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Does risperidone have a place in the treatment of nonschizophrenic patients?

Schweitzer, I.

International Clinical Psychopharmacology: January 2001 - Volume 16 - Issue 1 - p 1-19
Review
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There is a now a substantial body of evidence that suggests the new antipsychotic agent, risperidone, may be safe and effective for treating psychotic, affective or behavioural symptoms associated with various disorders other than schizophrenia, schizophreniform disorder or schizo-affective disorder. These conditions include bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, dementia, Lewy body disease, mental retardation, Parkinson's disease, idiopathic segmental dystonia and organic catatonia. Although much of the data is anecdotal or in the form of open studies, there is now emerging a small number of well controlled investigations supporting efficacy for mania, dementia, behavioural disturbance in mental retardation and conduct disorder. Conventional antipsychotics have long been used, either in a primary capacity or as an adjunct to treat these disorders; however, they have limited benefit, pose significant risks of extrapyramidal side-effects, and may cause the potentially life-threatening neuroleptic malignant syndrome. In contrast, risperidone at the recommended low doses may be efficacious and pose reduced risk of motor side-effects. This article reviews the evidence that risperidone may be an effective new treatment for disorders other than schizophrenia.

Department of Psychiatry, University of Melbourne, Victoria, Australia

Correspondence to Isaac Schweitzer, The Melbourne Clinic, 130 Church Street, Richmond, Victoria 3121, Australia. Tel: +61 39429 468; fax: +61 39428 5990; e-mail: i.schweitzer@medicine.unimelb.edu.au

Received 28 December 1999; accepted 7 September 2000

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INTRODUCTION

Risperidone, a benzisoxazole derivative that is a potent central serotonin and dopamine receptor antagonist, is an effective agent for the treatment of acute and chronic schizophrenia. Risperidone is hypothesized: (1) to relieve positive symptoms by antagonism of dopamine (D2) receptors in the mesolimbic pathway; (2) to relieve negative and affective symptoms by antagonism of 5-HT2 receptors, possibly through a modulatory effect on the dopamine system; and (3) to lessen the risk of extrapyramidal symptoms (EPS) by serotonin (5-HT2) antagonism, reducing D2 blockade in the nigrostriatal pathway. Its acceptance as a safe and efficacious antipsychotic is widespread.

Since the introduction of the first antipsychotic agents in 1952, these drugs have been widely used for the treatment of conditions other than schizophrenia. Conventional antipsychotics are often used for psychotic symptoms that may occur in a variety of psychiatric disorders. Therefore, it is not surprising to find that risperidone has followed a similar course of clinical application, with practitioners frequently using the drug for nonschizophrenic states.

Although conventional antipsychotics may resolve or reduce psychotic symptoms in mania, Tourette's tics, or dementia-related behavioural disturbances, their benefits are limited, and their chronic administration may exacerbate symptoms and cause long-term side-effects. The low-potency agents often cause anticholinergic side-effects, orthostatic hypotension, cognitive impairment, and sedation, whereas the high-potency agents such as haloperidol and fluphenazine are likely to cause EPS (including parkinsonism, dystonias and akathisia) and tardive dyskinesia and, infrequently, neuroleptic-malignant syndrome, a potentially life-threatening condition. Among patients taking conventional antipsychotics, between 50% and 75% experience EPS, approximately 20% experience tardive dyskinesia, and between 0.01% and 1% have neuroleptic malignant syndrome (Casey, 1997).

The novel or atypical antipsychotics offer several clinical advantages over the conventional agents in the treatment of schizophrenia, and they may also have greater applicability to nonschizophrenic conditions. EPS and cognitive side-effects occur less frequently with the atypical agents, and these compounds may have enhanced efficacy, particularly for negative symptoms. Clozapine, the first atypical agent, has limited application to nonschizophrenic states because its use carries a risk of agranulocytosis necessitating regular blood monitoring. In contrast, risperidone has an improved safety profile; within the range of 2-6 mg/day, the frequency and severity of EPS are comparable to those in patients given placebo, and reports of tardive dyskinesia or neuroleptic malignant syndrome have been few (Casey, 1997). There are numerous reports on the use of risperidone in psychotic symptoms or behavioural disturbances in patients with diagnoses other than schizophrenia. This article reviews the literature on the use of risperidone for conditions other than schizophrenia, discusses the implications for clinicians, and makes suggestions for future investigations.

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MOOD DISORDERS

Conventional neuroleptics have commonly been used with mood stabilizers or antidepressants as adjunctive treatment of acute mania and acute psychotic bipolar and unipolar depression (Keck et al., 2000). Antidepressants alone are relatively ineffective in the treatment of a psychotic depression, whereas in combination with an antipsychotic, efficacy approximates that of electroconvulsive therapy (ECT). However, there is evidence that mood disorder patients may be more liable to develop EPS and tardive dyskinesia (Post et al., 1996). Because atypical antipsychotics are less likely than conventional neuroleptics to cause tardive dyskinesia, risperidone has been increasingly investigated for use in the mood disorders (Table 1).

Table 1

Table 1

Table 1

Table 1

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Bipolar mood disorder

A double-blind trial found risperidone as monotherapy to be effective in the treatment of mania. Four open-label trials have also demonstrated the efficacy of risperidone as adjunctive therapy in patients with mania or bipolar disorder. Efficacy is further suggested by the results of retrospective studies and case reports.

In a double-blind, randomized comparison (Segal et al., 1998), risperidone was similar in efficacy to treatment with haloperidol alone and lithium alone in patients with mania. Enrolled patients met DSM-IV criteria for bipolar disorder, manic phase, and were randomly assigned to treatment with 6 mg/day of risperidone, 10 mg/day of haloperidol, or 800-1200 mg/day of lithium for 28 days. Patients in all treatment groups improved significantly (P < 0.001) from baseline on the Young Mania Rating Scale (YMRS) with no significant differences between groups. Sample sizes (45 patients per group) may have been too small to allow significant differences to emerge.

In an open trial of risperidone (mean dose, 3.5 mg/day), Jacobsen (1995) investigated the response of 20 patients with DSM-IV bipolar I, bipolar II, or major depressive disorder who were experiencing psychotic symptoms or agitation. All patients were being treated with other psychoactive medications before risperidone was added. The target symptoms of psychosis, rapid cycling and agitation improved completely or partially in 17 patients 2-22 weeks after risperidone was begun.

Tohen et al. (1996), in an open-label pilot study, added risperidone (mean dose 2.5 mg/day, range 2-6 mg/day) to the mood-stabilizing regimen (lithium, valproate, or carbamazepine) of 14 patients with acute psychotic mania. After 2 weeks, Brief Psychiatric Rating Scale scores improved by at least 25% in 13 patients and by 50% in eight patients. Similarly, the YMRS scores improved by at least 25% for 12 patients and by 50% for 10 patients. Thus risperidone as adjunctive therapy to mood-stabilizing drugs was efficacious and well-tolerated in patients with DSM-III-R acute mania.

In an open trial of risperidone in 10 patients with DSM-IV rapid cycling bipolar disorder who were refractory to lithium carbonate, carbamazepine, and valproate, eight completed the 6-month study and experienced significant (P < 0.02) reductions in both the frequency and the severity of affective episodes (Vieta et al., 1998). The remaining two patients dropped out, one because of agitation and one because of noncompliance. Risperidone dosages ranged from 2-6 mg/day, and mood-stabilizing therapy was maintained. Efficacy measures included the YMRS and the Hamilton Rating Scale for Depression.

Another open trial found risperidone (1-6 mg/day) to be effective as adjunctive medication in seven patients with DSM-IV bipolar disorder. All patients had failed treatment with lithium, carbamazepine, divalproex sodium, or a combination of these agents. Four of the patients showed mild to moderate improvement (McIntyre et al., 1997).

Ghaemi et al. (1997) described a retrospective study of adjunctive risperidone (mean maintenance dose 2.8 ± 1.8 mg/day) in 14 outpatients with DSM-III-R bipolar type I disorder. After a mean treatment duration of 6.4 (± 2.7) weeks, affective symptoms were much improved in nine (64%) patients, as rated on the clinical global assessment (CGI). Improvement was found in six of 11 (55%) patients taking concurrent mood stabilizers and in all three not taking concurrent mood stabilizers. The authors noted that in bipolar disorder, risperidone appeared efficacious at a lower dose than that recommended for schizophrenia.

Ghaemi and Sachs (1997) published a retrospective report of the outcome of adjunctive risperidone treatment (mean dose 2.75 mg/day, range 1.0-4.5 mg/day) for 6 months (range 0.5-72 weeks) in 12 patients with DSM-III bipolar disorder. These patients experienced breakthrough episodes of mania, hypomania or major depression despite adequate maintenance therapy of lithium, valproate carbamazepine or a combination of these. Three patients rated much better and one mildly better on CGI; four patients discontinued medication because of lack of efficacy or adverse events; three were unchanged or mildly worse and one relapsed into depressive episode at week 22.

A retrospective chart review of 28 juvenile patients (4-17 years) treated with risperidone alone (n = 1) or concomitantly with other medications (n = 27) showed reductions in the severity of manic (P < 0.1), aggressive (P < 0.1), psychotic (P < 0.001), and attention-deficit/hyperactivity disorder (ADHD) symptoms. Defined as a CGI improvement score ≥ 2, robust improvement was obtained for 82% of manic and aggressive symptoms, 69% of psychotic symptoms, and 8% of ADHD symptoms. Risperidone dosages were adjusted with the objective of using the lowest dose that provided acceptable clinical response. Optimal response was achieved with a mean risperidone dosage of 1.7 mg/day (Frazier et al., 1999).

There have been a small number of reports indicating that risperidone may precipitate or exacerbate manic symptoms. Risperidone's potent 5-HT2 receptor antagonism reportedly has antidepressive effects (Hillert et al., 1992; Keck et al., 1996). Dwight et al. (1994) reported exacerbations of manic symptoms in six schizoaffective bipolar patients receiving a high dose (8 mg/day) of risperidone without a mood stabilizer. Manic symptoms appeared to be dose-related in two cases reported by Lane et al. (1998). In the first case, the patient experienced a manic state with 3 mg/day risperidone, which subsided when the dose was reduced to 1.5 mg/day. In the second case, mania appeared after administration of 4 mg/day and was resolved when the dose was reduced to 2 mg/day. The authors proposed that the mood-altering properties of risperidone might be attributed to the dose-dependent differences in the forebrain dopamine disinhibiting effects of 5-HT2 antagonism, rather than in the receptor occupancy of the drug per se. Three additional reports describe the development of manic symptoms in patients receiving risperidone for schizophrenia. Two of the patients received 6 mg/day (O'Croinin et al., 1995; Tomlinson, 1996) and one received 9 mg/day (Diaz, 1996). Manic symptoms may not have been experienced with lower doses in these patients.

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Depression

Müller-Siecheneder et al. (1998) published a controlled study of risperidone in 123 patients (62 risperidone, 61 haloperidol plus amitriptyline) with DSM-III psychosis and depression (mixed diagnoses). Risperidone monotherapy (mean dose 6.9 mg/day) was less efficacious in patients with a major depressive episode and psychotic features than haloperidol (9 mg/day) plus amitriptyline (180 mg/day) after a minimum of 3 weeks, and to a lesser degree in patients with depressive-type schizoaffective disorder and schizophrenia or schizophreniform with major depressive symptoms. It was suggested that risperidone be combined with an antidepressant for these patients and that risperidone doses be lower than those used in this study.

In an open trial, augmentation of selective serotonin reuptake inhibitor (SSRI) therapy with risperidone in daily doses of 0.5-1 mg was followed by complete or almost complete remission in 8 patients with DSM-IV major depressive disorder without psychotic features. These patients had not responded to trials of SSRIs (fluoxetine or paroxetine) alone. Symptom reduction or declines in the Hamilton Depression Rating scale score were observed within 1 week or less of the introduction of risperidone in all cases (Ostroff and Nelson, 1999).

Hillert et al. (1992) reported results of an open trial in which risperidone (7 ± 2 mg/day) significantly reduced depressive and psychotic symptom ratings in all three patients with DSM-III-R depressive-type schizoaffective disorder and in four of seven patients with psychotic depression.

The concurrent use of risperidone (3-6 mg/day) in 10 patients receiving ECT for mood disorder caused no serious adverse events (Farah et al., 1995). The authors noted that in an uncontrolled setting it is difficult to determine whether this combination therapy speeded recovery, but they considered the results encouraging.

Keck et al. (1995) reviewed the records of 144 state hospital patients with DSM-III-R diagnoses of schizophrenia (34%), schizoaffective disorder bipolar type (40%), schizoaffective disorder depressive type (16%) bipolar disorder (8%) and major depression with psychotic features (2%). Risperidone was given alone in 55 patients and added to other psychoactive drugs in 89. Mean dosages were 7 mg/day in patients with no or minimal response and 6 mg/day in patients with moderate to marked response. Patients with a moderate to marked improvement were more likely to be younger, have a diagnosis of bipolar disorder or schizoaffective disorder, depressed type, and be less chronically ill. All three patients with psychotic depression responded to treatment.

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Summary

A double-blind study has been conducted in patients in the manic phase of bipolar disorder and risperidone monotherapy (6 mg/day) was found to be as efficacious as monotherapy with haloperidol or lithium. In several small open-label or retrospective studies, risperidone as an adjunct to mood stabilizers was efficacious in patients with acute psychotic mania, type I and II bipolar disorder, and for manic, aggressive and psychotic symptoms in juvenile patients. However, adjunctive risperidone (1.0-4.5 mg/day) was not effective in eight of 12 patients refractory to treatment with mood stabilizers. Dose-related manic symptoms have been reported with risperidone monotherapy. In a controlled study of patients with psychosis and depression, risperidone monotherapy (mean dose 6.9 mg/day) was not as efficacious as haloperidol plus an antidepressant. In open or retrospective trials in patients with depression, risperidone either alone or as an adjunct to antidepressant showed promise, and it was reported to be safe as an adjunct to ECT (at 3-6 mg/day).

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OBSESSIVE-COMPULSIVE DISORDER (OCD) AND OCD SPECTRUM DISORDERS

Obsessive thinking and compulsive behaviour occur in classic OCD and may also be found in Tourette's syndrome and in the irresistible urges of trichotillomania or compulsive gambling. Serotonin reuptake inhibitors are the treatment of choice for classic OCD but these alone usually only achieve a partial remission of symptoms. The addition of a neuroleptic for treatment-resistant patients is common, with reported efficacy in some patients. This is particularly the case when OCD occurs in the context of Tourette's tics, where conventional antipsychotics such as haloperidol have often been used. The anti-dopaminergic properties of antipsychotics may be useful in this disorder because dopamine levels have been found to parallel tic severity in children (Shaywitz et al., 1980). Frequent motor side-effects limit the use of conventional antipsychotics. Risperidone has been investigated as a first-line or adjunctive treatment for OCD, Tourette's syndrome, and trichotillomania. Its efficacy is suggested in four open-label studies and a retrospective chart review, as well as a number of case reports (Table 2).

Table 2

Table 2

In an open-label study, 21 patients with DSM-IV OCD refractory to SSRI treatment received adjunctive risperidone (range 0.5-8 mg/day), which significantly ameliorated their OCD symptoms. Fourteen (67%) patients had reduced OCD symptoms within 3 weeks, based on the investigators' clinical judgment and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Five patients with obsessive horrific mental imagery responded within 3 days. Five patients discontinued treatment because of side-effects including akathisia (n = 4), sedation (n = 2) and stiffness (n = 1). The high risperidone dosages may have accounted for the frequency of side-effects necessitating discontinuation. The authors suggest that adjunctive risperidone may enhance the effectiveness of SSRI by blocking serotonin receptors that have been down-regulated by chronic SSRI treatment (Saxena et al., 1996).

In an open study by Ravizza et al. (1996), seven of 14 patients with DSM-III-R OCD who had not responded to clomipramine alone or to clomipramine plus sertraline demonstrated good clinical improvement when 3 mg/day of risperidone was added to the regimen. Augmentation with risperidone was well tolerated.

Bruun and Budman (1996) gave risperidone to 38 patients with Tourette's syndrome in an open-label trial. The patients either had not responded to conventional treatments or had experienced intolerable side-effects. The mean risperidone dose at the end of the trial was 2.7 mg/day (range 0.5-9 mg/day). Of the 30 patients completing the 1-month trial, 22 (73%) were improved after treatment, as indicated by changes in the Yale Global Tic Severity Scale (Leckman et al., 1989), seven had no change in the severity of tics, and one patient worsened. Six (16%) of the 38 patients had EPS, and eight patients discontinued because of side-effects.

In another open study, Van der Linden et al. (1994) evaluated the efficacy and tolerability of risperidone in 11 patients with Tourette's syndrome. The patients had not responded to conventional neuroleptic drugs, which were withdrawn at least 1 week before the study. Risperidone was started at a dosage of 1 mg/day and gradually increased to a maximum of 6 mg/day at day 15. For the remaining 2 weeks of the trial, the dose was kept as constant as possible. Two patients withdrew from the study in the first 2 weeks, one because of lack of response and one because of feelings of depression. The remaining nine patients had reductions in the frequency and severity of their vocal and motor tics.

Stein et al. (1997) reviewed the charts of SSRI-refractory patients treated with an SSRI plus risperidone (1-4 mg/day) for OCD (n = 8), trichotillomania (n = 5) or Tourette's syndrome (n = 3). Three of the OCD patients were very much or much improved on the Y-BOCS, one was minimally to much improved, and three had no change in symptoms. Three of the five patients with trichotillomania had significant clinical improvement, one had good improvement and one was unchanged. The three patients with Tourette's syndrome had comorbid OCD, and only one showed significant improvement in tics and OCD symptoms. This patient discontinued risperidone treatment after 2 months because of worsening mood. Risperidone further improved tics in a second patient, whose symptoms were largely controlled by pimozide and fluoxetine. The third patient, whose symptoms were already controlled by pimozide and citalopram, had no further response to risperidone.

Four pediatric patients with OCD who had had an insufficient response to monotherapy with SSRI were treated with risperidone augmentation (Fitzgerald et al., 1999). Risperidone in doses of 0.5-1 mg/day improved symptoms in all four cases in the first 2 weeks.

Agid and Lerer (1999) reported a case of a man with severe DSM-IV OCD that was refractory to a variety of medications. The addition of 1.5 mg/day of risperidone to a paroxetine regimen markedly reduced the Y-BOCS obsessions score from 14 to 4 and the compulsions score from 20 to 2. The patient was able to function and interact, but in the third month of treatment symptoms of depression emerged. Withdrawal of medication led to return of OCD symptoms and the patient was restarted on paroxetine augmented with 0.5 mg/day of risperidone. At this dosage, OCD symptoms improved with fewer depressive symptoms.

A patient with Tourette's and OCD complicated by major depression, in a case presented by Giakas (1995), responded rapidly when risperidone (2-6 mg/day) was added to the fluoxetine regimen.

Two case reports further document successful treatment of Tourette's syndrome with risperidone. In the case described by Stamenkovic et al. (1994) a 35-year-old man had to stop treatment with haloperidol and fluphenazine because of severe side-effects or oversedation. After 1 week without medication, he was given 2 mg/day of risperidone, and the dose was slowly increased. After 2 weeks at a dose of 6 mg/day, the patient's severity of illness was reduced from a CGI score of 7 to a score of 5. Increasing the dose to 8 mg/day brought about no further improvement, but an increase to 12 mg/day resulted in a reduction of the CGI score to 3. Although this dose is substantially higher than that needed in most patients, this patient experienced no EPS throughout treatment with risperidone. In the second case, Shulman et al. (1995) described a 45-year-old man with an exacerbation of motor and vocal tics apparently precipitated by stress at work. He was started on 2 mg/day of risperidone. The tics diminished within 2 weeks despite the fact that his workplace situation remained unchanged. During the next 2 months, the risperidone dose was reduced to 1.5 mg/day because of akathisia. Nonetheless, risperidone continued to control the motor and vocal tics and the patient continued to take the medication.

Remington and Adams (1994) reported a case of a 56-year-old man with bipolar disorder in whom risperidone appeared to induce OCD. The patient had been maintained for some years on lithium and pimozide but switched to risperidone because of severe pimozide-induced tardive dyskinesia. With risperidone doses of 2-4 mg/day over the next 3 months, the tardive dyskinesia subsided somewhat, but the patient experienced increasing obsessive ruminations. When the dose was increased to 5 mg/day, an OCD syndrome returned that had not occurred in 30 years. These symptoms resolved within 2 days of discontinuation of risperidone. The authors theorized that risperidone's potent antiserotonergic action might further raise the increased dopaminergic activity postulated to be associated with OCD.

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Summary

No controlled trials of risperidone in patients with OCD or OCD-spectrum disorders have been conducted. In open-label studies or case reports, risperidone (0.5-8 mg/day) combined with an antidepressant was helpful in treatment-refractory OCD, and as an adjunct or alone was efficacious in Tourette's syndrome. Some patients discontinued treatment because of side-effects (mostly EPS) that may have been avoided if lower doses of risperidone had been used. There has been a case report of risperidone-induced (5 mg/day) OCD in a patient with bipolar disorder.

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DEMENTIA

Dementia related to Alzheimer's disease, multiple brain infarcts, diffuse Lewy body disease, or AIDS is often associated with behavioural symptoms (disinhibition, agitation, restlessness, aggression, wandering, inappropriate sexual behaviour, irritability and mood disturbance) as well as psychotic symptoms such as delusions and hallucinations (Reisberg et al., 1987; Tariot, 1996; Goldberg and Goldberg, 1997). Treatment of these behavioural signs and symptoms often depends on whether caregivers perceive the behaviour to be harmful to the patient, interfere with care, or endanger others. When caregivers cannot manage symptoms by avoiding precipitating factors or through behavioural modification programs, the patient may be a candidate for antipsychotic therapy.

The efficacy of risperidone in alleviating behavioural problems associated with dementia was confirmed in two double-blind, placebo-controlled, randomized trials involving more than 900 patients. Supporting evidence is provided by the results of an open trial, two retrospective studies, and a number of case reports (Table 3).

Table 3

Table 3

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Behavioural symptoms in dementia

Two 12-week double-blind studies established the superiority of risperidone over placebo in elderly patients with dementia. Katz et al. (1999) studied 625 patients with significant psychotic and behavioural symptoms associated with their dementia (DSM-IV Alzheimer's disease, vascular dementia, or both). Patients receiving 1 or 2 mg/day of risperidone had significantly greater reductions (P = 0.005 and P < 0.001, respectively) in the Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) at endpoint than did those receiving placebo. Among patients receiving 1 mg/day of risperidone, the frequency of EPS was not significantly greater than that among patients receiving placebo. Thus, the authors concluded that 1 mg/day of risperidone is appropriate for elderly patients with dementia with significant behavioural symptoms.

The double-blind study by De Deyn et al. (1999) included 344 elderly patients with dementia randomly assigned to placebo or flexible doses of risperidone (0.5-4 mg/day) or haloperidol. At week 12, risperidone-treated patients (mean dose 1.1 mg/day at endpoint) had significantly greater reductions in the BEHAVE-AD than did placebo-treated patients (P = 0.05), with aggressive symptoms showing the most pronounced improvement at both week 12 (P = 0.002) and at endpoint (P = 0.004). The severity of EPS with risperidone was not significantly different from that with placebo and was less than that with haloperidol.

Results of an open-label trial also suggest that risperidone can reduce behavioural disturbances in demented patients. Goldberg and Goldberg (1997) prospectively studied the effect of risperidone in 109 nursing home patients with dementia-related behavioural symptoms. Most patients received 0.25-0.5 mg of risperidone twice daily. The results showed risperidone was helpful in 38 of 100 patients evaluated for efficacy, moderately helpful in 26, slightly helpful in 17 and not helpful in 19. Seventeen patients discontinued risperidone because of over-sedation, postural hypotension, urinary retention, or agitation attributed to the drug. No adverse reactions were reported that were attributed to concurrent administration of risperidone and other medications (tricyclic antidepressants, SSRIs, antihypertensives, lithium, nitrates, digoxin, thyroid hormone, angiotensin-converting enzyme inhibitors, warfarin, insulin and H2 inhibitors).

Frenchman and Prince (1997) reported results of a retrospective review of risperidone (n = 60), haloperidol (n = 83), and thioridazine (n = 43) in patients with DSM-III-R or DSM-IV Alzheimer's dementia at 100 long-term care facilities. Patients were not receiving benzodiazepines. Target behaviours included violence (n = 74), shouting (n = 31), paranoia (n = 19), pacing (n = 3) or at least two such behaviours (n = 33). Staff evaluations showed the risperidone group (mean dose 1 mg/day, range 1-2 mg/day) had a significantly greater overall improvement than did the haloperidol and thioridazine groups (95%, 66% and 65%, respectively; P < 0.01). In addition, risperidone was associated with significantly fewer side-effects than haloperidol or thioridazine (7%, 22% and 18%, respectively; P < 0.001).

A chart review of outpatients who received risperidone for behavioural disturbances (agitation and hallucinations) associated with dementia yielded 41 patients for whom follow-up data were available. The mean risperidone dosage was 1.8 mg/day, and the mean duration of treatment was 4.2 months. The target symptoms of both agitation and psychosis were resolved completely in 15% of patients and partially in 41%; 32% of patients had new EPS or worsening of previous EPS, which was associated with longer duration of risperidone therapy (Irizarry et al., 1999).

In a report of five nursing home patients (four with DSM-IV Alzheimer's disease, one with vascular dementia), Jeanblanc and Davis (1995) demonstrated that risperidone (1.5-2.5 mg/day) resolved or markedly reduced dementia-related agitation or violent behaviour. These patients had not responded to conventional antipsychotics or benzodiazepines. The nursing home staff reported that behavioural improvement was maintained 12 weeks after discharge from the geropsychiatric unit.

Smaller case studies of the use of risperidone for dementia showed improvement in behavioural signs. Raheja et al. (1995) reported two cases in which risperidone resolved disruptive behaviour associated with vascular dementia. One patient, who was unresponsive to clonazepam, responded after 6 days of treatment with risperidone (1 mg three times daily). The second patient responded after 5 days of treatment with risperidone (1 mg twice daily) and clonazepam (0.5 mg/day). Risperidone (1.0-1.5 mg/day) reduced persistent purposeless vocalizations to less than 20% of baseline ratings in two geriatric inpatients with DSM-IV Alzheimer's and vascular dementia (Kopala and Honer, 1997). Both patients also experienced improved sleep duration but were not oversedated.

Jeste et al. (2000) prospectively studied 330 patients suffering from dementia for a median length of risperidone use of 273 days with a mean dose of 0.96 mg/day (SD 0.53). The 255 patients who commenced the study with no dyskinesia had a 1-year cumulative incidence of persistent emergent tardive dyskinesia of 2.6%. Patients with dyskinetic symptoms at baseline experienced significant reductions in the severity of dyskinesia at end of the study. The authors concluded that risperidone was less likely to cause tardive dyskinesia in this population than conventional neuroleptics.

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Lewy body disease

Reports are mixed concerning the EPS encountered in risperidone-treated patients with dementia associated with diffuse Lewy body disease. McKeith et al. (1995) warned that patients with Lewy body disease might be particularly sensitive to risperidone-induced parkinsonism. They reported three cases in which only 1 mg/day of risperidone caused severe EPS in elderly patients treated for persistent hallucinations associated with Lewy body disease. The authors postulated that this reaction is similar to the neuroleptic sensitivity that may be due to the steep reduction in striatal dopaminergic neurons that typically occurs with Lewy body disease, along with the inability to compensate by upregulating postsynaptic dopamine receptors. In another study, psychotic and behavioural symptoms in three patients with Lewy body disease were treated successfully with small doses of risperidone (0.5-1.0 mg/day) (Allen et al., 1995). The authors suggest that this treatment was useful but requires a controlled evaluation.

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AIDS-associated dementia

Conventional antipsychotics may fail to control psychotic or behavioural symptoms associated with AIDS dementia and may worsen existing AIDS-related movement disorders (Sewell et al., 1994). Singh et al. (1997) reported a case series of 21 patients with HIV or AIDS who received risperidone for psychosis (mean maximum dose, 3.3 mg/day; mean minimum dose, 1.8 mg/day). Of those, 13 patients (62%) became symptom-free, seven improved significantly, and one showed no response. Patients with manic symptoms fared particularly well. No serious adverse reactions were observed, and no haematotoxicity was associated with the drug.

Singh and Catalan (1994) also found risperidone (2-4 mg/day) to be effective in four men with HIV-related manic psychosis. All patients were receiving a variety of concomitant medications, and no EPS were observed.

Behavioural symptoms were safely controlled with risperidone (0.5-3.0 mg/day) in seven of nine patients with AIDS dementia-related agitation or restlessness. These patients had been unresponsive to haloperidol, fluphenazine, or thiothixene. All patients received lorazepam (0.5-1.0 mg/day) concomitantly (Belzie, 1996).

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Summary

In two large double-blind studies of risperidone in elderly patients with dementia, behavioural disturbances were significantly controlled (particularly aggression) and psychotic symptoms reduced. In both studies, a daily dose of 1 mg of risperidone was recommended. The results of several open-label studies or case reports of behavioural disturbances in dementia were similarly positive for risperidone (0.5-3 mg/day). Risperidone may not be appropriate for patients with Lewy body disease because of some evidence that it may induce parkinsonism. In AIDS-associated dementia, risperidone (0.5-4 mg/day) has improved psychotic and behavioural symptoms (open-label studies). Recent data suggest that risperidone is less likely than conventional neuroleptics to cause tardive dyskinesia in patients with dementia.

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PARKINSON'S DISEASE

Six open-label studies and a letter have described the use of risperidone in the treatment of L-dopa-induced hallucinations or psychosis in Parkinson's disease (Meco et al., 1997; Anguenot et al., 1998; Meco et al., 1998; Leopold, 2000)(Table 4). The most recent and largest open trial was that reported by Leopold (2000), in which 39 patients with parkinsonism and drug-related hallucinations received 0.5-3 mg/day of risperidone in addition to their antiparkinsonism drugs. The mean dose of risperidone was 1.1 mg/day. Twenty-three patients with Parkinson's disease had complete or almost complete (50-75% reduction in the Unified Parkinson's Disease Rating Scale) resolution of their hallucinations. Six had a lesser response, and six worsened. Five of the six patients who worsened had probable diffuse Lewy body disease. Risperidone (0.25-1.25 mg/day) reduced or eliminated chronic L-dopa induced hallucinations without worsening existing EPS in six patients with advanced Parkinson's disease (Meco et al., 1994). Workman et al. (1997) reported a significant improvement in agitation and in general psychiatric and global functioning in nine patients with Parkinson's disease who received risperidone (mean dose 1.9 ± 0.65 mg/day). These improvements were achieved without worsening EPS, further impairing cognition, or necessitating an increase in antidyskinetic medications. At a mean dosage of 1.1 mg/day, risperidone significantly reduced dopamine-induced psychosis and the severity of illness without exacerbating motor symptoms in an open-label trial in 17 patients treated for 12 weeks (Mohr et al., 1999). At endpoint, the Positive and Negative Syndrome Scale (PANSS) positive score dropped 66% from the baseline score (P < 0.001), principally reflecting improvements in delusions, hallucinations and suspiciousness or persecution.

Table 4

Table 4

In contrast, Ford and colleagues (1994) reported that risperidone at an average daily dose of 1.5 mg worsened parkinsonism in all six patients treated. The symptoms could not be corrected by increasing dopaminergic medication. Another report of six cases of psychosis in patients with akinetic-rigid syndromes who were treated with risperidone (range 1.0-4.0 mg/day) described exacerbation of parkinsonism in five patients (Rich et al., 1995). Four of these patients subsequently did well on clozapine therapy. Worsening of EPS might have been avoided, the authors noted, by using lower risperidone doses or increasing the dose more gradually.

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Summary

No controlled studies of risperidone for patients with Parkinson's disease have been published. In several open-label studies or case reports, risperidone (0.5-3 mg/day) controlled L-dopa-induced hallucinations and agitation without worsening existing EPS. However, there are two reports of worsened parkinsonism with risperidone at 1-4 mg/day.

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MENTAL RETARDATION AND OTHER DISORDERS OF CHILDHOOD

Antipsychotics are often used to manage aggressive or self-mutilating behaviour in persons with a developmental disability or mental retardation unresponsive to educational or behavioural modification programs. Conventional antipsychotics are not always effective, especially in autistic persons, and long-term treatment often causes EPS and tardive dyskinesia (Vanden Borre et al., 1993; Simon et al., 1996; Horrigan and Barnhill, 1997; Khan, 1997; McDougle et al., 1998). Safer and more effective agents are needed, particularly in view of evidence that behavioural symptoms in adolescence frequently continue into adult life and that longevity in this population is increasing.

One small double-blind, placebo-controlled, randomized trial has shown that risperidone is effective in reducing behavioural disturbances in mentally retarded patients and a second double-blind placebo-controlled study had similar findings in patients with conduct disorder without mental retardation. Additional supporting data for the efficacy of risperidone in childhood disorders are available from three open trials and a case report (Table 5).

Table 5

Table 5

Vanden Borre et al. (1993) conducted a double-blind, placebo-controlled crossover trial in 30 mentally retarded inpatients (aged 15-65 years). All patients had mild to profound mental retardation according to DSM-IV criteria. After a placebo run-in, patients received placebo or risperidone (4.0-12.0 mg/day) for 3 weeks as an add-on to existing medications (i.e. butyrophenones, phenothiazines, and benzodiazepines). This was followed by a 1-week, single-blind washout period and then another 3 weeks of crossover medication. In the first double-blind phase, responses were similar to both treatments. In the second double-blind phase, the total Aberrant Behaviour Checklist score declined in the risperidone-treated patients, whereas placebo had no effect. Although risperidone did not increase EPS, it frequently caused sedation or drowsiness.

Findling et al. (2000) treated 20 children (aged 5-14 years) with conduct disorder according to DSM-IV criteria but no mental retardation with risperidone or placebo for 10 weeks. Medications were increased at weekly intervals during the first 6 weeks of the study from an initial dose of 0.25 mg or 0.50 mg each morning, depending on patient weight. Patients weighing less than 50 kg had a maximum total daily dose of risperidone of 1.5 mg, while patients weighing 50 kg or more had a maximum total daily dose of risperidone of 3.0 mg. The primary outcome measure was the Rating of Aggression Against People and/or Property Scale. Risperidone was superior to placebo in ameliorating aggression on most measures and was reported to be well tolerated.

The effects of risperidone (3.0-8.0 mg/day) were determined in an open trial in 21 adults with moderate-to-profound mental retardation (IQ < 40) and various degrees of aggressive or self-mutilating behaviour. These patients were unresponsive to years of treatment with conventional antipsychotics and other psychotropic agents. Among eight patients treated for less than 1 year, behavioural symptoms became manageable in two patients at 3 months, two patients at 4-5 months, one patient at 6 months and two patients at 8-10 months. All 13 patients treated for more than 1 year improved markedly within 2-3 months; they were able to attend social and educational programs that they were previously unfit to attend. Risperidone was well tolerated without significant EPS, and pre-existing tardive dyskinesia improved in many patients within 3-6 months (Khan, 1997).

Lott et al. (1996) investigated the clinical and economic aspects of treating adults (aged 25-66 years) with mental retardation and behavioural disturbance with risperidone (1.0-8.0 mg/day). Of the 33 patients treated with risperidone in conjunction with behavioural intervention, 20 had (50% reduction in the frequency of one or more target behaviours. After 6 months of treatment, 85% were rated 'improved' and the rest were 'unchanged.' In addition, fewer staff workdays were lost because of assault by treated patients and treated patients increased their wage earnings.

Nicolson et al. (1998) in an open, prospective 12-week trial, assessed the benefits and side-effects of risperidone in young autistic children. All subjects were started at 0.5 mg daily with individual titration to a maximum of 6 mg or 0.1 mg/kg daily. Behavioural ratings, completed by the investigators and the children's parents, included CGI, Children's Psychiatric Rating Scale, Conners Parent-Teacher Questionnaire, Childhood Autism Rating Scale and Abnormal Involuntary Movement Scale. Ten boys (aged 4.5-10.8 years) were enrolled in the study and all completed the 12-week protocol. The mean final dose was 1.3 mg/day. On the basis of CGI-rated improvement, eight of the 10 children were considered to be responders. Improvement was also demonstrated on the other scales. Transient sedation was common, and the children gained an average of 3.5 kg over the 12 weeks of the study. There was no evidence of either EPS or tardive dyskinesia. The authors concluded that risperidone was safe and led to improvements in young children with autism.

Frischauf (1997) published a case study of an autistic man with auditory command hallucinations and depression who experienced remarkable and steady improvement, including a complete remission of the depression after administration of 1.5 mg of risperidone and 20.0 mg of buspirone twice daily for a few weeks

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Summary

In one controlled study of mentally retarded patients (adults and adolescents) and in one with children with conduct disorder, risperidone (4-12 mg/day in adults, 0.03-0.07 mg/kg/day in children) effectively controlled behavioural disturbances. In brief reports of uncontrolled studies, risperidone was also efficacious in ameliorating symptoms of autistic disorder in children (at 0.01-0.12 mg/kg/day) and an adult (at 1.5 mg of risperidone and 20 mg of buspirone twice daily).

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RISPERIDONE IN OTHER DISORDERS

An open trial and several case reports describe the use of risperidone in a variety of other disorders (Table 6).

Table 6

Table 6

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Organic catatonia

Catatonia associated with organic disorders, such as, infectious encephalopathies, metabolic derangements, hepatic or renal dysfunction, or drug toxicity often responds to benzodiazepines and ECT. In an unusual case report by Cook and colleagues (1996), catatonia that was refractory to a myriad of drugs, including antidepressants, clozapine, haloperidol, lithium, carbamazepine, trifluoperazine, thiothixene, amylobarbitone, lorazepam, alprazolam, clonazepam and propranolol, in addition to ECT, improved when the patient was given risperidone (6 mg/day). He appeared to arouse from catatonic stupor but had a relapse when the dose of risperidone was later reduced to 3 mg/day.

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Idiopathic segmental dystonia

Zuddas and Cianchetti (1996) found that risperidone (1.5-3.0 mg/day) reduced the duration and amplitude of sustained involuntary movements of idiopathic segmental dystonia in five patients (aged 17-65 years; age at onset, 7-61 years). Symptoms included spasmodic torticollis (n = 4), hemifacial or arm dystonia (n = 2), rotary arm movements with forced index-thumb opposition, flexion, and ulnar deviation of the wrist (n = 1). Symptoms had been unresponsive to anticholinergics and haloperidol. Risperidone was started after a 10-day washout period for previous medications, and patients were evaluated after four weeks of treatment. The efficacy of risperidone in these patients was consistent with the investigators' observation that a low-dose apomorphine test administered just before risperidone was started significantly ameliorated dystonias. Similar to risperidone, low-dose apomorphine acutely reduces dopamine and serotonin activity.

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Delirium

Risperidone may also be an effective alternative to conventional neuroleptics in the treatment of delirium. Sipahimalani and Masand (1997) presented their clinical experience with low doses of risperidone in two case histories (a 60-year-old man and a 14-year-old boy). Both patients improved significantly after starting treatment with risperidone (1.0-3.0 mg/day). The elderly man experienced some EPS, with upper-extremity stiffness and cogwheeling, but these were controlled with a dose adjustment.

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Personality disorder

Conventional antipsychotic agents are occasionally used in the management of severe personality disorders, such as the borderline type. These medications have been reported to be effective for the brief psychotic episodes these patients may experience as well as for reducing suicide risk. There is very little in the literature regarding the use of risperidone in personality disorder, although this medication may potentially have some usefulness (Szigethy and Schulz, 1997). This is suggested by a single case report in which risperidone (4 mg/day) dramatically decreased impulses in a patient with borderline personality disorder and a history of self-mutilation (Khouzam and Donnelly, 1997).

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Summary

No controlled trials in the treatment of other disorders have been published, but benefits of treatment with risperidone (1.0-6 mg/day) have been reported in organic catatonia (one patient), idiopathic segmental dystonia (five patients), delirium (two patients) and personality disorder (one patient)

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DISCUSSION

Although risperidone appears promising for a variety of disorders other than schizophrenia, much of the evidence has originated from uncontrolled studies, case series, or anecdotal reports. Moreover, many patients received multiple psychotropic agents and validated rating scales were not always used to evaluate efficacy. However, it is encouraging that there is now an emerging literature of controlled studies supporting risperidone's efficacy for a variety of conditions, particularly mood disorders, dementia and developmental disorders.

Antipsychotics are often used for the treatment of acute mania, particularly when there are psychotic features, are frequently added to mood stabilizers to rapidly control the psychotic symptoms that often occur in the manic phase of bipolar disorder and have a role in augmenting mood stabilizers in long-term therapy. Conventional antipsychotics may be more effective than mood stabilizers in acute mania, but there is no evidence that these agents have long-term benefits. Moreover, their chronic use may exacerbate depressive symptoms and increase EPS or tardive dyskinesia (Gelenberg and Hopkins, 1996; McElroy et al., 1996).

The efficacy of risperidone for acute or chronic therapy in affective patients must still be established through further double-blind controlled studies. At effective doses, risperidone poses less risk of EPS than do conventional agents and may be a useful alternative or adjunctive agent in this population. Its use in long-term management of bipolar disorder has not been established.

Reports have suggested that risperidone may have antidepressant as well as antipsychotic effects in patients with schizoaffective or psychotic mood disorder (Hillert et al., 1992; Keck et al., 1996). There have been a small number of reports of risperidone precipitating mania in predisposed patients.

Risperidone has also been studied in the obsessive-compulsive spectrum. It has been suggested that adjunctive risperidone may increase the effectiveness of SSRIs by blocking serotonin receptors that had been down-regulated by chronic SSRI treatment (Saxena et al., 1996; Stein et al., 1997).

Risperidone has also demonstrated efficacy in controlling dementia-related behavioural symptoms and is the only antipsychotic that has undergone well-controlled trials for this indication in two substantial studies. After reviewing clinical trials and expert opinions regarding the management of behavioural and psychotic symptoms associated with dementia, Defilippi and Crismon (2000) devised an algorithm in which they recommended risperidone as the drug of first choice for such patients. In fact, risperidone has recently been licensed for the treatment of behavioural symptoms in dementia in some countries. Two double-blind trials have shown that risperidone is significantly more effective than placebo for reducing psychosis and aggression in elderly patients with dementia (Katz et al., 1999; De Deyn, 1999). Dosages of approximately 1 mg/day are effective without a significant increase in EPS compared to placebo-treated patients. There is also one long-term study that indicates risperidone may be less likely to induce tardive dyskinesia in dementia patients than conventional neuroleptics (Jeste et al., 2000). While these data are encouraging, clinical trials that assess behaviour in demented patients are often confounded by a number of issues. These include selection, definition, and evaluation of target behaviours, target behaviours not defined in either the DSM or the ICD-10, Classification of Mental and Behavioural Disorders, the validity of existing rating instruments and selection of comparable treatment and control groups (Caine, 1996; Finkel and Cooler, 1996; Zaudig, 1996). Caine (1996) suggested that clinicians may be able to infer but never objectively measure the internal life of a patient with dementia.

Risperidone has also been shown to be effective in managing aggressive or self-mutilating behaviour in individuals with mental retardation (Vanden Borre et al., 1993; Khan, 1997), and it was well tolerated in these patients with no significant EPS. However, most of the data are short-term and the safety of risperidone in long-term use is not established. The use of risperidone in organic catatonia, idiopathic segmental dystonia, delirium and combination therapy with ECT provides further support for considering risperidone for indications other than schizophrenia.

The findings reported here encourage further studies to explore the use of risperidone and other atypical antipsychotics for indications other than schizophrenia. In particular, the risk-benefit ratio must be carefully assessed. Long-term treatment with conventional antipsychotics carries risks of serious adverse events, in particular, tardive dyskinesia. Increasing clinical experience suggests that the novel agents are associated with a lower risk for serious adverse events and tardive dyskinesia. Appropriate low-dose protocols are needed to maximize efficacy and minimize adverse events. Optimal doses have not been clinically established for the use of risperidone in many nonschizophrenic disorders other than dementia in elderly patients (1 ± 0.5 mg/day). However, based on the current literature, not necessarily on clinical evidence, conservative dosing guidelines for risperidone are suggested (Table 7). It should be kept in mind that the treatment can vary according to patient characteristics (including health, age, sex, diet, smoking status and other factors).

Table 7

Table 7

Until further indications are formally approved, risperidone should be used judiciously in nonschizophrenic patients, and a second opinion may be helpful. Close monitoring of symptoms and side-effects by use of standard rating scales is recommended. The medication should be withdrawn if clearly defined improvement is not observed within a specified period or if significant adverse events emerge. The growing body of literature suggesting that risperidone can be effective for a variety of conditions other than schizophrenia should be viewed positively and clearly deserves further investigation.

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      Keywords:

      risperidone; review; schizophrenia; mood disorders; obsessive-compulsive disorder; dementia; Parkinson's disease

      © 2001 Lippincott Williams & Wilkins, Inc.