Risperidone events

The U.S. sample was followed openly on risperidone (0.02-0.06 mg/kg/day) for an additional 48 weeks (Findling et ah, 2001). Some 50 children continued to end point, whereas 57 eventually withdrew from the trial for a variety of reasons (11, adverse events 11, insufficient response 35 other [loss to follow-up, withdrawal of consent, etc]). Subjects who received placebo in the acute trial had significant improvements as rated by parents on the Conduct Problem subscale of the NCBRF as they went on to active medication. Subjects already receiving risperidone in the acute trial continued to show improvement on the Conduct Problem subscale in the open-label continuation. Clinician CGI ratings also indicated improvement for participants who were switched from placebo to risperidone. 

A number of antidepressant drugs, particularly SSRIs, can increase plasma prolactin concentrations, although galactorrhea is uncommon. In a prescription event monitoring survey of about 65 000 patients, compared with SSRIs, moclobemide was associated with a relative risk of galactorrhea of 6.7 (95% Cl = 2.7, 15) (727). However, this was substantially less than the risk associated with the dopamine receptor antagonist risperidone (relative risk compared with SSRIs 32 95% Cl = 14, 70). 

The relation of prolactin concentrations and certain adverse events has been explored by using data from two large randomized, double-blind studies (n = 2725 813 women, 1912 men) (1018). Both risperidone and haloperidol produced dose-related increases in plasma prolactin concentrations in men and women, but they were not correlated with adverse events such as amenorrhea, galactorrhea, or reduced libido in women or with erectile dysfunction, ejaculatory dysfunction, gynecomastia, or reduced libido in men. Nevertheless, in five patients risperidone (1-8 mg/day) caused amenorrhea in association with raised serum prolactin concentrations (mean 122 ng/ml, range 61-230 ng/ml reference range 2.7-20 ng/ml) (1019). 

Kleinberg DL, Davis JM, de Coster R, Van Baelen B, Brecher M. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999 19(1) 57-61. 

In an open, 30-day trial, the pharmacokinetics, safety, and tolerability of a combination of risperidone 4 or 6 mg/ day with fluoxetine 20 mg/day were evaluated in 11 psychotic inpatients (52). CYP2D6 genotyping showed that three were poor metabolizers and eight were extensive metabolizers. The mean AUC of risperidone increased from 83 and 398 h.ng/ml to 341 and 514 h.ng/ml when risperidone was co-administered with fluoxetine in extensive and poor metabolizers respectively. However, despite this pharmacokinetic interaction, the severity and incidence of extrapyramidal symptoms and adverse events did not increase significantly when fluoxetine was added 10 of the 11 patients improved clinically. 

Clozapine and risperidone have been compared in 10 patients with psychosis in Parkinson s disease, who were randomized to risperidone or clozapine for 12 weeks (95). The mean improvement in the total BPRS score was 3.0 with clozapine (mean dose 62.5 mg/day) and 6.0 with risperidone (mean dose 1.2 mg/day). The white blood cell count fell below 3.0 x 109/1 after 10 weeks in one subject taking clozapine and rose to 5.0 x 109/1 after withdrawal. One subject taking clozapine had a marked increase in rigidity and incontinence of urine after 4 weeks, and there were similar effects in a patient who took risperidone for 10 weeks. All three adverse events resolved on withdrawal. 

There has been one comprehensive meta-analysis including over 80 studies and over 30 000 patients (489). A meta-analysis of trials of neuroleptic drugs showed the following mean weight gains in kg after 10 weeks of treatment clozapine, 4.5 olanzapine, 4.2 thioridazine, 3.2 sertindole, 2.9 chlorpromazine, 2.6 risperidone, 2.1 haloperidol, 1.1 fluphenazine, 0.43 ziprasidone 0.04 molindone, —0.39 placebo, —0.74 (490,491). In one study, excessive appetite was a more frequent adverse event in patients treated with olanzapine versus haloperidol (24 versus 12%) (185). Loss of weight has been observed after withdrawal of neuroleptic drugs (492). 

Smith DA, Beier MT. Association between risperidone treatment and cerebrovascular adverse events examining the evidence and postulating hypotheses for an underlying mechanism. J Am Med Dir Assoc 2004 5 129-32. 

In an 8-week study, pre-school-age children with bipolar disorder (aged 4-6 years) took either olanzapine (n = 15 mean age 5.0 years 10 boys mean dose 6.3 mg/day) or risperidone (n = 16 mean age 5.3 years 12 boys mean dose 1.4 mg/day) (59). There were significantly more dropouts with olanzapine (6 versus 1), including one patient who withdrew because of adverse events (increased appetite and hand tremor). The main adverse events, found with both treatments, were significant increases in prolactin concentrations and weight gain. With both treatments, increased appetite, flu-like symptoms, headaches, and sedation were the most commonly reported adverse effects. 

The medical records of 151 hospitalized elderly psychiatric patients (mean age 71 years) have been analysed (8). Of 114 patients treated with risperidone (mean duration of treatment 17 days mean dose 3 mg/day), 78% responded. Adverse events were reported in 20 patients, including new-onset extrapyramidal effects in four tremor in four sedation in three hypotension in three diarrhea in two tardive dyskinesia in two and chest pain, anxiety, restlessness, itching, insomnia, and falls in one each. 

Risperidone has also been used in combination with topiramate in a Spanish multicenter study in 58 patients (28 men and 30 women mean age 41 years) with bipolar I disorder, with manic but not mixed episodes (20). Risperidone (mean dose 2.7 mg/day) and topiramate (mean dose 236 mg/day) were started with a maximum 48-hour time difference risperidone was used for acute manic symptoms and topiramate for longer-term stabilization and prevention of relapse. The incidence of any adverse event was 64%, mostly somnolence, paresthesia, dizziness, tremor, weight loss (n = 27 mean change -1.1 kg), extrapyramidal disorders, gastrointestinal effects, and cognitive disturbances. One patient developed tardive dyskinesia during the study and there were five dropouts because of adverse effects adverse effects that required withdrawal of risperidone but not topiramate were amenorrhea (n = 3) and sexual dysfunction (n = 1). 

In a two-phase long-term multicenter study in 74 patients (mean age 30 years 56 men), the starting dose of risperidone was 1 mg/day, increased to 2 mg after 3 days and adjusted to 8 mg/day maximum treatment duration was 2 weeks for phase 1 (mean dose at the end 3.8 mg/day) and 1 year for phase 2 (mean dose at the end 3.5 mg/day) (26). Of 12 patients who did not complete phase 1, two had adverse events (agitation, somnolence, and self-harm) there were nine dropouts during phase 2, but none was apparently due to adverse events. 

In a 6-month multicenter study in 96 manic patients (mean age 41 years 50% women) who took risperidone monotherapy 4.2 mg/day, 16 withdrew from the study, in four cases because of adverse events akathisia, impotence, drowsiness, and weight gain (28). 

Similarly, risperidone caused extrapyramidal symptoms in fewer patients (24%) than haloperidol did (43%) in a two-phase study in patients with acute bipolar mania (phase I, 3 weeks, patients receiving either risperidone 1-6 mg/day, haloperidol 2-12 mg/day, or placebo (32). Plasma prolactin concentration was higher with risperidone (no data provided) prolactin-related adverse events included non-puerperal lactation, breast pain, dysmenorrhea, and reduced libido or sexual dysfunction these effects occurred in six patients on risperidone (4%) and in two on haloperidol (1.3%). 

Several adverse events, including one death (no further information provided), have been described with risperidone in a study in which elderly patients with schizophrenia (mean age 70 years) were randomly assigned to risperidone (n = 32) or olanzapine (n = 34) for 4 weeks (33). 

In a multicenter, randomized, double-blind, 12-week trial in Australia and New Zealand, 384 patients with dementia, mainly Alzheimer s disease, were initially enrolled and received at least one dose of risperidone (n = 167 71% women mean age 83 years modal dose 0.99 mg/day) or placebo (n = 170 72% women mean age 83 years) (47). Clinical improvement in aggression and psychotic symptoms was evidenced by means of specific scales 45 subjects taking risperidone and 56 taking placebo did not complete the trial, mainly because of insufficient responses and adverse effects. In the whole sample there was a high prevalence and variety of adverse events (94% of those taking risperidone and 92% of those taking placebo), mainly injuries, falls, somnolence, and urinary tract infections however, only the last two were more common in those taking risperidone than in those... 

In a 12-week, double-blind, randomized, placebo-controlled study in 40 patients with treatment-resistant schizophrenia (funded by Johnson Johnson Pharmaceutical Research Development), the addition of risperidone to clozapine improved overall symptoms and positive and negative symptoms (49). The adverse events profile of clozapine + risperidone was similar to that of clozapine + placebo. Clozapine + risperidone did not cause additional weight gain, agranulocytosis, or seizures compared with clozapine + placebo. All the patients completed 12 weeks of treatment however, the small sample size precluded definitive conclusions. 

In a two-phase placebo-controlled study with an initial sample of 45 patients, 39 of whom completed the study, the addition of low doses of risperidone (0.5 mg/day) appeared to improve symptoms in patients with obsessive-compulsive disorder taking fluvoxamine monotherapy (51). The main adverse events included transient sedation and mildly increased appetite. 

The debate about the need to restrict drug therapy in relation to the risk of cardiovascular events is open, and some authors have already expressed agreement (61) or disagreement about it (62), as well as pointing to the need for individual patient meta-analyses and significant changes to clinical trial methods in order to better assess the effectiveness, in contrast to the efficacy, of risperidone and other drugs in dementia (63). 

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