Antipsychotic drug adherence in patients with schizophrenia is a major concern for nurses and treatment team members. Poor adherence to medication regimens has been associated with a persistence of psychotic symptoms, relapse, and hospitalization (Morken, Widen, & Grawe, 2008
). An interruption in antipsychotic drug treatment of only 1 to 10 days has been shown to double the risk of hospitalization in patients with schizophrenia (Weiden, Kozma, Grogg, & Locklear, 2004
). Even in first-episode patients, those with a long duration of untreated psychosis have a significantly reduced likelihood of achieving remission (Marshall et al., 2005
), whereas a shorter duration of untreated psychosis correlates with a better treatment response to antipsychotic drugs across measures of positive and negative symptoms, global psychopathology, and functional outcomes (Perkins, Gu, Boteva, & Lieberman, 2005
). Antipsychotic medication adherence has also been significantly associated with achieving recovery in patients with schizophrenia (Novick, Haro, Suarez, Vieta, & Naber, 2009
Long-acting injectable (LAI) antipsychotic drugs were developed with the intention of improving overall long-term management and treatment of schizophrenia (Kane & Garcia-Ribera, 2009). Additionally, LAI antipsychotic drugs provide patients with schizophrenia an alternative treatment choice to oral antipsychotic drugs, which can have a burdensome daily dosing regimen. Currently, five LAI antipsychotic drug treatments are approved for use in the United States: long-acting formulations of fluphenazine decanoate (Prolixin®) and haloperidol decanoate (Haldol® decanoate) (categorized as “typical” or first-generation antipsychotic drugs [FGAs]) and long-acting formulations of risperidone (Risperdal® Consta®), paliperidone palmitate (Invega® Sustenna®), and olanzapine pamoate (Zyprexa® Relprevv™) (classified as “atypical” or second-generation antipsychotic drugs [SGAs]). The Table lists approval dates, indications, and dosage/administration for these medications. Details on full prescribing information can be accessed through the Drugs@FDA website ( http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). Characteristics associated with the newer atypical antipsychotic drugs include efficacy against positive symptoms, some effect on negative symptoms, lower propensity to cause extrapyramidal side effects, tardive dyskinesia, and lower prolactin increases compared with older FGAs (Bridler & Umbricht, 2003).
Table: Long-Acting Injectable (LAI) Antipsychotic Drugs Approved for Use in the United States
The appropriate selection of a particular medication for a select patient is critical for health care professionals in the successful treatment of their patients. Although a detailed profiling of the clinical use of each LAI antipsychotic drug is beyond the scope of this article, a recent systematic review attempted to analyze factors related to prescriber choices and use of LAIs in daily clinical practice (Rossi, Frediani, Rossi, & Rossi, 2012). Data in the literature could not be statistically analyzed to identify an ideal LAI patient; however, the need to ensure treatment delivery, provide good symptom control, reduced hospitalization, and safety all influence the prescriber’s LAI choice. Perceptions of, and attitudes toward, LAIs, adherence to LAIs, and patient insight are also crucial factors. Overall, the authors note that prescribers seeking to improve the therapeutic alliance and facilitate informed decisions for patients and their relatives should consider LAIs.
The issue of improving adherence becomes a priority when the opportunity to influence the chronic and often progressive course of schizophrenia is considered. Mental health nurses, in particular, are in a key position to support improved adherence to antipsychotic drug therapy because nurses are consistently highly trusted in the community (Jones, 2011) and they educate, advise, and spend so much time interacting with patients and caregivers. As a result, education for nurses on adherence has been described as even more important than for other health care professionals (McCann, Boardman, Clark, & Lu, 2008). Understanding the reasons for improving adherence—and that outcomes may differ with LAI and oral therapies for schizophrenia—may facilitate nursing interventions to improve adherence in these patients.
Reasons for Early and Aggressive Treatment in Schizophrenia
Schizophrenia is a progressive disorder characterized by frequent relapses and clinical deterioration that requires early and aggressive treatment. The process of relapses, treatment failure, and incomplete recovery leads many patients to a debilitating, chronic course of illness (Tandon, Nasrallah, & Keshavan, 2009). Research indicates that progression is characterized by measurable brain volume deterioration and loss (Bonilha et al., 2008).
A structural brain study by Bonilha et al. (2008), using magnetic resonance imaging, found significant decreases in gray matter (i.e., brain matter containing the nerve cell bodies) volume in multiple brain regions of 14 unmedicated patients with schizophrenia compared with 13 control patients. Patients in this study also underwent neuropsychological testing so that researchers could assess potential correlations between these structural brain abnormalities and cognitive deficits. Findings from this study showed that gray matter atrophy, specifically in the prefrontal cortex (i.e., the brain region responsible for overall executive cognitive function, such as analyzing, synthesizing, organizing, planning, and behavioral output), was directly related to distinct deficits in mental flexibility and set-shifting ability (i.e., capability to change or “shift” cognitive strategy in response to changes in a given task) (Bonilha et al., 2008).
The unmedicated patients in Bonilha et al.’s (2008) study demonstrated a relationship between an abnormal prefrontal cortex and the decreased mental flexibility that is a symptom of schizophrenia. Mental flexibility is required for an individual to evaluate his or her own thinking, decisions, and behavior through processing of relevant information and evaluation of alternative positions for individuals to function appropriately. In addition, a majority of individuals with schizophrenia have poor “insight” (disease awareness) regarding the fact that they have a psychotic illness (American Psychiatric Association, 2000). Schizophrenia’s potential impact on insight and the associated loss of insight that can accompany exacerbations of schizophrenia (Kane & Garcia-Ribera, 2009) complicates long-term pharmacotherapy for patients. Poor insight was associated with missed medical appointments, and patients with poor insight are twice as likely not to adhere to medications (Novak-Grubic & Tavcar, 2002). These findings, considered along with findings that certain antipsychotic drugs may reduce brain density loss (van Haren et al., 2007), suggest that early and aggressive antipsychotic drug treatment can help prevent permanent disability.
Given the strong evidence from studies of the potentially degenerative effects of untreated schizophrenia on the brain, it is not surprising that Ken Duckworth, MD, the Medical Director of the National Alliance on Mental Illness, recently issued a statement to emphasize the importance of focusing on psychiatric care earlier in the disease process: “Prevention and early intervention are two areas that the field needs to develop. For too long, the field of psychiatry has been a downstream service. The delivery model hasn’t focused on serving people upstream” (Reyers, 2011, para. 4).
Addressing Issues of Adherence: Oral Versus LAI Formulations
Patients with first-episode schizophrenia experience multiple barriers to treatment; therefore, increasing adherence to antipsychotic drug therapy is particularly important in this group. In a study of 104 patients with first-episode schizophrenia who were treated with oral antipsychotic drugs (fluphenazine [Prolixin®], haloperidol [Haldol®], molindone [Moban®], loxapine [Loxitane®], or clozapine [Clozaril®]), individuals who initially responded and then discontinued antipsychotic drug therapy had a nearly five-fold increase in the risk of psychotic relapse (Robinson et al., 1999). Furthermore, patients who experienced a first relapse then had high rates of second and third psychotic relapses. Many of these patients continued to refuse ongoing maintenance antipsychotic drug therapy despite multiple psychotic relapses.
Based on their study findings, the investigators suggested new strategies be sought to improve medication adherence, especially in the early years of the illness (Robinson et al., 1999). This situation continues to be an issue: In a 2011 study of 2,588 patients who were diagnosed with schizophrenia and hospitalized for the first time, only 46% of patients continued to take their initial prescribed antipsychotic drug medication (haloperidol, perphenazine, zuclopenthixol, or risperidone) for more than 30 days following hospital discharge (Tiihonen et al., 2011). During a mean follow-up period of 2 years, 54% of patients in the study discontinued their initial antipsychotic medication (started at any time during follow up): 50.6% of these patients discontinued medication because of a change in antipsychotic prescription, 34.3% were due to discontinuation, 14.8% because of hospitalization, and the remaining 0.3% due to death. These findings suggested that discontinuation occurs for several reasons throughout treatment, but support the importance of adherence for patients early in the disease process.
Predictors of patient nonadherence to antipsychotic drug treatment have been identified recently (Lang et al., 2010) and underscore the issues of nonadherence in first-episode patients and early schizophrenia. Such predictors include: starting treatment for the first time versus being a continuing user; younger age (up to 44); a baseline substance abuse diagnosis; use of a mood stabilizer, antidepressant, anxiolytic, or anticholinergic agent at baseline; and treatment with LAI FGAs (versus oral FGAs only) (Figure). The finding that LAIs predict risk of nonadherence appears contrary to findings that LAI treatment is associated with a lower risk of discontinuation than oral formulations (Tiihonen et al., 2011). Lang et al. (2010) explained this by stating that patients in the LAI cohort were also newly starting antipsychotic drug treatment for schizophrenia. Although the study provides no information on the individual relationship of side effects and nonadherence, the patients in the study may have experienced side effects associated with FGAs as a class (i.e., extrapyramidal side effects) and this needs further investigation. Notably, adherence was significantly greater in patients taking LAI SGAs versus oral SGAs alone and among patients taking LAI SGAs and LAI FGAs (Lang et al., 2010).
Figure. Predictors of nonadherence in patients with schizophrenia treated with antipsychotic medications. Nonadherence was defined as a medication possession ratio < 0.8. Note. OR = odds ratio; CI = confidence interval.From “Medication Adherence and Hospitalization Among Patients With Schizophrenia Treated With Antipsychotics,” by K. Lang et al., 2010, Psychiatric Services, 61, p. 1244. Reprinted with permission from Psychiatric Services (© 2010), American Psychiatric Association.
LAI antipsychotic medications have been associated with better treatment outcomes in patients with schizophrenia, reducing relapse rates by approximately 30% (Leucht et al., 2011), an effect considered mostly due to improved treatment adherence. The products in the Leucht et al. study included haloperidol decanoate, fluphenazine decanoate, fluphenazine enanthate, zuclopenthixol, and risperidone. In patients with schizophrenia and hospitalized for the first time, oral antipsychotic drug use was nearly three times more likely to lead to rehospitalization than LAI formulations of the same compound (Tiihonen et al., 2011). Moreover, combined results from multiple studies have shown that switching from an oral FGA to an LAI FGA (e.g., fluphenazine decanoate, fluphenazine enanthate) reduced the time that patients with schizophrenia spent hospitalized (Haddad, Taylor, & Niaz, 2009).
A study comparing 97 patients with schizophrenia who were treated with LAI antipsychotic drugs and 202 patients treated with the equivalent oral formulations (data from a larger nonrandomized study) found that patients treated with LAI antipsychotic drugs (haloperidol decanoate or fluphenazine decanoate) remained on their medications longer than with oral formulations (Zhu et al., 2008). Patients treated with the LAI formulations were also twice as likely to continue treatment (Zhu et al., 2008). The impact of LAI antipsychotic drugs was also examined in 147 patients (65 and younger) with schizophrenia comparing 6 months pre- and 6 months postinitiation of LAIs (Peng, Ascher-Svanum, Faries, Conley, & Schuh, 2011). LAI formulations of either risperidone, haloperidol, or fluphenazine increased treatment adherence, which was measured by a mean increase in the medication possession ratio (the proportion of days that a patient possesses antipsychotic medication throughout each 180-day period of observation), from 36.8% to 60.0% and resulted in both a decline in hospitalizations from a mean of 49.7% to 22.4% and a decrease in the duration of hospital stay from a mean of 7.3 to 4.7 days (Peng et al., 2011).
Despite evidence that LAIs can improve treatment adherence and, hence, can prevent the negative consequences that follow nonadherence (Kane & Garcia-Ribera, 2009), LAI antipsychotic medication use is not optimized. In the United States, prescription rates for LAIs have been estimated at only 8% of schizophrenia patients receiving treatment (estimated from the IMS Multinational Integrated Data Analysis System database, Q3 2011–Q2 2012 [Ray Lansigan, personal communication, February 13, 2013]). Underuse of LAI antipsychotic drug treatment in the United States could be attributable to a variety of access barriers. For example, patients undergoing LAI antipsychotic drug treatment must have the intramuscular injection administered by a nurse, physician, specially trained pharmacist, or other trained health care provider on a regular basis (typically every 2 to 4 weeks) and therefore require reliable access to transportation to reach their community mental health center. Additionally, although Medicaid and the majority of Medicare Part D plans cover most LAI treatment, patients who lack medical benefits or the resources to pay for injections are also at a treatment disadvantage.
How Nursing Interventions Aid in Adherence
One advantage of LAI antipsychotic drug treatment is the regular, repeated contact that the patients have with the nursing staff while undergoing treatment (Haddad et al., 2009). Nurses can help patients better understand the importance of adhering to treatment and will know precisely when a patient fails to return for the next injection and discontinues treatment. In a study by García et al. (2010) exploring this point, 160 mental health nurse practitioners answered an extensive questionnaire about their opinions and understanding regarding treatment adherence in patients with schizophrenia. The consensus was that nonadherence to medication in patients with schizophrenia was the primary cause of psychotic relapse (García et al., 2010). Responses highlighted important strategies to help manage and improve adherence in patients with schizophrenia who are receiving LAI antipsychotic drugs (medications not specified). Key strategies for preparing patients for treatment with LAI antipsychotic medications include: (a) providing background information to the patient regarding choice of medication and method of administration; (b) providing counting techniques to track injection dates; (c) reviewing the purpose and mechanism of action of the drug; (d) discussing the advantages of the method of drug administration chosen; and (e) emphasizing the potential adverse consequences of treatment nonadherence. From the survey results, other tactics critical to managing LAI antipsychotic drug treatment included assessing the therapeutic effects, helping the patient and any caregivers understand the benefits of sufficiently adhering to treatment, monitoring for adverse events, and managing appointments for medication administration (García et al., 2010).
Adherence to antipsychotic drug treatment plays a crucial role in minimizing symptoms, preventing psychotic relapse, reducing hospitalizations, and improving outcomes in patients with schizophrenia. As such, nurses, case managers, and members of the treatment team directly impact improving adherence to antipsychotic drug therapy by considering and proposing multiple treatment options, including LAIs, which continues to be a critical component in the care of patients with schizophrenia. Mental health nurses, in particular, are important personnel who can best use effective strategies to support high adherence to antipsychotic drug treatment, leading to improved outcomes for patients with schizophrenia.
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Long-Acting Injectable (LAI) Antipsychotic Drugs Approved for Use in the United Statesa
||U.S. FDA Approval Date
||Dosage and Administration
|Fluphenazine decanoate (Prolixin®)
||June 20, 1972
||Management of patients requiring prolonged parenteral neuroleptic therapy (e.g., chronic schizophrenia)
||12.5 to 25 mg (0.5 to 1 mL) may be given to initiate therapy. Subsequent injections and the dosage interval are determined in accordance with the patient’s response.
|Haloperidol decanoate (Haldol® decanoate)
||January 14, 1986
||10 to 20 times the previous daily dose in oral haloperidol equivalents monthly or every 4 weeks.
|Risperidone (Risperdal® Consta®)
||October 29, 2003
- Bipolar I disorder maintenance treatment: monotherapy or as adjunctive to lithium or valproate
|25 mg every 2 weeks. Patients not responding to 25 mg may benefit from a higher dose of 37.5 or 50 mg.
|Paliperidone palmitate (Invega® Sustenna®)
||July 31, 2009
||Initiate dosing with 234 mg on treatment Day 1 and 156 mg 1 week later. Recommended monthly maintenance dose is 117 mg. Some patients may benefit from lower or higher maintenance doses within the additional available strengths (39, 78, 156, and 234 mg).
|Olanzapine pamoate (Zyprexa® Relprevv™)
||December 11, 2009
||150 mg every 2 weeks, 300 mg every 4 weeks, 210 mg every 2 weeks, 405 mg every 4 weeks, or 300 mg every 2 weeks.