Antipsychotic Medication Nonadherence: Risk Factors and Remedies

Drug attitude correlates with adherence and refers to the patient’s overall appraisal of the risks and benefits associated with a particular medication (12). It can easily be measured with the Drug Attitude Inventory (13), originally a 30-item true/false scale (now often used in an abbreviated 10-item version) assessing subjective negative and positive effects of medication and beliefs about the meaning of taking medication. Antipsychotic side effects, such as extrapyramidal side effects, sedation, weight gain and sexual side effects make an important contribution to a negative drug attitude and increase the risk for nonadherence. Freudenreich and colleagues (14) did not find differences in drug attitude between patients taking first-generation agents and those taking second-generation agents, suggesting that the patient’s appraisal of side effect burden may be more important in determining drug attitude than the type of side effect. Moreover, Leucht and Davis’ (15) recent reappraisal of the problematic and arbitrary distinction between first- and second-generation antipsychotics cautions clinicians to simply make side effect assumptions based on the first- and second-generation distinction. Instead, clinicians need to comprehensively assess and monitor side effect profiles of antipsychotic medications regardless of class assignment.

In first-episode patients, treatment effectiveness has been shown to be a powerful predictor of adherence (16). Using data from the European First Episode Schizophrenia Trial (EUFEST), Gaebel and colleagues (12) found that drug attitude was a valid and the strongest predictor of later drug discontinuation. Sexual side effects and a high psychopathology score (consistent with lack of effectiveness) also predicted nonadherence in this population.

Although the concept of “insight” has played an important role in the classification and treatment of many psychiatric disorders, it is perhaps most central to psychotic disorders. In fact, “lack of insight” was identified in a seminal World Health Organization study as a pathognomonic, core symptom of schizophrenia (17). Retained insight is among the diagnostic criteria for the recently proposed illness category of “Attenuated Psychosis Syndrome” (18) (see DSM-5 website (19) for proposed criteria). Aubrey Lewis (20) defined insight as “a correct attitude to a morbid change in oneself.” Since his early definition, insight has been expanded into a multidimensional construct, comprising at least 3 agreed-upon dimensions (21): awareness of symptoms (i.e. capacity to relabel inner experiences as pathological symptoms); recognition of mental illness (i.e. attributing symptoms to a psychiatric illness), and acceptance of need for treatment. The latter dimension is generally meant to imply that patients accept psychiatry’s remedies in the form of medications. Subsequent authors (e.g. Kirmayer and colleagues (22)) have refined this definition, by including the socio-cultural dimension in recognition that a patient’s insight is not determined in a vacuum but instead by a clinician who measures a patient’s agreement with the clinician’s professional view. Insight can thus be understood as the end-result of an intersubjective construction of meaning. Tranulis and colleagues (23) proposed the term “narrative insight” to describe this construction of meaning about illness. Narrative insight is developed not only through abstract reasoning and introspection, but also through concrete interpersonal interactions and actual experiences of illness and treatment.

Better illness insight in schizophrenia matters with regards to medications as it is a robust predictor of better adherence (24). Conversely, many studies have shown that lack of insight is associated with treatment discontinuation and poorer outcomes (25). Moreover, a systematic literature review concluded that patients with poor insight are very likely to be deemed incompetent (26) which might have significant medical-legal implications. A subgroup of patients with poor insight seems to have a stable, anosognosia-like neurocognitive deficit (27). Incompetent patients with poor insight who actively refuse medications require court-mandated assisted treatment approaches in order to receive treatment. In many cases, however, there is partial insight (28) which is sufficient to enable clinicians and patients to collaborate productively with regards to psychiatric treatment needs and choice.

The remedies for nonadherence discussed in the next section are most appropriate for patients with at least partial insight and for those patients in whom nonadherence is inadvertent (e.g. forgetting to take medications due to memory problems). However, the adherence-improving measures described below can be applied to all patients who are willing to go along with treatment, regardless of degree of insight, as insight is a helpful but not necessary ingredient in adherence.

Especially in the early phases of treatment, it has been shown that perceived clinic or physician support is a powerful predictor of adherence (36). Indeed, when patients do not have direct experience with medications, trust might be the most important predictor of adherence. Trust was identified as one of the key predictors of adherence in first episode psychosis samples (37) and described retrospectively as a crucial initial factor in accepting treatment (38). In a sample of 228 patients with schizophrenia or schizoaffective disorder admitted with an acute exacerbation of psychosis, negative treatment attitudes were predicted by a less positive relationship with the prescriber, perceived coercion during admission, and low insight (36). Interventions should thus focus on improving the overall treatment experience as well as experience with specific medications, regardless of the patient’s explanatory framework. The most critical question is not whether a patient agrees with the clinician’s diagnosis but rather whether the patient sees the role of psychiatric treatment as at least potentially beneficial. Although it remains unclear if perceived coercion negatively affects short-term outcomes (39) it seems reasonable to suggest that clinicians and health care systems try to reduce the amount of perceived coercion to avoid alienating patients.

Beck and colleagues (40) have pointed out that targeting treatment-related attitudes has a better chance of improving adherence than interventions intended to increase global illness insight. Letting patients work out the benefits and risks from taking medications to facilitate more positive drug attitudes is a strategy consistent with a shared-decision making approach (41). Another way to increase positive medication attitude is to improve subjective well-being while taking antipsychotic medication (also referred to as “subjective well-being under neuroleptic treatment” or SWN for short) —for example by reducing dose to target itinerant side effects or by adding medications to decrease negative mood states such as anxiety or depression (42). Showing flexibility in dosing and switching medications are frequently necessary maneuvers to improve SWN. Unfortunately, psychiatric medications are often only partially effective and invariably have side effects. Patients learn that increased efficacy (e.g. taking a medication regularly) can lead to increased side effects (43).

The general interventions discussed above and the specific intervention strategies that will be described below can at least partially circumvent the issue of insight as insight is neither necessary nor sufficient with regards to treatment adherence. It remains to be seen to what extent insight can be improved in at least some patients with schizophrenia and if improved insight then increases antipsychotic adherence. A randomized, multisite trial that attempts to increase insight in schizophrenia is currently conducted in the Netherlands, comparing an insight-increasing social-cognitive treatment with cognitive remediation as the control group (25).

Compliance therapy (CT) is an approach rooted in cognitive-behavioral therapy and motivational interviewing that attempts to help patients weigh risks and benefits from treatment, similar to how patients would approach their treatment for hypertension or diabetes (44). A key component of motivational interviewing as it relates to CT is to assist the patient creating discrepancies between his or her goals and values vis-à-vis his or her current state in the service of enhancing adherence to facilitate increased life satisfaction. While an initial randomized-controlled trial of CT showed improved adherence and a reduced rate of relapse following hospital discharge (45), a subsequent multicenter effectiveness trial failed to replicate the benefit seen in the initial trial (46). It remains to be seen whether subgroups of patients may be more receptive to CT than others.

LAI are effective in reducing symptomatic exacerbations and relapse in the maintenance phase of patients with schizophrenia (47). A recent randomized trial in 369 schizophrenia patients who were either hospitalized or at high risk of hospitalization compared clinician-choice oral antipsychotics with long-acting injectable risperidone (48). No difference in hospitalization rates, symptom improvement and quality of life between the treatments was found, suggesting that in those patients willing to consider either oral medications or a LAI (a condition for participation in this trial) there is no benefit from long-acting formulations over oral antipsychotics. More generally, although LAI are often suggested for patients with no insight who do not want to take any medication, challenges remain in developing interventions to enhance motivation to accept LAIs.

Schizophrenia-associated neurocognitive impairment is an important factor that can contribute to inadvertent poor adherence (35). Velligan and colleagues (49) designed a multipronged intervention (cognitive adaptation training or CAT) to help patients adhere better to medication. The 9-month intervention consisted of tailored environmental support and compensatory strategies and improved adherence significantly compared with a treatment-as-usual control group. The effect of the intervention persisted beyond the intervention period, suggesting this may be a durable approach to improving adherence. Longer-term follow ups are needed to establish the durability of this approach.

In general medicine, directly observed therapy (DOT) is used for patients with infectious diseases like human immunodeficiency virus (HIV) or tuberculosis where a high degree of adherence is critical for good outcomes (50, 51). The main intervention in DOT is as the name implies directly observing and thus verifying that the patient actually takes the medication as prescribed. In psychiatric setting, this can easily be instituted in group homes. For patient’s living independently, visiting nurses or family members can be enlisted to achieve the same degree of supervision. Farooq and colleagues (52) adapted DOT for schizophrenia outpatients in a resource-poor area. They randomized 110 patients to family-supervised medication administration or treatment as usual (TAU). The intervention resulted in better adherence in the intervention group (complete adherence 67.3%) than in the TAU group (45.5%). In the future, information technology can play a greater role in directly monitoring patients and their adherence. Spaniel and colleagues (53) piloted a cell-phone based telemonitoring system to detect nonadherence and signs of early relapse in 45 patients. This intervention reduced hospitalizations by 60% compared with the same time period prior to participation.

Paying patients to take medications can improve medication adherence (54). In addiction medicine, giving patients vouchers in exchange for “clean” urines is one the most effective interventions (contingency management) (55, 56). Informally, nudging and subtle coercion by clinicians and family members (e.g. withholding money) are little discussed yet often employed tools (38). Providing financial incentives to take antipsychotic medications poses its own set of ethical questions (57, 58). Nevertheless, a pilot study in the Netherlands showed that acceptance of injections in 5 patients increased from 44% to 100%, leading to an almost 10-fold reduction in days spent in the hospital (59). The incentives approach is currently being studied in the randomized Financial Incentives for Adherence Trial (FIAT) in Great Britain (60).

Achieving good antipsychotic medication adherence is an important treatment goal in the care of patients with schizophrenia as good adherence improves clinical outcomes. Clinicians need to take into account specifically insight and drug attitude when working with this patient population. A wide variety of adherence-improving interventions that differ in intensity and intrusiveness are available for deployment in a stepped-up and tailored manner, depending on the etiology of poor adherence.