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19th Congress of the European College of Neuropsychopharmacology

Paris, France / September 16-20, 2006

With the availability of more effective antipsychotic treatments, criteria for successful treatment of schizophrenia have evolved to encompass improvement in both positive and negative symptoms, tolerability, functional outcome, sustained remission and subjective well-being and quality of life. “The most important change in the past decade is the long overdue consideration of the patient’s perspective. His/her own subjective well-being, often worsened by typical antipsychotics, was largely neglected [until the advent of the atypicals],” explained Dr. Dieter Naber, Department of Psychiatry and Psychotherapy, University of Hamburg, Germany.

It is now possible to measure subjective well-being and quality of life with several instruments, including the Short Form-36, World Health Organization (WHO) Quality of Life Questionnaire and several disease-specific instruments, such as the Neuroleptic Dysphoria Scale, Quality of Life Scale and Drug Response Index. Dr. Naber emphasized that the patient’s perspective should be measured because it is clinically meaningful.

Subjective well-being and quality of life correlate with depressive symptoms and somewhat with negative symptoms, Dr. Naber told delegates. Most important, however, is that these two areas are strongly related to compliance. He discussed findings from the three-year, prospective observational SOHO (Schizophrenia Outpatient Health Outcomes) study. Results indicated that the strongest predictor of two-year complete remission was early effective treatment with antipsychotic agents, emphasizing aggressive first-line treatment to achieve remission early in the course of disease. The same study showed that atypicals were 2.6 times more likely to achieve complete remission compared with conventional antipsychotics.

Dr. Naber stressed that without improvement in subjective well-being, the likelihood of response is low. All antipsychotic treatments have side effects and studies suggest that extrapyramidal side effects (EPS) are the most disturbing. Patients also find sexual side effects, weight gain and sedation bothersome. “The experience of side effects is individual and there is great intra-individual variability among patients regarding which side effects are most disturbing,” he noted.

Variability in Patient Factors

Patients treated with antipsychotic agents experience different treatment satisfaction, responses and outcomes. Pharmacologic factors also influence response; antipsychotic agents possess differences in receptor binding and pharmacotherapy delivery, stated Dr. Luca Pani, Institute of Biomedical Technologies, Milan, Italy.

The mathematical model of cluster analysis seeks to identify homogeneous factors in a heterogeneous population, such as patients with schizophrenia, he continued. In an attempt to match clinical features with pharmacologic features, cluster analysis has examined antipsychotic dosing patterns, predictors of neurological performance and morphological changes associated with disease progression, Dr. Pani explained.

Altering the pharmacokinetic profile can influence receptor interaction and binding profiles of antipsychotic agents, leading to a different treatment response and outcome. This recognition is the basis of developing extended-release and long-acting formulations of antipsychotic agents that have less variation in peak-to-trough levels and availability to receptors. Patient outcome could be improved by a sustained plasma concentration within a “therapeutic window,” maintenance of therapeutic effect and reduced incidence of side effects, Dr. Pani indicated, which should improve compliance.

The atypical antipsychotic paliperidone employs extended-release technology (OROS) to deliver the therapy over a 24-hour period, providing sustained dopamine 2 (D2) receptor occupancy within the therapeutic window. Dr. Pani noted that >65% D2 occupancy is needed for antipsychotic action and <80% D2 receptor occupancy is required for low levels of EPS.

Preclinical studies show that the same compounds in different formulations have different peak-to-trough levels and average plasma concentrations. Studies comparing long-acting injectable risperidone with oral risperidone and paliperidone immediate-release with paliperidone extended-release show pharmacokinetic differences that favour the new delivery systems, he told delegates. “Extended-release technology is becoming important in addressing delivery and compliance.”

Optimizing Treatment Efficacy

According to Dr. Samuel Keith, Chairman, Department of Psychiatry, University of New Mexico, Albuquerque, maintenance treatment with antipsychotic agents is necessary to optimize patient outcomes in schizophrenia, but a large proportion of patients fail to adhere to therapy. Five randomized controlled trials have shown that the risk of relapse is doubled when patients take intermittent therapy (i.e., take their medications on a “bad day”), he reported. A medication gap of one to 10 days in a one-year period increases the risk of relapse, Dr. Keith added.

Patient-related factors that compromise compliance include cognitive dysfunction and lack of insight, comorbidities and potential drug interactions. Medication-related factors include lack of efficacy, adverse events and complexity of dosing regimens. Dr. Keith emphasized that first-episode patients are at particular risk of partial compliance because they present with severe symptoms and have reduced insight and awareness. They are particularly susceptible to side effects, so they stop taking medications. “Side effects compromise compliance,” he noted.

CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness), a large “real-world” observational study, showed that a large proportion of patients with schizophrenia discontinue their medications within the first year of treatment. New formulations have been developed that may address current treatment challenges. These include long-acting injectable atypicals and extended-release tablets. Long-acting injectable formulations bypass the need for taking a medication every day and enable accurate monitoring of compliance. Extended-release formulations offer once-daily dosing with small fluctuations in peak-to-trough levels over 24 hours, reducing the likelihood of adverse events. Paliperidone does not undergo significant hepatic metabolism and is therefore unlikely to cause medication interactions, Dr. Keith noted.

A placebo-controlled trial of extended-release paliperidone presented by Dr. Michelle Kramer, Titusville, New Jersey, observed 205 patients with an acute episode of schizophrenia who were stabilized on open-label active treatment. In the double-blind phase when patients were randomized to either one of the study groups, active treatment demonstrated improved efficacy over placebo at the planned interim analysis at 43 days, when the study was terminated due to the improvement in the active arm. Patients taking the extended-release formulation had a recurrence rate of 22% vs. 52% on placebo. The time point at which 25% of placebo patients experienced a recurrence was 23 days vs. 68 days in those taking active treatment. The atypical was generally well tolerated, with treatment-emergent adverse events reported in 40% of patients in the active treatment cohort and in 35% of those on placebo. “Patients cannot get better if they are not compliant. We need to improve compliance and provide the safety and tolerability that patients deserve,” Dr. Keith concluded.

Functional Remission

Remission for six months is now a reasonable goal for patients with schizophrenia, according to criteria developed in 2005 (Andreasen et al. Am J Psychiatry 2005;162(3):441-9). Experts are setting new targets beyond remission that include recovery of cognition and functionality, reported Dr. Philip Gorwood, Department of Psychiatry, Louis Mourier Hospital and INSERM U675, Paris, France.

Dr. Gorwood noted that poor treatment outcomes are associated with increased ventricular volume in patients with schizophrenia and that early antipsychotic treatment has the potential to improve outcome and help patients achieve remission and recovery. According to patients’ perceptions and from a societal point of view, functional recovery is an important outcome measure in schizophrenia. Clinical instruments currently being used to measure function, such as Global Assessment of Functioning (GAF) and Social and Occupational Functional Assessment Scale (SOFAS), have limitations. A new instrument developed by Dr. Gorwood and colleagues is the Personal and Social Performance Scale (PSP), which promises to overcome some of the limitations of the older scales and have clinical utility. According to Dr. Gorwood, PSP is easier to use and more precise than the other instruments and a feasibility study of this new instrument is now being planned.

Summary

The availability of atypical antipsychotics has raised treatment expectations for patients with schizophrenia. Remission is now an attainable goal but achieving remission depends on compliance. Both patient and pharmacologic factors affect treatment response and compliance. New formulations of atypical agents have the potential to improve delivery and improve compliance. These formulations include long-acting injectables and extended-release agents.