists/ or medical personnel/ 6007 

21 (intervention or interventions or program* or reduce or reduction or patient-level* or system-level* or 

policy-level* or provider* or strateg* or enhanc* or improv* or increas* or device* or pill* or 

packag* or policy or policies or benefit* or insurance or insured or contain* or co-pay* or copay* or 

cost* or pharmacy* or pharmacies* or pharmacist* or pharmacologist* or remind* or refill* or re-fill* 

or inject* or depot* or LAI or dosing or tele* or email* or text* or virtual* or computer* or 

electronic* or internet or ehealth or online or interactive* or interdisciplinary or inter-disciplinary or 

technolog* or monitor* or record* or data* or manag* or self-manag* or counsel* or therap* or 

alliance or coordinat* or co-ordinat* or communicat* or cognitive or interview* or psychosocial or 

psycho-social or multicomponent or multi-component or support* or tailor* or coach* or diary or 

diaries or behavioral or behavioural or family* or families* or peer* or communit* or decision* or 

educat* or psychoeducation* or psychoeducation* or train* or incentiv* or facilitat* or "supervised 

treatment in out-patients for schizophren*" or STOPS or ((reduc* or remov*) adj2 barrier*) or "30-day 

Adherence Question" or "5-item Questionnaire" or "Adherence Attitude Inventory" or "Adherence 

Question" or "Adherence Questionnaire" or "Adherence Self-Report Questionnaire" or ASRQ or 

"Adherence Starts with Knowledge-12" or ASK-12 or "Adherence Starts with Knowledge-20" or 

ASK-20 or "Adherence to Refills and Medications Scale" or "Adherence Visual Analogue Scale" or 

"Beliefs about Medicines Questionnaire" or "Beliefs and Behaviour Questionnaire" or "Beliefs and 

Behavior Questionnaire" or "Brief Adherence Rating Scale" or "Brief Evaluation of Medication 

Influences and Beliefs" or BEMIB or "Brief Medication Questionnaire" or "Brooks Medication 

Adherence Scale" or BMAS or "Centre for Adherence Support Evaluation" or "CASE Adherence

Index" or "CASE Index" or "Compliance Questionnaire Rheumatology" or "Drug Attitude Inventory" 

or "Hill-Bone Compliance Scale" or "Immunosuppressant Therapy Adherence Scale" or ITAS or 

"Maastricht Utrecht Adherence in Hypertension Questionnaire" or MUAH or "Medication Adherence 

Assessment Tool" or MAAT or "Medication Adherence Questionnaire" or MAQ or "Medication 

Adherence Reasons Scale" or "Medication Adherence Report Scale*" or "Medication Adherence SelfEfficacy Scale" or MASES or "Medication Adherence Self-Efficacy Scale Revised" or MASES-R or 

"Morisky Medication Adherence Scale" or MMAS or "Modified Morisky Scale" or MMS or Morisky8 or MMS-8 or Morisky-4 or MMS-4 or "Osteoporosis-Specific Morisky Medication Adherence 

Scale" or OS-MMAS or "Reported Adherence to Medicine Scale" or "Self-Reported Adherence 

Questionnaire" or SERAD or "Simplified Medication Adherence Questionnaire" or SMAQ or "Stages 

of Change for Adherence" or SOCA or "The Patterns of Asthma Medication Use Questionnaire" or 

"The Self-Efficacy for Appropriate Medication Use Scale").ti,ab.

3621995

22 or/12-21 3623396

23 and/1,11,22 3802 

24 limit 23 to animal 38 

25 limit 24 to human 14 

26 24 not 25 24 

27 23 not 26 3778 

28 limit 27 to (childhood <birth to 12 years> or adolescence <13 to 17 years>) 246 

29 limit 28 to adulthood <18+ years> 176 

30 28 not 29 70 

31 27 not 30 3708 

32 limit 31 to (("0200 clinical case study" or 1400 nonclinical case study) and (chapter or 

"column/opinion" or "comment/reply" or editorial or encyclopedia entry or letter or obituary or poetry 

or publication information or reprint or review-book or review-media or review-software & other))

84 

33 31 not 32 3624 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

105

34 limit 33 to english language 3270 

EMBASE (Elsevier)

http://embase.com

Searched Date: January 29, 2015 

Set Search Strategy Results

#50 #49 AND [english]/lim 3,004

#49 #48 NOT 'case report'/de 3,508

#48 #47 NOT ([editorial]/lim OR [letter]/lim) 3,773

#47 #44 NOT #46 3,884

#46 #44 AND ([newborn]/lim OR [infant]/lim OR [child]/lim OR [preschool]/lim OR 

[school]/lim OR [adolescent]/lim) NOT ([young adult]/lim OR [adult]/lim OR [middle 

aged]/lim OR [aged]/lim OR [very elderly]/lim)

113

#44 #42 NOT #43 3,997

#43 #42 AND [animals]/lim NOT [humans]/lim 13

#42 #41 NOT [medline]/lim 4,010

#41 #6 AND #16 AND #40 9,802

#40 #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #27 OR #28 OR 

#29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39

15,867,816

#39 intervention:ab,ti OR interventions:ab,ti OR program*:ab,ti OR reduce:ab,ti OR 

reduction:ab,ti OR 'patient-level':ab,ti OR 'patient-levels':ab,ti OR 'system-level':ab,ti OR 

'system-levels':ab,ti OR 'policy-level':ab,ti OR 'policy-levels':ab,ti OR provider*:ab,ti OR 

strateg*:ab,ti OR enhanc*:ab,ti OR improv*:ab,ti OR increas*:ab,ti OR device*:ab,ti OR 

pill*:ab,ti OR packag*:ab,ti OR policy:ab,ti OR policies:ab,ti OR benefit*:ab,ti OR 

insurance:ab,ti OR insured:ab,ti OR contain*:ab,ti OR 'co-pay':ab,ti OR 'co-pays':ab,ti OR 

copay*:ab,ti OR cost*:ab,ti OR pharmacy*:ab,ti OR pharmacies*:ab,ti OR pharmacist*:ab,ti 

OR pharmacologist*:ab,ti OR remind*:ab,ti OR refill*:ab,ti OR 're-fill':ab,ti OR 're-fills':ab,ti 

OR inject*:ab,ti OR depot*:ab,ti OR lai:ab,ti OR dosing:ab,ti OR tele*:ab,ti OR email*:ab,ti 

OR text*:ab,ti OR virtual*:ab,ti OR computer*:ab,ti OR electronic*:ab,ti OR internet:ab,ti 

OR ehealth:ab,ti OR online:ab,ti OR interactive*:ab,ti OR interdisciplinary:ab,ti OR 'interdisciplinary':ab,ti OR technolog*:ab,ti OR monitor*:ab,ti OR record*:ab,ti OR data*:ab,ti 

OR manag*:ab,ti OR 'self-management':ab,ti OR 'self-managing':ab,ti OR counsel*:ab,ti OR 

therap*:ab,ti OR alliance:ab,ti OR coordinat*:ab,ti OR 'co-ordinated':ab,ti OR 'coordination':ab,ti OR communicat*:ab,ti OR cognitive:ab,ti OR interview*:ab,ti OR 

psychosocial:ab,ti OR 'psycho-social':ab,ti OR multicomponent:ab,ti OR 'multicomponent':ab,ti OR support*:ab,ti OR tailor*:ab,ti OR coach*:ab,ti OR diary:ab,ti OR 

diaries:ab,ti OR behavioral:ab,ti OR behavioural:ab,ti OR family*:ab,ti OR families*:ab,ti 

OR peer*:ab,ti OR communit*:ab,ti OR decision*:ab,ti OR educat*:ab,ti OR 

psychoeducation*:ab,ti OR 'psychoeducation':ab,ti OR 'psychoeducational':ab,ti OR 

train*:ab,ti OR incentiv*:ab,ti OR facilitat*:ab,ti OR 'supervised treatment in outpatients for 

schizophrenia':ab,ti OR stops:ab,ti OR barrier*:ab,ti OR '30-day adherence question':ab,ti 

OR '5-item questionnaire':ab,ti OR 'adherence attitude inventory':ab,ti OR 'adherence 

question':ab,ti OR 'adherence questionnaire':ab,ti OR 'adherence self-report 

questionnaire':ab,ti OR asrq:ab,ti OR 'adherence starts with knowledge-12':ab,ti OR 'ask 

12':ab,ti OR 'adherence starts with knowledge-20':ab,ti OR 'ask 20':ab,ti OR 'adherence to 

refills and medications scale':ab,ti OR 'adherence visual analogue scale':ab,ti OR 'beliefs 

about medicines questionnaire':ab,ti OR 'beliefs and behaviour questionnaire':ab,ti OR 

'beliefs and behavior questionnaire':ab,ti OR 'brief adherence rating scale':ab,ti OR 'brief 

evaluation of medication influences and beliefs':ab,ti OR bemib:ab,ti OR 'brief medication 

14,570,620
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

106

questionnaire':ab,ti OR 'brooks medication adherence scale':ab,ti OR bmas:ab,ti OR 'centre 

for adherence support evaluation':ab,ti OR 'case adherence index':ab,ti OR 'case index':ab,ti 

OR 'compliance questionnaire rheumatology':ab,ti OR 'drug attitude inventory':ab,ti OR 'hillbone compliance scale':ab,ti OR 'immunosuppressant therapy adherence scale':ab,ti OR 

itas:ab,ti OR 'maastricht utrecht adherence in hypertension questionnaire':ab,ti OR muah:ab,ti 

OR 'medication adherence assessment tool':ab,ti OR maat:ab,ti OR 'medication adherence 

questionnaire':ab,ti OR maq:ab,ti OR 'medication adherence reasons scale':ab,ti OR 

'medication adherence report scale':ab,ti OR 'medication adherence self-efficacy scale':ab,ti 

OR mases:ab,ti OR 'medication adherence self-efficacy scale revised':ab,ti OR 'mases r':ab,ti 

OR 'morisky medication adherence scale':ab,ti OR mmas:ab,ti OR 'modified morisky 

scale':ab,ti OR mms:ab,ti OR 'morisky 8':ab,ti OR 'mms 8':ab,ti OR 'morisky 4':ab,ti OR 

'mms 4':ab,ti OR 'osteoporosis-specific morisky medication adherence scale':ab,ti OR 'os 

mmas':ab,ti OR 'reported adherence to medicine scale':ab,ti OR 'self-reported adherence 

questionnaire':ab,ti OR serad:ab,ti OR 'simplified medication adherence questionnaire':ab,ti 

OR smaq:ab,ti OR 'stages of change for adherence':ab,ti OR soca:ab,ti OR 'the patterns of 

asthma medication use questionnaire':ab,ti OR 'the self-efficacy for appropriate medication 

use scale':ab,ti

#38 'hospital pharmacy'/de 12,567

#37 'disease management'/exp 1,803,597

#36 'program development'/de 17,753

#35 'socioeconomics'/exp 181,927

#34 'health services research'/de 27,052

#33 'drug packaging'/de 7,798

#32 'drug cost'/de 59,763

#31 'polypharmacy'/de 7,731

#30 'prescription drug'/de 4,089

#29 'primary health care'/exp 111,492

#28 'health maintenance organization'/de 17,030

#27 'health insurance'/exp 190,051

#25 'pharmacy'/de 56,409

#24 'health care policy'/de 146,123

#23 'health care delivery'/exp 2,034,947

#22 ‘medicaid’/exp 29,190

#21 'medicare'/exp 53,706

#20 'insurance'/exp 235,070

#19 'health care planning'/de 79,255

#18 'policy'/de 76,327

#17 'management'/exp 731,630

#16 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 346,198

#15 psychotic:ab,ti OR schizotyp*:ab,ti OR schizophren*:ab,ti OR schizoid*:ab,ti OR 

schizoaffective:ab,ti OR bipolar:ab,ti OR mania*:ab,ti OR hypomania*:ab,ti OR 'hypomania':ab,ti OR 'hypo-manias':ab,ti OR manic:ab,ti OR cyclothymic*:ab,ti OR ptsd*:ab,ti 

OR 'post-traumatic stress':ab,ti OR 'posttraumatic stress':ab,ti OR 'severe mental illness':ab,ti 

OR 'severely mentally ill':ab,ti OR 'serious mental illness':ab,ti OR 'seriously mentally 

ill':ab,ti OR 'chronic mental illness':ab,ti OR 'chronically mentally ill':ab,ti OR 'persistent 

mental illness':ab,ti OR 'persistently mentally ill':ab,ti

232,690

#14 'acute stress disorder'/de 980

#13 'posttraumatic stress disorder'/de 36,791

#12 'bipolar disorder'/exp 50,154

#11 'schizotypal personality disorder'/de 1,908

#10 'schizoidism'/de 2,514

#9 'shared psychotic disorder'/exp 219

#8 'schizophrenia'/exp 145,829

#7 'psychosis'/exp 224,632

#6 #1 OR #2 OR #3 OR #4 OR #5 187,065

#5 ((medication* OR pharmaceutical* OR drug* OR pharmacotherap* OR regimen* OR 108,783
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

107

therap* OR treat* OR prophylaxis OR psychotropic OR psychopharmac* OR pharmacolog* 

OR antipsychot* OR 'anti psychotic' OR 'anti psychotics' OR neuroleptic* OR 'mood 

stabilizer' OR 'mood stabilizers' OR antiepileptic* OR 'anti epileptic' OR 'anti epileptics' OR 

anticonvulsant* OR 'anti convulsant' OR 'anti convulsants' OR poor* OR patient* OR client* 

OR refus*) NEAR/3 (adheren* OR 'non adherent' OR 'non adherence' OR nonadheren* OR 

complian* OR 'non compliant' OR 'non compliance' OR noncomplian* OR persistent OR 

persistence OR 'non persistent' OR 'non persistence' OR nonpersistence OR nonpersistent OR 

reconciliat*)):ab,ti

#4 'medication compliance'/de 12,550

#3 'medication compliance'/de 3,630

#2 ‘patient compliacne’/de 99,293

#1 'medication compliance'/de 6,242

Cochrane Library (Ovid EBM Reviews)

Cochrane Central Register of Controlled Trials December 2014 

Cochrane Database of Systematic Reviews 2005 to December 2014 

Database of Abstracts of Reviews of Effects 4th Quarter 2014 

Health Technology Assessment 4th Quarter 2014 

NHS Economic Evaluation Database 4th Quarter 2014

Date Searched: January 29, 2015 

1 (((medication* or pharmaceutical* or drug* or pharmacotherap* or regimen* or therap* or treat* or 

prophylaxis or psychotropic or psychopharmac* or pharmacolog* or antipsychot* or anti-psychot* or 

neuroleptic* or mood stabilizer* or antiepileptic* or anti-epileptic* or anticonvulsant* or anticonvulsant* or poor* or patient* or client* or refus*) adj3 (adheren* or non-adheren* or nonadheren* 

or complian* or non-complian* or noncomplian* or persist* or non-persist* or nonpersist* or 

reconciliat*)) or medication therapy management).ti,ab. 

14975 

2 (psychotic or schizotyp* or schizophren* or schizoid* or schizoaffective or bipolar or mania* or 

hypomania* or hypo-mania* or manic or cyclothymic or PTSD or post-traumatic stress or 

posttraumatic stress or ((severe* or serious* or chronic* or persistent*) adj mental* ill*)).ti,ab. 

15934 

3 (intervention or interventions or program* or reduce or reduction or patient-level* or system-level* or 

policy-level* or provider* or strateg* or enhanc* or improv* or increas* or device* or pill* or 

packag* or policy or policies or benefit* or insurance or insured or contain* or co-pay* or copay* or 

cost* or pharmacy* or pharmacies* or pharmacist* or pharmacologist* or remind* or refill* or re-fill* 

or inject* or depot* or LAI or dosing or tele* or email* or text* or virtual* or computer* or 

electronic* or internet or ehealth or online or interactive* or interdisciplinary or inter-disciplinary or 

technolog* or monitor* or record* or data* or manag* or self-manag* or counsel* or therap* or 

alliance or coordinat* or co-ordinat* or communicat* or cognitive or interview* or psychosocial or 

psycho-social or multicomponent or multi-component or support* or tailor* or coach* or diary or 

diaries or behavioral or behavioural or family* or families* or peer* or communit* or decision* or 

educat* or psychoeducation* or psychoeducation* or train* or incentiv* or facilitat* or supervised 

treatment in out-patients for schizophren* or STOPS or (((reduc* or remov*) adj2 barrier*) or "30-day 

Adherence Question" or "5-item Questionnaire" or "Adherence Attitude Inventory" or "Adherence 

Question" or "Adherence Questionnaire" or "Adherence Self-Report Questionnaire" or ASRQ or 

"Adherence Starts with Knowledge-12" or ASK-12 or "Adherence Starts with Knowledge-20" or 

ASK-20 or "Adherence to Refills and Medications Scale" or "Adherence Visual Analogue Scale" or 

"Beliefs about Medicines Questionnaire" or "Beliefs and Behaviour Questionnaire" or "Beliefs and 

Behavior Questionnaire" or "Brief Adherence Rating Scale" or "Brief Evaluation of Medication 

Influences and Beliefs" or BEMIB or "Brief Medication Questionnaire" or "Brooks Medication 

Adherence Scale" or BMAS or "Centre for Adherence Support Evaluation" or "CASE Adherence 

Index" or "CASE Index" or "Compliance Questionnaire Rheumatology" or "Drug Attitude Inventory" 

or "Hill-Bone Compliance Scale" or "Immunosuppressant Therapy Adherence Scale" or ITAS or 

"Maastricht Utrecht Adherence in Hypertension Questionnaire" or MUAH or "Medication Adherence 

591600
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

108

Assessment Tool" or MAAT or "Medication Adherence Questionnaire" or MAQ or "Medication 

Adherence Reasons Scale" or "Medication Adherence Report Scale*" or "Medication Adherence SelfEfficacy Scale" or MASES or "Medication Adherence Self-Efficacy Scale Revised" or MASES-R or 

"Morisky Medication Adherence Scale" or MMAS or "Modified Morisky Scale" or MMS or Morisky8 or MMS-8 or Morisky-4 or MMS-4 or "Osteoporosis-Specific Morisky Medication Adherence 

Scale" or OS-MMAS or "Reported Adherence to Medicine Scale" or "Self-Reported Adherence 

Questionnaire" or SERAD or "Simplified Medication Adherence Questionnaire" or SMAQ or "Stages 

of Change for Adherence" or SOCA or "The Patterns of Asthma Medication Use Questionnaire" or 

"The Self-Efficacy for Appropriate Medication Use Scale")).ti,ab. 

4 and/1-3 700 

5 limit 4 to medline records [Limit not valid in CDSR,DARE,CLHTA,CLEED; records were retained] 419 

6 4 not 5 281 

7 limit 6 to english language [Limit not valid in CDSR,DARE; records were retained] 155 

 

EBSCOHost CINAHL Plus with Full Text

Date Searched: January 29, 2015 

Search 

ID# Search Terms Search Options Actions 

S40 S7 AND S16 AND S39 Limiters - English 

Language; Age Groups: 

Adult: 19-44 years, 

Middle Aged: 45-64 

years, Aged: 65+ years, 

Aged, 80 and over; 

Exclude MEDLINE 

records

152 

S39 S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR 

S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR 

S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR 

S38 

2,861,309 

S38 (AB intervention or interventions or program* or reduce or 

reduction or patient-level* or system-level* or policy-level* 

or provider* or strateg* or enhanc* or improv* or increas* or 

device* or pill* or packag* or policy or policies or benefit* 

or insurance or insured or contain* or co-pay* or copay* or 

cost* or pharmacy* or pharmacies* or pharmacist* or 

pharmacologist* or remind* or refill* or re-fill* or inject* or 

depot* or LAI or dosing or tele* or email* or text* or 

virtual* or computer* or electronic* or internet or ehealth or 

online or interactive* or interdisciplinary or inter-disciplinary 

or technolog* or monitor* or record* or data* or manag* or 

self-manag* or counsel* or therap* or alliance or coordinat* 

or co-ordinat* or communicat* or cognitive or interview* or 

psychosocial or psycho-social or multicomponent or multicomponent or support* or tailor* or coach* or diary or diaries 

or behavioral or behavioural or family* or families* or peer* 

or communit* or decision* or educat* or psychoeducation* 

or psychoeducation* or train* or incentiv* or facilitat* or 

"supervised treatment in out-patients for schizophren*" or 

STOPS or ((reduc* or remov*) adj2 barrier*) or "30-day 

2,838,440 
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Adherence Question" or "5-item Questionnaire" or 

"Adherence Attitude Inventory" or "Adherence Question" or 

"Adherence Questionnaire" or "Adherence Self-Report 

Questionnaire" or ASRQ or "Adherence Starts with 

Knowledge-12" or ASK-12 or "Adherence Starts with 

Knowledge-20" or ASK-20 or "Adherence to Refills and 

Medications Scale" or "Adherence Visual Analogue Scale" or 

"Beliefs about Medicines Questionnaire" or "Beliefs and 

Behaviour Questionnaire" or "Beliefs and Behavior 

Questionnaire" or "Brief Adherence Rating Scale" or "Brief 

Evaluation of Medication Influences and Beliefs" or BEMIB 

or "Brief Medication Questionnaire" or "Brooks Medication 

Adherence Scale" or BMAS or "Centre for Adherence 

Support Evaluation" or "CASE Adherence Index" or "CASE 

Index" or "Compliance Questionnaire Rheumatology" or 

"Drug Attitude Inventory" or "Hill-Bone Compliance Scale" 

or "Immunosuppressant Therapy Adherence Scale" or ITAS 

or "Maastricht Utrecht Adherence in Hypertension 

Questionnaire" or MUAH or "Medication Adherence 

Assessment Tool" or MAAT or "Medication Adherence 

Questionnaire" or MAQ or "Medication Adherence Reasons 

Scale" or "Medication Adherence Report Scale*" or 

"Medication Adherence Self-Efficacy Scale" or MASES or 

"Medication Adherence Self-Efficacy Scale Revised" or 

MASES-R or "Morisky Medication Adherence Scale" or 

MMAS or "Modified Morisky Scale" or MMS or Morisky-8 

or MMS-8 or Morisky-4 or MMS-4 or "OsteoporosisSpecific Morisky Medication Adherence Scale" or OSMMAS or "Reported Adherence to Medicine Scale" or "SelfReported Adherence Questionnaire" or SERAD or 

"Simplified Medication Adherence Questionnaire" or SMAQ 

or "Stages of Change for Adherence" or SOCA or "The 

Patterns of Asthma Medication Use Questionnaire" or "The 

Self-Efficacy for Appropriate Medication Use Scale"

S37 (TI intervention or interventions or program* or reduce or 

reduction or patient-level* or system-level* or policy-level* 

or provider* or strateg* or enhanc* or improv* or increas* or 

device* or pill* or packag* or policy or policies or benefit* 

or insurance or insured or contain* or co-pay* or copay* or 

cost* or pharmacy* or pharmacies* or pharmacist* or 

pharmacologist* or remind* or refill* or re-fill* or inject* or 

depot* or LAI or dosing or tele* or email* or text* or 

virtual* or computer* or electronic* or internet or ehealth or 

online or interactive* or interdisciplinary or inter-disciplinary 

or technolog* or monitor* or record* or data* or manag* or 

self-manag* or counsel* or therap* or alliance or coordinat* 

or co-ordinat* or communicat* or cognitive or interview* or 

psychosocial or psycho-social or multicomponent or multicomponent or support* or tailor* or coach* or diary or diaries 

or behavioral or behavioural or family* or families* or peer* 

or communit* or decision* or educat* or psychoeducation* 

or psychoeducation* or train* or incentiv* or facilitat* or 

"supervised treatment in out-patients for schizophren*" or 

STOPS or ((reduc* or remov*) adj2 barrier*) or "30-day 

Adherence Question" or "5-item Questionnaire" or 

"Adherence Attitude Inventory" or "Adherence Question" or 

2,839,476 
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"Adherence Questionnaire" or "Adherence Self-Report 

Questionnaire" or ASRQ or "Adherence Starts with 

Knowledge-12" or ASK-12 or "Adherence Starts with 

Knowledge-20" or ASK-20 or "Adherence to Refills and 

Medications Scale" or "Adherence Visual Analogue Scale" or 

"Beliefs about Medicines Questionnaire" or "Beliefs and 

Behaviour Questionnaire" or "Beliefs and Behavior 

Questionnaire" or "Brief Adherence Rating Scale" or "Brief 

Evaluation of Medication Influences and Beliefs" or BEMIB 

or "Brief Medication Questionnaire" or "Brooks Medication 

Adherence Scale" or BMAS or "Centre for Adherence 

Support Evaluation" or "CASE Adherence Index" or "CASE 

Index" or "Compliance Questionnaire Rheumatology" or 

"Drug Attitude Inventory" or "Hill-Bone Compliance Scale" 

or "Immunosuppressant Therapy Adherence Scale" or ITAS 

or "Maastricht Utrecht Adherence in Hypertension 

Questionnaire" or MUAH or "Medication Adherence 

Assessment Tool" or MAAT or "Medication Adherence 

Questionnaire" or MAQ or "Medication Adherence Reasons 

Scale" or "Medication Adherence Report Scale*" or 

"Medication Adherence Self-Efficacy Scale" or MASES or 

"Medication Adherence Self-Efficacy Scale Revised" or 

MASES-R or "Morisky Medication Adherence Scale" or 

MMAS or "Modified Morisky Scale" or MMS or Morisky-8 

or MMS-8 or Morisky-4 or MMS-4 or "OsteoporosisSpecific Morisky Medication Adherence Scale" or OSMMAS or "Reported Adherence to Medicine Scale" or "SelfReported Adherence Questionnaire" or SERAD or 

"Simplified Medication Adherence Questionnaire" or SMAQ 

or "Stages of Change for Adherence" or SOCA or "The 

Patterns of Asthma Medication Use Questionnaire" or "The 

Self-Efficacy for Appropriate Medication Use Scale")

S36 (MH "Drug Administration Schedule") 9,991 

S35 (MH "Pharmacy Service") 4,334 

S34 (MH "Disease Management") 9,150 

S33 (MH "Program Development") 16,877 

S32 (MH "Health Services Research") 9,793 

S31 (MH "Drug Packaging") 869 

S30 (MH "Polypharmacy") 2,179 

S29 (MH "Drugs, Prescription") 13,214 

S28 (MH "Primary Health Care/AM/EC") 3,452 

S27 (MH "Health Maintenance Organizations/AM") 413 

S26 (MH "Managed Care Programs") 10,452 

S25 (MH "Insurance, Pharmaceutical Services") 1,396 

S24 (MH "Pharmacy Service") 4,334 

S23 (MH "Formularies") 1,426 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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S22 (MH "Health Policy") 33,206 

S21 (MH "Health Services Accessibility") 51,804 

S20 (MH "Medicaid") 12,256 

S19 (MH "Medicare") 27,432 

S18 (MH "Public Policy") 14,087 

S17 (MH "Policy Making") 6,812 

S16 S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 50,411

S15 (AB psychotic or schizotyp* or schizophren* or schizoid* or 

schizoaffective or bipolar or mania* or hypomania* or hypomania* or manic or cyclothymic or PTSD or post-traumatic 

stress or posttraumatic stress or ((severe* or serious* or 

chronic* or persistent*) N1 mental* ill*)) 

39,775 

S14 (TI psychotic or schizotyp* or schizophren* or schizoid* or 

schizoaffective or bipolar or mania* or hypomania* or hypomania* or manic or cyclothymic or PTSD or post-traumatic 

stress or posttraumatic stress or ((severe* or serious* or 

chronic* or persistent*) N1 mental* ill*)) 

39,263 

S13 (MH "Stress Disorders, Post-Traumatic") 12,867 

S12 (MH "Bipolar Disorder") OR (MH "Cyclothymic Disorder") 7,216 

S11 (MH "Schizotypal Personality Disorder") 154

S10 (MH "Catatonia") 259 

S9 (MH "Schizophrenia") 15,895 

S8 (MH "Psychotic Disorders") OR (MH "Affective Disorders, 

Psychotic") OR (MH "Organic Mental Disorders, Psychotic") 

OR (MH "Postpartum Psychosis") OR (MH "Paranoid 

Disorders") 

7,494

S7 S1 OR S2 OR S3 OR S4 OR S5 OR S6 45,088 

S6 ((AB medication* or pharmaceutical* or drug* or 

pharmacotherap* or regimen* or therap* or treat* or 

prophylaxis or psychotropic or psychopharmac* or 

pharmacolog* or antipsychot* or anti-psychot* or 

neuroleptic* or mood stabilizer* or antiepileptic* or antiepileptic* or anticonvulsant* or anti-convulsant* or poor* or 

patient* or client* or refus*) N3 (AB adheren* or nonadheren* or nonadheren* or complian* or non-complian* or 

noncomplian* or persist* or non-persist* or nonpersist* or 

reconciliat*)) or (AB medication therapy management)

32,326 

S5 ((TI medication* or pharmaceutical* or drug* or 

pharmacotherap* or regimen* or therap* or treat* or 

prophylaxis or psychotropic or psychopharmac* or 

pharmacolog* or antipsychot* or anti-psychot* or 

neuroleptic* or mood stabilizer* or antiepileptic* or antiepileptic* or anticonvulsant* or anti-convulsant* or poor* or 

patient* or client* or refus*) N3 (TI adheren* or nonadheren* or nonadheren* or complian* or non-complian* or 

33,726 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

112

noncomplian* or persist* or non-persist* or nonpersist* or 

reconciliat*)) or (TI medication therapy management)

S4 (MH "Treatment Refusal") 3,723 

S3 (MH "Medication Reconciliation") 763 

S2 (MH "Patient Compliance") 20,473 

S1 (MH "Medication Compliance") 10,944 

ClinicalTrials.gov

Searched Date: January 29, 2013 

Search Strategy-Advanced Search Interface Result

SEARCH TERMS: adherence OR adherent OR non-adherence OR non-adherent OR nonadherence OR 

nonadherent OR compliance OR compliant OR non-compliant OR noncompliant OR non-compliance OR 

noncompliance OR persistence OR non-persistence OR nonpersistence OR reconciliation 

RECRUITMENT: Closed Studies

STUDY RESULTS: All Studies

STUDY TYPE: Interventional Studies 

CONDITIONS: psychosis OR psychotic OR schizotypal OR schizophrenia OR schizophreniform OR 

schizoidal OR schizoaffective OR bipolar OR mania OR manias OR hypomania OR hypo-mania OR 

cyclothymic OR PTSD OR post-traumatic stress OR posttraumatic stress 

439

WHO ICTRP (World Health Organization, International Clinical Trials Registry 

Platform) 

http://apps.who.int/trialsearch/AdvSearch.aspx 

Searched Date: January 29, 2015 

Search Strategy Result

TITLE SEARCH: adherence OR adherent OR non-adherence OR non-adherent OR 

nonadherence OR nonadherent OR compliance OR compliant OR non-compliant OR 

noncompliant OR non-compliance OR noncompliance OR persistence OR non-persistence OR 

nonpersistence OR reconciliation

AND

CONDITION SEARCH: psychosis OR psychotic OR schizotypal OR schizophrenia OR 

schizophreniform OR schizoidal OR schizoaffective OR bipolar OR mania OR manias OR 

hypomania OR hypo-mania OR cyclothymic OR PTSD OR post-traumatic stress OR 

posttraumatic stress

81 records for 

79 trials found
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

113

ISRCTN Registry

http://www.isrctn.com/editAdvancedSearch 

Searched Date: January 30, 2015 

Search Strategy Result

TEXT SEARCH: 

Adherence OR adherent OR non-adherence OR non-adherent OR nonadherence OR nonadherent

OR compliance OR compliant OR non-compliance OR non-compliant OR noncompliance OR 

noncompliant OR persistence OR non-persistence OR nonpersistence or reconciliation or 

“medication therapy management”

AND

CONDITION SEARCH: 

psychotic OR psychosis OR schizotypal OR schizophrenia OR schizophrenic OR 

schizophreniform OR schizoid OR schizoaffective OR bipolar OR mania OR manias OR 

hypomania OR hypomanias OR hypo-mania OR hypo-manias OR manic OR cyclothymic OR 

PTSD OR post-traumatic stress OR posttraumatic stress OR severely mentally ill OR severe 

mental illness OR seriously mentally ill OR serious mental illness OR chronically mentally ill 

OR chronic mental illness OR persistently mentally ill OR persistent mental illness

0

ProQuest Conference Papers Index

Searched Date: January 29, 2015 

Search Strategy (Command Line Search) Results

TI,AB(medication* or pharmaceutical* or drug* or pharmacotherap* or regimen* or therap* or 

treat* or prophylaxis or psychotropic or psychopharmac* or pharmacolog* or antipsychot* or 

anti-psychot* or neuroleptic* or mood stabilizer* or antiepileptic* or anti-epileptic* or 

anticonvulsant* or anti-convulsant* or poor* or patient* or client* or refus*)

AND TI,AB(adheren* or non-adheren* or nonadheren* or complian* or non-complian* or 

noncomplian* or persist* or non-persist* or nonpersist* or reconciliat*) 

AND TI,AB(psychotic or schizotyp* or schizophren* or schizoid* or schizoaffective or bipolar 

or mania* or hypomania* or hypo-mania* or manic or cyclothymic or PTSD or post-traumatic 

stress or posttraumatic stress or severe* mental* ill* or serious* mental* ill* or chronic* mental* 

ill* or persistent* mental* ill*) 

AND TI,AB(intervention or interventions or program* or reduce or reduction or patient-level* or 

system-level* or policy-level* or provider* or strateg* or enhanc* or improv* or increas* or 

device* or pill* or packag* or policy or policies or benefit* or insurance or insured or contain* 

or co-pay* or copay* or cost* or pharmacy* or pharmacies* or pharmacist* or pharmacologist* 

or remind* or refill* or re-fill* or inject* or depot* or LAI or dosing or tele* or email* or text* 

or virtual* or computer* or electronic* or internet or ehealth or online or interactive* or 

interdisciplinary or inter-disciplinary or technolog* or monitor* or record* or data* or manag* or 

self-manag* or counsel* or therap* or alliance or coordinat* or co-ordinat* or communicat* or 

cognitive or interview* or psychosocial or psycho-social or multicomponent or multi-component 

or support* or tailor* or coach* or diary or diaries or behavioral or behavioural or family* or 

families* or peer* or communit* or decision* or educat* or psychoeducation* or 

psychoeducation* or train* or incentiv* or facilitat* or supervised treatment in out-patients for 

schizophren* or STOPS or reduc* N/2 barrier* or remov* n/2 barrier* or "30-day Adherence 

Question" or "5-item Questionnaire" or "Adherence Attitude Inventory" or "Adherence 

Question" or "Adherence Questionnaire" or "Adherence Self-Report Questionnaire" or ASRQ or 

"Adherence Starts with Knowledge-12" or ASK-12 or "Adherence Starts with Knowledge-20" or 

ASK-20 or "Adherence to Refills and Medications Scale" or "Adherence Visual Analogue Scale" 

or "Beliefs about Medicines Questionnaire" or "Beliefs and Behaviour Questionnaire" or "Beliefs 

and Behavior Questionnaire" or "Brief Adherence Rating Scale" or "Brief Evaluation of 

Medication Influences and Beliefs" or BEMIB or "Brief Medication Questionnaire" or "Brooks 

Medication Adherence Scale" or BMAS or "Centre for Adherence Support Evaluation" or 

36
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

114

"CASE Adherence Index" or "CASE Index" or "Compliance Questionnaire Rheumatology" or 

"Drug Attitude Inventory" or "Hill-Bone Compliance Scale" or "Immunosuppressant Therapy 

Adherence Scale" or ITAS or "Maastricht Utrecht Adherence in Hypertension Questionnaire" or 

MUAH or "Medication Adherence Assessment Tool" or MAAT or "Medication Adherence 

Questionnaire" or MAQ or "Medication Adherence Reasons Scale" or "Medication Adherence 

Report Scale*" or "Medication Adherence Self-Efficacy Scale" or MASES or "Medication 

Adherence Self-Efficacy Scale Revised" or MASES-R or "Morisky Medication Adherence 

Scale" or MMAS or "Modified Morisky Scale" or MMS or Morisky-8 or MMS-8 or Morisky-4 

or MMS-4 or "Osteoporosis-Specific Morisky Medication Adherence Scale" or OS-MMAS or 

"Reported Adherence to Medicine Scale" or "Self-Reported Adherence Questionnaire" or 

SERAD or "Simplified Medication Adherence Questionnaire" or SMAQ or "Stages of Change 

for Adherence" or SOCA or "The Patterns of Asthma Medication Use Questionnaire" or "The 

Self-Efficacy for Appropriate Medication Use Scale")

ProQuest Dissertations & Theses Global

Searched Date: January 29, 2015 

TI,AB(medication* or pharmaceutical* or drug* or pharmacotherap* or regimen* or therap* or treat* or 

prophylaxis or psychotropic or psychopharmac* or pharmacolog* or antipsychot* or anti-psychot* or neuroleptic* 

or mood stabilizer* or antiepileptic* or anti-epileptic* or anticonvulsant* or anti-convulsant* or poor* or patient* or 

client* or refus*) AND TI,AB(adheren* or non-adheren* or nonadheren* or complian* or non-complian* or 

noncomplian* or persist* or non-persist* or nonpersist* or reconciliat*) AND TI,AB(psychotic or schizotyp* or 

schizophren* or schizoid* or schizoaffective or bipolar or mania* or hypomania* or hypo-mania* or manic or 

cyclothymic or PTSD or post-traumatic stress or posttraumatic stress or severe* mental* ill* or serious* mental* ill* 

or chronic* mental* ill* or persistent* mental* ill*) AND TI,AB(intervention or interventions or program* or 

reduce or reduction or patient-level* or system-level* or policy-level* or provider* or strateg* or enhanc* or 

improv* or increas* or device* or pill* or packag* or policy or policies or benefit* or insurance or insured or 

contain* or co-pay* or copay* or cost* or pharmacy* or pharmacies* or pharmacist* or pharmacologist* or remind* 

or refill* or re-fill* or inject* or depot* or LAI or dosing or tele* or email* or text* or virtual* or computer* or 

electronic* or internet or ehealth or online or interactive* or interdisciplinary or inter-disciplinary or technolog* or 

monitor* or record* or data* or manag* or self-manag* or counsel* or therap* or alliance or coordinat* or coordinat* or communicat* or cognitive or interview* or psychosocial or psycho-social or multicomponent or multicomponent or support* or tailor* or coach* or diary or diaries or behavioral or behavioural or family* or families* 

or peer* or communit* or decision* or educat* or psychoeducation* or psychoeducation* or train* or incentiv* or 

facilitat* or supervised treatment in out-patients for schizophren* or STOPS or reduc* N/2 barrier* or remov* n/2 

barrier* or "30-day Adherence Question" or "5-item Questionnaire" or "Adherence Attitude Inventory" or 

"Adherence Question" or "Adherence Questionnaire" or "Adherence Self-Report Questionnaire" or ASRQ or 

"Adherence Starts with Knowledge-12" or ASK-12 or "Adherence Starts with Knowledge-20" or ASK-20 or 

"Adherence to Refills and Medications Scale" or "Adherence Visual Analogue Scale" or "Beliefs about Medicines 

Questionnaire" or "Beliefs and Behaviour Questionnaire" or "Beliefs and Behavior Questionnaire" or "Brief 

Adherence Rating Scale" or "Brief Evaluation of Medication Influences and Beliefs" or BEMIB or "Brief 

Medication Questionnaire" or "Brooks Medication Adherence Scale" or BMAS or "Centre for Adherence Support 

Evaluation" or "CASE Adherence Index" or "CASE Index" or "Compliance Questionnaire Rheumatology" or "Drug 

Attitude Inventory" or "Hill-Bone Compliance Scale" or "Immunosuppressant Therapy Adherence Scale" or ITAS 

or "Maastricht Utrecht Adherence in Hypertension Questionnaire" or MUAH or "Medication Adherence Assessment 

Tool" or MAAT or "Medication Adherence Questionnaire" or MAQ or "Medication Adherence Reasons Scale" or 

"Medication Adherence Report Scale*" or "Medication Adherence Self-Efficacy Scale" or MASES or "Medication 

Adherence Self-Efficacy Scale Revised" or MASES-R or "Morisky Medication Adherence Scale" or MMAS or 

"Modified Morisky Scale" or MMS or Morisky-8 or MMS-8 or Morisky-4 or MMS-4 or "Osteoporosis-Specific 

Morisky Medication Adherence Scale" or OS-MMAS or "Reported Adherence to Medicine Scale" or "SelfReported Adherence Questionnaire" or SERAD or "Simplified Medication Adherence Questionnaire" or SMAQ or 

"Stages of Change for Adherence" or SOCA or "The Patterns of Asthma Medication Use Questionnaire" or "The 

Self-Efficacy for Appropriate Medication Use Scale")
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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APPENDIX C. STUDY SELECTION: INCLUSION/EXCLUSION 

CRITERIA FOR TITLE/ABSTRACT REVIEW 

Instructions: 

In Abstrackr, a √ designates a study as included, a ? as unknown, and an X will exclude the study. See

table below for inclusion/exclusion criteria.

When you are looking at an abstract, you will see a box to the left that is titled tags & notes. Please click

“tag study” and tag the following:

o If you are excluding a study or are unsure, but think it is appropriate background information,

please tag the study as B

o If the study meets all inclusion criteria except for study design, and the study is a crosssectional study, please exclude the study but add the tag CS.

o If the study meets all inclusion criteria except for study design, and the study is a systematic

review, please exclude the study but add the tag SR.

On the bottom of the screen, you will see a series of thumbs ups and thumbs downs next to a box with the

word “term” next to it. Adding a term highlights it in both the abstract you are viewing, as well as all 

subsequent abstracts viewed by yourself and others. This allows for faster screening. A thumbs up 

indicates that it is a relevant term (two thumbs up = highly relevant), and a thumbs down indicates that 

the term is not relevant. Using these terms is optional; however, if you do see terms in abstracts that 

would suggest that the study is relevant or not (eg, specific med adherence outcomes, “adult,” 

schizophrenia, bipolar, PTSD, common clinical outcomes, etc) that might make the screening process 

faster for everyone, feel free to use them!

Please note – if you are unsure about whether the study meets criteria (eg, population specifies mental

health disorders, but not which ones, or doesn’t state what they used to measure med adherence, please 

code ?, and we’ll look at the full text). 

While likely unnecessary, if you feel you need more guidance on the use of Abstrackr, see an instructional video: 

https://www.youtube.com/watch?v = 34Yb-ac9ULM

Include (Code √) if the study is/does 

(all criteria below must be met): 

Exclude (Code X) if the study is/does/has 

(any of the below): 

Language: English Language: Non-English Language

Population: Human Participants Population: Non-human “participants”

Age: Adults 18+ Age: < 18 years of age

Condition: Includes individuals diagnosed with 

Psychotic Spectrum Disorder –OR- Bipolar Disorder –

OR- PTSD

Condition: No diagnosis of Psychotic 

Spectrum Disorder –OR- Bipolar Disorder –

OR- PTSD

Intervention: Includes interventions designed 

specifically or are being specifically used to increase 

medication adherence

Intervention: No med adherence intervention, 

or the interventions are not specifically 

designed or used in a way to specifically 

addresses medication adherence (eg, broader 

more general group therapy or other types of 

therapies)

Comparator: Includes a comparison group (eg, another 

intervention, no intervention, usual care).

Comparator: No comparison group

Med Adherence Outcome(s): Must be the primary 

outcome –AND- must be an objective outcome (eg, 

medication container with electronic monitoring, pill 

counts, biological marker, observed intake, medication 

possession ratio [MPR], medication plasma level, 

electronic ingestible event marker) –OR- a validated 

subjective outcome (eg, self-report measure or scale such 

as the Morisky-9 [MMAS-8], Morisky-4 [MMAS-4 or 

MAQ]) 

Med Adherence Outcome(s): Not the primary 

outcome –OR- Patient self-report, caregiver 

report, case manager report, clinician’s view 

based on therapeutic response, and other nonvalidated subjective outcomes. 

Patient Outcome: Includes a patient outcome that is 

related to the medication adherence intervention AND 

medication adherence outcome reported.

Patient Outcome: No patient outcome that is 

related to the medication adherence intervention 

AND medication adherence outcome reported.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

116

Study Design: Trials, case-controlled, and cohort studies Study Design: Reviews (systematic or nonsystematic), case series, case study, case report, 

qualitative, commentary, letter to the editor, and 

any other study design not meeting inclusion 

criteria. 

Note. If at any time you are unsure of whether the study should be included, code ? 
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

117

APPENDIX D. STUDY SELECTION: INCLUSION/EXCLUSION 

CRITERIA FOR FULL-TEXT REVIEW

1. Language: Is the full text of the article in English? 

Yes.........................................................................................................................Proceed to #2

No ................................................................................................................Code X. STOP 

2. Population: Is the population human participants?

Yes .......................................................................................Proceed to #3

No ............... Code X. Add code B if retaining for background/discussion. STOP

3. Population: Are the participants adults (18 or over) in general mental health settings (inpatient or 

outpatient – forensic patients/prisoners are excluded)?

Yes ........................................................................................Proceed to #4

No ............... Code X. Add code B if retaining for background/discussion. STOP

4. Medication Adherence Intervention: Does the article include information relevant to interventions 

specifically designed to increase medication adherence?

Yes .........................................................................................Proceed to #5

No ............... Code X. Add code B if retaining for background/discussion. STOP

5. Disease Condition: Does the intervention focus on patients with psychotic spectrum disorders, bipolar 

disorder, or posttraumatic stress disorder (PTSD)?

Yes ........................................................................................Proceed to #6

No ............... Code X. Add code B if retaining for background/discussion. STOP

6. Comparator: Is there a comparison group (eg, another intervention, no intervention, usual care), or are 

there more than two time points if no comparison group exists?

Yes ........................................................................................Proceed to #7

No ............... Code X. Add code B if retaining for background/discussion. STOP

7. Medication Adherence Outcomes: Are the outcomes objective (eg, medication container with electronic 

monitoring [eg, MEMS], pill counts, biological markers, observed intake, medication possession ratio, 

medication plasma level, electronic ingestible event marker) or measured subjectively by a validated

patient self-report scale or measure (eg, not patient self-report or report by caregiver, case manager, not 

clinician’s view on adherence based on therapeutic response). 

Yes...............................................................................Proceed to #9

No .....................Code X. Add code B if retaining for background/discussion. STOP

8. Clinical Outcome: Is a clinical outcome related to the medication adherence intervention and the 

medication adherence outcome reported?

Yes..............................................................................Proceed to #10

 No.....................Code X. Add code B if retaining for background/discussion. STOP

9. Study Design: Is the study design a cross-sectional study or a simple pre-post, or qualitative study, or a 

non-systematic literature review, case study, case series, case report, commentary, or letter to the editor??

Yes...........................Code X. Add code B if retaining for background/discussion. STOP

No....................................................................................Code R. Stop

Unknown ...........................................................................Code U. Stop
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

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APPENDIX E. MEDICATION ADHERENCE OUTCOME

MEASURES 

Abbreviation Name Description Source

AMQ Attitude towards 

Medication 

Questionnaire

Semi-structured interview. Higher scores indicate a 

better attitude towards medication.

Clinician rated

CDR Concentration to 

Dose Ratio

Serum concentration for primary antipsychotic 

with higher CDRs indicating better adherence. 

Blood serum

CSRI Client Service 

Receipt Inventory

Measures the frequency and duration of service 

contacts. 

Self-report information, 

supplemented by case notes 

and hospital records

Kemp scale43 Compliance scale rated on a seven-point rating 

scale with higher scores indicating greater 

compliance

Multiple sources, including 

nurse assessed

DAI Drug Attitude 

Inventory

Shown to be associated with degree of adherence 

to psychotropic medication, and is a true/false 

questionnaire that assesses patients’ attitudes, 

experience, locus of control, attitudes towards 

medication. Scores range from 0-10 with higher 

scores indicating better attitudes towards 

medication.

Self-report

MAQ Medication 

Adherence 

Questionnaire

4-item measure that includes yes/no questions 

about forgetting to take medicine, carelessness 

with medicine, and discontinuation. A higher score 

indicates poorer treatment adherence.

Self-report

MARS Medication 

Adherence Rating 

Scale

10-item yes or no assessment of medication 

adherence, and was translated to Farsi and 

validated. (0-9 [one neutral question], higher 

scores indicate better adherence).

Self-report

MEMS Medication Event 

Monitoring 

System

Medication vial cap that electronically records the 

date/time of bottle opening.

Electronic monitoring

Morisky Scale Assesses medication adherence, feelings about 

medication, with higher scores indicating poorer 

adherence

Self-report

SAI-C Schedule for the 

Assessment of 

Insight - C

Therapist rating of adherence ranging from 1 

(complete refusal) to 7 (active participation in 

treatment) based on a semi-structured interview.

Clinician rated

TRQ Tablet Routine 

Questionnaire

Shows a high correlation with lithium levels and 

identifies partial and full adherence in the previous

7 and 30 days. 

Self-report
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APPENDIX F. PATIENT OUTCOME MEASURES

Abbreviation Name Description Source

Bech Rafaelsen 

Mania Scale

Assesses 11 items (elevated mood, pressure of speech, 

increased social contact, increased motor activity, sleep 

disturbances, social activities and distractibility, hostility 

and irritability, increased sexual activity, increased selfesteem, flight of thoughts, and noise level of speech and 

other vocal activity).

Self-report 

Administered by 

Psychologist

BPRS Brief Psychiatric 

Rating Scale

Consists of items measuring positive symptoms, negative 

symptoms, depression and anxiety and manic excitement 

or disorganization with higher scores indicating greater 

severity.

Clinician 

assessed

BPRS–E Brief Psychiatric 

Rating Scale – 

Expanded

Consists of 24 items measuring positive symptoms, 

negative symptoms, depression and anxiety and manic 

excitement or disorganization with higher scores 

indicating greater severity.

Clinician 

assessed

CGI Clinical Global 

Impression scale

Rating scale designed to assess severity and the degree of 

change from the immediately preceding phase and from 

the worst phase of illness. Higher scores indicate greater 

severity.

Clinician 

assessed

CGI –SGH Clinical Global 

Impression – 

Schizophrenia scale

Rating scale designed to assess severity and the degree of 

change from the immediately preceding phase and from 

the worst phase of illness. Higher scores indicate greater 

severity.

Clinician 

assessed

EQ-5D EuroQoL Assesses quality of life differences in patients with 

schizophrenia of differing degrees of severity. Higher 

values indicate higher quality of life ratings.

Self-report

GAF Global Assessment of 

Functioning

Assesses function impairment caused by illness, with 

scores ranging from 0-100 and higher scores indicating 

higher levels of functioning.

Clinician rated

GAS Global Assessment 

Scale

Assesses function impairment caused by illness, with 

scores ranging from 0-100 and higher scores indicating 

higher levels of functioning.

Clinician 

assessed

HAM-D Hamilton Depression 

Rating Scale

24 item scale assessing depression with scores ranging 

from 0-74, with higher scores indicating more severe 

depression.

Self-report 

LEE Level of Expressed 

Emotion

30 item measure assessing critical comments, emotional 

over-involvement, and hostility. 

Family rated

PANSS Positive and Negative 

Syndrome Scale

Used to rate positive symptoms (range 7-49), negative 

symptoms (range 7-49), and general symptoms (range 15-

112) of schizophrenia on a 7 point scale. Higher scores 

indicate higher severity.

Clinician 

assessed

QLF Quality of Life Scale 21-item scale based on semi-structured interview 

addressing intrapsychic foundations, interpersonal 

relations, instrumental role, and common objects and 

activities. 

Clinician 

assessed

SAI Schedule for 

Assessment of Insight

Scores expressed as a percentage of maximum insight. 

Higher values indicate greater insight

NR

SAI-E Schedule for 

Assessment of 

Insight- Expanded

Scores expressed as a percentage of maximum insight. 

Higher values indicate greater insight

NR
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Abbreviation Name Description Source

SF-36 Short Form Health 

Survey

Self-report multidimensional survey measure of healthrelated quality of life (QOL) and well-being. The mental 

component summary score (MCS) was used as the main 

QOL outcome measure, as it has been shown to have 

good sensitivity to change, which is uncommon among 

QOL measures.

Self-report

SOFAS Social and 

Occupational 

Functioning Scale

Assesses social, work and school functioning. Higher 

sores increase higher adaptive functioning 

Self-report

SWN Subjective Wellbeing on Neuroleptic 

Treatment Scale

20-item scale measuring mental functioning, social 

integration, emotional regulation, physical functioning, 

and self-control. 

Self-report

UKU UKU Side Effects 

Rating Scale

Semi-structured interview to assess the side effects of 

psychopharmacological interventions in the past 3 days.

Clinician 

assessed

WHOQOLBREF World Health 

Organization Quality 

of Life instrument – 

Abbreviated version

Quality of life questionnaire consisting of 26 items 

assessing physical, psychological, and social health and 

the environment. Scores for each domain are transformed 

to a 0-100 scale, with higher indicating better quality of 

life.

Self-report 

Administered by 

Psychologist

YMRS Young Mania Rating 

Scale

Assesses mania, with scores ranging from 0-44 with 

higher scores indicating more severe mania.

Self-report
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APPENDIX G. RISK OF BIAS: TRIALS

RISK OF BIAS: TRIALS, PART 1

Author, Year

Method of 

randomization 

adequate?

Allocation of treatment 

adequately concealed?

Were providers blinded 

to intervention or 

exposure status of 

participants?

Participants blinded to 

intervention or 

exposure status?

Outcome assessors 

blinded to intervention 

or exposure status of 

participants?

Bahredar et al, 201469 NR NR NR NR NR

Barkhof et al, 201358 Yes Yes No Yes Yes

Bechdolf et al, 200544 Yes Yes Yes Unclear Yes

Beebe et al, 201454 Yes Unclear No No Yes

Frangou et al, 200555 Yes No No No No

Gray et al, 200646 Yes Yes Yes No Yes

Hamann et al, 200759 Unclear Unclear No No No

Healey et al, 199842 Yes NR NR Unclear NR

Javadpour et al, 201368 Yes Yes Unclear Unclear Yes

Kemp et al, 199843 Yes NR Unclear Yes Yes

Kopelowicz et al, 201250 Yes Unclear Unclear No Yes

Montes et al, 201256 Yes Yes No No No

O’Donnell et al, 200347 Yes NR Yes NR Yes

Pitschel-Walz et al, 200651 Yes Yes Yes No Yes

Sajatovic et al, 200967 NR NR No No No

Schulz et al, 201348 Yes Yes Yes No Yes

Valencia et al, 201052 No No Yes No Yes

Velligan et al, 200860 Unclear Unclear Unclear No Yes

Velligan et al, 201357 Yes Yes Unclear Unclear Yes
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RISK OF BIAS: TRIALS, PART 2

Author, Year

Did strategy for 

recruiting 

participants into 

study differ across 

study groups?

Baseline characteristics 

similar between groups? 

If not, did analysis 

control for differences?

Impact from any 

concurrent intervention 

or unintended exposure 

that might bias results 

ruled out?

Did variation from 

study protocol 

compromise study 

conclusions?

High rate of 

differential or overall 

attrition?

Bahredar et al, 201469 NR Unclear NR NR No

Barkhof et al, 201358 No Yes Unclear Unclear No

Bechdolf et al, 200544 No Yes No NR Yes

Beebe et al, 201454 No Yes NR NR No

Frangou et al, 200555 No Yes Unclear Unclear No

Gray et al, 200646 No Yes Unclear No No

Hamann et al, 200759 Yes Yes NR NR No

Healey et al, 199842 Yes Yes Unclear NR Yes

Javadpour et al, 201368 Yes Yes Unclear Yes No

Kemp et al, 199843 No Yes No NR Yes

Kopelowicz et al, 201250 No Yes No No Yes

Montes et al, 201256 No Yes Unclear No No

O’Donnell et al, 200347 No Yes Yes NR No

Pitschel-Walz et al, 200651 No Yes Unclear Unclear No

Sajatovic et al, 200967 No Yes No NR Yes

Schulz et al, 201348 No No Yes Unclear Yes

Valencia et al, 201052 No Yes No Unclear Yes

Velligan et al, 200860 Yes Yes Unclear Unclear No

Velligan et al, 201357 No Yes Unclear No Yes
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RISK OF BIAS: TRIALS, PART 3

Author, Year

Did attrition result in 

difference in group 

characteristics between 

baseline (or 

randomization) and 

follow-up?

Analysis 

conducted on an 

intention-totreat (ITT) 

basis?

Inclusion/exclusion 

criteria measured 

using valid and 

reliable measures, 

implemented 

consistently across all 

study participants?

Medication adherence outcomes 

assessed using valid and reliable 

measures, implemented 

consistently across all study 

participants? When adherence 

requires skills (eg, pill bottle, 

SMS), does the intervention 

measure or account for varied skill 

levels?

Do authors justify 

medication 

adherence 

thresholds?

Bahredar et al, 201469 NR Yes Yes Unclear NA

Barkhof et al, 201358 No No Yes Yes NA

Bechdolf et al, 200544 No Yes Yes Unclear No

Beebe et al, 201454 NR Unclear Yes Yes Yes

Frangou et al, 200555 No Yes Yes Yes Yes

Gray et al, 200646 No Yes Yes Yes Yes

Hamann et al, 200759 No Yes Yes Yes Yes

Healey et al, 199842 Unclear NR Yes NA NA

Javadpour et al, 201368 No Unclear Yes Yes NR

Kemp et al, 199843 Unclear Unclear Yes Yes Yes

Kopelowicz et al, 201250 Unclear Yes Yes Yes Yes

Montes et al, 201256 No Yes Yes Yes Yes

O’Donnell et al, 200347 No Yes Yes Yes Yes

Pitschel-Walz et al, 200651 No No Yes Yes Yes

Sajatovic et al, 200967 Unclear NR Yes Unclear NA

Schulz et al, 201348 No Yes Yes Yes Yes

Valencia et al, 201052 No Unclear Yes Unclear Unclear

Velligan et al, 200860 No No Yes Yes No

Velligan et al, 201357 No Unclear Yes Yes Yes
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RISK OF BIAS: TRIALS, PART 4

Author, Year

Are health 

outcomes 

assessed using 

valid and reliable 

measures, 

implemented 

consistently 

across all study 

participants?

Harms assessed 

using valid and 

reliable 

measures, 

implemented 

consistently 

across all study 

participants?

Potential 

outcomes prespecified by 

researchers? Are 

all pre-specified 

outcomes 

reported?

Were 

incomplete 

outcome 

data 

adequately 

addressed?

Important 

confounding and 

modifying variables 

taken into account in 

the design and/or 

analysis? (eg, through 

matching, 

stratification, 

multivariable 

analysis, or other 

approaches?)

Additional Bias: 

Was the study 

apparently free 

of other 

problems that 

could put it at a 

high risk of bias? 

If no, please 

describe Risk of Bias

Bahredar et al, 201469 Yes NR Yes NR Yes Yes Moderate

Barkhof et al, 201358 Yes NR Yes Unclear No Yes Low

Bechdolf et al, 200544 Yes NR Yes Yes Yes Yes Moderate

Beebe et al, 201454 Yes NR Yes Unclear Yes Yes Moderate

Frangou et al, 200555 Yes NR Yes Unclear Yes Unclear High

Gray et al, 200646 Yes NR Yes Yes Yes Yes Low

Hamann et al, 200759 Yes NR Yes Yes Unclear Yes High

Healey et al, 199842 Yes NR Unclear Unclear Yes Yes High

Javadpour et al, 201368 Yes NR Unclear NR Unclear Yes Moderate

Kemp et al, 199843 Yes NR Yes No NR Yes High

Kopelowicz et al, 

201250 Yes NR Unclear Unclear No Unclear Moderate

Montes et al, 201256 Yes NR Yes NR NR Yes Moderate

O’Donnell et al, 200347 Yes NR Yes NR Unclear Yes Moderate

Pitschel-Walz et al, 

200651

Yes NR Yes Unclear Yes No Moderate

Sajatovic et al, 200967 Yes NR Yes NR Yes Yes Moderate

Schulz et al, 201348 Yes NR Yes Yes Yes Yes Low

Valencia et al, 201052 Yes NR Yes NR Yes Yes Moderate

Velligan et al, 200860 Yes NR Yes NR Yes Unclear Moderate

Velligan et al, 201357 Yes NR Yes NR Yes Yes Low
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APPENDIX H. RISK OF BIAS: OBSERVATIONAL STUDIES

RISK OF BIAS: OBSERVATIONAL STUDIES, PART 1

Author, Year

Were providers blinded 

to intervention or 

exposure status of 

participants?

Participants blinded 

to intervention or 

exposure status?

Outcome assessors 

blinded to intervention 

or exposure status of 

participants?

Did strategy for 

recruiting participants 

into study differ across 

study groups?

Baseline characteristics 

similar between groups? 

If not, did analysis control 

for differences?

Byerly et al, 200545 Unclear Unclear Yes No Yes

Kavanagh et al, 200353 Unclear Yes Unclear No Unclear

Lee et al, 201061 Unclear No Yes No Yes

Sajatovic et al, 201241 NA NA NR No NA

Sajatovic et al, 201362 NA NA NA No NA

Skarsholm et al, 201449 No No No No Yes

RISK OF BIAS: OBSERVATIONAL STUDIES, PART 2

Author, Year

Impact from any concurrent 

intervention or unintended 

exposure that might bias 

results ruled out?

Did variation from 

study protocol 

compromise study 

conclusions?

High rate of 

differential or 

overall attrition?

Did attrition result in difference 

in group characteristics between 

baseline (or randomization) and 

follow-up?

Analysis conducted 

on an intention-totreat (ITT) basis?

Byerly et al, 200545 Unclear Unclear NA NA Unclear

Kavanagh et al, 200353 NR Unclear No NA Unclear

Lee et al, 201061 Yes NR Yes No Yes

Sajatovic et al, 201241 No NR Yes NA NR

Sajatovic et al, 201362 Unclear Unclear Yes No Unclear

Skarsholm et al, 201449 Unclear No No No Yes
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RISK OF BIAS: OBSERVATIONAL STUDIES, PART 3

Author, Year

Inclusion/exclusion 

criteria measured using 

valid and reliable 

measures, implemented 

consistently across all 

study participants?

Medication adherence outcomes 

assessed using valid and reliable 

measures, implemented consistently 

across all study participants? When 

adherence requires skills (eg, pill 

bottle, SMS), does the intervention 

measure or account for varied skill 

levels?

Do authors 

justify 

medication 

adherence 

thresholds?

Are health outcomes 

assessed using valid 

and reliable measures, 

implemented 

consistently across all 

study participants?

Harms assessed using 

valid and reliable 

measures, 

implemented 

consistently across all 

study participants?

Byerly et al, 200545 Yes Yes Yes Yes NR

Kavanagh et al, 200353 Yes Yes Yes Yes NR

Lee et al, 201061 Yes Yes Yes Yes NR

Sajatovic et al, 201241 Yes Yes No Yes NR

Sajatovic et al, 201362 Yes Yes Unclear Yes Yes

Skarsholm et al, 201449 Yes Yes Yes Yes Yes

RISK OF BIAS: OBSERVATIONAL STUDIES, PART 4

Author, Year

Potential outcomes 

pre-specified by 

researchers? Are all 

pre-specified outcomes 

reported?

Were incomplete 

outcome data 

adequately 

addressed?

Important confounding and 

modifying variables taken into 

account in the design and/or 

analysis? (eg, through matching, 

stratification, multivariable 

analysis, or other approaches?)

Additional Bias: Was the 

study apparently free of 

other problems that could 

put it at a high risk of 

bias? If no, please 

describe Risk of Bias

Byerly et al, 200545 Yes Unclear Yes Yes High

Kavanagh et al, 200353 Yes NR Unclear Unclear High

Lee et al, 201061 Yes NR No Yes Moderate

Sajatovic et al, 201241 Yes No Unclear Yes Moderate

Sajatovic et al, 201362 Yes Unclear Yes Yes Moderate

Skarsholm et al, 201449 Yes Yes Yes Yes Moderate
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APPENDIX I. PEER REVIEW COMMENTS/AUTHOR RESPONSES 

Question 

Text

Reviewer 

Number Comment Response

Are the 

objectives, 

scope, and 

methods for 

this review 

clearly 

described?

1 Yes Noted.

3 Yes Noted.

4 Yes Noted.

5 Yes Noted.

6 Yes Noted.

Is there any 

indication of 

bias in our 

synthesis of 

the evidence?

1 No Noted.

3 No Noted.

4 No Noted.

5 No Noted.

6 No Noted.

Are there any 

published or 

unpublished

studies that we 

may have 

overlooked?

1 No Noted.

3 No Noted.

4 No Noted.

5 No Noted.

6 No Noted.

Additional 

suggestions or 

comments can 

be provided 

below. If 

applicable, 

please indicate 

the page and 

line numbers 

from the draft 

report.

1 On pg. 11, the last sentence (lines 12-18) is very long and somewhat difficult 

to read. Consider rewording.

Thank you, this section has been revised for clarity. 

On pg. 11 (lines 36-41) as it reads currently, it is assuming that the 

intervention group received more frequent interactions. Unless this can be 

quantified that the intervention group did indeed receive more frequent care 

interactions compared to usual care, consider removing or restating, especially 

the last sentence of the paragraph.

Thank you, this section has been revised for clarity. 

On pg. 89 there are two typos. Line 33 "will" should be "with". Line 39 "is" 

should be inserted before "warranted".

Thank you, these errors have been corrected.

3 This evidence based synthesis addresses medication adherence in adults with 

psychotic spectrum disorders, bipolar disorder, and PTSD. The questions are 

clinically important. The method for addressing the question is standard. It is 

unfortunate that the authors did all of this work, only to find that the literature 

is so poor that few conclusions can be drawn about interventions for these 

populations. Nonetheless, knowing that more well-designed and –conducted 

studies are needed is an important finding for researchers and policymakers. 

Several suggestions for improving the readability of this report are detailed by 

Noted.
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Question 

Text

Reviewer 

Number Comment Response

section below.

Executive summary

Study selection: • please address design of studies that were included. 

Consider using PICOTS terminology; interventions and comparators are not 

described but should be.

Thank you, this section has been revised.

Results: • It is difficult to understand the take-home message from each 

comparison due to the lack of clarity of writing. Each section describes the 

evidence in a confident manner, which is later undermined by “but the strength 

of evidence is poor.” It would be helpful to describe the strength of evidence 

first so that the reader can keep this in mind as reading the conclusions about 

the findings.

Thank you. Our summaries at the beginning of each 

section include a statement about the strength of 

evidence, and strength of evidence is detailed in 

subsequent tables (e.g., Table 14).

Results: • Wording of “Of the 518 clinical trials identified...” it is unclear how 

these are different from the 152 identified. This reviewer assumes that the 518 

were identified from clinicaltrials.gov but is unsure. Please specify the source 

of each.

Thank you, we have revised this sentence for clarity.

Results: • Unclear is the use of “controls.” Comparator might be a better term. 

There is heterogeneity in comparators, but the use of the word “controls” 

seems to imply that they are similar across studies.

Thank you. We have changed the term controls to 

comparators.

Results: • Use of “Compliance Therapy” as a proper noun is confusing. Is this 

a standard behavioral approach? If so, what is it?

Thank you, we have revised this sentence for clarity.

Results: • Unclear is the criterion for determining whether a study was 

considered significant. Is it effect size or type 2 error rate?

Thank you. Significance was determined according to 

the individual studies, and given the heterogeneity 

amongst studies and the qualitative nature of the review, 

we did not compute summary statistics. Tables in the 

main report (e.g., Table 4) provide data for clarity.

Results: • Please do not use the phrase “trend” when something was 

nonsignificant. Many published studies are underpowered, so trend could be 

misleading.

Thank you. We have removed the term trend from the 

report text.

Results: • System-level intervention definition is described as including emonitoring, yet in the results, e-monitoring is listed under technology 

interventions. Here and in the larger report, the authors need to be clear by 

what e-health interventions are and whether they are patient or system-level. 

This reviewer tends to think of them as patient-level.

Thank you. We have revised this sentence for clarity.

Results: • “Two RCTs examined e-monitoring...” Compared to what? Thank you. E-monitoring was compared to a variety of 

comparators in both studies. We have added this 

language for clarity.

Results: • Under technology interventions, the authors seem to be confusing Thank you. We have revised this sentence for clarity.
Interventions to Improve Pharmacological Adherence Evidence-based Synthesis Program

129

Question 

Text

Reviewer 

Number Comment Response

outcome with intervention “One study reported both a significant...”

Results: • P.7 section d: what was the finding related to the four studies? Thank you. We have revised this section for clarity.

Results: • P.8 section e: What is the effectiveness? It seems that an incremental 

cost effectiveness ratio is needed because the cost information alone is not 

helpful if comparing very different interventions.

Thank you, noted. As we conducted only a qualitative 

synthesis, we did not compute summary statistics not 

included in the original papers.

• Table 1: system-level intervention: this needs to be defined, perhaps as a 

footnote. As mentioned earlier, it is unclear whether this includes emonitoring, which is something that happens at the patient level. 

Thank you. We have removed e-monitoring as an 

example of a system-level intervention. 

• Table 1: In this table, it would be helpful to have a column for comparator. Thank you. Due to space considerations, we have added 

comparators to the findings column for clarity.

• Table 1: SMS needs to be defined in the footnote. Thank you, the definition for this abbreviation has been 

added.

Discussion: • A more extensive discussion of the types of comparator groups 

and the impact on conclusions is needed.

Thank you. We have revised this section for clarity.

Discussion: • Note that “medication” is often misspelled as “mediation” in this 

report.

Thank you, this has been corrected.

Full report 

Introduction: • The series of paragraphs are not joined by transitions, so it 

reads as a series of paragraphs instead of a coherent introduction.

Thank you. We have added subheadings to address. 

Introduction: • There are so much data on adherence and factors associated 

with adherence that the authors do not build a strong case for the need for this 

review. If so much is already known, why is this review needed?

Thank you. This paragraph discusses the factors related 

to non-adherence, as well as what is known about 

adherence among people with psychotic spectrum 

disorders generally and in the VHA. The purpose of the

review is to examine interventions potentially aimed at 

addressing these factors and increasing adherence. 

Study selection: • Which criteria are used to determine whether a self-report 

measure is “validated?” There is mixed opinion, for example, as to whether the 

Morisky measure meets criteria for validity and reliability, and this is true of 

other measures.

Thank you. We used Nguyen, La Caz, and Cotrell 

(2014) as a basis of self-report measure/validity. We 

have added this reference to Table 3.

Study selection: • What is the difference between no treatment and usual care? 

Are these really different? This can be difficult to discern given that many 

authors do not define usual care. Usual care differs by site. Consider using the 

typology of control groups by Ken Freedland. 

http://www.ncbi.nlm.nih.gov/pubmed/21536837

Thank you. And thank you for providing the article. For 

populations such as these, usual care (most often 

including treatment such as psychotherapy, contact with 

a psychiatrist to adjust medications, etc.) often differs 

from no treatment. Tables in the full report provide a 

description of the comparator. 

Key Question 1: As in the executive summary, the meaning of “Adherence 

Therapy” and “Compliance Therapy” is not clear. Definitions are needed. Did 

Thank you. This section has been revised for clarity.
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Question 

Text

Reviewer 

Number Comment Response

the studies using these types of interventions always come from the same 

groups of authors? If not, then did different research groups use the terms in 

the same way? It is important to recognize that what authors say they are 

measuring or doing is not always what they are actually doing. It is up to the 

systematic reviewer to make sense of it and then convey that to the audience.

Summary and discussion: As with the executive summary, there is tension 

between what the authors found and the risk of bias and strength of evidence. 

It is important to use precise wording to indicate why the evidence is poor or 

insufficient. It would be helpful to indicate primary reasons why, for example, 

the body of literature on (type of intervention in X population) is insufficient. 

Is it because the existing studies have high risk of bias, because there are too 

few studies, or other reasons? 

Thank you. The reasons for strength of evidence ratings 

are outlined in the details sections associated with each 

type of intervention, and outlined in subsequent tables 

(e.g., Table 14).

Limitations: The authors indicate that they used methodologically rigorous 

studies, but they included studies with high risk of bias, which seems to go 

against the statement that they only included rigorous studies. A more accurate 

statement would be that they included all studies (exclusion on the grounds of 

quality is an important limitation of some reviews) and then assessed risk of 

bias and used it to qualify their conclusions.

Thank you. We have revised this section for clarity.

Discussion: The conclusions about the status of PTSD literature are confusing. 

On the one hand, the authors assert that there is limited evidence that 

adherence is poor in this population. That would seem to indicate that perhaps 

there is no need to evaluate interventions. But the authors go on to say that 

future research is needed to evaluate interventions in this population.

Thank you. We have revised this section for clarity. 

This reviewer is left thinking that the studies are so poor that we simply cannot 

draw any conclusions about any medication adherence intervention in any of 

these populations. Is that the take-home message the authors want to convey?

Thank you. Yes, given the limited number of studies 

examining specific types of interventions/intervention 

components, and that the strength of evidence for all but 

family and technology interventions (both low) was 

insufficient, our conclusion is that the current state of 

the literature precludes strong conclusions and 

recommendations other than related to the need for 

future research.

4 Very thorough. Clear how articles were identified and selected. ROB ratings 

and how they are made are clear. Some suggestions for improvement:

Thank you, noted. 

Seems incomplete without a frank discussion of methodological issues 

including sample bias (most patients entering RTC’s for adherence are more 

adherent than most patients);

Thank you. This section has been revised to include this 

discussion.

Plasma levels are not appropriate for assessing degree of adherence (most 

patients take some medication which will show up);

Thank you, noted. We found that the few included 

studies assessing plasma levels differentiated adherence 
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131

Question 

Text

Reviewer 

Number Comment Response

by the amount of medication found; for example, the 

levels of medication found in the blood compared to 

levels that would be expected in a fully adherent patient. 

Many studies do not use objective measures (pill counts, electronic monitors) 

and should likely be weighted differently from those using objective measures 

of adherence.

Thank you. These factors were taken into consideration, 

along with others, in rating the strength of evidence. 

While I understand investigating whether LAI improves adherence, the focus 

of LAI therapy is not really on improving adherence it is on identifying when 

non-adherence occurs. Moreover, more than even studies of other 

methodologies, studies of LAI have incredibly high levels of sample bias that 

set them up to fail.

Thank you. We have added a statement to the discussion 

regarding this point.

It would have been good at the beginning to outline an example of a body of 

literature which indicates sufficient evidence. Citing AHRQ guidelines I don’t 

think is enough for the reader, especially since everything came out 

Insufficient. What would a body of evidence need to do to be sufficient? Are 

two positive studies enough where one is at least low ROI and neither are high 

ROB? Are 3 positive studies needed with all low ROB? Is standard treatment 

an adequate control? Do studies need the same active comparator to provide 

solid evidence or can an intervention use different active comparators in 

different studies and be considered a replication of the main finding? It is not 

clear how the authors took the data and made this final determination.

Thank you. There are numerous variables associated 

with strength of evidence, and the process is too 

complicated to outline in the body of this report. In this 

review, many of the interventions were evaluated by 

only one study, or there were inconsistent findings. For 

transparency, we provide details related to our rating in 

the comments sections of our tables (e.g., Table 1).

5 The report is well written and I believe it accurately reflects the literature on 

the key questions. The lack of literature limits interpretation which further 

limits reviewer comment.

Thank you, noted.

Page 11, lines 38-41 and Page 88, lines 38-41: It may not be necessary to 

control for increased attention if is inherent from the intervention, i.e., cannot 

be separated.

Thank you, noted. We have revised this section slightly, 

and included this discussion to raise the possibility of a 

positive effect due to increased attention.

6 I believe the review is comprehensive and well done. Thank you, noted.