Pierre Chue

Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets

A double-blind study of long-acting injectable risperidone and oral risperidone tablets was conducted in 640 patients with schizophrenia. All patients received flexible doses of 1-6 mg of oral risperidone for 8 weeks. Doses were stable during weeks 5-8. At the end of week 8, symptomatically stable patients were randomly assigned to receive long-acting risperidone (active injections, dummy oral) or continued oral risperidone (dummy injections, active oral) for 12 weeks. Significant improvements were demonstrated from baseline to endpoint in Positive and Negative Syndrome Scale (PANSS) total (P<0.001) and factor scores (P<0.05) in both groups. According to a noninferiority analysis, the two treatments showed comparable efficacy in total PANSS scores over the short-term. No unexpected adverse events were recorded. The findings indicate that symptomatically stable patients can be safely switched from oral risperidone to long-acting injectable risperidone without compromising efficacy.

Drug metabolism and atypical antipsychotics.

The introduction of the atypical antipsychotics clozapine, risperidone, olanzapine, quetiapine and sertindole for the treatment of schizophrenia has coincided with an increased awareness of the potential of drug-drug interactions, particularly involving the cytochrome P450 (CYP) enzymes. The current literature describing the pharmacokinetics of the metabolism of these agents, including their potential to influence the metabolism of other medications, is reviewed. Clozapine appears to be metabolized primarily by CYP1A2 and CYP3A4, with additional contributions by CYP2C19 and CYP2D6. In addition, clozapine may inhibit the activity of CYP2C9 and CYP2C19, and induce CYP1A, CYP2B and CYP3A. Risperidone is metabolized by CYP2D6, and possibly CYP3A4. In vitro data indicate that olanzapine is metabolized by CYP1A2 and CYP2D6. Quetiapine is metabolised by CYP3A4 and sertindole by CYP2D6. There is, however, a general paucity of in vivo data regarding the metabolism of the atypical antipsychotics, indicating a need for further research in this area.

The relationship between patient satisfaction and treatment outcomes in schizophrenia

In recent years, the goals of treatment in schizophrenia have evolved from objective improvements in psychotic symptoms to encompass patient-related factors such as subjective response and quality of life. In order to examine factors that influence patient satisfaction with treatment, subjective quality of life and subjective response to treatment, two literature searches were performed using PubMed. The first searched for articles of any kind with no time limits using the search parameters ‘schizophrenia AND satisfaction’, ‘antipsychotic AND satisfaction’, ‘schizophrenia AND subjective response’, ‘schizophrenia AND therapeutic alliance’, ‘schizophrenia AND psychosocial OR psychoeducation’. Secondly, PubMed was searched between January 1990 and December 2005 using the key words ‘satisfaction’, ‘subjective response’ and ‘quality of life’ in combination with an array of atypical agents. Results demonstrated that patient satisfaction with antipsychotic therapy is influenced by multiple factors. The most frequently reported reasons for dissatisfaction include drug side effects, lack of involvement in treatment planning or decision-making and lack of involvement of family members in the care plan. The majority of studies have demonstrated that the atypical antipsychotics are associated with significant improvements in quality of life, functional status and patient satisfaction compared with conventional agents. The therapeutic alliance is key to achieving optimal outcomes, by providing information and education to meet patients’ needs, while facilitating compliance with drug therapy to ensure better clinical outcomes. A long-acting atypical antipsychotic that can ensure medication delivery will provide a platform for psychosocial interventions, and thus may further increase patient satisfaction and, ultimately, improve long-term outcomes in schizophrenia.

Long-acting formulations of atypical antipsychotics: time to reconsider when to introduce depot antipsychotics.

The current availability of a long-acting injectable formulation of risperidone and the potential future availability of long-acting formulations of other atypical antipsychotics (such as paliperidone) should prompt a reconsideration of at what stage in the treatment of schizophrenia such long-acting agents should be introduced. At present, long-acting formulations, particularly of conventional antipsychotics (depots), are usually reserved for patients with chronic schizophrenia who are at high-risk of noncompliance. Recent and increasing data from other patient groups, such as those with first-episode psychosis, suggest that long-acting risperidone is associated with good efficacy and tolerability leading to high patient acceptance, and treatment continuation rates that are greater than with oral antipsychotics. The benefits of an atypical antipsychotic coupled with the assurance of medication delivery in the form of a long-acting injection imply that these novel formulations should be considered in first-episode patients, for whom optimal outcome is frequently compromised by early treatment discontinuation and poor adherence.

Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options

The negative symptoms of schizophrenia represent an impairment of normal emotional responses, thought processes and behaviors, and include blunting or flattening of affect, alogia/aprosody, avolition/apathy, anhedonia, and asociality. Negative symptoms contribute to a reduced quality of life, increased functional disability, increased burden of illness, and poorer long-term outcomes, to a greater degree than positive symptoms. Primary negative symptoms are prominent and persistent in up to 26% of patients with schizophrenia, and they are estimated to occur in up to 58% of outpatients at any given time. Negative symptoms respond less well to medications than positive symptoms, and to date treatment options for negative symptoms have been limited, with no accepted standard treatment. Modest benefits have been reported with a variety of different agents, including second-generation antipsychotics and add-on therapy with antidepressants and other pharmacological classes. Recent clinical research focusing on negative symptoms target novel biological systems, such as glutamatergic neurotransmission. Different approaches include: enhancing N-methyl-D-aspartate receptor function with agents that bind directly to the glycine ligand site or with glycine reuptake inhibitors; influencing the metabotropic glutamate receptor (mGluR2/3) with positive allosteric modulators; and stimulating nicotinic acetylcholine receptors. In conclusion, the lack of clearly efficacious pharmacological treatments for the management of negative symptoms represents a significant unmet need, especially considering the importance of these symptoms on patient outcomes. Hence, further research to identify and characterize novel pharmacological treatments for negative symptoms is greatly needed.

Investigation of Turner syndrome in schizophrenia.

Both Turner syndrome and schizophrenia are relatively infrequent conditions. Consequently, individuals having both illnesses are rare. Previous reviews of sex chromosome abnormalities in schizophrenia have focused primarily on the presence of supernumerary X-chromosomes. After identifying two female patients with schizophrenia and Turner syndrome, we reevaluated the available literature that survey female schizophrenics for the presence of chromosomal abnormalities. Eleven patients with Turner syndrome were identified among 6,483 females with schizophrenia in non-case-report studies. These survey results indicate that Turner syndrome occurs approximately three-fold more frequently in schizophrenic females than in the general female population (P < 0.02). Including 6 other case reports and our 2 cases, a total of 19 females with both schizophrenia and Turner syndrome were reported. Interestingly, whereas most Turner syndrome patients have the 45,X karyotype, the majority (18/19) of women with both illnesses have a mosaic karyotype (P < 0.0002). Given the potential role of genes on the X-chromosome in the pathogenesis of schizophrenia, the study of unique populations with abnormalities in this chromosome, such as women with Turner syndrome, may offer clues into this illness.

Acceptability and disintegration rates of orally disintegrating risperidone tablets in patients with schizophrenia or schizoaffective disorder.

Objective: To investigate the disintegration profile, acceptability, and tolerability of orally disintegrating risperidone tablets in patients with schizophrenia or schizoaffective disorder. Method: Ten patients stable for at least 10 days on monotherapy with oral risperidone 2 mg to 4 mg taken once daily were switched for 7 days to an equivalent dosage of orally disintegrating risperidone. Visual assessments for time to initial and complete disintegration were collected at each visit. Clinical Global Impression of Severity scores were collected at baseline and at the last visit. Patient acceptance of the new formulation, rated according to a visual analog scale, was obtained at the last visit. Results: All patients maintained stable clinical status. Mean time to initial disintegration was 5.1 seconds, SD 0.8, and mean time to complete disintegration was 29.4 seconds, SD 18.4. The formulation was rated as very acceptable. Adverse events were reported by 5 patients; all were mild. Conclusion: The orally disintegrating risperidone tablets were well tolerated and rated as very acceptable by all patients.

Risperidone long-acting injection

Risperidone long-acting is the first atypical antipsychotic medication available in an injectable sustained-action formulation, potentially conferring the advantages of an atypical antipsychotic together with assured medication delivery. In addition, unlike depots of conventional antipsychotics composed of a prodrug in a viscous oil vehicle, this formulation uses microsphere technology to encapsulate risperidone in a biodegradable polymer. Progressive hydrolysis of the microspheres results in gradual release of risperidone leading to predictable and sustained plasma levels with repeated injections.

Long-acting injectable antipsychotics: evidence of effectiveness and use.

Objective To review the evidence for the role of long-acting injectable (LAI) antipsychotics (APs), especially the second-generation AP (SGA) LAIs, in the treatment of schizophrenia and to discuss the use rates of LAIs in Canada. Method A search of online medical databases was conducted of the published literature (1995–2012) of the effects of LAIs on the domains of remission, adherence, relapse, and hospitalization. Results obtained from randomized controlled trials (RCTs), systematic reviews, meta-analyses, and large-scale observational studies were included. Expert consensus data were also solicited on LAI use within a Canadian context. Results While the efficacy of LAIs, compared with placebo, is well established, the evidence from RCTs is equivocal for any specific advantage for SGA LAIs, compared with oral medications, probably owing to challenges in conducting such RCTs. Evidence from methodologically less rigorous studies and from clinical practice suggests some advantages in achieving and maintaining remission, risk of relapse, and hospitalization. The rate of LAI (first-generation AP and SGA) use from published outpatient studies is low at 6.3% in Canada, compared with 15% to 80% worldwide. However, there is a relatively high rate of use in specific early psychosis programs and in conjunction with community treatment orders in Canada. Conclusions LAIs are at least as effective as oral APs in the treatment of psychotic disorders. The former may have specific advantages for patients who demonstrate covert nonadherence. The underuse of LAIs in Canada needs to be better understood and addressed.

Long-acting injectable antipsychotics: recommendations for clinicians.

A major source of limitation to the real effectiveness of antipsychotics is the high rate of patient nonadherence or, more frequently, partial adherence. using long-acting injectable (LAI) formulations is likely to reduce the impact of such adherence problems. Conversely, the use of LAIs in Canada remains low relative to many other jurisdictions. Based on effectiveness data from randomized control trials and other, less rigorous, studies, as well as our 2 qualitative studies exploring numerous issues around the use of LAIs, including their low use, we put forward 10 different recommendations for consideration by clinicians. These are also based on the experience of many clinicians and clinician scientists. These recommendations address mostly clinical challenges associated with the use of LAIs. Their application in clinical settings is illustrated in our report through several case examples highlighting the large variation across patients and different phases of illness. It is recommended that LAIs should be considered as a treatment option for psychotic disorders across all phases, including the first 2 to 5 critical years.