, Volume 19, Issue 5, pp 429-444
Date: 29 Aug 2012


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Risperidone (Risperdal®) is an atypical antipsychotic with high affinity for 5-hydroxytryptamine (5-HT)2A, dopamine D2 and α1- and α2-adrenergic receptors. Risperidone is now approved in the UK and the US for use in bipolar mania.

Risperidone ≤6 mg/day, as monotherapy or adjunctive therapy with first-line mood stabilisers, significantly improves moderate and severe bipolar mania and improves global functioning over 3 weeks. Improvements in Young Mania Rating Scale (YMRS) scores in double-blind trials were greater with risperidone than with placebo over 3 weeks, and similar to those with haloperidol over 3 and 12 weeks. Risperidone was reasonably well tolerated. Limited data are available on the combination of risperidone and carbamazepine. Risperidone, as monotherapy or combined therapy with lithium or valproate semisodium, is an effective treatment option in bipolar mania.

Pharmacological Profile

Risperidone is a benzisoxazole derivative with high in vitro affinity for 5-HT (serotonin)2A, dopamine D2 and α1- and α2-adrenergic receptors. Risperidone and its active metabolite 9-hydroxyrisperidone antagonise serotonin and dopamine. The neurotransmitter binding properties of risperidone provide the putative mechanisms for the antipsychotic and antimanic activity of risperidone and its generally improved adverse effect profile compared with older antipsychotics.

Oral risperidone is rapidly absorbed, reaching maximum plasma concentration after ≈1–2 hours, with a high bioavailability. Risperidone is largely hydroxylated by the cytochrome P450 (CYP) 2D6 enzyme to 9-hydroxyrisperidone. The elimination half-life (t1/2β) of risperidone plus 9-hydroxyrisperidone (total active moiety) is ≈20 hours. Excretion is mostly through the urine. Clearance is reduced and t1/2gb extended in elderly patients and those with renal impairment. Plasma protein binding is 90%; hepatic impairment increases unbound risperidone levels by 35%. Total active moiety plasma concentrations increase with coadministration of CYP2D6 or CYP3A4 inhibitors (e.g. fluoxetine) and decrease with CYP2D6 or CYP3A4 inducers (e.g. carbamazepine).

Therapeutic Efficacy

In 3- and 4-week double-blind trials in acute mania, risperidone at a mean modal dosage of 3.8–6 mg/day reduced mania significantly more than placebo (and similarly to haloperidol) when administered as monotherapy or adjunctive therapy, except when used as adjuvant therapy to carbamazepine. Mean baseline YMRS scores of 24.8–37.4 points decreased by 10.6–22 points with risperidone, 13.4–14.6 points with haloperidol, 12.7 points with lithium and 4.8–10.3 points with placebo, with or without mood stabilisers. When carbamazepine recipients, in whom plasma risperidone concentrations in adjuvant therapy were decreased by 40%, were included, decreases in YMRS scores in one trial were not significant versus placebo.

Remission (YMRS score ≤8 and Montgomery-Åsberg Depression Rating Scale score ≤12 points) was achieved within 3 weeks in 20% of risperidone monotherapy versus 9% of placebo recipients. Measures of illness severity, such as Clinical Global Impressions rating, improved more with risperidone than placebo; some measures (e.g. Brief Psychiatric Rating Scale scores) improved more quickly with risperidone than with haloperidol.

YMRS scores continued to improve (to ≈12 points), as did measures of patient functioning, with risperidone and haloperidol monotherapy in a subsequent 9-week double-blind trial; open-label studies reported similar results, with YMRS scores mostly <8 points after 3 months of risperidone treatment.


In addition to weight gain, common adverse events affecting >10% of recipients of risperidone, haloperidol or placebo in controlled trials were extrapyramidal symptoms (EPS), somnolence, hyperkinesia, headache, dizziness, dyspepsia, nausea and constipation. EPS were significantly more frequent with risperidone adjunctive therapy than with placebo, but the severity of symptoms was similar. Prolactin levels increased in two trials and hyperprolactinaemia, sometimes clinically relevant, occurred with risperidone.

Weight gain with risperidone was significant versus placebo, but data from single-blind and nonblind trials indicate that weight gain is generally lower than with olanzapine. Similarly, data from reviews indicates that plasma glucose is less affected by risperidone than byclozapine or olanzapine; plasma glucose was not affected by risperidone in trials in patients with mania.

Various sections of the manuscript reviewed by: F. Benazzi, Hecker Psychiatry Research Center and NHS Department of Psychiatry, Forli, Emilia Romagna, Italy; G. de Girolamo, Department of Mental Health, ASL di Bologna, Bologna, Italy; P. Fahnestock, Department of Psychiatry and Psychology, Washington University School of Medicine, St Louis, Missouri, USA; D.M. Hilty, Mood Disorders and Health Services Research Program and Telepsychiatry, University of California — Davis, Sacramento, California, USA; M. Isaac, South London and Maudsley NHS Trust, Beckenham, Kent, UK; D.J. Muzina, Bipolar Disorders and Schizophrenia Clinic, The Cleveland ClinicFoundation, Cleveland, Ohio, USA; J.W. Newcomer, Department of Psychiatry and Psychology, Washington University School of Medicine, St Louis, Missouri, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on risperidone, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: MEDLINE search terms were ‘risperidone’ and ‘manic’ or ‘mania’ or ‘bipolar’. EMBASE search terms were ‘risperidone’ and ‘manic’ or ‘mania’ or ‘bipolar’. AdisBase search terms were ‘risperidone’ and ‘manic’ or ‘mania’ or ‘bipolar’. Searches were last updated 19 April 2005.
Selection: Studies in patients with bipolar disorder who received risperidone. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Risperidone, bipolar disorder, atypical antipsychotic, mania, pharmacodynamics, pharmacokinetics, therapeutic use.