Risperidone (Risperdal)

Risperidone is an excellent atypical anti-psychotic and one of the most popular.  However, it does have a high rate of extrapyramidal side-effects and much more expensive in the U.S. than my favorite, ziprasidone (Geodon) ($4300 vs. $1500/year).  However, for a patient needing to purchase his or her own medication, risperidone can be purchased abroad for as little as $180 per year.  It should be very cheap when its U.S. patents expires.

Risperidone is the only atypical anti-psychotic with a long-acting injectable version Risperdal Consta.  This is an advantage for patients who are unwilling or discontinue their medications and deteriorate into severe psychosis.

Risperidone can cause a lot of weight gain and diabetes is some patients.  Patients should be monitored for increased thirst, increased appetite, and increased urination.  Risperidone should be use with caution in the elderly due to possible increases in strokes and death.  

Review: Risperidone is a potent serotonin 5-HT(2A) and Dopamine D2 receptor blocker. It is reportedly more effective than haldol with EPS similar to placebo. Start with 2 mg/day then increase to 6 mg and if necessary to a maximum of 10 mg. In 330 patients in an open phase IV study PANSS score decreased 40% (Positive And Negative Symptom Scale) with 75% saying better than prior anti-psychotic although they were only let into study if not treatment-resistant yet not doing that well on current meds. Side-effects: 9% insomnia, 6% nausea, headache, somnolence, dizzy, 5% tired, ejaculatory difficulty, 4% anxiety, and vomiting. Decreased dystonia and dyskinesia. G Chouinard, Montreal, Can J Psychiatry 43:1018, ’98. Ed: This review seems definitely biased in favor of the manufacturer.  Risperidone definitely causes extrapyramidal side-effects. Such an open trial study has very little research value.

Depot Risperidone Helpful But Not Impressive: 400 Schizophrenic patients in 41 centers given risperidone for 1 week and other anti-psychotics were tapered. Then for 12 weeks they received placebo or IM risperidone long-acting (Risperdal Consta) 25, 50, or 75 mg every 2 weeks. Oral risperidone or placebo was continued for first three weeks. Peak plasma levels reached at 4-6 weeks. 50% of 302 risperidone and 69% of 98 placebo patients did not complete with 12 weeks. 17% of risperidone withdrew due to insufficient response and 13% because of side-effect. PANSS decreased 7 points with risperidone vs. 3 points with placebo. 44% of risperidone patients improved vs. 17% of placebo and not dose related. ESP side-effects (supposedly non-existent according to Chouinard noted above) were 3%, 14%, and 23% for the three dosages. There was a 4 pound weight gain at highest dose. Kane J, Eerdekens M, Lindenmayer J, et al: Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 2003;160:1125-32. Johnson & Johnson.

Depot Medications Better than Oral: In a meta-analysis, the 1-year relapse rate for long-acting depot medication was 27% compared with 42% for patients who received oral medication. In the only study that lasted for 2 years, the risk of relapse decreased substantially in the depot-treated patients, suggesting that risk of noncompliance may be an even more important factor in relapse over extended periods of time. Relapse and rehospitalization: comparing oral and depot antipsychotics. Schooler NR. J Clin Psychiatry. 12/2003;64 Suppl 16:14-7.

As Good As Quetiapine: In an 8-week, DB PC Study of 673 patients with schizophrenia (DSM-IV diagnosis), quetiapine (200-800 mg/day) did just as well as risperidone (2-8 mg/day) with an average dose = 525 mg/day vs. risperidone 5.2 mg/day. Changes in glucose and weight were minimal and comparable. The rate of extrapyramidal symptom (EPS)-related adverse events was significantly higher with risperidone (22%) than quetiapine (13%; p < .01). Somnolence was more common with quetiapine (26%) than risperidone (20%; p = .04). Prolactin levels increased with risperidone (+35.5 ng/mL), but decreased with quetiapine (-11.5 ng/mL; p < .001). Comparison of Quetiapine and Risperidone in the Treatment of Schizophrenia: A Randomized, Double-Blind, Flexible-Dose, 8-Week Study. Zhong KX, et al. AstraZeneca Pharmaceuticals, University of North Carolina, and Columbia University. J Clin Psychiatry 2006 Jul;67(7):1093-1103.

Risperidone Add-On to Clozapine Didn't Help Treatment Resistant Schizophrenics: In a 6-week DB PC study of 30 schizophrenic patients only partially responsive to clozapine after 32 months of treatment, adding risperidone up to 6 mg/day did not significantly improve symptoms or quality of life. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. Anil Yagcioglu AE, Kivircik Akdede BB, et al. Hacettepe University , Ankara, Turkey. J Clin Psychiatry. 2005 Jan;66(1):63-72

Clozapine Claimed Better than Risperidone for Refractory: 35 patients in a 12 week open prospective study of refractory schizophrenia. Both groups did better although best results were with clozapine. Some EPS occurred with risperidone. Clozapine improvement occurred gradually while risperidone's benefit was earlier. J-P Mindenmayer '‘8 59:521-7 NYU. Ed: This is a very poor quality study and is virtually worthless.  It is very small and also an open trial with absolutely no controls over observer bias.

Perphenazine (Trilafon) Does Just as Well as Atypical Anti-Psychotics in Huge Study: In a huge 18-month DB PC study of 1493 patients with schizophrenia at 57 U.S. sites, patients received either olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the FDA. Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. The efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine, while a little more effective, was associated with greater weight gain and increases in measures of glucose and lipid metabolism. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. Lieberman JA, et al. N Engl J Med. 2005 Sep 19

Risperidone as Good as Clozapine: In a DB study of 86 patients given 6 mg risperidone vs. 300 mg/day of clozapine, both groups did equally well. Bondolfi, Lausanne, Am J Psychiatry 5/98;155:499

Added Risperidone No Help For Clozapine-Treated Schizophrenics: In an 8-week DB PC study of 68 schizophrenic patients on clozapine, the addition of 3 mg of risperidone made no statistically significant difference: 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment. Clozapine Alone versus Clozapine and Risperidone with Refractory Schizophrenia. Honer WG, et al. University of British Columbia. N Engl J Med 2006 Feb 2;354(5):472-482.

Review of 11 DB Slightly Better Than Haldol: Author says an analysis of 11 double-blind studies shows risperidone did only slightly better against psychosis than haloperidol (57% vs. 52%) with somewhat less EPS (22% vs. 38%). However, there was more weight gain with risperidone. Song, U York, J Psychopharm ’97;11:65.  Ed: For many patients, good management can eliminated EPS side-effects.

Risperidone Did Better than Haldol: Two industry funded DB placebo and haloperidol studies of 513 patients with chronic schizophrenia who were treated with risperidone 2, 6, 10, or 16 mg/day. PANSS showed risperidone best, especially with negative symptoms, e.g. hostility, anxiety, and depression even at 2 mg for negative symptoms. Stephen Marder, J Clin Psychiatry ’98 58:538-46; Patients on risperidone did better at perceiving emotion than those on Haldol. Schiz Res ‘98’31:159

Risperidone as Good as Haldol in 2 Yr Study: DB PC study of 63 schizophrenics. Equally effective although more EPS with haldol and better subjective feeling with risperidone. UCLA, Am J Psychiatry 2003 Aug;160(8):1405-12, Marder SR; Glynn SM; Wirshing WC; Wirshing DA; Ross D; Widmark C; Mintz J; Liberman RP; Blair KE

Haloperidol + Amitriptyline Better than Risperidone for Schizophenia with Depression: In a DB 6-week Univ. of Mainz study of risperidone 7 mg/day vs. haloperidol 9 mg/day + Amitriptyline 180 mg/day, there was slightly more EPS with risperidone. The combination of haloperidol and amitriptyline did better on both BPRS and on Depression ratings. Muller, J Clin Psychopharm ’98;18:111

Olanzapine Better than Risperidone: In a 339 patient DB PC study by Lilly, olanzapine's manufacturer, over 28 weeks using 10-20 mg/day of olanzapine vs. 4-12 mg/day of risperidone, olanzapine had a larger decrease negative symptoms affect, avolition, anhedonia and higher response rate (>39% improvement): 37% vs. 27%. 20% olanzapine patients were treated for EPS vs. 33% risperidone. Tran P et al: Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychoph 97;17:407. Ed: The bias of Lilly makes this study of minor importance.

Olanzapine and Quetiapine Changed Less Than Risperidone: In a CATIE randomized, double-blind study of 114 schizophrenic patients comparing olanzapine (7-30 mg/day), quetiapine (200-800), and risperidone (1.5-6) in patients who had just discontinued the older antipsychotic perphenazine, the time to treatment discontinuation was longer for patients treated with quetiapine (9.9 months) and olanzapine (7.1) than with risperidone (3.6). There were no significant differences between treatments on discontinuation due to inefficacy, intolerability, or patient decision. Effectiveness of Olanzapine, Quetiapine, and Risperidone in Patients With Chronic Schizophrenia After Discontinuing Perphenazine: A CATIE Study. Stroup TS, et al. University of North Carolina . [email protected]. Am J Psychiatry 2007 Mar;164(3):415-27.

Stroke and Death: Do Not Use Risperidone in the Elderly: In 4 placebo-controlled trials lasting 1–3 months and involving more than 1200 patients with Alzheimer's disease or vascular dementia, strokes were twice as common in the risperidone-treated group (4%) as in the placebo group (2%). A further search of international databases of postmarketing adverse events revealed 37 cases (1 in Canada) of such events in elderly dementia patients taking risperidone, of which 16 (43%) were fatal. Risperdal (risperidone) and cerebrovascular adverse events in placebo-controlled dementia trials [Dear Healthcare Professional Letter]. Toronto: Janssen–Ortho Inc.; 2002 Oct 11. Available: www .hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english /advisory /industry/risperdal1_e.pdf (accessed 2002 Oct 25).

Stroke Only Mildly Increased with Risperidone Compared to Traditional Antipsychotics: In a retrospective population-based cohort study of patients over the age of 66, patients treated with typical antipsychotics (N=1,015) were compared with those given risperidone (N=6,964) and olanzapine (N=3,421). Model-based estimates adjusted for covariates hypothesized to be associated with stroke risk revealed relative risk estimates of 1.1 for olanzapine and 1.4 for risperidone. Atypical antipsychotics and risk of cerebrovascular accidents. Herrmann N, Mamdani M, Lanctot KL. Am J Psychiatry. 2004 Jun;161(6):1113-5. Am J Psychiatry. 2004 Jun;161(6):1113-5. Ed: Since traditional antipsychotics have all but disappeared from clinical practice, I don't think that they are a fair comparison group.  The newer anti-psychotics, such as ziprasidone, would be much better.  Still, the increase with risperidone (40%) found was not huge.

Stroke Risk High with Olanzapine, too: Post-hoc analysis by the Eli Lilly drug company of 5 randomized clinical trials using olanzapine in patients with dementia, has shown that patients taking olanzapine have a risk of experiencing a stroke which is 3 times higher than patients taking placebo. van Marum RJ, Jansen PA. Universitair Medisch Centrum Utrecht, Netherlands. Ned Tijdschr Geneeskd. 2005 Jan 22;149(4):165-7.

Edema from Risperidone: Two cases marked generalized edema after risperidone added to valproate and a benzodiazepine required the stopping of risperidone. J Clin Psychiatry 98;59:689

Osteoporosis May Be Worsened: Serum prolactin levels averaged 25.9 ng/mL in the olanzapine group and 123 ng/mL in the risperidone. Small study found osteoporosis worse in risperidone pre-menopausal patients than olanzapine patients. J Clin Psychiatry 2003;64:761-766. Ed: Of the atypicals, only risperidone significantly increases prolactic. Ziprasidone (Geodon) would be a much better first line choice than olanzapine in view of its much higher cost, considerable weight gain, and significant risk of causing type 2 diabetes.

Fattened Children and Teens from Risperidone: In patient study 60 patients gained 19 pounds on risperidone, 7 pounds on conventional anti-psychotics, and lost 2 pounds on placebo. Weight gain in adolescents treated with risperidone and conventional antipsychotics over six months. Kelly DL, Conley RR, Love RC, Horn DS, Ushchak CM. J Child Adolesc Psychopharmacol 1998;8(3):151-9

Risperidone Better Manual Dexterity than Haldol: DB PC 56 pt 8wk probably due to less EPS. Kern, UCLA, Biol Psychiatry 10/98;44:726

EPS Risperidone vs. Clozapine vs. Conventional: Simpson Angus test for EPS and Barnes for akathesia in 23, 41, and 42 patients found 13%, 7%, and 24% got akathesia and 17%, 3%, and 30% got EPS with 8 (35%), 1 (2%), and 24 (58%) patients receiving antiparkinsonians. Carl Miller et al: The prevalence of acute extrapyramidal signs and symptoms in patients treated with clozapine, risperidone, and conventional antippsychotics. J Clin Psychiatry ’98 59:69-75, Univ. Innsbruck

Quetiapine Fewer Sexual Side-Effects than Risperidone: In a open label but random assignment study of 49 patients with schizophrenia treated for six week with quetiapine 200-1200 mg/day or risperidone 1-6 mg/day, found four of 25 quetiapine-treated patients (16%) and 12 of 24 risperidone-treated patients (50%) reported sexual dysfunction. While 33% in all had sexual side-effects, only 11% mentioned them spontaneously, emphasizing the need to specifically ask about them. A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning. Knegtering R, Castelein S, Bous H, Van Der Linde J, Bruggeman R, Kluiter H, Van Den Bosch RJ. J Clin Psychopharmacol. 2004 Feb;24(1):56-6

Risperidone Bad for Parkinson's Disease: Six patients with Parkinson’s Disease or akinetic rigidity were treated with risperidone. Five developed intolerable side-effects with increased Parkinson's symptoms and one had to be admitted to a nursing home and treated with an NG tube! Four did well with a switch to clozapine. Stuart Rich, Brown U, ’95 56:556-9.

Once a Day Just as Good: In a DB study of 200 patients, once a day risperidone did just as well as twice a day. J Clin Psychopharm ’98;18:104

Once a Day Risperidone Just As Good: 211 patients were randomized to 4 mg twice a day or 8 mg once a day. There was no difference in clinical efficacy, plasma levels, or side-effects. Jones B et al: Therapeutic equivalence of risperidone given once daily or twice daily in patients with schizophrenia. Internat Acad for Biomed & Drug Research Meeting, Florence Italy, March 10-12, 1995. Psyc Drug Alerts 3/97. Half-life is 20 hours (3-20 hours according to manufacturer) and active metabolite 9-hydroxyrisperidone (21-30 hours according to PDR) pharm profile similar to parent. Ann Clin Psyc 96;8:221

Fluoxetine Increases Risperidone Level 300%: 10 patients on 4-6 mg risperidone were treated with fluoxetine 20mg/d for depression. Blood levels increased 2-10 fold. Minor decrease in depression (18 to 14) and psychosis (61 to 56). J Clin Psychopharm 02;22:419-23

Risperidone Add-on of Minimal Value in Clozapine Treatment Failures: Only 13% improvement in PANSS scores after 8 weeks in five pts. Vaadyala, Creedmoor Psych, APA 5/30/98 Toronto

Risperidone Loading: 11 pt with acute psychosis. Orthostatic hypotension a concern with rapid titration. So exclude >55yo and those with a history of hypotension. Asked re lightheaded and check BP before 1^st and 1.5hr after each dose. Start 1mg, then if pat not BP drop of 15mm Hg and not lightheaded, give 2mg after 8 hr. If still OK, start 3 mg bid after 8 more hours. 3 pt. orthostatic hypotension after second dose, so had 2mg on third dose and 3mg on 4^th dose at 24 hours. One pt hypotension at 3mg and put on 2mg tid. Feifel, UCSD, NIMH funded, J Clin Psych 00;61:909

Risperidone Increase More Slowly: U Chicago study. Risperidone given to 1283. Standard doxing resulted in 15% discontinuation rate but slower 6-7 days schedule did better. Luchins D et al: Alterations in the recommended dosing schedule for risperidone. Amer J Psyc 98;155:365-6. Janssen funding. Not blinded.

Optimal Dose 4mg: DB study 112 pt. Europe. Eur Arch Psychiatry Clin Neurosci ’97;247:291

Risperidone 2 mg/d Worked for First Break: In an 8-week DB PC study of 49 first-break schizophrenics, both 2 and 4 mg of risperidone daily significantly reduced positive (p < .0001) and negative (p < .01) symptoms at 8 weeks. Although there were no significant differences in motor movements as measured using the Barnes Akathisia Scale and the Simpson-Angus Scale, computerized fine motor assessment showed significantly less motor dysfunction in the 2-mg/day group at 8 weeks. Drop out rates were 14% vs. 28%. Remission rates were 70% (2 mg/d) vs. 65%. Risperidone, 2 mg/day vs. 4 mg/day, in first-episode, acutely psychotic patients: treatment efficacy and effects on fine motor functioning. Merlo MC, Hofer H, Gekle W, Berger G, Ventura J, Panhuber I, Latour G, Marder SR. Hopitaux Universitaires de Geneve,  Switzerland.  J Clin Psychiatry. 2002 Oct;63(10):885-91

Risperidone 2 mg Did as Well as 4 mg/d: 49 first episode psychotic Swiss patients in 8 week DB study. Drop out rate 14% vs. 28%. Remission rate 70% (2 mg/d) vs. 65%. Merlo M, et al: Risperidone, 2 mg/day vs. 4 mg/day in first-episode, acutely psychotic patients: treatment efficacy and effects on fine motor functioning. J Clin Psychiatry 2002;63:885-891.

Celecoxib Helps Risperidone a Little: Schizophrenics have higher activating cytokines, e.g. IL-1, and IL-2. Atypical anti-psychotics down regulate immune response in CNS. Anti-inflammatory rx may add to this. DB PC 5wk German study of 50 acute schizophrenics treated with 2-6 risperidone +/- 400mg/d celecoxib. Rx group improved faster, especially weeks 2-4. Less biperiden and less benzodiazepines needed with celecoxib group. Mueller, Germany, Amer J Psychiatry 02;159:1029-34

Oral Risperidone Liquid=Haldol IM: Risperidone 2 mg liquid was as good as haldol 5 mg IM and lorazepam 2 mg IM at 30 min, 1 hour and 2 hours. J Clin Psych 3/01 62:153-7

Risperidone Reduces Superoxide Dismutase: 41 pt 12 week study. There was a significantly positive relationship between the change in SOD at pretreatment and posttreatment and the reduction in the PANSS negative subscore. These findings suggest that risperidone treatment significantly decreased the blood SOD levels of schizophrenic patients, a change which may be associated with the diminishment of symptoms. BeiDa. The effect of risperidone treatment on superoxide dismutase in schizophrenia. Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC. J Clin Psychopharmacol 2003 Apr;23(2):128-31