Summary of evidence and Expert Committee recommendations
The Expert Committee received two applications to include risperidone in the WHO Essential Medicines List, as follows: The Mount Sinai School of Medicine, Program in Global Mental Health, New York, NY, USA, proposed the inclusion of the second-generation antipsychotic risperidone formulations in the core and complementary EML and EMLc.
Massachusetts General Hospital, The Chester M. Pierce MD Division of Global Psychiatry, Boston, MA, USA, (Young Professionals Chronic Disease Network) proposed the inclusion of the second-generation antipsychotic risperidone in the core EML. Expert reviews were prepared by Mr Andrew Gray and Dr Kuruvilla Prasad Mathews. Comments were received from Dr Shekar Saxena, Director, Mental Health and Substance Abuse, WHO and Dr Myriam Henkens, International Medical Coordinator, Médecins Sans Frontières.
An application to add risperidone to the EML was first made in 1998. At that time risperidone had been available for only four years and it was still under patent and was expensive. A second application was made in 2009 several years after generic products of risperidone had become available but was rejected because of the incompleteness of the literature review and pricing data.
It is estimated that some 41.7 million people need treatment for schizophrenia and related disorders in low- and middle-income countries. The majority of these cases are in Asia (70%) and Africa (16%) (1). Schizophrenia is a significant contributor to the global disease burden, accounting for 1.1% of disability-adjusted life-years lost (2). The Mental Health Gap Action Programme Intervention Guide published by WHO in 2010 (3) has three antipsychotics (haloperidol, chlorpromazine and fluphenazine), all of which are currently in the EML. The intervention guide states that, if the responses to these medications are inadequate, providers may choose to treat patients with a second-generation antipsychotic, if available and affordable. An excerpt from the guide states: “If the response is inadequate to more than one antipsychotic medication using one medicine at a time at adequate dosage for adequate duration … consider second-generation antipsychotics (with the exception of clozapine), if cost and availability is not a constraint, as an alternative to haloperidol or chlorpromazine.”
A 2010 Cochrane review of 23 randomized controlled trials including 4445 patients found risperidone to be more effective than typical antipsychotics in treating schizophrenia and schizoaffective disorder (4). On the basis of pooled data from nine randomized controlled trials, risperidone was more likely than haloperidol to produce clinical improvement in the short and longer term. Another more recent Cochrane review found that risperidone was more efficacious than both quetiapine and ziprasidone, though less efficacious than clozapine and olanzapine. Importantly, risperidone has a safer side-effect profile than both clozapine and olanzapine (4-7). Other reviews have also shown the overall efficacy of risperidone compared with first-generation antipsychotics (8, 9).
While risperidone and other second-generation antipsychotics are less likely to cause extrapyramidal side-effects when compared with typical antipsychotics, they are more likely to cause metabolic side-effects such as weight gain, hyperlipidaemia and hyperglycaemia. The unit price of risperidone, including generics, has fallen substantially since 2008. A comparison of pre-generic and post-generic production data revealed the impact of generic production on the price. In 2002, the cost of a 2-mg tablet of risperidone ranged from US$ 0.070 to US$ 1.33, with the median price being roughly 70 US cents. In 2011, however, the cost of a 2-mg tablet of risperidone ranged from US$ 0.0080 to US$ 0.067, with the median price being just US$ 0.034 (or roughly 3 US cents) (10). Data were also compared in the Indian market. Among 12 branded generic manufacturers the price of 10 units of 1-mg tablets ranged from 7.00 rupees to 19.70 rupees (11). The Expert Committee considered the efficacy and safety of the atypical antipsychotics, apart from clozapine, to be broadly comparable but noted that availability of generics varies considerably.
The Expert Committee recommended that risperidone solid oral dosage forms should be added to the core list of the EML without the square box symbol. The Committee added that it would welcome further applications for additional second-generation (atypical) antipsychotics, based on careful consideration of suitable alternatives or additions to risperidone.
1. de Jesus MJ, Razzouk D, Thara R, Eaton J, Thornicroft G. Packages of care for schizophrenia in low- and middle-income countries. PLoS Med. 2009;6(10):e1000165. http://dx.doi.org/10.1371/ journal.pmed.1000165 PMID:19841735
2. The global burden of disease: 2004 update. Geneva: World Health Organization; 2008.
3. mhGAP intervention guide for mental, neurological and substance use disorders in nonspecialized health settings (mhGAP-IG). Geneva: World Health Organization; 2010 (http://www. who.int/mental_health/publications/mhGAP_intervention_guide/en/, accessed 21 March 2014).
4. Hunter RH, Joy CB, Kennedy E, Gilbody SM, Song F. Risperidone versus typical antipsychotic medication for schizophrenia. Cochrane Database Syst Rev. 2003;(2):CD000440. http://dx.doi. org/10.1002/14651858.CD000440 PMID:12804396
5. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al.; American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2) Suppl:1-56. PMID:15000267
6. Komossa K, Rummel-Kluge C, Schwarz S, Schmid F, Hunger H, Kissling W, et al. Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2011;(1):CD006626. http://dx.doi.org/10.1002/14651858.CD006626.pub2 PMID:21249678
7. Jayaram MB, Hosalli P. Risperidone versus olanzapine for schizophrenia. Cochrane Database Syst Rev. 2005;(2):CD005237. http://dx.doi.org/10.1002/14651858.CD005237 PMID:15846745
8. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31-41. http:// dx.doi.org/10.1016/S0140-6736(08)61764-X PMID:19058842
9. Zhang JP, Gallego JA, Robinson DG, Malhotra AK, Kane JM, Correll CU. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2013;16(6):1205-18. http:// dx.doi.org/10.1017/S1461145712001277 PMID:23199972
10. International drug price indicator guide. Cambridge (MA): Management Sciences for Health; 2012
11. PatientIndia (comparison of risperidone prices) [Internet]. Patientindia.com: Maharashtra; 2013 (http://patientindia.com/resultDetails.php?searchC=2&genId=1222&strength=1mg&form=4., accessed 27 November 2013).