Non-adherence to Psychotropic Medication Among Adolescents – A Systematic Review of the Literature
Abstract
Abstract.Introduction: Whether patients take their medication as prescribed is of increasing importance in adolescent psychiatry since both the number of efficacious pharmaceutical treatments and the rate of prescriptions of psychotropic compounds are on the rise. Previous research showed high rates of medication nonadherence among both adolescents with medical disorders and adult patients with psychiatric disorders. Methods: The present review was performed according to PRISMA guidelines and evaluates existing scientific literature concerning adherence to psychotropic medication among adolescents. The goal was to determine rates of nonadherence in this age group as well as the factors associated with it. Therefore, we conducted a comprehensive literature search of PubMed from its inception until 15 September 2015 using the keywords “adherence,” “compliance,” “adolescent,” and “psychotropic medication.” Results: A total of 607 pertinent articles were collected and screened; 15 publications were selected for detailed review. The studies differed, among other things, regarding sample characteristics, medication type, and indications. Furthermore, the definitions of what constitutes nonadherence and the methods used to assess it varied widely. Nonadherence rates ranged from 6 % to 62 % (median 33 %). Conclusion: Nonadherence to psychotropic medication is a clinically relevant problem among adolescents. Because of the methodological heterogeneity across studies and partially contradictory results, no conclusions could be drawn concerning the influence of factors such as psychopathology, medication type, side effects, the effectiveness of treatment, or family-related factors. Well-designed long-term studies of large patient samples and a consensus regarding definitions are therefore warranted. Such research would facilitate the design of tailored strategies to improve adherence in these patients.
Zusammenfassung.Einleitung: Die Frage, ob Patienten Medikamente wie verordnet einnehmen, ist im Bereich der Jugendpsychiatrie von besonderer Bedeutung, weil sowohl die Zahl effektiver medikamentöser Behandlungsoptionen als auch die Verschreibung von Psychopharmaka zunehmen. Studien haben gezeigt, dass die Raten für Nicht-Adhärenz bei Jugendlichen mit somatischen Krankheitsbildern und auch bei Erwachsenen mit psychiatrischen Störungen hoch sind. Methodik: Diese Übersichtsarbeit wurde entsprechend den PRISMA-Richtlinien durchgeführt und befasst sich mit der verfügbaren Literatur zu Nicht-Adhärenz hinsichtlich der Einnahme von Psychopharmaka bei Jugendlichen, um Raten für Nicht-Adhärenz und damit assoziierte Faktoren zu bestimmen. Ergebnisse: Von insgesamt 607 Artikeln konnten 15 Arbeiten einbezogen werden. Definitionen von Nicht-Adhärenz und Methoden, mit denen Adhärenz erfasst wurde, waren heterogen. Die Raten für Nicht-Adhärenz lagen zwischen 6 % und 62 % (Median 33 %). Schlussfolgerungen: Nicht-Adhärenz bezüglich der Einnahme von Psychopharmaka stellt bei Jugendlichen ein relevantes Problem dar. Aufgrund methodischer Unterschiede und zum Teil konträrer Ergebnisse ließen sich keine Schlussfolgerungen hinsichtlich relevanter Prädiktoren für Nicht-Adhärenz ableiten. Prospektive Studien an großen Patientenkollektiven sowie Konsens hinsichtlich Definition und Methodik wären hierfür erforderlich. Derartige Untersuchungen könnten dazu beitragen, Interventionen zu entwickeln, welche die Adhärenz jugendlicher Patienten in unserem Fachbereich verbessern.
Introduction
Whether patients actually take their medication as prescribed is of increasing importance in child and adolescent psychiatry since both the number of efficacious pharmaceutical treatments and the rate of prescriptions of psychotropic compounds are on the rise in this field (Datta et al., 2014; Harrison et al., 2012; Rani et al., 2008; Wong et al., 2004; Zito et al., 2003).
Research has shown that failure to take medication in accordance with the recommendations of the physician often renders treatment ineffective and results in reduced health-related quality of life for patients with medical disorders (Brown & Bussell, 2011; van Dulmen et al., 2007) as well as for patients with psychiatric disorders (Ahmed & Aslani, 2013; Julius et al., 2009). This behavior is also associated with a substantial increase in healthcare costs due to avoidable medical spending and the requirement for additional therapeutic interventions (New England Healthcare Institute, 2008).
In the medical literature and in clinical practice, two alternative terms are used when describing whether or not patients take their medication as recommended by the clinician: adherence and compliance. The two terms are often interpreted as being synonymous and are all too often used interchangeably (Cramer et al., 2008; De las Cuevas, 2011). Medication adherence is defined by the World Health Organization (WHO) as “the extent to which a person’s behavior [in] taking medication (…) corresponds with agreed recommendations from a health care provider” (World Health Organization, 2003), whereas compliance has been defined by as “the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen” (Cramer et al., 2008). Inherent in these alternative definitions are important differences in terms of the active agreement of the patient in the prescribing process. Cramer et al. also distinguish compliance from a second construct, persistence, which refers to the act of continuing the treatment for the prescribed duration (Cramer et al., 2008). These variations reflect the current lack of consensus regarding terminology and of any operational definition in clinical medicine and research for behavior related to taking medication.
In view of its growing importance in child and adolescent psychiatry, Hack and Chow performed a Medline search of all studies published between 1966 and August 2000 on what they termed “compliance” with pediatric psychopharmacology (Hack & Chow, 2001). Only seven studies were identified, and each of them had investigated compliance with psychostimulants in children (aged 5–13 years) undergoing treatment for attention-deficit/hyperactivity disorder (ADHD).
Hack and Chow (2001) found no studies of psychotropic noncompliance that focused on adolescents. However, they did point out that several studies had indicated high rates of noncompliance with treatments for medical illnesses in this age-group (Cromer & Tarnowski, 1989; Fotheringham & Sawyer, 1995; La Greca, 1990), and that research had indicated high rates of noncompliance in adult patients with psychiatric disorders (Cramer & Rosenheck, 1998). Furthermore, in their review of what they termed “medication adherence” in adults and children with ADHD, Adler and Nierenberg found evidence to suggest that rates of nonadherence to psychostimulants among adolescents may be high, although the reviewed studies had various methodological limitations (Adler & Nierenberg, 2010). These data and the observations of the present authors in routine child and adolescent psychiatric clinical practice suggest that failure to take medication in accordance with the recommendations of the clinician is common among adolescents with psychiatric disorders.
To investigate this hypothesis, we performed a systematic literature search. Our aims were to identify the rates of nonadherence or noncompliance to psychotropic medication among adolescents, to compare the definitions of these terms across studies, and to determine which particular clinical and other features were reported to influence these behaviors in this population.
Methods
This review was performed according to the guidelines set forth by the PRISMA statement for systematic reviews and meta-analyses (Moher et al., 2009a, 2009b).
Search Strategy
The PubMed library (http://www.ncbi.nlm.nih.gov/pubmed) was searched for English-language publications with the keywords “adherence” or “compliance” in combination with “adolescent” and “psychotropic medication.” Relevant articles were also selected from reference lists. The last search was conducted on September 17, 2015, and included all studies published by that date.
Selection of Studies
All studies resulting from the search strategy described were reviewed for eligibility by title and/or abstract by two of the authors. Any disagreement between reviewers was resolved through discussion within our research group. Those clinical trials were included that (1) reported rates of adherence or compliance, or nonadherence or noncompliance respectively, (2) examined a population of adolescents (age range according to European Medicines Agency [EMA] definition, 12–18 years), and (3) focused on the use of psychotropic medication. The following types of publication were excluded: case reports, interventional studies applying psychotherapeutic approaches in the absence of medication, and studies using targeted measures or programs to improve adherence/compliance.
Data Extraction
Data were extracted from full-text articles and included rates of (non)adherence/(non)compliance, definitions and assessments of (non)adherence/(non)compliance, and characteristics of the study and the study sample. Furthermore, (if available) correlates of and factors associated with (non)adherence/(non) compliance were recorded. Data of studies investigating what the authors called “adherence” and those investigating “compliance” were pooled.
Results
A total of 607 articles were collected and screened. Of these articles, 588 were excluded by title and/or abstract based on the inclusion and exclusion criteria (see above). Full-text searches were completed for the remaining articles. Six articles were excluded for the following reasons: (1) Four did not state (non)adherence or (non)compliance rates for adolescents; (2) one included participants older than 18 years of age; (3) one did not de facto examine noncompliance but expected noncompliance in case of hypothetical adverse events under psychopharmacological treatment. The remaining 13 publications were selected for review. One of these studies focused on “adolescents” but did not state an age range but a mean age and standard deviation. This study was not excluded. Two further articles could be added identified through searching reference lists. Figure 1 gives a graphic representation of the study selection.
In the 15 identified studies, rates of nonadherence ranged between 6 % and 62 % (median 33 %). The details of each study are presented and summarized in Table 1. The studies are presented in chronological order. For each study, data (e. g., percentages) and terminology are presented in the precise form used in the text of the respective publication.
Definitions of (Non)adherence/ Partial Adherence
Definitions of nonadherence varied widely (cf. Table 1). Nevertheless, most authors categorized patients as being either “adherent /compliant“ or “nonadherent/noncompliant” (cf. Table 1). However, DelBello et al. (2007) defined a “partial adherence” category, i. e., medication was taken between 25 % and 75 % of the time as prescribed. A similar subgroup can be identified in the study by Coletti et al. (2005). Patients who had failed to take their medication on at least two – but less than ten – occasions within the previous month were classified as neither “fully adherent” nor “poorly adherent.” Based on the results on a 4-point Likert-type questionnaire, Molteni et al. (2014) distinguished between “excellent compliance” (= always taking the medication), “moderate compliance” (= sometimes forgetting the medication, but less than ones a week), “poor compliance” (= more than once a week) and “the absence of compliance” (= never taking the medication).
Methods of Assessment
In ten of the studies, nonadherence was assessed on the basis of questionnaires or interviews with the parents and/or patients (cf. Table 1). Three studies interviewed patients only. In six studies, the parents or the parents and the adolescents were interviewed. Furthermore, some authors used postal questionnaires, while others used telephone or face-to-face interviews. These authors did not give further information on the structure and character of the interview or the questionnaires, particularly no psychometric information regarding reliability and validity. Three studies assessed adherence using data from a health service database rather than through any direct contact with patients and their families (cf. Table 1). One study used pill counts in addition to interviews with patients whose self-report was considered unreliable (Patel et al., 2005). In contrast, Woldu et al. (2011) assessed what they termed “nonadherence” via plasma levels (level-dose ratio =LDR) and pill counts (clinician pill counts =CPC) rather than relying on patient or parent reports. They reported varying results: Based on LDR, 36.3 % of the patients were considered as nonadherent vs. 49.2 % based on CPC.
Patel et al. (2005) and Nakonezny et al. (2010) were the only authors to assess nonadherence on a week-to-week basis. In ten studies, patients or their parents were asked to recall patterns of “nonadherence” or “noncompliance” over time intervals ranging from 4 weeks to more than 2 years (cf. Table 1). Gearing and Charach (2009) pointed out that the potential unreliability of information on adherence recalled by families 2 years or more post-discharge was a limitation of their study design. In the studies by Hodgkins et al. (2011), Fontanella et al. (2011) and Stewart and Baiden (2013), all data were retrospectively derived from healthcare databases that had not specifically been designed to collect data on medication adherence.
Sample Characteristics
The largest study sample was that investigated by Hodgkins et al. (n = 26,860; [Hodgkins et al., 2011]). In this study, the authors performed a retrospective analysis of a US medical and pharmacy claims database. Fontanella et al. (2011) conducted a retrospective cohort analysis using claims data from a state Medicaid-enrolled population of 1,650 youths with depression. Stewart and Baiden (2013) referred to the Resident Assessment Instrument for Mental Health dataset including records of 3,681 adolescents who received inpatient treatment in adult psychiatric facilities. Sample sizes for the other 12 studies ranged between n =21 and n =190 (mean, n =74.7), and, in the longitudinal study by Burns et al., nearly 50 % of the original sample of n =85 patients had been lost to follow-up by the final 2-year assessment (Burns et al., 2008). Furthermore, patients were largely recruited from hospital admissions rather than being population-based. Nine studies investigated samples recruited from consecutive or nonconsecutive inpatient admissions (cf. Table 1). Nakonezny et al. (2010) investigated a subsample of outpatients from two studies. Coletti et al. (2005) investigated patients recruited from outpatient services, while Woldu et al. (2011) included patients from both academic and community-based clinics. Five of the reviewed studies investigated patients recruited at university centers (cf. Table 1).
Predictors of Nonadherence
Several studies attempted to identify predictors of nonadherence or noncompliance. The specific factors examined varied across studies, in accordance with the particular research focus of the authors. Thus few data are available for each individual potential predictor.
Several authors investigated associations between nonadherence and various aspects of the psychotropic medication. Four studies investigated correlations with medication type and found no significant association (Ghaziuddin et al., 1999; Lloyd et al., 1998; Patel et al., 2005; Pogge et al., 2005). Although the study by Hodgkins et al. (2011) investigated patients taking various ADHD medications, the authors reported adherence rates only for one particular treatment group, i. e., those taking long-acting (LA) methylphenidate (MPH). In addition, Ghaziuddin et al. (1999) failed to find any correlation between noncompliance and the number of medications prescribed. Only a few studies investigated associations with “side effects” (adverse events). Pogge et al. reported an association between nonadherence and rapid weight gain (Pogge et al., 2005). Stewart and Baiden (2013) found that adolescents who experienced “medication side effects” were more than three times more likely to be nonadherent compared to those who reported no medication side effects – but the authors report neither which psychotropic medications were prescribed nor which adverse events could be observed. Patel et al. (2005) reported that rates of full adherence were comparable for antipsychotics and mood stabilizers/anticonvulsants, suggesting that medication type had no influence on nonadherence in their sample. Fontanella et al (2011) found that optimal follow-up visits, adequate antidepressant dosing, and the use of “other psychotropic medications” were associated with better adherence during acute and continuous treatment of depression – but their analyses were not focused on adolescents but rather on the total sample of youths aged 5 to 17 years.
Nonadherence and Clinical Effectiveness/Efficacy
Few authors investigated associations between nonadherence and medication efficacy. Pogge et al. (2005) found there was no significant association between adolescents’ subjective impression of efficacy and nonadherence, and that 50 % of nonadherent patients actually rated the medication as having been helpful. In contrast, Patel et al. (2005) reported that patients with a positive impression of medication benefit were less likely to be nonadherent. Adherence was significantly correlated with subjective ratings of drug helpfulness in “African-American adolescents” (r = –0.6; p = .02) as well as in “white adolescents” (r = –0.5; p = .04). Burns et al. (2008) also investigated the perceptions of parents and found that, although their perception of the helpfulness of treatment predicted compliance, the perception of the adolescent did not. In the Coletti et al. study (2005), the negative correlation between missed medication and parent perceptions of high effectiveness reached trend status.
Four studies discussed differences in clinical outcome between adherent or compliant and nonadherent or noncompliant patients. DelBello et al. (2007) found that, although nonadherence was associated with lower rates of syndromic recovery and longer time to syndromic recovery following initial hospitalization, these findings did not remain statistically significant in a stepwise Cox regression analysis. Similarly, Burns et al. (2008) reported that higher treatment compliance was not generally predictive of decreased suicidality.This was also the case in the study by Woldu et al. (2011), in which no association between adherence measured by CPC or LDR and the occurrence of suicidal ideation or the pace of decline in suicidal ideation was found. Woldu et al. (2011) also reported that clinical response (as measured using the Children’s Depression Rating Scale-Revised) was associated with adherence measured by CPC but not with adherence measured by LDR. Nakonezny et al. (2010) reported that the adjusted mean symptom severity in their sample of patients with MDD assessed by the Children´s Depression Rating Scale-Revised was significantly lower for the group of adherent patients (assessed via electronic monitoring) compared to the nonadherent group.
The two studies that also investigated partial adherence did not report on correlations between partial adherence and objectively rated clinical outcome (Coletti et al., 2005; DelBello et al., 2007).
Nonadherence and Symptomatology
Nine studies investigated correlations between nonadherence or noncompliance and psychiatric diagnosis or symptoms (cf. Table 1) (Burns et al., 2008; DelBello et al., 2007; Fontanella et al., 2011; Gearing & Charach, 2009; Ghaziuddin et al., 1999; Lloyd et al., 1998; Pogge et al., 2005; Woldu et al., 2011; Molteni et al., 2014). Six of the 15 studies investigated mixed samples, while nine investigated specific subpopulations, such as patients with psychosis (Gearing & Charach, 2009; Molteni et al., 2014), bipolar disorder (Coletti et al., 2005; DelBello et al., 2007; Patel et al., 2005), ADHD (Hodgkins et al., 2011), or depression (Fontanella et al., 2011; Nakonezny et al., 2010; Woldu et al., 2011). Four studies found a significant positive association between nonadherence or noncompliance and concomitant substance abuse (Burns et al., 2008; Lloyd et al., 1998; Pogge et al., 2005; Stewart & Baiden, 2013). Fontanella et al. (2011) also reported a significant positive association between nonadherence and concomitant substance abuse for youths with depression in the continuous phase of treatment (cf. Table 1), but – as mentioned before – their analyses did not focus on adolescents but youths 5 to 17 years of age. Stewart and Baiden (2013) found tobacco use, cannabis use, depressive symptoms, and positive symptoms of psychosis to be positively associated with medication nonadherence in their mixed-disorder sample of adolescents. Burns et al. (2008) found that adolescents with an affective/anxiety disorder diagnosis were at increased risk of medication noncompliance at 6-month follow-up compared to all other adolescents in the sample, while Gearing et al. (2009) reported an increased risk of nonadherence in patients with first-episode psychosis who were not prescribed concomitant medication for affective symptoms compared to those who received that medication. Hodgkins et al. (2011) reported that ADHD patients with comorbid psychiatric disorders were more likely to switch therapy and may thus have been at higher risk of nonadherence. On the other hand, Woldu et al. (2011) found that patients with major depressive disorder who were also prescribed psychostimulants for comorbid ADHD were less likely to be noncompliant. In contrast, other authors found no association between diagnosis and noncompliance (Ghaziuddin et al., 1999; Lloyd et al., 1998; Molteni et al., 2014).
Nonadherence to Medication Treatment and Psychotherapy
Several studies examined correlations between nonadherence or noncompliance to psychotherapy and medication. King et al. (1997) found that compliance with medication management sessions was higher than compliance with psychotherapy and hypothesized that medication may have been perceived as offering more prompt relief of symptoms and as allowing families to focus on discussion of pharmaceutical issues rather than family conflict. However, as pointed out by the authors, a major limitation of their approach was that they viewed attendance at these sessions per se as their measure of whether or not patients had actually ingested their medication, as opposed to more objective assessments of whether medication had actually been taken. Attendance at such a session may have represented a “nonthreatening” or “nonintrusive” form of therapy and support to the adolescent and their parents. In contrast, Lloyd et al. (1998) found that compliance with psychotherapy was the strongest predictor of compliance with medication. Similarly, Pogge et al. (2005) reported that patients who had discontinued psychotherapy were more likely to have discontinued their medication.
Family-Related Factors
Several studies investigated the influence of family-related factors on medication nonadherence. Ghaziuddin et al. (1999) found no association between family living arrangements and noncompliance, whereas Burns et al. (2008) observed that parental perceptions of the helpfulness of medication predicted compliance. Stewart and Baiden (2013) reported having a disturbed/dysfunctional relationship with immediate family members to be positively associated with medication nonadherence in their sample. Only one study found any significant correlation in terms of demographics. DelBello et al. (2007) reported an association between nonadherence and low socioeconomic status.
Discussion
The present literature review on nonadherence to psychotropic medication among adolescents identified rates of between 6 % and 62 % (median 33 %). This supports the hypothesis that nonadherence to psychotropic medication is a clinically relevant problem among adolescents. In view of the serious potential consequences of inadequate treatment (Barkley, 2002; Taddeo et al., 2008), further efforts and studies are indicated in order to improve medication adherence in this population.
The definitions of noncompliance/nonadherence in the 15 studies that could be included in the review varied widely. Furthermore, the authors used different methods to assess noncompliance/nonadherence. The discrepancies in definitions and methods of assessment render both cross-study comparisons and generalization of findings for application in routine clinical practice seriously problematic. Future studies in this field should consider this important methodological issue.
Within the 15 studies included in the review, different potential predictors of noncompliance/nonadherence were explored. Because of methodological heterogeneity across the studies (different definitions of nonadherence, methods of assessment, study samples, type of study etc.) and partially contradictory results (cf. Result section above), no conclusions could be drawn concerning the influence of factors such as psychopathology, medication type, side effects, effectiveness of treatment, or family related factors. However, despite discrepancies in their findings, previous authors are in agreement that further research into the issue of nonadherence to psychotropic medication among adolescents is warranted. The available data suggest that future research in this population should involve investigation of factors such as medication-related factors, family attitudes to psychiatric illness and treatment, psychiatric diagnosis, and comorbidity, in particular, substance abuse, and that investigation of population-based samples is necessary. Furthermore, there appear to be additional factors affecting medication adherence such as adolescents’ personal attitudes, worries, preoccupations, health-beliefs, insights, and self-concept. To investigate such factors, the use of reliable and valid instruments is required (Ferrin et al., 2012). Detailed biometrical and statistical evaluation of the methodology and data analyses of the reviewed studies is beyond the scope of the present paper. However, because of their methodological limitations, studies of nonadherence or noncompliance to psychotropic medications among adolescents performed to date do not provide definite evidence for the relevance of any particular clinical or another factor.
Limitations
One limitation of the methodology of this review lies in the restriction to one database and the restriction based on the search terms that were used. Furthermore, we did not search for articles published in languages other than English. Future research could enlarge our knowledge about this field by using a more comprehensive search strategy. However, the main findings – like the overall relevance of the issue of nonadherence accompanied by a lack of consensus across studies in terms of definition and assessments – remain unaffected by this circumstance.
Summary and Implications
Although few studies have investigated nonadherence or noncompliance with psychotropic medication among adolescents, available data support the hypothesis that nonadherence is common in this population. This suggests that the development and systematic evaluation of strategies to improve adherence in adolescents with psychiatric diagnoses are required. However, both the identification of clinical and other factors that influence nonadherence in these patients and evidence that adherence improves clinical outcomes are prerequisites for the development of effective counterstrategies. The interpretation of previous findings and the generalization of these findings to routine clinical practice are presently hampered by methodological shortcomings and a lack of consensus across studies in terms of definition. Well-designed, prospective research into nonadherence in adolescents with psychiatric disorders is therefore warranted. Future studies should involve differential analysis of nonadherence rates, i. e., of factors such as clinical diagnosis and substance group, and require agreement regarding definitions and methodology.
Conflicts of Interest: Dr. Häge received compensation for serving as consultant or speaker, or the institution he works for has received research support or royalties, from the companies or organizations indicated below: E. Lilly, Shire, Janssen-Cilag, Otsuka, Sunovion, Takeda, German Research Foundation (DFG), German Ministry of Education and Research (BMBF), European Union (EU FP7 program). The present work is unrelated to the above-mentioned relationships and grants.
Dr. Dittmann received compensation for serving as consultant or speaker, or has received research support or royalties from the companies or organizations indicated: EU (FP7 Programme), US National Institutes of Mental Health (NIMH), German Federal Ministry of Health/Regulatory Agency (BMG/BfArM), German Federal Ministry of Education and Research (BMBF), German Research Foundation (DFG), Volkswagen Foundation, Boehringer Ingelheim, Ferring, Janssen-Cilag, Lilly, Otsuka, Shire, Takeda, and Theravance. Dr. Dittmann owns Eli Lilly and Co. stock. The present work is unrelated to the above relationships and grants.
Konstantin Mechler served as subinvestigator in clinical trials funded by the European Union, Lundbeck, Shire, and Sunovion. The present work is unrelated to the above relationships and grants.
Dr. Weymann, Dr. Bliznak, and Dr. Märker have no potential conflicts of interest to declare.
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