for Med Statistics for Medicine, Evolène, Switzerland
Centro Studi e Ricerche in Psichiatria, Turin, Italy
Correspondence: Dr Carmine Munizza, Centro Studi e Ricerche in Psichiatria, Piazza del Donatore di Sangue 3, 10154 Torino, Italy
Declaration of interest The study was partially supported by Centro Studi e Ricerche in Psichiatria, Turin; Istituto Superiore di Sanità, Rome; and Ravizza Pharmaceuticals, Milan.
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ABSTRACT |
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Aims To review and summarise quantitative evidence on factors associated with adherence and of adherence-enhancing interventions.
Method A systematic review of computerised databases was carried out to identify quantitative studies of adherence in depression. Papers retained addressed unipolar depression and considered adherence as the primary end-point.
Results Of studies published between 1973 and 1999, 32 met the review criteria: epidemiological descriptive studies (n=14): non-random comparisons of control and intervention groups (n=3); randomised interventions (n=14); and meta-analysis (n=1). Patient education and medication clinics were the interventions most commonly tested, combined with a variety of other interventions.
Conclusions The studies did not give consistent indications of which interventions may be effective. Carefully designed clinical trials are needed to clarify the effect of single and combined interventions.
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INTRODUCTION |
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METHOD |
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This report focuses on publications in categories (a)(d).
Data extraction and synthesis
For all types of study we developed an ad hoc data extraction
form. The main information extracted concerned the setting of the study, a
clinical and demographic description of the patient sample, the length of the
observation, response rate, adherence rate and the factors associated with
adherence (for descriptive epidemiological studies only). As concerns
adherence data, each study applied its own definition and rates were extracted
as reported in the original publications. The measures of adherence were
grouped into five categories:
The methodological strength of the papers was evaluated on the basis of whether the sample size computations were reported. This aspect is of relevance since the smaller the expected difference in adherence rate among subgroups (for descriptive epidemiological studies) or between treatment arms (for non-randomised and randomised intervention studies) the larger the sample size should be for there to be a reasonable chance of detecting it. For randomised intervention studies we also considered whether a description of the randomisation procedure was reported.
For non-randomised and randomised studies we grouped the interventions into seven categories: (a) psychological treatment; (b) patient education; (c) education of the patient's family; (d) training of physicians; (e) training of nurses; (f) changes in patient management (e.g. case management, change in the frequency of follow-up, etc.); and (g) medication clinics (scheduled meetings with the patient to adjust medication and control side-effects). Given the multi-modality of the interventions, we adopted the following approach to assess the relative effect on adherence of their components. First, all pairwise comparisons for every trial were constructed. Two-arm trials therefore contributed one pairwise comparison each: trials that compared three arms (say arms A, B and C) contributed three pairwise comparisons (namely A v. B, A v. C and B v. C). Similarly, the single trial with four arms contributed six pairwise comparisons. Subsequently, we defined as offset of a pairwise comparison the component of the intervention common to both arms being compared. For instance, a trial where drug treatment plus education of patients was compared with drug treatment alone was classified as having drug treatment as an offset. We defined as contrast the actual interventions being compared ignoring the common offset. For the same example, the contrast would be patient education v. no intervention.
Data were extracted and reviewed by two of us (S.P. & P.B.), and disagreements resolved with discussion. An ad hoc database was created for the data extracted, linked to a commercial database containing all the relevant references. Given the nature of the material found, no formal meta-analytical approach was justified, and no specific statistical analysis tools have been used.
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RESULTS |
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The studies reviewed were conducted in a variety of settings, with the majority taking place in out-patient psychiatric services (n=12) and psychiatric hospitals (n=8), and the remainder in primary care settings. The diagnostic categories employed in the studies are reviewed in Table 1. The category mixed diagnoses with depression includes studies that considered other diagnoses besides depression (schizophrenia, bipolar disorders, etc.). With regard to measures of adherence, a majority of studies employed direct measures of drug intake, that is, the number of pills taken. Epidemiological studies employed quite often the number of appointments kept. Finally, only four studies used composite measures of drug intake and other indices.
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The duration of observation varied considerably, from 2 to 104 weeks. Overall, patients were observed for more than 24 weeks in eight studies out of 31 (the meta-analysis is excluded). The median duration of observation was 12 weeks.
Methodological strength of descriptive epidemiological studies,
non-randomised and randomised intervention studies
Epidemiological studies considered a total of 10 119 patients, with sample
sizes varying from 27 to 4052 subjects. Non-randomised studies totalled 190
subjects, with a range of 23 to 100 patients. Evidence from randomised studies
the best source of information was based on only 2145 patients
and sample size varied from 14 to 649, a median of 120 patients. Sample size
computations were performed and adequately reported in only two randomised
studies, while none of the other papers, whether a descriptive epidemiological
or non-randomised intervention study, mentioned the expected effect on
adherence of the factors or of the interventions respectively. Only three of
the randomised studies described explicitly the procedure for
randomisation.
Descriptive epidemiological studies
The main results of the 14 descriptive studies reviewed are reported in
Table 2. The table suggests a
very wide range of adherence rates (from 30 to 97%, median 63%). Factors
positively and significantly associated with increased adherence were reported
in nine studies; no systematic pattern was disclosed from the study of the
factors identified. The relationship between adherence and response was
reported in only one study.
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Non-randomised and randomised interventions
The three non-randomised studies were all two-arm trials, contributing
three contrasts, one per study. Ten randomised interventions also had two arms
each, thus contributing 10 comparisons. Three randomised studies compared
three arms each, contributing a total of nine comparisons. Similarly, the
single trial with four arms contributed six comparisons. Therefore, a total of
28 comparisons were available for evaluation. The combinations of contrasts
and offsets studied in the 17 trials are reported in Tables
3 and
4. Adherence rates varied
widely across studies. The interventions most commonly tested were patient
education and medication clinics. However, two reasons prevented a formal
quantitative assessment of their efficacy by means of meta-analysis: (a) the
great variety of offsets; (b) the heterogeneous combination of other
interventions, even among studies with the same offset. It was therefore not
possible to combine homogeneous data across studies.
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The six comparisons for which data were available comparing patient education with no intervention (with drug treatment only as the common offset) could, in theory, contribute to a pooled estimate of the effect of patient education. However, they showed such different adherence rates in the no intervention group, that we felt any formal meta-analytical effort would not be meaningful.
As a final remark, it should be noted that in Tables 3 and 4 those arms without or with fewer interventions (irrespective of the offset) almost invariably showed lower adherence rates.
Meta-analyses
We identified only one relevant meta-analysis
(Roter et al, 1998),
reporting results of 135 studies published between 1977 and 1994 on different
medical conditions and on a variety of treatment regimens. Thirteen studies on
mental health were part of the meta-analysis, including two randomised trials
in depression, which have been already reviewed above as part of the
randomised interventions.
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DISCUSSION |
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Quality of the evidence
It was not possible to extract meaningful indications on factors associated
with non-adherence from epidemiological studies because each study considered
its own set of potential predictors. Additionally, the important relationship
between adherence and outcome of treatment has been evaluated only in one
study. The methodological quality of the literature on medication adherence
can be evaluated by means of a recently published scoring system
(Nichol et al, 1999).
This score has not been applied here because its items are oriented to the
evaluation of pharmacological treatments through physical and laboratory
measurements. The majority of the comparative studies that we considered
presents interventions other than pharmacological, and would thus score very
low. We therefore assessed the methodological strength of the papers
considering sample size computation and randomisation procedure the
results pointed to the poor methodological strength of the available
contributions.
Complexity of study design
Intervention studies, and in particular randomised clinical trials,
investigated a variety of interventions to improve adherence. The exception
was one study where the intervention to increase adherence involved the
administration of amitriptyline v. fluoxetine. Many studies, by
implementing several interventions at the same time, could not provide
evidence on the separate effects of each of the components. This leaves
unaddressed the questions on which is the effect of each component and whether
all of them are needed in combination, a common problem in the adherence
literature (Haynes et al,
1996). Even looking at contrasts, as we have done, does not help
to disentangle the effect of each component. The concept of contrasts allows
the identification of the unconfounded components of each trial
(Haynes et al, 1996),
that is, of the difference in terms of interventions between two arms of a
trial. However, the offset may act on adherence in both arms of the trial
being compared and perhaps synergistically so with the unconfounded component.
The role of the offset can, therefore, hardly be allowed for. To complicate
matters, the same contrast may also be paired with different offsets across
studies: depending on the offset, the magnitude of the effect attributable to
a given contrast may therefore vary from study to study. Finally, the studies
addressed both minor and major depression as well as mixed diagnoses, making
it difficult to assess whether specific interventions were more appropriate
for specific diagnostic groups. Tables
3 and
4 none the less contain a
consistent trend: the arm with more interventions generally showed a higher
adherence rate. This suggests that improvements in adherence rates can indeed
be achieved through the kinds of intervention considered in the
literature.
Recommendations
Much is still to be done in the field of treatment adherence in depressive
disorders. Successive classes of antidepressant have only marginally increased
the proportion of patients actually benefiting from pharmacological treatment
(Greenberg & Fisher,
1997). It is unrealistic to hope that a new drug may by itself
reduce substantially the big proportion of patients who do not adhere to
treatment. Carefully designed clinical trials are therefore needed to clarify
the effect of single and combined interventions on adherence, as well as to
further investigate the factors affecting adherence. Such studies and the
proposed interventions should be feasible in busy clinical practices where the
majority of patients are seen (Kendrick,
2000) and where adherence problems may be even more acute than in
the setting of the common therapeutic clinical trials. Increasing the number
of patients who are put in a position to better adhere to the prescribed
treatment could in turn increase the response rate to antidepressant drugs
(Haynes et al,
1996).
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Clinical Implications and Limitations |
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LIMITATIONS
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APPENDIX STUDIES REVIEWED: Meta-analysis |
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APPENDIX STUDIES REVIEWED: Descriptive studies |
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Craig, T. G., Huffine, C. L. & Brooks, M. (1974) Completion of referral to psychiatric services by inner city residents. Archives of General Psychiatry, 31, 353 -357.[CrossRef][Medline]
Croghan, T. W., Lair, T. J., Engelhart, L., et al (1997) Effect of antidepressant therapy on health care utilization and costs in primary care. Psychiatric Services, 48, 1420 -1426.[Abstract]
Engstrom, F. W. (1991) Clinical correlates of antidepressant compliance. In Patient Compliance in Medical Practice and Clinical Trials (eds J. A. Cramer & B. Spilker), pp. 187-194. New York: Raven Press.
Hall, D., Wiles, D. H. & McCreadie, R. G. (1990) Compliance with antidepressant medication (letter). British Journal of Psychiatry, 157, 453 -454.
Johnson, D. A. W. (1981) Depression: treatment compliance in general practice. Acta Psychiatrica Scandinavica, 290 (suppl. 63), 447 -453.
Last, C. G., Thase, M. E., Hersen, M., et al (1985) Patterns of attrition for psychosocial and pharmacologic treatments of depression. Journal of Clinical Psychiatry, 46, 361 -366.[Medline]
Maddox, J. C., Levi, M. & Thompson, C. (1994) The compliance with antidepressants in general practice. Journal of Psychopharmacology, 8, 48-53.
Matas, M., Staley, D. & Griffin, W. (1992) A profile of the noncompliant patient: a thirty-month review of outpatient psychiatry referrals. General Hospital Psychiatry, 14, 124 -130.[Medline]
Melfi, C. A., Chawla, A. J. Croghan, T. W., et al
(1998) The effects of adherence to antidepressant treatment
guidelines on relapse and recurrence of depression. Archives of
General Psychiatry, 55,
1128
-1132.
Robinson, P., Bush, T., Von Korff, M., et al (1995) Primary care physician use of cognitive behavioral techniques with depressed patients. Journal of Family Practice, 40, 352 -357.[Medline]
Simon, G. E., Von Korff, M., Wagner, E. H., et al (1993) Patterns of antidepressant use in community practice. General Hospital Psychiatry, 15, 399 -408.[Medline]
Tedlow, J. R., Fava, M., Uebelacker, L. A., et al (1996) Are study dropouts different from completers? Biological Psychiatry, 40, 668 -670.[CrossRef][Medline]
Voris, J. C., Morin, C. & Kiel, J. S. (1983) Monitoring outpatients' plasma antidepressant-drug concentrations as a measure of compliance. American Journal of Hospital Pharmacy, 40, 119 -120.[Medline]
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APPENDIX STUDIES REVIEWED: Non-randomised interventions |
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Myers, E. D. & Calvert, E. J. (1976) The effect of forewarning on the occurrence of side-effects and discontinuance of medication in patients on dothiepin. International Journal of Medical Research, 4, 237 -240.
Seltzer, A., Roncari, I. & Garfinkel, P. (1980) Effect of patient education on medication compliance. Canadian Journal of Psychiatry, 25, 638 -645.[Medline]
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APPENDIX STUDIES REVIEWED: Randomised interventions |
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Demyttenaere, K., Van Ganse, E., Gregoire, J., et al (1998) Compliance in depressed patients treated with fluoxetine or amitriptyline. International Clinical Psychopharmacology, 13, 11 -17.[Medline]
Katon, W., Von Korff, M., Lin, E., et al (1995) Collaborative management to achieve treatment guidelines. Impact on depression in primary care. Journal of the American Medical Association, 273, 1026 -1031.[Abstract]
Katon, W., Robinson, P., Von Korff, M., et al (1996) A multifaceted intervention to improve treatment of depression in primary care. Archives of General Psychiatry, 53, 924 -932.[Abstract]
Katon, W., Von Korff, M., Lin, E., et al
(1999) Stepped collaborative care for primary care patients
with persistent symptoms of depression. Archives of General
Psychiatry, 56,
1109
-1115.
Kemp, R., Hayward, P., Applewhaite, G., et al
(1996) Compliance therapy in psychotic patients: randomised
controlled trial. British Medical Journal,
312,
345
-349.
Myers, E. D. & Branthwaite, A. (1992) Out-patient compliance with antidepressant medication. British Journal of Psychiatry, 160, 83 -86.[Abstract]
Myers, E. D. & Calvert, E. J. (1973) The effect of forewarning on the occurrence of side-effects and discontinuance of medication in patients on amitriptyline. British Journal of Psychiatry, 122, 461 -464.[Medline]
Myers, E. D. & Calvert, E. J. (1984) Information, compliance and side-effects: a study of patients on antidepressant medication. British Journal of Clinical Pharmacology, 17, 21 -25.[Medline]
Peveler, R., George, C., Kinmonth, A.-L., et al
(1999) Effect of antidepressant drug counselling and
information leaflets on adherence to drug treatment in primary care:
randomised controlled trial. British Medical Journal,
319,
612
-615.
Robinson, G. L., Gilbertson, A. D. & Litwack, L. (1986) The effects of a psychiatric patient education to medication program on post-discharge compliance. Psychiatric Quarterly, 58, 113 -118.[Medline]
Spooren, D., Van Heeringen, C. & Jannes, C. (1998) Strategies to increase compliance with out-patient aftercare among patients referred to a psychiatric emergency department: a multi-centre controlled intervention study. Psychological Medicine, 28, 949 -956.[CrossRef][Medline]
Wilkinson, G., Allen, P., Marshall, E., et al (1993) The role of the practice nurse in the management of depression in general practice: treatment adherence to antidepressant medication. Psychological Medicine, 23, 229 -237.[Medline]
Yousef, F. A. (1983) Compliance with therapeutic regimens: a follow-up study for patients with affective disorders. Journal of Advanced Nursing, 8, 513-517.[Medline]
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Received for publication November 15, 2000. Revision received March 19, 2001. Accepted for publication April 6, 2001.
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