The Effectiveness and Safety of Risperidone on Bipolar Disorders

Transcription

1 KISEP Review Clinical Psychopharmacology and Neuroscience 2003; 1(Supplement): The Effectiveness and Safety of Risperidone on Bipolar Disorders Won-Myong Bahk, Kyoung-Uk Lee KEY WORDS: INTRODUCTION Bipolar disorder is a mental illness with a relatively high incidence, high rate of recurrence and severe symptoms. The clinical symptoms of bipolar disorder vary extensively from mild hypomania or depression to severe mania or depression accompanied by psychotic symptoms. Longterm drug therapy is needed, because of the associated high rate of recurrence and suicide attempts, resulting in personally devastating outcomes that need to be prevented. The drugs of choice for the long-term or preventive treatment of bipolar disorder include lithium, valproate and carbamazepine. On the other hand, antipsychotics such as chlorpromazine and haloperidol have been used for a long time to treat bipolar patients before the introduction of lithium. 1,2 The primary reason for using antipsychotics in these patients is to quickly control the psychotic symptoms, excitement, agitation, and uncontrollable violent acts that would otherwise appear during the acute phase, since Address for correspondence: mood stabilizers including lithium require 12 weeks before taking effect. 3 Furthermore, it is known that for about 40% of patients with bipolar disorder during the early phase, and about 80% of patients with mixed manic and depressive episodes and rapid cycling episodes, a poor response to lithium is observed, so that antipsychotics have been used during the early phase in actual clinical settings. Although typical antipsychotics are effective for the treatment of acute mania, 4,5 they pose a high risk of tardive dyskinesia and extrapyramidal symptoms in bipolar patients, as compared with in schizophrenic patients. 6 Moreover, caution is needed when typical antipsychotics are used in manic patients, because typical antipsychotics could induce depression, worsen the cycles, and increase the risk of worsening the overall course of mania. 7,8 On the other hand, it was reported that atypical antipsychotics including risperidone are effective, not only for mania but also for depression in bipolar disorder, increasing the possibility of these drugs being used as mood stabilizers. It was also reported that these antipsychotics show few side effects. Recent studies of atypical antipsychotics focused on the efficacy of these drugs as mood stabilizers in the treatment of bipolar disorder. In Korea, risperidone was recently approved as an adjunctive drug in the treat- 157

2 158 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1supplement: ment of acute mania. Another atypical antipsychotic, olanzapine, was approved by the US FDA in 2001 for use in the treatment of acute mania alone or in with other drugs. Risperidone is also soon to be approved for the same indication. Although the number of double-blind studies on the efficacy and safety of risperidone has increased recently, it is still very small. Despite this limitation, the efficacy and safety of risperidone during the acute and maintenance phases of bipolar disorder, and the possibility of risperidone inducing mania, are discussed in the present study through a review of the literature. Trend of Using Risperidone in Bipolar Patients Clinically, typical antipsychotics have been used consistently and frequently in bipolar patients despite the risk of long-term side effects. According to previous studies, antipsychotics were administered in as little as 24%, up to as many as 100%, of bipolar patients Typical or atypical antipsychotics are used in the treatment of mania regardless of the presence of psychotic symptoms. Compared with the doses used in nonaffective psychoses, the doses of these typical or atypical antipsychotics used in bipolar patients do not differ at the early stage of hospitalization, but are significantly lower after discharge, although no difference was reported in the frequency of their administration. 13 Keck et al. 14 recently reported that the factors related with maintaining antipsychotics in bipolar patients are male gender, drug noncompliance before admission, the seriousness of manic symptoms, and the prescription of antipsychotics at the time of discharge. This trend is similar in Korea. According to the study by Kim et al. 15 who investigated the trend of drug treatment at one university hospital for 12 years from 1990 to 2001, antipsychotics were used along with mood stabilizers in 82.5% of males and 80.4% of females, and the degree to which these drugs were used in therapy did not change from 1990 to Most of the antipsychotics administered to bipolar patients were typical antipsychotics 95.3% until 1997, but atypical antipsychotics 87.8% have been used more frequently since Since 1998, risperidone was administered as an accompanying antipsychotic in 42.4% of patients. Furthermore, Bahk et al. 16 who investigated the trend of drug treatment in hospitalized bipolar patients due to acute mania in one university hospital, reported that antipsychotics were used along with mood stabilizers in 90.3% of the patients in 1998, and this rate increased to 100% in They also reported that the rate of combining the administration of risperidone with more than two anti-psychotics decreased from 38.7% in 1998 to 10.3% in 2001, whereas the rate of combining the administration of risperidone with only one antipsychotic increased from 54.8% in 1998 to 89.7% in The rate of combining the administration of risperidone with typical antipsychotics decreased from 38.7% in 1998 to 6.9% in 2001, whereas the rate of combining the administration of risperidone with atypical antipsychotics increased from 51.6% in 1998 to 93.1% in Risperidone was used in 37.9% of patients. The increased clinical use of atypical antipsychotics including risperidone in conjunction with mood stabilizers, both in Korea and abroad, may reflect the evolution of pharmacotherapy, as the efficacies of atypical antipsychotics become more widely known. Studies of Risperidone in Acute Mania As for the mood changing effect of risperidone, Hillert et al. 17 reported in 1992 that the depressive symptoms were improved in patients with psychotic depression, suggesting for the first time that risperidone has an antidepressive effect. In previous case studies, the effectiveness of risperidone was reported in bipolar or schizoaffective patients, mostly in the case of patients who did not respond to conventional mood stabilizers or could not tolerate their side effects. A series of case studies with a few patients 21 and studies that reviewed medical records11, reported that risperidone is effective in mood disorders. Open studies reported significant effects of risperidone alone or in with mood stabilizers. Open prospective studies about the efficacy of risperidone in bipolar disorder and schizoaffective disorder were investigated by screening Medline and reviewing studies conducted in Korea The number of patients, study period, diagnosis, average dose of risperidone, assessment tools, with mood stabilizers and rate of response were reviewed Table 1. In Korea, there were two retrospective studies 23,24 that reviewed medical records and three prospective study After evaluating CGI, global assessment of functioning GAF, and side effects in 97 patients who were admitted due to acute manic episodes 81 patients or acute depressive episodes 16 patients, Lee et al. 24 reported that the GAF score was higher in those patients with bipolar mania who were treated with lithium/risperidone 31 patients compared with those patients who were treated with lithium/haloperidol 50 patients, but this difference was not significant. However, the CGI score was significantly lower in those patients who were treated with risperidone/lithium. When those patients whose CGI scores were much improved or very much improved were considered as the response group, the rate of response was found to be 80.6% in those patients who were treated

3 159 Table 1. Summary on the effectiveness of risperidone in bipolar and schizoaffective disorders retrospective and open studies Study N Design Diagnosis Jacobsen et al 1995 Tohen et al 1996 Small et al 1996 McIntyre et al 1997 Ghaemi et al 1997 Ghaemi and Sachs1998 Vieta et al 1998 Licht et al 2001 Vieta et al 2001 Vieta et al 2001 Vieta et al 2002 Baik IH et al 1995 Lee MS et al 1999 Bahk WM et al 2001 Combination drug 013 open label bipolar disorder Mainly MS 008 open label acute mania 100% MS 011 single blind bipolar I disorder, LIC manic 007 open label 4 manic or hypomanic Mainly adjunct 2 depressed 1 euthymic 014 open label 5 manic/hypomanic 2 depressed, 5 mixed 1 psychosis 1 mood irritability 10 cases MS, 008 open label bipolar I dso Mainly MS 008 open label bipolar disorder 6 cases MS 014 open label bipolar disorder 5 cases MS, 095 open label schizoaffective disorder 541 open label 183schizoaffective, bipolar 299bipolar I dso 45bipolar II dso 14bipolar dso, NOS 84 cases MS 355 cases MS 174 open label bipolar I or II disorder Mainly MS 030 open label 30 mania Mainly MS 097 retrospective 81 acute mania Mainly LIC 16 acute depression 056 retropsective bipolar I disorder MSRPR 30 /MSOZP 26 Response criterion Duration wk Risperidone mean dose range mg/day Treatment response CGI % improved BPRS, YMRS BPRS25% YMRS75% CGI, GAS, % improved MRS, HAM-D CGI % improved CGI, GAF % improved CGI, GAF % improved YMRS, HAM-D % improved MAS, MES, CGI YMRS, HAM-D, CGI, BPRS YMRS, HAM-D, CGI, PANSS YMRS, PANSS, HAM-D, CGI 4 6 MAS 75% improved % improved % improved CGI84.2% improved or much improved CGI, BPRS % improved CGI, GAF LICRPR80.6% improved, LICHPD50% improved CGI, GAF % improved MS mood stabilizer, RPR risperidone, OZP olanzapine, LIC lithium, HPD haloperidol, CGIclinical global impression, YMRS Young mania rating scale, MRSmania rating scale, HAM-Dhamilton depression rating scale, PANSSpositive and negative syndrome scale, MAS bech-rafaelsen mania rating scale, MES bech-rafaelsen melancholia scale, BPRS brief psychiatric rating scale, GAFglobal assessment of functioning, with risperidone/lithium whereas 50% in those patients who were treated with haloperidol/lithium, showing a significant difference in the rate of response. Furthermore, no patient showed either occurrence or worsening of mania. However, present study has some limitations, such as it compared the CGI score rather than YMRS Young Mania Rating Scale score and the number of patients was quite small. According to Bahk et al. 23 who retrospectively investigated the medical charts of 56 patients diagnosed with bipolar disorder who were treated with risperidone average dose: mg or olanzapine average dose: mg in with mood stabilizers in a natural setting, both groups showed significant improvements after 4 weeks of admission compared with at the time of admission, when the treatment outcomes were evaluated by means of the CGI and GAF scores. However, the limitations of this study were the fact that it was a natural study and the treatment outcomes were evaluated only with the CGI and GAF scores. Paik et al. 35 who conducted an open study for 12 weeks in 42 bipolar mania treated with risperidone in with lithium or carbamazepine evaluated the efficacy and safety of risperidone using BPRS brief psychiatric rating scale, CGI, and the extrapyramidal symptom rating scale ESRS. They reported that risperidone was effective in the treatment of bipolar mania, since they found significant improvements in the CGI and BPRS scores in 30 patients

4 160 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1supplement: who completed the 12-week study out of total of 42 patients. However, there are some limitations of the current study. For example, it was a single open clinical study with insufficient number of participants. Also because the types and doses of the drugs varied according to the clinical symptoms from one week after the initial start of the study, accurate evaluation of the side effects and efficacy was difficult to measure. There is a large-scale clinical study, not yet been published. The study examined the prognosis in 400 bipolar patients for 6 weeks from May 7, 2002 in 50 major hospitals distributed throughout Korea. 36 Out of a total of 400 patients, 256 were inpatients and 144 were outpatients. The average age of these patients was years, and the average age of onset was years. The average number of previous hospitalizations was The number of patients with a history of previous treatment was %, and many of the patients were previously treated with mood stabilizers such as lithium or valporate along with benzodiapine. The average dose of risperidone was 3.09 mg/day. The most frequently used mood stabilizer was lithium at 53.4%, followed by valporate at 35.5% and carbamazepine at 9.1%. The average doses were mg/day Lithium, mg/day Valporate and mg/day Carbamazepine. Among all of the cases, 77.3% used a of drugs. The most frequently prescribed drug was benzodiazepine 176 cases. According to the YMRS, risperidone showed an efficacy within one week of its use. A more than 20 point-improvement was seen at the time of completion within 6 weeks of the study being started. Furthermore, less than 5% of the patients complained of slight side effects and the drop-out rate was also as little as 3.3%. Although this study is an open study without a control group, it is a large-scale study and its particular value is the fact that the efficacy of risperidone could be confirmed and epidemiological data were obtained for bipolar patients. Finally, there was a study which compared the effectiveness and tolerability of risperidone in with topiramate and divalproex for treating acute mania patients in a naturalistic treatment setting. 37 Seventy-four patients who met the DSM-IV criteria for bipolar mania were enrolled in this study. In order to assess the efficacy and the extrapyramidal symptoms EPS, the Young Mania Rating Scale YMRS, Clinical Global Impression CGI and Simpson-Angus Rating Scale SARS were measured at the baseline and at weeks 1, 3 and 6. From the baseline to the endpoint, the YMRS and CGI scores were reduced by 67.9% and 56.6% in the topiramate group TPMG. The YMRS and CGI scores were also reduced by 63.7% and 58.2% in the divalproex group DVPG. The weight and BMI increased significantly by 3.6% and 3.3% from the baseline to the endpoint in the DVPG, while they decreased by 0.5% and 0.4%, respectively, with no significant difference in the TPMG. There were no serious adverse events in either group. In this study, risperidone in addition to topiramate or valproate was effective and tolerable for treating acute mania. From these case studies, retrospective and open studies conducted both in and out of Korea, we concluded that risperidone could prevent the occurrence or worsening of mania, that it results in an anti-manic effect regardless of the presence of psychotic symptoms, and that it could be administered safely even in those patients who show side effects to typical antipsychotics, when it is administered in with mood stabilizers in bipolar patients. However, these open studies have some limitations, such as the bias of the evaluators or patients, and the lack of a placebo or control group. Also, it would be difficult to use these studies to draw general conclusions, since most of them did not include the sufficient number of participants. Furthermore, the effect of risperidone itself on bipolar mania could not be evaluated, since it was administered along with other mood stabilizers. An advance was made in the double-blind studies conducted to examine the efficacy of risperidone in acute manic patients Table 2. In 45 acute manic patients, Segal et al. 38 conducted a study comparing the treatment outcomes when using 6 mg of risperidone, 10 mg of haloperidol, or mg of lithium alone for 4 weeks. All evaluation scales including the BPRS, mania rating scale MRS, GAF, and CGI showed similar improvements in all 3 groups. The MRS score was decreased by 16.2 points in the risperidone treated group, by 14.6 points in the haloperidol treated group, and by 12.7 points in the lithium treated group; however, these differences were not significantly different. This study result suggests that risperidone alone is as effective as the other two drugs in controlling acute mania. Nonetheless, the limitation of this study was the fact that the number of participants was limited to 15 in each group, which created the possibility of significant differences being observed as the number of participants is increased. Although this study suggested that risperidone alone could be effective in the treatment of acute mania, it is frequently used in with other mood stabilizers in actual clinical settings. Therefore, double-blind studies were designed in which either risperidone or a placebo was administered in addition to mood stabilizers in patients with acute mania. A review of double-blind studies suggested that risperidone alone or in with mood stabilizers is effective in cont-

5 161 Table 2. Summary on the effectiveness of risperidone in bipolar and schizoaffective disordersdouble-blind studies Study N Design Diagnosis Combination Scale Segal et al 1998 Yatham et al 2000 Janicak et al 2001 Sachs et al double-blind randomized controlled LIC 15 HPD 15 RPR double-blind placebo controlled RPRMS /PLOMS 062 Double-blind, randomized RPR 30 HPD randomized, double-blind placebo controlled RPRMS 5251 HPDMS 53 PLOMS 51 bipolar I dso, manic mono MRS, BPRS, CGI, GAF bipolar disorder MS YMRS 3 33 schizoaffective, bipolar 29 schizoaffective, depressed mono PANSS, CARS-M, HAM-D Duration Dose wk mg 4 RPR 6, HPD 10, LIC RPR 5.5 HPD 10.8 bipolar disorder, mania MS YMRS 3 RPR 3,8 HPD 6.2 LIClithium, HPDhaloperidol, RPRrisperidone, MSmood stabilizer, PLOplacebo, YMRSyoung mania rating scale, PANSSpositive and negative syndrome scale, CARS-Mclinician administered rating scale for mania, BPRSbrief psychiatric rating scale, CGIclinical global impression, GAFglobal assessment of functioning rolling not only acute psychotic symptoms but also manic and depressive symptoms. Possibility of Risperidone Inducing Mania Risperidone is known to have both antimanic and antidepressive effects. Although it is used in both manic and depressive patients with mood disorders, previous studies reported that risperidone either induced mania in depressive patients, or worsening of the existing manic symptoms. 20,42-44 In Korea, Jung et al. 45 reported the first two cases of mania induced in schizophrenic patients, in which in one case mania developed within 23 days after administering risperidone at a total daily dose of 68 mg. The second patient showed an improvement in negative and positive symptoms with the use of 2 mg of risperidone for 38 days, but showed distinct hypomania within one week of the risperidone dose being increased to 3 mg. Mania was induced with the administration of risperidone alone in these two cases, in which no concurrent mood stabilizers were administered, there was no history of drug abuse, and no past or family history of mental illness or associated physical diseases. Jung et al. 45 reported that risperidone improved the negative symptoms of schizophrenia and affective symptoms by blocking serotonin and dopamine and showed an anti-depressive effect, and concluded that risperidone induced mania and hypomania in some patients. Chung et al. 46 also reported three cases of mania which developed due to risperidone in two schizophrenic patients and one patient with psychosis induced by amphetamine. They believed that the one schizophrenic patient might have developed affective disorder, with symptoms of excitement, elated facial expression, increased unstable activities. However, more detailed evaluation would be required whether these symptoms were indeed manic episodes. In the other schizophrenic case, ECT electroconvulsive therapy was conducted 22 times right up until the day before starting the administration of risperidone; thus, we could not tell whether the mood changes were due to ECT and whether risperidone was responsible for the symptomatic improvement which appeared when risperidone was maintained at 4 mg after it had previously been stopped and started again. From these results, differences in diagnosis probably constitute the single most important cause of the observed discrepancy between studies concerning the question as to whether or not risperidone induces mania. About 80% of the cases of risperidone-induced mania involved patients with schizophrenia or schizoaffective disorder, suggesting that differences in diagnosis might affect the reported occurrence of mania. Yoon 47 reported that the risk factors related to the induction/worsening of mania/hypomania and behavioral symptoms induced by risperidone are intractable mood disorder showing no antimanic effect with early treatment, intractable schizoaffective disorder especially of the bipolar type and cases showing no response to early treatment, acute worsening of chronic intractable schizophrenia especially in those cases showing response to early treatment, psychotic pattern, high dose especially, starting from the early phase of treatment, a sudden increase in dosage, the use of antidepres-

6 162 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1supplement: sants in intractable depression, and the use of risperidone alone for mania/hypomania. Furthermore, Aubry et al. 48 recently extensively reviewed previous manic cases induced by risperidone and olanzapine according to standard criteria. After reviewing 16 cases induced by risperidone and 10 cases induced by olanzapine, they reported that the causes of the induced mania were natural worsening due to an incomplete treatment effect, severe akathisia, the administration of additional antidepressants, temporary nonspecific behavior response to drugs, and sudden cessation or dose reduction of mood stabilizers. In short, despite the lack of sufficient case studies reporting that risperidone induces mania, it is generally accepted that risperidone, administered either alone or in with mood stabilizers, shows mood stabilizing effects including antimanic and antidepressive effects when the results of double-blind studies are compiled. Studies on the Tolerability of Risperidone It is known that typical antipsychotics pose high risks of inducing extrapyramidal symptoms and tardive dyskinesia and induce weight gain and sexual dysfunction when used in bipolar patients. 49,50 From the pharmacological viewpoint, an ideal drug would have an excellent efficacy, while inducing no side effects. Atypical antipsychotics come close to meeting these criteria and offer many benefits compared with typical antipsychotics when used in bipolar patients. According to the study that compared the extrapyramidal side effects of risperidone, clozapine, and typical antipsychotics in schizophrenics, 51 risperidone induced less extrapyramidal side effects compared with typical antipsychotics, but more compared with clozapine. Generally, risperidone induces fewer extrapyramidal side effects than typical antipsychotics with doses lower than 4 mg, while, at higher doses, the induction of side effects follows a dose-dependent pattern. 52 Meltzer 53 reported that risperidone induces extrapyramidal side effects in a dose dependent manner governed by the 5-HT2 : D2 ratio. When previous studies are reviewed comprehensively, the results are quite varied, ranging from one study that showed similar side effects of risperidone compared to those of haloperidol to another study, which reported that risperidone produced similar levels of side effects to that of a placebo. 22,29,33,38,40,54,55 One study conducted in Korea 24 reported that 8 patients treated with the haloperidol/lithium regimen experienced neurotoxic complications including delirium and confusion, to the point that this regimen was stopped. However, no side effects were seen with the risperidone/ lithium regimen, which indicated that combined risperidone therapy is safer. Furthermore, they found similar levels of extrapyramidal side effects in both groups. Twelve out of 45 subjects dropped out of the study conducted by Paik et al., 35 of which one dropped out due to severe extrapyramidal symptoms. When evaluating the extrapyramidal symptoms using ESRS, the scores of Parkinson symptoms, dystonia and dyskinesia were increased significantly by one week of drug therapy, but were not significantly different after 12 weeks, when compare to the pretreatment scores. The most frequent side effects, except for extrapyramidal symptom, were drowsiness 16 patients, followed by dry mouth, blurred vision, orthostatic dizziness, and nausea. Twenty 44% patients showed no side effects. Despite risperidone having almost no anticholinergic effect, they found that these side effects were probably due to the additional use of an antiparkisonian drug. Sedative effects such as drowsiness were probably due to lithium or carbamazepine. Despite the limitation in the study by Bahk et al., 36 due to their lack of objective rating scale for the neurological symptoms, they found the rate of extrapyramidal symptoms to be 17.9% 10 subjectsamong a total of 56 subjects in the group treated with both risperidone and olanzapine. Furthermore, akathisia was present in 30% of the patients treated with a of risperidone and one or more of drugs and 7.7% of the patients treated with a of olanzapine and one or more of drugs, showing a similar result as that observed in the study by Ghaemi, 56 who reported that akathisia is present in around 20% of patients treated with atypical antipsychotics. The other side effect of risperidone which has been reported is hyperprolactinemia, which occurs in a dose-dependent manner. 57 In a recent study conducted by Kim et al. 58 in patients with schizophrenia, the serum level of prolactine decreased when risperidone was switched over to olanzapine. Furthermore, another study reported that a sedative effect and a risk of diabetes are also seen with risperidone. 59 According to the study by Bahk et al., 36 the weight gain induced by risperidone is significantly lower than the weight gain induced by olanzapine in bipolar patients. In summary, the low doses of risperidone frequently used in mood disorders do not pose a substantial risk of neurologic symptoms such as extrapyramidal symptom and akathisia, and other side effects are slight, which suggests that it could be used safely for the treatment of bipolar patients. Studies on Mania in the Maintenance Phase There are fewer studies on risperidone in the treatment of mania during the maintenance phase than there

7 163 are during the acute phase, however amongst these there are two studies with a long-term follow-up period of 6 months. Ghaemi and Sachs 60 followed up 12 bipolar patients who were treated with mood stabilizers along with risperidone at 14.5 mg/day. They found that this regimen was effective in 8 participants, but that depressive episodes were seen in one subject. Four participants dropped out; two for due to side effects and remaining two for due to lack of efficacy. Unlike the response rate of 5060% found in acute mania, they found the response rate of 33%. Vieta et al. 31 investigated the efficacy and safety of risperidone in with mood stabilizers in bipolar and schizoaffective patients for 6 months. Among the total of 541 participants, 358 were bipolar patients and the rest 183 were schizoaffective patients. The 430 patients who completed the study showed significantly improved YMRS and HAM-D scores at 6-weeks and 6- months of treatment and significantly improved CGI and positive and negative syndrome scale PANSS scores at 4-weeks and 6-months of treatment. The average dose of risperidone was 3.9 mg/day. Although mania worsened in 2% of the patients within the first 6-weeks of treatment, this worsening was probably due to the natural course of bipolar disorder and schizoaffective disorder, and no serious side effects were present. This multi-center study, which included a large sample population in many centers and was performed over a long period of 6 months, showed the long-term efficacy of risperidone in bipolar disorder and schizoaffective disorder. These studies partially suggest that risperidone, when used for a long period of time, could be effective for depressive and manic episodes in patients with bipolar disorder. However, more studies on the maintenance phase are needed in order to come to an accurate conclusion. Efficacy of Risperidone in Bipolar Depression Although much is known about the treatment of unipolar depression, studies on drug treatment in bipolar depression are rare. Thus, bipolar depression is usually treated based on the treatment of unipolar depression. Clinicians experience much difficulty when treating bipolar depression, since there is not much data available on this topic and they need to prescribe a of drugs. 61,62 Bahk et al. 63 recommended mood stabilizers alone for the treatment of mild bipolar depression, a of mood stabilizers and antidepressants for moderate and severe bipolar depression, and a of mood stabilizers and antidepressants along with antipsychotics for the treatment of psychotic bipolar depression in Korea. Although typical antipsychotics are known to be effective for unipolar depression, 64,65 they increase the risk of depressive episodes in bipolar patients when used for long-term treatment. 7 On the other hand, atypical antipsychotics might be effective for treating bipolar depression, taking into consideration their action mechanisms and the results of previous studies in which they were used for the treatment of unipolar depression. 66 Nonetheless, no clear conclusion can be arrived yet, since there are almost no studies on the efficacy of risperidone in bipolar depression. Selection of Antipsychotics in Bipolar Disorder Both typical and atypical antipsychotics can be chosen for bipolar disorder. According to the Korean Medication Algorithm Project KMAP for bipolar disorder published by Bahk et al., 63 the initial drugs to choose for acute mania are a of mood stabilizers and atypical antipsychotics. Clinicians in Korea selected risperidone as the initial drug for the treatment of early psychotic, dysphoric, mixed and euphoric mania and hypomania and also preferred olanzapine and high-potency typical antipsychotics. Furthermore, they evaluated atypical antipsychotics as initial adjunct drugs for the treatment of bipolar depression with psychotic symptoms and adjunct drugs that could be used even in the early phase of rapid cycling type. Although various studies reported the antimanic effects of atypical antipsychotics when administered alone, Bahk et al. 63 in their KMAP for bipolar disorder recommend atypical antipsychotics in with traditional mood stabilizers for the treatment of mania, rather than atypical antipsychotics alone. And they recommended a of mood stabilizers and benzodiazepine for hypomania, and antipsychotics for psychotic mania. In the US on the other hand, risperidone, olanzapine, and high-potency typical antipsychotics are used as initial drugs for the treatment of psychotic mania; and olanzapine as the initial drug and risperidone and high-potency typical antipsychotics as the next line of drugs for dysphoric, mixed and euphoric mania. 67 CONCLUSION Treating bipolar disorder is a very difficult task for clinicians. The pathophysiology of bipolar disorder is difficult to understand and it is not easy to prepare a standard treatment protocol, due to the limited number of studies of bipolar disorder which have been conducted, as compared with the situation for schizophrenia.

8 164 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1supplement: At the current time, when we are better able to treat bipolar patients using many excellent drugs, and have a better understanding of the cause of bipolar disorder due to increased biological understanding, organizing the results of different studies, including clinical studies conducted in Korea and abroad on a certain drug, would be a very meaningful task. Furthermore, performing such a task would be in line with the KMAP prepared by compiling extensive experiences of psychiatrists in Korea for the treatment of bipolar disorder. Risperidone is a representative atypical antipsychotic that was first introduced in Korea in 1996 after it was approved by the US Food and Drug Administration FDA in Although clinicians in Korea have compiled much clinical experience in using risperidone over the past 7 years, there are only a few studies related to its use in the treatment of bipolar disorder in Korea and abroad. According to the studies that we examined in this paper, we are able to conclude that risperidone may be as effective as mood stabilizers with bipolar disorder, even when risperidone is used alone, and may be more effective when combined with mood stabilizers. We believe that the efficacy of risperidone persists during the acute and maintenance phases, and that risperidone has excellent long-term safety. However, it is still too early to come to a definite conclusion on the efficacy and side effects of risperidone, when it is used for a long period of time, such as longer than 6 months. We expect better results through more studies in the future. REFERENCES 1. Prien RF, Caffey EM Jr, Klett CJ. Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group. Arch Gen Psychiatry 1972; 26: Garfinkel PE, Stancer HC, Persad E. 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9 Ghaemi SN, Sachs GS, Baldassano CF, Truman CJ. Acute treatment of bipolar disorder with adjunctive risperidone in outpatients. Can J Psychiatry 1997;42: Ghaemi SN, Sachs GS. Long-term risperidone treatment in bipolar disorder: 6-month follow up. Int Clin Psychopharmacol 1997;12: Vieta E, Goikolea JM, Corbella B, Benabarre A, Reinares M, Martinez G, Fernandez A, Colom F, Martinez-Aran A, Torrent C. Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study. J Clin Psychiatry 2001;62: Licht RW, Bysted M, Christensen H. Fixed-dosed risperidone in mania: an open experimental trial. Int Clin Psychopharmacol 2001;16: Vieta E, Herraiz M, Fernandez A, Gasto C, Benabarre A, Colom F, Martinez-Aran A, Reinares M. Efficacy and safety of risperidone in the treatment of schizoaffective disorder: initial results from a large, multicenter surveillance study. 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10 166 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1supplement: antidepressant therapy. J Clin Psychiatry 2002;63: Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. The expert consensus guideline series: medication treatment of bipolar disorder Postgrad Med;2000. p DISCUSSION Kim SH Risperidone is recommended to be administered twice a day, but actually, many clinicians administer the drug once a day because of compliance. Does that administration seriously affect antipsychotic effect? Around 50% of my patients are administered twice a day and other 50% are administered once a day, but the latter doesn t seem to be harmed in recurrence. Would you like to share your experiences with me? Choi SK The Company recommends the once-a-day administration. Kim CH There is a report on the once-a-day administration, isn t there? The controlled study reported that there was no big difference between the once-a-day and the twicea-day administrations in efficacies. Kim SH However, the results seem to be incorrect in terms of pharmacokinetics, doesn t it? Choi SK The half-life of risperidone is longer than the half-life needed to twice-a-day dosing. Yoon DJ Typical antipsychotics are unidirectional with only antimanic effect and risperidone is bidirectional, but these are not hard to be considered to be mood-stabilizing effect. Also, although risperidone and clozapine are included in atypical antipsychotics, their thymoleptic effect is different each other. Risperidone serves as main drug for the monotheraphy to treat schizophrenia, but as to mood disorder, rather the thymoleptic effect than the antipsychotic effect of the drug is more useful. Should the dose of risperidone for monotherapy be different from that for mood stabilizer? Bahk WM In order to avoid confusion in bipolar disorder, therapy is mentioned separately. In addition, there have been few studies reporting the monotherapy of risperidone in bipolar disorder. Kwon JS Is the average dose of 4.4 mg of risperidone for therapy that is mentioned in the article written by Prof. Bahk? I remember that the data of my hospital was read in the CINP held in Belgium, According to the data that included the average dose for a year in mania, the average dose of risperidone in therapy was around 3 mg. The above-mentioned dose of 4.4 mg seems a bit high, and is similar to the dose to treat monotherapy for schizophrenia. What is also important is that the administration duration of risperidone when the drug is augmented. Bahk WM Although the dose of 4.4 mg was written, the article also mentioned that all the studies except one maintained the therapy. Prof. Kwon said that the dose might be decreased because of the, but considering the doses mentioned in foreign data or the data from the St. Mary s Hospital the average dose: 4.9 mg, the dose that is administered in actual clinical circumstance is not small. Although the dose might be decreased when the treatment became long-term, the initial dose should be high in order to control the irritability and agitation of manic patients. Also, olanzapine should be administered at a high dose in order to control the initial symptoms of bipolar mania, as 1520 mg of the drug is administered to treat schizophrenia in acute stage. A manic patient who was admitted to the St. Mary s Hospital was administered of 15.8 mg average of olanzapine during the admission. In other words, initial average dose shown in the data during admission may correspond to that in schizophrenia data. In fact the dose could be decreased in long-term treatment even though the data is not enough. Yoon JS I agree. Unless dopamine D2 is blocked more strongly by antipsychotics, symptoms are hard to control. Similarly, the initial dose of olanzapine should be high for short-term effect. Choi SK The top line results from studies to compare between risperidone-single therapy and placebo in bipolar disorder were issued at the end of last month. One study was performed in India, and the next one was in the U.S.A, and the results of both studies showed that risperidone was superior to placebo. The Company is prepar-

11 167 ing a submission to FDA for new indication. The average dose of the study in India was more than 5 mg, and that of the American study was about 4 mg. The Indian researchers attempted to increase the dose constantly. Yoon JS For clinicians who actually prescribed the drugs, the efficacies and side effects of drugs, for example, whether improve of aggravate mood symptoms should be clearly defined. That the difference of diagnosis could affect the efficacy or side effect is a vague explanation. Bahk WM Do you mean the possibility of risperidone to induce mania? In the article over three or four pages, I described controversial issues the possibility that the patient is not a real manic patient and, the mechanism that can be considered when mania is induced. Yoon JS According to the article of a foreign study that I have read, French researchers classify neuroleptics into unipolar and bipolar. Pharmacokinetically, risperidone is classified as a bipolar neuroleptic. The drug stimulates and irritates patients at a small dose, but make them sleepy at a high dose. On the other hand, olanzapine and quetiapine are unipolar neuroleptics. Because risperidone is not unidirectional based on the dose and the status of patient, the drug can produce therapeutic effect on some cases or side effects on other cases. Yoon DJ As I mentioned in the Ambiguity of Risperidone in Mood Disorder in the Journal of Biological Psychiatry Vol.4 No.2, 1997, the concept of the thymoleptic effects of antipsychotics was changed when SDA was introduced for clinicians. The blockade of serotonin produces antidepressant effect, while the blockade of dopamine produces antimanic effect. Due to its stronger blockade of serotonin, risperidone shows antidepressant effect at an initially small dose, and then gradually blocks dopamine when the dose is increased. As to the bipolar neuroleptics that were mentioned before, typical antipsychotics have only antimanic effect because the agents do not block serotonin, while SDAs have both antimanic and antidepressant effects but the degree is different based on the kinds. Conclusively, risperidone and olanzapine are considered to be superior in antidepressant effect, while clozapine is excellent in antimanic effect and has mood stabilizing effect that other SDAs do not have. Choi SK In the last symposium held by the Korean Society for Depressive and Bipolar disorders, it is controversial to determine the administration duration of lithium as mood stabilizer. However, the administration duration of anti-psychotics can be more critical issue. According to the data from the Seoul National University Hospital presented by Prof. Ha GS, the of antipsychotics was performed for 80% of the patients. Even in those cases, mood stabilizers should be maintained while anti-psychotics are excluded, as I knew. In addition, bipolar disorder has considerably different mechanism from schizophrenia. A question is always posed in the symposiums dealing with bipolar: what is the pathophysiology of bipolar disorder if antipsychotics, which is used to treat psychosis such as schizophrenia, should be constantly used for the treatment of bipolar disorder. Some say that antipsychotics can replace with mood stabilizers in the future. Would you present your future prospect on the subject, Prof. Bahk? Bahk WM In the principle for treating mania, antipsychotics were initially used in with mood stabilizers in order to control agitation by the antimanic effect, and in general, antipsychotics were replaced with mood stabilizers after the symptoms in acute stage were controlled. However, newly-developed atypical antipsychotics, as SDAs, serve as not only dopamine antagonists like typical antipsychotics but also serotonin antagonists, whose mechanism is different. Also, some researchers suggest that atypical antipsychotics are associated with various neurotransmitters to control mania and serve as mood stabilizer. In other words, atypical antipsychotics are being proved to have mood stabilizing effect. While only lithium and depakote out of many mood stabilizers are approved by FDA to be used to treat mania, olanzapine, which is newly put on sale, is already approved, and risperidone would be soon. This indicates the possibility of antipsychotics as mood stabilizer. The concept that atypical antipsychotics only serve as antipsychotics should be changed. The drugs can be used as psychotropic agent. We use carbamazepine as mood stabilizer, but we don't think the drug as anticonvulsant. Similarly, risperidone and olanzapine were initially developed as anti-psychotics but are being used as mood stabilizer as many reports suggest that the two drugs have positive results on bipolar disorder. I use the two as mood stabilizer in long-term therapy.