Schizophrenia Treatment Challenges

Achieving treatment adherence in schizophrenia is a great challenge. The reasons for lack of treatment adherence are complex, vary considerably from patient to patient, and have been categorized as follows: patient-related factors (e.g., persecutory delusions, lack of insight, health care beliefs), medication-related factors (e.g., lack of efficacy, distressing side effects), environmental factors (e.g., caregiver support, cost) and clinician-related factors (e.g., therapeutic alliance) (Fenton et al., 1997).

Conventional antipsychotic medications such as haloperidol (Haldol) and fluphenazine (Permitil, Prolixin) used to treat schizophrenia have a number of untoward extrapyramidal side effects (EPS), including severe restlessness, akathisia, parkinsonism and tardive dyskinesia (Ames et al., 1996). Patients who take these medications can also feel depressed or anxious if they experience antipsychotic-induced dysphoria (Van Putten and May, 1978). Sexual side effects and cognitive side effects--sedation and inability to concentrate--also negatively impact a patient's adherence. The only three approved long-acting antipsychotics that may improve adherence--because they offer an assured delivery system--are the conventional depot forms: fluphenazine decanoate, fluphenazine ethanoate and haloperidol decanoate. Some evidence from the literature on these agents does suggest decreased risk of relapse, however, their noxious side effects may prevent a person from continuing with the bimonthly injections--thus negatively impacting treatment adherence.

The level of denial of illness among people suffering from schizophrenia is quite high. Research on the reasons why patients with schizophrenia do not take their medication has indicated that patients with grandiose delusions are most likely to reject medication so as to avoid confrontation with a reality that is not so glamorous. For example, it is much better to be lost in the delusion of being Jesus than to confront suboptimal living circumstances, such as a homeless shelter. This phenomenon was noted by the late Theodore Van Putten, M.D., and his colleagues who realized that patients who had a negative initial impression of medication would be likely to discontinue medication in the future (Van Putten, 1974). Other researchers built upon this work and developed a scale that measures patients' attitudes toward medications (Awad et al., 1995).

The newer antipsychotics, including clozapine (Clozaril), risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa) and ziprasidone (Geodon)--and now aripiprazole (Abilify)--are better tolerated by patients due to their more favorable EPS profile (Wirshing et al., 1997). Some agents can be associated with significant side effects such as weight gain, diabetes, dyslipidemia and sexual dysfunction (Burke et al., 1994; Wirshing et al., 1999; Wirshing et al., 2002).

It is estimated that approximately 50% of patients with schizophrenia do not take their prescribed medications as directed (Lacro et al., 2002). Of these patients, 65% to 75% will relapse within one year of discontinuation. Lack of medication adherence translates into a huge economic burden of relapse and rehospitalizations (Norquist and Regier, 1996). Despite their improved tolerability in terms of EPS and dysphoria, recent work suggests that adherence to the newer, gentler, second-generation antipsychotic medications does not appear to be much better than adherence with conventional agents. Dolder and colleagues (2002) demonstrated rates of compliant refills of conventional antipsychotic medications to be 50.1%, compared to 54.9% for the second-generation medications. A recent study at the U.S. Department of Veterans Affairs, Serious Mental Illness Treatment, Research and Evaluation Center utilized the Medication Possession Ratio (MPR), a ratio of the number of days' supply of antipsychotic medication each veteran had received by the number of days' supply they needed to receive to take their antipsychotic continuously, and found that 49,003 patients with schizophrenia with poor adherence (MPR<0.8) were 2.4 times more likely to be admitted to the hospital than patients with high MPRs (Valenstein et al., 2002). These studies indicate that other interventions may be necessary to enhance medication taking behaviors in people with severe mental illness.

Although clinicians may avoid some nonadherence to medication by adequately addressing patient concerns about side effects of medication, other strategies need to be implemented to better engage patients in their own health care. Providing patients with education about their mental and physical health empowers them to collaborate with their clinicians to make rational treatment decisions. Existing options to increase adherence include psychosocial skills training and targeted adherence training. The Community Re-Entry Program is a brief set of classes developed by Robert Liberman, M.D., and colleagues that consists of multi-modal videotapes, workbooks and live classes (Lieberman et al., 1998). Active community outreach can and should be utilized in patients who are reluctant to come in for medication (Miller et al., 1999).

Simple rules clinicians may want to try in their practice to assist their patients with medication adherence are:

• Keep dosing regimens simple.
• Avoid polypharmacy if possible.The more pills a person must remember to take, the greater the difficulty in remembering them.
• In patients who are treatment reluctant, de-emphasize the long-term nature of the treatment and break it down into smaller time periods (Weiden, 2003) (see Case Study).
• Keep on top of side-effect issues. It is relatively simple to keep a checklist of side effects in a patient waiting area to remind you and the patient why prescribed medication may be destined for the garbage. The Approaches to Schizophrenia Communication (ASC) is a fairly straightforward side-effect rating scale that is quick and easy to use (Weiden and Miller, 2001).
• Help educate family members about strategies to deal with nonadherence. Resources for families include I Am Not Sick, I Don't Need Help by Xavier Amador, Ph.D., and Anna-Lica Johanson, Ph.D. (2000; Vida Press), and Surviving Schizophrenia by E. Fuller Torrey, M.D. (2001; Quill). Amador and Johanson's book draws from a new application of cognitive-behavioral therapy/compliance therapy (Kemp et al., 1998).
• Support from other families dealing with this illness can be very helpful. Referrals to local chapters of support groups such as the National Alliance of the Mentally Ill are useful.

In the near future we may be able to dispense the first long-acting formulation of a second-generation medication--risperidone microspheres (Risperdal Consta). This drug has already been approved in several countries. Because relapse rates are less for risperidone compared to conventional agents, as demonstrated in a well-designed study by Csernansky and colleagues (2002), we envision that a guaranteed delivery system will further boost these encouraging results. Long-acting formulations of several other second-generation medications may also be available in the near future and are under study. Many patients may benefit from the availability of long-acting formulations, since the need to take daily oral medication will be obviated by--in the case of risperidone--bimonthly injections. Other possible formulations of long-acting, surgically implanted antipsychotic medications, such as the formulation of haloperidol being developed with the support of the National Alliance for Research on Schizophrenia and Depression, are also promising (Siegel et al., 2002). A surgically implantable formulation would be much like the contraceptive levonorgestrel (Norplant), which is implanted in women for long-term prevention of pregnancy.

References:

• References 1.Ames D, Wirshing WC, Marder SR (1996), Advances in antipsychotic pharmacotherapy: clozapine, risperidone, and beyond. Essential Psychopharmacol 1:5-26.
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