Use Of Long-acting Risperidone Research Articles

The Cost Effectiveness of Long-Acting/Extended-Release Antipsychotics for the Treatment of Schizophrenia

Antipsychotic medication is the mainstay of treatment in schizophrenia. Long-acting medication has potential advantages over daily medication in improving compliance and thus reducing hospitalization and relapse rates. The high acquisition and administration costs of such formulations raise the need for pharmacoeconomic evaluation. The aim of this article is to provide a comprehensive review of the available evidence on the cost effectiveness of long-acting/extended-release antipsychotic medication and critically appraise the strength of evidence reported in the studies from a methodological viewpoint. Relevant studies were identified by searching five electronic databases: PsycINFO, MEDLINE, EMBASE, the NHS Economic Evaluation Database and the Health Technology Assessment database (HTA). Search terms included, but were not limited to, 'long-acting injection', 'economic evaluation', 'cost-effectiveness' and 'cost-utility'. No limits were applied for publication dates and language. Full economic evaluations on long-acting/extended-release antipsychotics were eligible for inclusion. Observational studies and clinical trials were also checked for cost-effectiveness information. Conference abstracts and poster presentations on the cost effectiveness of long-acting antipsychotics were excluded. Thirty-two percent of identified studies met the selection criteria. Pertinent abstracts were reviewed independently by two reviewers. Relevant studies underwent data extraction by one reviewer and were checked by a second, with any discrepancies being clarified during consensus meetings. Eligible studies were assessed for methodological quality using the quality checklist for economic studies recommended by the NICE guideline on interventions in the treatment and management of schizophrenia. After applying the selection criteria, the final sample consisted of 28 studies. The majority of studies demonstrated that risperidone long-acting injection, relative to oral or other long-acting injectable drugs, was associated with cost savings and additional clinical benefits and was the dominant strategy in terms of cost effectiveness. However, olanzapine in either oral or long-acting injectable formulation dominated risperidone long-acting injection in a Slovenian and a US study. Furthermore, in two UK studies, the use of long-acting risperidone increased the hospitalization days and overall healthcare costs, relative to other atypical or typical long-acting antipsychotics. Finally, paliperidone extended-release was the most cost-effective treatment compared with atypical oral or typical long-acting formulations. From a methodological viewpoint, most studies employed decision analytic models, presented results using average cost-effectiveness ratios and conducted comprehensive sensitivity analyses to test the robustness of the results. Variations in study methodologies restrict consistent and direct comparisons across countries. The exclusion of a large body of potentially relevant conference abstracts as well as some papers being unobtainable may have increased the likelihood of misrepresenting the overall cost effectiveness of long-acting antipsychotics. Finally, the review process was restricted to qualitative assessment rather than a quantitative synthesis of results, which could provide more robust conclusions. Atypical long-acting (especially risperidone)/extended-release antipsychotic medication is likely to be a cost-effective, first-line strategy for managing schizophrenia, compared with long-acting haloperidol and other oral or depot formulations, irrespective of country-specific differences. However, inconsistencies in study methodologies and in the reporting of study findings suggest caution needs to be applied in interpreting these findings.

A Case of Neurotoxic Syndrome With the Use of Long-Acting Risperidone and Subsequent Olanzapine and Paroxetine

To the Editor: Administration of medications that affect brain dopamine and serotonin neurotransmission are occasionally associated with neurotoxic, behavioral, and autonomic syndromes, variously described as the neuroleptic malignant syndrome (NMS) and the toxic serotonin syndrome.1 We describe such a syndrome with the use of long-acting risperidone and subsequent olanzapine and paroxetine. Case report. Ms A, a 38-year-old woman, presented to our emergency department in 2009 for difficulty with swallowing and talking and profound drooling of saliva. She had a history of paranoid schizophrenia and amphetamine and heroin dependence and had had a severe head injury 15 months previously for which she underwent temporal craniectomy (with evidence of a right temporal lobe gliosis on follow-up computed tomography scans). For the past year, she was being treated with long-acting risperidone injection 37.5 mg intramuscularly every 2 weeks, lithium carbonate 250 mg bid, and oral risperidone 3 mg, taken at night. She was observed to have extrapyramidal symptoms, which were treated with benztropine. In an attempt to reduce these symptoms, these medications were stopped, and she was prescribed olanzapine 10 mg, taken at night, and paroxetine 20 mg, taken in the morning. Benztropine was continued. Over the next month, she developed progressive dysphagia, severe sialorrhea, occasional low-grade fever, frequent and profuse sweating, unsteadiness of gait, falls, and progressively slowed movements. Over the course of hospitalization, we observed the following: muscle rigidity (lead-pipe, all 4 extremities), coarse tremors of the hands, tachycardia, labile blood pressure, severe nausea, and tongue fasciculations. She had no cognitive, psychotic, or affective symptoms. There was no evidence of agitation, myoclonus, hyperreflexia, incoordination, shivering, or diarrhea (Sternbach criteria for serotonin syndrome2). Findings of laboratory investigations were all within normal limits except for mildly elevated liver function tests. Serum creatine kinase level was 40 U/L. She met DSM-IV research criteria for NMS (333.92).3 She was treated with benztropine 4 mg/d, and all other medications were stopped. All symptoms resolved within 8 days. Two days prior to discharge, she had paranoid thinking. In light of her history and emerging symptoms, olanzapine 5 mg at night was instituted. There was no reemergence of physical or psychiatric symptoms on follow-up. This case provides several insights into the symptomatology and pathophysiology of NMS and serotonin syndrome. The patient developed NMS/serotonin syndrome symptoms on treatment with a combination of paroxetine and olanzapine. There were no features of NMS/serotonin syndrome in the preceding months when she was being treated with oral and depot risperidone and lithium carbonate, although she did have significant extrapyramidal symptoms. The patient met DSM-IV criteria for NMS. However, she did not have the symptoms of severe NMS, such as a marked creatine phosphokinase elevation, hyperthermia, and an altered sensorium. The fact that she was on treatment with an atypical antipsychotic and that her symptoms were detected early probably accounted for this. Several of the patient's symptoms could also be explained by a serotonin syndrome.1 Nausea, for example, is not a typical feature of NMS but is frequently seen in serotonin syndrome. Abrupt discontinuation of antipsychotic treatment is a well-recognized although rare predisposing factor for the development of NMS. Although her medications were stopped, the patient was on depot risperidone treatment and would have had therapeutic plasma concentrations for several weeks. Risperidone has high antagonistic D2 receptor affinity, and the institution of olanzapine would have had a similar effect, although olanzapine is a relatively weaker D2 antagonist than risperidone.4 This would have resulted in a hypodopaminergic state, which is one of the postulated mechanisms for the development of NMS.5 Paroxetine is a potent and specific inhibitor of 5-HT reuptake,6 whereas olanzapine has high antagonistic affinity at 5-HT2A receptors and low agonistic affinity at 5-HT1A receptors.4 This would have resulted in significantly increased serotonergic neurotransmission at the 5-HT1A receptor. Hyperstimulation of the 5-HT1A receptor in the brain stem and spinal cord has been implicated in the pathophysiology of both the serotonin syndrome and NMS.7 In addition, there is substantial evidence that the serotonin system inhibits dopaminergic function at the level of the origin of the dopamine system in the midbrain as well as at the terminal dopaminergic fields in the forebrain.8 Furthermore, studies suggest that traumatic brain injury patients show an increase in serotonergic and noradrenergic neurotransmission and a dysfunction in mesolimbic and mesocortical dopaminergic neurotransmission.5,9 The net effect of all these actions in this patient would have been a greatly increased serotonergic neurotransmission and a greatly decreased dopaminergic neurotransmission. This could explain the pathophysiology of the toxidrome in this case and explain the symptom overlap between NMS and serotonin syndrome that this patient displayed. This case highlights the need for caution and vigilance in the use of selective serotonin reuptake inhibitor–atypical antipsychotic combinations, particularly in patients with preexisting brain injury.

Use of long-acting risperidone in psychiatric disorders: focus on efficacy, safety and cost–effectiveness

Schizophrenia is a chronic disorder, usually necessitating lifelong treatment. Although atypical antipsychotic agents have improved outcomes in schizophrenia, their clinical potential remains limited by patients’ nonadherence to medication. Long-acting antipsychotics were developed in the 1960s to enhance treatment adherence and simplify the medication process. However, although conventional long-acting agents assure medication delivery, they are associated with similar side effects to their oral equivalents. The need for an agent combining the advantages of a long-acting formulation with those of an atypical antipsychotic was highlighted in 1997 by the American Psychiatric Association’s Practice Guideline for the Treatment of Patients with Schizophrenia. The first long-acting injectable atypical antipsychotic, long-acting risperidone (Risperdal® Consta®, Johnson & Johnson), has since been developed. This article discusses the efficacy, tolerability and cost–effectiveness of long-acting risperidone in schizophrenia and bipolar disorder patients, and suggests possibilities for how its role in clinical practice may change over the next 5 years.

Evaluation of a Treatment Manual for Risperidone Long-Acting Injectable

We evaluated the usefulness of a treatment manual to facilitate the use of long-acting injectable risperidone in community mental health centers (CMHCs) during an open-label observational study. Perceived clinical utility and clinician adherence to the manual were evaluated. Patient adherence to treatment satisfaction, Clinical Global Impression of Severity (CGI-S) and the Schizophrenia Quality-of-Life Scale (SQLS) were assessed. Mean score for overall utility of the guidebook was 4.2 +/- .6 (scale ratings ranged from 1 = not at all to 5 = extremely). Most clinicians (89-100%) found the guidebook useful, and were adherent to key aspects of appropriate treatment use including concomitant oral risperidone use and injection and dosing parameters for long-acting risperidone. Most patients were adherent to treatment (86.7%), preferred long-acting risperidone over oral risperidone (72.6%) or other oral antipsychotics (78.4%) and were satisfied with long-acting risperidone (90.1%). The open-label observational design limits interpretation of these data. However, in this study manual-supported use of long-acting risperidone was associated with successful implementation of this pharmacologic treatment in the CMHC setting.

Use of Long-acting Risperidone in the Treatment of Bipolar Patients

To the Editors:Bipolar illness has a complex clinical presentation and an even more complex treatment. There is more than 1 traditional clinical approach to treatment with a traditional difference between academic authorities in Europe (in favor of the use of antipsychotics and antidepressants) and

Long-Acting Injectable Risperidone Compared with Zuclopenthixol in the Treatment of Schizophrenia with Substance Abuse Comorbidity

This study aimed to compare the efficacy of long-acting risperidone and zuclopenthixol in subjects with schizophrenia and substance abuse. A total of 115 subjects with schizophrenia and substance use disorders were enrolled for an open, randomized, controlled, 6-month follow-up study. Fifty-seven subjects were selected for treatment with long-acting injectable risperidone, while another 58 were treated with zuclopenthixol-depot. Long-acting risperidone patients presented fewer positive urine tests (8.67 compared with 10.36, P = 0.005), showed improved scores on the Positive and Negative Syndrome Scale, and showed better compliance with the Substance Abuse Management program. The use of long-acting risperidone and less severe dependence explained the outcome at the end of the follow-up. Long-acting injectable risperidone was more effective than zuclopenthixol-depot in improving substance abuse and schizophrenia symptoms in subjects with dual diagnosis.

Pharmacoeconomics of long-acting risperidone: Results and validity of cost-effectiveness models

Relapse is the primary cost driver in schizophrenia and is closely related to levels of adherence (compliance) with therapy. Both atypical antipsychotic agents and depot preparations have been shown to be useful in improving therapeutic adherence compared with oral conventional antipsychotic agents. Long-acting risperidone is a new formulation of an atypical antipsychotic agent that combines the pharmacological advantages of the atypical drugs with those of its mode of administration. The likelihood of improved compliance compared with existing treatment regimens implies that the higher acquisition costs would be offset by reduced rates of relapse. Economic models, which represent the health and economic outcomes of patients or populations under a variety of scenarios, are used to evaluate the economic implications of schizophrenia treatment. These models need to reflect clinical reality while simultaneously remaining as simple as possible. The assumptions and results need to be made transparent; data quality must be described explicitly; areas of uncertainty must be comprehensively explored through sensitivity analysis; and individual models must be validated, for example by comparing them with others in the therapeutic area. In this article, cost-effectiveness models of long-acting risperidone developed for different countries are discussed in terms of design, data sources and robustness, and the implications of the results for the treatment of schizophrenia are also reviewed. A discrete event simulation (DES) model that was developed using UK cost and treatment assumptions, in order to provide a 'proof of concept', is described. Country-specific models forthe United States, Canada, Germany, the Netherlands, France, Belgium, Italy and Portugal, using either DES or decision analytical structures, are then discussed. Comprehensive sensitivity analyses were conducted to assess the robustness of the results. In each case, long-acting risperidone produced additional clinical benefit and cost savings compared with other treatment strategies, despite significant variations in cost effectiveness and therapeutic approaches. In particular, improved adherence arising through the use of long-acting risperidone provides a cost-effective strategy for treating patients with schizophrenia, irrespective of the country analysed. The information generated in this analysis therefore provides one potential method for improving resource allocation and reducing the health burden related to schizophrenia.

Use of Long-Acting Risperidone

Back to table of contents Previous article Next article LettersFull AccessUse of Long-Acting RisperidoneNarsimha R. Pinninti, M.B.B.S., M.D., and Rajnish Mago, M.D.Narsimha R. PinnintiSearch for more papers by this author, M.B.B.S., M.D., and Rajnish MagoSearch for more papers by this author, M.D.Published Online:1 Jan 2005https://doi.org/10.1176/appi.ps.56.1.105AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: In their article in the September 2004 issue, Dr. Keith and his colleagues (1) recommended the use of long-acting risperidone for different patient groups, including patients with schizophrenia who are experiencing their first episode of psychosis. They discussed the rationale for using depot antipsychotics for this group: improved medication adherence, more frequent contact with service providers, and lower likelihood of relapse.However, the use of long-acting risperidone for first-episode psychosis raises the important question of appropriate dosage, which was not adequately addressed. A MEDLINE and EMBASE search done on October 10, 2004, did not reveal any trial of long-acting risperidone in first-episode psychosis. Three different types of evidence support the use of lower dosages of antipsychotic medication for patients in this group than for patients experiencing subsequent episodes. First, comparisons of the treatment responses of patients experiencing a first episode and those who have chronic, multi-episode schizophrenia have shown that the former require dosages that are as much as 50 percent lower (2). In a double-blind study of first-episode psychosis among patients with schizophrenia, 2 mg of risperidone was found to be as effective as 4 mg, with a lower incidence of fine-motor dysfunction and a lower rate of treatment dropout (3). (Chlorpromazine-equivalent dosage is not established for long-acting risperidone. However, clinical trial data show that 25 mg is an adequate dosage for most patients with multi-episode schizophrenia. For first-episode psychosis, 50 percent of that dosage should be appropriate.)Second, when the dosage was titrated by using the neuroleptic threshold method (that is, the antipsychotic dosage was increased until cogwheel rigidity was detected), low-dose risperidone—2 to 4 mg—was found to be equally effective as higher doses, with a lower incidence of extrapyramidal side effects (4). Third, positron emission tomography (PET) studies have clarified the relationship between D2 receptor occupancy and clinical response, with occupancies greater than 65 percent showing antipsychotic efficacy and those greater than 78 percent showing extrapyramidal side effects. A PET study of drug-naive patients with schizophrenia showed that 3 mg of risperidone a day produced receptor occupancy of 72 percent, which is in the antipsychotic efficacy range (5). On the basis of these three studies, a target dosage of 2 to 3 mg a day is appropriate for most patients with first-episode psychosis.Currently long-acting risperidone is available in strengths of 25 mg, 37.5 mg, and 50 mg. Because the drug is distributed in micro-spherules and not uniformly dispersed throughout the vial, it is not possible to give doses that are lower than 25 mg, which is higher than the dose required for most patients with first-episode psychosis. Unless a smaller dose formulation is available, long-acting risperidone should not be a first-line option for most patients in this group. We recommend that the manufacturer of long-acting risperidone make it available in a lower strength of 12.5 mg to facilitate its use for patients with schizophrenia who are experiencing their first episode of psychosis.Dr. Pinninti is assistant professor of psychiatry in the School of Osteopathic Medicine at the University of Medicine and Dentistry of New Jersey in Cherry Hill. Dr. Mago is assistant professor of psychiatry in the department of psychiatry at Thomas Jefferson University in Philadelphia.

Use of Long-Acting Risperidone

Back to table of contents Previous article Next article LettersFull AccessUse of Long-Acting RisperidoneGeorge Parker, M.D.George ParkerSearch for more papers by this author, M.D.Published Online:1 Jan 2005https://doi.org/10.1176/appi.ps.56.1.105-aAboutSectionsView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: The lead article in the September 2004 issue by Dr. Keith and his colleagues styles itself as providing "practical advice" on the use of long-acting risperidone, based on a literature review and a panel discussion of international experts gathered in Dublin, Ireland, in spring 2003. As stated in the abstract, results, and acknowledgments, the entire effort was funded by an "educational grant" from Johnson & Johnson. Nowhere does it state that Janssen Pharmaceutica, the manufacturer of long-acting risperidone, is a member of the Johnson & Johnson "Family of Companies" (1), nor is the educational grant described as unrestricted. It is inherently misleading for such an article to masquerade as an academic review in a peer-reviewed journal, given its funding source.As further evidence of the bias inherent in this article, one need look no further than the next article in the same issue of Psychiatric Services, wherein Dr. Citrome and his coauthors present their case-control study on the risk of diabetes with use of second-generation antipsychotics (2). These investigators determined that risperidone monotherapy had an elevated, though not statistically significant, risk of diabetes and that study participants who were taking two second-generation drugs (69 percent of whom were taking risperidone) showed a significant elevation in diabetes risk. Dr. Keith and colleagues recommend a cross-over strategy for initiating treatment with long-acting risperidone that would entail at least several weeks of treatment with more than one second-generation drug. Curiously, I could not find a single mention of diabetes in the Keith article. Nor, although it purports to be a review article, does the paper cite any of the several articles on diabetes risk with atypical antipsychotics that were cited in the Citrome article. Given the morbidity of diabetes, surely it would be "practical" and prudent to alert practitioners to this risk.I must therefore question whether the article by Dr. Keith and his colleagues should have been published by Psychiatric Services. Given its provenance, it would have been better suited to one of the many journals that arrive, unbidden, in our mailboxes on a regular basis.Dr. Parker is associate professor of clinical psychiatry at Indiana University School of Medicine in Indianapolis.

Use of Long-Acting Risperidone

Use of Long-Acting Risperidone