Optimizing treatment of schizophrenia to minimize relapse

One of the most important predictors of relapse in schizophrenia is medication status. Continuous prophylactic antipsychotic treatment reduces the risk of relapse by approximately 70% [1]. Therefore, on one hand, relapse may be caused by discontinuation of antipsychotic medication and there is a real need to optimize patients’ adherence in clinical practice. On the other hand, relapse may be related to a lack of efficacy of antipsychotic treatment that can be improved. However, we must keep in mind that there is no consensual operational criteria for defining ‘relapse’ and that there can be a bias when comparing the different long-term studies evaluating efficacy of antipsychotics. In this editorial we will highlight the factors contributing to partial compliance and propose strategies that could help to improve adherence to treatment and also how to improve the effectiveness of treatment in schizophrenic patients.

Only a third of schizophrenic patients can be considered to be fully compliant and another third to be partially compliant (this can be defined as patients reducing the prescribed dose by themselves or only taking their treatment from time to time) [2]. A study has demonstrated that even short medication gaps – including periods from 1 to 10 days – are associated with an increase in the risk of hospitalization [3]. Noncompliance with antipsychotic medication is often considered to be the most important factor related to relapse [4]. The most commonly identified patient-related factors influencing compliance are poor insight, cognitive impairment and comorbidity. Treatment-related issues that may affect compliance are primarily related to the efficacy and tolerability of antipsychotics. Environmental factors, such as the degree of social support available, are also accurate predictors of compliance. The principle physician-related factor is the therapeutic alliance between patients and healthcare professionals [2]. In this editorial we will describe different strategies that could improve these factors to optimize adherence to treatment in schizophrenic patients.

Evaluation and detection of partial compliance and intervening in time to prevent relapse is difficult. Clinicians have been shown to dramatically underestimate the level of noncompliance in patients with schizophrenia [5]. Multiple objective methods have been used to assess compliance with medication but the best measure was obtained with microelectronic monitoring systems, such as the Medication Event Monitoring System (MEMS) cap, which records the occurrence and time of each bottle opening. Results from the study reported that the rate of noncompliance as assessed by the MEMS cap was considerably higher (52%) than clinician rating (24%), self-report (2%) and pill count (25%) [5]. However, the use of electronic monitoring devices is largely restricted to research.

In clinical practice, detection of partial compliance could be improved using direct and indirect evaluation methods. Direct methods include the use of standardized interviews (one of the most interesting is the Rating of Medication Influences [ROMI] [6]) or measuring the plasma levels of medication (where this is possible). Indirect methods include self-reports of Drug Attitude Inventory (DAI-30) [7] or Brief Adherence Rating Scale (BARS) [8], and pill counts or patients’ agendas monitoring medication. In everyday practice, indirect methods seem to be useful and may induce an increase in patient compliance to treatment combined with a good therapeutic alliance.

It has been shown that there is a direct relationship between the ‘class’ of antipsychotic used and the level of insight. Although a lack of insight appears to be associated with partial compliance in schizophrenic patients, very few studies have investigated this link. However, different authors have shown the beneficial effects of second-generation antipsychotics on patients’ insight [2]. Schizophrenic patients present deficits in a large number of neurocognitive domains. Different studies have shown the superior efficacy of second-generation antipsychotics compared with conventional antipsychotics in improving neurocognitive impairment in schizophrenic patients [9]. Olanzapine and risperidone both significantly improve global cognitive functions but olanzapine may improve executive function and processing speed, while risperidone improves working memory and verbal learning [10].

Compared with conventional neuroleptics, second-generation antipsychotics demonstrate superiority in terms of tolerability and reduced risk of extrapyramidal symptoms [2]. Nevertheless, this favorable tolerability profile does not guarantee that patients will take medication over a long period. Recent studies (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study [CUtLASS], Antipsychotic Trials of Intervention Effectiveness [CATIE] study) demonstrated that patients treated with neuroleptics and second-generation antipsychotics have a similar level of adherence with a high discontinuation rate [11,12]. These findings may be due in part to the fact that second-generation agents induced another range of side effects including weight gain, impaired glucose tolerance and dyslipidemia.

In the CATIE study, olanzapine was associated with a discontinuation time twice as long as other second-generation antipsychotics. Another systematic review on the effectiveness of second-generation antipsychotics demonstrated that olanzapine may have a superiority over other second-generation antipsychotics in terms of time to treatment discontinuation and adherence, even if this drug is also associated with a higher level of metabolic side effects [13]. In a post hoc analysis of a study conducted in Germany on a sample of schizophrenic patients’ their compliance to antipsychotic medication was strongly associated with subjective wellbeing; further factors were clinical symptoms and side effects [14].

The formulation of antipsychotic treatment appears to play an important role. If the efficacy and side-effect profile of antipsychotics does not guarantee adherence, the use of long-acting injectable antipsychotics is a good alternative. Several studies have shown a rate of relapse significantly lower with depot medication compared with oral medication [15]. Long-acting injectable antipsychotics improve adherence by assuring medication delivery, providing more predictable and stable plasma levels, and using a lower effective dose is associated with fewer side effects [16]. Another advantage is that there is no risk of recurrence of symptoms later on, with the active antipsychotic agents being present for some time in the patient’s blood.

Second-generation antipsychotics are associated with better insight, improvement of neurocognitive impairment, and an improved neurological side-effect profile compared with conventional antipsychotics. A long-acting formulation is also a guarantee of better compliance. Consequently, the improvement of compliance begins with the choice of antipsychotic and its formulation.

A good therapeutic alliance between physician and patient is a predictor of better adherence to treatment. The progression from nonadherence to adherence in patients with positive therapeutic alliance appeared to be faster [17]. Within the alliance, the patient and physician have to determine together how to optimize medication. All guidelines for the treatment of schizophrenia recommend the inclusion of the patient in the medical decision process. This patient involvement in treatment planning corresponds to the shared decision-making model. A study in which this model was used found a trend toward fewer rehospitalizations in long-term treatment of schizophrenic patients [18].

It has been demonstrated that the combination of antipsychotic medication with a specifically adapted intervention program significantly reduces relapse and increases adherence to medication. These specific interventions include cognitive–behavioral therapy, medication monitoring, family intervention, psychoeducation and social work. In a two-part prospective study, a specific cognitive–behavioral therapy-based intervention (‘compliance therapy’) demonstrated a significant superiority in terms of compliance and time to relapse compared with patients treated as usual [19].

In conclusion, after evaluation and detection of partial or noncompliance, different strategies have to be employed to improve compliance. For the majority of patients, second-generation antipsychotic medication contributes to improving compliance. The combination of these compounds with a good therapeutic alliance and specific intervention programs significantly improves compliance.

Another factor associated with relapse is partial efficacy of the antipsychotic medication. The risk of relapse can also be reduced by optimizing the clinical efficacy of antipsychotic treatment. Two recent meta-analyses have compared second-generation antipsychotics with conventional neuroleptics and second-generation antipsychotics head-to-head in terms of efficacy and side-effect profile [20,21]. Only amisulpride, clozapine, olanzapine and risperidone are more effective than conventional neuroleptics, even for negative symptoms. Olanzapine, risperidone and sertindole are significantly superior in terms of prevention of relapse compared with neuroleptics (aripiprazole, amisulpride and clozapine demonstrate no significant difference). Another meta-analysis found a difference in efficacy between some second-generation antipsychotics. Using the Positive and Negative Symptom Scale (PANSS) total score as the criterion, olanzapine is superior to aripiprazole, quetiapine, risperidone and ziprasidone, and risperidone is more effective than quetiapine and ziprasidone. If there is a trend among these different meta-analyses for some drugs to be superior to others in terms of efficacy or side-effect profile, we must consider that there is no single antipsychotic that is best for all schizophrenic patients. Individualized treatment requires the use of a multitude of antipsychotic options [22].

Optimizing antipsychotic treatment using expert recommendations or guidelines based on evidence is beneficial for reducing the incidence of inappropriate care. Therefore, there is a need to improve their application in everyday practice by physicians. All guidelines recommend the use of second-generation antipsychotics as first-line agents for schizophrenic patients. However, first-generation antipsychotics are still prescribed for many patients. Physicians’ prescription habits appear to be specifically associated with the number of years of practice rather than with evidence-based medicine. A study on medical decision-making in antipsychotic drug choice for schizophrenia demonstrated that older physicians are up to five-times more likely to prescribe first-generation antipsychotics and that patient variables do not significantly influence treatment decisions [23]. Guidelines also recommend the use of depot antipsychotics for patients noncompliant with oral antipsychotics but physicians seem not to apply this recommendation in clinical practice [24].

There is a real gap between theory and practice in clinical care. Strengthening education and disseminating evidence-based guidelines should favor the adherence of physicians to guidelines and recommendations and favor optimizing treatment. Reducing relapse is one of the main therapeutic objectives for long-term treatment in schizophrenic patients. Partial compliance and partial efficacy of treatment are associated with an increased risk of relapse.

Compliance is a complex phenomenon that is related to many factors, such as insight, cognition, efficacy and medication side effects. Second-generation antipsychotics present advantages in these different domains. Long-acting antipsychotics can also provide guaranteed medication delivery. Intervention programs based on specifically adapted interventions combined with antipsychotic medication significantly decrease relapses and improve adherence to medication, functioning and social reintegration. The choice of the most suitable antipsychotic is recommended to be taken with the patient involved as much as possible in decision-making. The adherence of physicians to the recommendations and guidelines is also key for increasing the effectiveness of the treatment.

Financial & competing interests disclosure

Pierre-Michel Llorca is a consultant for Eli Lilly, Janssen, Bristol Myers Squibb and Sanofi-Aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.