Medication adherence in patients with schizophrenia

Introduction

Compared to no medication, antipsychotics significantly reduce relapse rates in patients with schizophrenia stabilized on antipsychotics over one year. ¹ Unfortunately, nonadherence is common and medication nonadherence in patients with schizophrenia are reported to range from 20% to 89%. ² The National Institute of Mental Health sponsored trial assessing the effectiveness of first and second generation antipsychotic medications in patients with schizophrenia found that 74% of patients discontinued antipsychotic medication before 18 months. ³ In another study, median nonadherence rates are 55% in the first two years following a psychotic episode, and studies have found that patients that have historically been medication nonadherent are more likely to be nonadherent in the future.^1,2

Medication adherence is generally defined as the degree to which a patient’s medication use corresponds or aligns with the recommendations of the prescriber; “nonadherence” includes both underuse and overuse. ¹ In many studies, “medication nonadherence” is considered to be an “all or none” phenomenon where the patient is “nonadherent” if they miss 20% of the medication, which may predict hospitalization or negative sequelae.^1,4 This, however, varies across disease states and among patients.^1,2,4 In schizophrenia, the risk of recurrence, relapse, or rehospitalization may depend on factors such as baseline severity of illness and recurrence risk, degree of psychosocial support, and medication effectiveness. ¹ Partial adherence describes patterns of medication use involving patients who regularly or occasionally miss doses or take incorrect doses, as well as patients who cycle through various degrees of adherence over time.^1,5 Studies show that partial adherence or even brief periods of nonadherence may lead to worsened outcomes.^1,4 Missing medications for as little as 10 days may be associated with increased risk of hospitalization and missing at least 25% of doses over a minimum of two weeks significantly increases the risk of psychosis.^1,6 The risk of psychosis was defined as relapse or significant decompensation following remission or significant exacerbation after persistent symptoms. ⁶

Medication nonadherence is especially problematic in schizophrenia and results in consequences including symptom exacerbations or relapse, greater risk or rates of psychiatric hospitalization and use of emergency psychiatric services, and worse prognosis.^1,2,7 Antipsychotic nonadherence is the most common reason cited for hospitalization. ⁸ In patients who experience their first episode of schizophrenia and become medication nonadherent, the chance of readmission is five times higher in the first year.^2,6,9 Further, patients with schizophrenia and adherence issues in the first year predicted worse outcomes (represented by the following domains: signs and symptoms, cognitive and ego functioning, social functioning, major role performance, and recidivism) in the subsequent two years.^4,10 Repeated episodes of psychosis or relapse can lead to the development of chronic psychosis, longer time to symptomatic improvement/response, and/or possible resistance to antipsychotic medications.^4,7 Over time, repeated relapses may also lead to increased functional impairment and disability. ¹ Additional consequences of medication nonadherence in patients with schizophrenia include greater risk of comorbid substance use disorder; poorer cognitive functioning; reduced quality of life; increased rates of arrest, violence/aggression, or victimization; and increased risk of suicide.^1,7,11 All of these factors contribute to an even higher risk of medication nonadherence. The indirect costs and significant financial burden are a consequence dealt with by society.^2,7,8

Medication nonadherence in patients with schizophrenia may result from lack of insight or awareness, psychopathology, comorbid substance use disorder, tolerability issues associated with antipsychotic treatment, stigma, and problems with continuity of care among mental health services.^1,2,7,11 Other factors influencing adherence include a patient’s perceptions and attitudes toward illness and taking medications (e.g. thought to have addictive properties), cultural influences, or socioeconomic status.^2,7 For example, patients that are younger or have a shorter duration of illness may reflect negatively on the need for medication. ² Patients’ misunderstanding of schizophrenia or their cultural background, such as the belief that the psychosis is due to an external origin or acceptance of illness, may impact adherence. ¹² One study found that additional risk factors for future medication nonadherence were found to be prior hospitalizations, living independently, and exhibiting a baseline level of hostility. ⁹ Patients who deal with their illness by ignoring symptoms or pretending to be healthy are less likely to adhere to medications; however, patients who are accepting of their illness and have more positive coping strategies are not necessarily at lower risk for medication nonadherence.^1,13

The perceived effectiveness of medications influences adherence, and a good response is positively associated with appropriate medication use.^1,2,7 One study found that medication efficacy, measured by a reduction in the Positive and Negative Syndrome Scale Score, was a strong positive predictor of treatment adherence. ¹ The perceived ability of antipsychotic medications to “cure” the patient of schizophrenia, however, may lead patients to discontinue medication. ¹¹ Unfortunately, medication adherence does not guarantee that a patient will remain symptom free, stay protected from relapse, and maintain a good quality of life. ¹ Alternatively, nonadherence does not always lead to immediate decompensation. ¹ Some patients appear to be resistant to antipsychotic medication effects and specific symptoms, such as negative and cognitive symptoms, do not respond as readily to antipsychotic medications. ¹ All of these factors, including those previously discussed, impact adherence, outcomes, and functioning for the patient with schizophrenia. The purpose of this article is to discuss possible strategies to improve medication adherence in patients with schizophrenia.

Literature review

A review of interventions to increase adherence in patients with schizophrenia display mixed outcomes. Studies evaluating psychoeducational methods, which do increase medication or illness understanding and attitudes, alone were not very effective, while methods that included additional behavioral interventions had better efficacy.^1,2 Behavioral interventions include practicing skills, modeling, and reinforcing techniques. ¹ “Motivational interviewing” is a technique that influences behaviors by helping a patient identify and resolve ambivalence, allowing them to make conclusions about the benefits or consequences of their actions, such as not taking medications.^1,14 This technique was shown to be effective in other psychiatric illnesses. ¹⁴ More studies are needed, however, on motivational interviewing in patients with schizophrenia because studies evaluating the impact on previously nonadherent patients showed adherence did not improve. ¹⁴ Interventions aimed specifically at nonadherence were more effective than those targeting multiple problems, suggesting that a focused approach is better. ² Yet, intensive case management or assertive community treatment, that were not specifically focused on improving adherence, yielded good results on adherence.^2,8 Interventions that lasted longer and had more sessions seemed to do better than shorter interventions. ² Psychosocial interventions involving education approaches, skill training, family counseling, cognitive therapy, behavioral interventions, and group therapy techniques may be beneficial in combination. ⁷ Family therapy alone was deemed minimally effective, although those that included the patient’s support system in addition to other interventions were beneficial.^2,7 Overall, it appears that multimodal interventions fare better than single modality interventions for improving medication adherence. ¹

Antipsychotic-related factors, such as adverse effects, inefficacy, regimen complexity, or past experience with medication may also influence medication use. ¹ The benefit of prescribing lower doses of antipsychotics to avoid adverse effects may be offset by the inefficacy of the medication against symptoms of schizophrenia; similarly, prescribing higher doses to effectively control symptoms may be offset by the poor tolerability due to adverse effects. ¹ Adverse effects have been shown to be strongly and negatively associated with medication adherence, so patients should be educated about potential short-term and long-term adverse effects and strategies to mediate those adverse effects. ¹ Continually asking about any medication-related issues can help providers identify potential barriers to both intentional and unintentional adherence and offer options to address each barrier. Possible strategies include dosing at different times of the day, consolidating regimens (e.g. once-daily dosing), modifying doses, or prescribing additional medications to treat medication-induced adverse effects as a last resort. Second generation antipsychotics were thought to be better tolerated than first generation antipsychotics due to a lower incidence of extrapyramidal symptoms and tardive dyskinesia; however, they have a greater risk of metabolic adverse effects. Despite different tolerability profiles, evidence suggests that second generation antipsychotic medications do not necessarily improve patient adherence over first generation antipsychotics. ⁷ The choice of antipsychotic therapy should be based on the patient’s previous experience and adverse effect profile. ¹ Avoiding polypharmacy, when appropriate, is also important. ¹ When providers are unaware of the patient’s medication nonadherence and determine the patient’s medication to be ineffective at the prescribed regimen, inappropriate medication changes, such as dosage increases, addition of other medications or switching to a different antipsychotic, may be prescribed. ¹ This may lead to increased pill burden and risk of tolerability issues, further adding to potential reasons for future medication nonadherence. Simplifying regimens in schizophrenia has the same benefits as reducing polypharmacy across many other chronic conditions. ¹⁵ Patients with unintentional nonadherence, that forget to take their medications, may benefit from using various reminders, such as a pillbox, which not only help patients determine if they have missed a dose but also if they have taken the dose already.

Long-acting injectable (LAI) antipsychotics can help providers identify medication nonadherence more quickly than nonadherence associated with oral medication use based on whether the patient shows up to their injection appointments or not. ¹ Whether LAIs significantly improve adherence compared to oral antipsychotics is questionable, there is lack of evidence. ⁷ In theory, LAIs should improve medication nonadherence; however, patients with intentional nonadherence may choose not to show up to receive their injection, as they are generally only administered by a healthcare provider. The major benefits are in the rapid identification of medication nonadherence and a patient’s behavioral or symptom decompensation may be delayed as the drug remains in the body for a longer period of time. ⁷ Disadvantages of LAIs vary by specific medication but generally may include injection site pain, skin thickening, or nodules from frequent injections. Similar to choosing any other pharmacotherapeutic treatment, the choice of LAI should involve the patient and depend on a variety of factors such as past medication history, adverse effect profile, and regimen complexity.

Common reasons for a patient’s dissatisfaction with medication are also related to lack of involvement the patient and/or caregiver in treatment planning. ⁴ Involving patients in treatment and decision-making is important to enhancing adherence.^1,4 This should be tailored to the patient but can include listening to the patient to understand their attitudes, perspectives, and beliefs regarding treatment and their illness and to be able to address misperceptions and concerns. ¹ Discussions with the patient and/or caregiver(s) can be modified per his/her understanding and cognition but should include counseling on expectations for treatment effectiveness and short- and long-term treatment goals, in addition to education on adverse effects. ⁴ Thus, maintaining open communication with the patient from all members of the treatment team can also strengthen the therapeutic alliance or relationship with the patient. ¹

A good therapeutic alliance, which can be created through adequate planning, and consistent, accessible contact with patients, can also lead to improved medication adherence. ¹ Patients who were able to develop a beneficial alliance with their provider within the first six months of treatment were more likely to remain engaged in treatment, both psychotherapy and pharmacotherapy, and had improved outcomes after two years. ⁴ A therapeutic alliance is also beneficial to maintain with patients’ support system, if the patient’s consent is given, as this can help reduce stigma and change attitudes related to illness or medications.^1,2 To foster these relationships, patients and their support systems should be comfortable asking questions and discussing concerns in a non-judging, non-blaming environment. ⁴ The provider can also ask open-ended questions to encourage dialogue; doing so can also help the provider to identify and clarify misconceptions about the illness or treatment and ultimately build trust and mutual respect. ⁴ Again, accessibility of patients to services via elements such as minimal waiting times to see providers or timely responses to questions or requests for when issues or concerns arise can also enhance the therapeutic relationship. ¹ Unfortunately, because various mental health services may have different goals and objectives, fragmentation of care may occur. Special attention should be paid to patients transitioning through varying levels of care (such as inpatient to outpatient and vice versa) to maintain the continuity of treatment due to the risk that the patient is lost to follow-up. ⁴ Attention to the patient can further be enhanced not just by informing the patient about their treatment but also by clearly communicating with other providers in the organizations or services that the patient is transitioning through. ⁴ This open communication allows providers to be aware of relevant information that can influence the current and future treatment plans for the patient.

Other interventions that have been studied include electronic reminders, financial incentives, and a “smart pill” device. ¹ A variety of smart pill containers have been studied and usually involve a pill dispenser that gives a reminder signal (e.g. flash or beep) and then subsequently uploads data when the dispenser is opened to a server that the provider can monitor.^16,17 Data can be sent to specific providers when a prespecified number of doses are missed. A small microchip can also be placed on pills in order to monitor ingestion when the dose is taken. ¹⁶ Electronic reminders have been shown to aid in adherence while the patient is receiving these alerts, although adherence may drop after the reminders are discontinued. Additionally, patients may develop “alert fatigue” wherein they get tired of receiving messages or alarms. ¹ Financial compensation in modest amounts has been studied, although this method is controversial and some providers have voiced ethical concerns. ¹⁸ One study by Priebe et al. ¹⁸ demonstrated that adherence went from a baseline of 69% and 67% in the financial incentive group and placebo group, respectively, to 85% and 71% in each group, respectively. Substance use disorders should also be evaluated and treatment strategies should be offered to patients suffering from substance use disorders. A full discussion of treatment options is outside the scope of this article. Additional information can be found at the Substance Abuse and Mental Health Services Administration website at www.samhsa.gov.

Discussion

Because medication nonadherence may arise from multiple factors, interventions should be multifactorial to be most effective. ¹ Unfortunately, some interventions that are feasible to implement may not be effective or not yet studied and the interventions that are effective may require a significant amount of time, personnel, or other resources. ⁷ Studies have shown some individual interventions may help (such as changing antipsychotics or engaging caregivers in treatment) with adherence, and combination approaches could yield a synergistic effect. ⁸

Studies of medication adherence in schizophrenia have many limitations, which include variable interpretations on the definition or “cutoffs” for medication adherence vs. nonadherence and the categorization of adherence as a binary outcome. The specified outcome measure used to evaluate adherence may be subject to measurement bias depending on the subjective or objective interpretation of data (e.g. patient reported adherence vs. pill counts are not always accurate).^2,10 The consequences of medication nonadherence may not occur immediately following a specific number or percentage of missed doses, which makes interpretation of an intervention’s efficacy difficult to characterize. Additionally, not only are some studies evaluating multifactorial interventions, but these studies may also evaluate medication adherence as a secondary outcome, which makes determination of which component of the intervention was responsible for the improved medication adherence difficult. ¹⁰ Essentially, the determination of a direct cause and effect relationship cannot be established in these situations. Overall, the design of these studies is heterogeneous which results in a variety of inconsistent, weakly supported conclusions. It is possible, that with improved study methods and design, more accurate effects of these interventions on medication adherence could be observed. Thus, the previously discussed strategies should not be deemed entirely ineffective until further studies can be done.

In 2013, European experts with extensive experience working with patients with schizophrenia published the “STAY” initiative, standing for “Six principles to improve Treatment Adherence in Your patients.” These principles include recognizing that patients with schizophrenia are at risk for nonadherence throughout their illness, fostering therapeutic alliances by creating a trusting environment where the patient does not perceive themselves as being judged for discussing problems with adherence, and individualizing treatment. ⁴ Additionally, involving and engaging family and caregivers (with patient consent), optimizing care effectiveness, and making sure the patient receives continuous care can improve treatment adherence. All these principles have been previously mentioned in the literature, and this text serves to reinforce the strategies to reduce the risk of medication nonadherence. ⁴

Conclusions

There appears to be no single strategy to manage and prevent medication partial adherence or nonadherence. Based on a review of the literature, interventions that appear to be most effective are multidimensional and address different factors that are specific to the patient. With patient consent, they should involve the patient’s support system, such as caregivers, family, and friends. The barriers to medication adherence will be different for each patient and may change over time. Thus, it is important for providers to acknowledge that patients will, from time to time, become partially adherent or nonadherent. The risk for nonadherence should continually be assessed and addressed to minimize the risk of rehospitalization, relapse, loss of function and an overall worse prognosis.