Psychosocial predictors of non-adherence to chronic medication: systematic review of longitudinal studies

Figures & data

Table 1 Inclusion and exclusion criteria

Domain	Inclusion criteria	Exclusion criteria
Study population	Study population ≥18 years, living in a Western country and using chronic preventive maintenance medication for one or more somatic, chronic condition as specified in the search strategy	Studies exclusively recruiting subpopulations in special conditions, like alcohol addicts, prisoners, pregnant women*
Study types	Longitudinal retrospective or prospective study design, at least examining associations between predictor ‘X’ measured at baseline and outcome ‘Y’ measured ≥3 months after baseline^†	Study is cross-sectional, controlled trial, case report, (systematic) review, meta-analysis, editorial, letter, comment, interview, newspaper article, case-control study, intervention study, thesis* or validation study*
Outcome measure	Medication non-adherence is (one of) the primary outcomes of the study. All adherence instruments (eg, different questionnaires, refill data, MEMS) are eligible for inclusion	Outcome is discontinuation of medication
Psychosocial predictors	Psychosocial predictors are defined as predictors, pertaining to the influence of social factors on an individual’s mind or behavior, and to the interrelation of behavioral and social factors^Citation18 The term psychosocial also covers internal, psychological predictors (eg, anxiety) in this systematic review. All predictor instruments (eg, different questionnaires/scales) are eligible for inclusion	Predictors measuring addiction to stimulating agents, psychosocial co-morbidity (eg, diagnosed depression according to DSM-IV criteria, and cognitive impairment. Illness symptoms, however, like depressive mood states and anxiety, are included in the review), socio-demographics, knowledge, cognitive status, behavior, satisfaction about treatment and health care, overall outcome measures (eg, social functioning of patient, general health status, perceived quality of life, behavioral intentions), predictors outside perception of individual patient (eg, beliefs of physicians)* In addition, predictors for which it was unclear what they measured (eg, ‘HIV-mastery’^Citation19 or ‘coping’ without specifying the type of coping), predictors for which results had not been reported in studies*
Other	English abstract available^‡	No English abstract available, unpublished studies which could not be retrieved after substantial efforts

Notes:

* These criteria were formulated during the selection process. We did not exclude subpopulations based on socio-demographic features. Veterans or government employees, for example, are not in a special condition per se; ^†when the outcome is measured multiple times after baseline, and one summary measure over the total, observational time after baseline is calculated, than the observational time should be at least 6 months. For example, studies measuring daily adherence for 3 months after baseline and calculating one summary adherence measure for a patient over these 3 months are excluded, because the mean time point of the summary adherence measure is 1.5 months after baseline; ^‡please note that studies of all languages are eligible, but at least an English abstract should be available.

Abbreviations: DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision; HIV, human immunodeficiency virus; MEMS, medication event monitoring System.

Figure 1 Psychosocial categories.

Figure 2 Flowchart of study inclusion process.

Abbreviation: CPMM, chronic preventive maintenance medication.

Table 2 Study characteristics and results*

First author	Setting	Sample characteristics			Measures and results
		Sample size, % loss to follow-up	Age†, % female	Disease duration†	Adherence‡, follow-up period§	Psychosocial category, number of predictors||	Association present between category and adherence/non-adherence?¶	Number domains bias free**
Asthma (inhaled corticosteroids)
Ponieman^Citation33	USA; patients from general internal medicine clinic	261, 23%	48 (13), 82%	Age of onset ≤20 years: 50% of sample	Self-report (MARS), 3 months	AI, n=5 AIII, n=3	No (U: yes, M: no) No (U: no, M: no)	0 of 6
Diabetes (oral and/or parenteral antidiabetics)
Venturini^Citation34,††	USA; patients from HMO-providing health services	786, 0%	59 (mean), 24–92 (range), 49%	NR	Record review, last time point flexible, but within 24 months	EI, n=1	No (U: NR, M: no)	2 of 6
Heart disease and hypertension (cardiovascular medication)
Gazmararian^Citation35	USA; community-dwelling patients‡‡	1,549, UD	Age: 65–69: 35%, 70–74: 28%, 75–79: 20%, 80–84: 12%, >84: 6%, (female): 58%	UD	Record review, 12 months	CIII, n=1	No (U: no, M: NT)	3 of 6
Nabi^Citation26	Finland; local government employees	1,021, UD	26–63 (range), 32%	0–2 years: n=311 2–5 years: n=222 5–10 years: n=292 >10 years: n=196	Record review, 12 months	D, n=4 EI, n=2	Yes (U: no, M: yes) No (U: no, M: NT)	1 of 6
Grégoire^Citation36	Canada; hypertensive adults with prescriptions from network of pharmacies	692, 26%	59 (13), 56%	47 months (adherent group), 44 months (non-adherent group)	Self-report (Morisky scale), 3 months	AI, n=1 AII, n=5 CIII, n=1	No (U: no, M: no) No (U: no, M: no) No (U: no, M: no)	0 of 6
Miller^Citation37	Site not reported: patients from institutions providing cardiac rehabilitation programs¶¶	141, 21%	56 (mean), 32–70 (range), 22%	NR	Self-report (HBS), 6–9 months	AI, n=1 CII, n=1	No (U: NR, M: no) No (U: NR, M: no)	0 of 6
Molloy^Citation38	UK; patients admitted to hospitals with acute coronary syndrome¶¶	295, 11%	61 (mean), 32–87 (range), 23%	0 years (acute)	Self-report, 12 months	CIII, n=2	No (U: no, M: no)	1 of 6
HIV (antiretroviral medication)
Deschamps^Citation25	Belgium; outpatients at university hospital	60, 28%	43 (9) adherent group, 41 (8) non-adherent group, 16%	NR	MEMS, 5–6 months after measuring psychosocial constructs	AI, n=3 AIII, n=1 BI, n=3 BII, n=4 CIII, n=2 D, n=1 EI, n=2	No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR)	1 of 6
Holmes^Citation19	USA; HIV-clinic patients	116, 0%§§	44 (median), 25–69 (range), 19%	5 years (median)	MEMS, 12 months (or when viral load of ≥1,000 copies/mL was reached)	AI, n=1 AII, n=2 CI, n=1 CIII, n=1 EI, n=1 EII, n=1	No (U: no, M: no) No (U: no, M: no) No (U: no, M: NT) No (U: no, M: NT) No (U: no, M: no) No (U: no, M: no)	2 of 6
Delgado^Citation39	Canada; patients enrolled in community drug treatment program	316, 0%	NR, NR	NR	Record review, 12 months	EI, n=1	No (U: yes, M: no)	1 of 6
Singh^Citation40	USA; new, veteran patients seen at medical center	52, 12%	40 (median), 23–68 (range), 0%	NR	Record review, 6 months	BII, n=1 CIII, n=2 EI, n=4	No (U: no, M: no) No (U: no, M: no) No (U: no, M: no)	1 of 6
Singh^Citation41	Site not reported: patients in HIV-medical centers	138, 11%	41 (median), 24–71 (range), 7%	NR (but 7% therapy-naive)	Record review, 6 months	BI, n=3 BII, n=6 CIII, n=4 EI, n=1	No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR)	1 of 6
Bottonari^Citation42	USA; patients treated in immunodeficiency clinic	78, 69%	36 (7), 4%	NR	Self-report (straightforward), 6–9 months	D, n=2 EI, n=1 EII, n=3	No (U: no, M: NR) No: (U: no, M: NR) No: (U: no, M: NR)	0 of 6
Godin^Citation43	Canada; patients from medicalHIV-clinics	400, 6%	43 (8), 4%	>5 years HIV- infected: 73%	Self-report (straightforward), 12 months	AI, n=1 AIII, n=2 CI, n=1 CIII, n=1 D, n=1	Yes (U: NR, M: yes) No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no)	1 of 6
Kacanek^Citation44	USA; patients recruited by media and physician networks	225, 0%	45 (7), 23%	NR	Self-report (straightforward); maximum 30 months	EI, n=1	Yes (U: yes, M: NT)	2 of 6
Martini^Citation45	Italy; outpatients using combination therapy¶¶	214, 71%	<30: 13%, 30–39: 56%, >39: 31%, (female): 36%	NR	Self-report (straightforward); 12 months	AI, n=2 CI, n=1	No (U: no, M: NR) Yes (U: yes, M: NR)	0 of 6
Mellins^Citation46	USA; HIV-infected mothers recruited in waiting room of adult clinic	128, 25%	38 (mean), 22–66 (range), 100%	5 years	Self-report (AACTG, straightforward), T1 after 4–5 months, T2 8–18 months after T1	AIII, n=1 EI, n=1 EII, n=2	No (U: no, M: NR) No (U: no, M: NR) Yes (U: yes, M: NR)	0 of 6
Nilsson Schönnesson^Citation47	Sweden; patients recruited by clinic nurses	203, 29%	45 (9), 22%	Mean year of diagnosis =1990	Self-report (straightforward), 24 months	AI, n=3 AII, n=1 AIII, n=2 BII, n=2 CI, n=1 CIII, n=2 D, n=1 EI, n=3 EII, n=1	No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no)	1 of 6
Thrasher^Citation48	USA; patients in public use of HCSUS data set	1,911, 33%§§	Minority versus non-minority: <35: 35% minority group, 30% non-minority group. % female: 33% versus 12%, respectively	Mean year first diagnosed with HIV: 1992, minority group; 1990, non-minority group	Self-report (straightforward), 12 months	CIII, n=1 EI, n=2	No (U: no, M: NR) Yes (U: yes, M: NR)	1 of 6
Horne^Citation49	UK; outpatients, eligible to receive HAART	136, 14%	38 (9), NR	5 years	Self-report (straightforward), 12 months	AI, n=2 EI, n=1	Yes (U: yes, M: yes) No (U: no, M: NT)	3 of 6
Mugavero^Citation50	USA; patients receiving care at infectious disease clinics	474, 39%	40 (median), 35–46 (IQR), 29%	NR	Self-report (AACTG, straightforward), 27 months	EII, n=4	No (U: yes, M: no)	3 of 6
Carrieri^Citation51	France; patients starting HAART-regimen	1,110, 13%	37 (median), 22%	First time since first positive HIV-test in years: 3.8 (median), 0.5–8.2 (IQR)	Self-report (AACTG, straightforward), 60 months	CII, n=1 EI, n=1	Yes (U: yes, M: yes) Yes (U: yes, M: yes)	2 of 6
Transplant-related (immunosuppressant medication)
Stilley^Citation52	USA; transplant patients, recruited before hospital discharge or at early clinic visit	152, 29%	55 (10), 33%	NR	MEMS, 6 months	BI, n=1 CII, n=1 D, n=2 EI, n=1	No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR)	1 of 6
De Geest^Citation53	Belgium; convenience sample of outpatients	101, 0%	56 (median), 20–69 (range), 13%	3 (median), 1–6 (range) years since transplantation	MEMS, 6 months	AIII, n=1 CIII, n=1 EI, n=1 EII, n=1	Yes (U: NR, M: yes) No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no)	2 of 6
Russell^Citation54	USA; convenience sample of renal transplant patients	50, 26%	60 (5), 38%	NR	MEMS, 12 months	AIII, n=1 CIII, n=1 EI, n=2	No (U: no, M: NR) No (U: no, M: NR) No (U: no, M: NR)	0 of 6
Weng^Citation55	USA; patients recruited at time of renal transplantation	829, 66%	48 (median), 39–57 (IQR), 39%	NR	MEMS, 12 months post-transplantation	AIII, n=1 CII, n=1 EI, n=1 EII, n=1	No (U: yes, M: no) No (U: no, M: NT) No (U: no, M: NT) No (U: no, M: NT)	2 of 6
Dew^Citation56	USA; heart transplant patients from academic hospital|| ||	108, 22%	<50 years: 49%, (female): 16%	NR	Self-report (straightforward), 12 months post-transplantation	AIII, n=1 BI, n=2 BII, n=1 CII, n=2 EI, n=3	No (U: no, M: NT) No (U: no, M: NT) Yes (U: yes, M: yes) No (U: no, M: no) No (U: no, M: no)	2 of 6
Dew^Citation57	USA; patients receiving first lung transplantation in academic hospital	178, 29%	37% <50 years, (female): 48%	NR	Self-report (straightforward), 24 months	AIII, n=3 CII, n=2 D, n=1 EI, n=3	No (U: yes***, M: no) No (U: yes, M: no) No (U: yes, M: no) No (U: yes, M: no)	1 of 6
Dobbels^Citation58	Belgium; heart, liver and lung transplant patients listed at university hospitals	186, 24%	52 (12), 33%	NR	Self-report (straightforward), 12 months post-transplantation	CII, n=2 D, n=5 EI, n=2	No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no)	1 of 6
Other (diabetes and/or hypertension and/or heart disease)
DiMatteo^Citation59	USA; patients from five medical specialties in HMOs, large multispecialty groups or solo practices‡‡,¶¶	Max 1,828, UD	60 (8), 54%	NR	Self-report (straightforward), 24 months	BII, n=1 CI, n=2 CII, n=1 EI, n=1	No (U: NR, M: no) No (U: NR, M: no) No (U: NR, M: no) Yes (U: NR, M: yes)	0 of 6

* NS (non significant): as reported in the concerning study. UD (undetermined): because of inadequate description in the concerning study;

† mean (and for age: standard deviation) in years reported unless indicated otherwise;

‡ with straightforward, we mean that participants were directly asked to indicate how many medication doses they missed. For example: “How many pills did you take this week?”;

§ follow-up period = number of months between baseline (unless indicated otherwise) and last adherence measurement;

|| this column shows the number of psychosocial predictors measured in the concerning study, and the assigned psychosocial category. Details about the single predictors are presented in Table S2. A = Beliefs and cognitions about I) medication and treatment; II) illness; III) self-efficacy and locus of control. B = coping styles I) task oriented, II) emotion oriented. C = Social influences and social support I) regarding medical caregiver; II) regarding friends and family; III) in general. D = personality traits. E = psychological well-being: I) mood state; II) perceived stress/stressors;

¶ no = no significant association between psychosocial category and medication adherence/non-adherence within study when P≤0.05; Yes = significant association when P≤0.05; U: univariate; M: multivariate;

** to determine methodological quality, six bias domains per study were judged. Here, the total amount of bias free domains is reported (for further details, see Table S3);

†† retrospective design;

‡‡ diagnosis for coronary heart disease, hypertension, diabetes mellitus, and/or hyperlipidemia;

§§ % loss to follow-up assumed by HZ/BvdB;

|| || type of medication is immunosuppressants, antihypertensives, and/or antivirals;

¶¶ use of chronic preventive medication assumed;

*** significance of P≤0.05 assumed by HZ/BvdB.

Abbreviations: AACTG, adult AIDS clinical trials group; HAART, highly active antiretroviral therapy; HBS, health behavior scale; HCSUS, HIV cost and services utilization study; HIV, human immunodeficiency virus; HMO, health maintenance organization; IQR, interquartile range; MARS, medication adherence report scale; MEMS, medication event monitoring system; NR, not reported; NS, non significant; NT, not tested; UD, undetermined.

Table 3 Level of evidence for longitudinal associations between psychosocial categories and medication non-adherence

Psychosocial category	N of studies	Quality	Longitudinal association	Level of evidence
A. Beliefs and cognitions
I. About medication and treatment	9	All low	2 × yes^Citation43,Citation49 7 × no^Citation19,Citation25,Citation33,Citation36,Citation37,Citation45,Citation47	No association (limited evidence)
II. About illness	3	All low	3 × no^Citation19,Citation36,Citation47	No association (limited evidence)
III. Self-efficacy and locus of control	10	All low	1 × yes^Citation53 9 × no^Citation25,Citation33,Citation43,Citation46,Citation47,Citation54^–^Citation56,Citation57	No association (limited evidence)
B. Coping styles
I. Task-oriented	4	All low	4 × no^Citation25,Citation41,Citation52,Citation56	No association (limited evidence)
II. Emotion-oriented	6	All low	1 × yes^Citation56 5 × no^Citation25,Citation40,Citation41,Citation47,Citation59	No association (limited evidence)
C. Social influences and social support
I. Regarding medical caregiver	5	All low	1 × yes^Citation45 4 × no^Citation19,Citation43,Citation47,Citation59	No association (limited evidence)
II. Regarding friends and family	6	All low	1 × yes^Citation51 5 × no^Citation37,Citation52,Citation55^–^Citation57	No association (limited evidence)
III. In general	14	All low	14 × no^Citation19,Citation25,Citation35,Citation36,Citation38,Citation40,Citation41,Citation43,Citation47,Citation48,Citation53,Citation54,Citation58,Citation59	No association (limited evidence)
D. Personality traits	8	All low	1 × yes^Citation26 7 × no^Citation25,Citation42,Citation43,Citation47,Citation52,Citation57,Citation58	No association (limited evidence)
E. Psychosocial well-being
I. Mood state	21	All low	3 × yes^Citation44,Citation48,Citation51 18 × no^Citation19,Citation25,Citation26,Citation34,Citation39^–^Citation42,Citation46,Citation47,Citation49,Citation52^–^Citation58	No association (limited evidence)
II. Perceived stress/stressors	8	All low	2 × yes^Citation46,Citation59 6 × no^Citation19,Citation42,Citation47,Citation50,Citation53,Citation55	No association (limited evidence)

Table

A02BA01	Cimetidine
A02BA02	Ranitidine
A02BA03	Famotidine
A02BA04	Nizatidine
A02BA07	Ranitidinebismutcitrate
A02BB01	Misoprostol
A02BC01	Omeprazole
A02BC02	Pantoprazole
A02BC03	Lansoprazole
A02BC04	Rabeprazole
A02BC05	Esomeprazole
A07EA04	Betamethasone
A07EA06	Budesonide
A07EA07	Beclomethasone
A07EC01	Sulphasalazine
A07EC02	Mesalazine
A07EC03	Olsalazine
A10A	Insulin
A10BA02	Metformin
A10BB01	Glibenclamide
A10BB03	Tolbutamide
A10BB07	Glipizide
A10BB09	Gliclazide
A10BB12	Glimepiride
A10BF01	Acarbose
A10BG02	Rosiglitazone
A10BG03	Pioglitazone
A10BH01	Sitagliptine
A10BX02	Repaglinide
A11CC03	Alfacalcidol
A11CC04	Calcitriol
A11CC05	Colecalciferol
A12AA01	Calciumphosphate
A12AA02	Calciumglubionate
A12AA03	Calciumgluconate
A12AA04	Calciumcarbonate
A12AA05	Calciumlactate
A12AA07	Calciumchloride
A12AA12	Calciumacetate
A12AA30	Calciumlevulinate
B01AA03	Warfarin
B01AA04	Fenprocoumon
B01AA07	Acenocoumarol
B01AC04	Clopidogrel
B01AC06	Acetylsalicylic acid
B01AC07	Dipyridamole
B01AC08	Carbasalate calcium
B01AC09	Epoprostenol
B01AC21	Treprostinil
B03BB01	Folic acid
C01AA05	Digoxin
C01BA01	Quinine
C01BA02	Procainamide
C01BA03	Disopyramide
C01BB01	Lidocaine
C01BB04	Aprindine
C01BC03	Propafenone
C01BC04	Flecainide
C01BD01	Amiodarone
C01DA08	Isosorbidedinitrate
C01DA14	Isosorbidemononitrate
C01DX16	Nicorandil
C01EB17	Ivabradine
C02AB01	Methyldopa
C02CA01	Prazosin
C02CA04	Doxazosin
C02CA06	Urapidil
C02DB02	Hydralazine
C02DC01	Minoxidil
C02KD01	Ketanserin
C02KX01	Bosentan
C02KX03	Sitaxentan
C03AA03	Hydrochloorthiazide
C03AA04	Chlorthiazide
C03BA04	Chlortalidone
C03BA11	Indapamide
C03CA01	Furosemide
C03CA02	Bumetanide
C03DA01	Spironolactone
C03DA04	Eplerenone
C03DB01	Amiloride
C03DB02	Triamterene
C04AC01	Nicotinic acid
C04AD02	Xantinolnicotinate
C07AA02	Oxprenolol
C07AA03	Pindolol
C07AA05	Propranolol
C07AA07	Sotalol
C07AB02	Metoprolol
C07AB03	Atenolol
C07AB04	Acebutolol
C07AB05	Betaxolol
C07AB07	Bisoprolol
C07AB08	Celiprolol
C07AB12	Nebivolol
C07AG01	Labetalol
C07AG02	Carvedilol
C08CA01	Amlodipine
C08CA02	Felodipine
C08CA03	Isradipine
C08CA04	Nicardipine
C08CA05	Nifedipine
C08CA06	Nimodipine
C08CA07	Nisoldipine
C08CA08	Nitrendipine
C08CA09	Lacidipine
C08CA12	Barnidipine
C08CA13	Lercanidipine
C08DA01	Verapamil
C08DB01	Diltiazem
C09AA01	Captopril
C09AA03	Lisinopril
C09AA04	Perindopril
C09AA05	Ramipril
C09AA06	Quinapril
C09AA07	Benazepril
C09AA08	Cilazapril
C09AA09	Fosinopril
C09AA10	Trandolapril
C09AA15	Zofenopril
C09CA01	Losartan
C09CA02	Eprosartan
C09CA03	Valsartan
C09CA04	Irbesartan
C09CA06	Candesartan
C09CA07	Telmisartan
C09CA08	Olmesartan
C10AA01	Simvastatin
C10AA03	Pravastatin
C10AA04	Fluvastatin
C10AA05	Atorvastatin
C10AA07	Rosuvastatin
C10AB01	Clofibrate
C10AB02	Bezafibrate
C10AB04	Gemfibrozil
C10AB08	Ciprofibrate
C10AC01	Colestyramine
C10AC02	Colestipol
C10AC04	Colesevelam
C10AD02	Nicotinic acid
C10AD06	Acipimox
C10AX09	Ezetimib
G03XA01	Danazol
G03XC01	Raloxifene
G04BD02	Flavoxate
G04BD04	Oxybutynin
G04BD07	Tolterodine
G04BD08	Solifenacin
G04BD10	Darifenacin
G04CA01	Alfuzosin
G04CA02	Tamsulosin
G04CA03	Terazosin
G04CB01	Finasterid
G04CB02	Dutasterid
H02AA02	Fludrocortisone
H02AB01	Betamethasone
H02AB02	Dexamethasone
H02AB04	Methylprednisolone
H02AB06	Prednisolone
H02AB07	Prednisone
H02AB08	Triamcinolone
H02AB09	Hydrocortisone
H02AB10	Cortisone
J05AE01	Saquinavir
J05AE02	Indinavir
J05AE03	Ritonavir
J05AE04	Nelfinavir
J05AE05	Amprenavir
J05AE06	Lopinavir
J05AE07	Fosamprenavir
J05AE08	Atazanavir
J05AE09	Tipranavir
J05AE10	Darunavir
J05AF01	Zidovudine
J05AF02	Didanosine
J05AF03	Zalcitabine
J05AF04	Stavudine
J05AF05	Lamivudin
J05AF06	Abacavir
J05AF07	Tenofovir
J05AF08	Adefovir
J05AF09	Emtricitabine
J05AF10	Entecavir
J05AF11	Telbivudine
J05AG01	Nevirapine
J05AG03	Efavirenz
J05AX07	Enfuvirtide
L01AA01	Cyclophosphamide
L01BA01	Methotrexate
L02BG01	Aminoglutethimide
L02BG03	Anastrozole
L02BG04	Letrozole
L04AA06	Mycophenol acid
L04AA10	Sirolimus
L04AA13	Leflunomide
L04AA18	Everolimus
L04AB01	Etanercept
L04AB02	Infliximab
L04AB04	Adalimumab
L04AC03	Anakinra
L04AD01	Ciclosporine
L04AD02	Tacrolimus
L04AX01	Azathioprine
L04AX03	Methotrexate
M01CB01	Aurothiomalate
M01CB03	Auranofin
M01CC01	Penicillamine
M04AA01	Allopurinol
M04AB01	Probenecid
M04AB03	Benzbromarone
M05BA01	Etidronate
M05BA02	Clodronate
M05BA03	Pamidronate
M05BA04	Alendronate
M05BA05	Tiludronate
M05BA06	Ibandronate
M05BA07	Risedronate
M05BA08	Zoledronate
M05BX03	Strontiumranelate
N02CX01	Pizotifen
N02CX02	Clonidine
R03BA01	Beclomethasone
R03BA02	Budesonide
R03BA05	Fluticasone
R03BA08	Ciclesonid
R03BC01	Cromolyn sodium
R03BC03	Nedocromil
R03DC03	Montelukast
S01EA02	Dipivefrine
S01EA03	Apraclonidine
S01EA05	Brimonidine
S01EA51	Epinephrine
S01EB01	Pilocarpine
S01EB08	Aceclidine
S01EC01	Acetazolamide
S01EC03	Dorzolamide
S01EC04	Brinzolamide
S01ED01	Timolol
S01ED02	Betaxolol
S01ED03	Levobunolol
S01ED04	Metipranolol
S01ED05	Carteolol
S01ED06	Befunolol
S01EE01	Latanoprost
S01EE03	Bimatoprost
S01EE04	Travoprost

Table S1 Framework for judging methodological quality

Bias domain	Criterion	Score	Judgment	Final score
1. Study participation	1.1. The setting of the source population is adequately described by key characteristics (setting/geographical location)	○ Yes ○ Partly ○ No	5 × yes = yes 1 × no = no Else = partly	○ Yes ○ Partly ○ No
	1.2. The (baseline) study sample is adequately described by key characteristics (descriptive data about age, sex, diagnosis, disease duration and medication type/group), and no unacceptable level of bias is present	○ Yes ○ Partly ○ No
	1.3. The method of recruitment or sampling is adequately described. If method of recruitment is not ‘consecutive’, then, for example, descriptions are given about the sampling frame, numbers, methods to identify the sample (such as a description of referral patterns in health care) and period of recruitment, and no unacceptable level of bias is present	○ Yes ○ Partly ○ No
	1.4. Inclusion and exclusion criteria are adequately described, and no unacceptable level of bias is present	○ Yes ○ Partly ○ No
	1.5. There is adequate participation in the study by eligible individuals (power analysis is described or the sample size (n) is adequate in relation to the number of prognostic variables (K) in the statistical analyses (ratio n:K exceeds 10:1)	○ Yes ○ Partly ○ No
2. Study attrition	2.1. Response rate (ie, proportion of study sample completing the study and providing outcome data) is adequate If study sample size ≤50 participants: ‘yes’ when total number of participants lost to follow-up was <10% at follow-up ≥three months. ‘Partly’: if this percentage was between 10% and 20%. ‘No’: if this percentage was ≥20% If study sample size >50 participants: ‘yes’, when total number of participants lost to follow-up was <20% at follow-up $three months. ‘Partly’: if this percentage was between 20% and 33%. ‘No’: if this percentage was ≥33%	○ Yes ○ Partly ○ No	2.1 yes = yes (you can leave 2.2 open) 2.1 no = no OR 2.1 partly, 2.2 no = no Else = partly	○ Yes ○ Partly ○ No
	2.2. Attempts to collect information about participants who dropped out of the study are described: 1) reasons for loss to follow-up are provided OR 2) participants lost to follow-up are adequately described by key characteristics and outcomes. No unacceptable level of bias is present	○ Yes ○ Partly ○ No
3. Prognostic factor measurement	3.1. A clear description of the main prognostic factors is provided (not covariates) AND/OR measures/methods regarding the main prognostic factors, at baseline and follow-up are adequately described to allow assessment of their validity and reliability. No unacceptable level of bias is present  ○ Objective measures (such as number of life-changing events) and clear description is ‘yes’. Poor/no description = ‘partly’  ○ Validated, subjective measures (eg, opinions) and clear description = ‘yes’. Poor/no description = ‘partly’  ○ Non-validated, subjective measures and clear description = ‘partly’. Poor/no description = ‘no’	○ Yes ○ Partly ○ No	4 × yes = yes 3.1 or 3.2 no = no OR 3.1 or 3.2 partly (no no’s), 3.3 or 3.4 no = no Else = partly	○ Yes ○ Partly ○ No
	3.2. The method and setting of measurement are the same for all study participants at baseline and follow-up	○ Yes ○ Partly ○ No
	3.3. Continuous variables are reported or appropriate cut-off points are used	○ Yes ○ Partly ○ No
	3.4. Authors appropriately described and dealt with missing data on prognostic factors	○ Yes ○ Partly ○ No
4. Outcome measurement	4.1. A clear description of medication adherence is provided AND/OR measures/methods of medication adherence (at baseline and follow-up) are adequately described, to allow assessment of their validity and reliability. No unacceptable level of bias is present  ○ Objective measures (such as pill count, refill rates, MEMS) and clear description = ‘yes’. Poor/no description is ‘partly’  ○ Validated, subjective measures (eg, questionnaires) and clear description = ‘yes’. Poor/no description = ‘partly’  ○ Non-validated, subjective measures and clear description = ‘partly’. Poor/no description = ‘no’	○ Yes ○ Partly ○ No	3 × yes = yes 4.1 or 4.2 no = no OR 4.1 or 4.2 partly (no no’s), 4.3 no = no Else = partly	○ Yes ○ Partly ○ No
	4.2. The method and setting of measurement are the same for all study participants at baseline (if measured) and follow-up	○ Yes ○ Partly ○ No
	4.3. Authors appropriately described and dealt with missing outcome data	○ Yes ○ Partly ○ No
5. Confounding measurement and account	5.1. The most important confounders are measured Examples of possible confounders: age; socioeconomic status/educational level/financial situation/illiteracy; social support/networks; depression/anxiety/emotional distress/lack of acceptance of disease; fatigue/pain/physical disability; self-efficacy/coping; regimen complexity/route of administration/number of medications; satisfaction with patient-provider relationship/autonomy	○ Yes ○ Partly ○ No
	5.2. A clear description of the most important confounders measured is provided AND/OR measures/methods of the most important confounders (at baseline) are adequately described to allow assessment of their validity and reliability. No unacceptable level of bias is present  ○ Objective measures (such as age, sex) and clear description = ‘yes’. Poor/no description is ‘partly’  ○ Validated, subjective measures (eg, opinions) and clear description = ‘yes’. Poor/no description = ‘partly’  ○ Non-validated, subjective measures and clear description = ‘partly’. Poor/no description = ‘no’	○ Yes ○ Partly ○ No	One of 5.1 to 5.4 = no (if 5.1 no, you can leave 5.2 to 5.5 open) OR 5.1 to 5.4 partly, 5.5 no = no All partly = partly OR 5.1 to 5.4 partly, 5.5 yes = partly OR none of 5.1 to 5.4 no, 5.5 no = partly OR 5.1 to 5.4 yes, 5.5 not yes = partly Else = yes	○ Yes ○ Partly ○ No
	5.3. The method and setting of confounding measurement are the same for all study participants at baseline	○ Yes ○ Partly ○ No
	5.4. Important potential confounders are accounted for in the study design (eg, matching for key variables/restriction) OR in analysis (stratification/multivariate techniques)	○ Yes ○ Partly ○ No
	5.5. Authors appropriately described and dealt with missing confounding data	○ Yes ○ Partly ○ No
6. Analysis	6.1. There is sufficient presentation of data to assess the adequacy of the analysis ‘Yes’, if main findings of the study and statistical methods used are clearly described: simple outcome data, crude data and estimates of random variability should be reported, so that the reader can check the major analyses and conclusions	○ Yes ○ Partly ○ No	4 × yes = yes At least 1 × no = no Else = partly	○ Yes ○ Partly ○ No
	6.2. The statistical tests used to assess the main outcome are appropriate For example, non-parametric methods should be used for small sample sizes	○ Yes ○ Partly ○ No
	6.3. The strategy for model building (ie, inclusion of variables) is appropriate, and is based on conceptual thoughts, a framework or a model For example: variables that do not correlate with the main outcome of interest are not used in multivariate analysis. Proper variables are entered in logical steps into the multivariate model	○ Yes ○ Partly ○ No
	6.4. The selected model is adequate for the design of the study For example: in repeated measures, a repeated-measure model should be used. If outcome is binominal, logistic regression should be used, etcetera. If delta outcome is being investigated, models should to be adjusted for baseline outcome values	○ Yes ○ Partly ○ No

Table S2 explanation of measures and results*

First author	Setting, n patients	Measures		Psychcat||	Results¶		Direction of association (regarding adherence)**	N domains bias free††
		Adherence†, follow-up period‡	Psychosocial predictors§		Univariate	Multivariate
Asthma (inhaled corticosteroids)
Ponieman^Citation1	USA; patients from general internal medicine clinic, n=261	Adherence by self-report (MARS), 3 months	(Items derived from BMQ and Self-Regulation Theory): concerns beliefs: worried about side effects of ICS? Concerns beliefs: worried about getting addicted to ICS?	AI	OR =0.3 (0.2, 0.7), P<0.05	OR =0.52 (0.36, 0.74), P<0.001	U: − M: −	0 of 6
			Concerns beliefs: if I use ICS all the time they will stop working	AI	OR =0.4 (0.2, 0.8), P<0.05	NS‡‡	U: − M: 0
			Necessity beliefs: important to use ICS when symptomatic?	AI	OR =0.4 (0.2, 0.9), P<0.05	NS‡‡	U: − M: 0
			Necessity beliefs: important to use ICS when asymptomatic?	AI	NS	NS‡‡	U: 0 M: 0
			Self-efficacy: confident in ability to use ICS as prescribed	AI	OR =5.8 (2.3, 14.6), P<0.05	OR =4.15 (2.54, 6.77), P<0.001	U: + M: +
			Self-efficacy: confident in ability to control asthma	AIII	OR =3.5 (1.6, 7.6), P<0.05	OR =2.23 (1.42, 3.52), P<0.001	U: + M: +
			Self-efficacy: confident in controlling future health	AIII	NS	NS‡‡	U: 0 M: 0
				AIII	NS	NS‡‡	U: 0 M: 0
Diabetes (oral and/or parenteral anti-diabetics)
Venturini^Citation2,§§	USA; patients from HMO-providing health services, n=786	Adherence by record review (continuous measure corrected for self-reported baseline adherence), last time point flexible, but within 24 months	Perception of mental health (mood state, SF-36)	EI	NR	NS	U: NR M: 0	2 of 6
Heart disease and hypertension (cardiovascular medication)
Gazmararian^Citation3,|| ||	USA; community-dwelling patients, n=1,549	Non-adherence by record review, 12 months	Social support (instrument NR)	CIII	NS	NT	U: 0 M: NT	3 of 6
Nabi^Citation4	Finland: local government employees, n=1,021	Non-adherence by record review (ordinal measure), 12 months	Anxiety (ATS)	EI	NS	NT	U: 0 M: NT	1 of 6
			Hostility (FTSSH)	D	NS	NT	U: 0 M: NT
			Optimism (LOT-R)	D	NS	NT	U: 0 M: NT
			Pessimism (LOT-R)	D	NS	NT	U: 0 M: NT
			Psychological distress (GHQ)	EI	NS	NT	U: 0 M: NT
			Sense of coherence (SOC)	D	OR =0.62 (0.36, 1.05), P<0.10	OR =0.55 (0.31, 0.96), P<0.05	U: 0 M: +
Grégoire^Citation5	Canada: hypertensive adults with prescription from network of pharmacies, n=692	Non-adherence by self-report (Morisky Scale), 3 months	(Interview, self-developed items): beliefs concerning efficacy of antihypertensive medication	AI	NS	NS	U: 0 M: 0	0 of 6
			Beliefs concerning hypertension as risk factor for other diseases	AII	“No effect” versus “a lot of effect” (ref cat): OR =1.74 (1.08, 2.81), P=0.02	“No effect” versus “a lot of effect”: OR =2.00 (1.21, 3.33), P≤0.05	U: − M: −
			How much are you at risk of a heart attack because of your hypertension if you follow your doctor’s advice?	AII	NS	NS	U: 0 M: 0
			How much are you at risk of a stroke because of your hypertension if you follow your doctor’s advice?	AII	NS	NS	U: 0 M: 0
			How much are you at risk of heart attack because of your hypertension if you do not do anything about it?	AII	“Do not know” versus “no to moderate risk” (ref cat): OR =0.46 (0.19, 1.12), P=0.09	NS	U: 0 M: 0
			How much are you at risk of stroke because of your hypertension if you do not do anything about it?	AII	“Do not know” versus “no to moderate risk” (ref cat): OR =0.44 (0.17, 1.16), P=0.10	“Do not know” versus “no to moderate risk”: OR =0.40 (0.15, 1.09), P=0.07	U: 0 M: 0
			Social support (Pearlin et al^Citation31)	CIII	NS	NS	U: 0 M: 0
Miller^Citation6,§§§	Site not reported: patients from institutions providing cardiac rehabilitation programs, n=141	Adherence by self-report (continuous measure, HBS), 6–9 months	Attitude towards medication taking (MAS)	AI	NR	NS	U: NR M: 0	0 of 6
			Beliefs about which steps of the medical regimen people most important to them think they should perform (HIS)	CII		NS	U: NR M: 0
Molloy^Citation7,§§§	UK; patients admitted to one of four London hospitals with Acute Coronary Syndrome, n=295	Adherence by self-report, 12 months	Emotional support (derived from Berkman et al^Citation32 and Seeman et al^Citation33)	CIII	NS	NS	U: 0 M: 0	1 of 6
			Practical support	CIII	Number of patients providing practical support: 0: 39.7% adherent. 1: 40.5% adherent. Two or more: 59.2% adherent, P=0.004	OR =2.12 (1.06, 4.26), P=0.03	U: + M: +
HIV (antiretroviral medication)
Deschamps^Citation8	Belgium; outpatients of university hospital, n=60	Non-adherence by MEMS, 5–6 months after measuring psychosocial constructs	Anxiety (AMHI)	EI	NS	NR	U: 0 M: NR	1 of 6
			Coping style: confrontational (AWC)	BI	NS		U: 0 M: NR
			Coping style: distancing	BII	NS		U: 0 M: NR
			Coping style: self-controlling	BII	NS		U: 0 M: NR
			Coping style: seek social support	CIII	NS		U: 0 M: NR
			Coping style: accept responsibility	BII	NS		U: 0 M: NR
			Coping style: escape-avoidance (higher score = more escape-avoidance)	BII	Adherent patients 7.2, (2.2) versus non-adherent patients 10.1 (2.8), P=0.003		U: − M: NR
			Coping style: planful problem solving (higher score = more planful problem solving)|| || ||	BI	Adherent patients 7.5 (median), 3 (IQR) versus non-adherent patients 9 (median), 2 (IQR), P=0.049		U: − M: NR
			Coping style: positive reappraisal	BI	NS		U: 0 M: NR
			Depression (AMHI)	EI	NS		U: 0 M: NR
			Perceived benefits of treatment (APIAQ)	AI	Adherent patients 21 (3.5) versus non-adherent patients 18.7 (3.9), P=0.07		U: 0 M: NR
			Perceived severity of seriousness of implications when not taking medications adequately	AI	NS		U: 0 M: NR
			Perceived susceptibility of developing AIDS when not taking medications as prescribed	AI	NS		U: 0 M: NR
			Positive affect (eg, happiness person)	D	NS		U: 0 M: NR
			Received social support (AGSRP)	CIII	NS		U: 0 M: NR
			Self-efficacy in taking HAART medication (ALTMBSES)	AIII	NS		U: 0 M: NR
Holmes^Citation9	USA; HIV-clinic patients, n=116	Adherence by MEMS, 12 months (or when viral load of ≥1,000 copies/mL was reached)	Depressive symptoms (CES-D)	EI	High adherence 12.6 (11.3), low adherence 16.5 (11.7), P=0.06	NS	U: 0 M: 0	2 of 6
			HIV-disclosure worries (HAT-QOL)	AII	NS	NT	U: 0 M: NT
			Health worries (higher score = fewer worries)	AII	High adherence 79.2 (23.9), low adherence 70.4 (28.9), P=0.06	NS	U: 0 M: 0
			Medication worries (higher score = fewer worries)	AI	High adherence 86.1 (20.4), low adherence 83.3 (18.3), P=0.06	NS	U: 0 M: 0
			Provider trust	CI	NS	NT	U: 0 M: NT
			Social support (ISEL)	CIII	NS	NT	U: 0 M: NT
			Stress (PSS)	EII	High adherence 12.4 (7.8), low adherence 15.3 (8.2), P=0.07	NS	U: 0 M: 0
Delgado^Citation10	Canada; patients enrolled in community drug treatment program, n=316	Adherence by record review, 12 months	Depressive symptoms (CES-D)	EI	Not reporting depression: 79.8% adherent, reporting depression: 68.1% adherent, P=0.02	NS	U: − M: 0	1 of 6
Singh^Citation11	USA; new veteran patients seen at medical center, n=52	Non-adherence by record review, 6 months	Confusion and bewilderment (POMS)	BII	NS	NT	U: 0 M: NT	1 of 6
			Depression and dejection	EI	Adherent 14.2 (SEM 1.9), non-adherent 22.1 (SEM 3.4), P=0.04	NS	U: − M: 0
			Mood disturbance	EI	39% in adherent patients, 76% in non-adherent patients, P=0.03	OR =1.4 (1.1, 1.8), P=0.01	U: − M: −
			Religious support (instrument NR)	CIII	NS	NT	U: 0 M: NT
			Social support (instrument NR)	CIII	NS	NT	U: 0 M: NT
			Symptoms of depression (BDI)	EI	NS	NT	U: 0 M: NT
			Tension and anxiety (POMS)	EI	NS	NT	U: 0 M: NT
Singh^Citation12	Site not reported: patients in HIV-medical centers, n=138	Non-adherence by record review, 6 months	Coping style: active-behavioral focused (higher score = greater applicability of coping style to patient, BMICIS)	BI	(Mean score, SEM): non-adherent 5.2 (0.5) versus adherent 6.6 (0.2), P=0.01	NR	U: + M: NR	1 of 6
			Coping style: active-cognitive focused	BI	NS		U: 0 M: NR
			Coping style: avoidant coping	BII	Non-adherent 3.3 (0.3) versus adherent 2.6 (0.2), P=0.02		U: − M: NR
			Coping style: emotion-focused	BII	NS		U: 0 M: NR
			Coping style: problem-focused	BI	Non-adherent 6.0 (0.5) versus adherent 7.1 (0.2), P=0.02		U: + M: NR
			Hopelessness: future expectations	BII	NS		U: 0 M: NR
			Hopelessness: loss of motivation (higher score = more hopelessness, BHS)	BII	Non-adherent 1.75 (0.5), adherent 0.6 (0.1), P=0.006		U: − M: NR
			Hopelessness: negative feelings about future	BII	NS		U: 0 M: NR
			Hopelessness: total score	BII	NS		U: 0 M: NR
			Quality of life: psychological functioning (MOS SF-36)	EI	NS		U: 0 M: NR
			Satisfaction with social support: emotional (SSQ)	CIII	NS		U: 0 M: NR
			Satisfaction with social support: informational (higher scores = less satisfaction)	CIII	Non-adherent 7.9 (1.1), adherent 6.1 (0.3), P=0.04		U: + M: NR
			Satisfaction with social support: tangible	CIII	Non-adherent 7.7 (1.1), adherent 5.5 (0.3), P=0.07		U: 0 M: NR
			Satisfaction with social support: total score	CIII	Non-adherent 22.9 (3.3), adherent 16.8 (0.75), P=0.03		U: + M: NR
Bottonari^Citation13	USA; patients treated in immunodeficiency clinic, n=78	Adherence by self-report (straightforward), 6–9 months	Depressive symptoms (IDD)	EI	NS	NR	U: 0 M: NR	0 of 6
			Experience of general (stressful) life events (LES)	EII	NS		U: 0 M: NR
			HIV-specific (stressful) life events (BHLES)	EII	NS		U: 0 M: NR
			Neuroticism: personality style indicative of affective instability (NSEPQSS)	D	NS		U: 0 M: NR
			Perceived stress (PSS)	EII	OR =0.88 (0.77, 0.98), P=0.04		U: − M: NR
			Self-esteem (RSEQR)	D	NS		U: 0 M: NR
Godin^Citation14	Canada; patients from medical HIV-clinics, n=400	Adherence over time by self-report (straightforward), 12 months	Change in predictors related to adherence over time: attitude towards medication-taking (more positive attitude = greater adherence, self-developed scale)	AI	NR	OR =1.56 (1.18, 2.06), P≤0.05	U: NR M: +	1 of 6
			Optimism (DOS)	D		NS	U: NR M: 0
			Outcome expectations (eg, believe that specific course of action will lead to desired outcome, self-developed scale)	AIII		NS	U: NR M: 0
			Patient-doctor satisfaction (Pat SS)	CI		NS	U: NR M: 0
			Self-efficacy regarding medication taking (self-developed scale)	AIII		OR =1.68 (1.27, 2.22), P≤0.05	U: NR M: +
			Social support (SPS)	CIII		NS	U: NR M: 0
Kacanek^Citation15	USA; patients recruited by media and physician networks, n=225	Suboptimal adherence by self-report (straightforward): max 30 months	Development of depressive symptoms (BST)	EI	Suboptimal adherence in those who developed depressive symptoms =45.1% versus 25.9% in those with no depressive symptoms, P=0.01	NT	U: − M: NT	2 of 6
Martini^Citation16,§§§	Italy; outpatients using combination therapy, n=214	Adherence by self-report (ordinal measure, straightforward questionnaire), 12 months	(Interview, instrument NR): perception of therapy: reliable?	AI	In “high adherence” category, therapy perceived as “reliable” by 15.6%, and “not reliable” by 84.4%. In “variable adherence” cat 4.8% versus 95.2%. In “low adherence” cat 0% versus 100%, P=0.02	NR	U: + M: NR	0 of 6
			Perception of therapy: enslaving?	AI	NS		U: 0 M: NR
			Satisfied about doctor/patient discussion regarding clinical and therapeutic aspects of treatment?	CI	In “high adherence” category: “sufficient/highly satisfied” = 73.9%, “little/not satisfied” =26.1%. In “variable adherence” cat 80% versus 20%. in “low adherence” cat 50% versus 50%, P=0.05		U: ? M: NR
Mellins^Citation17	USA; HIV-infected mothers recruited in waiting room of adult clinic, n=128	Non-adherence by self-report (AACTG, straightforward), T1 after 4–5 months, T2 8–18 months after T1	Negative stressful events (PEI)	EII	OR =1.27 (1.09, 1.49), P<0.01 at T1, OR =1.28 (1.05, 1.57), P=0.02 at T2	NR	U: − M: NR	0 of 6
			Parenting stress (low scores = more stress, PPCS)	EII	OR =0.86 (0.76, 0.98), P=0.02 at T2		U: − M: NR
			Psychological distress (aggregated demoralization score, DSPERI)	EI	NS		U: 0 M: NR
			Self-efficacy in carrying out health-related behaviors (Chesney et al^Citation34)	AIII	NS		U: 0 M: NR
Nilsson Schönnesson^Citation18	Sweden; patients recruited by clinic nurses, n=203	Adherence by self-report (straightforward), 24 months	Anxiety symptoms (ASBSI)	EI	NR	NS	U: NR M: 0	1 of 6
			Belief in adherence necessity (one item)	AI		NS	U: NR M: 0
			Belief that ART prolongs one’s life (one item)	AI		NS	U: NR M: 0
			Belief in future HIV-related health problems (self-developed scale)	AII		NS	U: NR M: 0
			Belief in influencing HIV disease (MAH)	AII		NS	U: NR M: 0
			Beliefs in ART health concerns (eg, believe that medication makes sicker, one item)	AI		NS	U: NR M: 0
			Coping mode: helplessness (MAH)	BII		NS	U: NR M: 0
			Coping mode: resilience (MAH)	D		NS	U: NR M: 0
			Depressive symptoms (DSBSI)	EI		NS	U: NR M: 0
			Global social support satisfaction (one item)	CIII		NS	U: NR M: 0
			Hopelessness (BHS)	BII		NS	U: NR M: 0
			Life stress (LSS)	EII		NS	U: NR M: 0
			Patient-provider relationship (self-developed scale)	CI		NS	U: NR M: 0
			Perceived pressure to take HIV medication (self-developed scale)	CIII		NS	U: NR M: 0
			Posttraumatic stress disorder symptoms related to HIV diagnosis (HIE)	EI		NS	U: NR M: 0
			Self-efficacy in taking medication (self-developed scale)	AIII		NS	U: NR M: 0
Thrasher^Citation19	USA; patients in public use of HCSUS data-set, n=1,911	Adherence by self-report (straightforward),12 months	(Instruments NR): depressive symptoms	EI	OR =0.98 (0.96, 0.99), P=0.007	NR	U: − M: NR	1 of 6
			Dysthymia symptoms	EI	OR =0.92 (0.87, 0.96), P=0.001		U: − M: NR
			Social support	CIII	NS		U: 0 M: NR
Horne^Citation20	UK; outpatients, eligible to receive HAART, n=136	Adherence by self-report (VAS-scale from MASRI, straightforward), 12 months	Depressive symptoms (HADS)	EI	NS	NT	U: 0 M: NT	3 of 6
			HAART concern beliefs about medication (BMQ)	AI	High adherence 2.9 (0.6) versus low adherence 3.3 (0.6), P=0.005	OR =0.45 (0.22, 0.96), P=0.038	U: − M: −
			HAART necessity beliefs about medication	AI	High adherence 4.0 (0.6) versus low adherence 3.7 (0.6), P=0.006	OR =2.19 (1.02, 4.71), P=0.045	U: + M: +
Mugavero^Citation21	USA; patients receiving care at one of eight infectious disease clinics, n=474	Non-adherence by self-report (AACTG, straightforward, corrected for baseline non-adherence), 27 months	Number of severe stressful events (LES, modified version)	EII	OR (per event) =1.14 (1.03, 1.26)	NS	U: − M: 0	3 of 6
			Number of stressful events (moderate + severe stressful events)	EII	OR (per event) =1.09 (1.04, 1.13)	OR (per event) =1.10 (1.04, 1.16)	U: − M: −
			Number of traumatic events	EII	OR (per event) =1.73 (1.24, 2.39)	NS	U: − M: 0
			Number of types of lifetime traumatic experiences (composite measure of diverse questionnaires)	EII	NS	NS	U: 0 M: 0
Carrieri^Citation22	France; patients starting HAART-regimen including at least oneprotease inhibitor, n=1,110	Non-adherence by self-report (AACTG,straightforward), 60 months	Depressive symptoms (CES-D)	EI	b =0.22 (95% CI =0.12, 0.32), P<0.001	b =0.18 (0.07, 0.29)	U: − M: −	2 of 6
			Support from partner (whether principal or not, instrument NR)	CII	b =−0.16 (−0.26, −0.07), P=0.001	b =−0.15 (−0.25, −0.05)	U: + M: +
Transplant-related (immunosuppressant medication)
Stilley^Citation23	USA; transplant patients, recruited before hospital discharge or atearly clinic visit, n=152	Adherence by MEMS (continuous measure), 6 months	Affective dysregulation (degree of negative affectivity and irritability, DI)	EI	Correlation coefficient: NS¶¶	NR	U: 0 M: NR	1 of 6
			Behavioral dysregulation (impulsivity, sensation seeking, aggression)	D	r=0.26, P≤0.05***		U: −††† M: NR
			Cognitive dysregulation (less strategic thinking, problem solving, self-monitoring)	BI	NS¶¶		U: 0 M: NR
			Family environment (family support, FRI)	CII	NS¶¶		U: 0 M: NR
			Hostility (CMHS)	D	NS¶¶		U: 0 M: NR
De Geest^Citation24	Belgium; convenience sample of outpatients, n=101	Non-adherence by MEMS (ordinal measure, correction for past adherence), 6 months	Depressive symptoms (BDI)	EI	NR	NS	U: NR M: 0	2 of 6
			Self-efficacy in taking medication (LTMSES)	AIII		Median =4.85 (Q1 =4.70, Q3 =5.00) for excellent adherers, 4.81 (Q1 =4.70, Q3 =4.89) for moderate non-adherers, 4.41 (Q1 =4.30, Q3 =4.81) for minor adherers, P=0.04	U: NR M: +
			Social support (PRQ)	CIII		NS	U: NR M: 0
			Symptom distress (ATSFDS)	EII		NS	U: NR M: 0
Russell^Citation25	USA; convenience sample of renal transplant patients, n=50	Adherence by MEMS (ordinal measure), 12 months	Depressive symptoms (BDI)	EI	NS	NR	U: 0 M: NR	0 of 6
			Emotional burden (MS)	EI	NS		U: 0 M: NR
			Self-efficacy in taking medication (LTMSES)	AIII	NS		U: 0 M: NR
			Social support (SSAI)	CIII	NS		U: 0 M: NR
Weng^Citation26	USA; patients recruited at time of renal transplantation, n=829	Adherence by MEMS (ordinal measure), 12 months posttransplantation	Beliefs regarding who or what controls and influences one’s health (MHLCS)	AIII	OR =1.05 (1.00, 1.11), P=0.05 (powerful others subscale)	NS	U: + M: 0	2 of 6
			Depressive symptoms (CES-D)	EI	NS	NT	U: 0 M: NT
			Perceived stressfulness of transplant-related issues (TSQ)	EII	NS	NT	U: 0 M: NT
			Perceptions that social needs are being met (friends and family sub-score, SSAS)	CII	NS	NT	U: 0 M: NT
Dew^Citation27	USA; heart transplant patients at academic hospital‡‡‡, n=108	Non-adherence by self-report (straight-forward), 12 months post-transplantation	Coping strategies: use of active-behavioral coping (Coping checklist)	BI	NS	NT	U: 0 M: NT	2 of 6
			Coping strategies: use of active-cognitive coping	BI	NS	NT	U: 0 M: NT
			Coping strategies: use of avoidance coping (% high)	BII	Non-adherent 58.8%, adherent 29.9%, P<0.05	OR =9.71, P<0.05	U: − M: −
			Emotional status: anger-hostility symptoms (SCL-90)	EI	Non-adherent 47.1%, adherent 12.1%, P<0.001	OR =13.40, P<0.05	U: − M: −
			Emotional status: anxiety symptoms	EI	Non-adherent 82.4%, adherent 53%, P<0.05	NS	U: − M: 0
			Emotional status: depressive symptoms	EI	NS	NT	U: 0 M: NT
			Sense of mastery (ie, control over life, SMS)	AIII	NS	NT	U: 0 M: NT
			Social support: caregiver support (% poor) (Spanier,^Citation35 Pearlin and Schooler)^Citation36	CII	Non-adherent 52.9%, adherent 27.0%, P<0.05	NS	U: − M: 0
			Social support: friend support (Moos)^Citation37	CII	NS	NT	U: 0 M: NT
Dew^Citation28	USA; patients receiving first lung transplantation in academic hospital, n=178	Non-adherence by self-report (straightforward), 24 months	Anger-hostility symptoms (SC)	EI	(Correlation coefficient, significant if r≥0.15***): r≥0.15	NS	U: ? M: 0	1 of 6
			Anxiety symptoms (SC)	EI	r≥0.15	NS	U: ? M: 0
			Care provider locus of control (health outcomes due to professional? MHLCS)	AIII	r≥0.15	NS	U: ? M: 0
			Chance locus of control (health outcomes occur by chance?)	AIII	r≥0.15	NS	U: ? M: 0
			Degree to which one can rely on friends for emotional/practical support/friend support (Moos)^Citation37	CII	r≥0.15	NS	U: ? M: 0
			Depressive symptoms (SC)	EI	r≥0.15	NS	U: ? M: 0
			Expectations about the future/optimism (LOT)	D	r≥0.15	NS	U: ? M: 0
			Internal locus of control (can I influence my health outcome? MHLCS)	AIII	r≥0.15	NS	U: ? M: 0
			Supportiveness (both emotionally and practically) of recipient’s relationship with their primary family caregiver (when low = higher odds) (DAS)	CII	r≥0.15	OR =2.59 (1.20, 5.58), P<0.05	U: ? M: −
Dobbels^Citation29	Belgium: heart, liver and lung transplant patients listed at university hospitals, n=186	Non-adherence by self-report (straightforward, corrected for pre-transplant adherence), 12 months posttransplantation	Agreeableness (one’s orientation along continuum from compassion to antagonism, NEO-FFI)	D	NR	NT or NS	U: NR/NS M: 0	1 of 6
			Anxiety symptoms (HADS)	EI		NT or NS	U: NR/NS M: 0
			Conscientiousness (ie, degree of organization, NEO-FFI)	D		OR =0.80 (0.67, 0.95), P=0.01	U: NR/NS M: +
			Depressive symptoms (HADS)	EI		NT or NS	U: NR/NS M: 0
			Extraversion (capacity for joy, need for stimulation, NEO-FFI)	D		NT or NS	U: NR/NS M: 0
			General received practical and informational support (SSQ)	CIII		NT or NS	U: NR/NS M: 0
			Neuroticism (NEO-FFI)	D		NT or NS	U: NR/NS M: 0
			Openness to experience (toleration for and exploration of the unfamiliar, NEO-FFI)	D		NT or NS	U: NR/NS M: 0
			Received specific support with medication taking (SSQ)	CIII		OR =0.94 (0.89, 0.99), P=0.03	U: NR/NS M: +
DiMatteo^Citation30,|| ||	USA: patients from five medical specialties in HMOs, large multispecialty groups or solo practices, n=max 1,828§§§	Adherence by self-report (straightforward, continuous measure, correction for baseline adherence), 24 months	Health distress (instrument NR)	EII	NR	ß =−0.22, P=0.05	U: NR M: −	0 of 6
			Perceptions of physician’s authoritativeness (self-developed scale)	CI		NT or NS	U: NR M: 0
			Satisfaction with interpersonal medical care (Sherbourne)^Citation38	CI		NT or NS	U: NR M: 0
			Social support (composite measure, Sherbourne and Stewart)^Citation39	CIII		NT or NS	U: NR M: 0
			Tendency to use avoidance coping (instrument NR)	BII		NT or NS	U: NR M: 0

* NS (non significant): as reported in the concerning study. UD (undetermined): because of inadequate description in the concerning study.

† Binary outcome measure, unless indicated otherwise. With a straightforward question, we mean that participants were directly asked to indicate how many medication doses they missed. For example: “How many pills did you take this week?”;

‡ follow-up period = number of months between baseline (unless indicated otherwise) and last adherence measurement;

§ if no instrument is mentioned for predictor, then previous mentioned instrument is applicable;

|| psychosocial category, to which a predictor was assigned. A = Beliefs and cognitions about: I) medication and treatment; II) illness; III) self-efficacy and locus of control. B = coping styles: I) task oriented, II) emotion oriented. C = Social influences and social support: I) regarding medical caregiver; II) regarding friends and family; III) in general. D = personality traits. E = psychological well-being: I) mood state; II) perceived stress/stressors;

¶ OR: Odds Ratio (95% confidence interval). OR <1 = lower chance of being adherent or non-adherent (for direction in relevant study, see column “Adherence, follow-up period”) when predictor increases or when predictor ≠ reference category. OR > 1 = greater change of being adherent or non-adherent when predictor increases (or when predictor ≠ reference category). Scores other than OR are the mean predictor scores with standard deviation, unless indicated otherwise;

** + = higher level of predictor implies higher adherence at level P≤0.05; − = higher level of predictor implies less adherence at P≤0.05; 0 = no significant association between predictor and adherence at P≤0.05; ? = association present, but direction unclear;

†† to determine methodological quality, six bias domains per study were judged. Here, the total amount of bias free domains is reported (for further details, see table S3);

‡‡ assumed that all variables, tested by univariate analysis, were also tested by multivariate analysis;

§§ retrospective design;

|| || Diagnosis for coronary heart disease, hypertension, diabetes mellitus and/or hyperlipidaemia;

¶¶ not reported in study is interpreted by HZ/BvdB as not significant;

*** significance of P≤0.05 assumed by HZ/BvdB;

††† negative association assumed;

‡‡‡ type of medication is immunosuppressants, antihypertensives, and/or antivirals;

§§§ use of chronic preventive medication assumed;

|| || || unexpected direction.

Abbreviations: AACTG, adult AIDS clinical trials group; ALTMBSES, adapted long term medication behavior self efficacy scale; AGSRP, adapted gay service research project; AIDS, acquired immunodeficiency syndrome; AMHI, adapted mental health inventory; APIAQ, adapted protease inhibitor attitude questionnaire; ART, antiretroviral therapy; ASBSI, anxiety subscale of brief symptom inventory; ATS, anxiety trait scale; ATSFDS, adapted version of transplant symptom frequency and distress scale; AWC, adapted ways of coping BDI, beck depression inventory; BHLES, buffalo HIV life events survey; BHS, beck hopelessness scale; BMICIS, Billings and Moos inventory of coping with illness styles; BMQ, beliefs about medication questionnaire; BST, Burnam interviewer-administered 8-item screening tool; CES-D, center for epidemiologic studies depression scale; CMHS, Cook-Medley hostility scale; DAS, dyadic adjustment scale; DI, dysregulation inventory; DOS, dispositional optimism scale; DSBSI, depression subscale of brief symptom inventory; DSPERI, demoralization scale of psychiatric epidemiology research interview; FRI, family relations index (from family environment scale); FTSSH, Finnish twin study scale of hostility; GHQ, general health questionnaire; HAART, highly active antiretroviral therapy; HADS, hospital anxiety and depression scale; HAT-QOL, HIV/AIDS-targeted quality of life instrument; HBS, health behaviour scale; HCSUS, HIV cost and services utilization study; HIE, Horowitz impact of events scale; HIS, health intention scale; HIV, human immunodeficiency virus; HMO, health maintenance organization; ICS, inhaled corticosteroids; IDD, inventory to diagnose depression; IQR, interquartile range; ISEL, interpersonal support evaluation list; LES, life experience survey; LOT-R, life orientation test; LSS, life stressors scale; LTMSES, long term medication self-efficacy scale; MAH, mental adjustment to HIV; MARS, medication adherence report scale; MAS, Miller attitude scale; MASRI, medication adherence self-report inventory; MEMS, medication even monitoring system; MHLCS, multidimensional health locus of control scale; MOS, medical outcome study health survey; MS, Memphis survey; NEO-FFI, NEO five factor inventory; NR, not reported; NS, non-significant; NSEPQSS, neuroticism scale of the Eysenck personality questionnaire-revised short scale; NT, not tested; OR, odds ratio; Pat SS, patient satisfaction scale; PEI, psychiatric epidemiology interview; POMS, profiles of mood states; PPCS, perceived parenting competence scale; PRQ, personal resource questionnaire; PSS, perceived stress scale; RSEQR, Rosenberg self-esteem questionnaire; SC, symptom checklist; SCL-90, Symptom Checklist-90-R; SEM, standard error of the mean; SF-36, short form-36 health survey; SMS, sense of mastery scale; SOC, sense of coherence; SPS, social provision scale; SSAI, social support appraisals index; SSAS, social support appraisal scale; SSQ, social support questionnaire; TSQ, transplant stress questionnaire; VAS, visual analog scale.

Table S3 Results of judging methodologic quality

First author	Overall quality	Domain free of bias?
		Study participation	Study attrition	Prognostic factor measurement	Outcome measurement	Confounding measurement and account	Analysis
Bottonari^Citation13	Low	No	No	Partly	Partly	No	No
De Geest^Citation24	Low	No	Yes	Partly	Yes	No	Partly
Delgado^Citation10	Low	Partly	Yes	Partly	Partly	Partly	Partly
Deschamps^Citation8	Low	No	Partly	No	Yes	No	No
Dew^Citation27	Low	No	Yes	Yes	Partly	Partly	Partly
Dew^Citation28	Low	Yes	Partly	Partly	Partly	Partly	Partly
DiMatteo^Citation30	Low	Partly	No	Partly	No	No	No
Dobbels^Citation29	Low	Yes	Partly	Partly	Partly	Partly	No
Gazmararian^Citation3	Low	Yes	Partly	Partly	Yes	Partly	Yes
Godin^Citation14	Low	Partly	Yes	No	Partly	Partly	Partly
Grégoire^Citation5	Low	Partly	No	No	Partly	No	Partly
Holmes^Citation9	Low	Partly	Yes	Partly	Partly	Partly	Yes
Kacanek^Citation15	Low	No	Yes	Partly	Partly	No	Yes
Martini^Citation16	Low	Partly	No	No	Partly	No	No
Mellins^Citation17	Low	Partly	Partly	Partly	No	No	No
Miller^Citation6	Low	No	Partly	Partly	No	Partly	Partly
Nabi^Citation4	Low	Partly	Partly	Partly	Partly	Partly	Yes
Nilsson Schönnesson^Citation18	Low	Partly	Yes	Partly	No	Partly	No
Ponieman^Citation1	Low	No	No	Partly	Partly	Partly	Partly
Russell^Citation25	Low	No	No	Partly	Partly	No	Partly
Singh^Citation11	Low	No	Yes	Partly	Partly	Partly	No
Singh^Citation12	Low	Partly	Yes	Partly	Partly	No	No
Stilley^Citation23	Low	Yes	Partly	Partly	No	No	No
Thrasher^Citation19	Low	Yes	Partly	Partly	Partly	Partly	Partly
Venturini^Citation2	Low	Yes	Partly	Partly	Yes	Partly	Partly
Weng^Citation26	Low	Partly	No	Yes	Partly	Partly	Yes
Molloy^Citation7	Low	No	Yes	Partly	No	Partly	Partly
Horne^Citation20	Low	Yes	Yes	Partly	Partly	No	Yes
Mugavero^Citation21	Low	Yes	No	Yes	Partly	Partly	Yes
Carrieri^Citation22	Low	No	Yes	No	Partly	Partly	Yes

Table S4 Sensitivity analyses: methodological quality, disease, adherence measures, and statistical analyses

Alteration	Relevant studies	Categories affected	Change in level of evidence
Alterations in methodological quality cut-offs
High-quality study when all six bias domains judged at least as partly (and no no-judgment) instead of ≥four domains judged as yes	19,26,34,35,42,52,64 now high-quality, all other studies low-quality	AI, II, III and CI, II and EII	No association: moderate instead of limited evidence
		CIII and EI	No association: strong instead of limited evidence
Low-quality study when ≥four domains judged as no instead of <four domains judged as yes	19,26,33–36,38,39,42–44,46,47,49,51–60,64,65 now high-quality, all other studies still low-quality	All categories	No association: strong instead of limited evidence
Alterations in disease
Only focus on HIV disease	19,25,42–49,51–55 (studies in analysis)	AI	No association: conflicting instead of limited evidence
		CII and D	Level undetermined (≤one study available)
Only focus on transplant-related diseases	56–60,64,65 (studies in analysis)	AI, II, BII and CI	Level undetermined (≤one study available)
Focus on asthma, diabetes, heart disease/hypertension	26,33–36,38,39,66 (studies in analysis)	AII, III, BI, II, CI, II, D, EII	Level undetermined (≤one study available)
Alterations in adherence measures
Focus on objective adherence measures (MEMS, record review)	19,25,26,34,35,42–44,56–59 (studies in analysis)	D	No association: conflicting instead of limited evidence
		AII and CI	Level undetermined (≤one study available)
Focus on subjective adherence measures (self-report)	33,36,38,39,45–49,51–55,60,64–66 (studies in analysis)	AI	No association: conflicting instead of limited evidence
		BI	Level of evidence undetermined (≤one study available)
		BII and EI	No association: conflicting instead of limited evidence
Alterations in statistical analysis
Only focus on univariate analysis instead of multivariate analysis	34,38,46,51,57,65,66 (studies omitted due to lack of univariate analysis)	AI, AIII, CI, CIII, EI and EII	No association: conflicting instead of limited evidence

Notes: A = Beliefs and cognitions about: I) medication and treatment; II) illness; III) self-efficacy and locus of control. B = coping styles: I) task oriented, II) emotion oriented. C = Social influences and social support: I) regarding medical caregiver; II) regarding friends and family; III) in general. D = personality traits. E = psychological well-being: I) mood state; II) perceived stress/stressors.

Abbreviations: HIV, human immunodeficiency virus; MEMS, medication event monitoring system.

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