Patient Preference and Adherence Dovepress open access to scientific and medical research Open Access Full Text Article S t u dy P r o t o c o l Effectiveness and cost-effectiveness of a multicomponent intervention to improve medication adherence in people with depressive Patient Preference and Adherence downloaded from https://www.dovepress.com/ on 07-Feb-2022 disorders – MAPDep: a study protocol for a cluster randomized controlled trial This article was published in the following Dove Medical Press journal: Patient Preference and Adherence For personal use only. Tasmania del Pino-Sedeño, 1,2 Purpose: Depression is a widespread mental disorder which can be treated effectively. However, Wenceslao Peñate, 1 Carlos de low adherence to antidepressants is very common. The study of medication adherence in las Cuevas, 3 Cristina Valcarcel- depression (MAPDep study) assesses the effectiveness and cost-effectiveness of a multicom- Nazco, 2,4 Ascensión Fumero, 1 ponent strategy to enhance adherence toward medications in patients with depression. Pedro Guillermo Serrano- Intervention: The intervention is a multicomponent one consisting of an educational program Pérez, 5,6 Francisco Javier for psychiatrists and/or a collaborative care program for patients and relatives, plus a reminder Acosta Artiles, 7 Vanesa Ramos system that works through the use of an already available high-quality medication reminder García, 4 Beatriz León Salas, 4 application. Daniel Bejarano-Quisoboni, 8 Study design: MAPDep study is an open, multicenter, four-arm cluster randomized controlled María M Trujillo-Martín 2,4 trial. The clusters are mental health units where psychiatrists are invited to participate. The 1 Department of Clinical Psychology, clusters are randomly allocated to one of the three interventions or to usual care (control arm). Psychobiology and Methodology, University Patients (18–65 years of age) diagnosed with depressive disorder, those taking antidepressant of La Laguna, San Cristóbal de La Laguna, Canary Islands, Spain; 2Health Services medication for an existing diagnosis of depression, and mobile phone users are selected. In Research on Chronic Patients Network group 1, only patients and relatives receive intervention; in group 2, only psychiatrists receive (REDISSEC), Madrid, Spain; 3Department of Internal Medicine, Dermatology and intervention; and in group 3, patients/relatives and psychiatrists receive intervention. The primary Psychiatry, University of La Laguna, San outcome is adherence to the antidepressant drug. The calculated sample size is 400 patients. Cristóbal de La Laguna, Canary Islands, Spain; 4Canary Islands Foundation of Health To examine changes across time, generalized linear mixed model with repeated measures will Research (FUNCANIS), San Cristóbal de La be used. A cost-effectiveness analysis will be conducted. The effectiveness measure is quality- Laguna, Canary Islands, Spain; 5Department of Psychiatry, Hospital Universitari Vall d’ adjusted life years. Deterministic sensitivity analyses are planned. Hebron, Catalonia, Spain; 6Department of Psychiatry and Legal Medicine, Universitat Conclusion: MAPDep study aims to assess a multicomponent strategy to improve adherence Autònoma de Barcelona, Catalonia, Spain; toward medications in patients with depression, based not only on clinical effectiveness but also 7 Service of Mental Health, General Health Care Programs Direction, Canary Health on cost-effectiveness. This methodology will enhance the transferability of the expected results Service, Las Palmas de Gran Canaria, beyond mental health services (patients and psychiatrists) to health care policy decision making. Canary Islands, Spain; 8Center for Public Health Research (CSISP-FISABIO), Valencia, Clinical trial identifier: NCT03668457. Spain Keywords: depression, medication adherence, education, behavior modification, mobile phone technology, cost-effectiveness Correspondence: Carlos de las Cuevas Departamento de Medicina Interna, Introduction Dermatología y Psiquiatría, Universidad de La Laguna, Campus de Ofra, 38071 San Cristóbal Depression is a common mental disorder. Globally, more than 300 million people of de La Laguna, Canary Islands, Spain all ages suffer from depression.1–3 It is expected that by 2030, depression will be the Tel +34 609 521 405 Email cdelascuevas@gmail.com leading cause of disease burden globally.4 submit your manuscript | www.dovepress.com Patient Preference and Adherence 2019:13 309–319 309 Dovepress © 2019 del Pino-Sedeño et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php http://dx.doi.org/10.2147/PPA.S172963 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). del Pino-Sedeño et al Dovepress Depressive disorders account for 6% of total disease Multifaceted interventions directed to the patient and burden in terms of disability-adjusted life years. In Europe, physician are comparatively more effective in improving the total annual cost of depression has been estimated at medication adherence than interventions with a single com- Euro 118 billion, including direct and indirect costs, which ponent (such as information or education).59–61 Intervention corresponds to a cost of Euro 253 per inhabitant and a programs should attend to patients’ specific health beliefs 1% of European gross domestic product.5 The percentage and attitudes concerning their condition and antidepressant of the total economy of Spain is similar to that generally treatment,62 and patients’ perception of control over health observed in Europe.6 (psychological reactance and health locus of control).10,11 It Depression is often a chronic and/or recurrent dis- appears useful and important that mental health professionals order with consequences over the entire life span.7 At improve communication and negotiation skills to overcome least half of those who recover from a first episode of communication barriers with patients: doctors’ interventions depression will experience additional episodes, and which can cause nonadherence and hostile attitudes in the approximately 80% of those with a history of two episodes patients toward changes.63,64 Moreover, the complexity of will have another recurrence.8 Depression may become a adherence phenomenon requires multifaceted interventions serious health condition and is the leading cause of suicide. that can be reinforced by the use of information and com- Approximately 800,000 people commit suicide each year due munication technology.65–68 In this sense, health applications to depression.9 (apps), including medication reminder apps, are becoming Despite that there are effective pharmacological treat- more and more popular and are promising tools to improve ments for depression, nonadherence to appropriately medication adherence and decrease the costs of traditional prescribed medications compromises the effectiveness interventions on adherence.69–72 of available treatments and interferes with recovery. 10,11 There is a need for cost-effective alternative strategies Although the rates of early adherence to antidepressant involving patients, relatives, and physicians that improve medication have been estimated ranging from 72% to 78%,12 short- and long-term adherence to depression treatment. With approximately 50% of patients prematurely discontinue this purpose, the Adherence Improvement in Patients with antidepressant therapy.13–16 Despite the fact that 49%–84% of Depression study (Mejora de la Adherencia en Pacientes con the patients with depression perceive the need for antidepres- Depresión, MAPDep) is designed. The purpose of MAP- sant treatment,17 one-third of patients stop medication within Dep is to assess the effectiveness and cost-effectiveness of 6 weeks, and up to 55%, at 10–12 weeks.18 Moreover, the a multicomponent strategy to enhance adherence toward degree of nonadherence may vary according to the severity medications in patients with depression. of the disease and the evolutionary moment. Adherence is greater in patients with more severe symptoms.19 In the Methods maintenance phase of treatment, clinical improvement and Trial design previously acceptable adverse effects, such as sexual dys- MAPDep study is an open, multicenter, four-arm cluster function, may reduce adherence. Precisely, reduced perceived randomized controlled trial comparing three interventions effectiveness and increased perceived adverse effects are and usual care (control arm). In group 1, only patients related to higher nonadherence rates.17 and relatives receive intervention; in group 2, only psychia- Nonadherence to antidepressants has an impact on health trists receive intervention; and in group 3, patients and psy- care utilization and charges. Nonadherence is associated chiatrists receive intervention. In the control group, patients/ with relapse and recurrence, emergency department visits, relatives and psychiatrists receive the usual care provided by and higher hospitalization rates.20 Therefore, there is a need the Canary Islands Health Service (Figure 1). for effective and cost-effective interventions to improve adherence. Subjects There are many approaches to address adherence Mental health professionals issues in patients with depression, such as collaborative The unit of recruitment for psychiatrists is the Community care,21–33 counseling,34,35 cognitive-behavioral approaches,36–43 Mental Health Unit (CMHU). Psychiatrists working in the psycho-education, 37,44–48 support, 34,35,49–54 coaching, 55,56 selected CMHUs who volunteer to participate in the study and shared decision-making skills training.57,58 However, and have the intention to stay in their CMHU during the these approaches are only effective to improve short-term follow-up period will be included after signing informed adherence but insufficient to appreciate long-term effect. consent. 310 submit your manuscript | www.dovepress.com Patient Preference and Adherence 2019:13 Dovepress Powered by TCPDF (www.tcpdf.org) Dovepress del Pino-Sedeño et al &08VUHFUXLWPHQW 1  'DWDFROOHFWLRQ7 %DVHOLQH 1&08V  1SDWLHQWV  5DQGRPL]DWLRQ 1&0+8V  *URXS *URXS 8VXDOFDUH *URXS *URXS*URXS LQWHUYHQWLRQIRU LQWHUYHQWLRQIRUSDWLHQWV LQWHUYHQWLRQIRUSDWLHQWV SV\FKLDWULVWV DQGSV\FKLDWULVWV 6HVVLRQ &ROODERUDWLYH 6HVVLRQ 'DWDFROOHFWLRQ7 FDUHPDQDJHPHQW 'DWDFROOHFWLRQ7 'DWDFROOHFWLRQ7 'DWDFROOHFWLRQ7 PRQWKV LQWHUYHQWLRQ PRQWKV PRQWKV PRQWKV DGKHUHQFH%',,,+$'6 ±FRQWDFWV DGKHUHQFH%',,,+$'6 DGKHUHQFH%',,,+$'6 DGKHUHQFH%',,,+$'6 0HGLFDWLRQUHPLQGHUPRELOHDSS 'DWDFROOHFWLRQ7 'DWDFROOHFWLRQ7 'DWDFROOHFWLRQ7 'DWDFROOHFWLRQ7 PRQWKV PRQWKV PRQWKV PRQWKV DGKHUHQFH%',,,+$'66) DGKHUHQFH%',,,+$'66) DGKHUHQFH%',,,+$'66) DGKHUHQFH%',,,+$'66) (4'/KHDOWKFDUHXWLOL]DWLRQ (4'/KHDOWKFDUHXWLOL]DWLRQ (4'/KHDOWKFDUHXWLOL]DWLRQ (4'/KHDOWKFDUHXWLOL]DWLRQ DQGSURGXFWLYLW\ORVVHV DQGSURGXFWLYLW\ORVVHV DQGSURGXFWLYLW\ORVVHV DQGSURGXFWLYLW\ORVVHV 'DWDFROOHFWLRQ7 'DWDFROOHFWLRQ7 'DWDFROOHFWLRQ7 'DWDFROOHFWLRQ7 PRQWKV PRQWKV PRQWKV PRQWKV SDWLHQWVDGKHUHQFH%',,,+$'6 SDWLHQWVDGKHUHQFH%',,,+$'6 SDWLHQWVDGKHUHQFH%',,,+$'6 SDWLHQWVDGKHUHQFH%',,,+$'6 6)(4'/KHDOWKFDUH 6)(4'/KHDOWKFDUH 6)(4'/KHDOWKFDUH 6)(4'/KHDOWKFDUH XWLOL]DWLRQDQGSURGXFWLYLW\ORVVHV XWLOL]DWLRQDQGSURGXFWLYLW\ORVVHV XWLOL]DWLRQDQGSURGXFWLYLW\ORVVHV XWLOL]DWLRQDQGSURGXFWLYLW\ORVVHV SV\FKLDWULVWV3326DQG/$7&RQ,, SV\FKLDWULVWV3326DQG/$7&RQ,, SV\FKLDWULVWV3326DQG/$7&RQ,, SV\FKLDWULVWV3326DQG/$7&RQ,, Figure 1 Flowchart of MAPDep study procedures. Notes: *Patients: Demographic data, history of depression, depression health status, DAI-10, MHLC-C, HPRS, CPS, BMQ, adherence, BDI-II, HADS, SF-12, EQ-5D-5L; healthcare utilization and productivity losses (collected information will cover the six-month period prior to the study). Psychiatrists: Demographic data, years in practice, professional profile, PPOS and LATCon II. Abbreviations: BDI-II, Beck Depression Inventory-II; BMQ, Beliefs about Medicines Questionnaire; CMHU, Community Mental Health Unit; CPS, Control Preferences Scale; DAI-10, Drug Attitude Inventory – 10 Items; EQ-5D-5L, EuroQol-5D-5L; HADS, Hospital Anxiety and Depression Scale; HPRS, Hong Psychological Reactance Scale; LATCon II, Leeds Attitude Towards Concordance II Scale; MHLC-C, Multidimensional Health Locus of Control, Form C; PPOS, Patient-Practitioner Orientation Scale; SF-12, Short Form-12. Patients Setting and recruitment Inclusion criteria are as follows: (1) patients diagnosed with The setting is urban or rural CMHUs located on Tenerife depressive disorder (major depressive disorder and/or dys- (Canary Islands, Spain). From the total pool of CMHUs, thymia) according to the criteria of Diagnostic and Statistical eight will be randomly selected using computer-generated Manual of Mental Disorders, Fourth Edition, taking anti- randomization numbers. We will have an initial contact with depressant medication for an existing diagnosis of depres- psychiatrists working on each selected CMHU by e-mail or sion and (2) aged 18–65 years; (3) mobile phone users; telephone to give a brief explanation of the objectives of the (4) patients who have visited their CMHU at least once in study and to request their collaboration. A more detailed the last 6 months; and (5) consent to participate in the study. explanation of the study (objective, time frame and tasks, Exclusion criteria are as follows: (1) patients with bipolar expected resources utilization, and funding) will be subse- disorder and/or any psychotic disorder; (2) insufficient quently provided in a 60- to 80-minute face-to-face or virtual Spanish language skills; (3) pregnancy; and (4) participation meeting. To minimize information bias and selection bias, in another experimental study. all included psychiatrists will complete both an informed Patient Preference and Adherence 2019:13 submit your manuscript | www.dovepress.com 311 Dovepress Powered by TCPDF (www.tcpdf.org) del Pino-Sedeño et al Dovepress consent form and the baseline questionnaire, and then they patients’ attitudes toward pharmacological treatment of will consecutively invite patients meeting selection criteria to depression, medication-taking behaviors, and symptoms participate before CMHUs randomization. Accepting patients and emotional outcomes; 2) providing education concerning will sign an informed consent form and will complete the the appropriate use of antidepressants; 3) negotiating shared baseline questionnaires in their first visit. decisions about the use of antidepressants; and 4) promoting patients’ perception of control over health. Random assignment We will perform allocation by clusters – with the CMHUs as Behavioral activation the randomization unit. After professionals and patients are This is a brief structured intervention that aims to help people selected, an investigator blinded to CMHUs identity will ran- interrupt patterns of avoidance that maintain depression and domly assign participants to interventions or control group. increase engagement in adaptive activities. It is focused on developing a plan to reestablish daily activities and Blinding increase the number of both pleasant activities and positive Participating psychiatrists and patients from each selected interactions with their environment. CMHU will be blind to intervention assignment (groups 1–4) until the last patient is recruited. Psychiatrists and patients Supervision cannot be blinded after assignment to interventions or control Mental health specialists – psychiatrists and psychological group. The investigator responsible for data analysis will be therapists – supervise the researches. Supervisors help and blinded to the intervention assignment. support researchers to review the patient’s progress and the team’s plan for the patient. Interventions The study will evaluate the effectiveness and cost- Medication reminder mobile app effectiveness of interventions for psychiatrists and/or patients In the first session, participants will be informed about and relatives (Figure 1). These interventions are compared the use of a medication reminder mobile app. Participants with a control group receiving usual care. will download the app and enter their prescription data (medication, time of administration, and dose). Participants Intervention for patients will be required to use the medication reminder app along Groups 1 and 3 receive an intervention combining the fol- the 12-month follow-up. lowing components: 1) a collaborative care management intervention and 2) the use of an already available high- Intervention for psychiatrists quality medication reminder app. Participating psychiatrists of groups 2 and 3 receive an educational group program of 4-hour duration consisting Collaborative care management intervention in two interactive sessions, 1 month apart. Contents of the This intervention has been designed in accordance with first session have been designed to develop skills to promote the Chronic Care Model,73 including depression education, shared decision making and patient-centered care and to medication management, and behavioral activation. improve communication and negotiation abilities. To deliver Patients will receive a set of 6–12 contacts with research- this intervention, a set of short video films with role-playing ers along a period of no more than 3 months. Patient and exercises representing different types of complex sham relative, if accompanied, will receive the initial face-to-face patients will be used. contact that will last 30–40 minutes. Subsequent telephone Contents of the second session have been designed to sessions with patient will last 15–20 minutes. promote motivational interviewing methods and shared decision making in the context of the patient-centered care Depression education model. A mental health professional with expertise in patient- Its goal is to provide adequate information about depression centered care methods and communication skills will lead and antidepressant treatment. these sessions. Medication management Usual care Its goal is to support appropriate antidepressant use and Patients will receive care from their psychiatrists according reinforce information from the psychiatrists by: 1) assessing to usual activities provided by the Canary Islands Health 312 submit your manuscript | www.dovepress.com Patient Preference and Adherence 2019:13 Dovepress Powered by TCPDF (www.tcpdf.org) Dovepress del Pino-Sedeño et al Service, including antidepressant therapy and referral for Hospital Anxiety and Depression Scale (HADS) other treatments. Psychiatrists will not have access to the This is a 14-item self-reporting screening scale that contains educational group program. two seven-item Likert scales, one for anxiety and one for depression. Each item has a four-point (0–3) Likert scale, Outcome measures and the scores of both scales range from 0 to 21. Higher Primary outcome scores indicate greater anxiety and/or depression. HADS is The primary end point is rate of adherence to the antide- scored by summing the ratings for the 14 items to yield a pressant drug at 6 months assessed using the Sidorkiewicz total score, and by summing the ratings for the seven items adherence instrument in Spanish.74,75 This is a five-item of each subscale to yield separate scores for anxiety and instrument with two or three possible answers to assess dif- depression. HADS has been shown to be a valid and reliable ferent medication-taking behaviors for each individual drug measure.79,80 HADS score will be measured at baseline, at taken by patients. The results generate adherence levels rang- 3 months, at 6 months, and at 12 months. ing from 1 (high drug adherence) to 6 (drug discontinuation). Adherence will also be measured at baseline, at 3 months, Short Form-12 (SF-12) health survey and at 12 months (Table 1). This is a 12-item index designed to examine eight health domains to assess quality of life (physical functioning, role Secondary outcomes physical, bodily pain, general health, vitality, social func- Beck Depression Inventory-II (BDI-II) tioning, role emotional, and mental health). Two summary This is a 21-item self-report multiple-choice inventory used subscales may be derived from the SF-12, including a mental for measuring the severity of depression. Each item has a health summary and a physical health summary. Higher four-point (0–3) scale, and the score of scale ranges from 0 scores represent better health status.81 SF-12 is a reliable and to 63.76 Severity score ranges are as follows: 0–13 (minimal well-validated instrument.82 SF-12 will be administered at depression), 14–19 (mild depression), 20–28 (moderate baseline, at 6 months, and at 12 months. depression), and 29–63 (severe depression). The BDI-II is a reliable and well-validated measure for screening depres- EuroQol-5D-5L (EQ-5D-5L) sion symptoms in adults.76–78 Depression will be measured at This is a measure of health-related quality of life (HRQoL) baseline, at 3 months, at 6 months, and at 12 months. comprising five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is graded on five levels (no problems, slight Table 1 Outcome measurements problems, moderate problems, severe problems, and extreme Time Outcome measurements problems). 83 HRQoL will be measured at baseline, at Patients 6 months, and at 12 months. T1 Demographic data, history of depression, depression health status 1. Instruments used for self-reported outcomes measures Patient-Practitioner Orientation Scale (PPOS) T1 DAI-10, MHLC-C, HPRS, CPS, BMQ This is an 18-item reliable and validated self-administered T1, T2, T3, T4 Adherence, BDI-II, HADS tool that assesses patient-centeredness in both health care T1, T3, T4 SF-12, EQ-5D-5L professionals and patients. Each item is rated on a six-point 2. Health care utilization Likert scale (1–6).84,85 PPOS will be used to assess health T1, T3, T4 Visits to mental health services and primary care care professionals’ attitudes. The cutoffs used to clas- services, medication and doses, hospital admissions and length of stay, productivity lossesa sify professionals according to their patient-centeredness Psychiatrists score are: low (#4.57), medium (.4.57 and ,5), or high T1 Demographic data, years in practice, professional ($5).85 PPOS questionnaire will be administered at baseline profile and at 12 months. T1, T4 PPOS, LATCon II Notes: T1: baseline; T2: 3 months; T3: 6 months; T4: 12 months. aInformation collected at baseline will cover the 6-month period prior to the study. Leeds Attitude Towards Concordance II Scale (LATCon II) Abbreviations: BDI-II, Beck Depression Inventory-II; BMQ, Beliefs about Medicines This is a 20-item scale for measuring health care profes- Questionnaire; CPS, Control Preferences Scale; DAI-10, Drug Attitude Inventory – 10 Items; EQ-5D-5L, EuroQol-5D-5L; HADS, Hospital Anxiety and Depression Scale; sionals’ attitudes toward concordance in medicine taking. HPRS, Hong Psychological Reactance Scale; LATCon II, Leeds Attitude Towards Each item is rated on a six-point Likert scale (0–3). Scores Concordance II Scale; MHLC-C, Multidimensional Health Locus of Control, Form C; PPOS, Patient-Practitioner Orientation Scale; SF-12, Short Form-12. on the LATCon II range from 0 to 60, with higher scores Patient Preference and Adherence 2019:13 submit your manuscript | www.dovepress.com 313 Dovepress Powered by TCPDF (www.tcpdf.org) del Pino-Sedeño et al Dovepress representing more positive attitude toward concordance.86,87 on each subscale indicate a stronger belief in that kind LATCon II will be administered at baseline and at 12 months. of control.90,91 Health care utilization and productivity losses Hong Psychological Reactance Scale (HPRS) Costs will be assessed from the health care services HPRS is a 14-item self-report questionnaire to assess perspective, and the costs derived from the development individual differences in reactance proneness, that is, and use of all components for each intervention assessed individuals’ trait propensity to experience psychological (sessions, app, etc.) will be included. Information about reactance. Participants indicate the extent to which they prescribed medication and doses, contacts with mental health endorsed each statement on a five-point Likert scale ranging and primary care providers, hospital admissions and dura- from 1 (strongly disagree) to 5 (strongly agree).92,93 tion of stay, and productivity losses will be obtained from a self-administered questionnaire and the electronic clinical Control Preferences Scale (CPS) record. Collected information will cover the 6-month period CPS consists of five cards that illustrate different roles in prior to the study. Health care utilization and indirect costs decision making using a statement and a cartoon. Patients will be measured at baseline, at 6 months, and at 12 months. have to choose between the cards, observing them one at a time, to establish an order of preference that ranges Additional measures from a completely active role to a more passive style Sociodemographic and clinical data will be collected at (from 0 to 5; the higher the score, the more passive the baseline from the patients and the psychiatrists. Professionals style). There are six response categories: active–active, will be asked about their age, sex, and professional profile, active–collaborative, collaborative–active, collaborative– while patients will be asked about their type of depression, passive, passive–collaborative, and passive–passive. The number of prior episodes and the duration of the current responses can be further collapsed into the following episode, sex, age, education level, occupation, marital three categories of role responses: active (active–active or status, and family living status (alone or accompanied). The active–collaborative), collaborative (collaborative–active or prescription date, the quantity of prescribed medication, the collaborative–passive), and passive (passive–collaborative dispensation date, and the quantity of dispensed medication or passive–passive).94,95 will be downloaded from the electronic clinical record. In addition, the following measures will be collected at Beliefs about Medicines Questionnaire (BMQ) baseline from the patients. BMQ is an 18-item questionnaire that contains a specific and a general scale. The BMQ-Specific scale is subdivided Drug Attitude Inventory – 10 Items (DAI-10) into two subscales (Concern and Necessity) that assess DAI-10, a 10-item self-report scale, assesses psychiatric representations of medication prescribed for personal use. patients’ attitudes toward their psychopharmacological The BMQ-General scale is subdivided into two subscales medications. Response options are true/false, and each (Overuse and Harm) that assess beliefs about medicines in response is scored as +1 if correct or -1 if incorrect. The general. Patients are asked to rate, on a five-point Likert scale score of the scale ranges from -10 to -10, with positive scores ranging from 1 (strongly disagree) to 5 (strongly agree), the indicating positive attitudes and negative scores indicating degree of agreement with each statement.96,97 negative attitudes toward medication.88,89 Statistical methods Multidimensional Health Locus of Control, Form C To analyze changes in outcomes over time for the interven- (MHLC-C) tion and control groups, generalized linear mixed models MHLC-C is an 18-item self-report scale composed of one with repeated measures will be used. Intervention groups will scale on internal locus of control (six items), and three scales be treated as a “factor within”. For multiple comparisons, on external locus of control: Chance (six items), Doctors Bonferroni adjustment will be used. In order to incorporate (three items), and Others (three items); these scales assess cluster effects across three levels (patients, psychiatrist, and patients’ belief in their ability to control health. Patients are CMHU), a multilevel model approach will be implemented. asked to rate, on a six-point Likert scale, the degree to which A structural equation model will be applied to assess they agree or disagree with each statement. Higher scores the relationships among sociodemographic and clinical 314 submit your manuscript | www.dovepress.com Patient Preference and Adherence 2019:13 Dovepress Powered by TCPDF (www.tcpdf.org) Dovepress del Pino-Sedeño et al characteristics of patients, interventions, and results in the Ethics emotional variables and adherence. The Scientific and Ethics Committees of both the University Both per-protocol and intention-to-treat analyses will Hospital of the Nuestra Señora de Candelaria and the be performed. Missing data will be classified into the fol- University Hospital of Canary Islands have approved the lowing categories: mistakenly randomized; did not receive study protocol. allocated intervention; withdrew consent; did not adhere to The trial will be conducted in accordance with the latest the protocol; dropped out, crossed-over; or lost to follow-up.98 version of the Declaration of Helsinki and the Organic Law 15/1999, of 13 December, on the Protection of Personal Economic evaluation Data (LOPD). We will obtain informed consent from all Cost-effectiveness analysis of group 3 (multicomponent inter- participants of the study. vention) vs the control group (usual care) will be undertaken. The cost-effectiveness measure will be the incremental cost Trial status per quality-adjusted life year (QALY) gained. QALYs will This trial is not yet recruiting. be measured by the EQ-5D-5L questionnaire, which will be collected for each individual patient. The analyses will take Discussion the perspective of the National Health Service and personal The MAPDep study is a cluster randomized controlled trial social services; therefore, direct and indirect costs will be involving actors who play a role in decision making in depres- included. The direct costs per patient will be calculated based sion management in specialized mental health care (patients, on the use of health care resource utilization, and the indirect relatives, and psychiatrists). The effectiveness and cost- costs will be estimated focusing on productivity losses due effectiveness of three interventions promoting collaborative to the disorder applying the human capital approach. Results care, patient-centered care, and shared decision making with will be summarized as the incremental cost-effectiveness the aim of improving adherence to antidepressants among ratio (ICER). ICER is the ratio of the differences in costs to patients with depression against usual care will be assessed. the differences in effects observed. MAPDep offer tools for depressive patients and mental Nonparametric bootstrap methods for calculating health professionals to establish an appropriate engagement confidence regions for the ICERs will be used. The boot- with medication. These interventions could therefore help to strap replications will also be performed to construct a decrease the risks of disease relapse or recurrence and soften cost-effectiveness acceptability curve, which will reveal the the impact of depression on health care utilization and costs. probability that an intervention is cost-effective compared with the alternative for different values of willingness to Limitations pay for certain future QALY gains. We will also subject the This study is not free from limitations. Firstly, MAPDep results to one-, two-, and multi-way deterministic sensitivity interventions can be blinded neither to patients nor to psy- analysis. All analyses will be in line with accepted economic chiatrists. However, mental health professionals will be blind evaluation methods.99 to intervention assignment until the last patient is recruited The willingness-to-pay threshold is defined at to warrant patients’ and professionals’ cooperation. Euro 25,000/QALY on the basis of the values reported in Secondly, MAPDep intervention for psychiatrists has the latest Spanish literature.100 been developed to stimulate its uniform implementation through training psychiatrists to develop skills to promote Sample size shared decision making and patient-centered care and to For detecting a difference of at least 20 points in the rate improve communication and negotiation abilities. However, of adherence of patients to the drug assessed by use of the psychiatrists may differ in their motivation to include these Sidorkiewicz adherence instrument at 6 months, assuming resources in daily practice and the way in which motivation an alpha of 0.05 (two-tailed) with 80% power and an intra- influences their intervention engagement. On the other hand, cluster correlation coefficient of 0.01 (IQR 0–0.04) based this variability can be observed in daily patient care and on literature data, the estimated number of patients required thereby enhance the external validity. Another limitation is per arm is 91 (total in the study =364 patients). Assuming that, despite the information about the use of a medication losses of 10% at 6 months, a total sample of 400 patients reminder mobile app, misuse and nonuse of the app may is estimated. occur. To prevent nonuse, one session will be conducted in Patient Preference and Adherence 2019:13 submit your manuscript | www.dovepress.com 315 Dovepress Powered by TCPDF (www.tcpdf.org) del Pino-Sedeño et al Dovepress a face-to-face manner. Finally, there are concerns about the 3. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders validity of self-report measures due to their vulnerability to in the National comorbidity survey replication. Arch Gen Psychiatry. memory biases and social desirability that tend to overesti- 2005;62(6):593–602. mate adherence behavior compared with other assessment 4. World Health Organization. The Global Burden of Disease: 2004 Update. Geneva, Switzerland: World Health Organization; 2008. methods.101 However, self-reporting is the most simple and 5. Sobocki P, Jönsson B, Angst J, Rehnberg C. Cost of depression in inexpensive method of measuring adherence which can Europe. J Ment Health Policy Econ. 2006;9(2):87–98. 6. Parés-Badell O, Barbaglia G, Jerinic P, Gustavsson A, Salvador-Carulla L, feasibly be used in clinical settings.102 Alonso J. Cost of disorders of the brain in Spain. PLoS One. 2014; Despite all these limitations, few previous studies have 9(8):e104571. assessed not only the effectiveness but also the cost-effectiveness 7. Hardeveld F, Spijker J, De Graaf R, Nolen WA, Beekman AT. Preva- lence and predictors of recurrence of major depressive disorder in the of multicomponent interventions for all actors involved in adult population. Acta Psychiatr Scand. 2010;122(3):184–191. decision making in depression management in specialized 8. Kupfer DJ, Frank E, Wamhoff J. Mood disorders: update on prevention of recurrence. In: Mundt C, Goldstein MJ, Hahlweg K, Fiedler P, editors. mental health care through a randomized controlled design. Interpersonal Factors in the Origin and Course of Affective Disorders. London (UK): Gaskell/Royal College of psychiatrists; 1996:289–302. Conclusion 9. World Health Organization. Depression and Other Common, Mental Disorders: Global Health Estimates. Geneva, Switzerland: World Depression affects million people around globe, and numerous Health Organization; 2017. studies have consistently shown lower adherence toward medi- 10. De Las Cuevas C, De Leon J, Peñate W, Betancort M. Factors cations is associated with poor recovery among patients with influencing adherence to psychopharmacological medications in psychiatric patients: a structural equation modeling approach. Patient depression and higher treatment costs per patient. Therefore, Prefer Adherence. 2017;11:681–690. it is important to enhance medication adherence to improve 11. De Las Cuevas C, Peñate W, Cabrera C. Perceived health control: a promising step forward in our understanding of treatment adherence patient health and soften the impact of depression on health care in psychiatric care. J Clin Psychiatry. 2016;77(10):e1233–e1239. utilization and costs. The MAPDep study will show whether a 12. Simon GE, Johnson E, Stewart C, et al. Does patient adherence to multicomponent strategy to promote collaborative care, patient- antidepressant medication actually vary between physicians? J Clin Psychiatry. 2018;79(3):7–10. centered care, and shared decision making in the management 13. Bambauer KZ, Soumerai SB, Adams AS, Zhang F, Ross-Degnan D. of patients with depression is effective and cost-effective. Provider and patient characteristics associated with antidepressant nonadherence: the impact of provider specialty. J Clin Psychiatry. Acknowledgment 2007;68(6):867–873. 14. Lee MS, Lee HY, Kang SG, et al. Variables influencing antidepressant This work is supported by the Cabildo de Tenerife within the medication adherence for treating outpatients with depressive disorders. framework of the Agustín de Betancourt Program and the J Affect Disord. 2010;123(1–3):216–221. 15. Sawada N, Uchida H, Suzuki T, et al. Persistence and compliance to Institute of Health Carlos III (PI18/00767). The funding antidepressant treatment in patients with depression: a chart review. institution had no role in designing the study, in drafting, BMC Psychiatry. 2009;9(1):1–10. 16. Yeh MY, Sung SC, Yorker BC, Sun CC, Kuo YL. Predictors of adher- reviewing, and approving the manuscript, or in the decision ence to an antidepressant medication regimen among patients diagnosed to submit it for publication. with depression in Taiwan. Issues Ment Health Nurs. 2008;29(7): 701–717. Author contributions 17. Prins MA, Verhaak PF, Bensing JM, van der Meer K. Health beliefs and perceived need for mental health care of anxiety and depression – All authors contributed to the design of the study. In addition, the patients’ perspective explored. Clin Psychol Rev. 2008;28(6): all authors contributed toward drafting and critically revising 1038–1058. 18. Maddox JC, Levi M, Thompson C. 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