Risperidone as a Janus in Mood Disorder

KISEP Review Clinical Psychopharmacology and Neuroscience 2003; 1: 7-21 Risperidone as a Janus in Mood Disorder Doh Joon Yoon - Key points KEY WORDS: INTRODUCTION Address for correspondence: - - - - Risperidone is a novel antipsychotic agent reportedly more effective for the treatment of both the positive and negative symptoms of schizophrenia than typical antipsychotics, and the side effects of risperidone therapy have been shown to be relatively mild. 1 Considering its comparative merits of high therapeutic efficacy and mild side effect profile, the conducting of clinical trials of risperidone would represent a natural step forward, enabling us to examine its possible therapeutic application for the treatment of diverse mental illnesses, for which typical antipsychotics have been traditionally prescribed. Risperidone is indicated for various psychiatric conditions in a variety of age groups, including: obsessivecompulsive and related disorders, 2 delusional disorders, 3 tic disorders in children and adolescents, 4 adolescent psychoses, 5 pervasive developmental disorders, 6 beha- 7

8 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1: 7-21 vioral disturbances in patients with mental retardation, 7 self-mutilation in patients with Lesch-Nyhan disease, 8 dementia with psychotic symptoms, 9 organic mental disorders, 10 behavioral disorders and chronic psychoses in elderly patients, 11,12 senile dementia, 13,14 and hallucinations in patients with parkinsonism receiving L-dopa treatment. 15 On the other hand, it has also been reported that risperidone has a double-faced effect of both improving and exacerbating the symptoms of mood disorders. Firstly, we attempted to examine the therapeutic efficacy of risperidone in patients with mood disorders by reviewing published reports on risperidone therapy. Since clozapine, a prototype of serotonin-dopamine antagonist SDA, was proved to have antidepressant, antimanic, and mood-stabilizing effects, 16 studies of risperidone, as the other SDA, were also performed in order to evaluate its possible thymoleptic effects. The first report 17 which described risperidone s thymoleptic effects pointed out that risperidone alone demonstrated antidepressant effects in patients with psychotic major depression and schizoaffective disorder of the depressive type. Furthermore, risperidone therapy, either alone 18,19 or combined with mood stabilizers, 20-24 was shown to demonstrate antimanic effects in manic patients. The therapeutic efficacy of risperidone combined with mood stabilizers for refractory rapid cycling bipolar disorder was initially reported by Vieta, et al. 25 However, it has not yet been established that risperidone monotherapy has the same kind of mood stabilizing effect, as does clozapine. 26 On the contrary, there have been a few studies which suggested that risperidone induced or exacerbated the manic symptoms of mood disorders. Dwight, et al. 27 presented a quite intriguing observation that risperidone therapy for patients with schizoaffective disorder of the bipolar type, administered alone or concomitantly with mood stabilizers, induced mania in depressed patients and exacerbated existing manic symptoms in manic patientsthis happened to be the first paper on risperidone-induced mania. In contrast, risperidone monotherapy in depressed-type patients was reported to demonstrate an antidepressant effect without inducing mania. Furthermore, risperidone therapy, administered either alone 28 or in combination with mood stabilizers, 29 induced mania in patients with schizoaffective disorder of the depressive type. The results of these initial papers were corroborated by subsequent studies, in which the manic induction of risperidone added to antidepressants was observed in patients with psychotic major depression 30 or schizophrenia, 28,31-35 and the exacerbation of existing mania was observed in manic patients, following administration of risperidone either alone 19)36) or in combination with mood stabilizers. 28,29 These results suggested that risperidone might have antimanic as well as antidepressant efficacy, which is different from typical antipsychotics which manifest only antimanic efficacy. 37 If the dual efficacy of risperidone is proven, risperidone might have potential uses for patients with depression as well as with mania. On the other hand, risperidone could manifest psychiatric side effects by inducing mania in depressed patients or by exacerbating existing manic symptoms in manic patients. Before the introduction of risperidone to clinicians, manic induction was demonstrated only as psychiatric side effects following administration of antidepressant drugs. 38 Mood disorder is known as a risk factor for antidepressant-associated mania. 39 In this review article, we aimed to present a therapeutic guideline for the use of risperidone, by performing a review of the literature concerning mania induced by psychotropic drugs, the thymoleptic effects of antipsychotic drugs, the therapeutic efficacy of risperidone in mood disorders, manic induction and exacerbation following risperidone therapy in mental illnesses, and the mechanism, pathophysiology and clinical significance of its double-edged thymoleptic effects. PSYCHOTROPIC-INDUCED MANIA The administration of psychotropic drugs is sometimes complicated by their psychiatric side effects, including: 1 akathisia and neuroleptic dysphoria, anticholinergic syndrome, induction of rapid cycling in bipolar disorder, and supersensitivity psychosis and cholinergic rebound as withdrawal symptoms, following the administration of antipsychotic drugs, 2 anticholinergic syndrome, serotonin syndrome, induction of mania/hypomania in depression, induction of rapid cycling in bipolar disorder, induction of psychotic symptoms in schizophrenia, and cholinergic rebound as a withdrawal symptom following the administration of antidepressant drugs, 3 withdrawal symptoms and behavioral disinhibition caused by antianxiety drugs, and 4 induction of rapid cycling in bipolar disorder caused by lithium. 38 Rapid cycling bipolar disorder is not caused by the drugs themselves, but is due to the accelerated cycles of bipolar symptoms, which already existed, often with frequent relapses, even before the medication was administered. 40 However, manic induction, as a psychiatric side effect, had previously been reported only in cases of antidepressant medication.

9 Antidepressant-associated mania is observed in both depression of bipolar disorder and unipolar depression major depressive disorder, and it poses a more serious problem in the case of bipolar disorder, with a higher frequency being observed in type I than in type II. In bipolar I disorder, it is manifested as mania or hypomania, and in bipolar II disorder, only as hypomania. Antidepressant-associated mania is induced more often when the natural course of bipolar disorder progresses from mania to depression, than when it progresses from depression to mania. Moreover, in idiopathic bipolar disorder, the illness generally progresses from depression to mania and the healthy intervals become shorter with the progression of the illness, which makes it more difficult to differentiate the adverse effects of the medication from the natural course of the disease. 41 Because antidepressant-associated mania generally follows a mild and transient course, in comparison with idiopathic mania, the former might be considered as a different phenomenon, not as a true manic episode. 42 Furthermore, antidepressant-associated mania is a risk factor for rapid cycling bipolar disorder induced by antidepressant drugs. 43 In addition, two case reports were published, describing the induction of mania 44 or rapid cycling in bipolar disorders, 45 which followed the withdrawal or dosage reduction of antidepressants i.e., antidepressant-withdrawal mania. These findings were different from those of the antidepressant-induced mania described above. These initial studies were followed by numerous reports on antidepressant-associated mania in anxiety disorder, 46 panic disorder, 47,48 obsessive-compulsive disorder, 49,50 and schizophrenia. 51,52 All of these studies indicated that the side effects described above were common phenomena shared by many affective-spectrum disorders, 53 which are biologically related to mood disorders, such as panic disorder, phobia, obsessive-compulsive disorder, and eating disorder. In the group of patients in which mania emerged during the administration of antidepressants antidepressant-induced mania, the following risk factors were identified female gender, mood disorders especially, bipolar I disorder, past and family history of mood disorders especially, bipolar I disorder, long-term or high-dose medication, and combined therapy for refractory depression. In patients in which mania emerged following the withdrawal of antidepressant drugs antidepressant-withdrawal mania, the following risk factors were identifiedfemale gender, mood disorders especially, major depressive disorder, past and family history of mood disorders especially, major depressive disorder, long-term or high-dose medication, sudden discontinuation or dose reduction of antidepressants, and tricyclic antidepressants and monoamine oxidase MAO inhibitors but excluding reversible inhibitors of MAO-A. 39 THYMOLEPTIC EFFECTS OF ANTIPSYCHOTIC DRUGS With the introduction of SDAs, including clozapine and risperidone, the traditional concept of the thymoleptic effect of antipsychotic drugs has been called into question. Because typical antipsychotic drugs demonstrate only antimanic effect, not accompanied by antidepressant or mood-stabilizing effects, they have a tendency to accelerate the disease cycles in some patients, without preventing the recurrence of depression in the case of bipolar disorder. For some depressions without psychotic features which respond poorly to antidepressant medication, small-dose administration of typical antipsychotic drugs often helps to alleviate the symptoms. 53 Because clozapine demonstrates antimanic as well as mood-stabilizing effects related to dopaminergic blockade and antidepressant effects related to serotonergic blockadeless potent than its antimanic effect, it displays a higher therapeutic efficacy for schizoaffective and bipolar disorders than for schizophrenia. 37 Because risperidone manifests more potent antidepressant effect than antimanic effect, but no mood-stabilizing effect, 54 it would be expected to have moodstabilizing and antimanic effects when given in low doses or combined with mood stabilizers. On the other hand, high-dose risperidone monotherapy induces mania or exacerbate existing manic symptoms in patients with mood disorder, schizoaffective disorder, or schizophrenia, owing to its excessive antidepressant effect. 31,37 Therefore, risperidone is now belong to psychotropic drugs which could induce mania, in addition to antidepressant drug. THERAPEUTIC EFFICACY OF RISPERIDONE IN MOOD DISORDER In order to investigate double-faced thymoleptic effects of risperidone in mood disorders, we first categorized the published data on risperidone medication into two groups; one group demonstrating the anticipated therapeutic effects and the other group demonstrating manic induction/exacerbation following risperidone therapy. As an initial step for this study, we collected case reports and case series by searching the Medline data-

10 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1: 7-21 base, where risperidone was reported to have therapeutic effects without inducing or exacerbating mania in patients with mood disorders or schizoaffective disorders. Because the main focus of this study was the thymoleptic effect of risperidone, we did not pay much attention to side effects, other than the induction or exacerbation of mania, during our data analysis. Schizoaffective disorder is not classified as a mood disorder, but was included in the analysis because it also manifests mood symptoms. A careful search of the literature revealed a total of 12 case reports, for which the details of the diagnoses are as follows original articles listed in Table 1: 6 cases of treatment-resistant bipolar I disorder 4 mania, 2 dysphoric mania, 1 case of refractory major depression, 2 cases of refractory dysthymic disorder, and 3 cases of refractory schizoaffective disorder 2 bipolar type mania, 1 depressive type. All of these cases were characterized by refractoriness to treatment, which might reflect the fact that risperidone is generally prescribed when typical antipsychotics have failed or when the patients are obliged to stop taking typical antipsychotics due to intolerable side effects. For bipolar mania, risperidone monotherapy with an average maximum dose of 4.5 mg/day range 210, which is a relatively low dose, for a mean duration of 32.7 days range 1060 had antimanic effect in mania patients with psychotic features. Risperidone therapy following a similar schedule, while maintaining or adding mood stabilizers, was also effective in patients with dysphoric mania Clinical Global Impression CGI 6. The CGI scoring system consisted of 7-step scales: 1very much worse, 2 much worse, 3 worse, 4 unchanged, 5 mild improved, 6 much improved, Table 1. Case reports of risperidone therapy in mood and schizoaffective disorders Patient # Age/ Sex Diagnosis Dosage (mg/day) /Duration of therapy (days) Risperidone Maximal dose Mood disorder Titration pattern Bipolar disorder, manic Concurrent mood stabilizers & other drugs CGI Drug response Latency to first efficacy (days) 1 18 34/F Refractory bipolar I, manic with psychotic feature 10/21 G D/D:lithium 900/30, haloperidol 10/30 7 2 2 18 23/M Refractory bipolar I, manic with 3/10 CD D/B:lithium NA 7 Few psychotic feature 3* 19 33/M Refractory bipolar I, 2/56 CD 7 NA manic with psychotic feature 4* 19 44/M Refractory bipolar I, 2/28 CD D/D:valproate NA, 6 NA manic with psychotic feature haloperidol NA 5 24 43/F Refractory bipolar I, dysphoric mania 8/21 G M:lithium 1600/56, 6 Soon carbamazepine 800/56 6 24 31/M Refractory bipolar I, dysphoric mania 2/60 R C:carbamazepine 1000/NA 7 4 Depressive disorder 7 55 NA/M Refractory recurrent major depression 3/60 G M:phenelzine 6075/NA 7 2 8 56 31/F Refractory comorbid dysthymia & 2/180 G M:fluvoxamine 200300/NA 6 NA borderline personality disorder 9 57 27/M Refractory comorbid dysthymia & Pedophilia 6/NA G M:fluoxetine 2080/70 7 7 1 19 40/M Refractory schizoaffective disorder, manic with psychotic feature 2 13 67/F Refractory schizoaffective disorder, manic with psychotic feature & TD/senile dementia 3 58 69/F Refractory schizoaffective disor, depressive with psychotic feature Schizoaffective disorder Schizoaffective disorder, bipolar type, manic 6/NA CD C:fluphenazine 20/NA 6 NA 1.5/14 G M:lithium 1050/NA 7 7 Schizoaffective disorder, depressive type 6/28 R M:lorazepam 4/NA 7 NA :Discontinued due to side effects excluding manic induction or exacerbation, C:Combined at the beginning of risperidone RIS therapy, CD: Constant dose, CGI; 1: Very much worse, 2: Much worse, 3: Worse, 4: Unchanged, 5: Mild improved, 6: Much improved, 7:Very much improved, D/B:Discontinued at the beginning of RIS therapy, D/D:Discontinued during RIS therapy, G: Gradually increased from a low dose, M:Maintained both before and after the beginning of RIS therapy, NA:Not available, R: Reduced dose, TD:Tardive dyskinesia

11 and 7 very much improved. In 3 out of 4 cases of mania patients # 1 to 4 in Table 1, mood stabilizers were continued until the initiation of risperidone therapy or maintained for a while after the start of risperidone therapy only to be stopped at a later time. For major depression without psychotic features and dysthymic disorder, the addition of risperidone to maintained antidepressants demonstrated antidepressant effect CGI6, at an average maximum dosage of 3.6 mg/ day range 26, for 120.0 days on average range 60180; excluding 1 case, for which the duration of medication was not specified. For schizoaffective disorder manifesting psychotic features, risperidone therapy in combination with typical antipsychotics or the maintenance of mood stabilizers for bipolar type mania and risperidone monotherapy for depressive type demonstrated antimanic and antidepressant effects CGI6, respectively, at an average maximum dosage of 4.5 mg/day range 1.56 for 21.0 days on average 14 and 28 days, data obtained from 2 cases; 1 case was excluded, in which the duration of medication was not specified. Of a total of 12 cases, dose titration patterns were variedgradually increased from low doses in 6 cases, maintained at low doses in 3 cases, reduced in 2 cases, or maintained at a high dose in 1 case. Usually, the therapeutic effect began to emerge within one week of risperidone therapy excluding five cases, where relevant data were not available; see Table 1. The major findings of the above mentioned case-report analysis can be summarized as follows: 1 risperidone monotherapy demonstrated antimanic efficacy in patients with bipolar disorder mania patients # 1 to 4 in Table 1 with refractory cases and psychotic features at a relatively low dose, as compared with the recommended dose for schizophrenia but the effect of concomitant mood stabilizers should not be neglected in these cases, except for patient # 3, 2 for dysphoric mania, risperidone therapy in combination with the maintenance or addition of mood stabilizer was required due to its refractoriness to treatment, 3 in patients with depressive disorder, low-dose risperidone therapy, combined with the maintenance of antidepressants, but not mood stabilizers, demonstrated antidepressant effect without manic induction, 4 in patients with schizoaffective disorder of the bipolar type, risperidone therapy combined with typical antipsychotics or maintenance mood stabilizers demonstrated antimanic effect, 5 in patients with schizoaffective disorder of the depressive type, antidepressant effect was observed without the combination of mood stabilizers, 6 in most cases, risperidone medication was gradually increased from an initial low dose, maintained at a low dose or reduced, 7 therapeutic efficacy emerged after less than a week of medication, 8 antidepressant effect was observed following a gradual increase in dosage from an initial low level or the reduction of risperidone dose without the use of a concomitant mood stabilizer, and 9 risperidone monotherapy manifested antimanic effect at a maintenance dose of 2 to 3 mg/day patients # 2 to 4 or following a gradual increase up to the dose of 10 mg/day patient # 1. The Medline search brought up a total of 19 case series source references listed in Table 2, including 9 cases of bipolar disorders 8 type I, 1 type I and II, 3 cases of major depression, and 7 cases of schizoaffective disorders 2 bipolar, 3 depressive, and 2 unspecified types. In this analysis, a patient was judged to exhibit improvement when the CGI of the patient after treatment was above or equal to 5. For patients with bipolar disorder, the improvement rate CGI5 ranged from 33.3 to 100% following the administration of risperidone with a mean dosage ranging 1.9 to 6.5 mg/day 1 case series was excluded from the analysis, because it specified only the maximum dose for 19.9 weeks on average range 260, and in most cases mood stabilizers were maintained or added to the risperidone therapy. An improvement rate CGI5 of 100% was observed for the treatment of major depression, with risperidone monotherapy, at a mean dosage of 2.5 to 7.2 mg/day for 10.3 weeks on average range 615.5. For the treatment of schizoaffective disorders, the improvement rate CGI5 ranged from 50.0 to 100% 1 case series was excluded, because the relevant data was not specified at a mean dosage of 1.9 to 7.0 mg/day 1 case series was excluded, because the mean dosage was not specified for 6.8 weeks on average range 39.5; 2 case series were excluded, because the duration was not specified. In those case series of the bipolar type and in former case series in which the type was not specified, mood stabilizers were maintained, but in those case series of the depressive type and latter case series in which the type was not specified, risperidone was administered in the form of a monotherapy Table 2. The results of the above case series can be summarized as follows. In patients with bipolar disorders, manic induction/exacerbation could be avoided even following long-term, high-dose risperidone therapy, if mood stabilizers were combined or maintained during risperidone therapy. Furthermore, following risperidone

12 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1: 7-21 Table 2. Case series of risperidone therapy in mood and schizoaffective disorders Diagnosis Number of all patients Number of cases with CGI 5 % Mood disorder Bipolar disorder, manic Mean dosage mg/day/duration of therapy weeks Bipolar I disorder, manic 22 11 11 100 6.0/8 C:lithium Concurrent mood stabilizers Bipolar I disorder, manic 20 30 30 100 5.6/12 C:lithium, carbamazepine Bipolar I disorder, manic with psychotic feature 23 13 12 92.3 5.1/2 M:lithium, valproate, carbamazepine Bipolar disorder, manic, depressed &mixed Refractory bipolar I disorder, mixed with/ without psychotic feature 13 02 01 50.0 1.9/3 M:Ca antagonist, clonazepam Bipolar I II disorder, mania/hypomania, mixed with/without psychotic feature 59 16 14 87.5 3.3/9 M:lithium, valproate, carbamazepine n=12 Refractory bipolar I disorder, 4 manic/hypomanic, 2 depressed 21 06 04 66.7 16*/60 M:lithium, valproate, carbamazepine Refractory bipolar I disor, 2 manic/hypomanic, 3 depressed, 4 mixed, 3 rapid cycling 60 12 04 33.3 2.8/24 M:lithium, valproate, carbamazepine Refractory n=9 bipolar I disor, 5 manic/hypomanic, 2 depressed, 6 mixed with 1 psychotic feature 61 14 12 85.7 2.8/6.4 M:lithium, valproate, carbamazepine, felbamate n=11 Bipolar I disor, 7 manic, 2 depressed, 2 mixed 26 11 11 100 6.5/9.5 M:lithium, valproate, carbamazepine n=11 Depressive disorder Major depressive disor with psychotic feature 59 04 04 100 2.5/15.5 Major depressive disor with psychotic feature 26 03 03 100 6.5/9.5 Major depressive disor with psychotic feature 17 05 05 100 7.2/6 Schizoaffective disorder Schizoaffective disorder, bipolar type Refractory schizoaffective disor, bipolar 13 03 02 66.7 1.9/3 M:lithium, Ca antagonist Schizoaffective disor, bipolar 26 58 30 51.7 6.5/9.5 M:lithium, valproate, carbamazepine n=41 Schizoaffective disorder, type unspecified Refractory schizoaffective disor 62 04 02 50.0 6.1/6 M:valproate n=3 Refractory schizoaffective disor 63 14 NA NA NA Schizoaffective disorder, depressive type Schizoaffective disor, depressive 27 02 02 100 7.0/NA Schizoaffective disor, depressive 26 23 20 87.0 6.3/9.5 Schizoaffective disor, depressive 17 03 03 100 6.6/6 :Maximum dose, C:Combined at the beginning of risperidone RIStherapy, CGI;1:Very much worse, 2:Much worse, 3:Worse, 4:Unchanged, 5:Mild improved, 6:Much improved, 7:Very much improved, M:Maintained both before and after the beginning of RIS therapy, NA:Not available therapy with maintained or added mood stabilizers, the improvement rates were higher for patients with bipolar disorder manic type than for those patients with depressed, mixed, or rapid-cycling types of bipolar disorders. In addition, risperidone therapy for major depression demonstrated rather a high improvement rate, with or without concomitant mood stabilizers. Finally, the improvement rates were lower in patients with schizoaffective disorder of the bipolar type, even with the administration of concomitant mood stabilizers, as compared with those patients of the depressive type with risperidone monotherapy. MANIC INDUCTION AND EXACERBATION BY RISPERIDONE IN MENTAL ILLNESSES Analysis of Case Reports on Manic Induction/Exacerbation Following Risperidone Therapy in Mental Illnesses Antidepressant-associated mania is also reported to complicate patients with obsessive-compulsive disorder, panic disorder, phobia, generalized anxiety disorder, depersonalization disorder, or eating disorder, beside patients with mood disorder, for whom antidepressants are mainly prescribed. Accordingly, when utilizing the Medline database, the published case reports on rispe-

13 ridone-associated mania were searched for all mental illnesses, including mood disorders, for which risperidone is indicated. A review of the literatures indicated that the clinical features of risperidone-associated mania differed from those of antidepressant-associated mania in several aspects: 1 risperidone might induce behavioral stimulation such as anxiety, insomnia, and restlessness, characterized by less severe symptoms than those associated with mania and hypomania, 2 risperidone exacerbated the existing manic symptoms in some manic patients, and 3 no reports describing mania following risperidone withdrawal, manic induction in obsessive-compulsive disorder, or the induction of rapid cycling bipolar disorder were found in our search of the literature Table 3. The total number of case reports on risperidone induction/exacerbation of mania was 15 and the details of the diagnoses are as follows: 7 cases of schizophrenia, 6 cases of mood disorders 5 cases of mania of the bipolar I disorder, 1 major depression, and 2 cases of schizoaffective disorder all of the depressive type. All of the cases of mood and schizoaffective disorder included in these reports were refractory to treatment and manifested psychotic features, whereas all schizophrenic patients were chronic cases and manifested positive symptoms following the acute exacerbation of the disease, and 71% of schizophrenic patients were refractory to treatment. In patients with obsessive-compulsive disorders in whom antidepressant-associated mania was reported, 49,50 risperidone-induced mania had not been observed, which might be explained by the following observations: 1 risperidone is prescribed less often for obsessive-compulsive disorders than for cases of schizophrenia, schizoaffective disorders or mood disorders, 2 the pathophysiologic features of these illnesses and obsessivecompulsive disorders are different, or 3 the pharmacological actions of antidepressants and of risperidone are different. All cases of bipolar mania exhibited bipolar I disorder n=5, in which mania was exacerbated n=4 or behavioral stimulation became apparent n=1 following risperidone therapy with a mean maximum dose of 5.6 mg/day range 28 for 22.0 days on average range 360 days; 1 case was excluded, because the duration was not specified. Risperidone was administered alone in 2 cases, added to maintenance mood stabilizers in 2 cases, or substituted for lithium while maintaining typical antipsychotic drug in 1 case, and, in these cases, the improvement rate CGI5 reached 20.0% following the administration of risperidone. Compared with the cases presented in Table 1, which summarizes antimanic effects of risperidone therapy patients # 16, risperidone was started at higher doses than those commonly prescribed for obtaining antimanic effect, and mood stabilizers were often not maintained in these cases, which might account for the fact that manic exacerbation was occurred without any antimanic effect being produed. In these cases, manic exacerbation became apparent after a considerable duration, whereas antimanic effect appeared in less than a week in the cases presented in Table 1. This indicates that the antimanic effect and the exacerbation of mania depend on the duration of therapy as well as on the dosage of risperidone. In one case of major depressive disorder in which an antidepressant was maintained, risperidone induced mania without showing any antidepressant effect at a maximum dose of 4 mg/day for 8 days. In a similar to cases of depressive disorders without psychotic features patients # 78 of Table 1, risperidone treatment with gradual escalation of the dosage, starting from an initially low dose, induced mania at a comparable maximum dosage, without demonstrating any antidepressant effect. This indicates that the pathophysiology of depression might be different among these cases, depending on the presence or absence of psychotic symptoms. In 2 cases of schizoaffective disorder of the depressive type, mania was induced without any symptomatic improvement being observed, following risperidone therapy initiated at an average maximum dose of 3.2 mg/ day range 2.54 while discontinuing or maintaining mood stabilizers. In contrast, in patients with schizophrenia, a higher 85.7% improvement rate CGI5 was attained at an average maximum dose of 5.4 mg/ day range 1.59, but mania/hypomania or behavioral stimulation was also induced, following risperidone medication lasting 19.0 days on average range 143; 1 case was excluded because the duration was not specified. Patients # 6 and 7, with non-refractory diseases, manifested the induction of mania/hypomania as well as symptomatic improvement, following risperidone therapy with a low dose of 2.3 mg/day on average range 1.5 3see Table 3. In contrast to the dosage level administered in cases of mood disorder, here the risperidone dosage level was characterized by a relatively high dose being attained, in most cases, after gradually increasing it from an initially low-dose. In a total of 15 cases, the past histories of mental illnesses were as follows: 2 cases of chronic schizophrenia, 7 bipolar I disorders, 2 major depressions, and 2 schizoaffective disorders. Family psychiatric histories

14 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1: 7-21 were not available in 10 cases. Four cases did not have any family psychiatric history related to mental illness and 1 case had a family history of conduct disorder. Thus, in many cases, the family history information was not available. Accordingly, we were not able to exclude the possible contribution of family psychiatric history Table 3. Case reports of risperidone-induced mania/manic exacerbation in mood disorders and all other mental illnesses Patient # Age/ Sex Diagnosis 1 29 32/F Refractory bipolar I disor, manic with psychotic feature 2 28 47/M Refractory bipolar I disor, manic with psychotic features 3 19 42/M Refractory bipolar I disor, manic with psychotic feature 4 19 52/M Refractory bipolar I disor, manic with psychotic feature 5 19 45/M Refractory bipolar I disor, manic with psychotic feature 6 30 44/M Refractory recurrent major depressive disor with psychotic feature 1 29 29/M Refractory schizoaffective disor, depressive with psychotic features 2 28 42/M Refractory schizoaffective disor, depressive 1 35 46/M Refractory chronic schizophr, acute exacerbation & TD 2 34 31/F Refractory chronic paranoid schizophr, acute exacerbation 3 28 44/M Refractory chronic disorganized schizophr, acute exacerbation 4 33 50/M Refractory chronic schizophr, actue exacerbation & mild mental retardation 5 32 57/F Refractory chronic schizophr, acute exacerbation Risperidone Maximal dose Mood disorder Bipolar disorder, manic Depressive disorder Schizoaffective disorder Dosage mg/day Titration pattern Concurrent mood stabilizers & Other drugs 6 CD M:lithium, valproate 6 CD M:lithium, valproate Schizoaffective disorder, depressive Schizophrenia Refractory chronic schizophrenia Chronic schizophrenia 2 R 4 8 CD 4 6 CD D/B:lithium M:perphenazine 4 G M:doxepine, Alprazolam 2.5 NA M:valproate 4 4 CD D/B:lithium, perphenazine CGI 4 6* 4 4 4 Drug response Manic induction or exacerbation Latency to onset days/ Duration of RIM days Manic exacerbation 3/1.5 Manic exacerbation NA Manic exacerbation 3/NA Manic exacerbation 60/NA Behavioral stimulation** 21/NA Manic induction 8/3 Manic induction NA/2 Manic induction 2/14 6 G M:haloperidol 5*** Manic induction 21/60 6 G 4 Hypomanic induction 7/NA 6 NA 6 Manic induction NA 9 G 6*** Manic induction 40/39 6 G 6 Behavioral stimulation** 1/4 6 31 22/F Chronic schizophr, acute 1.5 CD C:alprazolam 5 Manic induction 7 31 29/M exacerbation Chronic paranoid schizophr, 3 G 6 2/NA Hypomanic induction acute exacerbation 43/5 :Improvement of psychotic symtpoms. :Behavioral stimulation:anxiety, insomnia, restlessness. :Improvement of negative symptoms, C:Combined at the beginning of risperidone RIS therapy, CD:Constant dose. CGI;1:Very much worse, 2:Much worse, 3:Worse, 4:Unchanged, 5:Mild improved, 6:Much improved, 7:Very much improved. D/B:Discontinued at the beginning of RIS therapy. G: Gradually increased from a low dose. M: Maintained both before and after the beginning of RIS threapy, NA: Not available, R:Reduced dose, RIM:RIS induced mania/manic exacerbation, TD:Tardive dyskinisia

15 towards the patient s present condition in these cases. In this respect, it should be pointed out that many of the authors concern did not recognize the importance of possible genetic vulnerability in those patients manifesting side effects of medications. As a treatment for manic induction/exacerbation following risperidone medication, risperidone was discontinued in 13 out of 15 cases, and the details of the discontinuation schedules were as follows; 1 risperidone was discontinued and replaced by typical antipsychotics in 4 cases, 2 risperidone was simply discontinued without any substituting medication in 3 cases, 3 risperidone was replaced by combined medication comprising typical antipsychotics and mood stabilizers in 2 cases, 4 risperidone was replaced by combination therapy of mood stabilizers and benzodiazepine in 2 cases, 5 risperidone was discontinued while maintaining mood stabilizers in conjunction with a typical antipsychotic in one case, 6 and risperidone was replaced by combined medication comprising typical antipsychotic, mood stabilizer, and benzodiazepine in 1 case. In one case of manic induction/exacerbation following risperidone therapy, risperidone dosage was reduced and in another case manifesting behavioral stimulation, benzodiazepine therapy was initiated while maintaining risperidone medication without any modification of dosage. The outcomes of these treatments were complete improvement in 11 cases, partial improvement in 2 cases, no improvement in 1 case, and unspecified in 1 case. Among these 13 cases, in which risperidone was discontinued, patient # 2 with bipolar I disorder manifesting psychotic features 28 experienced a temporary improvement of psychotic symptoms following medication comprising 6 mg/day of risperidone and the concomitant maintenance of mood stabilizer, which resulted in exacerbation of mania. In this patient, mania improved following the discontinuation of risperidone, but psychotic symptoms deteriorated leading tothe reinstitution of 3-mg/day risperidone medication. Antimanic and antipsychotic effects became apparent with the subsequent reduction of risperidone dose to 2 mg/day. The results of the case-report analysis described above were compared with those obtained from the analysis of Table 1, where both the antimanic and antidepressant effects of risperidone were observed without induction/ exacerbation of mania. Risperidone monotherapy for bipolar disorder mania exacerbated manic symptoms in patient # 3 of Table 3 even at a low dose 2 mg/day. However, in other patients with bipolar disorder mania, risperidone therapy initiated at a relatively high dose, exacerbated mania without manifesting any antimanic effect, irrespective of whether mood stabilizer was maintained or discontinued or whether typical antipsychotics were maintained. This observation is different from that of patients # 24 of Table 1, wherein risperidone monotherapy, initiated at a relatively low dose, demonstrated antimanic effect without manic exacerbation. In other words, in the patients with mania listed in Table 1, antimanic effect was observed within a week of risperidone monotherapy being given at low doses, while in the patients with mania of Table 3, mania was exacerbated well beyond the period when the antimanic effect became apparent in the patients listed in Table 1. This finding might be explained by the efficacy of risperidone being dose-dependent: risperidone has more of an antimanic effect at a low dose, whereas its antidepressant effect becomes more prominent with increasing dosage, eventually resulting in manic exacerbation. Thus, in patient # 2 of Table 3, in whom risperidone medication was discontinued, only to be reinstituted later on, manic induction was dependent on the risperidone dosage, which might be explained both by the peculiar pharmacokinetic property of risperidone, in that the ratio of the D 2 /5-HT 2 blockades induced by risperidone depended on the doses, and by the observation that the mania and psychotic symptoms might have different pathophysiological mechanisms. In patient # 1 of Table 1 mania of bipolar I disorder, antimanic effect was observed without manic exacerbation following risperidone monotherapy of 10 mg/day, which was achieved by a gradual increase from a small dose. However, in patient # 3 of Table 3 with the same diagnosis, mania of bipolar I disorder, only manic exacerbation was observed, without any antimanic effect being exhibited, following 2-mg/day risperidone monotherapy, wherein the dosage was only one fifth of that in patient # 1 of Table 1. The different responses in these two patients, following the administration of the same drug but with different doses, points to the importance of the gradual titration of the risperidone dosage, and to the fact that although these two patients had the same psychiatric diagnosis, their diseases might have different underlying pathophysiology. In addition, it is suggests that the manic induction/exacerbation could not easily have been predicted, based on the maximum dosage of risperidone and the presence of adjuvant mood stabilizers. In those patients with schizophrenia, the psychotic symptoms improved at first during risperidone treatment, while the dose was being gradually increased, but mania/ hypomania or behavioral stimulation was eventually induced, though at a higher dosage than that observed in

16 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1: 7-21 patients with mood and schizoaffective disorders. This observation suggests that the improvement of psychotic symptoms and induction of mania resulting from risperidone therapy might have different underlying mechanisms. Most of the cases of manic induction/exacerbation listed in Table 3 were refractory to treatment: 100% for both mood and schizoaffective disorders, and 71% for schizophrenia. Risperidone, whose pharmacological actions are different from those of typical antipsychotics, did not improve the symptoms of mood and schizoaffective disorders, whereas it improved the symptoms of schizophrenia at the initial stage of medication, though eventually producing psychiatric side effects. This suggests that risperidone exhibits different therapeutic efficacy and side effects, as compared to typical antipsychotics, and that these differences depend on the underlying pathophysiology of mental illnesses. All of the patients with schizophrenia were chronic cases and mania/hypomania was induced only when the positive symptoms worsened following the acute exacerbation of the disease, at which time acute changes in neurotransmissions are to be anticipated. This observation implies that the positive symptoms of schizophrenia and mania might share some common biological mechanism. Prevalence of Manic Induction/Exacerbation Following Risperidone Therapy in Mood Disorders as Revealed by the Analysis of the Case Series To examine the prevalence of manic induction/exacerbation during risperidone therapy, a Medline search was conducted for case series of mood disorders and schizoaffective disorders manifesting mood symptoms. A total of 3 case series of bipolar disorders and 1 case series of schizoaffective disorders were available for analysis source references listed in Table 4. Sixty percent of patients with mania/hypomania of refractory bipolar I disorder experienced exacerbation of mania or behavioral stimulation during risperidone treatment. Risperidone monotherapy excluding 1 case series, for which the use of monotherapy was not clearly stated of a mean dosage of 3.8 mg/day excluding 1 case series, for which the mean dosage was not specified resulted in a low improvement rate CGI5 ranging from 40.0 to 50.0%. This result is consistent with the observation summarized in Tables 1 and 3, that if antimanic effect was not observed at the initial stage of risperidone treatment, mania tended to deteriorate at a later stage of therapy. The close correlation of the low improvement rates and risperidone monotherapy in the patients listed in Table 4, and the high improvement rates and the concomitant use Table 4. Case series and prevalence of risperidone-induced mania/manic exacerbation in mood and schizoaffective disorders No. of cases & Prevalence % Risperidone-induced symptoms Diagnosis at time of treatment No. of cases with CGI 5 % Mood disorder No. of Patients Mean dose mg/day /Duration of therapy 6 60.0 5 50.0 10 0.51.0***/NA Dose-related behavioral stimulation* in 3 of the 5 patients experieced a therapeutic effects. Increase in hypomanic/manic symptoms in 3 of the 5 who did not experience a therapeutic response. Refractory bipolar I disorder, hypomanic/manic 36 3 60.0 2 40.0 5 NA Manic exacerbation Refractory bipolar I disorder, manic 63 Concurrent mood stabilizers 3 60.0 2 40.0 5 3.8/3 days-3 months D/Dvalproate n=1 NA Behavioral stimulation* n=1 Manic exacerbation n=2 D/Blithium n=1 Refractory bipolar I disorder, manic 19 Schizoaffective disorder 6 100 3 50.0** 6 7.0/NA Mlithium n=1 Switch of, or increase in, manic symptoms Cvalproate n=1 Schizoaffective disorder, bipolar 3 depressed**, 1 manic, 2 mixed 27 :Behavioral stimulation:anxiety, insomnia, restlessness, :Schizoaffective disorder, bipolar type, depressed, :Dose range. C:Combined at the beginning of risperidone RIS therapy. CGI;1:Very much worse, 2:Much worse, 3:Worse, 4:Unchanged, 5:Mild improved, 6:Much improved, 7:Very much improved. D/B:Discontinued at the beginning of RIS therapy, D/D:Discontinued during RIS therapy, M:Maintained both before and after the beginning of RIS therapy, NA:Not available

17 of mood stabilizers in the patients with the same mania listed in Table 1, is compatible with the observation that in the mania cases of Table 3, the improvement rate was low and the mania was also exacerbated, even with the concomitant administration of mood stabilizers. In mania/hypomania case series of refractory bipolar I disorder, antimanic effect was observed in some patients undergoing risperidone treatment, and with increased doses of risperidone, symptoms of behavioral stimulation began to appear, while in the other patients, mania/ hypomania was exacerbated, without any antimanic effect being manifested. 36 In another case series involving mania of refractory bipolar I disorder, some patients experienced exacerbation of mania and others symptoms of behavioral stimulation. 19 The results of these two reports might explain the observation that the wide spectrum of risperidone effects, i.e. antimanic effectbehavioral stimulation-exacerbation of mania/hypomania, is a dose-related phenomenon. In all schizoaffective disorders of the bipolar type 3 depressed, 1 manic, and 2 mixed types, manic induction/ exacerbation was observed during risperidone therapy. In these patients, the risperidone dosage was rapidly escalated to 7 mg/day, and the administration of mood stabilizer was maintained or added for only a few patients, which resulted in an initial improvement in patients with depression, but this was eventually followed by manic induction 27 see Table 4. Risk Factors for Manic Induction/Exacerbation From the analysis of the cases listed in Tables 1 to 4, the risk factors for mania induction/exacerbation during risperidone treatment were identified as follows: refractory mood disorders especially, when the antimanic effect was not observed at the initial stage of treatment for mania of bipolar I disorder; refractory schizoaffective disorders especially, bipolar type and others without any initial therapeutic effect; acute exacerbation of refractory, chronic cases of schizophrenia especially, if the initial treatment was effective; psychotic features; a high dosage especially, at the initial stage of medication; rapid escalation of dosage; combined therapy of antidepressants for refractory depression; and risperidone monotherapy for mania/hypomania. PHARMACOLOGICAL MECHANISM OF DOUBLE-FACED THYMOLEPTIC EFFECTS Risperidone has the unique neuropharmacological property of blocking both dopamine D 2 and serotonin 5-HT 2 receptors. Furthermore, it is reported that risperidone has a significantly higher affinity for D 2 receptors than for D 1 receptors, and that the ration of its affinity for D 2 /5-HT 2 receptors is rather low. Thus, potent blockade of serotonin receptors might cause improvement of some psychiatric symptoms such as anxiety, depression and anergia. Together with dopaminergic antagonism, serotonergic blockade also alleviates the negative and mood symptoms of schizophrenia. Schizophrenic patients with marked negative and mood symptoms were shown to have an increased serotonin receptor density, which might lead to increased serotonergic activity, tending to suppress dopamine release from the prefrontal cortex, and to diminished cognitive and social functions. Thus, the strong blockade of 5-HT 2 receptors by risperidone increases dopamine release from the prefrontal cortex, producing to an improvement in patients negative and mood symptoms. Nonetheless, excessive stimulation could induce mania/hypomania. 54 Although the different affinities of risperidone for D 2 and 5-HT 2 receptors form the basis of its dual pharmacological actions, in clinical settings, the disparate receptor occupancy of the various neurotransmitter receptors becomes more significant from a clinical perspective.animal studies with rats indicated that, while 5- HT 2 receptors are preferentially occupied at a low doses of risperidone, 64,65 the effects of D 2 blockade become significant at higher doses, becoming dominant when the dose of risperidone is sufficiently. 64,66 At low doses, the inhibition of the dopamine system can be attributed to the indirect modulation of dopaminergic transmission by the antagonistic action of risperidone on the 5-HT 2 receptors, whereas, at higher doses, it can be attributed to the direct action of risperidone on the dopamine receptors. 67 With a low dose of risperidone, sufficient to occupy 25% of the D 2 receptors of the striatal and limbic systems, 60% of the 5-HT 2 receptors and 25% of the other neurotransmitter receptors are found to be occupied. 68 With a relatively high dose of risperidone 6 mg/day, the images produced by positron emission tomography PET revealed a very high occupancy rate of D 2 receptors of the basal ganglia and 5-HT 2 receptors of the neocortex 80 and 90%, respectively. 69 Based on the results of animal studies and clinical trials, we might attempt to explain the dose-related, doublefaced thymoleptic effects of risperidone in patients with mood disorders manifesting derangement of the serotonin and dopamine systems. Although antidepressants without dopaminergic action might to expected to induce mania and rapid cycling bipolar disorder via serotonergic mechanism, risperidone does not induce rapid cycling

18 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1: 7-21 bipolar disorder, because it also acts on the dopamine system. If the patient is given a minimal effective dose of risperidone, by gradually titrating the dosage from an initially low dose, the effects of 5-HT 2 blockade emerge initially, with antidepressant effect, followed by the subsequent appearance of antimanic effect caused by gradual D 2 blockade. However, if the risperidone therapy is started using a high dosage level, above the minimal effective dose, or if the dosage is rapidly escalated, the initial potent blockade of serotonin receptors could surpass the effect of the gradually increasing blockade of dopamine receptors. Accordingly, the strong antidepressant effect of the serotonergic blockade might exceed the antimanic effect of the dopaminergic blockade, which would then give rise to manic induction/exacerbation. As a result, a cascade of risperidone effects occurs, consisting of a varying proportion of antidepressant effect-antimanic effect-behavioral stimulation-induction/exacerbation of mania and hypomania, depending on the risperidone dosage and the duration of medication. Manic induction in the case of mood disorder could be explained by means of the permissive hypothesis of serotonin, which constitutes one of the possible pathophysiological theories on mood disorder, and which presumes that manic induction results from a deficit of serotonin system, which normally suppress the norepinephrine and dopamine systems. 41 Thus, risperidone might cause the serotonin reservoir to become depleted, as seen in the case of mood disorder, resulting in increased levels of dopamine and norepinephrine, which might cause manic induction. 33 PATHOPHYSIOLOGICAL AND CLINICAL SIGNIFICANCE OF DOUBLE-FACED EFFECTS Antidepressant-associated mania has two main variables on which the pathophysiological mechanism of the symptoms depends, i.e. the various antidepressant and diverse mental illnesses such as, mood disorder, schizophrenia, phobia, panic disorder, obsessive-compulsive disorder, generalized anxiety disorder and eating disorder. In contrast, risperidone-induced mania is caused by a single causative agent risperidone, which has a constant pharmacological action in diverse mental illnesses, including mood disorder, schizoaffective disorder and schizophrenia. The observation that some patients with different mental illnesses may experience the common symptoms of mania, following the administration of either risperidone or antidepressants, which produce a constant pharmacological actions, suggests that these illnesses, which are diagnosed only on the basis of the manifested symptoms, without understanding the underlying causative factors, are actually heterogeneous disease entities, which might share certain biological factors. 53 The observation that risperidone has a dual pharmacological action might help clarify the underlying pathophysiology of these illnesses. In particular, the observation that mood disorder and schizophrenia are related to mania induced by antidepressants or risperidone strongly suggests that these diseases might have some close biological connection. It also indicates that the blockade of 5-HT 2 receptors plays an important role in the pharmacological action of some antidepressants, mood stabilizers, anti-anxiety drugs, and of risperidone. 70 Investigation of the relation between the unique thymoleptic effects and the effects on positive and negative symptoms of schizophrenia of these novel antipsychotic drugs, including clozapine and risperidone, would help illuminate the common pathophysiology of mood disorders and schizophrenias. 37 Risperidone administration leads to an improvement in a whole range of mental illnesses, including schizophrenia, mood disorder, obsessive-compulsive disorder, tic disorder, and pervasive developmental disorder, which indicates that the relationship between specific pathophysiological causes and the manifested psychiatric symptoms is clinically important. Accordingly, it is possible that the selection of an antipsychotic agent with a definite, well-proven pharmacological action for a particular mental illness could be decided from the perspective of the symptom-targeted psychopharmacology, and not of the diagnosis-targeted psychopharmacology. 71 Clinical symptoms responding well to new psychotropic drugs like risperidone, which have a more selective action on neurotransmitter receptors as than clozapine, a drug belonging to the same SDA category, and clinical data on psychiatric side effects induced by these drugs could be exploited in symptom-targeted psychopharmacology. 71 Looking back the history of psychopharmacology that prototypical psychotropic drugs, such as chlorpromazine, monoamine oxidase inhibitor MAOI, tricyclic antidepressant TCA, lithium, and clozapine, were discovered by change following scrupulous observation of psychiatric side effects, it is recommended that rather than waiting for the accidental, passive encounter with such a good luck, aggressive and systematic examination of psychiatric side effects could be exploited as a neurochemical probe to elucidate the causes of