Telemedicine as a Tool to Improve Medicine Adherence in Patients with Affective Disorders – A Systematic Literature Review

Figures & data

Table 1 Different Categories of Intervention Included in This Review, Which Were Formed by Using a Deductive-Inductive Content Analysis

Type of Intervention		Definition
Single-faceted intervention (focuses on one dimension of medication adherence or consists of one component)	Mobile intervention	mHealth is a component of eHealth. It can be defined as medical and public health practice supported by mobile devices, such as mobile phones, patient monitoring devices, personal digital assistants (PDAs), and other wireless devices. mHealth involves the use and capitalization on a mobile phone’s core utility of voice and short messaging service (SMS) as well as more complex functionalities and applications including general packet radio service (GPRS), third and fourth generation mobile telecommunications (3G and 4G systems), global positioning system (GPS), and Bluetooth technology.^Citation85
	Real-time Telehealth (via telephone or video consultations)	Remote delivery of health care to a patient through communication technology. Real-time (synchronous) telehealth is used to consult with, diagnose, and treat patients.^Citation86
Internet-based self-management programmes		Self-management interventions typically encompass information-based material and cognitive and/or behavioural strategies designed to increase participants’ knowledge, self-efficacy and use of self-management behaviours.^Citation87
Multi-faceted intervention		Multi-faceted interventions are interventions which address multiple components including pre-assessment of individual’s adherence level, counselling sessions, medication review, collaboration with physicians, and telephone or video calls.^Citation88

Table 2 Search Terms

Concept	Search Terms
Affective disorders	Mood, affective, maniac, bipolar, depressive
eHealth	ehealth, e-health, electronic health, mobile health, mhealth, m-health, telemedicine, digital health, digital-health, telecommunication technologies, tele health, tele-health, telehealth, tele care, tele-care, telecare, tele medical, tele-medical, telemedical, tele psychiatry, tele-psychiatry, telepsychiatry, phone call, phone-call, phonecall, medicalapps, medical apps, medical-apps, medical applications, medical-applications, webapp, web-app, web app, web application, web-application, webapplication, webportal, web-portal, web portal, internet monitoring, internet-monitoring, digital monitoring, digital-monitoring, internet delivered, internet-delivered, videoconference, video-conference, video conference, mobile intervention, mobile-intervention, mobileintervention
Medication adherence	Medication adherence, medication compliance, medication concordance, treatment adherence, treatment compliance, treatment concordance

Figure 1 PRISMA 2020 flow diagram (A “study” includes a defined group of participants and one or more interventions and outcomes and might have multiple “reports”, that can be any document providing information).

Table 3 Results of the Data Extraction

Reference	Type of Intervention*	Study Design	Trial Arms	Population (Intervention Group)	Setting / Provider Type	Personal Contact	Medication Assessed	Adherence Measure	Adherence Measure Outcome	Effect
Pauly et. al. 2015^Citation48	Multi-faceted intervention	CCT	Two: multi-dimensional and inter-sectoral program, TAU	Psychiatric patients with focus on depression and anxiety (n=269)	Stationary and Ambulatory setting	Yes	NI	MARS-5	Three months follow-up: 1. CG: mean 22.47 (SD 2.99) 2. IG: mean 23.75 (SD 2.08). Adjusted effect of the intervention 1.33 points (95% CI 0.73–1.93)	+ (significant)
Corden et al 2016^Citation37	Single-faceted intervention/mobile intervention	Pre-/post design	One: Mobile App, no CG	Patients with depression (n=11)	Ambulatory setting	No	Antidepressants	Pill counting	Baseline: 88.5% Follow-up: 73.0% (p=0.16).	- (not significant)
Schulze et al 2019^Citation25	Single-faceted intervention/ Telehealth	RCT	Two: Telephone intervention, TAU	Patients with Schizophrenia or BD (n=120)	Ambulatory setting	Yes	Antipsychotics	MARS-5-D	OR=4.11, 95% CI=1.47–11.45, p=0.007	+ (significant)
Gliddon et al 2019^Citation49	Internet-based self-management program	RCT	Three: Discussion forum only (Group 1), Discussion forum plus psychoeducational modules (Group 2) or plus psychoeducational modules and CBT-based interactive tools (Group 3)	Patients with Schizophrenia or BD (n=322)	No specific setting mentioned	Yes	NI	MARS-10	Cohen´s effect size: 1) Comparison Group 2 and Group 1 (12 months follow-up): −0.21, p = 0.48 2) Comparison Group 3 and Group 1: −0.45, p= 0.21	- (not significant)
Himelhoch et al 2013^Citation50	Single-faceted intervention/ Telehealth	RCT	Two: Telephone intervention, F2F	HIV infected patients with depression (n=147)	Ambulatory setting	Yes	HAART	Pill counting	(adherence = pills counted/pills prescribed) IG: 0.83 ± 0.27 vs CG: 0.68 ± 0.21, t = 2.07; p = 0.04, effect size: 0.60	+ (significant)
Hammonds et al 2015^Citation38	Single-faceted intervention/ mobile intervention	RCT	Two: Mobile App, TAU	Patients with depression (n=57)	No specific setting mentioned	No	Antidepressants	Pill counting	X² (1, N=40) = 3.64, 95% CI [0.945, 12.966], p=0.057, ɸ=0.30,	+ (not significant)
Cohen et al 2020^Citation52	Multi-faceted intervention	RCT	Two: Telehealth, TAU	Patients with diabetes and co-occurring depression (n=30)	No specific setting mentioned	Yes	Cardiovascular medications, antidepressants, adjunct antidepressants, diabetes medication and insulin, all medications combined	Pill counting	Follow-up mean difference between the groups (95% CI): 1. cardiovascular medications (10.3; 95% CI –10.0 to 30.6) 2. diabetes medications and insulin (8.9; 95% CI –20.0 to 37.4) 3. antidepressants (8.5; 95% CI –54.4 to 37.4) 4. adjunct antidepressants (15.3; 95% CI –40.4 to 71.1) 5. all medications combined (2.3; 95% CI –13.7 to 18.3)	+ (not significant)
Choudhry et al 2017^Citation39	Single-faceted intervention/ telehealth	RCT	Four: Three Devices (one of them eHealth), TAU	Patients with depression (n=15,948) Patients with other chronic conditions (n= 37,532)	No specific setting mentioned	No	Antidepressants or medication for cardiovascular disease or other non-depression chronic condition	MPR	Digital timer cap vs control: OR (95% CI) = 0.97 (0.84–1.11)	- (not significant)
Aikens et al 2015^Citation40	Single-faceted intervention/ mobile intervention	Pre-/post design	Two: IVR with support person, IVR TAU	Patients with depressions (n=221)	No specific setting mentioned	Yes	NI	MGL Scale	IG: the odds of antidepressant medication adherence increased in IG 31% per week (AOR=1.31, 95% CI: 1.16–1.47, p<0.001) vs 11% for controls (AOR=1.11, 95% CI: 0.99–1.24, p=0.070)	Not applicable, because no comparison with CG
Gervasoni et al 2010^Citation41	Single-faceted intervention/ telehealth	CCT	Two: Telephone intervention, TAU	Patients with depressions (n=131)	Ambulatory setting	Yes	Psychotropic drugs	Paroxetine plasma level	Paroxetine plasma level (ng/mL) intervention: Med=24, Range=1–87 control: Med=24, Range=7–126; p=0.88	0 (no difference)
Fortney et al 2007^Citation42	Multi-faceted intervention	RCT	Two: Telemedicine, TAU	Patients with depressions (n=395)	Ambulatory setting	Yes	NI	Single item from questionnaire (number of days tablets were taken as prescribed)	IG vs CG, 12 months: OR=2.7, p=0.01	+ (significant)
Sajatovic et al 2015^Citation45	Multi-faceted intervention	Pre-/post design	One: Device, no CG	Patients with BD (n=5)	No specific setting mentioned	No	NI	MGL Scale	Mean scores on the Morisky scale improved from baseline to follow-up (3.20–3.60)	+ (no further statistical details)
Lobban et al 2017^Citation46	Internet-based self-management program	RCT	Two: Online intervention, TAU	Patients with BD (n=109)	No specific setting mentioned	Yes	Mood stabilizer, other	MARS-10	48-week follow-up estimate: difference between beta estimates −0.356, CI 95% (−1.39 to 0.674), p=0.50	- (not significant)
Moore et al 2015^Citation51	Single-faceted intervention/ mobile intervention	RCT	Two: Texting, Active control	HIV infected patients with BD (n=62)	No specific setting mentioned	Yes	Psychiatric medication (PSY), antiretroviral medications (ARV)	Pill counting	Mean adherence: ARV (IG 86.2% vs CG 84.8%; p=0.95, Cliff’s d = 0.01) and PSY (IG 78.9% vs CG 77.3%; p = 0.43, Cliff’s d = −0.13) Dosing time (Median): ARV: IG: 27.8 vs CG: 77.0 min from target time; p=0.02, Cliff’s d = 0.37; 16PSY: IG: 46.8 vs CG: 66.5, p=0.42, Cliff’s d = 0.14	ARV: + (not significant) PSY: + (not significant) (but improved dosing time for ARV (significant)
Salisbury et al 2016^Citation43	Internet-based self-management program	RCT	Two: Telehealth, TAU	Patients with depression (n=726)	Ambulatory setting	Yes	Antidepressants	MGL Scale	Adjusted difference in means after 12 months’ follow-up (CI 95%): –0.1 (–0.2 to 0.1); p= 0.511	- (not significant)
Hungerbuehler et al 2016^Citation44	Single-faceted intervention/ telehealth	RCT	Two: Videoconferencing consultations, F2F	Patients with depression (n=107)	Ambulatory setting	Yes	Antidepressants	MGL Scale	Participants in the F2F group tended to be more adherent than participants in the videoconferencing group at 12 months (X2 = 2.864, p=0.07).	- (not significant)
Levin et al 2019^Citation47	Internet-based self-management program	Pre-/post design	One: Texting, no CG	Patients with BD (n=38)	Ambulatory setting	Yes	Bipolar medications, antihypertensives	Tablets Routine Questionnaire (TRQ) and pill bottle openings (eCAP)	Antihypertensive and bipolar drug adherence improvement was significant between screen and baseline, screen and V1, and screen and V2. 1. Past-Week-TRQ: 1.1 Hypertensives: χ2 (3) = 34.55, p< 0.001, W= 0.30 1.2 Bipolar medications: χ2 (3) = 18.97, p< 0.001, W= 0.17 2. Past-Month-TRQ: 2.1 Hypertensives: χ2 (3) = 35.39, p< 0.001, W= 0.31 2.2 Bipolar medications: χ2 (3) = 26.17, p< 0.001, W= 0.23 3. eCAP (Hypertensives): 3.1 Past-Week: χ2 (2) = 0.23, p= 0.89 3.2 Past-Month: χ2 (2) = 0.07, p= 0.97	+ (significant)

Notes: The column “effect” shows the direction of the results reported regarding medication adherence, with the assessment of significance followed the information given in the reports (‚+‘Positive effect, ‚0‘No effect, ‚-‘Negative effect). *See Table 4 for a detailed description of the intervention.

Abbreviations: AOR, adjusted odds ratio; BD, bipolar disorder; CCT, controlled clinical trial; CG, control group; CI, confidence interval; F2F, face to face; HAART, highly active antiretroviral therapy; IG, intervention group; IVR, interactive voice response; MARS-10, medication adherence rating scale by Thompson et al⁸⁹ MARS-5, medication adherence report scale by Horne;⁹⁰ MARS-5-D, medication adherence report scale by Horne (German edition);⁹⁰ MGL Scale, Morisky/Green/Levine medication adherence scale;⁹¹ MPR, medication possession ratio; NI, no information.

Table 4 Detailed Description of the Interventions of the Studies Included in This Review

Reference	Description of Intervention
Pauly et. al. 2015^Citation48	Multi-dimensional and inter-sectoral program that includes: Medication management with focus on simplification of therapy regimen; Counseling of patients during the hospital stay with verbal and written information and a medication plan at discharge; Phone calls 1.5 weeks and six weeks after discharge. Description of side effects in the information leaflets is adjusted for every patient.
Corden et al 2016^Citation37	A digital support system that intends to enhance antidepressant treatment processes and outcomes: Participants receive weekly alerts to read a unique didactic lesson and answer a set of questions to ensure knowledge about antidepressants and impart information. In the absence of a detectable medication adherence event within ten minutes of the patient’s dose time, users receive reminder notifications via android pop-ups.
Schulze et al 2019^Citation25	Proactive, regular telephone calls every second week for six months from three specially trained nurses in order to increase medication adherence. The telephone calls consist of standardized and individualized parts. If medication nonadherence or intolerable side effects are reported, participants are advised to see a physician. There is the option to receive individual text messages referring to a specific topic raised in the telephone calls.
Gliddon et al 2019^Citation49	Online self-guided intervention that includes educational modules, interactive tools, and discussion forums: Discussion forum plus psychoeducational modules (Group 2); Discussion forum, psychoeducational modules, plus cognitive behavioural therapy (CBT)-based interactive tools (Group 3). All participants have access to a peer discussion forum for the duration of the study period; with one forum per randomization arm. Before, discussion posts are screened by a moderator to going “live” for participants. There are five psychoeducational modules delivered bi-weekly followed by four booster modules delivered at three, six, nine, and twelve months. The CBT-based tools are delivered in conjunction with the initial five modules, but could only be accessed by Group 3.
Himelhoch et al 2013^Citation50	11-session manualized telephone CBT intervention: One initial evaluation session, five sessions of behavioural activation and five sessions of cognitive restructuring delivered over a 14-week period. Participants are given a study workbook and the name and telephone number of their therapist. The therapist contacts the participant to set up the first session.
Hammonds et al 2015^Citation38	A medication reminder app is installed to the participant’s smartphones and prescribed information regarding dosing are entered. The use of the reminder app is instructed and the understanding of the app’s functions are demonstrated. Participants are required to use the medication reminder app to indicate when they have taken their medication by responding to the message received.
Cohen et al 2020^Citation52	Pharmacist-led telehealth: One-on-one in-person visit divided into two parts. The first part lasts approximately 45 minutes and replicates the usual care visit. For the second part of the visit, patients are asked to bring in all of their medications, including non-prescription and alternative medications. The telehealth research pharmacist answers questions and concerns. All subsequent interactions between the pharmacist and the patient are completed via telehealth equipment and phone contacts. The patient’s primary care physician is alerted to all medication changes.
Choudhry et al 2017^Citation39	Patients in the intervention arms receive a free device in a mail along with an information card explaining how to use the device as well as contact information to obtain additional information during the trial. Patients randomized to the pill bottle strip with toggles arm or the digital timer cap arm receive one device for each targeted medication. Patients randomized to the standard pillbox arm received one device to use for all of their medications.
Aikens et al 2015^Citation53	Patients receive weekly IVR calls: The system makes up to nine call attempts at patient-selected day/time combinations. The program is provided to all patients for at least six months. Assessed are patients’ symptoms of depression, adherence and functional impairment. Clinician alerts can be triggered. After each completed call, patients’ designated support persons are emailed a summarized report with detailed suggestions on strategies for supporting the patient’s selfmanagement.
Gervasoni et al 2010^Citation41	Patients receive a brief high-intensity structured telephone intervention: Patients are contacted by phone on three occasions during the first two weeks by an experienced research nurse. Each contact included a brief structured assessment of current depressive symptoms, current use of antidepressant medication and antidepressant side-effects, and motivational support for study adherence. If a problem is reported, the nurse contacts the psychiatrist.
Fortney et al 2007^Citation42	Stepped-care model of depression treatment: Treatment intensity is increased for patients failing to respond to lower levels of care by involving a greater number of intervention personnel with increasing mental health expertise. Patients receive the intervention until a 6-month continuation phase is complete or for 12 months of acute phase treatment.
Sajatovic et al 2015^Citation45	The DialogMeds-BD (BD = Bipolar Disorder) components include: an automated pill cap with remote monitoring sensor, a multimedia adherence enhancement program and a treatment incentive program for motivating patients to remain adherent and to improve treatment-related knowledge and skills. System data are intended for viewing by clinicians in real-time.
Lobban et al 2017^Citation46	ERPonline (ERP = Enhanced Relapse Prevention) is a free-to-access, web-based, self-management resource. The aim is to help people develop a coherent working model of their mood changes, recognize and manage triggers and early warning signs, and develop coping strategies to manage these effectively. Each module includes information, suggested strategies, and case examples. Users interact with the site to input personal information relevant to their own triggers, early warning signs, and coping strategies. It is possible to involve a close friend or relative as supporter.
Moore et al 2015^Citation51	Two-way, text messaging system that includes: Face-to-face psychoeducation that lasts approximately 30 minutes and personalized daily text message as medication reminders and mood assessments. Separate messages are sent for each medication at each dosing time and are automated by a central server. After five days of failure to respond to text messages, the study coordinator calls the participant.
Salisbury et al 2016^Citation43	Integrated telehealth service that cover regular telephone calls from a health adviser who is supported by an interactive software. The advisers support participants in addressing their own health goals and direct them to relevant online resources. After an initial assessment and a goal-setting telephone call, the advisers call each participant on six occasions over four months, and make up to three more calls at two month intervals to provide reinforcement and to detect relapse. The advisers send regular progress reports to participants’ general practitioner and copy them to participants. In cases of inadequate treatment response, the advisers contact participants’ general practitioners.
Hungerbuehler et al 2016^Citation44	Participants perform monthly home-based consultations with their psychiatrists using live interactive videoconferencing: There are in-person consultation at the beginning of the study, after six months and after twelve months. In between those consultations, the participants in the intervention group underwent five home-based video consultations once a month. The medications for these patients are delivered to the patient’s home.
Levin et al 2019^Citation47	After a face-to-face, individually psychoeducation program, an automatic SMS intervention was administered. Month one: participants receive one daily text message with psychoeducational or motivational content and a daily question assessing mood. Month two: specific medication reminders, contextual cues and immediate reinforcement are added and daily mood rating continued. After three consecutive days of unacknowledged messages, the automated system sends an outreach message. The research assistant has real-time access to participants’ response logs to identify technical problems.

Figure 2 Effects on medication adherence reported in the included studies in relation to different types of intervention (n=17).

Figure 3 Effects on medication adherence reported by the included studies subdivided by interventions with and without personal contact including (n=17).

Table 5 Results of the Risk of Bias Analysis of Randomized Interventional Studies (RCTs) According to the RoB 2 Tool

Publication	Randomization Process (eg Imbalanced Prognostic Factors Between Intervention and Control Group and/or Controlling for Confounder is Missing)	Deviations from Intended Interventions	Missing Outcome Data	Measurement of the Outcome	Selection of the Reported Result	Overall Risk-of-Bias
Schulze et al, 2019^Citation25	Low	Low	Low	Low	Low	Low
Gliddon et al, 2019^Citation49	Low	Low	Low	Low	Low	Low
Himelhoch et al, 2013^Citation50	Low	Low	Low	Low	Low	Low
Hammonds et al, 2015^Citation38	Low	Some concerns	Low	Low	Low	Some concerns
Cohen et al, 2020^Citation52	Some Concerns	Low	Low	Low	Low	Some concerns
Choudhry et al, 2017^Citation39	Low	Low	Low	Low	Low	Low
Fortney et al, 2007^Citation42	Low	Low	Low	Low	Low	Low
Lobban et al, 2017^Citation46	Low	Some concerns	Low	Some concerns	Low	Some concerns
Moore et al, 2015^Citation51	Some Concerns	Some concerns	Low	Low	Low	Some concerns
Salisbury et al, 2016^Citation43	Low	Low	Low	Low	Low	Low
Hungerbuehler et al, 2016^Citation44	Low	Some concerns	Low	Low	Low	Some concerns

Table 6 Results of the Risk of Bias Analysis of Non-Randomized Interventional Studies According to the ROBINS 1 Tool

Publication	Bias Due to Confounding	Bias in Selection of Participants into the Study	Missing Outcome Data	Bias Due to Deviations from Intended Interventions	Bias Due to Missing Data	Bias in Measurement of Outcomes	Bias in Selection of the Reported Result	Overall Risk-of-Bias
Pauly et al, 2015^Citation48	Low	Low	Moderate	Low	Low	Moderate	Moderate	Moderate
Corden et al, 2016^Citation37	Critical	Low	Low	Low	Low	Moderate	Low	Critical
Aikens et al, 2015^Citation53	Moderate	Low	Low	Low	Low	Moderate	Low	Moderate
Gervasoni et al, 2010^Citation41	Serious	Low	Low	Low	Low	Moderate	Low	Serious
Sajatovic et al, 2015^Citation45	Moderate	Low	Low	Low	Low	Moderate	Low	Moderate
Levin et al, 2019^Citation47	Critical	Low	Low	Low	Low	Moderate	Low	Critical

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