Thinking Outside the Box: A Long-Term View of Antipsychotic Therapy

At an industry-sponsored symposium held October 19, 2002, in conjunction with the American College of Clinical Pharmacy’s Annual Meeting, three speakers addressed medication compliance issues, new advances in long-acting therapy and recommendations for improving treatment outcomes for patients with schizophrenia.

This program was supported by an unrestricted educational grant from Janssen Pharmaceutica Products, LP.

Issues in Treatment Adherence in Patients with Schizophrenia

“Compliance and partial compliance are issues in all chronic illnesses, but they present a greater issue in individuals with severe mental disorders, based on the nature of the illnesses and lack of insight,” said M. Lynn Crismon, PharmD, professor, Divisions of Pharmacy Practice, Pharmacy Administration, Pharmacotherapy, and the Center for Pharmacoeconomics Studies, University of Texas College of Pharmacy, Austin.

While psychiatrists often over-estimate patient compliance, various studies demonstrate that only a minority of patients are either fully compliant or fully noncompliant. “I think it is safe to say that up to 70% of patients with chronic mental disorders are only partially compliant with their medication regimens,” Dr. Crismon said.

Partial medical compliance represents a major hurdle in treatment outcomes, particularly for chronic illnesses including mental illness. Research on the impact of partial compliance among schizophrenia patients has demonstrated that, over time, missed doses of medication often result in a continuing deterioration that starts with demoralization and loss of confidence, moves on to job loss and family discord, and ends in rehospitalization and danger towards oneself and others.

A European study by Johnson indicated that medication discontinuation resulted in a range of social consequences, including lower levels of satisfactory work adjustment, job changes, and anti-social behavior (Acta Psychiatr Scand 1983,67: 339-352).

Studies conducted by Cramer and Rosenheck documented poor compliance among patients with chronic, asymptomatic disorders; complex treatment regimens; adverse effects; and social dysfunction. High levels of compliance were associated with patient satisfaction, continuity of care, and patient acceptance of the need for treatment (Psych Serv. 1998,49:196-201).

Other studies have identified a variety of patient, medication, environmental and clinician-related factors that can contribute to poor compliance in individuals with schizophrenia. Con-siderations include patients’ lack of insight, poor social support, multiple medications, and adverse side effects. Research on compliance among patients with bipolar disorder conducted by Keck and colleagues at the University of Cincinnati demonstrated 49% compliance, 31% noncompliance, and 20% partial compliance, and indicated that “denial of illness” was the leading reason (in 50% of patients) for noncompliance, while “side effects from mood stabilizers” was second (Psychopharmacol Bull 1997;33:87-91).

Various studies also indicate higher compliance among patients who stay with their original medication, have a favorable initial response to typical antipsychotics, score high on therapeutic alliance with their clinicians, and take clozapine. Recently published research points to somewhat higher adherence (as indicated by prescription refill rates) among patients on atypical, versus traditional agents (Am J Psychiatry 2002; 159:103-108). Additionally, a 1986 research review conducted by Young and colleagues discovered higher compliance with depot medications than with oral medications.

According to Dr. Crismon, patients’ concerns about medications frequently differ from psychiatrists’ concerns. A study conducted by Hellewell and Cantillon suggested that while EPS side effects were of low concern to psychiatrists, schizophrenia patients cited side effects as their number one consideration, and their main reason for noncompliance (Presentation, European College of Neuropsychopharmacology; Paris, 10/31-11/4/98; Abstract #P.2109). Side effects that may be associated with decreased compliance in schizophrenics include: EPS, dysphoric response, excessive drowsiness, cognitive impairment, sexual dysfunction, and weight gain. Dr. Crismon suggested that a patient’s perceptions of side effects or “patient burden” is probably more likely to relate to compliance than objective measures of side effects.

Dr. Crismon cautioned that limitations of compliance monitoring must be kept in mind when interpreting results of various compliance studies. Studies of compliance with psychotropic medications frequently rely on patient reports and physician interviews, and may therefore over-state results versus studies of compliance with medications for general medical disorders, where more invasive and precise means of compliance measuring are used (e.g., serum levels, pill counts, and so forth). Moreover, several studies of compliance with antipsychotic medication indicate higher default rates over time, illustrating the importance of conducting long-term versus short-term research of patient compliance.

Several methods have been proposed to enhance compliance, including more actively engaging the patient in treatment, enhancing the therapeutic alliance, and implementing psychoeducational programs. “We have a long way to go in terms of improving compliance in individuals with schizophrenia and all chronic illnesses,” Dr. Crismon acknowledged. He concluded that additional research is necessary, both to better understand the factors that relate to noncompliance and to develop methods to enhance compliance.

Technological Advance: The First Long-Acting Atypical Antipsychotic

“The development of long-acting depot formulations of antipsychotics and the advent of atypical antipsychotics were both important technological advances aimed at improving outcomes in schizophrenia treatment. Now, a new dosage form “combines the assured delivery benefits of depot injections with the benefits of atypical or second generation antipsychotics,” according to Raymond C. Love, PharmD, vice-chair, department of Pharmacy Practice and Science; professor, department of Psychiatry, School of Pharmacy, University of Maryland, Baltimore.

Since their advent, long-acting intramuscular depot (i.e., injectable esterified) formulations of typical antipsychotics have been associated with several advantages over conventional oral treatments. Benefits include: reduced re-hospitalization rates, shorter hospital stays, greater confidence in medication availability (e.g., more stable and predictable plasma levels), and patient convenience (freedom from daily pill-taking). In addition, frequent contact with the treatment team (necessary to obtain injections) appears to improve outcomes, and allows for early intervention for noncompliance. However, research by Hogarty and colleagues indicates that, while depot medications reduced relapse from the 75% levels seen with oral medications, they were still associated with a nearly 30% relapse rate (Arch Gen Psychiatry 1979, 36:1283- 1294).

A second series of advances aimed at improving patient compliance was the introduction of new, more effective and tolerable “second generation” antipsychotics. These preparations are associated with fewer EPS side effects, and improved efficacy (e.g., superior cognition, improvement of negative symptoms of schizophrenia). A recent study by Csemansky and colleagues demonstrated that patients treated with the second generation antipsychotic, oral risperidone, had significantly less likelihood of relapse than patients on haloperidol, the traditional “gold standard” for treating schizophrenia (N Engl J Med 2002; 246:16-22). Based on results of this research, the FDA now permits “second generation” antipsychotics to carry an indication for delaying relapse.

Initial attempts to develop injectable, long-acting second generation antipsychotics were met with difficulty, based on the newer agents’ lack of a hydroxyl group for esterification. However, researchers at Janssen Pharmaceutica Products have recently succeeded in adapting Medisorb technology (based on medically approved polymers of biologically present acids such as lactic and glycolic acids), to develop a long-acting, depot form of risperidone.

Company studies indicate that active moiety of this sustained-release preparation is greatest between weeks 3.5 and 6, with a peak occurring at 4 – 41/2 weeks. To account for this initial delay in delivery, several weeks of oral medication must be administered concurrently with the first dose. Preliminary evidence indicates dose conversions (based on similar AUC ratios) of 2 mg oral to 25 mg long-acting and four mg oral to 50 mg long-acting. Despite AUC similarities, there is evidence of dramatic differences in peak concentrations between oral and long-acting preparations. Lower peaks for the long-acting preparations may result in an improved side effect profile for these drugs. Additionally, reduction in fluctuation in serum levels is apparent with the injectable versus oral medication. Pharmacokinetic data also imply the potential for less than biweekly dosing, based on prolonged peaks of up to
7 weeks. (Table 1)

Clinical evidence from a randomized, double-blind study of 400 patients conducted by Kane indicated significant improvements in PANSS positive symptom scores, along with smaller improvements in PANSS negative symptom scores versus placebo at 12 weeks on 25, 50 and 75 mg doses of long-acting risperidone injection (Presentation, Annual Meeting APA Institute on Psychiatric Services, Oct 10-14, 2001; Orlando, FL). Similar improvements were seen in a one-year international open label trial of over 700 stable patients given biweekly injections of risperidone. While all doses provided continued improvement in target symptoms, most dramatic improvement occurred at the lowest doses.

Data from the short-term trial indicate that long-acting risperidone does not appear to cause the degree of weight gain associated with other second-generation antipsychotics, and is associated with either no change or slight improvement in extrapyramidal symptoms.

Data from the long-term trial indicate: improvement (in all dosage ranges) on all movement disorder side effects, including dyskinesia, that often appear with antipsychotics; an absence of consistent changes in laboratory values or in ECG; mean increase in body weight of 5 pounds; and minimal injection site pain.

Research conducted by Chue and colleagues demonstrated that long-acting risperidone surpassed older medications with regard to re-hospitalization rates (Presentation, Xxiii CINP Congress; June 23-27,2002; Montreal). Moreover, results from an international study of patient drug attitudes (DAI) conducted by Freyberger and colleagues indicated a range of positive attitudes following 12 weeks of long-acting risperidone (Annual Meeting of the CINP; June 23-27, 2002; Montreal, Canada).

Dr. Love concluded that “long-acting risperidone is a promising agent, with demonstrated efficacy, safety and improved tolerability in studies up to a year in duration.” Other significant benefits associated with its sustained efficacy include allowance for missed doses and greater patient convenience associated with less frequent dosing.

Increasing the Utilization of Long-Acting Antipsychotics: How Do We Get There from Here?

“We now know that we can treat schizophrenic patients well enough that many will assume the tasks of daily living,” said Larry Ereshefsky, PharmD, professor of pharmacology and psychiatry, University of Texas Health Science Center, San Antonio; Romeo Barchand Texas Regents professor, College of Pharmacy, University of Texas, Austin. Yet, according to Dr. Ereshefsky, high levels of both partial and noncompliance with drug therapy, along with current deficiencies in the U.S. healthcare system, are currently compromising outcomes for many schizophrenia patients.

Several positive interventions have been introduced in the treatment of schizophrenia in recent years. The introduction of depot therapy offers significant advantages over oral regimens, including the potential for increased rates of compliance.

However, at present, less than 10% of patients in the United States receive prescriptions for depot medications. Dr. Ereshefsky hypothesized that depot meds have been less widely accepted in the United States than in Europe and other regions for several reasons. He cited the presence of fewer available depot agents than in European countries, poor efficacy and tolerability profiles of available depot medications, inadequate dosing and conversion guidelines, and unclearly defined target populations. Other contributing factors mentioned included the stigma associated with injectable drugs, persistent concerns about EPS, and an emphasis on staff convenience versus patient needs. Dr. Ereshefsky proposed that the recent development of a new, long-acting atypical antipsychotic formulation of risperidone will likely be a catalyst for positive changes in treatment protocol.

Dr. Ereshefsky discussed how cognitive deficits associated with schizophrenia often impact a patient’s ability to comply with medications and adhere to routines of daily living. In the Cognitive Analytic Therapy (CAT) psychosocial intervention program, recently implemented in San Antonio by Ereshefsky and colleagues, healthcare providers set up prompts (e.g., alarm clocks, bathroom mirror instructions, and closet organizers) within a patient’s home to cue the patient to perform dressing, hygiene and medication routines. Preliminary results indicate significantly lower relapse and symptom exacerbation rates in CAT-treated patients. An ongoing five-year NIMH study will determine the relative importance of environmental manipulation versus targeted medication adherence strategies in improving patient outcomes.

Dr. Ereshefsky suggested that stigma associated with mental illness in the U.S. (in the minds of patients and the general public) represents another significant treatment obstacle. Research conducted by Sirey and colleagues demonstrated that patients with higher levels of perceived stigma were significantly more likely to be noncompliant with medication regimens (Psychiatr Serv 2001;52:1615-1620).

According to Dr. Ereshefsky, results from several studies demonstrate that the U.S. healthcare system often fails to provide mentally ill patients with effective treatment alliances that provide consistent, timely care and adequate patient follow-up. A study of the California Medicaid system conducted by McCombs and colleagues indicated that 24% of schizophrenia patients experienced delays in treatment initiation of at least 30 days and only 12% achieved one year of uninterrupted treatment (J Clin Psychiatry 1999;60:5-11). Moreover, according to Dr. Ereshefsky, inadequate duration of hospital stays can confound the effects of drug treatment and contribute to poor outcomes. Studies indicate that stays of longer than 30 days (versus the typical stay of 15 days or less) are associated with lower incidence of relapse.

Dr. Ereshefsky suggested that a redesign of the U.S. healthcare system could help pave the way toward improved patient care for the mentally ill. He recommended longer hospital stays, more effective use of information technologies, redesigned depot clinics that would “humanize” the delivery of depot meds, and an enhanced role for pharmacists as part of mental healthcare teams that would provide individualized, continuous treatment alliances to sustain healthy behavior. “We must provide rehabilitation and remediative therapies, for example, structuring environments as in the CAT study,” Dr. Ereshefsky said. He also suggested borrowing successful practices prevalent in Europe, including the use (in the UK) of “advanced directives,” whereby patients sign over permission to receive medication against their will in the event of illness. And, to eliminate stigma associated with depot treatment, Dr. Ereshefsky suggested attempting to shift patient attitudes to those prevalent in Europe and Japan, where injectable therapy is viewed as more convenient and powerful than oral therapy.

Dr. Ereshefsky emphasized the need to properly educate patients to allow them to participate (whenever possible) in their treatment decisions. “Interest and concern for patients’ well-being and the belief that medications are appropriate should be conveyed via clear and open communication,” he said. Dr. Ereshefsky proposed that effective interventions to enhance compliance will be as important as the introduction of breakthrough agents. “Depot drugs as part of a system of care could be a breakthrough,” he said. “We need to convey to a patient that long-term treatment will change your life, and that the only way to get there is to insure you take meds regularly, and depot is the best way to ensure that.”