22. Drug side effects

353

22. Drug Side Effects WEIGHT GAIN ASSOCIATED WITH CONVENTIONAL AND NEWER ANTIPSYCHOTICS: A META-ANALYSIS D.B. Allison, J.L. Mentore, M. Heo, P.J. Weiden, J.C. Cappelleri, L.P. Chandler St Luke’slRoosevelt 1090 Amsterdam

Hospital, Columbia Ave, New York 10025,

University, USA

The aim of this study was to estimate and compare the effects of both conventional and newer antipsychotics on body weight. A comprehensive literature search identified 78 studies that included data on weight change in patients treated with a specific antipsychotic. For each agent a meta-analysis and random effects regression estimated the change in weight at 10 weeks of treatment. Except for molindone, antipsychotic treatment was associated with weight gain. Placebo was associated with a weight reduction (mean 0.74 kg). Among conventional agents, thioridazine was associated with the greatest weight increase (3.19 kg). Among newer antipsychotics, mean increases were as follows: clozapine, 4.45 kg; olanzapine, 4.15 kg; sertindole, 2.92 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg 0, < 0.001 vs each of the former). Insufficient data were available to evaluate quetiapine. Both conventional and newer antipsychotics are associated with weight gain. Among newer agents, clozapine appears to have greatest potential to induce weight gain and ziprasidone has the least. These differences among newer agents may be relevant for health risks related to obesity and for drug selection.

which impair the patient’s nonverbal ability during social interaction. A direct measurement of the patients’ head movement behavior is established which shows high sensibility for drug-induced changes of the behavioral repertoire. In a longitudinal study, data collection on nonverbal behavior is done during a IO-minute interaction task by using small ultrasonic transducers, which are attached to various parts of the patient’s body (head and shoulders). Angle-positions of the head (in rotational, lateral, and sagittal dimensions) as well as identification, quantification, and classification of movement patterns are analyzed. Our data show highly restricted head movement patterns with a prevalence of minimal movements (70% of all head movements) and a reduced velocity of movements in patients treated with risperidone (2 or 4 mg). Patients that changed medication to clozapine (50-75 mg) displayed head movement behavior which includes more complex movement patterns and which is even comparable to normal controls. Based on additional communicative analyses, it is concluded that low-dose neuroleptic drug treatment with risperidone may impair the patient’s nonverbal activity during social interaction by reducing the nonverbal relational responsiveness. Furthermore, the presented methodological approach may be seen as a promising procedure either to investigate extrapyramida1 side effects of new or to monitor the treatment with common neuroleptic drugs. In this respect, head movement patterns may provide indirect evidence of subtle abnormalities in brain function, which are induced by neuroleptic medication.

THE EFFECTS OF TYPICAL AND ATYPICAL ANTIPSYCHOTICS ON DRUG-INDUCED PARKINSONISM MEASURED BY A COMPUTER-AIDED DEVICE G. Berger, H. Hofer, M.C.G. Merlo

THE ROLE OF DRUG SIDE EFFECTS IN SOCIAL INTERACTION: HEAD MOVEMENT ANALYSIS OF SCHIZOPHRENIC PATIENTS DURING TREATMENT WITH RISPERIDONE OR CLOZAPINE A. Altorfer, M.C.G. Merlo, M.L. KBsermann, N. Gilgen, H. Hofer, S. Jossen Psychiatric Institutions, University of Berne, I I I, CH-3000 Berne 60, Switzerland

Boilingenstrasse

Nonverbal behavior is regarded as an important variable for successful social interaction. On the one side, schizophrenic patients are said to show abnormal movement behavior (‘social withdrawal,’ ‘ stiff,’ ‘wooden,’ or ‘inhibited’ behavior). On the other side, neuroleptic drug treatment may influence the schizophrenic patient’s performance in social situations. In this respect, side effects may be seen as disturbing components,

Psychiatric CH-3000

Institutions, University Berne 60, Switzerland

of Berne.

Bolligenstrasse

II I,

Thirty-one early psychotic patients were successively recruited for testing extrapyramidal side effects during antipsychotic treatment. Tremor, precision of movement, rapidity of movement of arm and hand, and rapidity of movement of wrist and finger have been measured by a computer-aided device (Schuhfried: Das Wiener Testsystem) and were standardized by T-transformation. Three groups of patients have been formed: patients treated exclusively with typical and atypical antipsychotics and the combination of them. Especially ‘the time to follow a track’ (as a measurement of rigidity, precision, and tremor) was highly significantly slower in the group of patients treated with typical antipsychotics (for both hands). Also interestingly, we found that clozapine combined with typical antipsychotics had less parkinsonism that typical antipsychotics alone. These results are discussed in the context of low-dose regimens and the use of atypical antipsychotics in the treatment of early psychosis.

354

PROLACTIN RESPONSE TO RISPERIDONE IN BORDERLINE PERSONALITY DISORDER PATIENTS S.A.

Berry,

K.L.

Camlin,

S.C.

Schulz

Department of Psychiatry, Emory University, Atlanta, Georgia 30322 and Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio 44106, USA The antipsychotic medications have been associated with an increase in serum prolactin in schizophrenic patients. The effect of atypical antipsychotics on prolactin is less clear. Because of the favorable side-effect profile and indications of efficacy, atypical antipsychotics are now being used in the treatment of multiple psychiatric disorders, including borderline personality disorder. Therefore, it is crucial to evaluate the effect of atypical antipsychotics, such as risperidone, on prolactin levels when used in patient populations with diagnoses other than schizophrenia. Twenty patients with borderline personality disorder per DSM III-R criteria were treated with risperidone (l-4 mg, daily) or placebo in a double-blinded, I-week study. Serum prolactin levels were monitored at baseline and at the completion of the study (ave. 7.9 weeks). Serum prolactin was determined by radioimmunoassay in a commercial laboratory. Substantial increases in prolactin were noted in a significant number of patients. For example, prolactin levels were observed in the range of 3.1 to 33.0 ug/L at baseline. Prolactin levels of 50&110 ug/L were not uncommon upon completion of the study. Data will be presented comparing serum prolactin levels in placeboand risperidone-treated patients with borderline personality disorder.

FLUOXETINE-INDUCED DYSTONIC REACTION IN A SCHIZOPHRENIC PATIENT: A CASE REPORT AND LITERATURE REVIEW S.A.

Berry,

L. Temple,

Department of Psychiatry, 30322, USA

K. Jarboe, Emory

R. Lewine

University,

Atlanta,

Georgia

Fluoxetine is effective in treating major depression and is commonly used along with antipsychotics to treat major depression comorbid with schizophrenia. Extrapyramidal side effects have been described following fluoxetine administration, but are rare. Herein, we shall report on a schizophrenic patient who was participating in a double-blind research trial in which he was receiving haloperidol or olanzapine for treatment of psychotic symptoms associated with schizophrenia. During the course of this study, the patient was on a stable dose of the study medication (haloperidol or olanzapine). His psychotic symptoms diminished, but he complained of depressive symptoms which progressed over the next several weeks. The patient was treated with fluoxetine (1Omg qam), along with the antipsychotic medication. Within 48 hours, the patient began

to complain of muscle stiffness, primarily in the neck, which rapidly worsened. He was evaluated in an emergency room, where an oculogyric crisis was diagnosed, and treated with anticholinergic medication. Fluoxetine was discontinued. The extrapyramidal side effects resolved and did not recur, even though the antipsychotic medication dose was not adjusted and the antichohnergic medication was discontinued. This case will be discussed in the context of the existing literature. Possible biological mechanisms will be explored.

WEIGHT GAIN WITH CLOZAPINE COMPARED TO CONVENTIONAL ANTIPSYCHOTIC MEDICATIONS N.H.

Covell.

CT DMHAS MS#IIRSD, USA

S.M.

AS

Essock

Research Division, 410 Capitol Avenue PO Box 341431, Hartford, Connecticut

06134,

Weight gain is an important issue in terms of both medication compliance and health. Several non-experimental studies have documented weight gain during treatment with clozapine, and one randomized trial comparing clozapine to haloperidol concluded that patients gained significantly more weight while taking clozapine. However, because haloperidol is not associated with prominent weight gain, the aforementioned randomized trial could not address whether the weight gain during treatment with clozapine was similar to or greater than that associated with most other conventional antipsychotic medications This study presents findings from a randomized costeffectiveness study in which we were able to compare weight gain for patients taking clozapine with those taking conventional antipsychotic medications. Our data show that clozapine produces weight gain beyond that which is typically associated with conventional antipsychotic medications. This weight gain could present barriers to compliance and increase health risks for patients taking clozapine. Future studies should continue to monitor weight gain with clozapine and other atypical antipsychotic medications and should investigate the impact of weight gain on compliance, health, and cost of service utilization.

ELECTROCARDIOGRAPHIC CHANGES PATIENTS RECEIVING ANTIPSYCHOTIC MEDICATION U. Eder, M. Hochleitner, W.W. Fleischhacker

E. Weiss,

M.

IN

Hummer,

Department of Biological Psychiatry, Innsbruck University Clinics, Anichstrasse 35, A-6020 Innsbruck, Austria Antipsychotic medication side effects. A prolongation

carried the risk of cardiovascular of the QT interval requires particu-

355

lar attention since it may indicate an increased risk for ventricular tachyarrhythmias. A QTc interval >440 ms is considered pathological; an increase over 500 ms carries an increased risk for the development of torsade de pointes and subsequent ventricular fibrillation and cardiac arrest. In this currently ongoing prospective study, the cardiovascular safety of novel antipsychotics is investigated. ECGs are recorded in all patients receiving a monotherapy with zotepine, sertindole, risperidone, olanzapine, clozapine, or haloperidol, at baseline and on days 2, 4, 7, 14, 21, and 35 of treatment after a washout period of 1 week. So far, 42 patients have been included (29 males and 13 females). The average age of the patients is 32 years. None of these patients developed cardiac complications during the study, and no one showed a QTc prolongation over 440 ms. We compared 3 groups of patients treated with olanzapine (n = 8), risperidone (n =7), and sertindole (n =4). In the risperidone group, 4 of 7 patients showed a QTc increase (2.7-10.5%) compared to baseline. Of 4 sertindole-treated patients, 3 developed a QTc prolongation (5.ll7.7%). In the olanzapine group, no QTc prolongation was seen. Although we did see QTc prolongation in the risperidone and sertindole groups, all measured QTc intervals were within the normal range (<440 ms).

RISPERIDONE AND HEPATOTOXICITY IN PEDIATRIC PATIENTS: AN ASSOCIATION WITH WEIGHT GAIN? R.L. Findling, M. Wiznitzer, K. Maxwell, E.M. Szigethy

Department Cleveland,

Reserve

AND THE SYNDROME

L.R. Hammond University of New Mexico Mental Health Center, NE, Albuquerque, New Mexico 87131, USA

2600 Marble

There is controversy concerning whether the newer atypical antipsychotics pose a risk for NMS and whether the presentation of NMS would resemble cases seen with older antipsychotits. To help clarify these issues, this paper compares case reports of NMS involving clozapine, risperidone, and haloperidol. A Medline search was made for all English-language case reports of NMS involving clozapine (n = 19), risperidone (n = 14) and haloperidol (haloperidol cases limited to 1994 to 1996, n = 17). Cases were excluded if more than one neuroleptic was involved. Systematic comparisons were made based on signs of NMS as described in DSM-IV. Case reports of NMS associated with clozapine and with risperidone that fully met DSM-IV criteria for NMS were found. No new criteria were consistently suggested by the cases involving clozapine or risperidone. There were significant differences between the 3 drug groups in reporting of rigidity, diaphoresis, tremor, confusion, and tachycardia. These findings tended to reflect the differing side effect profiles of the antipsychotics. Typical NMS does occur in cases involving clozapine and risperidone. The existence of an ‘atypical NMS’ would need to be carefully differentiated from the known side effect profile of the antipsychotic involved.

SEXUAL DYSFUNCTION AND PROLACTIN LEVELS IN PATIENTS USING CLASSICAL ANTIPSYCHOTICS, RISPERIDONE OR OLANZAPINE

L.A. Branicky,

of Psychiatry, Case Western Ohio 44106, USA

ATYPICAL ANTIPSYCHOTICS NEUROLEPTIC MALIGNANT

University,

Risperidone has been used to treat pediatric patients with a variety of neuropsychiatric conditions. A recent report has raised the issue of whether risperidone-induced weight gain is associated with steatohepatitis in pediatric patients. The purpose of this chart review study was to examine whether hepatic dysfunction is a common phenomenon in pediatric patients given risperidone. The charts of 38 youths treated with risperidone for at least 4 weeks, who also had clinical laboratories obtained in order to assess for hepatic dysfunction, were identified. Most of these youths were treated with other psychotropic agents while being treated with risperidone. Despite this fact, only 1 subject had a clinically insignificant elevation in alanine aminotransferase (46 U/L). Of note, this was the only subject with a body mass index substantially above the 95th percentile. These data suggest that the risk of risperidoneinduced hepatotoxicity is probably low. However, weight gain during atypical antipsychotic pharmacotherapy may be a substantial therapeutic issue in pediatric patients.

H. Knegtering, University Hospital The Netherlands

C. Blijd, M. Boks Groningen,

P. 0. Box 30.001,

9700 RB,

In an ongoing open study started in 1997, all patients using antipsychotics for 6 weeks were asked to participate an evaluation of sexual dysfunction. We used a questionnaire assessing changes in libido, orgasm, ejaculation, menstruation, and galactorrhea related to recent use of antipsychotics. Serum levels of antipsychotics and prolactin were determined the same day. Ninety of 95 patients agreed to participate (45 using classical antipsychotics, 30 risperidone, 15 olanzapine). There were no significant differences in sociodemographical or clinical parameters among the patient groups (mean age 28, 34% women). The mean dosages were: 6.5 mg haloperidol equivalents/day for patients using classical antipsychotics, 3.4 mg/day risperidone, 10.2 mg/day olanzapine. Only 10% of the patients spontaneously reported sexual dysfunctions.

356

The percentages of patients reporting sexual dysfunctions in response to the questionnaire differed significantly among the groups; 50% with classical antipsychotics, 67% with risperidone, 27% with olanzapine. Serum prolactin levels differed significantly among the three groups: 750 ME/L, SD 721 classical; 1235 ME/L, SD 929 risperidone; 255 ME/L, SD 258 olanzapine (t test p < 0.05). Conclusion: Sexual dysfunctions are very common side effects of antipsychotics. Higher prolactin levels are associated with more sexual dysfunctions, occurring most frequently in patients using classical antipsychotics or risperidone. For sexual dysfunctions, olanzapine has the most favourable side-effect profile.

CARDIOLOGICAL EFFECTS OF SERTINDOLE, HALOPERIDOL, AND PLACEBO IN SCHIZOPHRENIC PATIENTS C. Lancon,

M.

Valli,

M. Toumi

University of Provence. Department Aix-Marseille II, France

of Psychiatry,

Sertindole is a new atypical antipsychotic agent that has been approved for the treatment of schizophrenia in most European countries. Sertindole has been reported to cause a sligh increase in the QTc interval, but there have not been any cases of torsade de pointe (TdP) during the development of sertindole (exposure 2263 patients, corresponding to 1578 patient years). Sertindole has clinically been compared with haloperidol, and the primary aim of this retrospective study was to compare sertindole and haloperidol with respect to possible cardiological effects. To assess the possible risk of TdP. we studied adverse events that might be early signs of TdP, indicated as a proxy TdP. A proxy TdP was defined as the occurrence of either seizures, syncope, or dizziness. The cumulative rates at 60 days of the above adverse events were as follows (95% confidence intervals in parentheses): Seizures: sertindole 0.004 (O~O.OOS), haloperidol 0.007 (O-0.018), placebo 0.008 (o-0.08). Syncope: sertindole 0.005 (0.00220.02), haloperidol 0.007 (O-0.03), placebo 0.005 (O-0.008). Dizziness: sertindole 0.120 (0.09-0.16), haloperidol 0.102 (0.05-0.16), placebo 0.130 (0.11-0.15). There were no significant differences among sertindole, haloperidol, and placebo for the rate of proxy TdP. The occurrence of proxy TdP was not dependent on dose of the drugs or the QTc interval, but patients who experienced proxy TdP were older and had more often a history of cardiac disease or metabolic/endocrine disease (e.g. diabetes, obesity). The data clearly show that there are no differences among sertindole, haloperidol, and placebo in the rate of proxy TdP (clinical signs of TdP). The rate of proxy TdP was higher in patients with cardiac and metabolic/endocrine disease. The results also indicate that it is unlikely that treatment with the new antipsychotic agent sertindole will lead to a significant risk of the development of TdP.

UTILITY OF A MEDICAID CLAIMS DATABASE FOR IDENTIFYING CASES OF NEUROLEPTICALLY INDUCED AMENORRHEA S. Leader, Pracon, Reston,

C. Brady,

K. Sadik,

A Division of Excerpta Virginia 20191. USA

R. Mahmoud

Medica,

1800 Robert

F&on

Dr,

Certain antipsychotic medications are associated with elevation of serum prolactin levels (Green and Brown 1988). Some believe that prolonged high levels of prolactin due to antipsychotic therapy may cause anovulation or amenorrhea in some women (Sullivan and Lukoff 1990). The incidence of neuroleptic-induced amenorrhea in actual practice is not well documented. To evaluate the utility of a large Medicaid claims database to study the incidence of neuroleptic-induced amenorrhea, all 435 enrolled females with ZCD-9 schizophrenia and amenorrhea diagnoses in 1996 were identified. A subset of 45 females was randomly selected. Their complete medical and prescription histories covering 6 months prior and 6 months after the first amenorrhea diagnosis in 1996 were extracted. Case histories were reviewed independently by a gynecologist, an endocrinologist, and a psychiatrist. Using standard rating forms, each expert evaluated the casual relationship between antipsychotic therapy and amenorrhea. Initial agreement on cases due to neuroleptic was low (kappa = 0.24, p = 0.002); agreement between the gynecologist and endocrinologist was considerably higher (kappa = 0.51, p = 0.03). Consensus on discordant cases was reached in group discussion, and factors useful for systematic identification of amenorrhea cases due to neuroleptic, using data from a claims database, were identified. Diagnostic criteria developed by this process may assist in future research on this side effect.

SUICIDE AND SUDDEN DEATH DURING TREATMENT WITH ATYPICAL NEUROLEPTICS: A COMPARISON OF SERTINDOLE, OLANZAPINE, AND RISPERIDONE N. Moore,

R. Lagnaoui,

Department of Pharmacology, Bordeaux 2. France

M.

Toumi, University

B. BCgaud Victor

Sgalen-

Sudden death in schizophrenic patients has been associated with most neuroleptics, possibly related to acute arrhythmia caused by QT prolongation. To assess sudden death during treatment with atypical neuroleptics, we reviewed data from the clinical trials of sertindole (S) and compared this to publicly available data concerning clinical trials of olanzapine (0) and risperidone (R). There were 30 deaths during S trials, 13 of which were considered cardiac (sudden deaths for which arrhythmia could possibly have been a causal or contributing factor, whether other causes were present or not) and 8 suicides

351

in 2263 patients exposed a total of 1578 person-years (PY), mean 0.70 PY. For 0, there were 20 deaths, 6 cardiac, 10 suicides, for 2461 patients (1122 PY, mean 0.46 PY), and for R 16 deaths, 2 cardiac, 10 suicides, for 2322 patients (858 PY, mean 0.37 PY). Overall fatality rates were identical (19% PY, 95% confidence interval [poisson] 12 to 30). Suicide rates were S: 5.1% PY (95% CI 2.2 lo), 0: 8.9 (1.3 16.4) and R: 11.7 (5.6-21.4). Cardiac death rates were 8.2 (4.4-14.1), 5.3 (2-11.6), and 2.3 (0.3-8.4), respectively. They were inversely proportional to duration of follow-up. Hazard function curves for cardiac deaths were superimposed for S and 0 for the first 9 months of follow-up. The rates of cardiac death are therefore not different across compounds. Higher suicide rates with risperidone could be related to different exclusion criteria in clinical trials. Conversely, the apparent differences in cardiac deaths among the drugs appear related to duration of follow-up. In the sertindole trials, cardiac deaths occurred in patients who were older and had more often a previous history of cardiac or metabolic (diabetes) disease. There was no clear relationship of death to QT changes. Further studies are needed to clarify the role of neuroleptics in sudden death of schizophrenic patients.

ANTIPSYCHOTIC AGENTS, SIDE EFFECTS, AND COMPLIANCE - A COMPLEX ISSUE D.G.C. Owens, A. Carroll, S. Fattah, E.C. Johnstone Department of Psychiatry, Scotland, UK

University

of Edinburgh,

Edinburgh,

Side effects of antipsychotic drugs are thought to be a major cause of poor compliance in schizophrenia. This study has sought to explore this issue by rating 110 schizophrenic inpatients on side effects, attitudes to treatment, and level of depression, just before discharge from inpatient care. The results show that treatment attitude scores were unrelated to severity of side effects, depression scores, or medication variables. Depression scores were higher in subjects with more severe ‘psychic’ and extrapyramidal side effects. Subjects on depot medication received a higher dose and suffered more extrapyramidal side effects. From this we conclude that although worse side effects are related to lower mood, they do not appear to influence attitudes to treatment. The effect on treatment attitude and compliance of reducing side effects, at least in patients in whom they are not severe, is therefore likely to be minimal.

ORAL GLUCOSE CHALLENGE, TEST ABNORMALITIES WITH ATYPICAL ANTIPSYCHOTIC USE T.I. Prior, P.S. Chue, P. Tibbo Department of Psychiatry, 8440-12 Street, Edmonton,

University of Alberta Hospital, Alberta, Canada T6G2B7

The development and introduction of atypical antipsychotics has arguably revolutionized the treatment of schizophrenia. These agents bind to cell surface receptors in patterns and affinities that are unique and different from conventional neuroleptics. Although their site of action in treating schizophrenia is within the brain, they also have peripheral binding sites that may be contributory to particular side-effect profiles. There have been a number of clinical reports of the development of hyperglycemia in patients receiving clozapine, some of which report death from subsequent diabetic ketoacidosis. The purpose of our study was to examine the possibility of abnormalities in glucose metabolism, using fasting blood sugars followed by oral glucose tolerance testing in individuals who were on one of three atypical antipsychotics (clozapine, risperidone, olanzapine) and compare them to individuals on haloperidol. None of the patients recruited had a history of diabetes, and none had abnormal fasting blood sugars. In summary, patients receiving atypical antipsychotics showed an increased likelihood of having an abnormal result to a glucose challenge. This will be further discussed in relation to clinical variables, stratified by medication, and to possible characteristics of those patients at risk. Thus, it appears from this preliminary and ongoing study that the atypical antipsychotics may affect glucose metabolism and that suitable clinical monitoring may be prudent.

A POSITRON-EMISSION TOMOGRAPHY (PET) STUDY OF AKATHISIA A.R. Saklad, A.L. Miller, J.G. Olsen, H. Mayberg, P.T. Fox, F. Zamarippa Department of Psychiatry - University at San Antonio 7703 Floyd Curl Drive, 78284-7792, USA

of Texas Health Center San Antonio, Texas

Akathisia, a movement disorder of subjective and objective restlessness is among the primary causes of noncompliance with typical neuroleptic medications. No previous brain imaging work has been done to identify neural systems involved in producing this ‘urge to move.’ Ten patients with neurolepticinduced akathisia were studied using PET (H,“O) at rest, ten, and twenty minutes motionless, and with overt movement. MR and PET images were spatially normalized to the atlas of Talairach and Tournoux (1988). Logical image techniques illustrate significant @ < 0.01) between-region and betweenhemisphere effects for the moving and motionless conditions when subtracted from the resting state. Three-factor (condition, hemisphere, region) ANOVA showed significant differences in anterior cingulate gyrus (Brodman Area 24), which was activated bilaterally in the moving condition. In the left hemisphere, activation significantly decreased at 10 minutes motionless, but returned to baseline at 20 minutes motionless. The right cingulate is inhibited increasing from 10 to 20 minutes motionless. These areas of activation/inhibition are consistent with suppressing previously practiced movements and are attributed to the attention functions of the cingulate. Future research will further our understanding of the pathophysiology of akathisia by examining these same patients on atypical antipsychotics, which cause lower rates of akathisia.

358

LONG-TERM SAFETY OF OLANZAPINE THE TREATMENT OF BIPOLAR 1 DISORDER T.M. K.S.

Sanger, Gannon,

M. Tohen, T. Jacobs, G.D. Tollefson

Eli Lilly and Company, Indiana 46285, USA

Lilly

Corporate

M.

IN

Greaney,

Center,

Indianapolis,

Clinical studies suggest that exposure to typical antipsychotits is associated with increased risk of developing extrapyramida1 symptoms (EPS) and tardive dyskinesia (Kane et al., 1988). Some atypical antipsychotics are reported to pose a risk of severe cardiac abnormalities by increasing the corrected QT (QTc) interval. We hypothesized that the novel antipsychotic olanzapine would have a more favorable safety profile in patients treated for bipolar 1 disorder. To assess long-term effects of olanzapine, a 53-week, open-label olanzapine extension phase was conducted after a 3-week, double-blind, randomized study of olanzapine versus placebo in bipolar 1 patients, manic or mixed episode. Patients (n = 113) in the open-label extension received 5-20mg per day of olanzapine (average modal dose = 14.0 mg/d) for an average of 145 days at the time of analysis. Safety assessment of olanzapine included: EPS, including pseudo-parkinsonism (Simpson-Angus Scale), akathisia (Barnes Akathisia Rating Scale), and dyskinesias (AIMS); discontinuations due to adverse events; ECGs and depressive symptoms (HAMD-21). There were statistically significant improvements in mean change from baseline to endpoint on the Simpson-Angus (-0.49, p = 0.015) and Barnes Akathisia (-0.17, p = 0.028) Scales; and no statistically significant worsening on the AIMS total (0.03,~ = 0.727). No patient experienced tardive dyskinesia during the study. Six (5.3%) patients discontinued therapy due to an adverse event. There was no significant mean change from baseline to endpoint in QTc interval (-0.31, p=O.919). Mean improvement from baseline to endpoint on the HAMD-21 was - 6.13 (p < 0.00 1) In conclusion, olanzapine does not appear to share the safety concerns found with other antipsychotics in the treatment of acute bipolar 1 disorder, although these findings need to be confirmed in controlled maintenance studies.

SEX STEROIDS AFFECT SIDE EFFECT SEVERITY IN WOMEN WITH PSYCHOSIS K. Thompson,

A. Sergejew,

J. Kulkarni

Monash University Research Centrefor Women’s Health, Dandenong Area Mental Health Service, Dandenong, Melbourne. Victoria 3175, Australia

Mental PO Box 956,

It has been clinically observed that women suffer more parkinsonism and tardive dyskinesia than men, the latter being linked to the reduction in estrogen at menopause. However, while Seeman and Lang (1990) hypothesised that estrogen may be responsible for this gender difference, to date no study has

examined this in humans. The present study aimed to investigate neuroleptic side effect severity in women with psychosis over the menstrual cycle. Based on the estrogen hypothesis of a synergistic relationship between estrogen and neuroleptics, it was hypothesised that estrogen would exacerbate extrapyramida1 symptoms. Thirty-two psychotic women were assessed using the ESRS and blood hormone analysis. Testing was conducted twice, 2 weeks apart, in a randomised crossover design. Contrary to expectations, the results indicated that high levels of estrogen reduce hyperkinetic symptoms in women with psychosis, and this effect appears to be further potentiated when both estrogen and progesterone are high. On the basis of these findings, and receptor studies in animals, it is concluded that estrogen has different affects on dopamine dynamics in the mesolimbic and mesostriatal pathways.

SAFETY OF THE NOVEL ANTIPSYCHOTIC OLANZAPINE IN THE ACUTE TREATMENT OF BIPOLAR 1 DISORDER M. M.

Tohen, Greaney,

T. Jacobs, T.M. Sanger, V. Toma, K.S. Gannon,

Eli Lilly and Company, Indiana 46285. USA

Lilly

Corporate

S. Grundy, G.D. Tollefson Center,

Indianapolis,

Typical antipsychotic use for the treatment of bipolar 1 disorder presents several safety concerns. Clinical studies suggest that exposure to typical antipsychotics is associated with increased risk of extrapyramidal symptoms (EPS), tardive dyskinesia, and induction of depressive symptoms (Kane et al., 1988; Kukopoulos et al., 1980). Hence, we hypothesized that the novel antipsychotic olanzapine would have a more favorable safety profile in patients treated for bipolar 1 disorder. In a placebo-controlled, double-blind, 3-week study of 139 bipolar 1 patients (70 treated with olanzapine), with and without psychotic features, the following were assessed: EPS, including pseudo-pdrkinsonism (Simpson-Angus Scale), akathisia (Barnes Akathisia Rating Scale), and dyskinesias (AIMS); discontinuations due to adverse events; and depressive symptoms (HAMD-21). There were no statistically significant treatment differences in mean change from baseline to endpoint on the Simpson-Angus (placebo, 0.05; olanzapine, -0.15; p = 0.989) Barnes Akathisia (placebo, -0.11; olanzapine, -0.17; p = 0.408) and AIMS total (placebo, 0.00; olanzapine, -0.25; p = 0.384). No olanzapine-treated patients discontinued therapy due to an adverse event, whereas 2 (2.9%) placebo-treated patients discontinued therapy due to an adverse event. The HAMD-21 total showed no statistically significant difference in depressive symptoms between olanzapine (-2.90) and placebo (-3.00) from baseline to endpoint during the 3-week acute phase (p = 0.871). The latter result suggests that olanzapine does not have depressogenic effects in bipolar disorder in the short-term treatment of acute mania. In conclusion, olanzapine does not appear to share the safety concerns found with typical antipsychotics in the treatment of acute bipolar 1 disorder, although these findings need to be confirmed in controlled maintenance studies.

359

OBSESSIVE-COMPULSIVE CLOZAPINE TREATMENT

SYMPTOMS

AND

A.L. Tricarichi, M.A. Fuller, H.B. Gano, J.E. Werkner, D.W. Brescan Mental Medical

Health Services, Department of Veterans Center, Brecksville, Ohio 44141. USA

Affairs

Clozapine, a well-known medication for the treatment of refractory psychosis, is associated with many adverse side effects due to its unique pharmacologic profile. Because of its serotonin blockade, it has been hypothesized that clozapine may contribute to the manifestation of obsessive-compulsive (OC) symptoms. This hypothesis is supported largely by anecdotal evidence. Within the setting of the largest clozapine clinic in the Veterans Affairs national network, patients were assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Y-BOCS Symptom Checklist, a questionnaire that helps patients identify specific obsessive and compulsive symptoms. Patients were interviewed at length, with attention to assuring appropriate comprehension of items. Patients were classified as having significant OC symptoms if they were scored as moderate or above on the Y-BOCS. Analysis of these data showed that significantly more OC symptoms were observed among clozapine-treated subjects as compared to the expected rate of OC in all patients with schizophrenia (chi-square = 38.37, df = 1, p < 0.01). This result supports the hypothesis that clozapine treatment is associated with OC symptoms, Further studies are needed to establish whether this is a causal relationship. These studies would include pre- and post-clozapine treatment assessments and case studies of patients exhibiting significant OC symptoms.

VISUO-MANUAL TESTING IN THE DIAGNOSIS OF EXTRA-PYRAMIDAL SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS M. Weiser, M. Schnaider-Beeri, S. Reiss, N. Nakash, N. Brill, S. Hirschmann, S. Hocherman, M. Davidson Chaim

Sheba Medical

Center,

Tel-Hashomer,

Israel

Visuo-Manual Testing (VMT) is a novel procedure which yields quantitative information on the ability to control the direction and speed of hand motion. This procedure consists of a digitizing tablet hidden from the subject’s view by an overlying board, upon which a computer monitor is placed. Paths for tracing and tracking are displayed on the computer monitor. A screen cursor represents the location of an unseen

handle, which is free to move over the digitizing tablet. The location of the handle is read by the computer. Objectives: To assess the sensitivity of the VMT in quantifying antipsychotic induced extrapyramidal side effects (EPS) induced by typical (haloperidol) and atypical antipsychotics (olanzapine, risperidone). Methods: Forty-one patients suffering from schizophrenia, treated with typical and atypical anti-psychotic agents, were assessed with the VMT and the ESRS. Results: As expected, VMT scores were significantly lower (less EPS) in patients receiving atypical antipsychotics, in comparison to patients receiving typical anti-psychotics (p = O.Ol), and differed among the atypicals. EPS, as measured by the ESRS, did not differentiate between typical and atypical drugs. Conclusions: VMT can quantitatively evaluate subtle, antipsychotic drug-induced EPS, which are not discerned by the ESRS.

EVALUATION ENHANCING MEDICATION

OF TOOLS FOR REPORTING OF SIDE EFFECTS

L. Whitehorne, D. Whitehorn, L.C. Kopala Department of Psychiatry, Scotia, Canada B3HZE2

Dalhousie

University,

Halifax,

Nova

Introduction: Communication between patients and health care professionals about the side effects of psychiatric medications is a key component of optimal care, yet significant side effects often go unreported. As part of a larger pilot study, we participated in an evaluation of two scales developed by the Approaches to Schizophrenia Communication (ASC) programme (Awad et al. in press). The ASC-SR (self report) is a check list of common side effects. The ASC-C is a structured interview conducted by a health care professional. Methods: 16 patients in a community-based psychosocial rehabilitation program participated (age, 28-42; illness duration, 5-18 years; diagnosis, schizophrenia). The evaluation was conducted by the first author, a nurse in the program. Results: On the ASC-SR, 15 patients reported side effects which they attributed to medication. Only 1 patient wanted to discuss all the reported side effects with their doctor or nurse and 4 did not wish to discuss any of the side effects. During the ASC-C interview, 7 patients, when asked, reported sexual dysfunction. Only 1 had indicated this problem on the ASC-SR. Discussion: Patients did not report sexual dysfunction on the ASC-SR, but did so when asked directly in the ASC-C. Most patients preferred to discuss only certain side effects with their doctor or nurse. The results support the usefulness of the ASC-SR and ASC-C.