John M. Kane, MD

In the treatment of schizophrenia, as in any chronic medical illness, adherence with treatment remains a major obstacle. In a disease like schizophrenia, there is an even broader array of factors which can contribute to problems in adherence, as shown in the 

. At the same time, there are a number of important approaches to facilitating adherence, including: good therapeutic alliance; psychoeducation; minimization of adverse effects; convenient regimen; minimum number of appropriate/effective medications; psychosocial treatment; compliance therapy; and medication formulations tailored to specific patient needs.

Adherence is often a difficult problem with which clinicians have to deal, because on some level, it is narcissistic injury. After all of the effort and care that goes into making an appropriate diagnosis and developing the indicated treatment plan, it is difficult to fully and appropriately acknowledge the very real possibility that the patient will not follow through with the prescribed treatment. The same also applies equally to proscribed behaviors (e.g., drugs of abuse, unhealthy diet).

As a result of what may be cognitive dissonance on the part of clinicians, the consideration and ascertainment of nonadherence is given inadequate attention. In addition, it can be very difficult to accurately determine adherence levels. There are no ideal measures. Asking the patient is a first step, but the results can often be misleading. Patients might not be prepared to acknowledge or may not even realize the full extent of nonadherence. They could be concerned about hurting the doctors' feelings or angering the clinician. Given the extent of cognitive difficulties that many patients experience, remembering if and when medication was taken is not straightforward. Pill counts can be helpful, but are by no means consistently accurate. Blood levels can provide a qualitative assessment, but are impractical to do on a regular basis. An antipsychotic blood level could be informative when patients present to a hospital or emergency room in a state of psychotic relapse, yet this is rarely obtained.

Microelectronic monitoring devices have also been used. This technology involves a microchip placed in the cap of the medication bottle that records the exact date and time at which the bottle is opened. This may come closest to an accurate objective measure, but opening the bottle does not necessarily mean taking (or taking the correct amount of) medication. In addition, these devices are costly and can be easily lost or misplaced.

Although the methods to assess adherence are neither foolproof nor easy to apply routinely, their use has provided a wealth of data on the scope of the problem. It is clear that nonadherence or partial adherence is a major problem in schizophrenia. This is not confined to the minority of patients, but is something that affects the average patient.

In addition, numerous studies have shown a dramatic relationship between degrees of nonadherence and increasing levels of psychopathology or rates of rehospitalization (Valenstein et al., 2002). This underscores the fact that adherence is not an all-or-none phenomenon and that even partial adherence can have a clinically significant impact on outcome.

This is critical in highlighting one of the major problems in clinician's attitudes towards nonadherence. First, there is often an unrealistic sense that the clinician will be able to find out from the patient, or readily determine in some other way, if and when nonadherence is occurring. Second, physicians also believe they will be particularly able to tell when nonadherence is occurring to a point that would be cause for concern. There are two critical problems with these assumptions. Study after study has shown that clinicians grossly underestimate the degree of nonadherence found when it is measured concurrently by other strategies (Byerly et al., 2005). Second, there is no readily detectable or identifiable threshold when the degree of nonadherence becomes a risk for clinically significant consequences.

It is important to emphasize that most nonadherence among patients with schizophrenia is not explicit, willful medication refusal (Lacro et al., 2002). Typically, the patient is unable to take medication on a regular basis without necessarily having made a conscious decision to discontinue taking it.

There are a number of pharmacologic strategies that can be employed to facilitate adherence. Available formulations for atypical antipsychotic medications now include liquid preparations (risperidone [Risperdal]) and fast-dissolving oral preparations (olanzapine [Zydis], risperidone (Risperdal M-Tab]) as well as long-acting injectable formulations (risperidone [Risperdal Consta]).

Liquid and fast-dissolve formulations can be very helpful in hospital, day or partial hospital programs or any situation where someone (e.g., family member) can help administer and observe medication-taking. However, there have not been any large-scale formal studies to assess advantages in patient outcome. These formulations make it difficult for patients to "cheek" medication or otherwise avoid swallowing because they disintegrate within seconds in the mouth. Although these preparations can be very helpful in some settings, they do not necessarily facilitate adherence among patients who are not under close or regular supervision because in those situations remembering or actually taking medicine is not assured.

Long-acting injectable medications have been available for many years in the United States (e.g., fluphenazine [Modecate] and haloperidol [Haldol]). However, since the introduction of the second-generation antipsychotics, the use of long-acting injectable conventional antipsychotics has declined substantially. Even at the peak use of conventional, long-acting medication, utilization rates were considerably lower in the Unites States than in many European countries (Glazer and Kane, 1992).

Risperidone is the first second-generation medication to become available in a long-acting injectable formulation. Hopefully others will follow in the not-too-distant future. A long-acting injectable olanzapine is undergoing clinical trials. Long-acting risperidone relies on a different technology than traditional decanoates or enanthates. The risperidone molecule has no hydroxy group to esterify. Therefore, risperidone is embedded in a biodegradable polymer matrix (similar to biodegradable sutures) composed of lactic and glycolic acid. When the polymer is injected (via a water-based vehicle) into muscle, it gradually breaks down into carbon dioxide and water, and the active medication is released.

This formulation has now been shown to be safe and effective in both short- (Kane et al., 2003) and long-term trials (Fleischhacker et al., 2003) and is available in many countries outside the United States. Unfortunately, in my experience, there is a widespread lack of appreciation as to the potential benefits and a reluctance to encourage utilization of long-acting medication among a broad range of patients.

Two particular concerns are frequently expressed in discussions of utilization of long-acting injectable medication. First, some argue that long-acting injections do not assure adherence, as the patient may not take them. This is certainly true, but the critical difference is that there is no covert noncompliance (Young et al., 1986). If a patient misses an injection, nonadherence is immediately apparent and can be brought to the attention of all relevant parties. As has been demonstrated (Byerly et al., 2005), it is the covert nonadherence that is so common and worrisome (Fenton et al., 1997). The clinician is unaware that the patient is not receiving medication and, therefore, is not in a position to intervene to avoid a potential relapse.

A second concern is the issue of preference. Some argue that long-acting injectable medication should only be administered if the patient voices a preference for it. Few, if any, patients will articulate a preference for receiving medication by injection (most patients would prefer not to take medication at all). However, data suggest that among those patients who have had experience with long-acting injectable medication many prefer them to oral medication. Walburn et al. (2001) reviewed the literature on patient satisfaction with and attitude toward long-acting injectable antipsychotics. Five out of six studies comparing long-acting injectable with oral medication showed patient preference for the former. The critical issue is how the initial experience is achieved. It is important that clinicians take the time to provide a thorough explanation as to the potential benefits and risks of long-acting injectable medication. Needless to say, the clinical team must share the conviction that this approach is indicated. This process rarely occurs in one discussion, and it is necessary at times to ask the patient to just try one or two injections before dismissing it out of hand.

Many clinicians only consider long-acting medication after the patient has repeatedly demonstrated poor adherence with consequent relapse or exacerbation. Other clinicians believe that patients have to learn from repeated relapses that medication is critical. Unfortunately, a tremendous amount has been lost by that point, and we should be much more proactive in trying to avoid any and all relapses.

As long as thousands of avoidable relapses occur in a very serious illness, we should carefully consider what is at stake. The use of new formulations to help facilitate adherence is an important opportunity. We also hope that the pharmaceutical industry and academia can develop even better technological alternatives for facilitating appropriate medication delivery.

 Byerly M, Fisher R, Whatley K et al. (2005), A comparison of electronic monitoring vs. clinician rating of antipsychotic adherence in outpatients with schizophrenia. Psychiatry Res 133(2-3):129-133.
 

 Fenton W, Blyler C, Heinssen R (1997), Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull 23(4):637-751.
 

 Fleischhacker WW, Eerdekens M, Karcher K et al. (2003), Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. J Clin Psychiatry 64(10):1250-1257.
 

 Glazer W, Kane JW (1992), Depot neuroleptic therapy: an underutilized treatment option. J Clin Psychiatry 53(12):426-433 [see comment].
 

 Kane JM, Eerdekens, M, Lindenmayer JP et al. (2003), Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 160(6):1125-1132.
 

 Lacro J, Dunn L, Dolder C et al. (2002), Prevalence of and risk factors for medication non-adherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 63(10):892-909.
 

 Valenstein M, Copeland LA, Blow FC et al. (2002), Pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission. Med Care 40(8):630-639.
 

 Walburn J, Gray R, Gournay K et al. (2001), Systematic review of patient and nurse attitudes to depot antipsychotic medication. Br J Psychiatry 179:300-307 [see comment].
 

 Young J, Zonana H, Shepler L (1986), Medication noncompliance in schizophrenia: codification and update. Bull Am Acad Psychiatry Law 14(2):105-122.

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Compliance is a major issue in treatment of schizophrenia. How can compliance be improved, and can newer formulations make that compliance easier?

John M. Kane, MD

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